Sample records for soluble activin type

  1. Soluble activin receptor type IIB decoy receptor differentially impacts murine osteogenesis imperfecta muscle function.

    PubMed

    Jeong, Youngjae; Daghlas, Salah A; Kahveci, Alp S; Salamango, Daniel; Gentry, Bettina A; Brown, Marybeth; Rector, R Scott; Pearsall, R Scott; Phillips, Charlotte L

    2018-02-01

    Osteogenesis imperfecta (OI) is characterized by skeletal fragility and muscle weakness. In this study we investigated the effects of soluble activin type IIB receptor (sActRIIB-mFc) on muscle mass and function in 2 distinct mouse models of OI: osteogenesis imperfecta murine (oim) and +/G610C. Wild-type (WT), +/G610C, and oim/oim mice were treated from 2 to 4 months of age with Tris-buffered saline (vehicle) or sActRIIB-mFc and their hindlimb muscles evaluated for mass, morphology, and contractile function. sActRIIB-mFc-treated WT, +/G610C, and oim/oim mice had increased hindlimb muscle weights and myofiber cross-sectional area compared with vehicle-treated counterparts. sActRIIB-mFc-treated oim/oim mice also exhibited increased contractile function relative to vehicle-treated counterparts. Blocking endogenous ActRIIB was effective at increasing muscle size in mouse models of OI, and increasing contractile function in oim/oim mice. ActRIIB inhibitors may provide a potential mutation-specific therapeutic option for compromised muscle function in OI. Muscle Nerve 57: 294-304, 2018. © 2017 Wiley Periodicals, Inc.

  2. Treatment with soluble activin type IIB-receptor improves bone mass and strength in a mouse model of Duchenne muscular dystrophy.

    PubMed

    Puolakkainen, Tero; Ma, Hongqian; Kainulainen, Heikki; Pasternack, Arja; Rantalainen, Timo; Ritvos, Olli; Heikinheimo, Kristiina; Hulmi, Juha J; Kiviranta, Riku

    2017-01-19

    Inhibition of activin/myostatin pathway has emerged as a novel approach to increase muscle mass and bone strength. Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to progressive muscle degeneration and also high incidence of fractures. The aim of our study was to test whether inhibition of activin receptor IIB ligands with or without exercise could improve bone strength in the mdx mouse model for DMD. Thirty-two mdx mice were divided to running and non-running groups and to receive either PBS control or soluble activin type IIB-receptor (ActRIIB-Fc) once weekly for 7 weeks. Treatment of mdx mice with ActRIIB-Fc resulted in significantly increased body and muscle weights in both sedentary and exercising mice. Femoral μCT analysis showed increased bone volume and trabecular number (BV/TV +80%, Tb.N +70%, P < 0.05) in both ActRIIB-Fc treated groups. Running also resulted in increased bone volume and trabecular number in PBS-treated mice. However, there was no significant difference in trabecular bone structure or volumetric bone mineral density between the ActRIIB-Fc and ActRIIB-Fc-R indicating that running did not further improve bone structure in ActRIIB-Fc-treated mice. ActRIIB-Fc increased bone mass also in vertebrae (BV/TV +20%, Tb.N +30%, P < 0.05) but the effects were more modest. The number of osteoclasts was decreased in histological analysis and the expression of several osteoblast marker genes was increased in ActRIIB-Fc treated mice suggesting decreased bone resorption and increased bone formation in these mice. Increased bone mass in femurs translated into enhanced bone strength in biomechanical testing as the maximum force and stiffness were significantly elevated in ActRIIB-Fc-treated mice. Our results indicate that treatment of mdx mice with the soluble ActRIIB-Fc results in a robust increase in bone mass, without any additive effect by voluntary running. Thus ActRIIB-Fc could be an attractive option in the treatment

  3. Dual specificity of activin type II receptor ActRIIb in dorso-ventral patterning during zebrafish embryogenesis.

    PubMed

    Nagaso, H; Suzuki, A; Tada, M; Ueno, N

    1999-04-01

    Members of the transforming growth factor-beta (TGF-beta) superfamily are thought to regulate specification of a variety of tissue types in early embryogenesis. These effects are mediated through a cell surface receptor complex, consisting of two classes of ser/thr kinase receptor, type I and type II. In the present study, cDNA encoding zebrafish activin type II receptors, ActRIIa and ActRIIb was cloned and characterized. Overexpression of ActRIIb in zebrafish embryos caused dorsalization of embryos, as observed in activin-overexpressing embryos. However, in blastula stage embryos, ActRIIb induced formation of both dorsal and ventro-lateral mesoderm. It has been suggested that these inducing signals from ActRIIb are mediated through each specific type I receptor, TARAM-A and BMPRIA, depending on activin and bone morphogenetic protein (BMP), respectively. In addition, it was shown that a kinase-deleted form of ActRIIb (dnActRIIb) suppressed both activin- and BMP-like signaling pathways. These results suggest that ActRIIb at least has dual roles in both activin and BMP signaling pathways during zebrafish embryogenesis.

  4. Activin C Antagonizes Activin A in Vitro and Overexpression Leads to Pathologies in Vivo

    PubMed Central

    Gold, Elspeth; Jetly, Niti; O'Bryan, Moira K.; Meachem, Sarah; Srinivasan, Deepa; Behuria, Supreeti; Sanchez-Partida, L. Gabriel; Woodruff, Teresa; Hedwards, Shelley; Wang, Hong; McDougall, Helen; Casey, Victoria; Niranjan, Birunthi; Patella, Shane; Risbridger, Gail

    2009-01-01

    Activin A is a potent growth and differentiation factor whose synthesis and bioactivity are tightly regulated. Both follistatin binding and inhibin subunit heterodimerization block access to the activin receptor and/or receptor activation. We postulated that the activin-βC subunit provides another mechanism regulating activin bioactivity. To test our hypothesis, we examined the biological effects of activin C and produced mice that overexpress activin-βC. Activin C reduced activin A bioactivity in vitro; in LNCaP cells, activin C abrogated both activin A-induced Smad signaling and growth inhibition, and in LβT2 cells, activin C antagonized activin A-mediated activity of an follicle-stimulating hormone-β promoter. Transgenic mice that overexpress activin-βC exhibited disease in testis, liver, and prostate. Male infertility was caused by both reduced sperm production and impaired sperm motility. The livers of the transgenic mice were enlarged because of an imbalance between hepatocyte proliferation and apoptosis. Transgenic prostates showed evidence of hypertrophy and epithelial cell hyperplasia. Additionally, there was decreased evidence of nuclear Smad-2 localization in the testis, liver, and prostate, indicating that overexpression of activin-βC antagonized Smad signaling in vivo. Underlying the significance of these findings, human testis, liver, and prostate cancers expressed increased activin-βC immunoreactivity. This study provides evidence that activin-βC is an antagonist of activin A and supplies an impetus to examine its role in development and disease. PMID:19095948

  5. Drosophila Activin- and the Activin-like product Dawdle function redundantly to regulate proliferation in the larval brain.

    PubMed

    Zhu, Changqi C; Boone, Jason Q; Jensen, Philip A; Hanna, Scott; Podemski, Lynn; Locke, John; Doe, Chris Q; O'Connor, Michael B

    2008-02-01

    The Drosophila Activin-like ligands Activin-beta and Dawdle control several aspects of neuronal morphogenesis, including mushroom body remodeling, dorsal neuron morphogenesis and motoneuron axon guidance. Here we show that the same two ligands act redundantly through the Activin receptor Babo and its transcriptional mediator Smad2 (Smox), to regulate neuroblast numbers and proliferation rates in the developing larval brain. Blocking this pathway results in the development of larvae with small brains and aberrant photoreceptor axon targeting, and restoring babo function in neuroblasts rescued these mutant phenotypes. These results suggest that the Activin signaling pathway is required for producing the proper number of neurons to enable normal connection of incoming photoreceptor axons to their targets. Furthermore, as the Activin pathway plays a key role in regulating propagation of mouse and human embryonic stem cells, our observation that it also regulates neuroblast numbers and proliferation in Drosophila suggests that involvement of Activins in controlling stem cell propagation may be a common regulatory feature of this family of TGF-beta-type ligands.

  6. Anti-activin A antibody (IgY) specifically neutralizes various activin A activities.

    PubMed

    Murata, T; Saito, S; Shiozaki, M; Lu, R Z; Eto, Y; Funaba, M; Takahashi, M; Torii, K

    1996-01-01

    Activin A (beta A beta A), originally isolated from ovarian follicular fluids as a follicule-stimulating hormone (FSH) secretion stimulator, has also been identified as an erythroid differentiation factor (EDF), a neuron survival factor and a mesoderm-inducing factor. Thus, activin A is a multifunctional factor, and further studies on its physiological function are important. However, it is very difficult to produce a specific antibody to neutralize the activity of activin A because of its highly conserved amino acid sequence across mammalian species. In this study, we succeeded in generating an antibody against activin A, which can neutralize several activities of activin A, such as the stimulation of FSH secretion from pituitary cells and the induction of the differentiation of erythrocytes in vitro. This antibody did not affect the activity of activin B (beta B beta B), which induces the differentiation of erythrocytes in vitro, and the activity of inhibin A (alpha beta A), which inhibits FSH secretion from pituitary in vitro, but slightly neutralized that of activin AB (beta A beta B). Western blotting analysis showed that this antibody recognized both dimeric and monomeric forms of the beta A subunit of activin and inhibin. These results suggest that this antibody recognizes the beta A subunit of activin and specifically neutralizes the activity of a dimer of the beta A subunit, activin A. Furthermore, by the addition of this antibody to the culture medium, the development of murine embryos was suppressed, suggesting that endogenous activin A plays an important role in murine development. These results indicate the usefulness of this antibody for studies of endogenous activin actions.

  7. Administration of soluble activin receptor 2B increases bone and muscle mass in a mouse model of osteogenesis imperfecta

    PubMed Central

    DiGirolamo, Douglas J.; Singhal, Vandana; Chang, Xiaoli; Lee, Se-Jin; Germain-Lee, Emily L.

    2015-01-01

    Osteogenesis imperfecta (OI) comprises a group of heritable connective tissue disorders generally defined by recurrent fractures, low bone mass, short stature and skeletal fragility. Beyond the skeletal complications of OI, many patients also report intolerance to physical activity, fatigue and muscle weakness. Indeed, recent studies have demonstrated that skeletal muscle is also negatively affected by OI, both directly and indirectly. Given the well-established interdependence of bone and skeletal muscle in both physiology and pathophysiology and the observations of skeletal muscle pathology in patients with OI, we investigated the therapeutic potential of simultaneous anabolic targeting of both bone and skeletal muscle using a soluble activin receptor 2B (ACVR2B) in a mouse model of type III OI (oim). Treatment of 12-week-old oim mice with ACVR2B for 4 weeks resulted in significant increases in both bone and muscle that were similar to those observed in healthy, wild-type littermates. This proof of concept study provides encouraging evidence for a holistic approach to treating the deleterious consequences of OI in the musculoskeletal system. PMID:26161291

  8. Activin receptor ligand traps in chronic kidney disease.

    PubMed

    Jelkmann, Wolfgang

    2018-05-29

    Sotatercept and luspatercept are recombinant soluble activin type-II receptor-IgG-Fc fusion proteins that are tested in clinical trials for the treatment of various types of anemias, including renal anemia. The mechanism of the action of the novel drugs is incompletely understood, but it seems to be based on the inactivation of soluble proteins of the transforming growth factor-ß (TGFß) family. This review considers pros and cons of the clinical use of the drugs in reference to the current therapy with recombinant erythropoiesis-stimulating agents (ESAs). One or more activin type-II receptor (ActRII) ligands appear to inhibit erythroid precursors, for example growth and differentiation factor 11. Trapping of these ligands by the recombinant ActRII fusion proteins, sotatercept and luspatercept increases red blood cell numbers and hemoglobin levels in humans. Reportedly, the novel compounds were well tolerated in trials on healthy volunteers and patients suffering from anemia due to chronic kidney disease or malignancies. On approval, the drugs may prove particularly useful in patients suffering from ineffective erythropoiesis, such as in myelodysplastic syndrome, multiple myeloma or ß-thalassemia, where ESAs are of little use. Independent of their effect on erythropoiesis, ActRII ligand traps were found to exert beneficial effects on renal tissue in experimental animals. ESAs are likely to remain standard of care in renal anemia. There is a need for a better understanding of the effects of ActRII ligand traps on TGFß-like proteins. The novel drugs have not been approved for sale as therapeutics so far. Their long-term efficacy and safety still needs to be proven, particularly with respect to immunogenicity. Antifibrotic effects may be worthy to be investigated in humans.

  9. Myostatin, follistatin and activin type II receptors are highly expressed in adenomyosis.

    PubMed

    Carrarelli, Patrizia; Yen, Chih-Fen; Arcuri, Felice; Funghi, Lucia; Tosti, Claudia; Wang, Tzu-Hao; Huang, Joseph S; Petraglia, Felice

    2015-09-01

    To evaluate the expression pattern of activins and related growth factor messenger RNA (mRNA) levels in adenomyotic nodules and in their endometrium. Prospective study. University hospital. Symptomatic premenopausal women scheduled to undergo hysterectomy for adenomyosis. Samples from adenomyotic nodules and homologous endometria were collected. Endometrial tissue was also obtained from a control group. Quantitative real-time polymerase chain reaction (PCR) analysis and immunohistochemical localization of activin-related growth factors (activin A, activin B, and myostatin), binding protein (follistatin), antagonists (inhibin-α, cripto), and receptors (ActRIIa, ActRIIb) were performed. Myostatin mRNA levels in adenomyotic nodule were higher than in eutopic endometrium and myostatin, activin A, and follistatin concentrations were higher than in control endometrium. No difference was observed for inhibin-α, activin B, and cripto mRNA levels. Increased mRNA levels of ActRIIa and ActRIIb were observed in adenomyotic nodules compared with eutopic endometrium and control endometrium. Immunofluorescent staining for myostatin and follistatin confirmed higher protein expression in both glands and stroma of patients with adenomyosis than in controls. The present study showed for the first time that adenomyotic tissues express high levels of myostatin, follistatin, and activin A (growth factors involved in proliferation, apoptosis, and angiogenesis). Increased expression of their receptors supports the hypothesis of a possible local effect of these growth factors in adenomyosis. The augmented expression of ActRIIa, ActRIIb, and follistatin in the endometrium of these patients may play a role in adenomyosis-related infertility. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  10. Elevated expression of activins promotes muscle wasting and cachexia.

    PubMed

    Chen, Justin L; Walton, Kelly L; Winbanks, Catherine E; Murphy, Kate T; Thomson, Rachel E; Makanji, Yogeshwar; Qian, Hongwei; Lynch, Gordon S; Harrison, Craig A; Gregorevic, Paul

    2014-04-01

    In models of cancer cachexia, inhibiting type IIB activin receptors (ActRIIBs) reverse muscle wasting and prolongs survival, even with continued tumor growth. ActRIIB mediates signaling of numerous TGF-β proteins; of these, we demonstrate that activins are the most potent negative regulators of muscle mass. To determine whether activin signaling in the absence of tumor-derived factors induces cachexia, we used recombinant serotype 6 adeno-associated virus (rAAV6) vectors to increase circulating activin A levels in C57BL/6 mice. While mice injected with control vector gained ~10% of their starting body mass (3.8±0.4 g) over 10 wk, mice injected with increasing doses of rAAV6:activin A exhibited weight loss in a dose-dependent manner, to a maximum of -12.4% (-4.2±1.1 g). These reductions in body mass in rAAV6:activin-injected mice correlated inversely with elevated serum activin A levels (7- to 24-fold). Mechanistically, we show that activin A reduces muscle mass and function by stimulating the ActRIIB pathway, leading to deleterious consequences, including increased transcription of atrophy-related ubiquitin ligases, decreased Akt/mTOR-mediated protein synthesis, and a profibrotic response. Critically, we demonstrate that the muscle wasting and fibrosis that ensues in response to excessive activin levels is fully reversible. These findings highlight the therapeutic potential of targeting activins in cachexia.

  11. Activins and activin antagonists in the human ovary and ovarian cancer.

    PubMed

    Reader, Karen L; Gold, Elspeth

    2015-11-05

    Activins are members of the transforming growth factor β superfamily that play an important role in controlling cell proliferation and differentiation in many organs including the ovary. It is essential that activin signalling be tightly regulated as imbalances can lead to uncontrolled cell proliferation and cancer. This review describes the expression and function of the activins and their known antagonists in both normal and cancerous human ovaries. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. Activins in reproductive biology and beyond.

    PubMed

    Wijayarathna, R; de Kretser, D M

    2016-04-01

    Activins are members of the pleiotrophic family of the transforming growth factor-beta (TGF-β) superfamily of cytokines, initially isolated for their capacity to induce the release of FSH from pituitary extracts. Subsequent research has demonstrated that activins are involved in multiple biological functions including the control of inflammation, fibrosis, developmental biology and tumourigenesis. This review summarizes the current knowledge on the roles of activin in reproductive and developmental biology. It also discusses interesting advances in the field of modulating the bioactivity of activins as a therapeutic target, which would undoubtedly be beneficial for patients with reproductive pathology. A comprehensive literature search was carried out using PUBMED and Google Scholar databases to identify studies in the English language which have contributed to the advancement of the field of activin biology, since its initial isolation in 1987 until July 2015. 'Activin', 'testis', 'ovary', 'embryonic development' and 'therapeutic targets' were used as the keywords in combination with other search phrases relevant to the topic of activin biology. Activins, which are dimers of inhibin β subunits, act via a classical TGF-β signalling pathway. The bioactivity of activin is regulated by two endogenous inhibitors, inhibin and follistatin. Activin is a major regulator of testicular and ovarian development. In the ovary, activin A promotes oocyte maturation and regulates granulosa cell steroidogenesis. It is also essential in endometrial repair following menstruation, decidualization and maintaining pregnancy. Dysregulation of the activin-follistatin-inhibin system leads to disorders of female reproduction and pregnancy, including polycystic ovary syndrome, ectopic pregnancy, miscarriage, fetal growth restriction, gestational diabetes, pre-eclampsia and pre-term birth. Moreover, a rise in serum activin A, accompanied by elevated FSH, is characteristic of female

  13. Activins and inhibins: Novel regulators of thymocyte development

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Licona-Limon, Paula; Aleman-Muench, German; Chimal-Monroy, Jesus

    2009-04-03

    Activins and inhibins are members of the transforming growth factor-{beta} superfamily that act on different cell types and regulate a broad range of cellular processes including proliferation, differentiation, and apoptosis. Here, we provide the first evidence that activins and inhibins regulate specific checkpoints during thymocyte development. We demonstrate that both activin A and inhibin A promote the DN3-DN4 transition in vitro, although they differentially control the transition to the DP stage. Whereas activin A induces the accumulation of a CD8{sup +}CD24{sup hi}TCR{beta}{sup lo} intermediate subpopulation, inhibin A promotes the differentiation of DN4 to DP. In addition, both activin A andmore » inhibin A appear to promote CD8{sup +}SP differentiation. Moreover, inhibin {alpha} null mice have delayed in vitro T cell development, showing both a decrease in the DN-DP transition and reduced thymocyte numbers, further supporting a role for inhibins in the control of developmental signals taking place during T cell differentiation in vivo.« less

  14. Expression and function of activin receptors in human endometrial adenocarcinoma cells.

    PubMed

    Tanaka, Tetsuji; Toujima, Saori; Otani, Tsutomu; Minami, Sawako; Yamoto, Mareo; Umesaki, Naohiko

    2003-09-01

    Menstrual cycle-dependent expressions of activin A in normal human endometrial tissues have been reported. Expression of activin receptor mRNAs and increased activin A production were also observed in human endometrial adenocarcinoma tissues, suggesting that activin A might enhance cell proliferation and inhibit apoptotic signaling in endometrial cancer cells. In this study, we have examined the effects of activin A on cell proliferation, anticancer drug-induced apoptosis and Fas-mediated apoptosis in 3 differentiated human endometrial adenocarcinoma cell lines, namely HEC-1, HHUA and Ishikawa. Flow cytometric analyses revealed moderate expressions of all 4 types of activin receptor subunits on the cell surfaces of the 3 cell lines. The proliferations of the 3 endometrial cancer cells were completely unaffected by activin A, whereas it suppressed the cell proliferation of a human ovarian endometrioid adenocarcinoma cell line, OVK-18, in a dose-dependent manner. Moreover, activin A did not affect the apoptotic changes in the 3 endometrial adenocarcinoma cells treated with 4 different anticancer drugs, namely CDDP, paclitaxel, etoposide and SN38. The apoptotic changes in HHUA cells treated with anti-Fas IgM were also unaffected by activin A. These results indicate that the increased activin A production in human endometrial adenocarcinoma tissues in vivo may not stimulate carcinoma cell proliferation or inhibit apoptotic signaling in carcinoma cells. Insensitivity to the usual growth suppression signals induced by activin A might be one of the mechanisms of immortality of human endometrial adenocarcinoma cells.

  15. An Antibody Blocking Activin Type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy

    PubMed Central

    Minetti, Giulia C.; Sheppard, KellyAnn; Ibebunjo, Chikwendu; Feige, Jerome N.; Hartmann, Steffen; Brachat, Sophie; Rivet, Helene; Koelbing, Claudia; Morvan, Frederic; Hatakeyama, Shinji

    2014-01-01

    The myostatin/activin type II receptor (ActRII) pathway has been identified to be critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody (bimagrumab, or BYM338) to prevent binding of ligands to the receptors and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts and counteracts the inhibition of differentiation induced by myostatin or activin A. BYM338 prevents myostatin- or activin A-induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing the myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin mutant mice, further confirming a beneficial effect on muscle growth beyond myostatin inhibition alone through blockade of ActRII ligands. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings. PMID:24298022

  16. Regional localization of activin-βA, activin-βC, follistatin, proliferation, and apoptosis in adult and developing mouse prostate ducts.

    PubMed

    Gold, Elspeth; Zellhuber-McMillan, Sylvia; Risbridger, Gail; Marino, Francesco Elia

    2017-01-01

    Activins and inhibins, members of the TGF-β superfamily, are growth and differentiation factors involved in the regulation of several biological processes, including reproduction, development, and fertility. Previous studies have shown that the activin-β A subunit plays a pivotal role in prostate development. Activin-A inhibits branching morphogenesis in the developing prostate, and its expression is associated with increased apoptosis in the adult prostate. Follistatin, a structurally unrelated protein to activins, is an antagonist of activin-A. A balance between endogenous activin-A and follistatin is required to maintain prostatic branching morphogenesis. Deregulation of this balance leads to branching inhibition or excessive branching and increased maturation of the stroma surrounding the differentiating epithelial ducts. Recent work identified another member of the TGF-β superfamily, the activin-β C subunit, as a novel antagonist of activin-A. Over-expression of activin-C (β C -β C ) alters prostate homeostasis, by interfering with the activin-A signaling. The current study characterized the spatiotemporal localization of activin-A, activin-C and follistatin in the adult and developing mouse prostate using immunohistochemical analysis. Results showed activin-C and follistatin are differentially expressed during prostate development and suggested that the antagonistic property of follistatin is secondary to the action of activin-C. In conclusion, the present study provides evidence to support a role of activin-C in prostate development and provides new insights in the spatiotemporal localization of activins and their antagonists during mouse prostate development. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Role of activin A in carbon tetrachloride-induced acute liver injury.

    PubMed

    Wang, Dong-Hui; Wang, Yi-Nan; Ge, Jing-Yan; Liu, Hai-Yan; Zhang, Hong-Jun; Qi, Yan; Liu, Zhong-Hui; Cui, Xue-Ling

    2013-06-28

    To investigate the expression and role of activin A in a mouse model of acute chemical liver injury. Acute liver injury in C57BL/6 male mice was induced by intraperitoneal injection with carbon tetrachloride (CCl4) (0.5 mL/kg, body weight) dissolved in olive oil (1:19 v/v). Mice were sacrificed 1, 3, 5 and 7 d after the treatment. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum were examined and pathological changes of liver observed by hematoxylin and eosin staining to evaluate the liver injury. Activin A protein levels in serum and hepatic tissue homogenate of mice were detected by enzyme-linked immunosorbent assay, and the expression pattern of activin A protein in livers of mice was examined by immunohistochemistry. Activin type IIA receptor (ActRIIA) and Smad3 expressions in the liver were analyzed by real-time quantitative reverse transcription-polymerase chain reaction. In order to further investigate the role of activin A, we also utilized activin A blocking experiment by anti-activin A antibody (500 μg/kg, body weight) injection into mouse tail vein. In CCl4-treated mice, serum ALT and AST levels were significantly increased, compared with that in control mice (P < 0.01). Furthermore, the serious necrosis was observed around hepatic portal areas in CCl4-treated mice. Simultaneously, activin A levels in serum and hepatic tissue homogenate of mice treated with CCl4 for 1, 3 and 5 d increased significantly, compared with that in control mice (P < 0.01). Activin A protein expression in hepatocytes not within the necrotic area was also upregulated in mice following CCl4 treatment. Not only activin A, but also ActRIIA and activin signaling molecule Smad3 mRNA expressions in injury liver induced by CCl4 were significantly higher than that in control liver. In addition, levels of serum ALT and AST in CCl4-treated mice were significantly decreased by injection of anti-activin A antibody to block endogenous activin A

  18. Decidual activin: its role in the apoptotic process and its regulation by prolactin.

    PubMed

    Tessier, Christian; Prigent-Tessier, Anne; Bao, Lei; Telleria, Carlos M; Ferguson-Gottschall, Susan; Gibori, Gil B; Gu, Yan; Bowen-Shauver, Jennifer M; Horseman, Nelson D; Gibori, Geula

    2003-05-01

    Successful pregnancy requires profound differentiation and reorganization of the uterine tissues including, as pregnancy progresses, extensive apoptosis of decidual tissue to accommodate the developing conceptus. We have previously shown a positive correlation between expression of activin A and apoptosis in the decidua and have also shown that expression of activin A occurs at the time when prolactin (PRL) receptors disappear from decidual cells. The goals of this study were to examine whether activin A plays a role in decidual apoptosis and whether expression of activin A in the decidua is regulated by PRL and placental lactogens. Studies were carried out using primary rat decidual cells, a decidual cell line (GG-AD), and PRL null mice. Treatment of decidual cells with activin A significantly increased DNA degradation, caspase 3 activity, and caspase 3 mRNA expression. However, this effect was observed only in the absence of endogenous activin production by these cells. Addition of follistatin to decidual cells that were producing activin A decreased both caspase 3 activity and mRNA expression. Similarly, addition of activin-blocking antibodies to cultures of GG-AD cells, which also produce activin A, caused a reduction in both DNA degradation and caspase 3 activity. PRL and placental lactogens caused an inhibition of activin A mRNA expression in primary decidual cells. Even more convincingly, decidua of PRL null mice expressed abundant activin A at a time when no expression of this hormone is detected in wild-type mice and treatment of PRL null mice with PRL caused a profound inhibition of activin A mRNA expression. In summary, our investigations into the role and regulation of decidual activin have revealed that activin A can induce cell death in the decidua and that its expression is under tight regulation by PRL and placental lactogens.

  19. New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration

    PubMed Central

    Pasteuning-Vuhman, Svitlana; Boertje-van der Meulen, Johanna W.; van Putten, Maaike; Overzier, Maurice; ten Dijke, Peter; Kiełbasa, Szymon M.; Arindrarto, Wibowo; Wolterbeek, Ron; Lezhnina, Ksenia V.; Ozerov, Ivan V.; Aliper, Aleksandr M.; Hoogaars, Willem M.; Aartsma-Rus, Annemieke; Loomans, Cindy J. M.

    2017-01-01

    Skeletal muscle fibrosis and impaired muscle regeneration are major contributors to muscle wasting in Duchenne muscular dystrophy (DMD). Muscle growth is negatively regulated by myostatin (MSTN) and activins. Blockage of these pathways may improve muscle quality and function in DMD. Antisense oligonucleotides (AONs) were designed specifically to block the function of ALK4, a key receptor for the MSTN/activin pathway in skeletal muscle. AON-induced exon skipping resulted in specific Alk4 down-regulation, inhibition of MSTN activity, and increased myoblast differentiation in vitro. Unexpectedly, a marked decrease in muscle mass (10%) was found after Alk4 AON treatment in mdx mice. In line with in vitro results, muscle regeneration was stimulated, and muscle fiber size decreased markedly. Notably, when Alk4 was down-regulated in adult wild-type mice, muscle mass decreased even more. RNAseq analysis revealed dysregulated metabolic functions and signs of muscle atrophy. We conclude that ALK4 inhibition increases myogenesis but also regulates the tight balance of protein synthesis and degradation. Therefore, caution must be used when developing therapies that interfere with MSTN/activin pathways.—Pasteuning-Vuhman, S., Boertje-van der Meulen, J. W., van Putten, M., Overzier, M., ten Dijke, P., Kiełbasa, S. M., Arindrarto, W., Wolterbeek, R., Lezhnina, K. V., Ozerov, I. V., Aliper, A. M., Hoogaars, W. M., Aartsma-Rus, A., Loomans, C. J. M. New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration. PMID:27733450

  20. Activin-A, transforming growth factor-beta, and myostatin signaling pathway in experimental dilated cardiomyopathy.

    PubMed

    Mahmoudabady, Maryam; Mathieu, Myrielle; Dewachter, Laurence; Hadad, Ielham; Ray, Lynn; Jespers, Pascale; Brimioulle, Serge; Naeije, Robert; McEntee, Kathleen

    2008-10-01

    The pathogenic mechanisms of dilated cardiomyopathy are still uncertain. A number of cytokines and growth factors participate in the remodeling process of the disease. We investigated the cardiac myostatin, transforming growth factor (TGF)beta, and activin-A/Smad growth inhibitory signaling pathway in experimental dilated cardiomyopathy. Transvenous endomyocardial biopsies of the interventricular septum were taken weekly in 15 beagle dogs during the development of heart failure (HF) induced by rapid pacing over a period of 7 weeks. Genes involved in the myostatin-TGFbeta-activin-A/Smad signaling pathway and the cardiac hypertrophic process were quantified by real-time quantitative polymerase chain reaction. Left ventricular volume, function, and mass were evaluated by echocardiography. Overpacing was associated with increased left ventricular volumes and decreased ejection fraction, whereas the left ventricular mass remained unchanged. TGFbeta was increased in moderate HF. Activin-A mRNA expression was 4-fold higher in overt congestive HF than at baseline. A 2-fold decrease of activin type II receptors and activin receptor interacting protein 2 gene expressions were observed, as well as a transient decrease of follistatin. Activin type I receptors, activin receptor interacting protein 1, follistatin-related gene, and myostatin remained unchanged. The inhibitory Smad 7, a negative feedback loop regulator of the Smad pathway, was overexpressed in severe HF. Gene expression of the cyclin-dependent kinase inhibitor p21, a direct target gene of the Smad pathway, was 8-fold up-regulated in HF, whereas cyclin D1 was down-regulated. We conclude that tachycardia-induced dilated cardiomyopathy is characterized by gene overexpression of the TGFbeta-activin-A/Smad signaling pathway and their target gene p21 and by the absence of ventricular hypertrophy.

  1. [Measurement of umbilical activin A level in preterm infants].

    PubMed

    Zhong, Ying; Li, Juan; Wei, Ke-Lun

    2011-10-01

    To evaluate the clinical significance of umbilical activin A in preterm infants. Forty-one preterm infants (gestation 28 to 36 weeks) were enrolled. Fetal membranes, umbilical cords and blood samples from umbilical vein were obtained. Umbilical activin A level was measured using ELISA. The histological examinations of fetal membranes and umbilical cords were performed. The umbilical level of activin A averaged 2069 pg/mL in the 41 preterm infants. The umbilical activin A level in the 5 infants with intrauterine infection was higher than in those without intrauterine infection (2510 pg/mL vs 1975 pg/mL; P<0.01). Umbilical activin A level at cutoff of 2490 pg/mL showed a sensitivity of 80.0% and a specificity of 90.6% as a marker of intrauterine infection. There were no significant differences in the umbilical activin A level between the infants with and without respiratory distress syndrome. Umbilical activin A level was positively correlated with the duration of postnatal oxygen therapy (r=0.326, P<0.05). Umbilical activin A may serve a marker of intrauterine infection in preterm infants. The umbilical activin A level is correlated with the duration of postnatal oxygen therapy.

  2. Overexpression of activin-A and -B in malignant mesothelioma – Attenuated Smad3 signaling responses and ERK activation promote cell migration and invasive growth

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tamminen, Jenni A.; Yin, Miao; Transplantation Laboratory, Haartman Institute, University of Helsinki

    Activin-A and activin-B, members of the TGF-β superfamily, are regulators of reproductive functions, inflammation and wound healing. These dimeric molecules regulate various cellular activities such as proliferation, migration and suvival. Malignant mesothelioma is an asbestos exposure related tumor affecting mainly pleura and it usually has a dismal prognosis. Here, we demonstrate that both activin-A and -B are abundantly expressed in mesothelioma tumor tissue as well as in cultured primary and established mesothelioma cells. Migratory and invasive mesothelioma cells were also found to have attenuated activation of the Smad2/3 pathway in response to activins. Migration and invasive growth of the cellsmore » in three-dimentional matrix was prevented by inhibition of activin activity using a soluble activin receptor 2B (sActR2B-Fc). This was associated with decreased ERK activity. Furthermore, migration and invasive growth was significantly inhibited by blocking ERK phosphorylation. Mesothelioma tumors are locally invasive and our results clearly suggest that acivins have a tumor-promoting function in mesothelioma through increasing expression and switching from canonical Smad3 pathway to non-canonical ERK pathway signaling. Blocking activin activity offers a new therapeutic approach for inhibition of mesothelioma invasive growth. - Highlights: • Activin-A and activin-B are highly expressed in mesothelioma. • Mesothelioma cell migration and invasive growth can be blocked with sActR2B. • Activin induced Smad3 activity is attenuated in invasive mesothelioma cells. • Activins induce ERK activity in mesothelioma cells.« less

  3. Virtual High-Throughput Screening To Identify Novel Activin Antagonists

    PubMed Central

    Zhu, Jie; Mishra, Rama K.; Schiltz, Gary E.; Makanji, Yogeshwar; Scheidt, Karl A.; Mazar, Andrew P.; Woodruff, Teresa K.

    2015-01-01

    Activin belongs to the TGFβ superfamily, which is associated with several disease conditions, including cancer-related cachexia, preterm labor with delivery, and osteoporosis. Targeting activin and its related signaling pathways holds promise as a therapeutic approach to these diseases. A small-molecule ligand-binding groove was identified in the interface between the two activin βA subunits and was used for a virtual high-throughput in silico screening of the ZINC database to identify hits. Thirty-nine compounds without significant toxicity were tested in two well-established activin assays: FSHβ transcription and HepG2 cell apoptosis. This screening workflow resulted in two lead compounds: NUCC-474 and NUCC-555. These potential activin antagonists were then shown to inhibit activin A-mediated cell proliferation in ex vivo ovary cultures. In vivo testing showed that our most potent compound (NUCC-555) caused a dose-dependent decrease in FSH levels in ovariectomized mice. The Blitz competition binding assay confirmed target binding of NUCC-555 to the activin A:ActRII that disrupts the activin A:ActRII complex’s binding with ALK4-ECD-Fc in a dose-dependent manner. The NUCC-555 also specifically binds to activin A compared with other TGFβ superfamily member myostatin (GDF8). These data demonstrate a new in silico-based strategy for identifying small-molecule activin antagonists. Our approach is the first to identify a first-in-class small-molecule antagonist of activin binding to ALK4, which opens a completely new approach to inhibiting the activity of TGFβ receptor superfamily members. in addition, the lead compound can serve as a starting point for lead optimization toward the goal of a compound that may be effective in activin-mediated diseases. PMID:26098096

  4. Identification of activin A and follistatin in human milk.

    PubMed

    Luisi, Stefano; Calonaci, Giulia; Florio, Pasquale; Lombardi, Ilaria; De Felice, Claudio; Bagnoli, Franco; Petraglia, Felice

    2002-09-01

    Activin A is a dimeric protein member of the transforming growth factor-beta (TGF-beta) family: it is synthesized by a variety of organs and follistatin is an activin-binding protein. A sensitive and specific assays for bioactive dimeric activin A and follistatin have recently allowed to measure these proteins in blood and other biological fluids, giving a new insights into their possible physiological role. Since human breast is able to produce activin A, the aim of the present study was to evaluate whether it and follistatin are measurable in breast milk of women during lactation. Concentrations of activin A and follistatin were measured in milk samples collected at 3, 5 and 30 days after delivery by using specific and sensitive two-site ELISAs. For the first time the presence of immunoreactive activin A and follistatin in human milk has been shown; no significant different concentration between the third and the fifth day after delivery was found. Furthermore, no difference of activin A and follistatin concentration between the whole and the skim milk or between spontaneous delivery and cesarean section was found. Milk activin A and follistatin concentrations after 1 month of lactation were significantly decreased (P < 0.01). Activin A and follistatin are present in human milk in high concentrations in the first week of lactation, while decrease after a month suggesting a possible role as growth factors in human milk.

  5. Activin type IB receptor signaling in prostate cancer cells promotes lymph node metastasis in a xenograft model

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nomura, Masatoshi, E-mail: nomura@med.kyushu-u.ac.jp; Tanaka, Kimitaka; Wang, Lixiang

    Highlights: Black-Right-Pointing-Pointer ActRIB signaling induces Snail and S100A4 expressions in prostate cancer cells. Black-Right-Pointing-Pointer The prostate cancer cell lines expressing an active form of ActRIB were established. Black-Right-Pointing-Pointer ActRIB signaling promotes EMT and lymph node metastasis in xenograft model. -- Abstract: Activin, a member of the transforming growth factor-{beta} family, has been known to be a growth and differentiating factor. Despite its pluripotent effects, the roles of activin signaling in prostate cancer pathogenesis are still unclear. In this study, we established several cell lines that express a constitutive active form of activin type IB receptor (ActRIBCA) in human prostate cancermore » cells, ALVA41 (ALVA-ActRIBCA). There was no apparent change in the proliferation of ALVA-ActRIBCA cells in vitro; however, their migratory ability was significantly enhanced. In a xenograft model, histological analysis revealed that the expression of Snail, a cell-adhesion-suppressing transcription factor, was dramatically increased in ALVA-ActRIBCA tumors, indicating epithelial mesenchymal transition (EMT). Finally, mice bearing ALVA-ActRIBCA cells developed multiple lymph node metastases. In this study, we demonstrated that ActRIBCA signaling can promote cell migration in prostate cancer cells via a network of signaling molecules that work together to trigger the process of EMT, and thereby aid in the aggressiveness and progression of prostate cancers.« less

  6. Structure and activation of pro-activin A

    PubMed Central

    Wang, Xuelu; Fischer, Gerhard; Hyvönen, Marko

    2016-01-01

    Activins are growth factors with multiple roles in the development and homeostasis. Like all TGF-β family of growth factors, activins are synthesized as large precursors from which mature dimeric growth factors are released proteolytically. Here we have studied the activation of activin A and determined crystal structures of the unprocessed precursor and of the cleaved pro-mature complex. Replacing the natural furin cleavage site with a HRV 3C protease site, we show how the protein gains its bioactivity after proteolysis and is as active as the isolated mature domain. The complex remains associated in conditions used for biochemical analysis with a dissociation constant of 5 nM, but the pro-domain can be actively displaced from the complex by follistatin. Our high-resolution structures of pro-activin A share features seen in the pro-TGF-β1 and pro-BMP-9 structures, but reveal a new oligomeric arrangement, with a domain-swapped, cross-armed conformation for the protomers in the dimeric protein. PMID:27373274

  7. Activin A, B and AB decrease progesterone production by down-regulating StAR in human granulosa cells.

    PubMed

    Chang, Hsun-Ming; Cheng, Jung-Chien; Huang, He-Feng; Shi, Feng-Tao; Leung, Peter C K

    2015-09-05

    Activins are homo- or heterodimers of inhibin β subunits that play important roles in the reproductive system. Our previous work has shown that activins A (βAβA), B (βBβB) and AB (βAβB) induce aromatase/estradiol, but suppress StAR/progesterone production in human granulosa-lutein cells. However, the underlying molecular determinants of these effects have not been examined. In this continuing study, we used immortalized human granulosa cells (SVOG) to investigate the effects of activins in regulating StAR/progesterone and the potential mechanisms of action. In SVOG cells, activins A, B and AB produced comparable down-regulation of StAR expression and progesterone production. In addition, all three activin isoforms induced equivalent phosphorylation of both SMAD2 and SMAD3. Importantly, the activin-induced down-regulation of StAR, increase in SMAD2/3 phosphorylation, and decrease in progesterone were abolished by the TGF-β type I receptor inhibitor SB431542. Interestingly, the small interfering RNA-mediated knockdown of ALK4 but not ALK5 reversed the activin-induced suppression of StAR. Furthermore, the knockdown of SMAD4 or SMAD2 but not SMAD3 abolished the inhibitory effects of all three activin isoforms on StAR expression. These results provide evidence that activins A, B and AB down-regulate StAR expression and decrease progesterone production in human granulosa cells, likely via an ALK4-mediated SMAD2/SMAD4-dependent pathway. Our findings provide important insights into the molecular mechanisms underlying the regulatory effects of activins on human granulosa cell steroidogenesis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  8. Effects of Activin and TGFβ on p21 in Colon Cancer

    PubMed Central

    Cabral, Jennifer; Gomez, Jessica; Jung, Barbara

    2012-01-01

    Activin and TGFβ share SMAD signaling and colon cancers can inactivate either pathway alone or simultaneously. The differential effects of activin and TGFβ signaling in colon cancer have not been previously dissected. A key downstream target of TGFβ signaling is the cdk2 inhibitor p21 (p21cip1/waf1). Here, we evaluate activin-specific effects on p21 regulation and resulting functions. We find that TGFβ is a more potent inducer of growth suppression, while activin is a more potent inducer of apoptosis. Further, growth suppression and apoptosis by both ligands are dependent on SMAD4. However, activin downregulates p21 protein in a SMAD4-independent fashion in conjunction with increased ubiquitination and proteasomal degradation to enhance migration, while TGFβ upregulates p21 in a SMAD4-dependent fashion to affect growth arrest. Activin-induced growth suppression and cell death are dependent on p21, while activin-induced migration is counteracted by p21. Further, primary colon cancers show differential p21 expression consistent with their ACVR2/TGFBR2 receptor status. In summary, we report p21 as a differentially affected activin/TGFβ target and mediator of ligand-specific functions in colon cancer, which may be exploited for future risk stratification and therapeutic intervention. PMID:22761777

  9. Quantitative RT-PCR for inhibin/activin subunits: measurements of rat hypothalamic and ovarian inhibin/activin subunit mRNAs during the estrous cycle.

    PubMed

    Murata, T; Takizawa, T; Funaba, M; Fujimura, H; Murata, E; Takahashi, M; Torii, K

    1997-02-01

    Inhibins (alpha-beta(A) and alpha-beta(B)) and activins (beta(A)-beta(A), beta(A)-beta(B) and beta(B)-beta(B)) were originally isolated from ovarian follicular fluids as FSH secretion modifiers. Inhibin/activin subunits, alpha, beta(A) and beta(B), are widely distributed in several tissues, including gonads and brain, and inhibins and activins have been reported to be involved in ovarian or hypothalamic functions. In this study, we established and employed a competitive RT-PCR assay system for rat inhibin/activin subunits by capillary electrophoresis to determine rat hypothalamic and ovarian inhibin/activin subunit mRNA levels during the estrous cycle. Linearity of standards for alpha, beta(A), and beta(B) subunit assays were between 0.01-0.3 amol, 0.003-0.09 amol and 0.002-0.02 amol of each fragment DNA as a standard, respectively. Hypothalamic beta(A) subunit mRNA during the estrous morning (1000 h) tended to be increased compared with that of the proestrous evening (1700 h), although they were not significantly different. Ovarian alpha subunit mRNA levels tended to be increased during the proestrous morning (1000 h) and were significantly increased in the proestrous evening (1700 h), compared with diestrus and estrus (P < 0.05). Ovarian beta(A) subunit mRNA was also significantly higher in the proestrous evening, compared with diestrus and estrus (P < 0.05), but in the case of beta(B) subunit mRNA there was no difference among diestrus, proestrus and estrus. We thus established a sensitive competitive RT-PCR system for the measurement of inhibin/activin alpha, beta(A) and beta(B) subunits, and this assay system would be helpful for the study of inhibin/activin action in brain and other tissues where these factors are expressed at low levels.

  10. Activin B is produced early in antral follicular development and suppresses thecal androgen production

    PubMed Central

    Young, J M; Henderson, S; Souza, C; Ludlow, H; Groome, N; McNeilly, A S

    2012-01-01

    Little is known about the role of activin B during folliculogenesis. This study investigated the expression levels of activin/inhibin subunits (βA, βB, and α), steroid enzyme, and gonadotrophin receptors in theca (TC) and granulosa cells (GC) by QPCR and activin A and B and inhibin A protein levels in follicular fluid (FF) of developing sheep follicles during estrus and anestrus. The effect of activin B on androgen production from primary TC cultures in vitro was also assessed. During folliculogenesis, in anestrus and estrus, FF activin B concentrations and thecal and GC activin βB mRNA levels decreased as follicle diameter increased from 1–3 to >6 mm regardless of estrogenic status. Estrogenic preovulatory follicles had reduced concentrations of FF activins B and A, and TC and GCs expressed higher levels of activin βA mRNA at 3–4 mm, and TCs more inhibin α mRNA at >4 mm stages of development compared with nonestrogenic follicles. Activin B decreased androstenedione production from primary TCs in vitro, an effect blocked by inhibin A. Thus, sheep follicles 1–3 mm in diameter contained high FF levels of activin B, which decreased as the follicle size increased, and, like activin A, suppressed thecal androgen production in vitro, an effect blocked by inhibin. Furthermore, the theca of large estrogenic follicles expressed high levels of inhibin α and activin βA mRNA suggesting local thecal derived inhibin A production. This would inhibit the negative effects of thecal activins B and A ensuring maximum androgen production for enhanced estradiol production by the preovulatory follicle(s). PMID:22450673

  11. Activin B promotes initiation and development of hair follicles in mice.

    PubMed

    Jia, Qin; Zhang, Min; Kong, Yanan; Chen, Shixuan; Chen, Yinghua; Wang, Xueer; Zhang, Lei; Lang, Weiya; Zhang, Lu; Zhang, Lin

    2013-01-01

    Activin B has been reported to promote the regeneration of hair follicles during wound healing. However, its role in the development and life cycle of hair follicles has not been elucidated. In our study, the effect of activin B on mouse hair follicles of cultured and neonatal mouse skin was investigated. In these models, PBS or activin B (5, 10 or 50 ng/ml) was applied, and hair follicle development was monitored. Hair follicle initiation and development was examined using hematoxylin and eosin staining, alkaline phosphatase activity staining, Oil Red O+ staining, and the detection of TdT-mediated dUTP-biotin nick end-labeling cell apoptosis. Activin B was found to efficiently induce the initiation of hair follicles in the skin of both cultured and neonatal mice and to promote the development of hair follicles in neonatal mouse skin. Moreover, activin-B-treated hair follicles were observed to enter the anagen stage from the telogen stage and to remain in the anagen stage. These results demonstrate that activin B promotes the initiation and development of hair follicles in mice.

  12. Differential Muscle Hypertrophy Is Associated with Satellite Cell Numbers and Akt Pathway Activation Following Activin Type IIB Receptor Inhibition in Mtm1 p.R69C Mice

    PubMed Central

    Lawlor, Michael W.; Viola, Marissa G.; Meng, Hui; Edelstein, Rachel V.; Liu, Fujun; Yan, Ke; Luna, Elizabeth J.; Lerch-Gaggl, Alexandra; Hoffmann, Raymond G.; Pierson, Christopher R.; Buj-Bello, Anna; Lachey, Jennifer L.; Pearsall, Scott; Yang, Lin; Hillard, Cecilia J.; Beggs, Alan H.

    2015-01-01

    X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1δ4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence of hypertrophy in gastrocnemius muscles but not in quadriceps or triceps. The ability of the muscles to respond to activin receptor type IIB inhibitor treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. Treatment-responsive Mtm1 p.R69C gastrocnemius muscles displayed lower levels of phosphorylated ribosomal protein S6 and higher levels of phosphorylated eukaryotic elongation factor 2 kinase than were observed in Mtm1 p.R69C quadriceps muscle or in muscles from wild-type littermates. Hypertrophy in the Mtm1 p.R69C gastrocnemius muscle was associated with increased levels of phosphorylated ribosomal protein S6. Our findings indicate that muscle-, fiber type-, and mutation-specific factors affect the response to hypertrophic therapies that will be important to assess in future therapeutic trials. PMID:24726641

  13. Activin in acute pancreatitis: Potential risk-stratifying marker and novel therapeutic target.

    PubMed

    Staudacher, Jonas J; Yazici, Cemal; Carroll, Timothy; Bauer, Jessica; Pang, Jingbo; Krett, Nancy; Xia, Yinglin; Wilson, Annette; Papachristou, Georgios; Dirmeier, Andrea; Kunst, Claudia; Whitcomb, David C; Fantuzzi, Giamila; Jung, Barbara

    2017-10-06

    Acute Pancreatitis is a substantial health care challenge with increasing incidence. Patients who develop severe disease have considerable mortality. Currently, no reliable predictive marker to identify patients at risk for severe disease exists. Treatment is limited to rehydration and supporting care suggesting an urgent need to develop novel approaches to improve standard care. Activin is a critical modulator of inflammatory responses, but has not been assessed in pancreatitis. Here, we demonstrate that serum activin is elevated and strongly correlates with disease severity in two established murine models of acute pancreatitis induced by either cerulein or IL-12 + IL-18. Furthermore, in mice, inhibition of activin conveys survival benefits in pancreatitis. In addition, serum activin levels were measured from a retrospective clinical cohort of pancreatitis patients and high activin levels in patients at admission are predictive of worse outcomes, indicated by longer overall hospital and intensive care unit stays. Taken together, activin is a novel candidate as a clinical marker to identify those acute pancreatitis patients with severe disease who would benefit from aggressive treatment and activin may be a therapeutic target in severe acute pancreatitis.

  14. Expression of Activin During and After Chemotherapy in Peripheral Blood of Patients with Primary Breast Cancer.

    PubMed

    Jueckstock, Julia; Burkhardt, Natalie; Kuhn, Christina; Blankenstein, Thomas; Mahner, Sven; Schindlbeck, Christian; Janni, Wolfgang; Rack, Brigitte; Mylonas, Ioannis

    2016-05-01

    Activins are dimeric glycoproteins that play a significant role in reproduction and in endocrine-active tumors. The aim of this study was to evaluate the potential correlation between the concentration of activins (activin A, activin B, and activin AB) in patients receiving adjuvant chemotherapy for breast cancer. The serum concentration of activins in 30 patients receiving chemotherapy within the German SUCCESS A study was analyzed using different enzyme-linked immunosorbent assays at three time points: After primary surgery, but before chemotherapy; 4 weeks after the end of chemotherapy; and 2 years after chemotherapy during recurrence-free follow-up. The activin concentration decreased in all patients after chemotherapy. Premenopausal patients had significantly lower concentrations of activin AB during follow-up than postmenopausal women (p=0.037). Thirteen out of 16 premenopausal patients developed chemotherapy-related amenorrhea (CRA) but did not significantly differ in their activin concentrations compared to the other premenopausal women. A positive human epidermal growth factor receptor 2/neu status was associated with a significant reduction of activin AB concentration (p=0.02), and trastuzumab treatment correlated with significantly decreased activin A concentration (p=0.012). Serial measurements of activin A concentration might be used for monitoring trastuzumab treatment. A sudden increase of activin concentration could be an early indicator of disease recurrence. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  15. Differential muscle hypertrophy is associated with satellite cell numbers and Akt pathway activation following activin type IIB receptor inhibition in Mtm1 p.R69C mice.

    PubMed

    Lawlor, Michael W; Viola, Marissa G; Meng, Hui; Edelstein, Rachel V; Liu, Fujun; Yan, Ke; Luna, Elizabeth J; Lerch-Gaggl, Alexandra; Hoffmann, Raymond G; Pierson, Christopher R; Buj-Bello, Anna; Lachey, Jennifer L; Pearsall, Scott; Yang, Lin; Hillard, Cecilia J; Beggs, Alan H

    2014-06-01

    X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1δ4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence of hypertrophy in gastrocnemius muscles but not in quadriceps or triceps. The ability of the muscles to respond to activin receptor type IIB inhibitor treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. Treatment-responsive Mtm1 p.R69C gastrocnemius muscles displayed lower levels of phosphorylated ribosomal protein S6 and higher levels of phosphorylated eukaryotic elongation factor 2 kinase than were observed in Mtm1 p.R69C quadriceps muscle or in muscles from wild-type littermates. Hypertrophy in the Mtm1 p.R69C gastrocnemius muscle was associated with increased levels of phosphorylated ribosomal protein S6. Our findings indicate that muscle-, fiber type-, and mutation-specific factors affect the response to hypertrophic therapies that will be important to assess in future therapeutic trials. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  16. Role of Activins in Hepcidin Regulation during Malaria.

    PubMed

    Spottiswoode, Natasha; Armitage, Andrew E; Williams, Andrew R; Fyfe, Alex J; Biswas, Sumi; Hodgson, Susanne H; Llewellyn, David; Choudhary, Prateek; Draper, Simon J; Duffy, Patrick E; Drakesmith, Hal

    2017-12-01

    Epidemiological observations have linked increased host iron with malaria susceptibility, and perturbed iron handling has been hypothesized to contribute to the potentially life-threatening anemia that may accompany blood-stage malaria infection. To improve our understanding of these relationships, we examined the pathways involved in regulation of the master controller of iron metabolism, the hormone hepcidin, in malaria infection. We show that hepcidin upregulation in Plasmodium berghei murine malaria infection was accompanied by changes in expression of bone morphogenetic protein (BMP)/sons of mothers against decapentaplegic (SMAD) pathway target genes, a key pathway involved in hepcidin regulation. We therefore investigated known agonists of the BMP/SMAD pathway and found that Bmp gene expression was not increased in infection. In contrast, activin B, which can signal through the BMP/SMAD pathway and has been associated with increased hepcidin during inflammation, was upregulated in the livers of Plasmodium berghei -infected mice; hepatic activin B was also upregulated at peak parasitemia during infection with Plasmodium chabaudi Concentrations of the closely related protein activin A increased in parallel with hepcidin in serum from malaria-naive volunteers infected in controlled human malaria infection (CHMI) clinical trials. However, antibody-mediated neutralization of activin activity during murine malaria infection did not affect hepcidin expression, suggesting that these proteins do not stimulate hepcidin upregulation directly. In conclusion, we present evidence that the BMP/SMAD signaling pathway is perturbed in malaria infection but that activins, although raised in malaria infection, may not have a critical role in hepcidin upregulation in this setting. Copyright © 2017 Spottiswoode et al.

  17. Activin B regulates adipose-derived mesenchymal stem cells to promote skin wound healing via activation of the MAPK signaling pathway.

    PubMed

    Zhang, Lei; Xu, Pengcheng; Wang, Xueer; Zhang, Min; Yan, Yuan; Chen, Yinghua; Zhang, Lu; Zhang, Lin

    2017-06-01

    Adipose-derived stem cells (ADSCs) are multipotent stromal cells that can differentiate into a variety of cell types, including skin cells, and they can provide an abundant source of cells for skin tissue engineering and skin wound healing. The purpose of this study is to explore the therapeutic effects of activin B in combination with ADSCs and the possible signaling mechanism. In this study, we found that activin B was able to promote ADSC migration by inducing actin stress fiber formation in vitro. In vivo, activin B in combination with ADSCs was capable of enhancing α-SMA expression and wound closure. This combined treatment also promoted fibroblast and keratinocyte proliferation and accelerated re-epithelialization and collagen deposition. Moreover, activin B in combination with ADSCs boosted angiogenesis in the wound area. Further study of the mechanism revealed that activation of JNK and ERK signaling, but not p38 signaling, were required for activin B-induced ADSC actin stress fiber formation and cell migration. These results showed that activin B was able to activate JNK and ERK signaling pathways to induce actin stress fiber formation and ADSC migration to promote wound healing. These results suggest that combined treatment with activin B and ADSCs is a promising therapeutic strategy for the management of serious skin wounds. Copyright © 2017. Published by Elsevier Ltd.

  18. Two highly-related regulatory subunits of PP2A exert opposite effects on TGF-β/Activin/Nodal signalling

    PubMed Central

    Batut, Julie; Schmierer, Bernhard; Cao, Jing; Raftery, Laurel A.; Hill, Caroline S.; Howell, Michael

    2016-01-01

    Summary We identify Bα (PPP2R2A) and Bδ (PPP2R2D), two highly-related members of the B family of regulatory subunits of the protein phosphatase PP2A, as important modulators of TGF-β/Activin/Nodal signalling, which affect the pathway in opposite ways. Knockdown of Bα in Xenopus embryos or mammalian tissue culture cells suppresses TGF-β/Activin/Nodal-dependent responses, whereas knockdown of Bδ enhances these responses. Moreover, in Drosophila, overexpression of Smad2 rescues a severe wing phenotype caused by overexpression of the single Drosophila PP2A B subunit, Twins. We show that in vertebrates Bα enhances TGF-β/Activin/Nodal signalling by stabilising the basal levels of type I receptor, whereas Bδ negatively modulates these pathways by restricting receptor activity. Thus, these highly-related members of the same subfamily of PP2A regulatory subunits differentially regulate TGF-β/Activin/Nodal signalling to elicit opposing biological outcomes. PMID:18697906

  19. Role of Activin-A and Myostatin and Their Signaling Pathway in Human Myometrial and Leiomyoma Cell Function

    PubMed Central

    Islam, Md Soriful; Catherino, William H.; Protic, Olga; Janjusevic, Milijana; Gray, Peter Clarke; Giannubilo, Stefano Raffaele; Ciavattini, Andrea; Lamanna, Pasquale; Tranquilli, Andrea Luigi; Petraglia, Felice

    2014-01-01

    Context: Uterine leiomyomas are highly prevalent benign tumors of premenopausal women and the most common indication for hysterectomy. However, the exact etiology of this tumor is not fully understood. Objective: The objective of the study was to evaluate the role of activin-A and myostatin and their signaling pathways in human myometrial and leiomyoma cells. Design: This was a laboratory study. Setting: Myometrial and leiomyoma cells (primary and cell lines) were cultured in vitro. Patients: The study included premenopausal women who were admitted to the hospital for myomectomy or hysterectomy. Interventions: Primary myometrial and leiomyoma cells and/or cell lines were treated with activin-A (4 nM) and myostatin (4 nM) for different days of interval (to measure proliferation rate) or 30 minutes (to measure signaling molecules) or 48 hours to measure proliferating markers, extracellular matrix mRNA, and/or protein expression by real-time PCR, Western blot, and/or immunocytochemistry. Results: We found that activin-A and myostatin significantly reduce cell proliferation in primary myometrial cells but not in leiomyoma cells as measured by a CyQUANT cell proliferation assay kit. Reduced expression of proliferating cell nuclear antigen and Ki-67 were also observed in myometrial cells in response to activin-A and myostatin treatment. Activin-A also significantly increased mRNA expression of fibronectin, collagen1A1, and versican in primary leiomyoma cells. Finally, we found that activin-A and myostatin activate Smad-2/3 signaling but do not affect ERK or p38 signaling in both myometrial and leiomyoma cells. Conclusions: This study results suggest that activin-A and myostatin can exert antiproliferative and/or fibrotic effects on these cell types via Smad-2/3 signaling. PMID:24606069

  20. Activin A prevents neuron-like PC12 cell apoptosis after oxygen-glucose deprivation☆

    PubMed Central

    Xu, Guihua; He, Jinting; Guo, Hongliang; Mei, Chunli; Wang, Jiaoqi; Li, Zhongshu; Chen, Han; Mang, Jing; Yang, Hong; Xu, Zhongxin

    2013-01-01

    In this study, PC12 cells were induced to differentiate into neuron-like cells using nerve growth factor, and were subjected to oxygen-glucose deprivation. Cells were treated with 0, 10, 20, 30, 50, 100 ng/mL exogenous Activin A. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide assay and Hoechst 33324 staining showed that the survival percentage of PC12 cells significantly decreased and the rate of apoptosis significantly increased after oxygen-glucose deprivation. Exogenous Activin A significantly increased the survival percentage of PC12 cells in a dose-dependent manner. Reverse transcription-PCR results revealed a significant increase in Activin receptor IIA, Smad3 and Smad4 mRNA levels, which are key sites in the Activin A/Smads signaling pathway, in neuron-like cells subjected to oxygen-glucose deprivation, while mRNA expression of the apoptosis-regulation gene caspase-3 decreased. Our experimental findings indicate that exogenous Activin A plays an anti-apoptotic role and protects neurons by means of activating the Activin A/Smads signaling pathway. PMID:25206395

  1. Chronic gonadotropin-releasing hormone inhibits activin induction of the ovine follicle-stimulating hormone beta-subunit: involvement of 3',5'-cyclic adenosine monophosphate response element binding protein and nitric oxide synthase type I.

    PubMed

    Shafiee-Kermani, Farideh; Han, Sang-oh; Miller, William L

    2007-07-01

    FSH is induced by activin, and this expression is modulated by GnRH through FSHB expression. This report focuses on the inhibitory effect of GnRH on activin-induced FSHB expression. Activin-treated primary murine pituitary cultures robustly express mutant ovine FSHBLuc-DeltaAP1, a luciferase transgene driven by 4.7 kb of ovine FSHB promoter. This promoter lacks two GnRH-inducible activator protein-1 sites, making it easier to observe GnRH-mediated inhibition. Luciferase expression from this transgene was decreased 94% by 100 nM GnRH with a half-time of approximately 4 h in pituitary cultures, and this inhibition was independent of follistatin. Activators of cAMP and protein kinase C like forskolin and phorbol 12-myristate 3-acetate (PMA), respectively, mimicked GnRH action. Kinetic studies of wild-type ovine FSHBLuc in LbetaT2 cells showed continuous induction by activin (4-fold) over 20 h. Most of this induction (78%) was blocked, beginning at 6 h. cAMP response element binding protein (CREB) was implicated in this inhibition because overexpression of its constitutively active mutant mimicked GnRH, and its inhibitor (inducible cAMP early repressor isoform II) reversed the inhibition caused by GnRH, forskolin, or PMA. In addition, GnRH, forskolin, or PMA increased the expression of a CREB-responsive reporter gene, 6xCRE-37PRL-Luc. Inhibition of nitric oxide type I (NOSI) by 7-nitroindazole also reversed GnRH-mediated inhibition by 60%. It is known that GnRH and CREB induce production of NOSI in gonadotropes and neuronal cells, respectively. These data support the concept that chronic GnRH inhibits activin-induced ovine FSHB expression by sequential activation of CREB and NOSI through the cAMP and/or protein kinase C pathways.

  2. Relationship of activin A levels with clinical presentation, extent, and severity of coronary artery disease.

    PubMed

    Bouzidi, Nadia; Betbout, Fethi; Maatouk, Faouzi; Gamra, Habib; Miled, Abdelhedi; Ferchichi, Salima

    2017-12-01

    We aimed to evaluate the relationship of serum activin A levels with risk factors, clinical presentation, biochemical marker levels, extent, and severity of atherosclerotic coronary artery disease (CAD). In total, 310 CAD patients [92 with ST-segment elevation myocardial infarction (STEMI), 111 with non-STEMI (NSTEMI), and 107 with unstable angina (UA)] and 207 healthy subjects (controls) were enrolled. Activin A levels in all participants were measured using ELISA. Angiographic measurements were performed in patients and not in the healthy subjects. Activin A levels were higher in all patient groups than in controls (patients vs. controls, p=0.041; NSTEMI vs. UA, p=0.744; STEMI vs. UA, p=0.172; NSTEMI vs. STEMI, p=0.104). According to the cut-off value of activin A level, patients with high and low activin A levels had a similar distribution of clinical and biochemical variables but the prevalence of severe stenosis was observed in groups with high activin A levels. Our results revealed that activin A levels did not decrease as thrombolysis in myocardial infarction (risk score increased (p=0.590). The area under the ROC curve for activin A levels in patients was 0.590±0.047 (95% CI: 0.439-0.591, p=0.193). In multiple analysis of the overall population, male gender (ß=-0.260; 95% CI: -617.39 to -110.04; p=0.005) was an independent predictor of activin A levels. This study indicated that activin A can not be a predictive marker in CAD and is not associated with extensive and severe CAD. In contrast, the increase in activin A levels in patients, especially in patients with different clinical groups of acute coronary syndromes, suggested its involvement in atherosclerosis.

  3. Mast cells are dispensable for normal and activin-promoted wound healing and skin carcinogenesis.

    PubMed

    Antsiferova, Maria; Martin, Caroline; Huber, Marcel; Feyerabend, Thorsten B; Förster, Anja; Hartmann, Karin; Rodewald, Hans-Reimer; Hohl, Daniel; Werner, Sabine

    2013-12-15

    The growth and differentiation factor activin A is a key regulator of tissue repair, inflammation, fibrosis, and tumorigenesis. However, the cellular targets, which mediate the different activin functions, are still largely unknown. In this study, we show that activin increases the number of mature mast cells in mouse skin in vivo. To determine the relevance of this finding for wound healing and skin carcinogenesis, we mated activin transgenic mice with CreMaster mice, which are characterized by Cre recombinase-mediated mast cell eradication. Using single- and double-mutant mice, we show that loss of mast cells neither affected the stimulatory effect of overexpressed activin on granulation tissue formation and reepithelialization of skin wounds nor its protumorigenic activity in a model of chemically induced skin carcinogenesis. Furthermore, mast cell deficiency did not alter wounding-induced inflammation and new tissue formation or chemically induced angiogenesis and tumorigenesis in mice with normal activin levels. These findings reveal that mast cells are not major targets of activin during wound healing and skin cancer development and also argue against nonredundant functions of mast cells in wound healing and skin carcinogenesis in general.

  4. Tissue absence initiates regeneration through follistatin-mediated inhibition of activin signaling.

    PubMed

    Gaviño, Michael A; Wenemoser, Danielle; Wang, Irving E; Reddien, Peter W

    2013-09-10

    Regeneration is widespread, but mechanisms that activate regeneration remain mysterious. Planarians are capable of whole-body regeneration and mount distinct molecular responses to wounds that result in tissue absence and those that do not. A major question is how these distinct responses are activated. We describe a follistatin homolog (Smed-follistatin) required for planarian regeneration. Smed-follistatin inhibition blocks responses to tissue absence but does not prevent normal tissue turnover. Two activin homologs (Smed-activin-1 and Smed-activin-2) are required for the Smed-follistatin phenotype. Finally, Smed-follistatin is wound-induced and expressed at higher levels following injuries that cause tissue absence. These data suggest that Smed-follistatin inhibits Smed-Activin proteins to trigger regeneration specifically following injuries involving tissue absence and identify a mechanism critical for regeneration initiation, a process important across the animal kingdom. DOI:http://dx.doi.org/10.7554/eLife.00247.001.

  5. Microglial cells and peritoneal macrophages release activin A upon stimulation with Toll-like receptor agonists.

    PubMed

    Ebert, Sandra; Zeretzke, Moritz; Nau, Roland; Michel, Uwe

    2007-02-21

    Activin A levels are elevated in the cerebrospinal fluid (CSF) of patients with meningitis and in the sera of patients with sepsis. The source(s) of the elevated concentrations of activin A in CSF and serum have not yet been discovered. Here we demonstrate that primary mouse microglial cells and peritoneal macrophages release activin A after treatment with agonists of Toll-like receptor (TLR) 2, 4, and 9. These findings provide further evidence for a role of activin in the innate immune response and suggest that microglial cells and macrophages are a source of elevated activin A concentrations observed in the CSF during bacterial meningitis and in the systemic circulation during sepsis.

  6. Activin A and Late Postpartum Cardiac Dysfunction Among Women With Hypertensive Disorders of Pregnancy.

    PubMed

    Shahul, Sajid; Ramadan, Hadi; Nizamuddin, Junaid; Mueller, Ariel; Patel, Vijal; Dreixler, John; Tung, Avery; Lang, Roberto M; Weinert, Lynn; Nasim, Rabab; Chinthala, Sireesha; Rana, Sarosh

    2018-07-01

    Women with hypertensive disorders of pregnancy have an increased risk of subsequent heart failure and cardiovascular disease when compared with women with normotensive pregnancies. Although the mechanisms underlying these findings are unclear, elevated levels of the biomarker activin A are associated with myocardial dysfunction and may have predictive value. We hypothesized that elevated levels of antepartum activin A levels would correlate with postpartum cardiac dysfunction in women with hypertensive disorders of pregnancy. We prospectively studied 85 women to determine whether increased antepartum activin A levels were associated with cardiac dysfunction at 1 year postpartum as measured by global longitudinal strain. Thirty-two patients were diagnosed with preeclampsia, 28 were diagnosed with gestational or chronic hypertension, and the remainder were nonhypertensive controls. Activin A levels were measured with ELISA both in the third antepartum trimester and at 1 year postpartum. Comprehensive echocardiograms including measurement of global longitudinal strain were also performed at enrollment and at 1 year postpartum. Antepartum activin A levels correlated with worsening antepartum global longitudinal strain ( r =0.70; P =0.0001). Across the entire cohort, elevated antepartum activin A levels were associated with the development of abnormal global longitudinal strain at 1 year (C statistic 0.74; P =0.004). This association remained significant after multivariable adjustment for clinically relevant confounders (C statistic 0.93; P =0.01). Postpartum activin A levels also correlated with increasing left ventricular mass index ( P =0.02), increasing mean arterial pressures ( P =0.02), and decreasing E' values ( P =0.01). Activin A may be a useful tool for identifying and monitoring patients at risk for postpartum development of cardiovascular disease. © 2018 American Heart Association, Inc.

  7. Role of Activin A in Immune Responses to Breast Cancer

    DTIC Science & Technology

    2013-12-01

    Demaria. APPENDIX 2 ( PS4 -57) Radiation-induced activin-a fosters tumor-mediated immunosuppression in breast cancer. Claire Vanpouille-Box, Julie...with immunotherapy in the clinic.   APPENDIX 2 ( PS4 -57) Radiation-induced activin-a fosters tumor-mediated immunosuppression in breast cancer...Claire Vanpouille-Box, Julie Diamond, Silvia Formenti and Sandra Demaria. POSTER PRESENTATION – 59th RRS annual Meeting. ( PS4 -57) Radiation-induced

  8. Role of Activin A in Immune Response to Breast Cancer

    DTIC Science & Technology

    2016-12-01

    the response to radiotherapy (RT). 2 KEYWORDS Breast cancer, metastasis, transforming growth factor-beta (TGFβ) superfamily, activin- A, radiotherapy... Transforming Growth Factor-beta (TGFβ) and activin A (actA) are members of the TGFβ superfamily with overlapping as well as distinct functions in many...Vaccination C. Vanpouille-Box, S. Formenti, and S. Demaria; Weill Cornell Medical College, New York, NY Purpose/Objective(s): Transforming Growth

  9. Activin-A as an intraovarian modulator: actions, localization, and regulation of the intact dimer in human ovarian cells.

    PubMed Central

    Rabinovici, J; Spencer, S J; Doldi, N; Goldsmith, P C; Schwall, R; Jaffe, R B

    1992-01-01

    The actions, localization, and regulation of activin in the human ovary are unknown. Therefore, the aims of this study were (a) to define the effects of recombinant activin-A and its structural homologue, inhibin-A, on mitogenesis and steroidogenesis (progesterone secretion and aromatase activity) in human preovulatory follicular cells; (b) to localize the activin-A dimer in the human ovary by immunohistochemistry; and (c) to examine regulation of intracellular activin-A production in cultured human follicular cells. In addition to stimulating mitogenic activity, activin-A causes a dose- and time-dependent inhibition of basal and gonadotropin-stimulated progesterone secretion and aromatase activity in human luteinizing follicular cells on day 2 and day 4 of culture. Inhibin-A exerts no effects on mitogenesis, basal or gonadotropin-stimulated progesterone secretion and aromatase activity, and does not alter effects observed with activin-A alone. Immunostaining for dimeric activin-A occurs in granulosa and cumulus cells of human ovarian follicles and in granulosa-lutein cells of the human corpus luteum. cAMP, and to a lesser degree human chorionic gonadotropin and follicle-stimulating hormone, but not inhibin-A, activin-A, or phorbol 12-myristate 13-acetate, increased the immunostaining for activin-A in cultured granulosa cells. These results indicate that activin-A may function as an autocrine or paracrine regulator of follicular function in the human ovary. Images PMID:1569191

  10. Inhibin removes the inhibitory effects of activin on steroid enzyme expression and androgen production by normal ovarian thecal cells

    PubMed Central

    Young, J M; McNeilly, A S

    2012-01-01

    Activin and inhibin are important local modulators of theca cell steroidogenesis in the ovary. Using a serum-free primary theca cell culture system, this study investigated the effects of inhibin on theca cell androgen production and expression of steroidogenic enzymes. Androstenedione secretion from theca cells cultured in media containing activin, inhibin and follistatin was assessed by RIA over 144 h. Activin (1–100 ng/ml) suppressed androstenedione production. Inhibin (1–100 ng/ml) blocked the suppressive effects of added activin, but increased androstenedione production when added alone, suggesting it was blocking endogenous activin produced by theca cells. Addition of SB-431542 (activin receptor inhibitor) and follistatin (500 ng/ml) increased androstenedione production, supporting this concept. Infection of theca cells with adenoviruses expressing inhibitory Smad6 or 7 increased androstenedione secretion, confirming that the suppressive effects of activin required activation of the Smad2/3 pathway. Activin decreased the expression levels of steroidogenic acute regulatory protein (STAR), whereas STAR expression was increased by inhibin and SB-431542, alone and in combination. CYP11A was unaffected. The expression of CYP17 encoding 17α-hydroxylase was unaffected by activin but increased by inhibin and SB-431542, and when added in combination the effect was further enhanced. The expression of 3β-hydroxysteroid dehydrogenase (3β-HSD) was significantly decreased by activin, while inhibin alone and in combination with SB-431542 both potently increased the expression of 3β-HSD. In conclusion, activin suppressed theca cell androstenedione production by decreasing the expression of STAR and 3β-HSD. Inhibin and other blockers of activin action reversed this effect, supporting the concept that endogenous thecal activin modulates androgen production in theca cells. PMID:22082494

  11. Exercise restores decreased physical activity levels and increases markers of autophagy and oxidative capacity in myostatin/activin-blocked mdx mice.

    PubMed

    Hulmi, Juha J; Oliveira, Bernardo M; Silvennoinen, Mika; Hoogaars, Willem M H; Pasternack, Arja; Kainulainen, Heikki; Ritvos, Olli

    2013-07-15

    The importance of adequate levels of muscle size and function and physical activity is widely recognized. Myostatin/activin blocking increases skeletal muscle mass but may decrease muscle oxidative capacity and can thus be hypothesized to affect voluntary physical activity. Soluble activin receptor IIB (sActRIIB-Fc) was produced to block myostatin/activins. Modestly dystrophic mdx mice were injected with sActRIIB-Fc or PBS with or without voluntary wheel running exercise for 7 wk. Healthy mice served as controls. Running for 7 wk attenuated the sActRIIB-Fc-induced increase in body mass by decreasing fat mass. Running also enhanced/restored the markers of muscle oxidative capacity and autophagy in mdx mice to or above the levels of healthy mice. Voluntary running activity was decreased by sActRIIB-Fc during the first 3-4 wk correlating with increased body mass. Home cage physical activity of mice, quantified from the force plate signal, was decreased by sActRIIB-Fc the whole 7-wk treatment in sedentary mice. To understand what happens during the first weeks after sActRIIB-Fc administration, when mice are less active, healthy mice were injected with sActRIIB-Fc or PBS for 2 wk. During the sActRIIB-Fc-induced rapid 2-wk muscle growth period, oxidative capacity and autophagy were reduced, which may possibly explain the decreased running activity. These results show that increased muscle size and decreased markers of oxidative capacity and autophagy during the first weeks of myostatin/activin blocking are associated with decreased voluntary activity levels. Voluntary exercise in dystrophic mice enhances the markers of oxidative capacity and autophagy to or above the levels of healthy mice.

  12. Activin Modulates the Transcriptional Response of LβT2 Cells to Gonadotropin-Releasing Hormone and Alters Cellular Proliferation

    PubMed Central

    Zhang, Hao; Bailey, Janice S.; Coss, Djurdjica; Lin, Bo; Tsutsumi, Rie; Lawson, Mark A.; Mellon, Pamela L.; Webster, Nicholas J. G.

    2009-01-01

    Both GnRH and activin are crucial for the correct function of pituitary gonadotrope cells. GnRH regulates LH and FSH synthesis and secretion and gonadotrope proliferation, whereas activin is essential for expression of FSH. Little is known, however, about the interplay of signaling downstream of these two hormones. In this study, we undertook expression profiling to determine how activin pre-treatment alters the transcriptional response of LβT2 gonadotrope cells to GnRH stimulation. Activin treatment alone altered the transcriptional profile of 303 genes including inducing that of the 17β-hydroxysteroid dehydrogenase B1 gene that converts estrone to 17β-estradiol, altering the sensitivity of the cells to estrone. Furthermore, activin had a dramatic effect on the response of LβT2 cells to GnRH. Hierarchical clustering of 2453 GnRH-responsive genes identified groups of genes the response of which to GnRH was either enhanced or blunted after activin treatment. Mapping of these genes to gene ontology classifications or signaling pathways highlighted significant differences in the classes of altered genes. In the presence of activin, GnRH regulates genes in pathways controlling cell energetics, cytoskeletal rearrangements, organelle organization, and mitosis in the absence of activin, but genes controlling protein processing, cell differentiation, and secretion. Therefore, we demonstrated that activin enhanced GnRH induction of p38MAPK activity, caused GnRH-dependent phosphorylation of p53, and reduced the ability of GnRH to cause G1 arrest. Thus, although activin alone changes a modest number of transcripts, activin pretreatment dramatically alters the response to GnRH from an antiproliferative response to a more differentiated, synthetic response appropriate for a secretory cell. PMID:16772531

  13. Activin Signaling Targeted by Insulin/dFOXO Regulates Aging and Muscle Proteostasis in Drosophila

    PubMed Central

    Bai, Hua; Kang, Ping; Hernandez, Ana Maria; Tatar, Marc

    2013-01-01

    Reduced insulin/IGF signaling increases lifespan in many animals. To understand how insulin/IGF mediates lifespan in Drosophila, we performed chromatin immunoprecipitation-sequencing analysis with the insulin/IGF regulated transcription factor dFOXO in long-lived insulin/IGF signaling genotypes. Dawdle, an Activin ligand, is bound and repressed by dFOXO when reduced insulin/IGF extends lifespan. Reduced Activin signaling improves performance and protein homeostasis in muscles of aged flies. Activin signaling through the Smad binding element inhibits the transcription of Autophagy-specific gene 8a (Atg8a) within muscle, a factor controlling the rate of autophagy. Expression of Atg8a within muscle is sufficient to increase lifespan. These data reveal how insulin signaling can regulate aging through control of Activin signaling that in turn controls autophagy, representing a potentially conserved molecular basis for longevity assurance. While reduced Activin within muscle autonomously retards functional aging of this tissue, these effects in muscle also reduce secretion of insulin-like peptides at a distance from the brain. Reduced insulin secretion from the brain may subsequently reinforce longevity assurance through decreased systemic insulin/IGF signaling. PMID:24244197

  14. Transforming Growth Factor β/Activin signaling in neurons increases susceptibility to starvation.

    PubMed

    Chng, Wen-Bin Alfred; Koch, Rafael; Li, Xiaoxue; Kondo, Shu; Nagoshi, Emi; Lemaitre, Bruno

    2017-01-01

    Animals rely on complex signaling network to mobilize its energy stores during starvation. We have previously shown that the sugar-responsive TGFβ/Activin pathway, activated through the TGFβ ligand Dawdle, plays a central role in shaping the post-prandial digestive competence in the Drosophila midgut. Nevertheless, little is known about the TGFβ/Activin signaling in sugar metabolism beyond the midgut. Here, we address the importance of Dawdle (Daw) after carbohydrate ingestion. We found that Daw expression is coupled to dietary glucose through the evolutionarily conserved Mio-Mlx transcriptional complex. In addition, Daw activates the TGFβ/Activin signaling in neuronal populations to regulate triglyceride and glycogen catabolism and energy homeostasis. Loss of those neurons depleted metabolic reserves and rendered flies susceptible to starvation.

  15. A Pdx-1-Regulated Soluble Factor Activates Rat and Human Islet Cell Proliferation

    PubMed Central

    Hayes, Heather L.; Zhang, Lu; Becker, Thomas C.; Haldeman, Jonathan M.; Stephens, Samuel B.; Arlotto, Michelle; Moss, Larry G.; Newgard, Christopher B.

    2016-01-01

    The homeodomain transcription factor Pdx-1 has important roles in pancreas and islet development as well as in β-cell function and survival. We previously reported that Pdx-1 overexpression stimulates islet cell proliferation, but the mechanism remains unclear. Here, we demonstrate that overexpression of Pdx-1 triggers proliferation largely by a non-cell-autonomous mechanism mediated by soluble factors. Consistent with this idea, overexpression of Pdx-1 under the control of a β-cell-specific promoter (rat insulin promoter [RIP]) stimulates proliferation of both α and β cells, and overexpression of Pdx-1 in islets separated by a Transwell membrane from islets lacking Pdx-1 overexpression activates proliferation in the untreated islets. Microarray and gene ontology (GO) analysis identified inhibin beta-B (Inhbb), an activin subunit and member of the transforming growth factor β (TGF-β) superfamily, as a Pdx-1-responsive gene. Overexpression of Inhbb or addition of activin B stimulates rat islet cell and β-cell proliferation, and the activin receptors RIIA and RIIB are required for the full proliferative effects of Pdx-1 in rat islets. In human islets, Inhbb overexpression stimulates total islet cell proliferation and potentiates Pdx-1-stimulated proliferation of total islet cells and β cells. In sum, this study identifies a mechanism by which Pdx-1 induces a soluble factor that is sufficient to stimulate both rat and human islet cell proliferation. PMID:27620967

  16. Anterograde Activin signaling regulates postsynaptic membrane potential and GluRIIA/B abundance at the Drosophila neuromuscular junction.

    PubMed

    Kim, Myung-Jun; O'Connor, Michael B

    2014-01-01

    Members of the TGF-β superfamily play numerous roles in nervous system development and function. In Drosophila, retrograde BMP signaling at the neuromuscular junction (NMJ) is required presynaptically for proper synapse growth and neurotransmitter release. In this study, we analyzed whether the Activin branch of the TGF-β superfamily also contributes to NMJ development and function. We find that elimination of the Activin/TGF-β type I receptor babo, or its downstream signal transducer smox, does not affect presynaptic NMJ growth or evoked excitatory junctional potentials (EJPs), but instead results in a number of postsynaptic defects including depolarized membrane potential, small size and frequency of miniature excitatory junction potentials (mEJPs), and decreased synaptic densities of the glutamate receptors GluRIIA and B. The majority of the defective smox synaptic phenotypes were rescued by muscle-specific expression of a smox transgene. Furthermore, a mutation in actβ, an Activin-like ligand that is strongly expressed in motor neurons, phenocopies babo and smox loss-of-function alleles. Our results demonstrate that anterograde Activin/TGF-β signaling at the Drosophila NMJ is crucial for achieving normal abundance and localization of several important postsynaptic signaling molecules and for regulating postsynaptic membrane physiology. Together with the well-established presynaptic role of the retrograde BMP signaling, our findings indicate that the two branches of the TGF-β superfamily are differentially deployed on each side of the Drosophila NMJ synapse to regulate distinct aspects of its development and function.

  17. Anterograde Activin Signaling Regulates Postsynaptic Membrane Potential and GluRIIA/B Abundance at the Drosophila Neuromuscular Junction

    PubMed Central

    Kim, Myung-Jun; O’Connor, Michael B.

    2014-01-01

    Members of the TGF-β superfamily play numerous roles in nervous system development and function. In Drosophila, retrograde BMP signaling at the neuromuscular junction (NMJ) is required presynaptically for proper synapse growth and neurotransmitter release. In this study, we analyzed whether the Activin branch of the TGF-β superfamily also contributes to NMJ development and function. We find that elimination of the Activin/TGF-β type I receptor babo, or its downstream signal transducer smox, does not affect presynaptic NMJ growth or evoked excitatory junctional potentials (EJPs), but instead results in a number of postsynaptic defects including depolarized membrane potential, small size and frequency of miniature excitatory junction potentials (mEJPs), and decreased synaptic densities of the glutamate receptors GluRIIA and B. The majority of the defective smox synaptic phenotypes were rescued by muscle-specific expression of a smox transgene. Furthermore, a mutation in actβ, an Activin-like ligand that is strongly expressed in motor neurons, phenocopies babo and smox loss-of-function alleles. Our results demonstrate that anterograde Activin/TGF-β signaling at the Drosophila NMJ is crucial for achieving normal abundance and localization of several important postsynaptic signaling molecules and for regulating postsynaptic membrane physiology. Together with the well-established presynaptic role of the retrograde BMP signaling, our findings indicate that the two branches of the TGF-β superfamily are differentially deployed on each side of the Drosophila NMJ synapse to regulate distinct aspects of its development and function. PMID:25255438

  18. Activin B is a novel biomarker for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) diagnosis: a cross sectional study.

    PubMed

    Lidbury, Brett A; Kita, Badia; Lewis, Donald P; Hayward, Susan; Ludlow, Helen; Hedger, Mark P; de Kretser, David M

    2017-03-16

    Investigations of activin family proteins as serum biomarkers for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). CFS/ME is a disease with complex, wide-ranging symptoms, featuring persistent fatigue of 6 months or longer, particularly post exertion. No definitive biomarkers are available. A cross-sectional, observational study of CFS/ME patients fulfilling the 2003 Canadian Consensus Criteria, in parallel with healthy non-fatigued controls, was conducted. Comparisons with a previously defined activin reference population were also performed. For the total study cohort the age range was 18-65 years with a female: male participant ratio of greater than 3:1. All participants were assessed via a primary care community clinic. Blood samples were collected for pathology testing after physical examination and orthostatic intolerance assessment. Cytokines, activin A, activin B and follistatin were also measured in sera from these samples. All data were compared between the CFS/ME and control cohorts, with the activins and follistatin also compared with previously defined reference intervals. Serum activin B levels for CFS/ME participants were significantly elevated when compared to the study controls, as well as the established reference interval. Serum activin A and follistatin were within their normal ranges. All routine and special pathology markers were within the normal laboratory reference intervals for the total study cohort, with no significant differences detected between CFS/ME and control groups. Also, no significant differences were detected for IL-2, IL-4, IL-6, IL-10, IL-17A, TNF or IFN-gamma. Elevated activin B levels together with normal activin A levels identified patients with the diagnostic symptoms of CFS/ME, thus providing a novel serum based test. The activins have multiple physiological roles and capture the diverse array of symptoms experienced by CFS/ME patients.

  19. Inhibition of Activin Receptor Type IIB Increases Strength and Lifespan in Myotubularin-Deficient Mice

    PubMed Central

    Lawlor, Michael W.; Read, Benjamin P.; Edelstein, Rachel; Yang, Nicole; Pierson, Christopher R.; Stein, Matthew J.; Wermer-Colan, Ariana; Buj-Bello, Anna; Lachey, Jennifer L.; Seehra, Jasbir S.; Beggs, Alan H.

    2011-01-01

    X-linked myotubular myopathy (XLMTM) is a congenital disorder caused by deficiency of the lipid phosphatase, myotubularin. Patients with XLMTM often have severe perinatal weakness that requires mechanical ventilation to prevent death from respiratory failure. Muscle biopsy specimens from patients with XLMTM exhibit small myofibers with central nuclei and central aggregations of organelles in many cells. It was postulated that therapeutically increasing muscle fiber size would cause symptomatic improvement in myotubularin deficiency. Recent studies have elucidated an important role for the activin-receptor type IIB (ActRIIB) in regulation of muscle growth and have demonstrated that ActRIIB inhibition results in significant muscle hypertrophy. To evaluate whether promoting muscle hypertrophy can attenuate symptoms resulting from myotubularin deficiency, the effect of ActRIIB-mFC treatment was determined in myotubularin-deficient (Mtm1δ4) mice. Compared with wild-type mice, untreated Mtm1δ4 mice have decreased body weight, skeletal muscle hypotrophy, and reduced survival. Treatment of Mtm1δ4 mice with ActRIIB-mFC produced a 17% extension of lifespan, with transient increases in weight, forelimb grip strength, and myofiber size. Pathologic analysis of Mtm1δ4 mice during treatment revealed that ActRIIB-mFC produced marked hypertrophy restricted to type 2b myofibers, which suggests that oxidative fibers in Mtm1δ4 animals are incapable of a hypertrophic response in this setting. These results support ActRIIB-mFC as an effective treatment for the weakness observed in myotubularin deficiency. PMID:21281811

  20. Differential Effects of IL6 and Activin A in the Development of Cancer-Associated Cachexia.

    PubMed

    Chen, Justin L; Walton, Kelly L; Qian, Hongwei; Colgan, Timothy D; Hagg, Adam; Watt, Matthew J; Harrison, Craig A; Gregorevic, Paul

    2016-09-15

    Cachexia is a life-threatening wasting syndrome lacking effective treatment, which arises in many cancer patients. Although ostensibly induced by multiple tumor-produced cytokines (tumorkines), their functional contribution to initiation and progression of this syndrome has proven difficult to determine. In this study, we used adeno-associated viral vectors to elevate circulating levels of the tumorkines IL6 and/or activin A in animals in the absence of tumors as a tactic to evaluate hypothesized roles in cachexia development. Mice with elevated levels of IL6 exhibited 8.1% weight loss after 9 weeks, whereas mice with elevated levels of activin A lost 11% of their body weight. Co-elevation of both tumorkines to levels approximating those observed in cancer cachexia models induced a more rapid and profound body weight loss of 15.4%. Analysis of body composition revealed that activin A primarily triggered loss of lean mass, whereas IL6 was a major mediator of fat loss. Histologic and transcriptional analysis of affected organs/tissues (skeletal muscle, fat, and liver) identified interactions between the activin A and IL6 signaling pathways. For example, IL6 exacerbated the detrimental effects of activin A in skeletal muscle, whereas activin A curbed the IL6-induced acute-phase response in liver. This study presents a useful model to deconstruct cachexia, opening a pathway to determining which tumorkines are best targeted to slow/reverse this devastating condition in cancer patients. Cancer Res; 76(18); 5372-82. ©2016 AACR. ©2016 American Association for Cancer Research.

  1. The Association Between Serum Activin A Levels and Hypertension in the Elderly: A Cross-Sectional Analysis From I-Lan Longitudinal Aging Study.

    PubMed

    Tsai, Yi-Lin; Chang, Chun-Chin; Liu, Li-Kuo; Huang, Po-Hsun; Chen, Liang-Kung; Lin, Shing-Jong

    2018-02-09

    Hypertension is an important risk factor for cardiovascular disease. Activin A, a member of the transforming growth factor-β cytokine family, has been shown to regulate blood pressure through the renin-angiotensin system. However, the relationship between activin A and blood pressure remains uncertain. The objective of this study was to determine whether serum activin A levels are associated with blood pressure. A total of 470 participants of I-Lan longitudinal Aging Study (ILAS) were eligible for this study. Serum levels of activin A were assessed by enzyme-linked immunosorbent assay. Cross-sectional analyses were performed, including comparisons of demographic characteristics, hypertensive status, and activin A levels. Among the study participants (50% men, mean age, 69 years), 236 (50.2%) were hypertensive and 234 (49.8%) were normotensive. Hypertensive patients had significantly higher serum activin A levels than normotensives (normotensive vs. hypertensive: 507 ± 169 vs. 554 ± 176 pg/ml, mean ± SD, P < 0.001). All subjects were divided into 3 tertiles on the basis of serum activin A levels. Increasing tertiles of activin A were associated with higher systolic blood pressure (SBP), diastolic blood pressure and pulse pressure (PP) (all P < 0.001). After adjusting for all the potential confounding factors, serum activin A concentration was still significantly associated with SBP (P = 0.02) and PP (P = 0.03). Serum activin A level was associated with SBP and PP. Further studies are required to assess their causal relationship and the clinical relevance. © American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  2. Effects of activin A and its downstream ERK1/2 in oxygen and glucose deprivation after isoflurane-induced postconditioning.

    PubMed

    Wang, Qin; Yin, Jiangwen; Wang, Sheng; Cui, Di; Lin, Hong; Ge, Mingyue; Dai, Zhigang; Xie, Liping; Si, Junqiang; Ma, Ketao; Li, Li; Zhao, Lei

    2016-12-01

    Isoflurane postconditioning (ISPOC) plays a neuroprotection role in the brain. Previous studies confirmed that isoflurane postconditioning can provide better protection than preconditioning in acute hypoxic-ischemic brain damage, such as acute craniocerebral trauma and ischemic stroke. Numerous studies have reported that activin A can protect rat's brain from cell injury. However, whether activin A and its downstream ERK1/2 were involved in isoflurane postconditioning-induced neuroprotection is unknown. A total of 80 healthy Sprague-Dawley rats weighing 50-70g were randomly divided into 10 groups of 8: normal control, oxygen and glucose deprivation (OGD), 1.5% ISPOC, 3.0% ISPOC, 4.5% ISPOC, blocker of activin A (SB431542), blocker of ERK1/2 (U0126), 3.0% ISPOC+SB431542, 3.0% ISPOC+U0126, and vehicle (dimethyl sulfoxide(DMSO)) group. Blockers (SB431542 and U0126) were used in each concentration of isoflurane before OGD. Hematoxylin-eosin staining, 2,3,5-triphenyl tetrazolium chloride staining, and propidium iodide (PI) staining were conducted to assess the reliability in the brain slices. Immunofluorescence, Western blot, and quantitative real-time PCR(Q-PCR) were performed to validate the protein expression levels of activin A, Smad2/3, P-Smad2/3, ERK1/2, and phosphorylation ERK1/2 (P-ERK1/2). The number of damaged neurons and mean fluorescence intensity(MFI) of PI staining increased, but formazan generation, expression levels of activin A and P-ERK1/2 protein, and mRNA synthesis level of activin A decreased in the OGD group compared with the normal control group (p<0.05). The number of damaged neurons and MFI of PI staining decreased, but formazan production, expression levels of activin A, P-Smad2/3, and P-ERK1/2, and mRNA synthesis level of activin A increased significantly in the 1.5% ISPOC and 3.0% ISPOC groups (p<0.05) compared with the OGD group. The result in the 4.5% ISPOC group, was completely opposite to the 1.5% ISPOC and 3.0% ISPOC groups. The number

  3. ActivinB Is Induced in Insulinoma To Promote Tumor Plasticity through a β-Cell-Induced Dedifferentiation

    PubMed Central

    Ripoche, Doriane; Charbord, Jérémie; Hennino, Ana; Teinturier, Romain; Bonnavion, Rémy; Jaafar, Rami; Goehrig, Delphine; Cordier-Bussat, Martine; Ritvos, Olli; Zhang, Chang X.; Andersson, Olov

    2015-01-01

    Loss of pancreatic β-cell maturity occurs in diabetes and insulinomas. Although both physiological and pathological stresses are known to promote β-cell dedifferentiation, little is known about the molecules involved in this process. Here we demonstrate that activinB, a transforming growth factor β (TGF-β)-related ligand, is upregulated during tumorigenesis and drives the loss of insulin expression and β-cell maturity in a mouse insulinoma model. Our data further identify Pax4 as a previously unknown activinB target and potent contributor to the observed β-cell dedifferentiation. More importantly, using compound mutant mice, we found that deleting activinB expression abolishes tumor β-cell dedifferentiation and, surprisingly, increases survival without significantly affecting tumor growth. Hence, this work reveals an unexpected role for activinB in the loss of β-cell maturity, islet plasticity, and progression of insulinoma through its participation in β-cell dedifferentiation. PMID:26711255

  4. Loss of Activin Receptor Type 1B Accelerates Development of Intraductal Papillary Mucinous Neoplasms in Mice With Activated KRAS.

    PubMed

    Qiu, Wanglong; Tang, Sophia M; Lee, Sohyae; Turk, Andrew T; Sireci, Anthony N; Qiu, Anne; Rose, Christian; Xie, Chuangao; Kitajewski, Jan; Wen, Hui-Ju; Crawford, Howard C; Sims, Peter A; Hruban, Ralph H; Remotti, Helen E; Su, Gloria H

    2016-01-01

    Activin, a member of the transforming growth factor-β (TGFB) family, might be involved in pancreatic tumorigenesis, similar to other members of the TGFB family. Human pancreatic ductal adenocarcinomas contain somatic mutations in the activin A receptor type IB (ACVR1B) gene, indicating that ACVR1B could be a suppressor of pancreatic tumorigenesis. We disrupted Acvr1b specifically in pancreata of mice (Acvr1b(flox/flox);Pdx1-Cre mice) and crossed them with LSL-KRAS(G12D) mice, which express an activated form of KRAS and develop spontaneous pancreatic tumors. The resulting Acvr1b(flox/flox);LSL-KRAS(G12D);Pdx1-Cre mice were monitored; pancreatic tissues were collected and analyzed by histology and immunohistochemical analyses. We also analyzed p16(flox/flox);LSL-Kras(G12D);Pdx1-Cre mice and Cre-negative littermates (controls). Genomic DNA, total RNA, and protein were isolated from mouse tissues and primary pancreatic tumor cell lines and analyzed by reverse-transcription polymerase chain reaction, sequencing, and immunoblot analyses. Human intraductal papillary mucinous neoplasm (IPMN) specimens were analyzed by immunohistochemistry. Loss of ACVR1B from pancreata of mice increased the proliferation of pancreatic epithelial cells, led to formation of acinar to ductal metaplasia, and induced focal inflammatory changes compared with control mice. Disruption of Acvr1b in LSL-KRAS(G12D);Pdx1-Cre mice accelerated the growth of pancreatic IPMNs compared with LSL-KRAS(G12D);Pdx1-Cre mice, but did not alter growth of pancreatic intraepithelial neoplasias. We associated perinuclear localization of the activated NOTCH4 intracellular domain to the apical cytoplasm of neoplastic cells with the expansion of IPMN lesions in Acvr1b(flox/flox);LSL-KRAS(G12D);Pdx1-Cre mice. Loss of the gene that encodes p16 (Cdkn2a) was required for progression of IPMNs to pancreatic ductal adenocarcinomas in Acvr1b(flox/flox);LSL-Kras(G12D);Pdx1-Cre mice. We also observed progressive loss of

  5. The ESA scenario gets complex: from biosimilar epoetins to activin traps.

    PubMed

    Jelkmann, Wolfgang

    2015-04-01

    Recombinant human erythropoietin (rhEpo, epoetin) has proved beneficial in preventing transfusion-dependent anaemia in patients with chronic kidney disease. Apart from copied epoetins distributed in less regulated markets, 'biosimilar' epoetins have gained currency in many regions, where they compete with the originals and with rhEpo analogues with prolonged survival in circulation ('biobetter'). Recombinant erythropoiesis stimulating agents are potent and well tolerated. However, their production is costly, and they must be administered by the parenteral route. Hence, other anti-anaemia treatments are being evaluated. Clinical trials are being performed with stabilizers of the hypoxia-inducible transcription factors (HIFs), which increase endogenous Epo production. HIF stabilizers are chemical drugs and they are active on oral administration. However, there is fear that they may promote tumour growth. Epo mimetic peptides have also raised expectations. Yet the prototype peginesatide was recalled after just 1 year of its widespread use in the USA because of serious side-effects including cases of death. Most recently, clinical trials have been initiated with sotatercept, a recombinant soluble activin receptor type 2A IgG-Fc fusion protein. Sotatercept binds distinct members of the transforming growth factor-β family, thereby preventing the inhibitory action of these factors in erythropoiesis. Taken together, rhEpo and its long-acting recombinant analogues will likely remain mainstay of anti-anaemia therapies in the near future. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  6. Effects of the activin A-myostatin-follistatin system on aging bone and muscle progenitor cells

    PubMed Central

    Bowser, Matthew; Herberg, Samuel; Arounleut, Phonepasong; Shi, Xingming; Fulzele, Sadanand; Hill, William D.; Isales, Carlos M.; Hamrick, Mark W.

    2013-01-01

    The activin A-myostatin-follistatin system is thought to play an important role in the regulation of muscle and bone mass throughout growth, development, and aging; however, the effects of these ligands on progenitor cell proliferation and differentiation in muscle and bone are not well understood. In addition, age-associated changes in the relative expression of these factors in musculoskeletal tissues have not been described. We therefore examined changes in protein levels of activin A, follistatin, and myostatin (GDF-8) in both muscle and bone with age in C57BL6 mice using ELISA. We then investigated the effects of activin A, myostatin and follistatin on the proliferation and differentiation of primary myoblasts and mouse bone marrow stromal cells (BMSCs) in vitro. Myostatin levels and the myostatin:follistatin ratio increased with age in the primarily slow-twitch mouse soleus muscle, whereas the pattern was reversed with age in the fast-twitch extensor digitorum longus muscle. Myostatin levels and the myostatin: follistatin ratio increased significantly (+75%) in mouse bone marrow with age, as did activin A levels (+17%). Follistatin increased the proliferation of primary myoblasts from both young and aged mice, whereas myostatin increased proliferation of younger myoblasts but decreased proliferation of older myoblasts. Myostatin reduced proliferation of both young and aged BMSCs in a dose-dependent fashion, and activin A increased mineralization in both young and aged BMSCs. Together these data suggest that aging in mice is accompanied by changes in the expression of activin A and myostatin, as well as changes in the response of bone and muscle progenitor cells to these factors. Myostatin appears to play a particularly important role in the impaired proliferative capacity of muscle and bone progenitor cells from aged mice. PMID:23178301

  7. ActivinB Is Induced in Insulinoma To Promote Tumor Plasticity through a β-Cell-Induced Dedifferentiation.

    PubMed

    Ripoche, Doriane; Charbord, Jérémie; Hennino, Ana; Teinturier, Romain; Bonnavion, Rémy; Jaafar, Rami; Goehrig, Delphine; Cordier-Bussat, Martine; Ritvos, Olli; Zhang, Chang X; Andersson, Olov; Bertolino, Philippe

    2015-12-28

    Loss of pancreatic β-cell maturity occurs in diabetes and insulinomas. Although both physiological and pathological stresses are known to promote β-cell dedifferentiation, little is known about the molecules involved in this process. Here we demonstrate that activinB, a transforming growth factor β (TGF-β)-related ligand, is upregulated during tumorigenesis and drives the loss of insulin expression and β-cell maturity in a mouse insulinoma model. Our data further identify Pax4 as a previously unknown activinB target and potent contributor to the observed β-cell dedifferentiation. More importantly, using compound mutant mice, we found that deleting activinB expression abolishes tumor β-cell dedifferentiation and, surprisingly, increases survival without significantly affecting tumor growth. Hence, this work reveals an unexpected role for activinB in the loss of β-cell maturity, islet plasticity, and progression of insulinoma through its participation in β-cell dedifferentiation. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  8. RhoA regulates Activin B-induced stress fiber formation and migration of bone marrow-derived mesenchymal stromal cell through distinct signaling.

    PubMed

    Wang, Xueer; Tang, Pei; Guo, Fukun; Zhang, Min; Chen, Yinghua; Yan, Yuan; Tian, Zhihui; Xu, Pengcheng; Zhang, Lei; Zhang, Lu; Zhang, Lin

    2017-01-01

    In our previous study, Activin B induced actin stress fiber formation and cell migration in Bone marrow-derived mesenchymal stem cells (BMSCs) in vitro. However, the underlying molecular mechanisms are not well studied. RhoA is recognized to play a critical role in the regulation of actomyosin cytoskeletal organization and cell migration. Pull-down assay was performed to investigate the activity of RhoA. The dominant-negative mutants of RhoA (RhoA(N19)) was used to determine whether RhoA has a role in Activin B-induced cytoskeleton organization and cell migration in BMSCs. Cytoskeleton organization was examined by fluorescence Rhodamine-phalloidin staining, and cell migration by transwell and cell scratching assay. Western blot was carried out to investigate downstream signaling cascade of RhoA. Inhibitor and siRNAs were used to detect the role of downstream signaling in stress fiber formation and/or cell migration. RhoA was activated by Activin B in BMSCs. RhoA(N19) blocked Activin B-induced stress fiber formation and cell migration. ROCK inhibitor blocked Activin B-induced stress fiber formation but enhanced BMSCs migration. Activin B induced phosphorylation of LIMK2 and Cofilin, which was abolished by ROCK inhibition. Both of siRNA LIMK2 and siRNA Cofilin inhibited Activin B-induced stress fiber formation. RhoA regulates Activin B-induced stress fiber formation and migration of BMSCs. A RhoA-ROCK-LIMK2-Cofilin signaling node exists and regulates actin stress fiber formation. RhoA regulates Activin B-induced cell migration independent of ROCK. Better understanding of the molecular mechanisms of BMSCs migration will help optimize therapeutic strategy to target BMSCs at injured tissues. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Role of satellite cells versus myofibers in muscle hypertrophy induced by inhibition of the myostatin/activin signaling pathway.

    PubMed

    Lee, Se-Jin; Huynh, Thanh V; Lee, Yun-Sil; Sebald, Suzanne M; Wilcox-Adelman, Sarah A; Iwamori, Naoki; Lepper, Christoph; Matzuk, Martin M; Fan, Chen-Ming

    2012-08-28

    Myostatin and activin A are structurally related secreted proteins that act to limit skeletal muscle growth. The cellular targets for myostatin and activin A in muscle and the role of satellite cells in mediating muscle hypertrophy induced by inhibition of this signaling pathway have not been fully elucidated. Here we show that myostatin/activin A inhibition can cause muscle hypertrophy in mice lacking either syndecan4 or Pax7, both of which are important for satellite cell function and development. Moreover, we show that muscle hypertrophy after pharmacological blockade of this pathway occurs without significant satellite cell proliferation and fusion to myofibers and without an increase in the number of myonuclei per myofiber. Finally, we show that genetic ablation of Acvr2b, which encodes a high-affinity receptor for myostatin and activin A specifically in myofibers is sufficient to induce muscle hypertrophy. All of these findings are consistent with satellite cells playing little or no role in myostatin/activin A signaling in vivo and render support that inhibition of this signaling pathway can be an effective therapeutic approach for increasing muscle growth even in disease settings characterized by satellite cell dysfunction.

  10. Activin A stimulates IkappaB-alpha/NFkappaB and RANK expression for osteoclast differentiation, but not AKT survival pathway in osteoclast precursors.

    PubMed

    Sugatani, T; Alvarez, U M; Hruska, K A

    2003-09-01

    Recent studies have reported that activin A enhances osteoclastogenesis in cultures of mouse bone marrow cells stimulated with receptor activator of nuclear factor-kappaB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). However, the exact mechanisms by which activin A functions during osteoclastogenesis are not clear. RANKL stimulation of RANK/TRAF6 signaling increases nuclear factor-kappaB (NFkappaB) nuclear translocation and activates the Akt/PKB cell survival pathway. Here we report that activin A alone activates IkappaB-alpha, and stimulates nuclear translocation of NFkappaB and receptor activator of nuclear factor-kappaB (RANK) expression for osteoclastogenesis, but not Akt/PKB survival signal transduction including BAD and mammalian target of rapamycin (mTOR) for survival in osteoclast precursors in vitro. Activin A alone failed to activate Akt, BAD, and mTOR by immunoblotting, and it also failed to prevent apoptosis in osteoclast precursors. While activin A activated IkappaB-alpha and induced nuclear translocation of phosphorylated-NFkappaB, and it also enhanced RANK expression in osteoclast precursors. Moreover, activin A enhanced RANKL- and M-CSF-stimulated nuclear translocation of NFkappaB. Our data suggest that activin A enhances osteoclastogenesis treated with RANKL and M-CSF via stimulation of RANK, thereby increasing the RANKL stimulation. Activin A alone activated the NFkappaB pathway, but not survival in osteoclast precursors in vitro, but it is, thus, insufficient as a sole stimulus to osteoclastogenesis. Copyright 2003 Wiley-Liss, Inc.

  11. Growth differentiation factor 9 reverses activin A suppression of steroidogenic acute regulatory protein expression and progesterone production in human granulosa-lutein cells.

    PubMed

    Shi, Feng-Tao; Cheung, Anthony P; Klausen, Christian; Huang, He-Feng; Leung, Peter C K

    2010-10-01

    We have reported that growth differentiation factor 9 (GDF9) can enhance activin A (β(A)β(A))-induced inhibin B (αβ(B)) secretion in human granulosa-lutein (hGL) cells, but its effects on steroidogenic acute regulatory protein (StAR), ovarian steroidogenic enzymes, and progesterone production are unknown. We undertook this study to further evaluate GDF9 in this regard. hGL cells from women undergoing in vitro fertilization treatment were cultured with and without small interfering RNA (siRNA) transfection targeted at inhibin α-subunit or GDF9 before treatment with GDF9, activin A, FSH, or combinations. We compared StAR, P450 side-chain cleavage enzyme, and 3β-hydroxysteroid dehydrogenase expression in hGL cells and progesterone levels in culture media after these treatments. mRNA, protein, and hormone levels were assessed with real-time RT-PCR, immunoblotting, and ELISA, respectively. Data were analyzed by ANOVA followed by Tukey's test. Activin A alone reduced basal and FSH-induced progesterone production by decreasing the expression of StAR protein, which regulates the rate-limiting step in steroidogenesis but not P450 side-chain cleavage enzyme and 3β-hydroxysteroid dehydrogenase. GDF9 attenuated these activin A effects on StAR and progesterone. After transfection of α-subunit siRNA, activin A level increased (P < 0.001), whereas basal and activin A-induced inhibin B levels (with and without GDF9) decreased. Furthermore, the effects of GDF9 in reversing activin A suppression of progesterone production were attenuated (P < 0.001). Transfection of GDF9 siRNA decreased GDF9 as expected and led to lower StAR expression and progesterone secretion than those observed with activin A treatment alone. GDF9 attenuates the suppressive effects of activin A on StAR expression and progesterone production by increasing the expression of inhibin B, which acts as an activin A competitor.

  12. Regulation of the activins-follistatins-inhibins axis by energy status: Impact on reproductive function.

    PubMed

    Perakakis, Nikolaos; Upadhyay, Jagriti; Ghaly, Wael; Chen, Joyce; Chrysafi, Pavlina; Anastasilakis, Athanasios D; Mantzoros, Christos S

    2018-05-09

    We have previously demonstrated that the adipose tissue derived hormone leptin controls reproductive function by regulating the hypothalamic-pituitary-gonadal axis in response to energy deficiency. Here, we evaluate the activins-follistatins-inhibins (AFI) axis during acute (short-term fasting in healthy people) and chronic energy deficiency (women with hypothalamic amenorrhea due to strenuous exercise [HA]) and investigate their relation to leptin and reproductive function in healthy subjects and subjects with HA. The AFI axis was investigated in: a) A double-blinded study in healthy subjects having three randomly assigned admissions, each time for four days: in the isocaloric fed state, complete fasting with placebo treatment, complete fasting with leptin replacement, b) A case-control study comparing women with HA vs healthy controls, c) An open-label interventional study investigating leptin treatment in women with HA over a period of up to three months, d) A randomized interventional trial investigating leptin treatment vs placebo in women with HA for nine months. The circulating levels of activin A, activin B, follistatin and follistatin-like 3 change robustly in response to acute and chronic energy deficiency. Leptin replacement in acute energy deprivation does not affect the levels of these hormones suggesting an independent regulation by these two hormonal pathways. In chronic energy deficiency, leptin replacement restores only activin B levels, which are in turn associated with an increase in the number of dominant follicles. We demonstrate for the first time that the AFI axis is affected both by acute and chronic energy deficiency. Partial restoration of a component of the axis, i.e. activin B only, through leptin replacement is associated with improved reproductive function in women with HA. Copyright © 2018. Published by Elsevier Inc.

  13. Signaling through the TGF Beta-Activin Receptors ALK4/5/7 Regulates Testis Formation and Male Germ Cell Development

    PubMed Central

    Stringer, Jessica M.; van den Bergen, Jocelyn A.; Wilhelm, Dagmar; Sinclair, Andrew H.; Western, Patrick S.

    2013-01-01

    The developing testis provides an environment that nurtures germ cell development, ultimately ensuring spermatogenesis and fertility. Impacts on this environment are considered to underlie aberrant germ cell development and formation of germ cell tumour precursors. The signaling events involved in testis formation and male fetal germ cell development remain largely unknown. Analysis of knockout mice lacking single Tgfβ family members has indicated that Tgfβ's are not required for sex determination. However, due to functional redundancy, it is possible that additional functions for these ligands in gonad development remain to be discovered. Using FACS purified gonadal cells, in this study we show that the genes encoding Activin's, TGFβ's, Nodal and their respective receptors, are expressed in sex and cell type specific patterns suggesting particular roles in testis and germ cell development. Inhibition of signaling through the receptors ALK4, ALK5 and ALK7, and ALK5 alone, demonstrated that TGFβ signaling is required for testis cord formation during the critical testis-determining period. We also show that signaling through the Activin/NODAL receptors, ALK4 and ALK7 is required for promoting differentiation of male germ cells and their entry into mitotic arrest. Finally, our data demonstrate that Nodal is specifically expressed in male germ cells and expression of the key pluripotency gene, Nanog was significantly reduced when signaling through ALK4/5/7 was blocked. Our strategy of inhibiting multiple Activin/NODAL/TGFβ receptors reduces the functional redundancy between these signaling pathways, thereby revealing new and essential roles for TGFβ and Activin signaling during testis formation and male germ cell development. PMID:23342175

  14. Gilz-Activin A as a Novel Signaling Axis Orchestrating Mesenchymal Stem Cell and Th17 Cell Interplay

    PubMed Central

    Luz-Crawford, Patricia; Espinosa-Carrasco, Gabriel; Ipseiz, Natacha; Contreras, Rafael; Tejedor, Gautier; Medina, Daniel A.; Vega-Letter, Ana-Maria; Ngo, Devi; Morand, Eric F.; Pène, Jérôme; Hernandez, Javier; Jorgensen, Christian; Djouad, Farida

    2018-01-01

    Mesenchymal stem cells (MSC) are highly immunosuppressive cells able to reduce chronic inflammation through the active release of mediators. Recently, we showed that glucocorticoid-induced leucine zipper (Gilz) expression by MSC is involved in their therapeutic effect by promoting the generation of regulatory T cells. However, the mechanisms underlying this pivotal role of Gilz remain elusive. Methods and Results In this study, we have uncovered evidence that Gilz modulates the phenotype and function of Th1 and Th17 cells likely by upregulating the level of Activin A and NO2 secreted by MSC. Adoptive transfer experiments sustained this Gilz-dependent suppressive effect of MSC on Th1 and Th17 cell functions. In immunoregulatory MSC, obtained by priming with IFN-γ and TNF-α, Gilz was translocated to the nucleus and bound to the promoters of inos and Activin βA to induce their expression. The increased expression of Activin A directly impacted on Th17 cells fate by repressing their differentiation program through the activation of Smad3/2 and enhancing IL-10 production. Conclusion Our results reveal how Gilz controls inos and Activin βA gene expression to ultimately assign immunoregulatory status to MSC able to repress the pathogenic Th17 cell differentiation program and uncover Activin A as a novel mediator of MSC in this process. PMID:29344311

  15. Gilz-Activin A as a Novel Signaling Axis Orchestrating Mesenchymal Stem Cell and Th17 Cell Interplay.

    PubMed

    Luz-Crawford, Patricia; Espinosa-Carrasco, Gabriel; Ipseiz, Natacha; Contreras, Rafael; Tejedor, Gautier; Medina, Daniel A; Vega-Letter, Ana-Maria; Ngo, Devi; Morand, Eric F; Pène, Jérôme; Hernandez, Javier; Jorgensen, Christian; Djouad, Farida

    2018-01-01

    Mesenchymal stem cells (MSC) are highly immunosuppressive cells able to reduce chronic inflammation through the active release of mediators. Recently, we showed that glucocorticoid-induced leucine zipper (Gilz) expression by MSC is involved in their therapeutic effect by promoting the generation of regulatory T cells. However, the mechanisms underlying this pivotal role of Gilz remain elusive. Methods and Results In this study, we have uncovered evidence that Gilz modulates the phenotype and function of Th1 and Th17 cells likely by upregulating the level of Activin A and NO 2 secreted by MSC. Adoptive transfer experiments sustained this Gilz-dependent suppressive effect of MSC on Th1 and Th17 cell functions. In immunoregulatory MSC, obtained by priming with IFN-γ and TNF-α, Gilz was translocated to the nucleus and bound to the promoters of inos and Activin βA to induce their expression. The increased expression of Activin A directly impacted on Th17 cells fate by repressing their differentiation program through the activation of Smad3/2 and enhancing IL-10 production. Conclusion Our results reveal how Gilz controls inos and Activin βA gene expression to ultimately assign immunoregulatory status to MSC able to repress the pathogenic Th17 cell differentiation program and uncover Activin A as a novel mediator of MSC in this process.

  16. The Effect of Holder Pasteurization on Activin A Levels in Human Milk.

    PubMed

    Peila, Chiara; Coscia, Alessandra; Bertino, Enrico; Li Volti, Giovanni; Galvano, Fabio; Barbagallo, Ignazio; Visser, Gerard H A; Gazzolo, Diego

    2016-11-01

    There is evidence that mother's own milk is the best nutrient in terms of multiorgan protection and infection prevention. However, when maternal milk is scarce, the solution can be represented by donor milk (DM), which requires specific storage procedures such as Holder Pasteurization (HoP). HoP is not free from side effects since it is widely known that it causes qualitative/quantitative changes in milk composition, particularly in the protein content. Therefore, the aim of this study is to investigate the effects of HoP on Activin A, a neurobiomarker known to play an important role in the development and protection of the central nervous system. In 24 mothers who delivered preterm (n = 12) and term (n = 12) healthy newborns, we conducted a pretest/test study where the milk donors acted as their own controls. Each sample was divided into two parts: the first was frozen at -80°C (Group 1); the second was Holder-pasteurized before freezing at -80°C (Group 2). Activin A was quantified using an ELISA test. Activin A was detected in all samples. There were no significant differences (p > 0.05) between the two groups, also when the analysis was stratified for gestational age at delivery and milk maturation degree (p > 0.05, for both). The present findings on the absence of any side effects of HoP on the milk concentration of Activin A offer additional support to the efficacy of HoP in DM storage. Our data open up to further investigations on neurobiomarkers' assessment in human milk and their preanalytical stability according to storage procedures.

  17. A truncated, activin-induced Smad3 isoform acts as a transcriptional repressor of FSHβ expression in mouse pituitary

    PubMed Central

    Kim, So-Youn; Zhu, Jie; Woodruff, Teresa K.

    2011-01-01

    The receptor-regulated protein Smad3 is key player in the signaling cascade stimulated by the binding of activin to its cell surface receptor. Upon phosphorylation, Smad3 forms a heterocomplex with Smad2 and Smad4, translocates to the nucleus and acts as a transcriptional co-activator. We have identified a unique isoform of Smad3 that is expressed in mature pituitary gonadotropes. 5' RACE revealed that this truncated Smad3 isoform is transcribed from an ATG site within exon 4 and consists of 7 exons encoding half of the linker region and the MH2 region. In pituitary cells, the truncated Smad3 isoform was phosphorylated upon activin treatment, in a manner that was temporally distinct from the phosphorylation of full-length Smad3. Activin-induced phosphorylation of Smad3 and the truncated Smad3 isoform was blocked by both follistatin and siRNA-mediated knockdown of Smad3. The truncated Smad3 isoform antagonized Smad3-mediated, activin-responsive promoter activity. We propose that the pituitary gonadotrope contains an ultra-short, activin-responsive feedback loop utilizing two different isoforms of Smad3, one which acts as an agonist (Smad3) and another that acts as an intracrine antagonist (truncated Smad3 isoform) to regulate FSHβ production. PMID:21664424

  18. FGF9, activin and TGFβ promote testicular characteristics in an XX gonad organ culture model.

    PubMed

    Gustin, Sonja E; Stringer, Jessica M; Hogg, Kirsten; Sinclair, Andrew H; Western, Patrick S

    2016-11-01

    Testis development is dependent on the key sex-determining factors SRY and SOX9, which activate the essential ligand FGF9. Although FGF9 plays a central role in testis development, it is unable to induce testis formation on its own. However, other growth factors, including activins and TGFβs, also present testis during testis formation. In this study, we investigated the potential of FGF9 combined with activin and TGFβ to induce testis development in cultured XX gonads. Our data demonstrated differing individual and combined abilities of FGF9, activin and TGFβ to promote supporting cell proliferation, Sertoli cell development and male germ line differentiation in cultured XX gonads. FGF9 promoted proliferation of supporting cells in XX foetal gonads at rates similar to those observed in vivo during testis cord formation in XY gonads but was insufficient to initiate testis development. However, when FGF9, activin and TGFβ were combined, aspects of testicular development were induced, including the expression of Sox9, morphological reorganisation of the gonad and deposition of laminin around germ cells. Enhancing β-catenin activity diminished the testis-promoting activities of the combined growth factors. The male promoting activity of FGF9 and the combined growth factors directly or indirectly extended to the germ line, in which a mixed phenotype was observed. FGF9 and the combined growth factors promoted male germ line development, including mitotic arrest, but expression of pluripotency genes was maintained, rather than being repressed. Together, our data provide evidence that combined signalling by FGF9, activin and TGFβ can induce testicular characteristics in XX gonads. © 2016 Society for Reproduction and Fertility.

  19. Sheng-ji Hua-yu formula promotes diabetic wound healing of re-epithelization via Activin/Follistatin regulation.

    PubMed

    Kuai, Le; Zhang, Jing-Ting; Deng, Yu; Xu, Shun; Xu, Xun-Zhe; Wu, Min-Feng; Guo, Dong-Jie; Chen, Yu; Wu, Ren-Jie; Zhao, Xing-Qiang; Nian, Hua; Li, Bin; Li, Fu-Lun

    2018-01-29

    Sheng-ji Hua-yu(SJHY) formula is one of the most useful Traditional Chinese medicine (TCM) in the treatment of the delayed diabetic wound. However, elucidating the related molecular biological mechanism of how the SJHY Formula affects excessive inflammation in the process of re-epithelialization of diabetic wound healing is a task urgently needed to be fulfilled. The objectives of this study is to evaluate the effect of antagonisic expression of pro-/anti-inflammatory factors on transforming growth factor-β(TGF-β) superfamily (activin and follistatin) in the process of re-epithelialization of diabetic wound healing in vivo, and to characterize the involvement of the activin/follistatin protein expression regulation, phospho-Smad (pSmad2), and Nuclear factor kappa B p50 (NF-kB) p50 in the diabetic wound healing effects of SJHY formula. SJHY Formula was prepared by pharmaceutical preparation room of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine. Diabetic wound healing activity was evaluated by circular excision wound models. Wound healing activity was examined by macroscopic evaluation. Activin/follistatin expression regulation, protein expression of pSmad2 and NF-kB p50 in skin tissue of wounds were analyzed by Real Time PCR, Western blot, immunohistochemistry and hematoxylin and eosin (H&E) staining. Macroscopic evaluation analysis showed that wound healing of diabetic mice was delayed, and SJHY Formula accelerated wound healing time of diabetic mice. Real Time PCR analysis showed higher mRNA expression of activin/follistatin in diabetic delayed wound versus the wound in normal mice. Western Blot immunoassay analysis showed reduction of activin/follistatin proteins levels by SJHY Formula treatment 15 days after injury. Immunohistochemistry investigated the reduction of pSmad2 and NF-kB p50 nuclear staining in the epidermis of diabetic SJHY versus diabetic control mice on day 15 after wounding. H&E staining revealed that SJHY Formula

  20. Inhibition of the Activin Receptor Type-2B Pathway Restores Regenerative Capacity in Satellite Cell-Depleted Skeletal Muscle.

    PubMed

    Formicola, Luigi; Pannérec, Alice; Correra, Rosa Maria; Gayraud-Morel, Barbara; Ollitrault, David; Besson, Vanessa; Tajbakhsh, Shahragim; Lachey, Jennifer; Seehra, Jasbir S; Marazzi, Giovanna; Sassoon, David A

    2018-01-01

    Degenerative myopathies typically display a decline in satellite cells coupled with a replacement of muscle fibers by fat and fibrosis. During this pathological remodeling, satellite cells are present at lower numbers and do not display a proper regenerative function. Whether a decline in satellite cells directly contributes to disease progression or is a secondary result is unknown. In order to dissect these processes, we used a genetic model to reduce the satellite cell population by ~70-80% which leads to a nearly complete loss of regenerative potential. We observe that while no overt tissue damage is observed following satellite cell depletion, muscle fibers atrophy accompanied by changes in the stem cell niche cellular composition. Treatment of these mice with an Activin receptor type-2B (AcvR2B) pathway blocker reverses muscle fiber atrophy as expected, but also restores regenerative potential of the remaining satellite cells. These findings demonstrate that in addition to controlling fiber size, the AcvR2B pathway acts to regulate the muscle stem cell niche providing a more favorable environment for muscle regeneration.

  1. Inhibition of the Activin Receptor Type-2B Pathway Restores Regenerative Capacity in Satellite Cell-Depleted Skeletal Muscle

    PubMed Central

    Formicola, Luigi; Pannérec, Alice; Correra, Rosa Maria; Gayraud-Morel, Barbara; Ollitrault, David; Besson, Vanessa; Tajbakhsh, Shahragim; Lachey, Jennifer; Seehra, Jasbir S.; Marazzi, Giovanna; Sassoon, David A.

    2018-01-01

    Degenerative myopathies typically display a decline in satellite cells coupled with a replacement of muscle fibers by fat and fibrosis. During this pathological remodeling, satellite cells are present at lower numbers and do not display a proper regenerative function. Whether a decline in satellite cells directly contributes to disease progression or is a secondary result is unknown. In order to dissect these processes, we used a genetic model to reduce the satellite cell population by ~70–80% which leads to a nearly complete loss of regenerative potential. We observe that while no overt tissue damage is observed following satellite cell depletion, muscle fibers atrophy accompanied by changes in the stem cell niche cellular composition. Treatment of these mice with an Activin receptor type-2B (AcvR2B) pathway blocker reverses muscle fiber atrophy as expected, but also restores regenerative potential of the remaining satellite cells. These findings demonstrate that in addition to controlling fiber size, the AcvR2B pathway acts to regulate the muscle stem cell niche providing a more favorable environment for muscle regeneration. PMID:29881353

  2. A truncated, activin-induced Smad3 isoform acts as a transcriptional repressor of FSHβ expression in mouse pituitary.

    PubMed

    Kim, So-Youn; Zhu, Jie; Woodruff, Teresa K

    2011-08-06

    The receptor-regulated protein Smad3 is key player in the signaling cascade stimulated by the binding of activin to its cell surface receptor. Upon phosphorylation, Smad3 forms a heterocomplex with Smad2 and Smad4, translocates to the nucleus and acts as a transcriptional co-activator. We have identified a unique isoform of Smad3 that is expressed in mature pituitary gonadotropes. 5' RACE revealed that this truncated Smad3 isoform is transcribed from an ATG site within exon 4 and consists of 7 exons encoding half of the linker region and the MH2 region. In pituitary cells, the truncated Smad3 isoform was phosphorylated upon activin treatment, in a manner that was temporally distinct from the phosphorylation of full-length Smad3. Activin-induced phosphorylation of Smad3 and the truncated Smad3 isoform was blocked by both follistatin and siRNA-mediated knockdown of Smad3. The truncated Smad3 isoform antagonized Smad3-mediated, activin-responsive promoter activity. We propose that the pituitary gonadotrope contains an ultra-short, activin-responsive feedback loop utilizing two different isoforms of Smad3, one which acts as an agonist (Smad3) and another that acts as an intracrine antagonist (truncated Smad3 isoform) to regulate FSHβ production. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. Activin A increases phagocytosis of Escherichia coli K1 by primary murine microglial cells activated by toll-like receptor agonists.

    PubMed

    Diesselberg, Catharina; Ribes, Sandra; Seele, Jana; Kaufmann, Annika; Redlich, Sandra; Bunkowski, Stephanie; Hanisch, Uwe-Karsten; Michel, Uwe; Nau, Roland; Schütze, Sandra

    2018-06-07

    Bacterial meningitis is associated with high mortality and long-term neurological sequelae. Increasing the phagocytic activity of microglia could improve the resistance of the CNS against infections. We studied the influence of activin A, a member of the TGF-β family with known immunoregulatory and neuroprotective effects, on the functions of microglial cells in vitro. Primary murine microglial cells were treated with activin A (0.13 ng/ml-13 μg/ml) alone or in combination with agonists of TLR2, 4, and 9. Phagocytosis of Escherichia coli K1 as well as release of TNF-α, IL-6, CXCL1, and NO was assessed. Activin A dose-dependently enhanced the phagocytosis of Escherichia coli K1 by microglial cells activated by agonists of TLR2, 4, and 9 without further increasing NO and proinflammatory cytokine release. Cell viability of microglial cells was not affected by activin A. Priming of microglial cells with activin A could increase the elimination of bacteria in bacterial CNS infections. This preventive strategy could improve the resistance of the brain to infections, particularly in elderly and immunocompromised patients.

  4. USP4 inhibits SMAD4 monoubiquitination and promotes activin and BMP signaling.

    PubMed

    Zhou, Fangfang; Xie, Feng; Jin, Ke; Zhang, Zhengkui; Clerici, Marcello; Gao, Rui; van Dinther, Maarten; Sixma, Titia K; Huang, Huizhe; Zhang, Long; Ten Dijke, Peter

    2017-06-01

    SMAD4 is a common intracellular effector for TGF-β family cytokines, but the mechanism by which its activity is dynamically regulated is unclear. We demonstrated that ubiquitin-specific protease (USP) 4 strongly induces activin/BMP signaling by removing the inhibitory monoubiquitination from SMAD4. This modification was triggered by the recruitment of the E3 ligase, SMURF2, to SMAD4 following ligand-induced regulatory (R)-SMAD-SMAD4 complex formation. Whereas the interaction of the negative regulator c-SKI inhibits SMAD4 monoubiquitination, the ligand stimulates the recruitment of SMURF2 to the c-SKI-SMAD2 complex and triggers c-SKI ubiquitination and degradation. Thus, SMURF2 has a role in termination and initiation of TGF-β family signaling. An increase in monoubiquitinated SMAD4 in USP4-depleted mouse embryonic stem cells (mESCs) decreased both the BMP- and activin-induced changes in the embryonic stem cell fate. USP4 sustained SMAD4 activity during activin- and BMP-mediated morphogenic events in early zebrafish embryos. Moreover, zebrafish depleted of USP4 exhibited defective cell migration and slower coordinated cell movement known as epiboly, both of which could be rescued by SMAD4. Therefore, USP4 is a critical determinant of SMAD4 activity. © 2017 The Authors.

  5. Activin- and Nodal-related factors control antero-posterior patterning of the zebrafish embryo.

    PubMed

    Thisse, B; Wright, C V; Thisse, C

    2000-01-27

    Definition of cell fates along the dorso-ventral axis depends on an antagonistic relationship between ventralizing transforming growth factor-beta superfamily members, the bone morphogenetic proteins and factors secreted from the dorsal organizer, such as Noggin and Chordin. The extracellular binding of the last group to the bone morphogenetic proteins prevents them from activating their receptors, and the relative ventralizer:antagonist ratio is thought to specify different dorso-ventral cell fates. Here, by taking advantage of a non-genetic interference method using a specific competitive inhibitor, the Lefty-related gene product Antivin, we provide evidence that cell fate along the antero-posterior axis of the zebrafish embryo is controlled by the morphogenetic activity of another transforming growth factor-beta superfamily subgroup--the Activin and Nodal-related factors. Increasing antivin doses progressively deleted posterior fates within the ectoderm, eventually resulting in the removal of all fates except forebrain and eyes. In contrast, overexpression of activin or nodal-related factors converted ectoderm that was fated to be forebrain into more posterior ectodermal or mesendodermal fates. We propose that modulation of intercellular signalling by Antivin/Activin and Nodal-related factors provides a mechanism for the graded establishment of cell fates along the antero-posterior axis of the zebrafish embryo.

  6. The role of myostatin and activin receptor IIB in the regulation of unloading-induced myofiber type-specific skeletal muscle atrophy.

    PubMed

    Babcock, Lyle W; Knoblauch, Mark; Clarke, Mark S F

    2015-09-15

    Chronic unloading induces decrements in muscle size and strength. This adaptation is governed by a number of molecular factors including myostatin, a potent negative regulator of muscle mass. Myostatin must first be secreted into the circulation and then bind to the membrane-bound activin receptor IIB (actRIIB) to exert its atrophic action. Therefore, we hypothesized that myofiber type-specific atrophy observed after hindlimb suspension (HLS) would be related to myofiber type-specific expression of myostatin and/or actRIIB. Wistar rats underwent HLS for 10 days, after which the tibialis anterior was harvested for frozen cross sectioning. Simultaneous multichannel immunofluorescent staining combined with differential interference contrast imaging was employed to analyze myofiber type-specific expression of myostatin and actRIIB and myofiber type cross-sectional area (CSA) across fiber types, myonuclei, and satellite cells. Hindlimb suspension (HLS) induced significant myofiber type-specific atrophy in myosin heavy chain (MHC) IIx (P < 0.05) and MHC IIb myofibers (P < 0.05). Myostatin staining associated with myonuclei was less in HLS rats compared with controls, while satellite cell staining for myostatin remained unchanged. In contrast, the total number myonuclei and satellite cells per myofiber was reduced in HLS compared with ambulatory control rats (P < 0.01). Sarcoplasmic actRIIB staining differed between myofiber types (I < IIa < IIx < IIb) independent of loading conditions. Myofiber types exhibiting the greatest cytoplasmic staining of actRIIB corresponded to those exhibiting the greatest degree of atrophy following HLS. Our data suggest that differential expression of actRIIB may be responsible for myostatin-induced myofiber type-selective atrophy observed during chronic unloading. Copyright © 2015 the American Physiological Society.

  7. Activin A Modulates CRIPTO-1/HNF4α+ Cells to Guide Cardiac Differentiation from Human Embryonic Stem Cells

    PubMed Central

    Duelen, Robin; Gilbert, Guillaume; Patel, Abdulsamie; de Schaetzen, Nathalie; De Waele, Liesbeth; Roderick, Llewelyn; Sipido, Karin R.; Verfaillie, Catherine M.; Buyse, Gunnar M.

    2017-01-01

    The use of human pluripotent stem cells in basic and translational cardiac research requires efficient differentiation protocols towards cardiomyocytes. In vitro differentiation yields heterogeneous populations of ventricular-, atrial-, and nodal-like cells hindering their potential applications in regenerative therapies. We described the effect of the growth factor Activin A during early human embryonic stem cell fate determination in cardiac differentiation. Addition of high levels of Activin A during embryoid body cardiac differentiation augmented the generation of endoderm derivatives, which in turn promoted cardiomyocyte differentiation. Moreover, a dose-dependent increase in the coreceptor expression of the TGF-β superfamily member CRIPTO-1 was observed in response to Activin A. We hypothesized that interactions between cells derived from meso- and endodermal lineages in embryoid bodies contributed to improved cell maturation in early stages of cardiac differentiation, improving the beating frequency and the percentage of contracting embryoid bodies. Activin A did not seem to affect the properties of cardiomyocytes at later stages of differentiation, measuring action potentials, and intracellular Ca2+ dynamics. These findings are relevant for improving our understanding on human heart development, and the proposed protocol could be further explored to obtain cardiomyocytes with functional phenotypes, similar to those observed in adult cardiac myocytes. PMID:28163723

  8. Regulation of Drosophila hematopoietic sites by Activin-β from active sensory neurons

    PubMed Central

    Makhijani, Kalpana; Alexander, Brandy; Rao, Deepti; Petraki, Sophia; Herboso, Leire; Kukar, Katelyn; Batool, Itrat; Wachner, Stephanie; Gold, Katrina S.; Wong, Corinna; O’Connor, Michael B.; Brückner, Katja

    2017-01-01

    An outstanding question in animal development, tissue homeostasis and disease is how cell populations adapt to sensory inputs. During Drosophila larval development, hematopoietic sites are in direct contact with sensory neuron clusters of the peripheral nervous system (PNS), and blood cells (hemocytes) require the PNS for their survival and recruitment to these microenvironments, known as Hematopoietic Pockets. Here we report that Activin-β, a TGF-β family ligand, is expressed by sensory neurons of the PNS and regulates the proliferation and adhesion of hemocytes. These hemocyte responses depend on PNS activity, as shown by agonist treatment and transient silencing of sensory neurons. Activin-β has a key role in this regulation, which is apparent from reporter expression and mutant analyses. This mechanism of local sensory neurons controlling blood cell adaptation invites evolutionary parallels with vertebrate hematopoietic progenitors and the independent myeloid system of tissue macrophages, whose regulation by local microenvironments remain undefined. PMID:28748922

  9. Complete reversal of muscle wasting in experimental cancer cachexia: Additive effects of activin type II receptor inhibition and β-2 agonist.

    PubMed

    Toledo, Míriam; Busquets, Sílvia; Penna, Fabio; Zhou, Xiaolan; Marmonti, Enrica; Betancourt, Angelica; Massa, David; López-Soriano, Francisco J; Han, H Q; Argilés, Josep M

    2016-04-15

    Formoterol is a highly potent β2-adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species. Myostatin/activin inhibition reverses skeletal muscle loss and prolongs survival of tumor-bearing animals. The aim of this investigation was to evaluate the effects of a combination of the soluble myostatin receptor ActRIIB (sActRIIB) and the β2-agonist formoterol in the cachectic Lewis lung carcinoma model. The combination of formoterol and sActRIIB was extremely effective in reversing muscle wasting associated with experimental cancer cachexia in mice. Muscle weights from tumor-bearing animals were completely recovered following treatment and this was also reflected in the measured grip strength. This combination increased food intake in both control and tumor-bearing animals. The double treatment also prolonged survival significantly without affecting the weight and growth of the primary tumor. In addition, it significantly reduced the number of metastasis. Concerning the mechanisms for the preservation of muscle mass during cachexia, the effects of formoterol and sActRIIB seemed to be additive, since formoterol reduced the rate of protein degradation (as measured in vitro as tyrosine release, using incubated isolated individual muscles) while sActRIIB only affected protein synthesis (as measured in vivo using tritiated phenylalanine). Formoterol also increased the rate of protein synthesis and this seemed to be favored by the presence of sActRIIB. Combining formoterol and sActRIIB seemed to be a very promising treatment for experimental cancer cachexia. Further studies in human patients are necessary and may lead to a highly effective treatment option for muscle wasting associated with cancer. © 2015 UICC.

  10. The Drosophila TGF-beta/Activin-like ligands Dawdle and Myoglianin appear to modulate adult lifespan through regulation of 26S proteasome function in adult muscle

    PubMed Central

    Langerak, Shaughna; Kim, Myung-Jun; Lamberg, Hannah; Godinez, Michael; Main, Mackenzie; Winslow, Lindsey; O'Connor, Michael B.

    2018-01-01

    ABSTRACT The Drosophila Activin signaling pathway employs at least three separate ligands – Activin-β (Actβ), Dawdle (Daw), and Myoglianin (Myo) – to regulate several general aspects of fruit fly larval development, including cell proliferation, neuronal remodeling, and metabolism. Here we provide experimental evidence indicating that both Daw and Myo are anti-ageing factors in adult fruit flies. Knockdown of Myo or Daw in adult fruit flies reduced mean lifespan, while overexpression of either ligand in adult muscle tissues but not in adipose tissues enhanced mean lifespan. An examination of ubiquitinated protein aggregates in adult muscles revealed a strong inverse correlation between Myo- or Daw-initiated Activin signaling and the amount of ubiquitinated protein aggregates. We show that this correlation has important functional implications by demonstrating that the lifespan extension effect caused by overexpression of wild-type Daw or Myo in adult muscle tissues can be completely abrogated by knockdown of a 26S proteasome regulatory subunit Rpn1 in adult fly muscle, and that the prolonged lifespan caused by overexpression of Daw or Myo in adult muscle could be due to enhanced protein levels of the key subunits of 26S proteasome. Overall, our data suggest that Activin signaling initiated by Myo and Daw in adult Drosophila muscles influences lifespan, in part, by modulation of protein homeostasis through either direct or indirect regulation of the 26S proteasome levels. Since Myo is closely related to the vertebrate muscle mass regulator Myostatin (GDF8) and the Myostatin paralog GDF11, our observations may offer a new experimental model for probing the roles of GDF11/8 in ageing regulation in vertebrates. This article has an associated First Person interview with the first author of the paper. PMID:29615416

  11. Activin signalling and response to a morphogen gradient.

    PubMed

    Gurdon, J B; Harger, P; Mitchell, A; Lemaire, P

    1994-10-06

    Using combinations of amphibian embryo tissues, it is shown that the selection of genes expressed by a cell is determined by its distance from a source of activin, a peptide growth factor contained in vegetal cells and able to induce other cells to form mesoderm. This long-range signal spreads over at least 10 cell diameters in a few hours. It does so by passive diffusion, because it can by-pass cells that do not themselves respond to the signal nor synthesize protein. These results provide direct support for the operation of a morphogen concentration gradient in vertebrate development.

  12. FGF signaling via MAPK is required early and improves Activin A-induced definitive endoderm formation from human embryonic stem cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sui, Lina, E-mail: linasui@vub.ac.be; Mfopou, Josue K.; Geens, Mieke

    2012-09-28

    Highlights: Black-Right-Pointing-Pointer Deep study the FGF signaling role during DE specification in the context of hESCs. Black-Right-Pointing-Pointer DE differentiation from hESCs has an early dependence on FGF signaling. Black-Right-Pointing-Pointer A serum-free DE protocol is developed based on the findings. Black-Right-Pointing-Pointer The DE cells showed potential to differentiate into pancreatic progenitor cells. -- Abstract: Considering their unlimited proliferation and pluripotency properties, human embryonic stem cells (hESCs) constitute a promising resource applicable for cell replacement therapy. To facilitate this clinical translation, it is critical to study and understand the early stage of hESCs differentiation wherein germ layers are defined. In this study,more » we examined the role of FGF signaling in Activin A-induced definitive endoderm (DE) differentiation in the absence of supplemented animal serum. We found that activated FGF/MAPK signaling is required at the early time point of Activin A-induced DE formation. In addition, FGF activation increased the number of DE cells compared to Activin A alone. These DE cells could further differentiate into PDX1 and NKX6.1 positive pancreatic progenitors in vitro. We conclude that Activin A combined with FGF/MAPK signaling efficiently induce DE cells in the absence of serum. These findings improve our understanding of human endoderm formation, and constitute a step forward in the generation of clinical grade hESCs progenies for cell therapy.« less

  13. Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A

    PubMed Central

    Manavski, Yosif; Abel, Tobias; Hu, Junhao; Kleinlützum, Dina; Buchholz, Christian J.; Belz, Christina; Augustin, Hellmut G.; Dimmeler, Stefanie

    2017-01-01

    Endothelial cells (ECs) not only are important for oxygen delivery but also act as a paracrine source for signals that determine the balance between tissue regeneration and fibrosis. Here we show that genetic inactivation of flow-induced transcription factor Krüppel-like factor 2 (KLF2) in ECs results in reduced liver damage and augmentation of hepatocyte proliferation after chronic liver injury by treatment with carbon tetrachloride (CCl4). Serum levels of GLDH3 and ALT were significantly reduced in CCl4-treated EC-specific KLF2-deficient mice. In contrast, transgenic overexpression of KLF2 in liver sinusoidal ECs reduced hepatocyte proliferation. KLF2 induced activin A expression and secretion from endothelial cells in vitro and in vivo, which inhibited hepatocyte proliferation. However, loss or gain of KLF2 expression did not change capillary density and liver fibrosis, but significantly affected hepatocyte proliferation. Taken together, the data demonstrate that KLF2 induces an antiproliferative secretome, including activin A, which attenuates liver regeneration. PMID:28348240

  14. Altered Sex Hormone Concentrations and Gonadal mRNA Expression Levels of Activin Signaling Factors in Hatchling Alligators From a Contaminated Florida Lake

    PubMed Central

    MOORE, BRANDON C.; KOHNO, SATOMI; COOK, ROBERT W.; ALVERS, ASHLEY L.; HAMLIN, HEATHER J.; WOODRUFF, TERESA K.; GUILLETTE, LOUIS J.

    2014-01-01

    Activins and estrogens participate in regulating the breakdown of ovarian germ cell nests and follicle assembly in mammals. In 1994, our group reported elevated frequencies of abnormal, multioocytic ovarian follicles in 6 month old, environmental contaminant-exposed female alligators after gonadotropin challenge. Here, we investigated if maternal contribution of endocrine disrupting contaminants to the egg subsequently alters estrogen/inhibin/activin signaling in hatchling female offspring, putatively predisposing an increased frequency of multioocytic follicle formation. We quantified basal and exogenous gonadotropin-stimulated concentrations of circulating plasma steroid hormones and ovarian activin signaling factor mRNA abundance in hatchling alligators from the same contaminated (Lake Apopka) and reference (Lake Woodruff) Florida lakes, as examined in 1994. Basal circulating plasma estradiol and testosterone concentrations were greater in alligators from the contaminated environment, whereas activin/inhibin βA subunit and follistatin mRNA abundances were lower than values measured in ovaries from reference lake animals. Challenged, contaminant-exposed animals showed a more robust increase in plasma estradiol concentration following an acute follicle stimulating hormone (FSH) challenge compared with reference site alligators. Aromatase and follistatin mRNA levels increased in response to an extended FSH challenge in the reference site animals, but not in the contaminant-exposed animals. In hatchling alligators, ovarian follicles have not yet formed; therefore, these endocrine differences are likely to affect subsequent ovarian development, including ovarian follicle assembly. PMID:20166196

  15. [Low expression of activin A in mouse and human embryonic teratocarcinoma cells].

    PubMed

    Gordeeva, O F

    2014-01-01

    TGFP3 family factors play an important role in regulating the balance of self-renewal and differentiation of mouse and human pluripotent stem and embryonic teratocarcinoma cells. The expression patterns of TGFbeta family signaling ligands and functional roles of these signaling pathways differ significantly in mouse and human embryonic stem cells, but the activity and functional role of these factors in mouse and human embryonic teratocarcinoma cells were not sufficiently investigated. Comparative quantitative real-time PCR analysis of the expression of TGF@[beta] family factors in mouse embryonic stem, embryonic germ, and embryonic teratocarcinoma cells showed that embryonic teratocarcinoma cells express lower ActivinA than pluripotent stem cells but similar levels of factors Nodal, Lefty 1, TGFbeta1, BMP4, and GDF3. In human nullipotent embryonic teratocarcinoma PA-1 cells, most factors of the TGFbeta family (ACTIVINA, NODAL, LEFTY 1, BMP4, and GDF3) are expressed at lower levels than in human embryonic stem cells: Thus, in mouse and human nullipotent teratocarcinoma cells, theexpression of ActivinA is significantly reduced com- pared ivith embryonic stem cells. Presumably, these differences may be associated with changes in the functional activity of the respective signaling pathways and deregulation of proliferative and antiproliferative mechanisms in embryonic teratocarcinoma cells.

  16. Activin Plays a Key Role in the Maintenance of Long-Term Memory and Late-LTP

    ERIC Educational Resources Information Center

    Ageta, Hiroshi; Ikegami, Shiro; Miura, Masami; Masuda, Masao; Migishima, Rika; Hino, Toshiaki; Takashima, Noriko; Murayama, Akiko; Sugino, Hiromu; Setou, Mitsutoshi; Kida, Satoshi; Yokoyama, Minesuke; Hasegawa, Yoshihisa; Tsuchida, Kunihiro; Aosaki, Toshihiko; Inokuchi, Kaoru

    2010-01-01

    A recent study has revealed that fear memory may be vulnerable following retrieval, and is then reconsolidated in a protein synthesis-dependent manner. However, little is known about the molecular mechanisms of these processes. Activin [beta]A, a member of the TGF-[beta] superfamily, is increased in activated neuronal circuits and regulates…

  17. Transcriptional activation of mouse mast cell Protease-7 by activin and transforming growth factor-beta is inhibited by microphthalmia-associated transcription factor.

    PubMed

    Funaba, Masayuki; Ikeda, Teruo; Murakami, Masaru; Ogawa, Kenji; Tsuchida, Kunihiro; Sugino, Hiromu; Abe, Matanobu

    2003-12-26

    Previous studies have revealed that activin A and transforming growth factor-beta1 (TGF-beta1) induced migration and morphological changes toward differentiation in bone marrow-derived cultured mast cell progenitors (BMCMCs). Here we show up-regulation of mouse mast cell protease-7 (mMCP-7), which is expressed in differentiated mast cells, by activin A and TGF-beta1 in BMCMCs, and the molecular mechanism of the gene induction of mmcp-7. Smad3, a signal mediator of the activin/TGF-beta pathway, transcriptionally activated mmcp-7. Microphthalmia-associated transcription factor (MITF), a tissue-specific transcription factor predominantly expressed in mast cells, melanocytes, and heart and skeletal muscle, inhibited Smad3-mediated mmcp-7 transcription. MITF associated with Smad3, and the C terminus of MITF and the MH1 and linker region of Smad3 were required for this association. Complex formation between Smad3 and MITF was neither necessary nor sufficient for the inhibition of Smad3 signaling by MITF. MITF inhibited the transcriptional activation induced by the MH2 domain of Smad3. In addition, MITF-truncated N-terminal amino acids could associate with Smad3 but did not inhibit Smad3-mediated transcription. The level of Smad3 was decreased by co-expression of MITF but not of dominant-negative MITF, which resulted from proteasomal protein degradation. The changes in the level of Smad3 protein were paralleled by those in Smad3-mediated signaling activity. These findings suggest that MITF negatively regulates Smad-dependent activin/TGF-beta signaling in a tissue-specific manner.

  18. Activin-like signal activates dorsal-specific maternal RNA between 8- and 16-cell stages of Xenopus.

    PubMed

    Hainski, A M; Moody, S A

    1996-01-01

    In many animals the dorsal-ventral axis forms by an initial localization of maternal molecules, which then regulate the spatial location of signals that directly influence the expression of axis-specific fates. Several recent studies have demonstrated that dorsal-animal blastomeres of the Xenopus morula (8-32 cells) are biased toward dorsal fates prior to mesoderm inductive signaling. In this study we ask whether the dorsal bias is the result of autonomous expression of maternal molecules specifically localized within dorsal cells or of early activating signals. It was found that although 16-cell dorsal-animal blastomeres (D1.1) can differentiate into dorsal tissues when cultured alone, the 8-cell mothers (D1) can not. Likewise, although RNA extracted from D1.1 can induce an extra dorsal axis when injected into vegetal blastomeres, RNA extracted from D1 can not. However, D1 does express dorsal tissues if co-cultured with dorsal-vegetal cells or with culture medium containing a mixture of activins (PIF-medium). Furthermore, short-term culture of D1 in PIF-medium enables the D1 RNA to induce an ectopic dorsal axis. Ventral-animal blastomeres also can express dorsal axial tissues when co-cultured with dorsal-vegetal blastomeres or in PIF-medium, but the RNA from the activin-treated ventral cells cannot induce ectopic dorsal axes. These studies demonstrate that there are maternal RNAs that, shortly after fertilization, are present only in the dorsal-animal region. They do not act cell autonomously, but require an activin-like signal. These RNAs may function by increasing the responsiveness of dorsal-animal blastomeres to the mesoderm inductive signals present in both the morula and the blastula.

  19. EFFECT OF PROFLAVINE ON THE SYNTHESIS OF ADENOVIRUS, TYPE 5, AND ASSOCIATED SOLUBLE ANTIGENS

    PubMed Central

    Wilcox, Wesley C.; Ginsberg, Harold S.

    1962-01-01

    Wilcox, Wesley C. (University of Pennsylvania, Philadelphia) and Harold S. Ginsberg. Effect of proflavine on the synthesis of adenovirus, type 5, and associated soluble antigens. J. Bacteriol. 84:526–533. 1962.—The synthesis of type 5 adenovirus in HeLa cells was suppressed to a considerable extent by low concentrations of proflavine, an acridine dye. In comparison, the processes leading to the production of soluble complement-fixing antigens and toxin were less sensitive to the action of this chemical. Addition of proflavine to infected cells at different times during the virus growth cycle revealed that the processes leading to the synthesis of soluble antigens began prior to the first appearance of newly synthesized virus. This observation is compatible with the hypothesis that the soluble antigens may represent virus subunits or precursor materials. In addition, these data indicate that it is possible to interrupt the latter stages of the virus synthetic process by addition of proflavine late in the eclipse period. PMID:14000661

  20. Pluripotency Gene Expression and Growth Control in Cultures of Peripheral Blood Monocytes during Their Conversion into Programmable Cells of Monocytic Origin (PCMO): Evidence for a Regulatory Role of Autocrine Activin and TGF-β

    PubMed Central

    Ungefroren, Hendrik; Hyder, Ayman; Hinz, Hebke; Groth, Stephanie; Lange, Hans; El-Sayed, Karim M. Fawzy; Ehnert, Sabrina; Nüssler, Andreas K.; Fändrich, Fred; Gieseler, Frank

    2015-01-01

    Previous studies have shown that peripheral blood monocytes can be converted in vitro to a stem cell-like cell termed PCMO as evidenced by the re-expression of pluripotency-associated genes, transient proliferation, and the ability to adopt the phenotype of hepatocytes and insulin-producing cells upon tissue-specific differentiation. However, the regulatory interactions between cultured cells governing pluripotency and mitotic activity have remained elusive. Here we asked whether activin(s) and TGF-β(s), are involved in PCMO generation. De novo proliferation of PCMO was higher under adherent vs. suspended culture conditions as revealed by the appearance of a subset of Ki67-positive monocytes and correlated with down-regulation of p21WAF1 beyond day 2 of culture. Realtime-PCR analysis showed that PCMO express ActRIIA, ALK4, TβRII, ALK5 as well as TGF-β1 and the βA subunit of activin. Interestingly, expression of ActRIIA and ALK4, and activin A levels in the culture supernatants increased until day 4 of culture, while levels of total and active TGF-β1 strongly declined. PCMO responded to both growth factors in an autocrine fashion with intracellular signaling as evidenced by a rise in the levels of phospho-Smad2 and a drop in those of phospho-Smad3. Stimulation of PCMO with recombinant activins (A, B, AB) and TGF-β1 induced phosphorylation of Smad2 but not Smad3. Inhibition of autocrine activin signaling by either SB431542 or follistatin reduced both Smad2 activation and Oct4A/Nanog upregulation. Inhibition of autocrine TGF-β signaling by either SB431542 or anti-TGF-β antibody reduced Smad3 activation and strongly increased the number of Ki67-positive cells. Furthermore, anti-TGF-β antibody moderately enhanced Oct4A/Nanog expression. Our data show that during PCMO generation pluripotency marker expression is controlled positively by activin/Smad2 and negatively by TGF-β/Smad3 signaling, while relief from growth inhibition is primarily the result of reduced

  1. Signaling via the transcriptionally regulated activin receptor 2B is a novel mediator of neuronal cell death during chicken ciliary ganglion development.

    PubMed

    Koszinowski, S; Buss, K; Kaehlcke, K; Krieglstein, K

    2015-04-01

    The TGF-β ligand superfamily members activin A and BMP control important aspects of embryonic neuronal development and differentiation. Both are known to bind to activin receptor subtypes IIA (ActRIIA) and IIB, while in the avian ciliary ganglion (CG), so far only ActRIIA-expression has been described. We show that the expression of ACVR2B, coding for the ActRIIB, is tightly regulated during CG development and the knockdown of ACVR2B expression leads to a deregulation in the execution of neuronal apoptosis and therefore affects ontogenetic programmed cell death in vivo. While the differentiation of choroid neurons was impeded in the knockdown, pointing toward a reduction in activin A-mediated neural differentiation signaling, naturally occurring neuronal cell death in the CG was not prevented by follistatin treatment. Systemic injections of the BMP antagonist noggin, on the other hand, reduced the number of apoptotic neurons to a similar extent as ACVR2B knockdown. We therefore propose a novel pathway in the regulation of CG neuron ontogenetic programmed cell death, which could be mediated by BMP and signals via the ActRIIB. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. Activin A amplifies dysregulated BMP signaling and induces chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP).

    PubMed

    Wang, Haitao; Shore, Eileen M; Pignolo, Robert J; Kaplan, Frederick S

    2018-04-01

    Fibrodysplasia ossificans progressiva (FOP), is caused by mutations in the type I BMP receptor ACVR1 that lead to increased activation of the BMP-pSmad1/5/8 signaling pathway. Recent findings suggest that Activin A (Act A) promiscuously stimulates the bone morphogenetic protein (BMP) signaling pathway in vitro and mediates heterotopic ossification (HO) in mouse models of FOP, but primary data from FOP patient cells are lacking. To examine BMP-pSmad1/5/8 pathway signaling and chondro-osseous differentiation in response to endogenous and exogenous Act A in primary connective tissue progenitor cells [CTPCs; also known as stem cells from human exfoliated deciduous teeth (SHED) cells] from patients with FOP. These cells express the common FOP mutation, ACVR1 (R206H). We found that Act A amplifies dysregulated BMP pathway signaling in human FOP primary CTPCs cells through the Smad1/5/8 pathway and induces chondro-osseous differentiation. Amplification of BMP-pSmad1/5/8 signaling was inhibited by Follistatin and by a neutralizing antibody to Activin A. The increased basal pSmad1/5/8 activity, as well as the hypoxia-induced stimulation of FOP CTPCs cells, were BMP4 and Act A independent. Importantly, either BMP4 or Act A stimulated pSmad1/5/8 pathway signaling but BMP4 signaling was not dependent on Activin A and vice versa. Circulating plasma levels of Act A or BMP4 are similar in controls compared to FOP patients, and suggest the potential for an autocrine or paracrine route for pathological signaling. The mutated FOP receptor [ACVR1 (R206H)] is hypersensitive to BMP4 and uniquely sensitive (compared to the wild type receptor) to Act A. Both canonical and non-canonical ligands have a synergistic effect on BMP-pSmad1/5/8 signaling in FOP CTPCs and may cooperate to alter the threshold for HO in FOP. Our findings in primary human FOP CTPCs have important implications for the design of clinical trials to inhibit dysregulated BMP pathway signaling in humans who have FOP

  3. Klotho and activin A in kidney injury: plasma Klotho is maintained in unilateral obstruction despite no upregulation of Klotho biosynthesis in the contralateral kidney.

    PubMed

    Nordholm, Anders; Mace, Maria L; Gravesen, Eva; Hofman-Bang, Jacob; Morevati, Marya; Olgaard, Klaus; Lewin, Ewa

    2018-05-01

    In a new paradigm of etiology related to chronic kidney disease-mineral and bone disorder (CKD-MBD), kidney injury may cause induction of factors in the injured kidney that are released into the circulation and thereby initiate and maintain renal fibrosis and CKD-MBD. Klotho is believed to ameliorate renal fibrosis and CKD-MBD, while activin A might have detrimental effects. The unilateral ureter obstruction (UUO) model is used here to examine this concept by investigating early changes related to renal fibrosis in the obstructed kidney, untouched contralateral kidney, and vasculature which might be affected by secreted factors from the obstructed kidney, and comparing with unilateral nephrectomized controls (UNX). Obstructed kidneys showed early Klotho gene and protein depletion, whereas plasma Klotho increased in both UUO and UNX rats, indicating an altered metabolism of Klotho. Contralateral kidneys had no compensatory upregulation of Klotho and maintained normal expression of the examined fibrosis-related genes, as did remnant UNX kidneys. UUO caused upregulation of transforming growth factor-β and induction of periostin and activin A in obstructed kidneys without changes in the contralateral kidneys. Plasma activin A doubled in UUO rats after 10 days while no changes were seen in UNX rats, suggesting secretion of activin A from the obstructed kidney with potentially systemic effects on CKD-MBD. As such, increased aortic sclerostin was observed in UUO rats compared with UNX and normal controls. The present results are in line with the new paradigm and show very early vascular effects of unilateral kidney fibrosis, supporting the existence of a new kidney-vasculature axis.

  4. MicroRNA-424/503 cluster members regulate bovine granulosa cell proliferation and cell cycle progression by targeting SMAD7 gene through activin signalling pathway.

    PubMed

    Pande, Hari Om; Tesfaye, Dawit; Hoelker, Michael; Gebremedhn, Samuel; Held, Eva; Neuhoff, Christiane; Tholen, Ernst; Schellander, Karl; Wondim, Dessie Salilew

    2018-05-01

    The granulosa cells are indispensable for follicular development and its function is orchestrated by several genes, which in turn posttranscriptionally regulated by microRNAs (miRNA). In our previous study, the miRRNA-424/503 cluster was found to be highly abundant in bovine granulosa cells (bGCs) of preovulatory dominant follicle compared to subordinate counterpart at day 19 of the bovine estrous cycle. Other study also indicated the involvement of miR-424/503 cluster in tumour cell resistance to apoptosis suggesting this miRNA cluster may involve in cell survival. However, the role of miR-424/503 cluster in granulosa cell function remains elusive Therefore, this study aimed to investigate the role of miRNA-424/503 cluster in bGCs function using microRNA gain- and loss-of-function approaches. The role of miR-424/503 cluster members in granulosa cell function was investigated by overexpressing or inhibiting its activity in vitro cultured granulosa cells using miR-424/503 mimic or inhibitor, respectively. Luciferase reporter assay showed that SMAD7 and ACVR2A are the direct targets of the miRNA-424/503 cluster members. In line with this, overexpression of miRNA-424/503 cluster members using its mimic and inhibition of its activity by its inhibitor reduced and increased, respectively the expression of SMAD7 and ACVR2A. Furthermore, flow cytometric analysis indicated that overexpression of miRNA-424/503 cluster members enhanced bGCs proliferation by promoting G1- to S- phase cell cycle transition. Modulation of miRNA-424/503 cluster members tended to increase phosphorylation of SMAD2/3 in the Activin signalling pathway. Moreover, sequence specific knockdown of SMAD7, the target gene of miRNA-424/503 cluster members, using small interfering RNA also revealed similar phenotypic and molecular alterations observed when miRNA-424/503 cluster members were overexpressed. Similarly, to get more insight about the role of miRNA-424/503 cluster members in activin signalling

  5. Atypical Activin A and IL-10 Production Impairs Human CD16+ Monocyte Differentiation into Anti-Inflammatory Macrophages.

    PubMed

    González-Domínguez, Érika; Domínguez-Soto, Ángeles; Nieto, Concha; Flores-Sevilla, José Luis; Pacheco-Blanco, Mariana; Campos-Peña, Victoria; Meraz-Ríos, Marco A; Vega, Miguel A; Corbí, Ángel L; Sánchez-Torres, Carmen

    2016-02-01

    Human CD14(++)CD16(-) and CD14(+/lo)CD16(+) monocyte subsets comprise 85 and 15% of blood monocytes, respectively, and are thought to represent distinct stages in the monocyte differentiation pathway. However, the differentiation fates of both monocyte subsets along the macrophage (Mϕ) lineage have not yet been elucidated. We have now evaluated the potential of CD14(++) CD16(-) and CD16(+) monocytes to differentiate and to be primed toward pro- or anti-inflammatory Mϕs upon culture with GM-CSF or M-CSF, respectively (subsequently referred to as GM14, M14, GM16, or M16). Whereas GM16 and GM14 were phenotypic and functionally analogous, M16 displayed a more proinflammatory profile than did M14. Transcriptomic analyses evidenced that genes associated with M-CSF-driven Mϕ differentiation (including FOLR2, IL10, IGF1, and SERPINB2) are underrepresented in M16 with respect to M14. The preferential proinflammatory skewing of M16 relative to M14 was found to be mediated by the secretion of activin A and the low levels of IL-10 produced by M16. In fact, activin A receptor blockade during the M-CSF-driven differentiation of CD16(+) monocytes, or addition of IL-10-containing M14-conditioned medium, significantly enhanced their expression of anti-inflammatory-associated molecules while impairing their acquisition of proinflammatory-related markers. Thus, we propose that M-CSF drives CD14(++)CD16- monocyte differentiation into bona fide anti-inflammatory Mϕs in a self-autonomous manner, whereas M-CSF-treated CD16(+) monocytes generate Mϕs with a skewed proinflammatory profile by virtue of their high activin A expression unless additional anti-inflammatory stimuli such as IL-10 are provided. Copyright © 2016 by The American Association of Immunologists, Inc.

  6. Activation of platelet-rich plasma using soluble type I collagen.

    PubMed

    Fufa, Duretti; Shealy, Blake; Jacobson, May; Kevy, Sherwin; Murray, Martha M

    2008-04-01

    Platelet-rich plasma (PRP) has recently been found to be a useful delivery system for growth factors important to oral tissue healing. But application of PRP in a liquid form to a wound site within the oral cavity can be complicated by significant loss of the PRP into the surrounding oral space unless gelation through the clotting mechanism is accomplished. Gelation is currently accomplished using bovine thrombin; however, rare but serious complications of this method have led to the search for alternative clotting mechanisms, including the use of soluble collagen as a clotting activator. In this work, our hypothesis was that soluble type I collagen would be as effective as bovine thrombin in causing clotting of the PRP and stimulating growth factor release from the platelets and granulocytes. PRP from human donors was clotted using type I collagen or bovine thrombin. Clot retraction was determined by measuring clot diameters over time. The release of platelet-derived growth factor (PDGF)-AB, transforming growth factor (TGF)-beta1, and vascular endothelial growth factor (VEGF) from both types of clots was measured over 10 days using enzyme-linked immunosorbent assasy. Clots formed using type I collagen exhibited far less retraction than those formed with bovine thrombin. Bovine thrombin and type I collagen stimulated similar release of PDGF-AB and VEGF between 1 and 10 days; however, thrombin activation resulted in a greater release of TGF-beta1 during the first 5 days after activation. The use of type I collagen to activate clotting of PRP may be a safe and effective alternative to bovine thrombin. The use of collagen results in less clot retraction and equal release of PDGF-AB and VEGF compared with currently available methods of clot activation.

  7. ACTIVATION OF PLATELET-RICH PLASMA USING SOLUBLE TYPE I COLLAGEN

    PubMed Central

    Fufa, Duretti; Shealy, Blake; Jacobson, May; Kevy, Sherwin; Murray, Martha M.

    2008-01-01

    PURPOSE Platelet-rich plasma (PRP) has recently been found to be a useful delivery system for growth factors important in oral tissue healing. However, application of PRP in a liquid form to a wound site within the oral cavity can be complicated by significant loss of the PRP into the surrounding oral space unless gelation via the clotting mechanism is accomplished. Gelation is currently accomplished using bovine thrombin; however, rare but serious complications of this method have led to the search for alternative clotting mechanisms, including the use of soluble collagen as a clotting activator. In this paper, our hypothesis was that soluble Type I collagen would be as effective as bovine thrombin in causing clotting of the PRP and of stimulating growth factor release from the platelets and granulocytes. MATERIALS AND METHODS PRP from human donors was clotted using Type I collagen or bovine thrombin. Clot retraction was determined by measuring clot diameters over time. The release of PDGF-AB, TGF-β1 and VEGF from both types of clots was measured over 10 days using ELISA. RESULTS Clots formed using Type I collagen had far less retraction than those formed with bovine thrombin. Bovine thrombin and Type I collagen stimulated similar release of PDGF-AB and VEGF between 1 and 10 days; however, thrombin activation resulted in a greater release of TGF-β1 during the first five days after activation. CONCLUSIONS The use of Type I collagen to activate clotting of PRP may be a safe and effective alternative to bovine thrombin. The use of collagen results in less clot retraction and equal release of PDGF-AB and VEGF when compared to currently available methods of clot activation. PMID:18355591

  8. Systemic Activin signaling independently regulates sugar homeostasis, cellular metabolism, and pH balance in Drosophila melanogaster

    PubMed Central

    Ghosh, Arpan C.; O’Connor, Michael B.

    2014-01-01

    The ability to maintain cellular and physiological metabolic homeostasis is key for the survival of multicellular organisms in changing environmental conditions. However, our understanding of extracellular signaling pathways that modulate metabolic processes remains limited. In this study we show that the Activin-like ligand Dawdle (Daw) is a major regulator of systemic metabolic homeostasis and cellular metabolism in Drosophila. We find that loss of canonical Smad signaling downstream of Daw leads to defects in sugar and systemic pH homeostasis. Although Daw regulates sugar homeostasis by positively influencing insulin release, we find that the effect of Daw on pH balance is independent of its role in insulin signaling and is caused by accumulation of organic acids that are primarily tricarboxylic acid (TCA) cycle intermediates. RNA sequencing reveals that a number of TCA cycle enzymes and nuclear-encoded mitochondrial genes including genes involved in oxidative phosphorylation and β-oxidation are up-regulated in the daw mutants, indicating either a direct or indirect role of Daw in regulating these genes. These findings establish Activin signaling as a major metabolic regulator and uncover a functional link between TGF-β signaling, insulin signaling, and metabolism in Drosophila. PMID:24706779

  9. Learning induces the translin/trax RNase complex to express activin receptors for persistent memory.

    PubMed

    Park, Alan Jung; Havekes, Robbert; Fu, Xiuping; Hansen, Rolf; Tudor, Jennifer C; Peixoto, Lucia; Li, Zhi; Wu, Yen-Ching; Poplawski, Shane G; Baraban, Jay M; Abel, Ted

    2017-09-20

    Long-lasting forms of synaptic plasticity and memory require de novo protein synthesis. Yet, how learning triggers this process to form memory is unclear. Translin/trax is a candidate to drive this learning-induced memory mechanism by suppressing microRNA-mediated translational silencing at activated synapses. We find that mice lacking translin/trax display defects in synaptic tagging, which requires protein synthesis at activated synapses, and long-term memory. Hippocampal samples harvested from these mice following learning show increases in several disease-related microRNAs targeting the activin A receptor type 1C (ACVR1C), a component of the transforming growth factor-β receptor superfamily. Furthermore, the absence of translin/trax abolishes synaptic upregulation of ACVR1C protein after learning. Finally, synaptic tagging and long-term memory deficits in mice lacking translin/trax are mimicked by ACVR1C inhibition. Thus, we define a new memory mechanism by which learning reverses microRNA-mediated silencing of the novel plasticity protein ACVR1C via translin/trax.

  10. Identification and expression of Smads associated with TGF-beta/activin/nodal signaling pathways in the rainbow trout (Oncorhynuchus mykiss)

    USDA-ARS?s Scientific Manuscript database

    The Smad proteins are essential components of the TGF-beta/activin/nodal family signaling pathway. We report the identification and characterization of transcripts representing 3 receptor Smads (Smad2a, Smad2b, Smad3), 2 common Smads (Smad4a, Smad4b) and one inhibitory Smad (Smad7). Phylogenetic an...

  11. The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development.

    PubMed

    Reissmann, E; Jörnvall, H; Blokzijl, A; Andersson, O; Chang, C; Minchiotti, G; Persico, M G; Ibáñez, C F; Brivanlou, A H

    2001-08-01

    Nodal proteins have crucial roles in mesendoderm formation and left-right patterning during vertebrate development. The molecular mechanisms of signal transduction by Nodal and related ligands, however, are not fully understood. In this paper, we present biochemical and functional evidence that the orphan type I serine/threonine kinase receptor ALK7 acts as a receptor for mouse Nodal and Xenopus Nodal-related 1 (Xnr1). Receptor reconstitution experiments indicate that ALK7 collaborates with ActRIIB to confer responsiveness to Xnr1 and Nodal. Both receptors can independently bind Xnr1. In addition, Cripto, an extracellular protein genetically implicated in Nodal signaling, can independently interact with both Xnr1 and ALK7, and its expression greatly enhances the ability of ALK7 and ActRIIB to respond to Nodal ligands. The Activin receptor ALK4 is also able to mediate Nodal signaling but only in the presence of Cripto, with which it can also interact directly. A constitutively activated form of ALK7 mimics the mesendoderm-inducing activity of Xnr1 in Xenopus embryos, whereas a dominant-negative ALK7 specifically blocks the activities of Nodal and Xnr1 but has little effect on other related ligands. In contrast, a dominant-negative ALK4 blocks all mesoderm-inducing ligands tested, including Nodal, Xnr1, Xnr2, Xnr4, and Activin. In agreement with a role in Nodal signaling, ALK7 mRNA is localized to the ectodermal and organizer regions of Xenopus gastrula embryos and is expressed during early stages of mouse embryonic development. Therefore, our results indicate that both ALK4 and ALK7 can mediate signal transduction by Nodal proteins, although ALK7 appears to be a receptor more specifically dedicated to Nodal signaling.

  12. The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development

    PubMed Central

    Reissmann, Eva; Jörnvall, Henrik; Blokzijl, Andries; Andersson, Olov; Chang, Chenbei; Minchiotti, Gabriella; Persico, M. Graziella; Ibáñez, Carlos F.; Brivanlou, Ali H.

    2001-01-01

    Nodal proteins have crucial roles in mesendoderm formation and left–right patterning during vertebrate development. The molecular mechanisms of signal transduction by Nodal and related ligands, however, are not fully understood. In this paper, we present biochemical and functional evidence that the orphan type I serine/threonine kinase receptor ALK7 acts as a receptor for mouse Nodal and Xenopus Nodal-related 1 (Xnr1). Receptor reconstitution experiments indicate that ALK7 collaborates with ActRIIB to confer responsiveness to Xnr1 and Nodal. Both receptors can independently bind Xnr1. In addition, Cripto, an extracellular protein genetically implicated in Nodal signaling, can independently interact with both Xnr1 and ALK7, and its expression greatly enhances the ability of ALK7 and ActRIIB to respond to Nodal ligands. The Activin receptor ALK4 is also able to mediate Nodal signaling but only in the presence of Cripto, with which it can also interact directly. A constitutively activated form of ALK7 mimics the mesendoderm-inducing activity of Xnr1 in Xenopus embryos, whereas a dominant-negative ALK7 specifically blocks the activities of Nodal and Xnr1 but has little effect on other related ligands. In contrast, a dominant-negative ALK4 blocks all mesoderm-inducing ligands tested, including Nodal, Xnr1, Xnr2, Xnr4, and Activin. In agreement with a role in Nodal signaling, ALK7 mRNA is localized to the ectodermal and organizer regions of Xenopus gastrula embryos and is expressed during early stages of mouse embryonic development. Therefore, our results indicate that both ALK4 and ALK7 can mediate signal transduction by Nodal proteins, although ALK7 appears to be a receptor more specifically dedicated to Nodal signaling. PMID:11485994

  13. Heterozygous disruption of activin receptor-like kinase 1 is associated with increased renal fibrosis in a mouse model of obstructive nephropathy.

    PubMed

    Muñoz-Félix, José M; López-Novoa, José M; Martínez-Salgado, Carlos

    2014-02-01

    Tubulointerstitial fibrosis is characterized by an accumulation of extracellular matrix in the renal interstitium, myofibroblast activation, cell infiltration, and tubular cell apoptosis, leading to chronic renal failure. Activin receptor-like kinase 1 (ALK1) is a transforming growth factor-β1 type I receptor with a pivotal role in endothelial proliferation and migration, but its role in the development of renal fibrosis is unknown. To assess this we used the unilateral ureteral obstruction model of tubulointerstitial fibrosis in ALK1 haploinsufficient (ALK1(+/-)) and wild-type mice. After 15 days, there was an increase in extracellular matrix protein expression in the obstructed kidneys from both ALK1(+/+) and ALK1(+/-) mice, but obstructed kidneys from ALK1(+/-) mice showed significantly higher expression of type I collagen than those from wild-type mice. Ureteral obstruction increased kidney myofibroblasts markers (α-smooth muscle actin and S100A4), without differences between mouse genotypes. ALK1 expression was increased after ureteral obstruction, and this increased expression was located in myofibroblasts. Moreover, cultured renal fibroblasts from ALK1(+/-) mice expressed more collagen type I and fibronectin than fibroblasts derived from wild-type mice. Thus, ALK1 modulates obstruction-induced renal fibrosis by increased extracellular matrix synthesis in myofibroblasts, but without differences in myofibroblast number.

  14. The Activin A-Peroxisome Proliferator-Activated Receptor Gamma Axis Contributes to the Transcriptome of GM-CSF-Conditioned Human Macrophages.

    PubMed

    Nieto, Concha; Bragado, Rafael; Municio, Cristina; Sierra-Filardi, Elena; Alonso, Bárbara; Escribese, María M; Domínguez-Andrés, Jorge; Ardavín, Carlos; Castrillo, Antonio; Vega, Miguel A; Puig-Kröger, Amaya; Corbí, Angel L

    2018-01-01

    GM-CSF promotes the functional maturation of lung alveolar macrophages (A-MØ), whose differentiation is dependent on the peroxisome proliferator-activated receptor gamma (PPARγ) transcription factor. In fact, blockade of GM-CSF-initiated signaling or deletion of the PPARγ-encoding gene PPARG leads to functionally defective A-MØ and the onset of pulmonary alveolar proteinosis. In vitro , macrophages generated in the presence of GM-CSF display potent proinflammatory, immunogenic and tumor growth-limiting activities. Since GM-CSF upregulates PPARγ expression, we hypothesized that PPARγ might contribute to the gene signature and functional profile of human GM-CSF-conditioned macrophages. To verify this hypothesis, PPARγ expression and activity was assessed in human monocyte-derived macrophages generated in the presence of GM-CSF [proinflammatory GM-CSF-conditioned human monocyte-derived macrophages (GM-MØ)] or M-CSF (anti-inflammatory M-MØ), as well as in ex vivo isolated human A-MØ. GM-MØ showed higher PPARγ expression than M-MØ, and the expression of PPARγ in GM-MØ was found to largely depend on activin A. Ligand-induced activation of PPARγ also resulted in distinct transcriptional and functional outcomes in GM-MØ and M-MØ. Moreover, and in the absence of exogenous activating ligands, PPARγ knockdown significantly altered the GM-MØ transcriptome, causing a global upregulation of proinflammatory genes and significantly modulating the expression of genes involved in cell proliferation and migration. Similar effects were observed in ex vivo isolated human A-MØ, where PPARγ silencing led to enhanced expression of genes coding for growth factors and chemokines and downregulation of cell surface pathogen receptors. Therefore, PPARγ shapes the transcriptome of GM-CSF-dependent human macrophages ( in vitro derived GM-MØ and ex vivo isolated A-MØ) in the absence of exogenous activating ligands, and its expression is primarily regulated by activin A

  15. Bioinformatic Analysis of Pathogenic Missense Mutations of Activin Receptor Like Kinase 1 Ectodomain

    PubMed Central

    Scotti, Claudia; Olivieri, Carla; Boeri, Laura; Canzonieri, Cecilia; Ornati, Federica; Buscarini, Elisabetta; Pagella, Fabio; Danesino, Cesare

    2011-01-01

    Activin A receptor, type II-like kinase 1 (also called ALK1), is a serine-threonine kinase predominantly expressed on endothelial cells surface. Mutations in its ACVRL1 encoding gene (12q11-14) cause type 2 Hereditary Haemorrhagic Telangiectasia (HHT2), an autosomal dominant multisystem vascular dysplasia. The study of the structural effects of mutations is crucial to understand their pathogenic mechanism. However, while an X-ray structure of ALK1 intracellular domain has recently become available (PDB ID: 3MY0), structure determination of ALK1 ectodomain (ALK1EC) has been elusive so far. We here describe the building of a homology model for ALK1EC, followed by an extensive bioinformatic analysis, based on a set of 38 methods, of the effect of missense mutations at the sequence and structural level. ALK1EC potential interaction mode with its ligand BMP9 was then predicted combining modelling and docking data. The calculated model of the ALK1EC allowed mapping and a preliminary characterization of HHT2 associated mutations. Major structural changes and loss of stability of the protein were predicted for several mutations, while others were found to interfere mainly with binding to BMP9 or other interactors, like Endoglin (CD105), whose encoding ENG gene (9q34) mutations are known to cause type 1 HHT. This study gives a preliminary insight into the potential structure of ALK1EC and into the structural effects of HHT2 associated mutations, which can be useful to predict the potential effect of each single mutation, to devise new biological experiments and to interpret the biological significance of new mutations, private mutations, or non-synonymous polymorphisms. PMID:22028876

  16. Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

    PubMed Central

    Dutta, Dipankar J.; Zameer, Andleeb; Mariani, John N.; Zhang, Jingya; Asp, Linnea; Huynh, Jimmy; Mahase, Sean; Laitman, Benjamin M.; Argaw, Azeb Tadesse; Mitiku, Nesanet; Urbanski, Mateusz; Melendez-Vasquez, Carmen V.; Casaccia, Patrizia; Hayot, Fernand; Bottinger, Erwin P.; Brown, Chester W.; John, Gareth R.

    2014-01-01

    In the embryonic CNS, development of myelin-forming oligodendrocytes is limited by bone morphogenetic proteins, which constitute one arm of the transforming growth factor-β (Tgfβ) family and signal canonically via Smads 1/5/8. Tgfβ ligands and Activins comprise the other arm and signal via Smads 2/3, but their roles in oligodendrocyte development are incompletely characterized. Here, we report that Tgfβ ligands and activin B (ActB) act in concert in the mammalian spinal cord to promote oligodendrocyte generation and myelination. In mouse neural tube, newly specified oligodendrocyte progenitors (OLPs) are first exposed to Tgfβ ligands in isolation, then later in combination with ActB during maturation. In primary OLP cultures, Tgfβ1 and ActB differentially activate canonical Smad3 and non-canonical MAP kinase signaling. Both ligands enhance viability, and Tgfβ1 promotes proliferation while ActB supports maturation. Importantly, co-treatment strongly activates both signaling pathways, producing an additive effect on viability and enhancing both proliferation and differentiation such that mature oligodendrocyte numbers are substantially increased. Co-treatment promotes myelination in OLP-neuron co-cultures, and maturing oligodendrocytes in spinal cord white matter display strong Smad3 and MAP kinase activation. In spinal cords of ActB-deficient Inhbb−/− embryos, apoptosis in the oligodendrocyte lineage is increased and OLP numbers transiently reduced, but numbers, maturation and myelination recover during the first postnatal week. Smad3−/− mice display a more severe phenotype, including diminished viability and proliferation, persistently reduced mature and immature cell numbers, and delayed myelination. Collectively, these findings suggest that, in mammalian spinal cord, Tgfβ ligands and ActB together support oligodendrocyte development and myelin formation. PMID:24917498

  17. Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination.

    PubMed

    Dutta, Dipankar J; Zameer, Andleeb; Mariani, John N; Zhang, Jingya; Asp, Linnea; Huynh, Jimmy; Mahase, Sean; Laitman, Benjamin M; Argaw, Azeb Tadesse; Mitiku, Nesanet; Urbanski, Mateusz; Melendez-Vasquez, Carmen V; Casaccia, Patrizia; Hayot, Fernand; Bottinger, Erwin P; Brown, Chester W; John, Gareth R

    2014-06-01

    In the embryonic CNS, development of myelin-forming oligodendrocytes is limited by bone morphogenetic proteins, which constitute one arm of the transforming growth factor-β (Tgfβ) family and signal canonically via Smads 1/5/8. Tgfβ ligands and Activins comprise the other arm and signal via Smads 2/3, but their roles in oligodendrocyte development are incompletely characterized. Here, we report that Tgfβ ligands and activin B (ActB) act in concert in the mammalian spinal cord to promote oligodendrocyte generation and myelination. In mouse neural tube, newly specified oligodendrocyte progenitors (OLPs) are first exposed to Tgfβ ligands in isolation, then later in combination with ActB during maturation. In primary OLP cultures, Tgfβ1 and ActB differentially activate canonical Smad3 and non-canonical MAP kinase signaling. Both ligands enhance viability, and Tgfβ1 promotes proliferation while ActB supports maturation. Importantly, co-treatment strongly activates both signaling pathways, producing an additive effect on viability and enhancing both proliferation and differentiation such that mature oligodendrocyte numbers are substantially increased. Co-treatment promotes myelination in OLP-neuron co-cultures, and maturing oligodendrocytes in spinal cord white matter display strong Smad3 and MAP kinase activation. In spinal cords of ActB-deficient Inhbb(-/-) embryos, apoptosis in the oligodendrocyte lineage is increased and OLP numbers transiently reduced, but numbers, maturation and myelination recover during the first postnatal week. Smad3(-/-) mice display a more severe phenotype, including diminished viability and proliferation, persistently reduced mature and immature cell numbers, and delayed myelination. Collectively, these findings suggest that, in mammalian spinal cord, Tgfβ ligands and ActB together support oligodendrocyte development and myelin formation. © 2014. Published by The Company of Biologists Ltd.

  18. Platelet-rich plasma-induced feedback inhibition of activin A/follistatin signaling: A mechanism for tumor-low risk skin rejuvenation in irradiated rats.

    PubMed

    Omar, Nesreen Nabil; Rashed, Rasha R; El-Hazek, Rania M; El-Sabbagh, Walaa A; Rashed, Engy R; El-Ghazaly, Mona A

    2018-03-01

    Platelet-rich plasma (PRP) is a source of natural growth factors and is emerging as a treatment modality to mitigate radiotherapy- induced adverse effects. Activin A (ACTA) is a member of the transforming growth factor-β (TGF-β) superfamily, which has been shown to modulate the inflammatory response and macrophages polarization between different phenotypes. The aim of this study is to determine the value of PRP in preventing radiation-induced malignancies in light of the cross-talk between PRP and activin A type II receptors (ActR-IIA)/follistatin (FST) signaling pathways where the inflammatory responses at 2 different time points were evaluated. Male albino rats were exposed to radiation and given PRP over the course of 6 days. Rats were sacrificed on day 7 or day 28 post radiation. Quantitative real-time reverse transcriptase polymerase chain reaction (QRT-PCR) and western-blot showed that after 7 days of administrating of PRP, ActR-IIA/FST signaling was markedly induced and was associated with the expressions of inflammatory, natural killer and M1 macrophages markers, TNF-α, IL-1β, IFN-γ and IL-12. By contrast, on day 28 of PRP administration, ActR-IIA/FST signaling and the expressions of proinflammatory cytokines were downregulated in parallel with inducing M2 macrophages phenotype as indicated by arginase-1, IL-10 and dectin-1. The suppression of inflammation and induction of M2 macrophages phenotype in response to PRP administration were found significantly linked to ActR-IIA/FST signaling downregulation. Furthermore, the specific M2 macrophage subtype was found to express dectin-1 receptors which have high affinity for tumor cells thereby is expected to reduce the potential for developing tumors after radiotherapy. Copyright © 2018 Elsevier B.V. All rights reserved.

  19. Activin receptor inhibition by Smad2 regulates Drosophila wing disc patterning through BMP-response elements

    PubMed Central

    Peterson, Aidan J.; O'Connor, Michael B.

    2013-01-01

    Imaginal disc development in Drosophila requires coordinated cellular proliferation and tissue patterning. In our studies of TGFβ superfamily signaling components, we found that a protein null mutation of Smad2, the only Activin subfamily R-Smad in the fruit fly, produces overgrown wing discs that resemble gain of function for BMP subfamily signaling. The wing discs are expanded specifically along the anterior-posterior axis, with increased proliferation in lateral regions. The morphological defect is not observed in mutants for the TGFβ receptor baboon, and epistasis tests showed that baboon is epistatic to Smad2 for disc overgrowth. Rescue experiments indicate that Baboon binding, but not canonical transcription factor activity, of Smad2 is required for normal disc growth. Smad2 mutant discs generate a P-Mad stripe that is narrower and sharper than the normal gradient, and activation targets are correspondingly expressed in narrowed domains. Repression targets of P-Mad are profoundly mis-regulated, with brinker and pentagone reporter expression eliminated in Smad2 mutants. Loss of expression requires a silencer element previously shown to be controlled by BMP signaling. Epistasis experiments show that Baboon, Mad and Schnurri are required to mediate the ectopic silencer output in the absence of Smad2. Taken together, our results show that loss of Smad2 permits promiscuous Baboon activity, which represses genes subject to control by Mad-dependent silencer elements. The absence of Brinker and Pentagone in Smad2 mutants explains the compound wing disc phenotype. Our results highlight the physiological relevance of substrate inhibition of a kinase, and reveal a novel interplay between the Activin and BMP pathways. PMID:23293296

  20. Angiomodulin is required for cardiogenesis of embryonic stem cells and is maintained by a feedback loop network of p63 and Activin-A.

    PubMed

    Wolchinsky, Zohar; Shivtiel, Shoham; Kouwenhoven, Evelyn Nathalie; Putin, Daria; Sprecher, Eli; Zhou, Huiqing; Rouleau, Matthieu; Aberdam, Daniel

    2014-01-01

    The transcription factor p63, member of the p53 gene family, encodes for two main isoforms, TAp63 and ΔNp63 with distinct functions on epithelial homeostasis and cancer. Recently, we discovered that TAp63 is essential for in vitro cardiogenesis and heart development in vivo. TAp63 is expressed by embryonic endoderm and acts on cardiac progenitors by a cell-non-autonomous manner. In the present study, we search for cardiogenic secreted factors that could be regulated by TAp63 and, by ChIP-seq analysis, identified Angiomodulin (AGM), also named IGFBP7 or IGFBP-rP1. We demonstrate that AGM is necessary for cardiac commitment of embryonic stem cells (ESCs) and its regulation depends on TAp63 isoform. TAp63 directly activates both AGM and Activin-A during ESC cardiogenesis while these secreted factors modulate TAp63 gene expression by a feedback loop mechanism. The molecular circuitry controlled by TAp63 on AGM/Activin-A signaling pathway and thus on cardiogenesis emphasizes the importance of p63 during early cardiac development. © 2013.

  1. Strategies to overcome pH-dependent solubility of weakly basic drugs by using different types of alginates.

    PubMed

    Gutsche, S; Krause, M; Kranz, H

    2008-12-01

    Weakly basic drugs demonstrate higher solubility at lower pH, thus often leading to faster drug release at lower pH. The objective of this study was to achieve pH-independent release of weakly basic drugs from extended release formulations based on the naturally occurring polymer sodium alginate. Three approaches to overcome the pH-dependent solubility of the weakly basic model drug verapamil hydrochloride were investigated. First, matrix tablets were prepared by direct compression of drug substance with different types of sodium alginate only. Second, pH-modifiers were added to the drug/alginate matrix systems. Third, press-coated tablets consisting of an inner pH-modifier tablet core and an outer drug/sodium alginate coat were prepared. pH-Independent drug release was achieved from matrix tablets consisting of selected alginates and drug substance only. Alginates are better soluble at higher pH. Therefore, they are able to compensate the poor solubility of weakly basic drugs at higher pH as the matrix of the tablets dissolves faster. This approach was successful when using alginates that demonstrated fast hydration and erosion at higher pH. The approach failed for alginates with less-pronounced erosion at higher pH. The addition of fumaric acid to drug/alginate-based matrix systems decreased the microenvironmental pH within the tablets thus increasing the solubility of the weakly basic drug at higher pH. Therefore, pH-independent drug release was achieved irrespective of the type of alginate used. Drug release from press-coated tablets did not provide any further advantages as compound release remained pH-dependent.

  2. [Molecular cloning of the DNA sequence of activin beta A subunit gene mature peptides from panda and related species and its application in the research of phylogeny and taxonomy].

    PubMed

    Wang, Xiao-Jing; Wang, Xiao-Xing; Wang, Ya-Jun; Wang, Xi-Zhong; He, Guang-Xin; Chen, Hong-Wei; Fei, Li-Song

    2002-09-01

    Activin, which is included in the transforming growth factor-beta (TGF beta) superfamily of proteins and receptors, is known to have broad-ranging effects in the creatures. The mature peptide of beta A subunit of this gene, one of the most highly conserved sequence, can elevate the basal secretion of follicle-stimulating hormone (FSH) in the pituitary and FSH is pivotal to organism's reproduction. Reproduction block is one of the main reasons which cause giant panda to extinct. The sequence of Activin beta A subunit gene mature peptides has been successfully amplified from giant panda, red panda and malayan sun bear's genomic DNA by using polymerase chain reaction (PCR) with a pair of degenerate primers. The PCR products were cloned into the vector pBlueScript+ of Esherichia coli. Sequence analysis of Activin beta A subunit gene mature peptides shows that the length of this gene segment is the same (359 bp) and there is no intron in all three species. The sequence encodes a peptide of 119 amino acid residues. The homology comparison demonstrates 93.9% DNA homology and 99% homology in amino acid among these three species. Both GenBank blast search result and restriction enzyme map reveal that the sequences of Activin beta A subunit gene mature peptides of different species are highly conserved during the evolution process. Phylogeny analysis is performed with PHYLIP software package. A consistent phylogeny tree has been drawn with three different methods. The software analysis outcome accords with the academic view that giant panda has a closer relationship to the malayan sun bear than the red panda. Giant panda should be grouped into the bear family (Uersidae) with the malayan sun bear. As to the red panda, it would be better that this animal be grouped into the unique family (red panda family) because of great difference between the red panda and the bears (Uersidae).

  3. Hanging drop cultures of human testis and testis cancer samples: a model used to investigate activin treatment effects in a preserved niche.

    PubMed

    Jørgensen, A; Young, J; Nielsen, J E; Joensen, U N; Toft, B G; Rajpert-De Meyts, E; Loveland, K L

    2014-05-13

    Testicular germ cell tumours of young adults, seminoma or non-seminomas, are preceded by a pre-invasive precursor, carcinoma in situ (CIS), understood to arise through differentiation arrest of embryonic germ cells. Knowledge about the malignant transformation of germ cells is currently limited by the lack of experimental models. The aim of this study was to establish an experimental tissue culture model to maintain normal and malignant germ cells within their niche and allow investigation of treatment effects. Human testis and testis cancer specimens from orchidectomies were cultured in 'hanging drops' and effects of activin A and follistatin treatment were investigated in seminoma cultures. Testis fragments with normal spermatogenesis or CIS cells were cultured for 14 days with sustained proliferation of germ cells and CIS cells and without increased apoptosis. Seminoma cultures survived 7 days, with proliferating cells detectable during the first 5 days. Activin A treatment significantly reduced KIT transcript and protein levels in seminoma cultures, thereby demonstrating a specific treatment response. Hanging drop cultures of human testis and testis cancer samples can be employed to delineate mechanisms governing growth of normal, CIS and tumorigenic germ cells retained within their niche.

  4. Hanging drop cultures of human testis and testis cancer samples: a model used to investigate activin treatment effects in a preserved niche

    PubMed Central

    Jørgensen, A; Young, J; Nielsen, J E; Joensen, U N; Toft, B G; Rajpert-De Meyts, E; Loveland, K L

    2014-01-01

    Background: Testicular germ cell tumours of young adults, seminoma or non-seminomas, are preceded by a pre-invasive precursor, carcinoma in situ (CIS), understood to arise through differentiation arrest of embryonic germ cells. Knowledge about the malignant transformation of germ cells is currently limited by the lack of experimental models. The aim of this study was to establish an experimental tissue culture model to maintain normal and malignant germ cells within their niche and allow investigation of treatment effects. Methods: Human testis and testis cancer specimens from orchidectomies were cultured in ‘hanging drops' and effects of activin A and follistatin treatment were investigated in seminoma cultures. Results: Testis fragments with normal spermatogenesis or CIS cells were cultured for 14 days with sustained proliferation of germ cells and CIS cells and without increased apoptosis. Seminoma cultures survived 7 days, with proliferating cells detectable during the first 5 days. Activin A treatment significantly reduced KIT transcript and protein levels in seminoma cultures, thereby demonstrating a specific treatment response. Conclusions: Hanging drop cultures of human testis and testis cancer samples can be employed to delineate mechanisms governing growth of normal, CIS and tumorigenic germ cells retained within their niche. PMID:24781282

  5. FZD4S, a splicing variant of frizzled-4, encodes a soluble-type positive regulator of the WNT signaling pathway.

    PubMed

    Sagara, N; Kirikoshi, H; Terasaki, H; Yasuhiko, Y; Toda, G; Shiokawa, K; Katoh, M

    2001-04-06

    Frizzled-1 (FZD1)-FZD10 are seven-transmembrane-type WNT receptors, and SFRP1-SFRP5 are soluble-type WNT antagonists. These molecules are encoded by mutually distinct genes. We have previously isolated and characterized the 7.7-kb FZD4 mRNA, encoding a seven-transmembrane receptor with the extracellular cysteine-rich domain (CRD). Here, we have cloned and characterized FZD4S, a splicing variant of the FZD4 gene. FZD4S, corresponding to the 10.0-kb FZD4 mRNA, consisted of exon 1, intron 1, and exon 2 of the FZD4 gene. FZD4S encoded a soluble-type polypeptide with the N-terminal part of CRD, and was expressed in human fetal kidney. Injection of synthetic FZD4S mRNA into the ventral marginal zone of Xenopus embryos at the 4-cell stage did not induce axis duplication by itself, but augmented the axis duplication potential of coinjected Xwnt-8 mRNA. These results indicate that the FZD4 gene gives rise to soluble-type FZD4S as well as seven-transmembrane-type FZD4 due to alternative splicing, and strongly suggest that FZD4S plays a role as a positive regulator of the WNT signaling pathway. Copyright 2001 Academic Press.

  6. Inhibin/activin-betaC and -betaE subunits in the Ishikawa human endometrial adenocarcinoma cell line.

    PubMed

    Kimmich, Tanja; Brüning, Ansgar; Käufl, Stephanie D; Makovitzky, Josef; Kuhn, Christina; Jeschke, Udo; Friese, Klaus; Mylonas, Ioannis

    2010-08-01

    Inhibins and activins are important regulators of the female reproductive system. Recently, two novel inhibin subunits, named betaC and betaE, have been identified and shown to be expressed in several human tissues. However, only limited data on the expression of these novel inhibin subunits in normal human endometrial tissue and endometrial adenocarcinoma cell lines exist. Samples of proliferative and secretory human endometrium were obtained from five premenopausal, non-pregnant patients undergoing gynecological surgery for benign diseases. Normal endometrial tissue and Ishikawa endometrial adenocarcinoma cell lines were analyzed by immunohistochemistry, immunofluorescence and RT-PCR. Expression of the inhibin betaC and betaE subunits could be demonstrated at the protein level by means of immunohistochemical evaluation and at the transcriptional level by establishing a betaC- and betaE-specific RT-PCR analysis in normal human endometrial tissue and the parental Ishikawa cell line. Interestingly, in a highly de-differentiated subclone of the Ishikawa cell line lacking estrogen receptor expression, the expression of the inhibin-betaC subunit appeared strongly reduced. Here, we show for the first time that the novel inhibin/activin-betaC and -betaE subunits are expressed in normal human endometrium and the estrogen receptor positive human endometrial carcinoma cell line Ishikawa using RT-PCR and immunohistochemical detection methods. Interestingly, the Ishikawa minus cell line (lacking estrogen receptor expression) demonstrated no to minimal expression of the betaC subunit as observed with immunofluorescence and RT-PCR, suggesting a possible hormone- dependency of this subunit in human endometrial cancer cells. Moreover, because the Ishikawa cell line minus is thought to be a more malignant endometrial cell line than its estrogen receptor positive counterpart, inhibin-betaC subunit might be substantially involved in the pathogenesis and malignant transformation in

  7. Fabrication and optical nonlinearities of composite films derived from the water-soluble Keplerate-type polyoxometalate and chloroform-soluble porphyrin.

    PubMed

    Shi, Zonghai; Zhou, Yunshan; Zhang, Lijuan; Yang, Di; Mu, Cuncun; Ren, Haizhou; Shehzad, Farooq Khurum; Li, Jiaqi

    2015-03-07

    Composite films derived from the water-soluble Keplerate-type polyoxometalate (NH4)42[Mo132O372(CH3COO)30(H2O)72]·ca. 300H2O·ca. 10CH3COONH4 (denoted (NH4)42{Mo132}) and chloroform-soluble tetraphenylporphyrin perchlorate [H2TPP](ClO4)2 are successfully fabricated by a layer-by-layer self-assembly method and characterized by UV-vis spectroscopy and X-ray photoelectron spectroscopy (XPS). The structure of the {Mo132} and [H2TPP](2+) in the films remain intact in light of the results of UV-vis spectroscopy and XPS. UV-vis spectra measurements reveal that the amounts of deposition of {Mo132} and [H2TPP](2+) remain constant in every adsorption cycle in the composite films assembly process. Nonlinear optical properties of the composite films have been investigated by using the Z-scan technique at a wavelength of 532 nm and pulse width of 7 ns. The results show that the composite films have notable nonlinear saturated absorption and self-defocusing effects. The combination of {Mo132} with [H2TPP](2+) can result in composite films with remarkably enhanced optical nonlinearities. The interfacial charge transfer induced by laser from porphyrin to POM in the films is thought to play a key role in the enhancement of NLO response. The third-order NLO susceptibility χ((3)) of the composite films increases with the increase of film thickness.

  8. Humidity effects on soluble core mechanical and thermal properties (polyvinyl alcohol/microballoon composite) type CG extendospheres, volume 2

    NASA Technical Reports Server (NTRS)

    1993-01-01

    This document constitutes the final report for the study of humidity effects and loading rate on soluble core (PVA/MB composite material) mechanical and thermal properties under Contract No. 100345. This report describes test results procedures employed, and any unusual occurrences or specific observations associated with this test program. The primary objective of this work was to determine if cured soluble core filler material regains its tensile and compressive strength after exposure to high humidity conditions and following a drying cycle. Secondary objectives include measurements of tensile and compressive modulus, and Poisson's ratio, and coefficient of thermal expansion (CTE) for various moisture exposure states. A third objective was to compare the mechanical and thermal properties of the composite using 'SG' and 'CG' type extendospheres. The proposed facility for the manufacture of soluble cores at the Yellow Creek site incorporates no capability for the control of humidity. Recent physical property tests performed with the soluble core filler material showed that prolonged exposure to high humidity significantly degradates in strength. The purpose of these tests is to determine if the product, process or facility designs require modification to avoid imparting a high risk condition to the ASRM.

  9. Water-soluble dietary fibers and cardiovascular disease.

    PubMed

    Theuwissen, Elke; Mensink, Ronald P

    2008-05-23

    One well-established way to reduce the risk of developing cardiovascular disease (CVD) is to lower serum LDL cholesterol levels by reducing saturated fat intake. However, the importance of other dietary approaches, such as increasing the intake of water-soluble dietary fibers is increasingly recognized. Well-controlled intervention studies have now shown that four major water-soluble fiber types-beta-glucan, psyllium, pectin and guar gum-effectively lower serum LDL cholesterol concentrations, without affecting HDL cholesterol or triacylglycerol concentrations. It is estimated that for each additional gram of water-soluble fiber in the diet serum total and LDL cholesterol concentrations decrease by -0.028 mmol/L and -0.029 mmol/L, respectively. Despite large differences in molecular structure, no major differences existed between the different types of water-soluble fiber, suggesting a common underlying mechanism. In this respect, it is most likely that water-soluble fibers lower the (re)absorption of in particular bile acids. As a result hepatic conversion of cholesterol into bile acids increases, which will ultimately lead to increased LDL uptake by the liver. Additionally, epidemiological studies suggest that a diet high in water-soluble fiber is inversely associated with the risk of CVD. These findings underlie current dietary recommendations to increase water-soluble fiber intake.

  10. R7 Photoreceptor Axon Growth Is Temporally Controlled by the Transcription Factor Ttk69, Which Inhibits Growth in Part by Promoting Transforming Growth Factor-β/Activin Signaling

    PubMed Central

    Kniss, Jonathan S.; Holbrook, Scott

    2013-01-01

    Work on axon growth has classically focused on understanding how extrinsic cues control growth cone dynamics independent of the cell body. However, more recently, neuron-intrinsic transcription factors have been shown to influence both normal and regenerative axon growth, suggesting that understanding their mechanism of action is of clinical importance. We are studying axon targeting in the Drosophila visual system and here show that the BTB/POZ zinc-finger transcription factor Tramtrack69 (Ttk69) plays an instructive role in inhibiting the growth of R7 photoreceptor axon terminals. Although ttk69 mutant R7 axons project to the correct medullar target layer, M6, their terminals fail to remain retinotopically restricted and instead grow laterally within M6. This overgrowth is not caused by an inability to be repelled by neighboring R7 axons or by an inability to recognize and initiate synapse formation with postsynaptic targets. The overgrowth is progressive and occurs even if contact between ttk69 mutant R7 axons and their normal target layer is disrupted. Ttk69 is first expressed in wild-type R7s after their axons have reached the medulla; ttk69 mutant R7 axon terminal overgrowth begins shortly after this time point. We find that expressing Ttk69 prematurely in R7s collapses their growth cones and disrupts axon extension, indicating that Ttk69 plays an instructive role in this process. A TGF-β/Activin pathway was shown previously to inhibit R7 axon terminal growth. We find that Ttk69 is required for normal activation of this pathway but that Ttk69 likely also inhibits R7 axon growth by a TGF-β/Activin-independent mechanism. PMID:23345225

  11. Activin Decoy Receptor ActRIIB:Fc Lowers FSH and Therapeutically Restores Oocyte Yield, Prevents Oocyte Chromosome Misalignments and Spindle Aberrations, and Increases Fertility in Midlife Female SAMP8 Mice.

    PubMed

    Bernstein, Lori R; Mackenzie, Amelia C L; Lee, Se-Jin; Chaffin, Charles L; Merchenthaler, István

    2016-03-01

    Women of advanced maternal age (AMA) (age ≥ 35) have increased rates of infertility, miscarriages, and trisomic pregnancies. Collectively these conditions are called "egg infertility." A root cause of egg infertility is increased rates of oocyte aneuploidy with age. AMA women often have elevated endogenous FSH. Female senescence-accelerated mouse-prone-8 (SAMP8) has increased rates of oocyte spindle aberrations, diminished fertility, and rising endogenous FSH with age. We hypothesize that elevated FSH during the oocyte's FSH-responsive growth period is a cause of abnormalities in the meiotic spindle. We report that eggs from SAMP8 mice treated with equine chorionic gonadotropin (eCG) for the period of oocyte growth have increased chromosome and spindle misalignments. Activin is a molecule that raises FSH, and ActRIIB:Fc is an activin decoy receptor that binds and sequesters activin. We report that ActRIIB:Fc treatment of midlife SAMP8 mice for the duration of oocyte growth lowers FSH, prevents egg chromosome and spindle misalignments, and increases litter sizes. AMA patients can also have poor responsiveness to FSH stimulation. We report that although eCG lowers yields of viable oocytes, ActRIIB:Fc increases yields of viable oocytes. ActRIIB:Fc and eCG cotreatment markedly reduces yields of viable oocytes. These data are consistent with the hypothesis that elevated FSH contributes to egg aneuploidy, declining fertility, and poor ovarian response and that ActRIIB:Fc can prevent egg aneuploidy, increase fertility, and improve ovarian response. Future studies will continue to examine whether ActRIIB:Fc works via FSH and/or other pathways and whether ActRIIB:Fc can prevent aneuploidy, increase fertility, and improve stimulation responsiveness in AMA women.

  12. Circulating irisin levels are lower in patients with either stable coronary artery disease (CAD) or myocardial infarction (MI) versus healthy controls, whereas follistatin and activin A levels are higher and can discriminate MI from CAD with similar to CK-MB accuracy.

    PubMed

    Anastasilakis, Athanasios D; Koulaxis, Dimitrios; Kefala, Nikoleta; Polyzos, Stergios A; Upadhyay, Jagriti; Pagkalidou, Eirini; Economou, Fotios; Anastasilakis, Chrysostomos D; Mantzoros, Christos S

    2017-08-01

    Several myokines are produced by cardiac muscle. We investigated changes in myokine levels at the time of acute myocardial infarction (MI) and following reperfusion in relation to controls. Patients with MI (MI Group, n=31) treated with percutaneous coronary intervention (PCI) were compared to patients with stable coronary artery disease (CAD) subjected to scheduled PCI (CAD Group, n=40) and controls with symptoms mimicking CAD without stenosis in angiography (Control Group, n=43). The number and degree of stenosis were recorded. Irisin, follistatin, follistatin-like 3, activin A and B, ALT, AST, CK and CK-MB were measured at baseline and 6 or 24h after the intervention. MI and CAD patients had lower irisin than controls (p<0.001). MI patients had higher follistatin, activin A, CK, CK-MB and AST than CAD patients and controls (all p≤0.001). None of the myokines changed following reperfusion. Circulating irisin was associated with the degree of stenosis in all patients (p=0.05). Irisin was not inferior to CK-MB in predicting MI while folistatin and activin A could discriminate MI from CAD patients with similar to CK-MB accuracy. None of these myokines was altered following PCI in contrast to CK-MB. Irisin levels are lower in MI and CAD implying that their production may depend on myocadial blood supply. Follistatin and activin A are higher in MI than in CAD suggesting increased release due to myocardial necrosis. They can predict MI with accuracy similar to CK-MB and their role in the diagnosis of MI remains to be confirmed by prospective large clinical studies. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Solubility of 238U radionuclide from various types of soil in synthetic gastrointestinal fluids using "US in vitro" digestion method

    NASA Astrophysics Data System (ADS)

    Rashid, Nur Shahidah Abdul; Sarmani, Sukiman; Majid, Amran Ab.; Mohamed, Faizal; Siong, Khoo Kok

    2015-04-01

    238U radionuclide is a naturally occuring radioactive material that can be found in soil. In this study, the solubility of 238U radionuclide obtained from various types of soil in synthetic gastrointestinal fluids was analysed by "US P in vitro" digestion method. The synthetic gastrointestinal fluids were added to the samples with well-ordered, mixed throughly and incubated according to the human physiology digestive system. The concentration of 238U radionuclide in the solutions extracted from the soil was measured using Induced Coupling Plasma Mass Spectrometer (ICP-MS). The concentration of 238U radionuclide from the soil samples in synthetic gastrointestinal fluids showed different values due to different homogenity of soil types and chemical reaction of 238U radionuclide. In general, the solubility of 238U radionuclide in gastric fluid was higher (0.050 - 0.209 ppm) than gastrointestinal fluids (0.024 - 0.050 ppm). It could be concluded that the US P in vitro digestion method is practicle for estimating the solubility of 238U radionuclide from soil materials and could be useful for monitoring and risk assessment purposes applying to environmental, health and contaminated soil samples.

  14. Method for enhancing the solubility of dopants in silicon

    DOEpatents

    Sadigh, Babak; Lenosky, Thomas J.; De La Rubia, Tomas Diaz

    2003-09-30

    A method for enhancing the equilibrium solid solubility of dopants in silicon, germanium and silicon-germanium alloys. The method involves subjecting silicon-based substrate to biaxial or compression strain. It has been determined that boron solubility was largely enhanced (more than 100%) by a compressive bi-axial strain, based on a size-mismatch theory since the boron atoms are smaller than the silicon atoms. It has been found that the large enhancement or mixing properties of dopants in silicon and germanium substrates is primarily governed by their, and to second order by their size-mismatch with the substrate. Further, it has been determined that the dopant solubility enhancement with strain is most effective when the charge and the size-mismatch of the impurity favor the same type of strain. Thus, the solid solubility of small p-type (e.g., boron) as well as large n-type (e.g., arsenic) dopants can be raised most dramatically by appropriate bi-axial (compressive) strain, and that solubility of a large p-type dopant (e.g, indium) in silicon will be raised due to size-mismatch with silicon, which favors tensile strain, while its negative charge prefers compressive strain, and thus the two effects counteract each other.

  15. Uterine activin receptor-like kinase 5 is crucial for blastocyst implantation and placental development

    PubMed Central

    Peng, Jia; Monsivais, Diana; You, Ran; Zhong, Hua; Pangas, Stephanie A.; Matzuk, Martin M.

    2015-01-01

    Members of the transforming growth factor β (TGF-β) superfamily are key regulators in most developmental and physiological processes. However, the in vivo roles of TGF-β signaling in female reproduction remain uncertain. Activin receptor-like kinase 5 (ALK5) is the major type 1 receptor for the TGF-β subfamily. Absence of ALK5 leads to early embryonic lethality because of severe defects in vascular development. In this study, we conditionally ablated uterine ALK5 using progesterone receptor-cre mice to define the physiological roles of ALK5 in female reproduction. Despite normal ovarian functions and artificial decidualization in conditional knockout (cKO) mice, absence of uterine ALK5 resulted in substantially reduced female reproduction due to abnormalities observed at different stages of pregnancy, including implantation defects, disorganization of trophoblast cells, fewer uterine natural killer (uNK) cells, and impairment of spiral artery remodeling. In our microarray analysis, genes encoding proteins involved in cytokine–cytokine receptor interactions and NK cell-mediated cytotoxicity were down-regulated in cKO decidua compared with control decidua. Flow cytometry confirmed a 10-fold decrease in uNK cells in cKO versus control decidua. According to these data, we hypothesize that TGF-β acts on decidual cells via ALK5 to induce expression of other growth factors and cytokines, which are key regulators in luminal epithelium proliferation, trophoblast development, and uNK maturation during pregnancy. Our findings not only generate a mouse model to study TGF-β signaling in female reproduction but also shed light on the pathogenesis of many pregnancy complications in human, such as recurrent spontaneous abortion, preeclampsia, and intrauterine growth restriction. PMID:26305969

  16. Cytokine-like factor-1, a novel soluble protein, shares homology with members of the cytokine type I receptor family.

    PubMed

    Elson, G C; Graber, P; Losberger, C; Herren, S; Gretener, D; Menoud, L N; Wells, T N; Kosco-Vilbois, M H; Gauchat, J F

    1998-08-01

    In this report we describe the identification, cloning, and expression pattern of human cytokine-like factor 1 (hCLF-1) and the identification and cloning of its murine homologue. They were identified from expressed sequence tags using amino acid sequences from conserved regions of the cytokine type I receptor family. Human CLF-1 and murine CLF-1 shared 96% amino acid identity and significant homology with many cytokine type I receptors. CLF-1 is a secreted protein, suggesting that it is either a soluble subunit within a cytokine receptor complex, like the soluble form of the IL-6R alpha-chain, or a subunit of a multimeric cytokine, e.g., IL-12 p40. The highest levels of hCLF-1 mRNA were observed in lymph node, spleen, thymus, appendix, placenta, stomach, bone marrow, and fetal lung, with constitutive expression of CLF-1 mRNA detected in a human kidney fibroblastic cell line. In fibroblast primary cell cultures, CLF-1 mRNA was up-regulated by TNF-alpha, IL-6, and IFN-gamma. Western blot analysis of recombinant forms of hCLF-1 showed that the protein has the tendency to form covalently linked di- and tetramers. These results suggest that CLF-1 is a novel soluble cytokine receptor subunit or part of a novel cytokine complex, possibly playing a regulatory role in the immune system and during fetal development.

  17. Analysis of chemical concepts as the basic of virtual laboratory development and process science skills in solubility and solubility product subject

    NASA Astrophysics Data System (ADS)

    Syafrina, R.; Rohman, I.; Yuliani, G.

    2018-05-01

    This study aims to analyze the concept characteristics of solubility and solubility products that will serve as the basis for the development of virtual laboratory and students' science process skills. Characteristics of the analyzed concepts include concept definitions, concept attributes, and types of concepts. The concept analysis method uses concept analysis according to Herron. The results of the concept analysis show that there are twelve chemical concepts that become the prerequisite concept before studying the solubility and solubility and five core concepts that students must understand in the solubility and Solubility product. As many as 58.3% of the definitions of the concepts contained in high school textbooks support students' science process skills, the rest of the definition of the concept is memorized. Concept attributes that meet three levels of chemical representation and can be poured into a virtual laboratory have a percentage of 66.6%. Type of concept, 83.3% is a concept based on principle; and 16.6% concepts that state the process. Meanwhile, the science process skills that can be developed based on concept analysis are the ability to observe, calculate, measure, predict, interpret, hypothesize, apply, classify, and inference.

  18. Effect of hydrotalcite-like compounds on the aqueous solubility of some poorly water-soluble drugs.

    PubMed

    Ambrogi, Valeria; Fardella, Giuseppe; Grandolini, Giuliano; Nocchetti, Morena; Perioli, Luana

    2003-07-01

    A new approach of improving drug dissolution properties is described. This method exploits the property of a carrier owing to the hydrotalcite-type anionic clays (HTlc). HTlc is an inorganic layered solid that lodges anionic compounds among its layers. As HTlc dissolves at acidic pH values (pH < 4), the anions intercalated among the layers are promptly released in the medium. In this article some nonsteroidal antiinflammatory drugs were chosen as models of poorly water-soluble drugs. They were intercalated in HTlc and solubility measurements in acidic medium were performed. A remarkable improvement of drug solubility was observed especially in the case of indomethacin. Copyright 2003 Wiley-Liss, Inc. and the American Pharmacists Association

  19. TGFβ Superfamily Members Mediate Androgen Deprivation Therapy-Induced Obese Frailty in Male Mice

    PubMed Central

    Pan, Chunliu; Singh, Shalini; Sahasrabudhe, Deepak M.; Chakkalakal, Joe V.; Krolewski, John J.

    2016-01-01

    First line treatment for recurrent and metastatic prostate cancer is androgen deprivation therapy (ADT). Use of ADT has been increasing in frequency and duration, such that side effects increasingly impact patient quality of life. One of the most significant side effects of ADT is sarcopenia, which leads to a loss of skeletal muscle mass and function, resulting in a clinical disability syndrome known as obese frailty. Using aged mice, we developed a mouse model of ADT-induced sarcopenia that closely resembles the phenotype seen in patients, including loss of skeletal muscle strength, reduced lean muscle mass, and increased adipose tissue. Sarcopenia onset occurred about 6 weeks after castration and was blocked by a soluble receptor (ActRIIB-Fc) that binds multiple TGFβ superfamily members, including myostatin, growth differentiation factor 11, activin A, activin B, and activin AB. Analysis of ligand expression in both gastrocnemius and triceps brachii muscles demonstrates that each of these proteins is induced in response to ADT, in 1 of 3 temporal patterns. Specifically, activin A and activin AB levels increase and decline before onset of strength loss at 6 weeks after castration, and myostatin levels increase coincident with the onset of strength loss and then decline. In contrast, activin B and growth differentiation factor 11 levels increase after the onset of strength loss, 8–10 weeks after castration. The observed patterns of ligand induction may represent differential contributions to the development and/or maintenance of sarcopenia. We hypothesize that some or all of these ligands are targets for therapy to ameliorate ADT-induced sarcopenia in prostate cancer patients. PMID:27611336

  20. Vascular Injury Triggers Krüppel-Like Factor 6 (KLF6) Mobilization and Cooperation with Sp1 to Promote Endothelial Activation through Upregulation of the Activin Receptor-Like Kinase 1 (ALK1) Gene

    PubMed Central

    Garrido-Martín, Eva M.; Blanco, Francisco J.; Roquè, Mercé; Novensà, Laura; Tarocchi, Mirko; Lee, Ursula E.; Suzuki, Toru; Friedman, Scott L.; Botella, Luisa M.; Bernabéu, Carmelo

    2012-01-01

    Rationale Activin receptor-Like Kinase-1 (ALK1) is an endothelial TGF-β receptor involved in angiogenesis. ALK1 expression is high in the embryo vasculature, becoming less detectable in the quiescent endothelium of adult stages. However, ALK1 expression becomes rapidly increased after angiogenic stimuli such as vascular injury. Objective To characterize the molecular mechanisms underlying the regulation of ALK1 upon vascular injury. Methods and Results Alk1 becomes strongly upregulated in endothelial (EC) and vascular smooth muscle cells (vSMC) of mouse femoral arteries after wire-induced endothelial denudation. In vitro, denudation of monolayers of Human Umbilical Vein Endothelial Cells (HUVEC) also leads to an increase in ALK1. Interestingly, a key factor in tissue remodeling, Krüppel-like factor 6 (KLF6), translocates to the cell nucleus during wound healing, concomitantly with an increase in the ALK1 gene transcriptional rate. KLF6 knock down in HUVECs promotes ALK1 mRNA downregulation. Moreover, Klf6+/− mice have lower levels of Alk1 in their vasculature compared with their wild type siblings. Chromatin immunoprecipitation assays show that KLF6 interacts with ALK1 promoter in ECs, and this interaction is enhanced during wound healing. We demonstrate that KLF6 is transactivating ALK1 gene, and this transactivation occurs by a synergistic cooperative mechanism with Sp1. Finally, Alk1 levels in vSMCs are not directly upregulated in response to damage, but in response to soluble factors, such as IL-6, released from ECs after injury. Conclusions ALK1 is upregulated in ECs during vascular injury by a synergistic cooperative mechanism between KLF6 and Sp1, and in vSMCs by an EC-vSMC paracrine communication during vascular remodeling. PMID:23048070

  1. Combined Measurement of Soluble ST2 and Amino-Terminal Pro-B-Type Natriuretic Peptide Provides Early Assessment of Severity in Cardiogenic Shock Complicating Acute Coronary Syndrome.

    PubMed

    Tolppanen, Heli; Rivas-Lasarte, Mercedes; Lassus, Johan; Sadoune, Malha; Gayat, Etienne; Pulkki, Kari; Arrigo, Mattia; Krastinova, Evguenia; Sionis, Alessandro; Parissis, John; Spinar, Jindrich; Januzzi, James; Harjola, Veli-Pekka; Mebazaa, Alexandre

    2017-07-01

    Mortality in cardiogenic shock complicating acute coronary syndrome is high, and objective risk stratification is needed for rational use of advanced therapies such as mechanical circulatory support. Traditionally, clinical variables have been used to judge risk in cardiogenic shock. The aim of this study was to assess the added value of serial measurement of soluble ST2 and amino-terminal pro-B-type natriuretic peptide to clinical parameters for risk stratification in cardiogenic shock. CardShock (www.clinicaltrials.gov NCT01374867) is a prospective European multinational study of cardiogenic shock. The main study introduced CardShock risk score, which is calculated from seven clinical variables at baseline, and was associated with short-term mortality. Nine tertiary care university hospitals. Patients with cardiogenic shock caused by acute coronary syndrome (n=145). In this substudy, plasma samples from the study patients were analyzed at eight time points during the ICU or cardiac care unit stay. Additional prognostic value of the biomarkers was assessed with incremental discrimination improvement. The combination of soluble ST2 and amino-terminal pro-B-type natriuretic peptide showed excellent discrimination for 30-day mortality (area under the curve, 0.77 at 12 hr up to 0.93 at 5-10 d after cardiogenic shock onset). At 12 hours, patients with both biomarkers elevated (soluble ST2, ≥ 500 ng/mL and amino-terminal pro-B-type natriuretic peptide, ≥ 4,500 ng/L) had higher 30-day mortality (79%) compared to those with one or neither biomarkers elevated (31% or 10%, respectively; p < 0.001). Combined measurement of soluble ST2 and amino-terminal pro-B-type natriuretic peptide at 12 hours added value to CardShock risk score, correctly reclassifying 11% of patients. The combination of results for soluble ST2 and amino-terminal pro-B-type natriuretic peptide provides early risk assessment beyond clinical variables in patients with acute coronary syndrome

  2. Characterization of soluble glycoprotein D-mediated herpes simplex virus type 1 infection

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tsvitov, Marianna; Frampton, Arthur R.; Shah, Waris A.

    2007-04-10

    Herpes simplex virus type 1 (HSV-1) entry into permissive cells involves attachment to cell-surface glycosaminoglycans (GAGs) and fusion of the virus envelope with the cell membrane triggered by the binding of glycoprotein D (gD) to cognate receptors. In this study, we characterized the observation that soluble forms of the gD ectodomain (sgD) can mediate entry of gD-deficient HSV-1. We examined the efficiency and receptor specificity of this activity and used sequential incubation protocols to determine the order and stability of the initial interactions required for entry. Surprisingly, virus binding to GAGs did not increase the efficiency of sgD-mediated entry andmore » gD-deficient virus was capable of attaching to GAG-deficient cells in the absence of sgD. These observations suggested a novel binding interaction that may play a role in normal HSV infection.« less

  3. Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice.

    PubMed

    Bondulich, Marie K; Jolinon, Nelly; Osborne, Georgina F; Smith, Edward J; Rattray, Ivan; Neueder, Andreas; Sathasivam, Kirupa; Ahmed, Mhoriam; Ali, Nadira; Benjamin, Agnesska C; Chang, Xiaoli; Dick, James R T; Ellis, Matthew; Franklin, Sophie A; Goodwin, Daniel; Inuabasi, Linda; Lazell, Hayley; Lehar, Adam; Richard-Londt, Angela; Rosinski, Jim; Smith, Donna L; Wood, Tobias; Tabrizi, Sarah J; Brandner, Sebastian; Greensmith, Linda; Howland, David; Munoz-Sanjuan, Ignacio; Lee, Se-Jin; Bates, Gillian P

    2017-10-27

    Huntington's disease (HD) is an inherited neurodegenerative disorder of which skeletal muscle atrophy is a common feature, and multiple lines of evidence support a muscle-based pathophysiology in HD mouse models. Inhibition of myostatin signaling increases muscle mass, and therapeutic approaches based on this are in clinical development. We have used a soluble ActRIIB decoy receptor (ACVR2B/Fc) to test the effects of myostatin/activin A inhibition in the R6/2 mouse model of HD. Weekly administration from 5 to 11 weeks of age prevented body weight loss, skeletal muscle atrophy, muscle weakness, contractile abnormalities, the loss of functional motor units in EDL muscles and delayed end-stage disease. Inhibition of myostatin/activin A signaling activated transcriptional profiles to increase muscle mass in wild type and R6/2 mice but did little to modulate the extensive Huntington's disease-associated transcriptional dysregulation, consistent with treatment having little impact on HTT aggregation levels. Modalities that inhibit myostatin signaling are currently in clinical trials for a variety of indications, the outcomes of which will present the opportunity to assess the potential benefits of targeting this pathway in HD patients.

  4. Impact of polymer type on bioperformance and physical stability of hot melt extruded formulations of a poorly water soluble drug.

    PubMed

    Mitra, Amitava; Li, Li; Marsac, Patrick; Marks, Brian; Liu, Zhen; Brown, Chad

    2016-05-30

    Amorphous solid dispersion formulations have been widely used to enhance bioavailability of poorly soluble drugs. In these formulations, polymer is included to physically stabilize the amorphous drug by dispersing it in the polymeric carrier and thus forming a solid solution. The polymer can also maintain supersaturation and promote speciation during dissolution, thus enabling better absorption as compared to crystalline drug substance. In this paper, we report the use of hot melt extrusion (HME) to develop amorphous formulations of a poorly soluble compound (FaSSIF solubility=1μg/mL). The poor solubility of the compound and high dose (300mg) necessitated the use of amorphous formulation to achieve adequate bioperformance. The effect of using three different polymers (HPMCAS-HF, HPMCAS-LF and copovidone), on the dissolution, physical stability, and bioperformance of the formulations was demonstrated. In this particular case, HPMCAS-HF containing HME provided the highest bioavailability and also had better physical stability as compared to extrudates using HPMCAS-LF and copovidone. The data demonstrated that the polymer type can have significant impact on the formulation bioperformance and physical stability. Thus a thorough understanding of the polymer choice is imperative when designing an amorphous solid dispersion formulation, such that the formulation provides robust bioperformance and has adequate shelf life. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. [Study on solubility of Chinese herbal compound by solubility parameter].

    PubMed

    Wu, Dezhi; Chen, Lihua; Wang, Sen; Zhu, Weifeng; Guan, Yongmei

    2010-02-01

    To demonstrate the solubility of Chinese herbal compound with solubility parameters. The solubility parameters of Liangfu effective components and Liangfu compound were determined by inverse gas chromatograph (IGC) and group contribution. Hansen ball was plotting by HSPiP, which could be used to investigate the solubility of Liangfu effective components and Liangfu compound in different solvents. And the results were verified by approximate solubility. Liangfu effective components and Liangfu compound could be dissolved in chloroform, ethyl acetate, acetone, octanol and ether, and were slightly soluble in glycerol, methanol, ethanol and propanediol, but could not be dissolved in water. They were all liposoluble, and the results were the same as the test results of the approximate solubility. The solubility of Chinese herbal compound can be expressed by solubility parameters, and it is accurate, convenient and visual.

  6. Wettability, water sorption and water solubility of seven silicone elastomers used for maxillofacial prostheses.

    PubMed

    Hulterström, Anna Karin; Berglund, Anders; Ruyter, I Eystein

    2008-01-01

    The wettability, water sorption and solubility of silicone elastomers used for maxillofacial prostheses were studied. The hypothesis was, that a material that has absorbed water would show an increase in the wettability and thus also the surface free energy of the material. Seven silicone elastomers, both addition- and condensation type polymers, were included. Five specimens of each material were subjected to treatment according to ISO standards 1567:1999 and 10477: 2004 for water sorption and solubility. The volumes of the specimens were measured according to Archimedes principle. The contact angle was measured with a contact angle goniometer at various stages of the sorption/solubility test. Wettability changed over the test period, but not according to theory. The addition type silicones showed little or no sorption and solubility, but two of the condensation type polymers tested had a significant sorption and solubility. This study showed that condensation type polymers may show too large volumetric changes when exposed to fluids, and therefore should no longer be used in prosthetic devices. The results of this study also suggests that it might be of interest to test sorption and solubility of materials that are to be implanted, since most of the materials had some solubility.

  7. Soluble 1:1 complexes and insoluble 3:2 complexes - Understanding the phase-solubility diagram of hydrocortisone and γ-cyclodextrin.

    PubMed

    Schönbeck, Christian; Madsen, Tobias L; Peters, Günther H; Holm, René; Loftsson, Thorsteinn

    2017-10-15

    The molecular mechanisms underlying the drug-solubilizing properties of γ-cyclodextrin were explored using hydrocortisone as a model drug. The B S -type phase-solubility diagram of hydrocortisone with γ-cyclodextrin was thoroughly characterized by measuring the concentrations of hydrocortisone and γ-cyclodextrin in solution and the solid phase. The drug-solubilizer interaction was also studied by isothermal titration calorimetry from which a precise value of the 1:1 binding constant (K 11 =4.01mM -1 at 20°C) was obtained. The formation of water-soluble 1:1 complexes is responsible for the initial increase in hydrocortisone solubility while the precipitation of entities with a 3:2 ratio of γ-cyclodextrin:hydrocortisone is responsible for the plateau and the ensuing strong decrease in solubility once all solid hydrocortisone is used up. The complete phase-solubility diagram is well accounted for by a model employing the 1:1 binding constant and the solubility product of the precipitating 3:2 entity (K 32 S =5.51 mM 5 ). For such systems, a small surplus of γ-cyclodextrin above the optimum concentration may result in a significant decrease in drug solubility, and the implications for drug formulations are briefly discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Estimating the Aqueous Solubility of Pharmaceutical Hydrates.

    PubMed

    Franklin, Stephen J; Younis, Usir S; Myrdal, Paul B

    2016-06-01

    Estimation of crystalline solute solubility is well documented throughout the literature. However, the anhydrous crystal form is typically considered with these models, which is not always the most stable crystal form in water. In this study, an equation which predicts the aqueous solubility of a hydrate is presented. This research attempts to extend the utility of the ideal solubility equation by incorporating desolvation energetics of the hydrated crystal. Similar to the ideal solubility equation, which accounts for the energetics of melting, this model approximates the energy of dehydration to the entropy of vaporization for water. Aqueous solubilities, dehydration and melting temperatures, and log P values were collected experimentally and from the literature. The data set includes different hydrate types and a range of log P values. Three models are evaluated, the most accurate model approximates the entropy of dehydration (ΔSd) by the entropy of vaporization (ΔSvap) for water, and utilizes onset dehydration and melting temperatures in combination with log P. With this model, the average absolute error for the prediction of solubility of 14 compounds was 0.32 log units. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  9. Estimating the Aqueous Solubility of Pharmaceutical Hydrates

    PubMed Central

    Franklin, Stephen J.; Younis, Usir S.; Myrdal, Paul B.

    2016-01-01

    Estimation of crystalline solute solubility is well documented throughout the literature. However, the anhydrous crystal form is typically considered with these models, which is not always the most stable crystal form in water. In this study an equation which predicts the aqueous solubility of a hydrate is presented. This research attempts to extend the utility of the ideal solubility equation by incorporating desolvation energetics of the hydrated crystal. Similar to the ideal solubility equation, which accounts for the energetics of melting, this model approximates the energy of dehydration to the entropy of vaporization for water. Aqueous solubilities, dehydration and melting temperatures, and log P values were collected experimentally and from the literature. The data set includes different hydrate types and a range of log P values. Three models are evaluated, the most accurate model approximates the entropy of dehydration (ΔSd) by the entropy of vaporization (ΔSvap) for water, and utilizes onset dehydration and melting temperatures in combination with log P. With this model, the average absolute error for the prediction of solubility of 14 compounds was 0.32 log units. PMID:27238488

  10. Solubility of guaifenesin in the presence of common pharmaceutical additives.

    PubMed

    Mani, Narasimhan; Jun, H W; Beach, J Warren; Nerurkar, Jayanti

    2003-01-01

    The aqueous solubility of guaifenesin, a highly water-soluble drug, in the presence of salts, sugars, and cosolvents was determined at 25 degrees C and 40 degrees C. The solubility of drug at both temperatures was reduced with increasing concentrations of salts and sugars. The extent of reduction in drug solubility was dependent on the type of salts and sugars used. The salting-out coefficient of additives was calculated by plotting log-linear solubility profiles of the drug against the concentrations of the additives. The solubility of guaifenesin, a neutral compound, was found to be higher at lower pH values, which could be due to hydrogen-bonding effects. At 25 degrees C, glycerin, PEG 300, and propylene glycol increased the solubility of drug at low solvent concentrations while the solubility was reduced at high concentrations. At 40 degrees C, the solubility of drug was reduced at all concentrations of cosolvents. The thermodynamic events accompanying the solubility process were discussed to explain the solubility phenomena observed in the presence of additives. The reduced aqueous solubility of guaifenesin in the presence of additives greatly improved the entrapment of drug into controlled-release wax microspheres.

  11. Role of Activin A and myostatin in human cancer cachexia.

    PubMed

    Loumaye, Audrey; de Barsy, Marie; Nachit, Maxime; Lause, Pascale; Frateur, Lena; van Maanen, Aline; Trefois, Pierre; Gruson, Damien; Thissen, Jean-Paul

    2015-05-01

    Cachexia is a multifactorial syndrome, characterized by the loss of skeletal muscle mass and not fully reversible by nutritional support. Recent animal observations suggest that production of Activin A (ActA) and Myostatin (Mstn) by some tumors might contribute to cancer cachexia. Our goal was to investigate the role of ActA and Mstn in the development of the human cancer cachexia. The ACTICA study is a cross-sectional study, which prospectively enrolled patients from a tertiary-care center between January 2012 and March 2014. Subjects/Outcome Measures: One hundred fifty two patients with colorectal or lung cancer had clinical, nutritional and functional assessment. Body composition was measured by CT-scan, anthropometry, and bioimpedance. Plasma concentrations of ActA, Mstn, and Follistatin were determined. Cachexia was associated with reduced lean and fat mass (p < .01 and p < .001), reduced physical function, lower quality of life, and increased symptoms (QLQC30; p < .001). Anorexia (SNAQ score < 14) was more common in cachectic patients (CC) than in noncachectic patients (CNC) (p < .001). ActA concentrations in CC patients were higher than in CNC patients (+40%; p < .001) and were correlated positively with weight loss (R = 0.323; p < .001) and negatively with the SNAQ score (R = -0.225; p < .01). In contrast, Mstn concentrations were decreased in CC patients compared to CNC patients (-35%; p < .001). These results demonstrate an association between circulating concentrations of ActA and the presence of the anorexia/cachexia syndrome in cancer patients. Given the known muscle atrophic effects of ActA, our study suggests that increased circulating concentrations of ActA may contribute to the development of cachexia in cancer patients.

  12. Solubility of lysozyme in the presence of aqueous chloride salts: common-ion effect and its role on solubility and crystal thermodynamics.

    PubMed

    Annunziata, Onofrio; Payne, Andrew; Wang, Ying

    2008-10-08

    Understanding protein solubility is important for a rational design of the conditions of protein crystallization. We report measurements of lysozyme solubility in aqueous solutions as a function of NaCl, KCl, and NH4Cl concentrations at 25 degrees C and pH 4.5. Our solubility results are directly compared to preferential-interaction coefficients of these ternary solutions determined in the same experimental conditions by ternary diffusion. This comparison has provided new important insight on the dependence of protein solubility on salt concentration. We remark that the dependence of the preferential-interaction coefficient as a function of salt concentration is substantially shaped by the common-ion effect. This effect plays a crucial role also on the observed behavior of lysozyme solubility. We find that the dependence of solubility on salt type and concentration strongly correlates with the corresponding dependence of the preferential-interaction coefficient. Examination of both preferential-interaction coefficients and second virial coefficients has allowed us to demonstrate that the solubility dependence on salt concentration is substantially affected by the corresponding change of protein chemical potential in the crystalline phase. We propose a simple model for the crystalline phase based on salt partitioning between solution and the hydrated protein crystal. A novel solubility equation is reported that quantitatively explains the observed experimental dependence of protein solubility on salt concentration.

  13. Solubilization of poorly water-soluble compounds using amphiphilic phospholipid polymers with different molecular architectures.

    PubMed

    Mu, Mingwei; Konno, Tomohiro; Inoue, Yuuki; Ishihara, Kazuhiko

    2017-10-01

    To achieve stable and effective solubilization of poorly water-soluble bioactive compounds, water-soluble and amphiphilic polymers composed of hydrophilic 2-methacryloyloxyethyl phosphorylcholine (MPC) units and hydrophobic n-butyl methacrylate (BMA) units were prepared. MPC polymers having different molecular architectures, such as random-type monomer unit sequences and block-type sequences, formed polymer aggregates when they were dissolved in aqueous media. The structure of the random-type polymer aggregate was loose and flexible. On the other hand, the block-type polymer formed polymeric micelles, which were composed of very stable hydrophobic poly(BMA) cores and hydrophilic poly(MPC) shells. The solubilization of a poorly water-soluble bioactive compound, paclitaxel (PTX), in the polymer aggregates was observed, however, solubilizing efficiency and stability were strongly depended on the polymer architecture; in other words, PTX stayed in the poly(BMA) core of the polymer micelle formed by the block-type polymer even when plasma protein was present in the aqueous medium. On the other hand, when the random-type polymer was used, PTX was transferred from the polymer aggregate to the protein. We conclude that water-soluble and amphiphilic MPC polymers are good candidates as solubilizers for poorly water-soluble bioactive compounds. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Analysis of the phase solubility diagram of a phenacetin/competitor/beta-cyclodextrin ternary system, involving competitive inclusion complexation.

    PubMed

    Ono, N; Hirayama, F; Arima, H; Uekama, K

    2001-01-01

    The competitive inclusion complexations in the ternary phenacetin/competitors/beta-cyclodextrin (beta-CyD) systems were investigated by the solubility method, where m-bromobenzoic acid (m-BBA) and o-toluic acid (o-TA) were used as competitors. The solubility changes of the drug and competitors as a function of beta-CyD concentration in the ternary systems were formulated using their stability constants and intrinsic solubilities. The decrease in solubility of phenacetin by the addition of competitors could be quantitatively simulated by the formulation, when both drug and competitor give A(L) type solubility diagrams. On the other hand, when one of the guests gives a B(S) type solubility diagram, its solubility change was clearly reflected in that of the another guest, i.e., phenacetin gave an A(L) type solubility diagram in the binary phenacetin/beta-CyD system and o-TA gave a B(S) type diagram in the binary o-TA/beta-CyD system, but in the ternary phenacetin/o-TA/beta-CyD system, a new plateau region appeared in the original A(L) type diagram of phenacetin. This was explained by the solubilization theory of Higuchi and Connors. The solubility analysis of the ternary drug/competitor/CyD systems may be particularly useful for determination of the stability constant of a drug whose physicochemical and spectroscopic analyses are difficult, because they can be calculated by monitoring the solubility change of a competitor, without monitoring that of a drug. Furthermore, the present results suggest that attention should be paid to the type of the phase solubility diagram, as well as the magnitude of the stability constant and the solubility of the complex, for a rational formulation design of CyD complexes.

  15. Semiconductor material and method for enhancing solubility of a dopant therein

    DOEpatents

    Sadigh, Babak; Lenosky, Thomas J.; Rubia, Tomas Diaz; Giles, Martin; Caturla, Maria-Jose; Ozolins, Vidvuds; Asta, Mark; Theiss, Silva; Foad, Majeed; Quong, Andrew

    2003-09-09

    A method for enhancing the equilibrium solubility of boron and indium in silicon. The method involves first-principles quantum mechanical calculations to determine the temperature dependence of the equilibrium solubility of two important p-type dopants in silicon, namely boron and indium, under various strain conditions. The equilibrium thermodynamic solubility of size-mismatched impurities, such as boron and indium in silicon, can be raised significantly if the silicon substrate is strained appropriately. For example, for boron, a 1% compressive strain raises the equilibrium solubility by 100% at 1100.degree. C.; and for indium, a 1% tensile strain at 1100.degree. C., corresponds to an enhancement of the solubility by 200%.

  16. Method for enhancing the solubility of boron and indium in silicon

    DOEpatents

    Sadigh, Babak; Lenosky, Thomas J.; Diaz de la Rubia, Tomas; Giles, Martin; Caturla, Maria-Jose; Ozolins, Vidvuds; Asta, Mark; Theiss, Silva; Foad, Majeed; Quong, Andrew

    2002-01-01

    A method for enhancing the equilibrium solubility of boron and indium in silicon. The method involves first-principles quantum mechanical calculations to determine the temperature dependence of the equilibrium solubility of two important p-type dopants in silicon, namely boron and indium, under various strain conditions. The equilibrium thermodynamic solubility of size-mismatched impurities, such as boron and indium in silicon, can be raised significantly if the silicon substrate is strained appropriately. For example, for boron, a 1% compressive strain raises the equilibrium solubility by 100% at 1100.degree. C.; and for indium, a 1% tensile strain at 1100.degree. C., corresponds to an enhancement of the solubility by 200%.

  17. Solubility and Solubility Product Determination of a Sparingly Soluble Salt: A First-Level Laboratory Experiment

    ERIC Educational Resources Information Center

    Bonomo, Raffaele P.; Tabbi, Giovanni; Vagliasindi, Laura I.

    2012-01-01

    A simple experiment was devised to let students determine the solubility and solubility product, "K"[subscript sp], of calcium sulfate dihydrate in a first-level laboratory. The students experimentally work on an intriguing equilibrium law: the constancy of the product of the ion concentrations of a sparingly soluble salt. The determination of…

  18. Heterozygous disruption of activin receptor-like kinase 1 is associated with increased arterial pressure in mice

    PubMed Central

    González-Núñez, María; Riolobos, Adela S.; Castellano, Orlando; Fuentes-Calvo, Isabel; de los Ángeles Sevilla, María; Oujo, Bárbara; Pericacho, Miguel; Cruz-Gonzalez, Ignacio; Pérez-Barriocanal, Fernando; ten Dijke, Peter; López-Novoa, Jose M.

    2015-01-01

    ABSTRACT The activin receptor-like kinase 1 (ALK-1) is a type I cell-surface receptor for the transforming growth factor-β (TGF-β) family of proteins. Hypertension is related to TGF-β1, because increased TGF-β1 expression is correlated with an elevation in arterial pressure (AP) and TGF-β expression is upregulated by the renin-angiotensin-aldosterone system. The purpose of this study was to assess the role of ALK-1 in regulation of AP using Alk1 haploinsufficient mice (Alk1+/−). We observed that systolic and diastolic AP were significantly higher in Alk1+/− than in Alk1+/+ mice, and all functional and structural cardiac parameters (echocardiography and electrocardiography) were similar in both groups. Alk1+/− mice showed alterations in the circadian rhythm of AP, with higher AP than Alk1+/+ mice during most of the light period. Higher AP in Alk1+/− mice is not a result of a reduction in the NO-dependent vasodilator response or of overactivation of the peripheral renin-angiotensin system. However, intracerebroventricular administration of losartan had a hypotensive effect in Alk1+/− and not in Alk1+/+ mice. Alk1+/− mice showed a greater hypotensive response to the β-adrenergic antagonist atenolol and higher concentrations of epinephrine and norepinephrine in plasma than Alk1+/+ mice. The number of brain cholinergic neurons in the anterior basal forebrain was reduced in Alk1+/− mice. Thus, we concluded that the ALK-1 receptor is involved in the control of AP, and the high AP of Alk1+/− mice is explained mainly by the sympathetic overactivation shown by these animals, which is probably related to the decreased number of cholinergic neurons. PMID:26398936

  19. Solubility Database

    National Institute of Standards and Technology Data Gateway

    SRD 106 IUPAC-NIST Solubility Database (Web, free access)   These solubilities are compiled from 18 volumes (Click here for List) of the International Union for Pure and Applied Chemistry(IUPAC)-NIST Solubility Data Series. The database includes liquid-liquid, solid-liquid, and gas-liquid systems. Typical solvents and solutes include water, seawater, heavy water, inorganic compounds, and a variety of organic compounds such as hydrocarbons, halogenated hydrocarbons, alcohols, acids, esters and nitrogen compounds. There are over 67,500 solubility measurements and over 1800 references.

  20. Poly(aspartic acid) with adjustable pH-dependent solubility.

    PubMed

    Németh, Csaba; Gyarmati, Benjámin; Abdullin, Timur; László, Krisztina; Szilágyi, András

    2017-02-01

    Poly(aspartic acid) (PASP) derivatives with adjustable pH-dependent solubility were synthesized and characterized to establish the relationship between their structure and solubility in order to predict their applicability as a basic material for enteric coatings. Polysuccinimide, the precursor of PASP, was modified with short chain alkylamines, and the residual succinimide rings were subsequently opened to prepare the corresponding PASP derivatives. Study of the effect of the type and concentration of the side groups on the pH-dependent solubility of PASP showed that solubility can be adjusted by proper selection of the chemical structure. The Henderson-Hasselbalch (HH) and the extended HH equations were used to describe the pH-dependent solubility of the polymers quantitatively. The estimate provided by the HH equation is poor, but an accurate description of the pH-dependent solubility can be found with the extended HH equation. The dissolution rate of a polymer film prepared from a selected PASP derivative was determined by fluorescence marking. The film dissolved rapidly when the pH was increased above its pK a . Cellular viability tests show that PASP derivatives are non-toxic to a human cell line. These polymers are thus of great interest as starting materials for enteric coatings. Poly(amino acid) type biocompatible polymers were synthesized for future use as pharmaceutical film coatings. To this end, we tailored the pH-dependent solubility of poly(aspartic acid) (PASP). It was found that both the solubility and the pK a values of the modified PASP depended strongly on composition. Fluorescent marking was used to characterize the dissolution of a chosen PASP derivative. In acidic media only a negligible amount of the polymer dissolved, but dissolution was very fast and complete at the pH values that prevail in the small intestine. As a consequence, enteric coatings based on such PASP derivatives may be used for drug delivery in the gastrointestinal tract

  1. Trade-offs between enzyme fitness and solubility illuminated by deep mutational scanning

    PubMed Central

    Bacik, John-Paul; Wrenbeck, Emily E.; Michalczyk, Ryszard; Whitehead, Timothy A.

    2017-01-01

    Proteins are marginally stable, and an understanding of the sequence determinants for improved protein solubility is highly desired. For enzymes, it is well known that many mutations that increase protein solubility decrease catalytic activity. These competing effects frustrate efforts to design and engineer stable, active enzymes without laborious high-throughput activity screens. To address the trade-off between enzyme solubility and activity, we performed deep mutational scanning using two different screens/selections that purport to gauge protein solubility for two full-length enzymes. We assayed a TEM-1 beta-lactamase variant and levoglucosan kinase (LGK) using yeast surface display (YSD) screening and a twin-arginine translocation pathway selection. We then compared these scans with published experimental fitness landscapes. Results from the YSD screen could explain 37% of the variance in the fitness landscapes for one enzyme. Five percent to 10% of all single missense mutations improve solubility, matching theoretical predictions of global protein stability. For a given solubility-enhancing mutation, the probability that it would retain wild-type fitness was correlated with evolutionary conservation and distance to active site, and anticorrelated with contact number. Hybrid classification models were developed that could predict solubility-enhancing mutations that maintain wild-type fitness with an accuracy of 90%. The downside of using such classification models is the removal of rare mutations that improve both fitness and solubility. To reveal the biophysical basis of enhanced protein solubility and function, we determined the crystallographic structure of one such LGK mutant. Beyond fundamental insights into trade-offs between stability and activity, these results have potential biotechnological applications. PMID:28196882

  2. Soluble Human Leukocyte Antigen-G in the Bronchoalveolar Lavage of Lung Cancer Patients.

    PubMed

    Montilla, Dayana; Pérez, Mario; Borges, Lérida; Bianchi, Guillermo; Cova, José-Angel

    2016-08-01

    The main function of the HLA-G molecule in its membrane-bound and soluble forms is to inhibit the immune response by acting on CD4+ T cells, cytotoxic T cells, NK cells and dendritic cells. Lung cancer is a leading cause of death worldwide, and annual incidence is high in both women and men. Some studies have reported an increase of HLA-G serum levels in lung cancer, probably generated by tumor cells escaping the antitumor immune response. In this study the concentration of soluble HLA-G in bronchoalveolar lavage (BAL) in patients with primary and metastatic lung cancer was measured to determine its relation with tumor histological type and overall patient status according to the Karnofsky scale. Thirty-one lung cancer patients were included. A tumor biopsy was obtained by bronchoscopy and the tumor type was determined by hematoxylin and eosin staining. BAL samples were obtained to measure soluble HLA-G concentrations in an ELISA sandwich assay. The average value of soluble HLA-G was 49.04ng/mL. No correlation between soluble HLA-G levels and age, gender or smoking was observed. A highly significant difference was observed in the levels of soluble HLA-G in BAL from patients with different histological types of lung cancer, especially in metastatic tumors. The Karnofsky index showed a significant and inverse correlation with soluble HLA-G levels in BAL. Soluble HLA-G protein is significantly associated with metastatic tumors and patients with lower Karnofsky index and may be useful as a prognostic marker in lung cancer. Copyright © 2016 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

  3. Development of a small-molecule screening method for inhibitors of cellular response to myostatin and activin A.

    PubMed

    Cash, Jennifer N; Angerman, Elizabeth B; Kirby, R Jason; Merck, Lisa; Seibel, William L; Wortman, Matthew D; Papoian, Ruben; Nelson, Sandra; Thompson, Thomas B

    2013-08-01

    Myostatin, a member of the transforming growth factor (TGF)-β family of secreted ligands, is a strong negative regulator of muscle growth. As such, therapeutic inhibitors of myostatin are actively being investigated for their potential in the treatment of muscle-wasting diseases such as muscular dystrophy and sarcopenia. Here, we sought to develop a high-throughput screening (HTS) method for small-molecule inhibitors that target myostatin. We created a HEK293 stable cell line that expresses the (CAGA)12-luciferase reporter construct and robustly responds to signaling of certain classes of TGF-β family ligands. After optimization and miniaturization of the assay to a 384-well format, we successfully screened a library of compounds for inhibition of myostatin and the closely related activin A. Selection of some of the tested compounds was directed by in silico screening against myostatin, which led to an enrichment of target hits as compared with random selection. Altogether, we present an HTS method that will be useful for screening potential inhibitors of not only myostatin but also many other ligands of the TGF-β family.

  4. A Semiconductor Material And Method For Enhancing Solubility Of A Dopant Therein

    DOEpatents

    Sadigh, Babak; Lenosky, Thomas J.; Diaz de la Rubia, Tomas; Giles, Martin; Caturla, Maria-Jose; Ozolins, Vidvuds; Asta, Mark; Theiss, Silva; Foad, Majeed; Quong, Andrew

    2005-03-29

    A method for enhancing the equilibrium solubility of boron ad indium in silicon. The method involves first-principles quantum mechanical calculations to determine the temperature dependence of the equilibrium solubility of two important p-type dopants in silicon, namely boron and indium, under various strain conditions. The equilibrium thermodynamic solubility of size-mismatched impurities, such as boron and indium in silicon, can be raised significantly if the silicon substrate is strained appropriately. For example, for boron, a 1% compressive strain raises the equilibrium solubility by 100% at 1100.degree. C.; and for indium, a 1% tensile strain at 1100.degree. C., corresponds to an enhancement of the solubility by 200%.

  5. Solubility of ocular therapeutic agents in self-emulsifying oils. I. Self-emulsifying oils for ocular drug delivery: solubility of indomethacin, aciclovir and hydrocortisone.

    PubMed

    Czajkowska-Kośnik, Anna; Sznitowska, Małgorzata

    2009-01-01

    Self-emulsifying drug delivery systems (SEDDS) were prepared by dissolving Cremophor EL, Tween 20, Tween 80 and Span 80 (1% or 5%) in oils (Miglyol 812 or castor oil). Solubilities of three ophthalmic drugs, namely aciclovir, hydrocortisone and indomethacin were determined in these systems. In addition, the effect of a small amount of water (0.5% and 2%) on solubilization properties of the systems was estimated. Of the three substances, indomethacin showed the best solubility in Miglyol while aciclovir was practically insoluble in this oil. The surfactants usually increased drug solubility in the oily phase. Only Tween 20 was found to decrease the solubility of aciclovir and hydrocortisone in Miglyol. Addition of a small amount of water to the oil/surfactant system increased solubility of hydrocortisone, but not of indomethacin. The results of the current study may be utilized to design a suitable composition of SEDDS and allow continuation of research on this type of drug carriers.

  6. Effect of novel water soluble curcumin derivative on experimental type- 1 diabetes mellitus (short term study)

    PubMed Central

    2012-01-01

    Background Diabetes mellitus type 1 is an autoimmune disorder caused by lymphocytic infiltration and beta cells destruction. Curcumin has been identified as a potent inducer of heme-oxygenase-1 (HO-1), a redoxsensitive inducible protein that provides protection against various forms of stress. A novel water soluble curcumin derivative (NCD) has been developed to overcome low in vivo bioavailability of curcumin. The aim of the present work is to evaluate the anti diabetic effects of the “NCD” and its effects on diabetes-induced ROS generation and lipid peroxidation in experimental type- 1 diabetes mellitus. We also examine whether the up regulation of HO-1 accompanied by increased HO activity mediates these antidiabetic and anti oxidant actions. Materials and methods Rats were divided into control group, control group receiving curcumin derivative, diabetic group, diabetic group receiving curcumin derivative and diabetic group receiving curcumin derivative and HO inhibitor ZnPP. Type-1 diabetes was induced by intraperitoneal injection of streptozotocin. Curcumin derivative was given orally for 45 days. At the planned sacrification time (after 45 days), fasting blood samples were withdrawn for estimation of plasma glucose, plasma insulin and lipid profile . Animals were sacrificed; pancreas, aorta and liver were excised for the heme oxygenase - 1 expression, activity and malondialdehyde estimation. Results NCD supplementation to diabetic rats significantly lowered the plasma glucose by 27.5% and increased plasma insulin by 66.67%. On the other hand, the mean plasma glucose level in the control group showed no significant difference compared to the control group receiving the oral NCD whereas, NCD supplementation to the control rats significantly increased the plasma insulin by 47.13% compared to the control. NCD decreased total cholesterol, triglycerides, LDL cholesterol and increased HDL cholesterol levels. Also, it decreased lipid peroxides (malondialdehyde

  7. Cocrystal Transition Points: Role of Cocrystal Solubility, Drug Solubility, and Solubilizing Agents.

    PubMed

    Lipert, Maya P; Rodríguez-Hornedo, Naír

    2015-10-05

    In this manuscript we bring together concepts that are relevant to the solubilization and thermodynamic stability of cocrystals in the presence of drug solubilizing agents. Simple equations are derived that allow calculation of cocrystal solubilization and transition point solubility. Analysis of 10 cocrystals in 6 different solubilizing agents shows that cocrystal solubilization is quantitatively predicted from drug solubilization. Drug solubilizing agents such as surfactants and lipid-based media are also shown to induce cocrystal transition points, where drug and cocrystal solubilities are equal, and above which the cocrystal solubility advantage over drug is eliminated. We have discovered that cocrystal solubility at the transition point (S*) is independent of solubilizing agent, and can be predicted from knowledge of only the aqueous solubilities of drug and cocrystal. For 1:1 cocrystals, S* = (Scocrystal,aq)(2)/Sdrug,aq. S* is a key indicator of cocrystal thermodynamic stability and establishes the upper solubility limit below which cocrystal is more soluble than the constituent drug. These findings have important implications to tailor cocrystal solubility and stability in pharmaceutical formulations from commonly available drug solubility descriptors.

  8. Influence of type and level of water-soluble additives on drug release and surface and mechanical properties of Surelease films.

    PubMed

    Rohera, Bhagwan D; Parikh, Nilesh H

    2002-11-01

    Ethylcellulose in combination with water-soluble additives has been used in the development of microporous membrane-coated dosage forms. In the present study, application of three types of water-soluble additives, namely polyethylene glycols (PEG 400, 3350, and 8000), maltodextrins (Maltrin M150, M100, and M040 in the order of lower to higher average polymer size and molecular weight; dextrose equivalence 16.9, 11.1, and 4.8, respectively), and xylitol, as porosity modifiers in the films of a commercially available aqueous ethylcellulose dispersion (Surelease/E-7-7060 plasticized with glyceryl tricaprylate/caprate) was investigated. The effect of type and level of these additives on drug release characteristics and surface and mechanical properties of the polymeric films was studied. Each additive was incorporated at 20 and 30% levels in the polymeric dispersion based on its solids content. Ibuprofen tablets were coated using the polymeric dispersion with and without additive at 3% w/w coat level in a fluid-bed equipment. The coated tablets were evaluated for their drug release rate, coat reflectivity (gloss), Brinell hardness, and elastic modulus. Differential scanning calorimetric analysis of the films was performed to determine the physico-chemical changes in the applied film-coats. The rate of drug release, hence film porosity, was observed to be dependent on the type and level of the additive added. The molecular weight of the additive and its concentration in the polymeric dispersion had significant influence on the rate of drug release, hardness, and elasticity of the film-coats.

  9. Molecular Pathways: Cachexia Signaling-A Targeted Approach to Cancer Treatment.

    PubMed

    Miyamoto, Yuji; Hanna, Diana L; Zhang, Wu; Baba, Hideo; Lenz, Heinz-Josef

    2016-08-15

    Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass, which negatively affects quality of life and portends a poor prognosis. Numerous molecular substrates and mechanisms underlie the dysregulation of skeletal muscle synthesis and degradation observed in cancer cachexia, including proinflammatory cytokines (TNFα, IL1, and IL6), and the NF-κB, IGF1/AKT/mTOR, and myostatin/activin-SMAD pathways. Recent preclinical and clinical studies have demonstrated that anti-cachexia drugs (such as MABp1 and soluble receptor antagonist of myostatin/activin) not only prevent muscle wasting but also may prolong overall survival. In this review, we focus on the significance of cachexia signaling in patients with cancer and highlight promising drugs targeting tumor cachexia in clinical development. Clin Cancer Res; 22(16); 3999-4004. ©2016 AACR. ©2016 American Association for Cancer Research.

  10. The activin-βA/BMP-2 chimera AB204 is a strong stimulator of adipogenesis.

    PubMed

    Kim, Meejung; Kim, Jong In; Kim, Jae Bum; Choe, Senyon

    2017-05-01

    Several of the bone morphogenetic proteins (BMPs) have been reported to induce white as well as brown adipogenesis. Here, we characterized the adipogenic potential of AB204, a recombinant chimeric protein of activin-βA and BMP-2, in in vitro, ex vivo and in vivo settings. BMP-2 is generally known to promote adipogenesis. When compared with BMP-2, which previously showed varying degrees of adipogenesis, AB204 displayed superior in vitro adipogenic differentiation of mouse 3 T3-L1 pre-adipocytes and human adipose-derived stem cells (hASCs). Surprisingly, implantation of hASCs, preconditioned with AB204 for as short a time as 48 h, into the subcutaneous space of athymic nude mice effectively produced fat pads, but not with BMP-2. When BMP-2 and AB204 were injected intraperitoneally, AB204 promoted dramatic systemic adipogenesis of C57BL/6 mice on a high-fat diet very effectively. The results implicate the novel clinical potential of AB204, including induction of fat tissue ex vivo or in vivo for tissue re-engineering and regenerative medicinal purposes, more than any known natural protein ligand. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  11. Evaluation of detergents for the soluble expression of alpha-helical and beta-barrel-type integral membrane proteins by a preparative scale individual cell-free expression system.

    PubMed

    Klammt, Christian; Schwarz, Daniel; Fendler, Klaus; Haase, Winfried; Dötsch, Volker; Bernhard, Frank

    2005-12-01

    Cell-free expression has become a highly promising tool for the fast and efficient production of integral membrane proteins. The proteins can be produced as precipitates that solubilize in mild detergents usually without any prior denaturation steps. Alternatively, membrane proteins can be synthesized in a soluble form by adding detergents to the cell-free system. However, the effects of a representative variety of detergents on the production, solubility and activity of a wider range of membrane proteins upon cell-free expression are currently unknown. We therefore analyzed the cell-free expression of three structurally very different membrane proteins, namely the bacterial alpha-helical multidrug transporter, EmrE, the beta-barrel nucleoside transporter, Tsx, and the porcine vasopressin receptor of the eukaryotic superfamily of G-protein coupled receptors. All three membrane proteins could be produced in amounts of several mg per one ml of reaction mixture. In general, the detergent 1-myristoyl-2-hydroxy-sn-glycero-3-[phospho-rac-(1-glycerol)] was found to be most effective for the resolubilization of membrane protein precipitates, while long chain polyoxyethylene-alkyl-ethers proved to be most suitable for the soluble expression of all three types of membrane proteins. The yield of soluble expressed membrane protein remained relatively stable above a certain threshold concentration of the detergents. We report, for the first time, the high-level cell-free expression of a beta-barrel type membrane protein in a functional form. Structural and functional variations of the analyzed membrane proteins are evident that correspond with the mode of expression and that depend on the supplied detergent.

  12. Students' mental models on the solubility and solubility product concept

    NASA Astrophysics Data System (ADS)

    Rahmi, Chusnur; Katmiati, Siti; Wiji, Mulyani, Sri

    2017-05-01

    This study aims to obtain some information regarding profile of students' mental models on the solubility and solubility product concept. A descriptive qualitative method was the method employed in the study. The participants of the study were students XI grade of a senior high school in Bandung. To collect the data, diagnostic test on mental model-prediction, observation, explanation (TDM-POE) instrument was employed in the study. The results of the study revealed that on the concept of precipitation formation of a reaction, 30% of students were not able to explain the precipitation formation of a reaction either in submicroscopic or symbolic level although the microscopic have been shown; 26% of students were able to explain the precipitation formation of a reaction based on the relation of Qsp and Ksp, but they were not able to explain the interaction of particles that involved in the reaction and to calculate Qsp; 26% of students were able to explain the precipitation formation of a reaction based on the relation of Qsp and Ksp, and determine the particles involved, but they did not have the knowledge about the interactions occured and were uncapable of calculating Qsp; and 18% of students were able to explain the precipitation formation of a reaction based on the relation of Qsp and Ksp, and determine the interactions of the particles involved in the reactions but they were not able to calculate Qsp. On the effect of adding common ions and decreasing pH towards the solubility concept, 96% of students were not able to explain the effect of adding common ions and decreasing pH towards the solubility either in submicroscopic or symbolic level although the microscopic have been shown; while 4% of students were only able to explain the effect of adding common ions towards the solubility based on the chemical equilibrium shifts and predict the effect of decreasing pH towards the solubility. However, they were not able to calculate the solubility before and after

  13. Growth and differentiation factor 11 (GDF11): Functions in the regulation of erythropoiesis and cardiac regeneration.

    PubMed

    Rochette, Luc; Zeller, Marianne; Cottin, Yves; Vergely, Catherine

    2015-12-01

    Members of the TGF-β superfamily transduce their signals through type I and II receptor serine/threonine kinases. The regulation of members of the TGF-β family is known to be complex, because many proteins able to bind the ligands and inhibit their activities have been identified. Growth and differentiation factor 11 (Gdf11) as activins belong to the TGF-β family. GDF11, like other members of the TGF-β superfamily, is produced from precursor proteins by proteolytic processing. The binding of activins to activin type IIA (ActRIIA) or type IIB (ActRIIB) receptors induces the recruitment and phosphorylation of an activin type I receptor which then phosphorylates the Smad2 and Smad3 intracellular signaling proteins. GDF11 signal through the ActRIIB pathway. Recent studies have reported that GDF11-ActRIIB-Smad2/3-dependent signaling is a key regulatory mechanism in proliferating erythroid precursors as it controls their late-stage maturation. The administration of GDF11 is effective in experimental cardiac hypertrophy, and the identification of GDF11 as a "rejuvenating factor" opens up perspectives for the treatment of age-related cardiac dysfunction. Recent studies of the heart indicate that exposure to young blood reverses age-related impairments. GDF11 could be one of the circulating molecules that influence the aging of different tissues. Is GDF11 an "elixir of youth"? Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Improved Performance and Reproducibility of Perovskite Solar Cells by Well-Soluble Tris(pentafluorophenyl)borane as a p-Type Dopant.

    PubMed

    Ye, Tengling; Wang, Junhai; Chen, Wenbo; Yang, Yulin; He, Dongqing

    2017-05-31

    In this work, well-soluble tris(pentafluorophenyl)borane (BCF) is introduced for the first time into 2,2',7,7'-tetrakis(N,N'-di-p-methoxyphenylamine)-9,9'-spirobifluorene (spiro-OMeTAD) as a p-dopant. The conductivity of spiro-OMeTAD films is dramatically enhanced. When the BCF-doped spiro-OMeTAD film is used as a hole-transport layer (HTL) in perovskite solar cells (PSCs), nearly double increase in power conversion efficiency (PCE) is obtained compared to that of the PSCs based on a pristine spiro-OMeTAD HTL. By the introduction of lithium bis(trifluoromethanesulfonyl)imide and 4-tert-butylpyridine into the BCF-doped spiro-OMeTAD film, the conductivity of spiro-OMeTAD film can be further enhanced, and an optimum PCE of 14.65% is obtained. In addition, the average efficiency of the device and the reproducibility of BCF-based PSCs are better than those of FK209-based PSCs. The working mechanism of the BCF doping effect on spiro-OMeTAD is studied in detail. The strong electron-accepting ability, excellent solubility in common organic solvents, and the low cost make BCF a very attractive p-type dopant for spiro-OMeTAD.

  15. Serologic assessment of type 1 and type 2 immunity in healthy Japanese adults.

    PubMed

    Birmann, Brenda M; Mueller, Nancy; Okayama, Akihiko; Hsieh, Chung-Cheng; Tachibana, Nobuyoshi; Tsubouchi, Hirohito; Lennette, Evelyne T; Harn, Donald; Stuver, Sherri

    2004-08-01

    We assessed the informativeness of several serologic biomarkers of immune function using serum specimens collected in the Miyazaki Cohort Study from subjects who were seronegative for anti-human T-cell lymphotrophic virus I and anti-hepatitis C virus. To broadly characterize type 1 immune status, we measured EBV antibody titers, because titer profiles associated with cellular immune suppression are well described. We also tested for three type 2 biomarkers: total serum IgE, soluble CD23, and soluble CD30. Nonreactivity to a tuberculin purified protein derivative (PPD) skin test is indicative of diminished delayed-type hypersensitivity (type 1) responsiveness in the study population due to a history of tuberculosis exposure or Bacillus Calmette-Guérin vaccination. We therefore evaluated the serologic markers as predictors of PPD nonreactivity using logistic regression. Subjects whose EBV antibody profiles were consistent with deficient type 1 immunity were more than thrice as likely to be PPD nonreactive as persons with "normal" antibody titers. Elevated total IgE was also strongly associated with PPD nonreactivity (odds ratio 3.4, 95% confidence interval 1.2-9.9); elevated soluble CD23 had a weaker, but positive, odds ratio, whereas soluble CD30 levels were not predictive of PPD status. Therefore, PPD nonreactivity is associated, in this population, with a pattern of serum biomarkers that is indicative of diminished type 1 and elevated type 2 immunity. We conclude that, with the exception of soluble CD30, the serologic markers are informative for the characterization of type 1/type 2 immune status using archived sera from study populations of healthy adults.

  16. Detection on immunoblot of new proteins from the soluble fraction of the cell recognized either by anti-liver-kidney microsome antibodies type 1 or by anti-liver cytosol antibodies type 1--relationship with hepatitis C virus infection.

    PubMed

    Ballot, E; Desbos, A; Monier, J C

    1996-09-01

    Antibodies directed against liver cytosol protein, called anti-liver cytosol type 1 (LC1 Ab), have been described by both immunofluorescence (IF) and immunodiffusion techniques in sera from patients with autoimmune hepatitis (AIH). They have never been found in association with antibodies directed against the hepatitis C virus (HCV), unlike the anti-liver-kidney microsome antibodies type 1 (LKM1 Ab), the serological marker of AIH type 2. This suggests that there are two subgroups of AIH type 2, i.e., HCV-related and non-HCV-related. In this study, immunoblotting experiments were performed using proteins from the soluble phase of the rat liver cell; 141 sera which tested positive for LKM1 Ab by IF, 24 identified as having LC1 Ab by IF, and 50 from blood donors as controls were analyzed. Three bands were stained by LC1 Ab sera more often than by the control sera, and with a statistically significant frequency. These 3 proteins were located at apparent Mr 50,000, 55,000, and 60,000. The LKM1 Ab-positive sera as defined by IF stained six bands with a statistically significant frequency compared to the controls. Their apparent Mr were 35,000, 39,000, 47,000, 50,000, 55,000, and 60,000. LKM1 Ab-positive sera which were anti-HCV negative recognized a 60,000 protein belonging to the soluble phase of the cell, with a statistically significant frequency compared to LKM1 Ab-positive sera which were anti-HCV positive. This 60,000 protein was also recognized by LC1 Ab-positive sera, which were almost always anti-HCV negative. The presence of antibodies against a 60,000 protein from the soluble phase of the cell is discussed in terms of the anti-HCV serological markers found in the sera from patients with AIH.

  17. Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers.

    PubMed

    Ahuja, Naveen; Katare, Om Prakash; Singh, Bhupinder

    2007-01-01

    Role of various water-soluble carriers was studied for dissolution enhancement of a poorly soluble model drug, rofecoxib, using solid dispersion approach. Diverse carriers viz. polyethylene glycols (PEG 4000 and 6000), polyglycolized fatty acid ester (Gelucire 44/14), polyvinylpyrollidone K25 (PVP), poloxamers (Lutrol F127 and F68), polyols (mannitol, sorbitol), organic acid (citric acid) and hydrotropes (urea, nicotinamide) were investigated for the purpose. Phase-solubility studies revealed AL type of curves for each carrier, indicating linear increase in drug solubility with carrier concentration. The sign and magnitude of the thermodynamic parameter, Gibbs free energy of transfer, indicated spontaneity of solubilization process. All the solid dispersions showed dissolution improvement vis-à-vis pure drug to varying degrees, with citric acid, PVP and poloxamers as the most promising carriers. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model and the drug release kinetics primarily as Fickian diffusion. Solid state characterization of the drug-poloxamer binary system using XRD, FTIR, DSC and SEM techniques revealed distinct loss of drug crystallinity in the formulation, ostensibly accounting for enhancement in dissolution rate.

  18. Activin A/BMP2 chimera AB235 drives efficient redifferentiation of long term cultured autologous chondrocytes.

    PubMed

    Jiménez, G; López-Ruiz, E; Kwiatkowski, W; Montañez, E; Arrebola, F; Carrillo, E; Gray, P C; Izpisua Belmonte, J C; Choe, S; Perán, M; Marchal, J A

    2015-11-13

    Autologous chondrocyte implantation (ACI) depends on the quality and quantity of implanted cells and is hindered by the fact that chondrocytes cultured for long periods of time undergo dedifferentiation. Here we have developed a reproducible and efficient chondrogenic protocol to redifferentiate chondrocytes isolated from osteoarthritis (OA) patients. We used morphological, histological and immunological analysis together with a RT-PCR detection of collagen I and collagen II gene expression to show that chondrocytes isolated from articular cartilage biopsies of patients and subjected to long-term culture undergo dedifferentiation and that these cells can be redifferentiated following treatment with the chimeric Activin A/BMP2 ligand AB235. Examination of AB235-treated cell pellets in both in vitro and in vivo experiments revealed that redifferentiated chondrocytes synthesized a cartilage-specific extracellular matrix (ECM), primarily consisting of vertically-orientated collagen fibres and cartilage-specific proteoglycans. AB235-treated cell pellets also integrated into the surrounding subcutaneous tissue following transplantation in mice as demonstrated by their dramatic increase in size while non-treated control pellets disintegrated upon transplantation. Thus, our findings describe an effective protocol for the promotion of redifferentiation of autologous chondrocytes obtained from OA patients and the formation of a cartilage-like ECM that can integrate into the surrounding tissue in vivo.

  19. Anti-soluble liver antigen (SLA) antibodies in chronic HCV infection.

    PubMed

    Vitozzi, Susana; Lapierre, Pascal; Djilali-Saiah, Idriss; Marceau, Gabriel; Beland, Kathie; Alvarez, Fernando

    2004-05-01

    Hepatitis C infection is associated with autoimmune disorders, such as the production of autoantibodies. Anti-LKM1 and anti-LC1, immunomarkers of type 2 autoimmune hepatitis, have been previously associated with a HCV infection. Anti-Soluble-Liver-Antigen autoantibodies (SLA) are specifically associated with type 1 and type 2 autoimmune hepatitis and more closely related to patients who relapse after steroid therapy. The recent molecular cloning of the soluble liver antigen provides the opportunity to develop more specific tests for the detection of antibodies against it. The aim of this work is to characterize anti-soluble-liver autoantibodies in sera from patients chronically infected by HCV. A recombinant cDNA from activated Jurkat cells coding for the full length tRNP(Ser)Sec/SLA antigen was obtained. ELISA, Western Blot and immunoprecipitation tests were developed and used to search for linear and conformational epitopes recognized by anti-SLA antibodies in sera from patients chronically infected by HCV. Anti-soluble liver antigen antibodies were found in sera from 10.4% of HCV-infected patients. The prevalence was significantly increased to 27% when anti-LKM1 was also present. Most anti-SLA reactivity was directed against conformational epitopes on the antigen. The means titers by ELISA were lower than those obtained in type 2 AIH. The result of autoantibody isotyping showed a subclass restriction to IgG1 and also IgG4. This study shows the presence of anti-SLA antibodies in approximately 10% of HCV infected patients. The prevalence of SLA autoantibodies in HCV infected patients increases when LKM1 autoantibodies are also present. The relationship between the prevalence of this characteristic autoimmune hepatitis autoantibody and the implication of an autoimmune phenomenon in the liver injury of patients chronically infected by HCV needs further investigation.

  20. Soluble vs. insoluble fiber

    MedlinePlus

    ... soluble and insoluble. Both are important for health, digestion, and preventing diseases. Soluble fiber attracts water and turns to gel during digestion. This slows digestion. Soluble fiber is found in ...

  1. A myostatin and activin decoy receptor enhances bone formation in mice.

    PubMed

    Bialek, P; Parkington, J; Li, X; Gavin, D; Wallace, C; Zhang, J; Root, A; Yan, G; Warner, L; Seeherman, H J; Yaworsky, P J

    2014-03-01

    Myostatin is a member of the bone morphogenetic protein/transforming growth factor-β (BMP/TGFβ) super-family of secreted differentiation factors. Myostatin is a negative regulator of muscle mass as shown by increased muscle mass in myostatin deficient mice. Interestingly, these mice also exhibit increased bone mass suggesting that myostatin may also play a role in regulating bone mass. To investigate the role of myostatin in bone, young adult mice were administered with either a myostatin neutralizing antibody (Mstn-mAb), a soluble myostatin decoy receptor (ActRIIB-Fc) or vehicle. While both myostatin inhibitors increased muscle mass, only ActRIIB-Fc increased bone mass. Bone volume fraction (BV/TV), as determined by microCT, was increased by 132% and 27% in the distal femur and lumbar vertebrae, respectively. Histological evaluation demonstrated that increased BV/TV in both locations was attributed to increased trabecular thickness, trabecular number and bone formation rate. Increased BV/TV resulted in enhanced vertebral maximum compressive force compared to untreated animals. The fact that ActRIIB-Fc, but not Mstn-mAb, increased bone volume suggested that this soluble decoy receptor may be binding a ligand other than myostatin, that plays a role in regulating bone mass. This was confirmed by the significant increase in BV/TV in myostatin deficient mice treated with ActRIIB-Fc. Of the other known ActRIIB-Fc ligands, BMP3 has been identified as a negative regulator of bone mass. However, BMP3 deficient mice treated with ActRIIB-Fc showed similar increases in BV/TV as wild type (WT) littermates treated with ActRIIB-Fc. This result suggests that BMP3 neutralization is not the mechanism responsible for increased bone mass. The results of this study demonstrate that ActRIIB-Fc increases both muscle and bone mass in mice. Therefore, a therapeutic that has this dual activity represents a potential approach for the treatment of frailty. Copyright © 2013 The Authors

  2. Toward a Molecular Understanding of Protein Solubility: Increased Negative Surface Charge Correlates with Increased Solubility

    PubMed Central

    Kramer, Ryan M.; Shende, Varad R.; Motl, Nicole; Pace, C. Nick; Scholtz, J. Martin

    2012-01-01

    Protein solubility is a problem for many protein chemists, including structural biologists and developers of protein pharmaceuticals. Knowledge about how intrinsic factors influence solubility is limited due to the difficulty of obtaining quantitative solubility measurements. Solubility measurements in buffer alone are difficult to reproduce, because gels or supersaturated solutions often form, making it impossible to determine solubility values for many proteins. Protein precipitants can be used to obtain comparative solubility measurements and, in some cases, estimations of solubility in buffer alone. Protein precipitants fall into three broad classes: salts, long-chain polymers, and organic solvents. Here, we compare the use of representatives from two classes of precipitants, ammonium sulfate and polyethylene glycol 8000, by measuring the solubility of seven proteins. We find that increased negative surface charge correlates strongly with increased protein solubility and may be due to strong binding of water by the acidic amino acids. We also find that the solubility results obtained for the two different precipitants agree closely with each other, suggesting that the two precipitants probe similar properties that are relevant to solubility in buffer alone. PMID:22768947

  3. Application To Bilayer System With Water-Soluble Contrast Enhancing Material

    NASA Astrophysics Data System (ADS)

    Yabuta, Mitsuo; Ito, Naoki; Yamazaki, Hiroyuki; Nakayama, Toshimasa

    1987-09-01

    We have developed ,a water-soluble contrast enhancing material, TAD-436 ( Tokyo Ohka. Anti-Defocus Material ) which is consisted of a water-soluble diazonium salt as bleaching compounds and a water-soluble anion type polymer as binder polymers. Needless to say that water is used as solvent in TAD; therefore, it can be spincoated directly on a positive photoresist layer of a quinonediazide-novolak resin type without causing intermixing and furtheremore the bilayer can be developed without stripping TAD immediately after exposure. TAD shows a satisfactory bleaching characteristics on g-line, increases r-value of underlying photoresist and reduces the thickness loss of photoresist layer in unexposed area. Application to bilayer system with TAD will raise the resolution of underlying photoresist and when the focus depth is changed it will make the change in the resist profile small. As the result of it, the notches in the resist patterns on steps is reduced, making the difference in the linewidth between the top and the bottom of steps small.

  4. Structural and functional characterizations of activin type 2B receptor (acvr2b) ortholog from the marine fish, gilthead sea bream, Sparus aurata: evidence for gene duplication of acvr2b in fish.

    PubMed

    Funkenstein, Bruria; Krol, Ekaterina; Esterin, Elena; Kim, Yong-Soo

    2012-12-01

    Myostatin (MSTN), a negative regulator of muscle growth and a member of the transforming growth factor-β superfamily, can bind the two activin type 2 receptors (ACVR2). It has been previously shown that WT mice injected with ACVR2B extracellular domain (ACVR2B-ECD) had higher muscle mass. Likewise, fish larvae immersed in Pichia pastoris culture supernatant, containing goldfish Acvr2b-ECD, showed enhanced larval growth. However, it is not clear whether fish Mstn1 and Mstn2 signal through the same receptor and whether fish express more than one acvr2b gene. In the current study, three cDNAs encoding acvr2b (saacvr2b-1, saacvr2b-2a, and saacvr2b-2b) were cloned from gilthead sea bream. All three contain the short extracellular binding domain, a short transmembrane region, and a conserved catalytic domain of serine/threonine protein kinase. Bioinformatics analysis provided evidence for the existence of two acvr2b genes (acvr2b-1 and acvr2b-2) in several other fish species as well, probably as a result of gene or genome duplication. The two isoforms differ in their amino acid sequences. The direct inhibitory effect of Acvr2b-ECD on Mstn activity was tested in vitro. The saAcvr2b-1-ECD was expressed in the yeast P. pastoris. Evidence is provided for N-glycosylation of Acvr2b-1-ECD. The affinity-purified Acvr2b-1-ECD inhibited recombinant mouse/rat/human mature MSTN activity when determined in vitro using the CAGA-luciferase assay in A204 cells. A lower inhibitory activity was obtained when unprocessed purified, furin-digested, and activated saMstn1 was used. Results of this study demonstrate for the first time the existence of two acvr2b genes in fish. In addition, the study shows that bioactive fish Acvr2b-ECD can be produced from P. pastoris.

  5. The interaction of nifedipine with selected cyclodextrins and the subsequent solubility-permeability trade-off.

    PubMed

    Beig, Avital; Miller, Jonathan M; Dahan, Arik

    2013-11-01

    The purpose of this study was to investigate the interaction of 2-hydroxypropyl-β-cyclodextrin (HPβCD) and 2,6-dimethyl-β-cyclodextrin (DMβCD) with the lipophilic drug nifedipine and to investigate the subsequent solubility-permeability interplay. Solubility curves of nifedipine with HPβCD and DMβCD in MES buffer were evaluated using phase solubility methods. Then, the apparent permeability of nifedipine was investigated as a function of increasing HPβCD/DMβCD concentration in the hexadecane-based PAMPA model. The interaction with nifedipine was CD dependent; significantly higher stability constant was obtained for DMβCD in comparison with HPβCD. Moreover, nifedipine displays different type of interaction with these CDs; a 1:1 stoichiometric inclusion complex was apparent with HPβCD, while 1:2 stoichiometry was apparent for DMβCD. In all cases, decreased apparent intestinal permeability of nifedipine as a function of increasing CD level and nifedipine apparent solubility was obtained. A quasi-equilibrium mass transport analysis was developed to explain this solubility-permeability interplay; the model enabled excellent quantitative prediction of nifedipine's permeability as a function of CD concentrations. This work demonstrates that when using CDs in solubility-enabling formulations, a trade-off exists between solubility increase and permeability decrease that must not be overlooked. This trade-off was found to be independent of the type of CD-drug interaction. The transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Prediction and analysis of protein solubility using a novel scoring card method with dipeptide composition

    PubMed Central

    2012-01-01

    Background Existing methods for predicting protein solubility on overexpression in Escherichia coli advance performance by using ensemble classifiers such as two-stage support vector machine (SVM) based classifiers and a number of feature types such as physicochemical properties, amino acid and dipeptide composition, accompanied with feature selection. It is desirable to develop a simple and easily interpretable method for predicting protein solubility, compared to existing complex SVM-based methods. Results This study proposes a novel scoring card method (SCM) by using dipeptide composition only to estimate solubility scores of sequences for predicting protein solubility. SCM calculates the propensities of 400 individual dipeptides to be soluble using statistic discrimination between soluble and insoluble proteins of a training data set. Consequently, the propensity scores of all dipeptides are further optimized using an intelligent genetic algorithm. The solubility score of a sequence is determined by the weighted sum of all propensity scores and dipeptide composition. To evaluate SCM by performance comparisons, four data sets with different sizes and variation degrees of experimental conditions were used. The results show that the simple method SCM with interpretable propensities of dipeptides has promising performance, compared with existing SVM-based ensemble methods with a number of feature types. Furthermore, the propensities of dipeptides and solubility scores of sequences can provide insights to protein solubility. For example, the analysis of dipeptide scores shows high propensity of α-helix structure and thermophilic proteins to be soluble. Conclusions The propensities of individual dipeptides to be soluble are varied for proteins under altered experimental conditions. For accurately predicting protein solubility using SCM, it is better to customize the score card of dipeptide propensities by using a training data set under the same specified

  7. Plasma glucose and insulin responses after consumption of breakfasts with different sources of soluble fiber in type 2 diabetes patients: a randomized crossover clinical trial.

    PubMed

    de Carvalho, Cláudia M; de Paula, Tatiana P; Viana, Luciana V; Machado, Vitória Mt; de Almeida, Jussara C; Azevedo, Mirela J

    2017-11-01

    Background: The amount and quality of carbohydrates are important determinants of plasma glucose after meals. Regarding fiber content, it is unclear whether the intake of soluble fibers from foods or supplements has an equally beneficial effect on lowering postprandial glucose. Objective: The aim of our study was to compare the acute effect of soluble fiber intake from foods or supplements after a common meal on postprandial plasma glucose and plasma insulin in patients with type 2 diabetes (T2D). Design: A randomized crossover clinical trial was conducted in patients with T2D. Patients consumed isocaloric breakfasts (mean ± SD: 369.8 ± 9.4 kcal) with high amounts of fiber from diet food sources (total fiber: 9.7 g; soluble fiber: 5.4 g), high amounts of soluble fiber from guar gum supplement (total fiber: 9.1 g; soluble fiber: 5.4 g), and normal amounts of fiber (total fiber: 2.4 g; soluble fiber: 0.8 g). Primary outcomes were postprandial plasma glucose and insulin (0-180 min). Data were analyzed by repeated measures ANOVA and post hoc Bonferroni test. Results: A total of 19 patients [aged 65.8 ± 7.3 y; median (IQR), 10 (5-9) y of T2D duration; glycated hemoglobin 7.0% ± 0.8%; body mass index (in kg/m 2 ) 28.2 ± 2.9] completed 57 meal tests. After breakfast, the incremental area under the curve (iAUC) for plasma glucose [mg/dL · min; mean (95% CI)] did not differ between high fiber from diet (HFD) [7861 (6257, 9465)] and high fiber from supplement (HFS) [7847 (5605, 10,090)] ( P = 1.00) and both were lower than usual fiber (UF) [9527 (7549, 11,504)] ( P = 0.014 and P = 0.037, respectively). iAUCs [μIU/mL · min; mean (95% CI)] did not differ ( P = 0.877): HFD [3781 (2513, 5050)], HFS [4006 (2711, 5302), and UF [4315 (3027, 5603)]. Conclusions: Higher fiber intake was associated with lower postprandial glucose at breakfast, and the intake of soluble fiber from food and supplement had a similar effect in patients with T2D. This trial was registered at

  8. Development of High Temperature Type Vacuum Insulation Panel using Soluble Polyimide and Characteristic Evaluation

    NASA Astrophysics Data System (ADS)

    Araki, Kuninari; Kamoto, Daigorou; Matsuoka, Shin-Ichi

    The utilization is expected from the high-insulated characteristic as a tool for energy saving also in the high temperature insulation fields as in vacuum insulation panels (VIP) in the future. For high temperature, the material composition and process of VIP were reviewed, the SUS foil was adopted as packaging material, and soluble polyimide was developed as the thermo compression bonding material for high temperature VIP at 150°C. To lower the glass-transition temperature (Tg) under 200°C, we elaborated the new soluble polyimide using aliphatic diamine copolymer, and controlled Tg to about 176°C. By making from trial VIP and evaluations, it was possible to be maintain high performance concerning the coefficient of thermal conductivity [λ<0.008 W/(m·K) at 150°C].

  9. Enhanced neuroinvasion by smaller, soluble prions.

    PubMed

    Bett, Cyrus; Lawrence, Jessica; Kurt, Timothy D; Orru, Christina; Aguilar-Calvo, Patricia; Kincaid, Anthony E; Surewicz, Witold K; Caughey, Byron; Wu, Chengbiao; Sigurdson, Christina J

    2017-04-21

    Infectious prion aggregates can propagate from extraneural sites into the brain with remarkable efficiency, likely transported via peripheral nerves. Yet not all prions spread into the brain, and the physical properties of a prion that is capable of transit within neurons remain unclear. We hypothesized that small, diffusible aggregates spread into the CNS via peripheral nerves. Here we used a structurally diverse panel of prion strains to analyze how the prion conformation impacts transit into the brain. Two prion strains form fibrils visible ultrastructurally in the brain in situ, whereas three strains form diffuse, subfibrillar prion deposits and no visible fibrils. The subfibrillar strains had significantly higher levels of soluble prion aggregates than the fibrillar strains. Primary neurons internalized both the subfibrillar and fibril-forming prion strains by macropinocytosis, and both strain types were transported from the axon terminal to the cell body in vitro. However in mice, only the predominantly soluble, subfibrillar prions, and not the fibrillar prions, were efficiently transported from the tongue to the brain. Sonicating a fibrillar prion strain increased the solubility and enabled prions to spread into the brain in mice, as evident by a 40% increase in the attack rate, indicating that an increase in smaller particles enhances prion neuroinvasion. Our data suggest that the small, highly soluble prion particles have a higher capacity for transport via nerves. These findings help explain how prions that predominantly assemble into subfibrillar states can more effectively traverse into and out of the CNS, and suggest that promoting fibril assembly may slow the neuron-to-neuron spread of protein aggregates.

  10. PETROLEUM RESIDUA SOLUBILITY PARAMETER/POLARITY MAP: STABILITY STUDIES OF RESIDUA PYROLYSIS

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    John F. Schabron; A. Troy Pauli; Joseph F. Rovani, Jr.

    1999-04-30

    A new molecular weight/polarity map based on the Scatchard-Hildebrand solubility equation has been developed for petroleum residua. A series of extractions are performed with solvents of increasing solubility parameter, and the fractions are analyzed by vapor pressure osmometry for number average molecular weight and by analytical-scale size exclusion chromatography for molecular weight spread. Work was performed for a heavy oil material subjected to three increasing severities of thermal treatment prior to and through the onset of coke formation. The results are diagnostic of the layers of solvations by resin-type molecules around a central asphaltene core. Two additional stability diagnostic methodsmore » were also used. These were the Heithaus titration ''P-index'' and Gaestel ''G'' index, which have been applied to paving asphalts for decades. The Heithaus titration involves the titration of three toluene solutions of a residuum at three concentrations with a poor solvent, such as isooctane, to the point of asphaltene flocculation. In the present work, the significance of the data are developed in terms of the Hildebrand solubility parameter. The Heithaus results are combined with data from the new molecular weight/polarity map. The solubility parameters for the toluene-soluble asphaltene components are measured, and the solubility parameters of the maltenes can be calculated. As thermal treatment progresses, the solubility parameters of asphaltene materials increase and the molecular weights decrease. A new coking index is proposed based on Heithaus titration data. Preliminary results suggest that an alternative, simpler coking index may be developed by measuring the weight percent of cyclohexane solubles in heptane asphaltenes. Coking onset appears to coincide with the depletion of these resin-type asphaltene solubilizing components of residua. The objective of the present study was to develop a mapping tool that will enhance understanding of the changes

  11. Effect of guava (Psidium guajava Linn.) leaf soluble solids on glucose metabolism in type 2 diabetic rats.

    PubMed

    Shen, Szu-Chuan; Cheng, Fang-Chi; Wu, Ning-Jung

    2008-11-01

    This study investigated the effect of aqueous and ethanol soluble solid extracts of guava (Psidium guajava Linn.) leaves on hypoglycemia and glucose metabolism in type 2 diabetic rats. Low-dose streptozotocin (STZ) and nicotinamide were injected into Sprague-Dawley (SD) rats to induce type 2 diabetes. Acute and long-term feeding tests were carried out, and an oral glucose tolerance test (OGTT) to follow the changes in plasma glucose and insulin levels was performed to evaluate the antihyperglycemic effect of guava leaf extracts in diabetic rats.The results of acute and long-term feeding tests showed a significant reduction in the blood sugar level in diabetic rats fed with either the aqueous or ethanol extract of guava leaves (p < 0.05). Long-term administration of guava leaf extracts increased the plasma insulin level and glucose utilization in diabetic rats. The results also indicated that the activities of hepatic hexokinase, phosphofructokinase and glucose-6-phosphate dehydrogenase in diabetic rats fed with aqueous extracts were higher than in the normal diabetic group (p < 0.05). On the other hand, diabetic rats treated with the ethanol extract raised the activities of hepatic hexokinase and glucose-6-phosphate dehydrogenase (p < 0.05) only. The experiments provided evidence to support the antihyperglycemic effect of guava leaf extract and the health function of guava leaves against type 2 diabetes.

  12. A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease

    PubMed Central

    Spinale, Joann M.; Mariani, Laura H.; Kapoor, Shiv; Zhang, Jidong; Weyant, Robert; Song, Peter X.; Wong, Hetty N.; Troost, Jonathan P.; Gadegbeku, Crystal A.; Gipson, Debbie S.; Kretzler, Matthias; Nihalani, Deepak; Holzman, Lawrence B.

    2014-01-01

    It has been suggested that soluble urokinase receptor (suPAR) is a causative circulating factor for and a biomarker of focal and segmental glomerulosclerosis (FSGS). Here we undertook validation of these assumptions in both mouse and human models. Injection of recombinant suPAR in wild-type mice did not induce proteinuria within 24 hours. Moreover, a disease phenotype was not seen in an inducible transgenic mouse model that maintained elevated suPAR concentrations for 6 weeks. Plasma and urine suPAR concentrations were evaluated as clinical biomarkers in 241 patients with glomerular disease from the prospective, longitudinal multi-center observational NEPTUNE cohort. The serum suPAR concentration at baseline inversely correlated with estimated glomerular filtration rate (eGFR) and the urine suPAR/creatinine ratio positively correlated with the urine protein/creatinine ratio. After adjusting for eGFR and urine protein, neither the serum nor urine suPAR level was an independent predictor of FSGS histopathology. A multivariable mixed-effects model of longitudinal data evaluated the association between the change in serum suPAR concentration from baseline with eGFR. After adjusting for baseline suPAR concentration, age, gender, proteinuria and time, the change in suPAR from baseline was associated with eGFR, but this association was not different for patients with FSGS as compared to other diagnoses. Thus, these results do not support a pathological role for suPAR in FSGS. PMID:25354239

  13. A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease.

    PubMed

    Spinale, Joann M; Mariani, Laura H; Kapoor, Shiv; Zhang, Jidong; Weyant, Robert; Song, Peter X; Wong, Hetty N; Troost, Jonathan P; Gadegbeku, Crystal A; Gipson, Debbie S; Kretzler, Matthias; Nihalani, Deepak; Holzman, Lawrence B

    2015-03-01

    It has been suggested that soluble urokinase receptor (suPAR) is a causative circulating factor for and a biomarker of focal and segmental glomerulosclerosis (FSGS). Here we undertook validation of these assumptions in both mouse and human models. Injection of recombinant suPAR in wild-type mice did not induce proteinuria within 24 h. Moreover, a disease phenotype was not seen in an inducible transgenic mouse model that maintained elevated suPAR concentrations for 6 weeks. Plasma and urine suPAR concentrations were evaluated as clinical biomarkers in 241 patients with glomerular disease from the prospective, longitudinal multicenter observational NEPTUNE cohort. The serum suPAR concentration at baseline inversely correlated with estimated glomerular filtration rate (eGFR) and the urine suPAR/creatinine ratio positively correlated with the urine protein/creatinine ratio. After adjusting for eGFR and urine protein, neither the serum nor urine suPAR level was an independent predictor of FSGS histopathology. A multivariable mixed-effects model of longitudinal data evaluated the association between the change in serum suPAR concentration from baseline with eGFR. After adjusting for baseline suPAR concentration, age, gender, proteinuria, and time, the change in suPAR from baseline was associated with eGFR, but this association was not different for patients with FSGS as compared with other diagnoses. Thus these results do not support a pathological role for suPAR in FSGS.

  14. Characterization of EDTA-soluble polysaccharides from the scape of Musa paradisiaca (banana).

    PubMed

    Raju, T S; Jagadish, R L; Anjaneyalu, Y V

    2001-02-01

    The polysaccharide components present in the scape of Musa paradisiaca (banana) were fractionated into water-soluble (WSP), EDTA-soluble (EDTA-SP), alkali-soluble (ASP) and alkali-insoluble (AISP) polysaccharide fractions [Anjaneyalu, Jagadish and Raju (1997) Glycoconj. J. 14, 507-512]. The EDTA-SP was further fractionated by iso-amyl alcohol into EDTA-SP-A and EDTA-SP-B. The homogeneity of these two polysaccharides was established by repeated precipitation with iso-amyl alcohol, gel-filtration chromatography and sedimentation analysis. The polysaccharides were characterized by monosaccharide composition analysis, methylation linkage analysis, iodine affinity, ferricyanide number, blue value, hydrolysis with alpha-amylase, gold-electron microscopy and X-ray diffraction spectroscopy. Data from all of these studies suggest that EDTA-SP-A is a branched amylose-type alpha-D-glucan and that EDTA-SP-B is a highly branched amylopectin-type polymer. The nature of the branching patterns of these polysaccharides suggests that they are unique to M. paradisiaca.

  15. Comparative c-type cytochrome expression analysis in Shewanella oneidensis strain MR-1 and Anaeromyxobacter dehalogenans strain 2CP-C grown with soluble and insoluble oxidised metal electron acceptors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nissen, Silke; Liu, Xiaoxin; Chourey, Karuna

    2012-01-01

    The genomes of Shewanella oneidensis strain MR-1 and Anaeromyxobacter dehalogenans strain 2CP-C encode 40 and 69 putative c-type cytochrome genes, respectively. Deletion mutant and biochemical studies have assigned specific functions to a few c-type cytochromes involved in electron transfer to oxidised metals in Shewanella oneidensis strain MR-1. Although promising, the genetic approach is limited to gene deletions that produce a distinct phenotype, and organism for which a genetic system is available. To more comprehensively investigate and compare c-type cytochrome expression in Shewanella oneidensis strain MR-1 and Anaeromyxobacter dehalogenans strain 2CP-C, proteomic measurements were used to characterise lysates of cells grownmore » with soluble Fe(III) (as ferric citrate) and insoluble Mn(IV) (as MnO2) as electron acceptors. Strain MR-1 expressed 19 and 20, and strain 2CP-C expressed 27 and 25 c-type cytochromes when grown with Fe(III) and Mn(IV), respectively. The majority of c-type cytochromes (77% for strain MR-1 and 63% for strain 2CP-C) were expressed under both growth conditions; however, the analysis also revealed unique c-type cytochromes that were specifically expressed in cells grown with soluble Fe(III) or insoluble Mn(IV). Proteomic characterisation proved to be a promising approach for determining the c-type cytochrome complement expressed under different growth conditions, and will help elucidating the specific functions of more c-type cytochromes that are the basis for Shewanella and Anaeromyxobacter respiratory versatility.« less

  16. [Preliminary study on correlation between diversity of soluble proteins and producing area of Cordyceps sinensis].

    PubMed

    Ren, Yan; Qiu, Yi; Wan, De-Guang; Lu, Xian-Ming; Guo, Jin-Lin

    2013-05-01

    To analyze the content and type of soluble proteins in Cordyceps sinensis from different producing areas and processed with different methods with bradford method and 2-DE technology, in order to discover significant differences in soluble proteins in C. sinensis processed with different methods and from different producing areas. The preliminary study indicated that the content and diversity of soluble proteins were related to producing areas and processing methods to some extent.

  17. Effect of cyclodextrin complexation on the aqueous solubility and solubility/dose ratio of praziquantel.

    PubMed

    Maragos, Stratos; Archontaki, Helen; Macheras, Panos; Valsami, Georgia

    2009-01-01

    Praziquantel (PZQ), the primary drug of choice in the treatment of schistosomiasis, is a highly lipophilic drug that possesses high permeability and low aqueous solubility and is, therefore, classified as a Class II drug according to the Biopharmaceutics Classification System (BCS). In this work, beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) were used in order to determine whether increasing the aqueous solubility of a drug by complexation with CDs, a BCS-Class II compound like PZQ could behave as BCS-Class I (highly soluble/highly permeable) drug. Phase solubility and the kneading and lyophilization techniques were used for inclusion complex preparation; solubility was determined by UV spectroscopy. The ability of the water soluble polymer polyvinylpyrolidone (PVP) to increase the complexation and solubilization efficiency of beta-CD and HP-beta-CD for PZQ was examined. Results showed significant improvement of PZQ solubility in the presence of both cyclodextrins but no additional effect in the presence of PVP. The solubility/dose ratios values of PZQ-cyclodextrin complexes calculated considering the low (150 mg) and the high dose (600 mg) of PZQ, used in practice, indicate that PZQ complexation with CDs may result in drug dosage forms that would behave as a BCS-Class I depending on the administered dose.

  18. Oral formulation strategies to improve solubility of poorly water-soluble drugs.

    PubMed

    Singh, Abhishek; Worku, Zelalem Ayenew; Van den Mooter, Guy

    2011-10-01

    In the past two decades, there has been a spiraling increase in the complexity and specificity of drug-receptor targets. It is possible to design drugs for these diverse targets with advances in combinatorial chemistry and high throughput screening. Unfortunately, but not entirely unexpectedly, these advances have been accompanied by an increase in the structural complexity and a decrease in the solubility of the active pharmaceutical ingredient. Therefore, the importance of formulation strategies to improve the solubility of poorly water-soluble drugs is inevitable, thus making it crucial to understand and explore the recent trends. Drug delivery systems (DDS), such as solid dispersions, soluble complexes, self-emulsifying drug delivery systems (SEDDS), nanocrystals and mesoporous inorganic carriers, are discussed briefly in this review, along with examples of marketed products. This article provides the reader with a concise overview of currently relevant formulation strategies and proposes anticipated future trends. Today, the pharmaceutical industry has at its disposal a series of reliable and scalable formulation strategies for poorly soluble drugs. However, due to a lack of understanding of the basic physical chemistry behind these strategies, formulation development is still driven by trial and error.

  19. Bioconcentration factors and lipid solubility

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Banerjee, S.; Baughman, G.L.

    1991-03-01

    The log-log relationship between bioconcentration and hydrophobicity breaks down for several medium and high molecular weight solutes that bioconcentrate either to a small extent or not at all. Much of the failure is attributed to the relatively low solubility of these compounds in lipid. Inclusion of a term in octanol solubility (in place of lipid solubility, which is generally unavailable) considerably improves the quality of the relationship (r = 0.95). It is speculated that the octanol solubility term compensates for the relatively low solubility of large compounds in lipid.

  20. The solubility-permeability interplay and its implications in formulation design and development for poorly soluble drugs.

    PubMed

    Dahan, Arik; Miller, Jonathan M

    2012-06-01

    While each of the two key parameters of oral drug absorption, the solubility and the permeability, has been comprehensively studied separately, the relationship and interplay between the two have been largely ignored. For instance, when formulating a low-solubility drug using various solubilization techniques: what are we doing to the apparent permeability when we increase the solubility? Permeability is equal to the drug's diffusion coefficient through the membrane times the membrane/aqueous partition coefficient divided by the membrane thickness. The direct correlation between the intestinal permeability and the membrane/aqueous partitioning, which in turn is dependent on the drug's apparent solubility in the GI milieu, suggests that the solubility and the permeability are closely associated, exhibiting a certain interplay between them, and the current view of treating the one irrespectively of the other may not be sufficient. In this paper, we describe the research that has been done thus far, and present new data, to shed light on this solubility-permeability interplay. It has been shown that decreased apparent permeability accompanies the solubility increase when using different solubilization methods. Overall, the weight of the evidence indicates that the solubility-permeability interplay cannot be ignored when using solubility-enabling formulations; looking solely at the solubility enhancement that the formulation enables may be misleading with regards to predicting the resulting absorption, and hence, the solubility-permeability interplay must be taken into account to strike the optimal solubility-permeability balance, in order to maximize the overall absorption.

  1. Protein solubility modeling

    NASA Technical Reports Server (NTRS)

    Agena, S. M.; Pusey, M. L.; Bogle, I. D.

    1999-01-01

    A thermodynamic framework (UNIQUAC model with temperature dependent parameters) is applied to model the salt-induced protein crystallization equilibrium, i.e., protein solubility. The framework introduces a term for the solubility product describing protein transfer between the liquid and solid phase and a term for the solution behavior describing deviation from ideal solution. Protein solubility is modeled as a function of salt concentration and temperature for a four-component system consisting of a protein, pseudo solvent (water and buffer), cation, and anion (salt). Two different systems, lysozyme with sodium chloride and concanavalin A with ammonium sulfate, are investigated. Comparison of the modeled and experimental protein solubility data results in an average root mean square deviation of 5.8%, demonstrating that the model closely follows the experimental behavior. Model calculations and model parameters are reviewed to examine the model and protein crystallization process. Copyright 1999 John Wiley & Sons, Inc.

  2. Different small, acid-soluble proteins of the alpha/beta type have interchangeable roles in the heat and UV radiation resistance of Bacillus subtilis spores.

    PubMed Central

    Mason, J M; Setlow, P

    1987-01-01

    Spores of Bacillus subtilis strains which carry deletion mutations in one gene (sspA) or two genes (sspA and sspB) which code for major alpha/beta-type small, acid-soluble spore proteins (SASP) are known to be much more sensitive to heat and UV radiation than wild-type spores. This heat- and UV-sensitive phenotype was cured completely or in part by introduction into these mutant strains of one or more copies of the sspA or sspB genes themselves; multiple copies of the B. subtilis sspD gene, which codes for a minor alpha/beta-type SASP; or multiple copies of the SASP-C gene, which codes for a major alpha/beta-type SASP of Bacillus megaterium. These findings suggest that alpha/beta-type SASP play interchangeable roles in the heat and UV radiation resistance of bacterial spores. Images PMID:3112127

  3. Impact of type 2 diabetes on the plasma levels of vascular endothelial growth factor and its soluble receptors type 1 and type 2 in patients with peripheral arterial disease.

    PubMed

    Wieczór, Radosław; Gadomska, Grażyna; Ruszkowska-Ciastek, Barbara; Stankowska, Katarzyna; Budzyński, Jacek; Fabisiak, Jacek; Suppan, Karol; Pulkowski, Grzegorz; Rość, Danuta

    2015-11-01

    Type 2 diabetes coexistent with lower extremity artery disease (peripheral arterial disease (PAD)) can be observed in numerous patients. The mechanism compensating for ischemia and contributing to healing is angiogenesis-the process of forming new blood vessels. The purpose of this study was to assess the likely impact of type 2 diabetes on the plasma levels of proangiogenic factor (vascular endothelial growth factor A (VEGF-A)) and angiogenesis inhibitors (soluble VEGF receptors type 1 and type 2 (sVEGFR-1 and sVEGFR-2)) in patients with PAD. Among 46 patients with PAD under pharmacological therapy (non-invasive), we identified, based on medical history, a subgroup with coexistent type 2 diabetes (PAD-DM2+, n=15) and without diabetes (PAD-DM2-, n=31). The control group consisted of 30 healthy subjects. Plasma levels of VEGF-A, sVEGFR-1, and sVEGFR-2 were measured using the enzyme-linked immunosorbent assay (ELISA) method. The subgroups of PAD-DM2+ and PAD-DM2- revealed significantly higher concentrations of VEGF-A (P=0.000 007 and P=0.000 000 1, respectively) and significantly lower sVEGFR-2 levels (P=0.02 and P=0.000 01, respectively), when compared with the control group. Patients with PAD and coexistent diabetes tended to have a lower level of VEGF-A and higher levels of sVEGFR-1 and sVEGFR-2 comparable with non-diabetic patients. The coexistence of type 2 diabetes and PAD is demonstrated by a tendency to a lower plasma level of proangiogenic factor (VEGF-A) and higher levels of angiogenesis inhibitors (sVEGFR-1 and sVEGFR-2) at the same time. Regardless of the coexistence of type 2 diabetes, hypoxia appears to be a crucial factor stimulating the processes of angiogenesis in PAD patients comparable with healthy individuals, whereas hyperglycemia may have a negative impact on angiogenesis in lower limbs.

  4. Soluble polymer conjugates for drug delivery.

    PubMed

    Minko, Tamara

    2005-01-01

    The use of water-soluble polymeric conjugates as drug carriers offers several possible advantages. These advantages include: (1) improved drug pharmacokinetics; (2) decreased toxicity to healthy organs; (3) possible facilitation of accumulation and preferential uptake by targeted cells; (4) programmed profile of drug release. In this review, we will consider the main types of useful polymeric conjugates and their role and effectiveness as carriers in drug delivery systems.: © 2005 Elsevier Ltd . All rights reserved.

  5. Enhanced solubility and bioavailability of sibutramine base by solid dispersion system with aqueous medium.

    PubMed

    Li, Dong Xun; Jang, Ki-Young; Kang, Wonku; Bae, Kyoungjin; Lee, Mann Hyung; Oh, Yu-Kyoung; Jee, Jun-Pil; Park, Young-Joon; Oh, Dong Hoon; Seo, Youn Gee; Kim, Young Ran; Kim, Jong Oh; Woo, Jong Soo; Yong, Chul Soon; Choi, Han-Gon

    2010-01-01

    To develop a novel sibutramine base-loaded solid dispersion with improved solubility bioavailability, various solid dispersions were prepared with water, hydroxypropylmethyl cellulose (HPMC), poloxamer and citric acid using spray-drying technique. The effect of HPMC, poloxamer and citric acid on the aqueous solubility of sibutramine was investigated. The physicochemical properties of solid dispersion were investigated using scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction. The dissolution and pharmacokinetics in rats of solid dispersion were evaluated compared to the sibutramine hydrochloride monohydrate-loaded commercial product (Reductil). The sibutramine base-loaded solid dispersion gave two type forms. Like conventional solid dispersion system, one type appeared as a spherical shape with smooth surface, as the carriers and drug with relatively low melting point were soluble in water and formed it. The other appeared as an irregular form with relatively rough surface. Unlike conventional solid dispersion system, this type changed no crystalline form of drug. Our results suggested that this type was formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting from changing the hydrophobic drug to hydrophilic form. The sibutramine-loaded solid dispersion at the weight ratio of sibutramine base/HPMC/poloxamer/citric acid of 5/3/3/0.2 gave the maximum drug solubility of about 3 mg/ml. Furthermore, it showed the similar plasma concentration, area under the curve (AUC) and C(max) of parent drug, metabolite I and II to the commercial product, indicating that it might give the similar drug efficacy compared to the sibutramine hydrochloride monohydrate-loaded commercial product in rats. Thus, this solid dispersion system would be useful to deliver poorly water-soluble sibutramine base with enhanced bioavailability.

  6. Overexpression of Activin Receptor-like Kinase 7 in Breast Cancer Cells Is Associated with Decreased Cell Growth and Adhesion.

    PubMed

    Hu, Tingting; Su, Fengxi; Jiang, Wenguo; Dart, D Alwyn

    2017-07-01

    To examine the expression and function of activin receptor-like kinase 7 (ALK7) in breast cancer, its association with disease prognosis, and its impact on breast cancer cell function. A cohort of patients with breast cancer were examined for ALK7 expression in association with pathological and clinical aspects. In vitro cell assays of ALK7 were investigated using an expression plasmid. Overall higher levels of ALK7 transcripts were seen in the breast cancer samples vs. normal tissue. However, within the cancer cohort, lower levels of ALK7 transcript were associated with poor prognosis. Patients with lower expression of ALK7 also had shorter survival. Overexpression of ALK7 reduced proliferation and adhesion of breast cancer cells in vitro. We found that overexpressed ALK7 had complex effects on the MCF-7 cell sensitivity to chemotherapy drugs. Decreased expression of ALK7 in breast cancer is correlated with poor prognosis. ALK7 is a negative regulator of adhesion and proliferation of breast cancer cells. This suggests that ALK7 is a potential tumor suppressor in breast cancer. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  7. Head-To-Head Comparison of Different Solubility-Enabling Formulations of Etoposide and Their Consequent Solubility-Permeability Interplay.

    PubMed

    Beig, Avital; Miller, Jonathan M; Lindley, David; Carr, Robert A; Zocharski, Philip; Agbaria, Riad; Dahan, Arik

    2015-09-01

    The purpose of this study was to conduct a head-to-head comparison of different solubility-enabling formulations, and their consequent solubility-permeability interplay. The low-solubility anticancer drug etoposide was formulated in several strengths of four solubility-enabling formulations: hydroxypropyl-β-cyclodextrin, the cosolvent polyethylene glycol 400 (PEG-400), the surfactant sodium lauryl sulfate, and an amorphous solid dispersion formulation. The ability of these formulations to increase the solubility of etoposide was investigated, followed by permeability studies using the parallel artificial membrane permeability assay (PAMPA) and examination of the consequent solubility-permeability interplay. All formulations significantly increased etoposide's apparent solubility. The cyclodextrin-, surfactant-, and cosolvent-based formulations resulted in a concomitant decreased permeability that could be modeled directly from the proportional increase in the apparent solubility. On the contrary, etoposide permeability remained constant when using the ASD formulation, irrespective of the increased apparent solubility provided by the formulation. In conclusion, supersaturation resulting from the amorphous form overcomes the solubility-permeability tradeoff associated with other formulation techniques. Accounting for the solubility-permeability interplay may allow to develop better solubility-enabling formulations, thereby maximizing the overall absorption of lipophilic orally administered drugs. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  8. Solubilization of poorly water-soluble drugs using solid dispersions.

    PubMed

    Tran, Thao T-D; Tran, Phuong H-L; Khanh, Tran N; Van, Toi V; Lee, Beom-Jin

    2013-08-01

    Many new drugs have been discovered in pharmaceutical industry and exposed their surprised potential therapeutic effects. Unfortunately, these drugs possess low absorption and bioavailability since their solubility limitation in water. Solid dispersion (SD) is the current technique gaining so many attractions from scientists due to its effect on improving solubility and dissolution rate of poorly water-soluble drugs. A number of patents including the most recent inventions have been undertaken in this review to address various respects of this strategy in solubilization of poorly watersoluble drugs including type of carriers, preparation methods and view of technologies used to detect SD properties and mechanisms with the aim to accomplish a SD not only effective on enhanced bioavailability but also overcome difficulties associated with stability and production. Future prospects are as well discussed with an only hope that many developments and researches in this field will be successfully reached and contributed to commercial use for treatment as much as possible.

  9. The solubility-permeability interplay and oral drug formulation design: Two heads are better than one.

    PubMed

    Dahan, Arik; Beig, Avital; Lindley, David; Miller, Jonathan M

    2016-06-01

    Poor aqueous solubility is a major challenge in today's biopharmaceutics. While solubility-enabling formulations can significantly increase the apparent solubility of the drug, the concomitant effect on the drug's apparent permeability has been largely overlooked. The mathematical equation to describe the membrane permeability of a drug comprises the membrane/aqueous partition coefficient, which in turn is dependent on the drug's apparent solubility in the GI milieu, suggesting that the solubility and the permeability are closely related, exhibit a certain interplay between them, and treating the one irrespectively of the other may be insufficient. In this article, an overview of this solubility-permeability interplay is provided, and the available data is analyzed in the context of the effort to maximize the overall drug exposure. Overall, depending on the type of solubility-permeability interplay, the permeability may decrease, remain unchanged, and even increase, in a way that may critically affect the formulation capability to improve the overall absorption. Therefore, an intelligent design of solubility-enabling formulation needs to consider both the solubility afforded by the formulation and the permeability in the new luminal environment resulting from the formulation. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Solubility behavior and biopharmaceutical classification of novel high-solubility ciprofloxacin and norfloxacin pharmaceutical derivatives.

    PubMed

    Breda, Susana A; Jimenez-Kairuz, Alvaro F; Manzo, Ruben H; Olivera, María E

    2009-04-17

    The hydrochlorides of the 1:3 aluminum:norfloxacin and aluminum:ciprofloxacin complexes were characterized according to the Biopharmaceutics Classification System (BCS) premises in comparison with their parent compounds. The pH-solubility profiles of the complexes were experimentally determined at 25 and 37 degrees C in the range of pH 1-8 and compared to that of uncomplexed norfloxacin and ciprofloxacin. Both complexes are clearly more soluble than the antibiotics themselves, even at the lowest solubility pHs. The increase in solubility was ascribed to the species controlling solubility, which were analyzed in the solid phases at equilibrium at selected pHs. Additionally, permeability was set as low, based on data reported in the scientific literature regarding oral bioavailability, intestinal and cell cultures permeabilities and also considering the influence of stoichiometric amounts of aluminum. The complexes fulfill the BCS criterion to be classified as class 3 compounds (high solubility/low permeability). Instead, the active pharmaceutical ingredients (APIs) currently used in solid dosage forms, norfloxacin and ciprofloxacin hydrochloride, proved to be BCS class 4 (low solubility/low permeability). The solubility improvement turns the complexes as potential biowaiver candidates from the scientific point of view and may be a good way for developing more dose-efficient formulations. An immediate release tablet showing very rapid dissolution was obtained. Its dissolution profile was compared to that of the commercial ciprofloxacin hydrochloride tablets allowing to dissolution of the complete dose at a critical pH such as 6.8.

  11. TitaniQ in reverse: backing out the equilibrium solubility of titanium in quartz

    NASA Astrophysics Data System (ADS)

    Thomas, J. B.

    2014-12-01

    There is close agreement among three of the four experimental studies that have 'calibrated' the P-T dependencies of Ti-in-quartz solubility. New experiments were conducted to identify potential experimental disequilibrium, and determine which Ti-in-quartz solubility calibration is most accurate. Quartz and rutile were synthesized from SiO2- and TiO2saturated aqueous fluids in a forward-type experiment at 925°C and 10 kbar in a piston-cylinder apparatus. A range of crystal sizes was examined to determine if growth rate affected Ti incorporation in quartz. Cathodoluminescence (CL) images and electron microprobe measurements show that intercrystalline and intracrystalline variations in Ti concentrations are remarkably small regardless of crystal size. The average Ti-in-quartz concentration from the forward-type experiment is 392±1 ppm Ti, which is within 95% confidence interval of data from the 10 kbar isobar of Wark and Watson (2006) and Thomas et al. (2010). Quartz from the forward-type experiment was used as starting material for reversal-type experiments. The high-Ti quartz starting material was recrystallized at 925°C and 20 kbar to reduce the solubility of Ti in recrystallized quartz to the equilibrium solubility concentration of the reversed P-T condition. The 'dry' and 'wet' reversal experiments produced polycrystalline quartzites. Rutile occurs as inclusions in quartz, and as individual crystals dispersed along quartz/quartz grain boundaries. Quartz that recrystallized during the reversal-type experiment has substantially lower Ti concentrations than the quartz starting material because Ti solubility at 20 kbar is significantly lower than at 10 kbar. Dark cathodoluminescent quartz with low Ti concentrations shows that extensive quartz recrystallization occurred at the reversal P-T condition. The average Ti concentration in quartz from reversal experiments is 94±2 ppm Ti, which is within the 95% confidence interval of a linear fit to the 20 kbar data of

  12. [Characteristics of aerosol water-soluble inorganic ions in three types air-pollution incidents of Nanjing City].

    PubMed

    Zhang, Qiu-Chen; Zhu, Bin; Su, Ji-Feng; Wang, Hong-Lei

    2012-06-01

    In order to compare aerosol water-soluble inorganic species in different air-pollution periods, samples of PM10, PM2.1, PM1.1 and the main water-soluble ions (NH4+, Mg2+, Ca2+, Na+, K+, NO2(-), F(-), NO3(-), Cl(-), SO4(2-)) were measured, which were from 3 air-pollution incidents (continued pollution in October 16-30 of 2009, sandstorm pollution in April 27-30 of 2010, and crop burning pollution in June 14 of 2010. The results show that aerosol pollution of 3 periods is serious. The lowest PM2.1/PM10 is only 0.27, which is from sandstorm pollution period, while the largest is 0. 7 from crop burning pollution period. In continued pollution periods, NO3(-) and SO4(2-) are the dominant ions, and the total anions account for an average of 18.62%, 32.92% and 33.53% of PM10, PM2.1 and PM1.1. Total water-soluble ions only account for 13.36%, 23.72% and 28.54% of PM10, PM2.1 and PM1.1 due to the insoluble species is increased in sandstorm pollution period. The mass concentration of Ca2+ in sandstorm pollution period is higher than the other two pollution periods, and which is mainly in coarse particles with diameter larger than 1 microm. All the ten water-soluble ions are much higher in crop burning pollution especially K+ which is the tracer from crop burning. The peak mass concentrations of NO3(-), SO4(2-) and NH4+ are in 0.43-0.65 microm.

  13. Follistatin induces muscle hypertrophy through satellite cell proliferation and inhibition of both myostatin and activin.

    PubMed

    Gilson, Hélène; Schakman, Olivier; Kalista, Stéphanie; Lause, Pascale; Tsuchida, Kunihiro; Thissen, Jean-Paul

    2009-07-01

    Follistatin (FS) inhibits several members of the TGF-beta superfamily, including myostatin (Mstn), a negative regulator of muscle growth. Mstn inhibition by FS represents a potential therapeutic approach of muscle atrophy. The aim of our study was to investigate the mechanisms of the FS-induced muscle hypertrophy. To test the role of satellite cells in the FS effect, we used irradiation to destroy their proliferative capacity. FS overexpression increased the muscle weight by about 37% in control animals, but the increase reached only 20% in irradiated muscle, supporting the role of cell proliferation in the FS-induced hypertrophy. Surprisingly, the muscle hypertrophy caused by FS reached the same magnitude in Mstn-KO as in WT mice, suggesting that Mstn might not be the only ligand of FS involved in the regulation of muscle mass. To assess the role of activin (Act), another FS ligand, in the FS-induced hypertrophy, we electroporated FSI-I, a FS mutant that does not bind Act with high affinity. Whereas FS electroporation increased muscle weight by 32%, the muscle weight gain induced by FSI-I reached only 14%. Furthermore, in Mstn-KO mice, FSI-I overexpression failed to induce hypertrophy, in contrast to FS. Therefore, these results suggest that Act inhibition may contribute to FS-induced hypertrophy. Finally, the role of Act as a regulator of muscle mass was supported by the observation that ActA overexpression induced muscle weight loss (-15%). In conclusion, our results show that satellite cell proliferation and both Mstn and Act inhibition are involved in the FS-induced muscle hypertrophy.

  14. Correlation of second virial coefficient with solubility for proteins in salt solutions.

    PubMed

    Mehta, Chirag M; White, Edward T; Litster, James D

    2012-01-01

    In this work, osmotic second virial coefficients (B(22)) were determined and correlated with the measured solubilities for the proteins, α-amylase, ovalbumin, and lysozyme. The B(22) values and solubilities were determined in similar solution conditions using two salts, sodium chloride and ammonium sulfate in an acidic pH range. An overall decrease in the solubility of the proteins (salting out) was observed at high concentrations of ammonium sulfate and sodium chloride solutions. However, for α-amylase, salting-in behavior was also observed in low concentration sodium chloride solutions. In ammonium sulfate solutions, the B(22) are small and close to zero below 2.4 M. As the ammonium sulfate concentrations were further increased, B(22) values decreased for all systems studied. The effect of sodium chloride on B(22) varies with concentration, solution pH, and the type of protein studied. Theoretical models show a reasonable fit to the experimental derived data of B(22) and solubility. B(22) is also directly proportional to the logarithm of the solubility values for individual proteins in salt solutions, so the log-linear empirical models developed in this work can also be used to rapidly predict solubility and B(22) values for given protein-salt systems. Copyright © 2011 American Institute of Chemical Engineers (AIChE).

  15. Solubility and transdermal permeation properties of a dehydroepiandrosterone cyclodextrin complex from hydrophilic and lipophilic vehicles.

    PubMed

    Ceschel, GianCarlo; Bergamante, Valentina; Maffei, Paola; Lombardi Borgia, Simone; Calabrese, Valeria; Biserni, Stefano; Ronchi, Celestino

    2005-01-01

    The permeation ability of a compound is due principally to its concentration in the vehicle and to its aptitude to cross the stratum corneum of the skin. In this work ex-vivo permeation studies on newly developed formulations containing dehydroepiandrosterone (DHEA) were carried out to investigate vehicles that increase drug permeation through the skin. To enhance the solubility of DHEA, its complex form with alpha-cyclodextrin was used. In addition, the two forms (pure drug and complex form) were introduced in hydrophilic (water), lipophilic (paraffin oil), and microemulsion vehicles to evaluate the synergic effect of cyclodextrins and microemulsion vehicles on solubility and permeation. From the results, DHEA solubility is notably conditioned by the type of the vehicle used: the highest solubilities (both for pure and complex drug forms) were obtained with microemulsion, followed by paraffin oil and water. Moreover, in all the studied vehicles, the c-DHEA was more soluble than DHEA. Permeation profile fluxes showed very interesting differences. That reflect the varying drug forms (pure drug and complex form), vehicles used, and drug concentrations in the vehicles. The major flux was obtained in complex of DHEA with alpha-cyclodextrins in the microemulsion vehicle. Therefore, this type of vehicle and drug form would be very useful in the development of a topical formulation containing DHEA.

  16. Cyclodextrin-water soluble polymer ternary complexes enhance the solubility and dissolution behaviour of poorly soluble drugs. Case example: itraconazole.

    PubMed

    Taupitz, Thomas; Dressman, Jennifer B; Buchanan, Charles M; Klein, Sandra

    2013-04-01

    The aim of the present series of experiments was to improve the solubility and dissolution/precipitation behaviour of a poorly soluble, weakly basic drug, using itraconazole as a case example. Binary inclusion complexes of itraconazole with two commonly used cyclodextrin derivatives and a recently introduced cyclodextrin derivative were prepared. Their solubility and dissolution behaviour was compared with that of the pure drug and the marketed formulation Sporanox®. Ternary complexes were prepared by addition of Soluplus®, a new highly water soluble polymer, during the formation of the itraconazole/cyclodextrin complex. A solid dispersion made of itraconazole and Soluplus® was also studied as a control. Solid state analysis was performed for all formulations and for pure itraconazole using powder X-ray diffraction (pX-RD) and differential scanning calorimetry (DSC). Solubility tests indicated that with all formulation approaches, the aqueous solubility of itraconazole formed with hydroxypropyl-β-cyclodextrin (HP-β-CD) or hydroxybutenyl-β-cyclodextrin (HBen-β-CD) and Soluplus® proved to be the most favourable formulation approaches. Whereas the marketed formulation and the pure drug showed very poor dissolution, both of these ternary inclusion complexes resulted in fast and extensive release of itraconazole in all test media. Using the results of the dissolution experiments, a newly developed physiologically based pharmacokinetic (PBPK) in silico model was applied to compare the in vivo behaviour of Sporanox® with the predicted performance of the most promising ternary complexes from the in vitro studies. The PBPK modelling predicted that the bioavailability of itraconazole is likely to be increased after oral administration of ternary complex formulations, especially when itraconazole is formulated as a ternary complex comprising HP-β-CD or HBen-β-CD and Soluplus®. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Controlled poorly soluble drug release from solid self-microemulsifying formulations with high viscosity hydroxypropylmethylcellulose.

    PubMed

    Yi, Tao; Wan, Jiangling; Xu, Huibi; Yang, Xiangliang

    2008-08-07

    The objective of this work was the development of a controlled release system based on self-microemulsifying mixture aimed for oral delivery of poorly water-soluble drugs. HPMC-based particle formulations were prepared by spray drying containing a model drug (nimodipine) of low water solubility and hydroxypropylmethylcellulose (HPMC) of high viscosity. One type of formulations contained nimodipine mixed with HPMC and the other type of formulations contained HPMC and nimodipine dissolved in a self-microemulsifying system (SMES) consisting of ethyl oleate, Cremophor RH 40 and Labrasol. Based on investigation by transmission electron microscopy (TEM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction, differences were found in the particle structure between both types of formulations. In vitro release was performed and characterized by the power law. Nimodipine release from both types of formulations showed a controlled release profile and the two power law parameters, n and K, correlated to the viscosity of HPMC. The parameters were also influenced by the presence of SMES. For the controlled release solid SMES, oil droplets containing dissolved nimodipine diffused out of HPMC matrices following exposure to aqueous media. Thus, it is possible to control the in vitro release of poorly soluble drugs from solid oral dosage forms containing SMES.

  18. Simulation of soluble waste transport and buildup in surface waters using tracers

    USGS Publications Warehouse

    Kilpatrick, Frederick A.

    1992-01-01

    Soluble tracers can be used to simulate the transport and dispersion of soluble wastes that might have been introduced or are planned for introduction into surface waters. Measured tracer-response curves produced from the injection of a known quantity of soluble tracer can be used in conjunction with the superposition principle to simulate potential waste buildup in streams, lakes, and estuaries. Such information is particularly valuable to environmental and water-resource planners in determining the effects of proposed waste discharges.The theory, techniques, analysis, and presentation of results of tracer-waste simulation tests in rivers, lakes, and estuaries are described. This manual builds on other manuals on dye tracing with emphasis on the expanded use of time-of-travel type data.

  19. Airway exchange of highly soluble gases.

    PubMed

    Hlastala, Michael P; Powell, Frank L; Anderson, Joseph C

    2013-03-01

    Highly blood soluble gases exchange with the bronchial circulation in the airways. On inhalation, air absorbs highly soluble gases from the airway mucosa and equilibrates with the blood before reaching the alveoli. Highly soluble gas partial pressure is identical throughout all alveoli. At the end of exhalation the partial pressure of a highly soluble gas decreases from the alveolar level in the terminal bronchioles to the end-exhaled partial pressure at the mouth. A mathematical model simulated the airway exchange of four gases (methyl isobutyl ketone, acetone, ethanol, and propylene glycol monomethyl ether) that have high water and blood solubility. The impact of solubility on the relative distribution of airway exchange was studied. We conclude that an increase in water solubility shifts the distribution of gas exchange toward the mouth. Of the four gases studied, ethanol had the greatest decrease in partial pressure from the alveolus to the mouth at end exhalation. Single exhalation breath tests are inappropriate for estimating alveolar levels of highly soluble gases, particularly for ethanol.

  20. Airway exchange of highly soluble gases

    PubMed Central

    Powell, Frank L.; Anderson, Joseph C.

    2013-01-01

    Highly blood soluble gases exchange with the bronchial circulation in the airways. On inhalation, air absorbs highly soluble gases from the airway mucosa and equilibrates with the blood before reaching the alveoli. Highly soluble gas partial pressure is identical throughout all alveoli. At the end of exhalation the partial pressure of a highly soluble gas decreases from the alveolar level in the terminal bronchioles to the end-exhaled partial pressure at the mouth. A mathematical model simulated the airway exchange of four gases (methyl isobutyl ketone, acetone, ethanol, and propylene glycol monomethyl ether) that have high water and blood solubility. The impact of solubility on the relative distribution of airway exchange was studied. We conclude that an increase in water solubility shifts the distribution of gas exchange toward the mouth. Of the four gases studied, ethanol had the greatest decrease in partial pressure from the alveolus to the mouth at end exhalation. Single exhalation breath tests are inappropriate for estimating alveolar levels of highly soluble gases, particularly for ethanol. PMID:23305981

  1. Students’ misconceptions on solubility equilibrium

    NASA Astrophysics Data System (ADS)

    Setiowati, H.; Utomo, S. B.; Ashadi

    2018-05-01

    This study investigated the students’ misconceptions of the solubility equilibrium. The participants of the study consisted of 164 students who were in the science class of second year high school. Instrument used is two-tier diagnostic test consisting of 15 items. Responses were marked and coded into four categories: understanding, misconception, understand little without misconception, and not understanding. Semi-structured interviews were carried out with 45 students according to their written responses which reflected different perspectives, to obtain a more elaborated source of data. Data collected from multiple methods were analyzed qualitatively and quantitatively. Based on the data analysis showed that the students misconceptions in all areas in solubility equilibrium. They had more misconceptions such as in the relation of solubility and solubility product, common-ion effect and pH in solubility, and precipitation concept.

  2. Transforming growth factor beta 1 increases collagen content, and stimulates procollagen I and tissue inhibitor of metalloproteinase-1 production of dental pulp cells: Role of MEK/ERK and activin receptor-like kinase-5/Smad signaling.

    PubMed

    Lin, Po-Shuen; Chang, Hsiao-Hua; Yeh, Chien-Yang; Chang, Mei-Chi; Chan, Chiu-Po; Kuo, Han-Yueh; Liu, Hsin-Cheng; Liao, Wan-Chuen; Jeng, Po-Yuan; Yeung, Sin-Yuet; Jeng, Jiiang-Huei

    2017-05-01

    In order to clarify the role of transforming growth factor beta 1 (TGF-β1) in pulp repair/regeneration responses, we investigated the differential signaling pathways responsible for the effects of TGF-β1 on collagen turnover, matrix metalloproteinase-3 (MMP-3), and tissue inhibitor of metalloproteinase-1 (TIMP-1) production in human dental pulp cells. Pulp cells were exposed to TGF-β1 with/without pretreatment and coincubation by 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenyl mercapto)butadiene (U0126; a mitogen-activated protein kinase kinase [MEK]/extracellular signal-regulated kinase [ERK] inhibitor) and 4-(5-benzol[1,3]dioxol-5-yl-4-pyrldin-2-yl-1H- imidazol-2-yl)-benzamide hydrate (SB431542; an activin receptor-like kinase-5/Smad signaling inhibitor). Sircol collagen assay was used to measure cellular collagen content. Culture medium procollagen I, TIMP-1, and MMP-3 levels were determined by enzyme-linked immunosorbent assay. TGF-β1 increased the collagen content, procollagen I, and TIMP-1 production, but slightly decreased MMP-3 production of pulp cells. SB431542 and U0126 prevented the TGF-β1-induced increase of collagen content and TIMP-1 production of dental pulp cells. These results indicate that TGF-β1 may be involved in the healing/regeneration processes of dental pulp in response to injury by stimulation of collagen and TIMP-1 production. These events are associated with activin receptor-like kinase-5/Smad2/3 and MEK/ERK signaling. Copyright © 2016. Published by Elsevier B.V.

  3. Detailed study of precipitation of a poorly water soluble test compound using methodologies as in activity and solubility screening - mixing and automation effects.

    PubMed

    Gillespie, Cheska; Kennedy, Alan R; Edwards, Darren; Dowden, Lee; Daublain, Pierre; Halling, Peter

    2013-09-01

    Storage of pharmaceutical discovery compounds dissolved in dimethylsulfoxide (DMSO) is commonplace within industry. Often, the DMSO stock solution is added to an aqueous system (e.g. in bioassay or kinetic solubility testing)- since most test compounds are hydrophobic, precipitation could occur. Little is known about the factors affecting this precipitation process at the low (µM) concentrations used in screening analyses. Here, a poorly water soluble test compound (tolnaftate) was used to compare manual and automated pipetting, and explore the effect of mixing variables on precipitation. The amount of drug present in the supernatant after precipitation and centrifugation of the samples was quantified. An unusual result was obtained in three different laboratories: results of experiments performed initially were statistically significantly higher than those performed after a few days in the same lab. No significant differences were found between automated and manual pipetting, including in variability. Vortex mixing was found to give significantly lower supernatant amounts compared to milder mixing types. The mixing employed affects the particle growth of the precipitate. These findings are of relevance to discovery stage bioassay and kinetic solubility analyses.

  4. The Solubility Parameters of Ionic Liquids

    PubMed Central

    Marciniak, Andrzej

    2010-01-01

    The Hildebrand’s solubility parameters have been calculated for 18 ionic liquids from the inverse gas chromatography measurements of the activity coefficients at infinite dilution. Retention data were used for the calculation. The solubility parameters are helpful for the prediction of the solubility in the binary solvent mixtures. From the solubility parameters, the standard enthalpies of vaporization of ionic liquids were estimated. PMID:20559495

  5. Physicochemical characterization of Capstone depleted uranium aerosols IV: in vitro solubility analysis.

    PubMed

    Guilmette, Raymond A; Cheng, Yung Sung

    2009-03-01

    As part of the Capstone Depleted Uranium (DU) Aerosol Study, the solubility of selected aerosol samples was measured using an accepted in vitro dissolution test system. This static system was employed along with a SUF (synthetic ultrafiltrate) solvent, which is designed to mimic the physiological chemistry of extracellular fluid. Using sequentially obtained solvent samples, the dissolution behavior over a 46-d test period was evaluated by fitting the measurement data to two- or three-component negative exponential functions. These functions were then compared with Type M and S absorption taken from the International Commission on Radiological Protection Publication 66 Human Respiratory Tract Model. The results indicated that there was a substantial variability in solubility of the aerosols, which in part depended on the type of armor being impacted by the DU penetrator and the particle size fraction being tested. Although some trends were suggested, the variability noted leads to uncertainties in predicting the solubility of other DU-based aerosols. Nevertheless, these data provide a useful experimental basis for modeling the intake-dose relationships for inhaled DU aerosols arising from penetrator impact on armored vehicles.

  6. Filtrates & Residues: An Experiment on the Molar Solubility and Solubility Product of Barium Nitrate.

    ERIC Educational Resources Information Center

    Wruck, Betty; Reinstein, Jesse

    1989-01-01

    Provides a two hour experiment using direct gravimetric methods to determine solubility constants. Provides methodology and sample results. Discusses the effect of the common ion on the solubility constant. (MVL)

  7. Intrinsic solubility estimation and pH-solubility behavior of cosalane (NSC 658586), an extremely hydrophobic diprotic acid.

    PubMed

    Venkatesh, S; Li, J; Xu, Y; Vishnuvajjala, R; Anderson, B D

    1996-10-01

    The selection of cosalane (NSC 658586) by the National Cancer Institute for further development as a potential drug candidate for the treatment of AIDS led to the exploration of the solubility behavior of this extremely hydrophobic drug, which has an intrinsic solubility (S0 approaching 1 ng/ml. This study describes attempts to reliably measure the intrinsic solubility of cosalane and examine its pH-solubility behavior. S0 was estimated by 5 different strategies: (a) direct determination in an aqueous suspension: (b) facilitated dissolution; (c) estimation from the octanol/water partition coefficient and octanol solubility (d) application of an empirical equation based on melting point and partition coefficient; and (e) estimation from the hydrocarbon solubility and functional group contributions for transfer from hydrocarbon to water. S0 estimates using these five methods varied over a 5 x 107-fold range Method (a) yielded the highest values, two-orders of magnitude greater than those obtained by method (b) (facilitated dissolution. 1.4 +/- 0.5 ng/ml). Method (c) gave a value 20-fold higher while that from method (d) was in fair agreement with that from facilitated dissolution. Method (e) yielded a value several orders-of-magnitude lower than other methods. A molecular dynamics simulation suggests that folded conformations not accounted for by group contributions may reduce cosalane's effective hydrophobicity. Ionic equilibria calculations for this weak diprotic acid suggested a 100-fold increase in solubility per pH unit increase. The pH-solubility profile of cosalane at 25 degrees C agreed closely with theory. These studies highlight the difficulty in determining solubility of very poorly soluble compounds and the possible advantage of the facilitated dissolution method. The diprotic nature of cosalane enabled a solubility enhancement of > 107-fold by simple pH adjustment.

  8. Comparative studies on soluble protein profiles and isozyme patterns of seven Trichinella isolates.

    PubMed

    Fukumoto, S; Takechi, M; Kamo, H; Yamaguchi, T

    1987-01-01

    Soluble protein profiles and isozyme patterns of eight enzymes were compared for extracts of muscle stage larvae of the seven Trichinella isolates, using isoelectric focusing in polyacrylamide gel. Soluble protein profiles and isozyme patterns of four enzymes: malic enzyme, glucosephosphate isomerase, phosphoglucomutase, superoxide dismutase of them were clearly divided into four types. T. pseudospiralis from a racoon and the Polar strain from a polar bear formed type 1 and type 2. The Iwasaki strain from a Japanese black bear and the Yamagata strain from a racoon dog, both from Japan, were type 3. Type 4 consisted of three remaining strains, the Polish strain from a wild pig, the USA strain from a pig and the Thai strain from a human case, which have similar infectivities to pigs. The Thai strain varied a bit electrophoretically from other members of type 4. Zymograms of adenylate kinase and malate dehydrogenase were similar in types 2 and 3. The 6-phosphogluconate dehydrogenase zymogram of type 3, similar to that of type 4, was different from that of type 2. It is assumed from the data that type 3 (Japanese strain) was genetically intermediate to types 2 and 4. T. pseudospiralis and the Polar strain had a common main isozyme of 6-phosphogluconate dehydrogenase. The zymogram of lactate dehydrogenase was common except for T. pseudospiralis.

  9. Solubility Enhancement of a Poorly Water Soluble Drug by Forming Solid Dispersions using Mechanochemical Activation

    PubMed Central

    Rojas-Oviedo, I.; Retchkiman-Corona, B.; Quirino-Barreda, C. T.; Cárdenas, J.; Schabes-Retchkiman, P. S.

    2012-01-01

    Mechanochemical activation is a practical cogrinding operation used to obtain a solid dispersion of a poorly water soluble drug through changes in the solid state molecular aggregation of drug-carrier mixtures and the formation of noncovalent interactions (hydrogen bonds) between two crystalline solids such as a soluble carrier, lactose, and a poorly soluble drug, indomethacin, in order to improve its solubility and dissolution rate. Samples of indomethacin and a physical mixture with a weight ratio of 1:1 of indomethacin and lactose were ground using a high speed vibrating ball mill. Particle size was determined by electron microscopy, the reduction of crystallinity was determined by calorimetry and transmission electron microscopy, infrared spectroscopy was used to find evidence of any interactions between the drug and the carrier and the determination of apparent solubility allowed for the corroboration of changes in solubility. Before grinding, scanning electron microscopy showed the drug and lactose to have an average particle size of around 50 and 30 μm, respectively. After high speed grinding, indomethacin and the mixture had a reduced average particle size of around 5 and 2 μm, respectively, showing a morphological change. The ground mixture produced a solid dispersion that had a loss of crystallinity that reached 81% after 30 min of grinding while the drug solubility of indomethacin within the solid dispersion increased by 2.76 fold as compared to the pure drug. Drug activation due to hydrogen bonds between the carboxylic group of the drug and the hydroxyl group of lactose as well as the decrease in crystallinity of the solid dispersion and the reduction of the particle size led to a better water solubility of indomethacin. PMID:23798775

  10. Novel electrosprayed nanospherules for enhanced aqueous solubility and oral bioavailability of poorly water-soluble fenofibrate.

    PubMed

    Yousaf, Abid Mehmood; Mustapha, Omer; Kim, Dong Wuk; Kim, Dong Shik; Kim, Kyeong Soo; Jin, Sung Giu; Yong, Chul Soon; Youn, Yu Seok; Oh, Yu-Kyoung; Kim, Jong Oh; Choi, Han-Gon

    2016-01-01

    The purpose of the present research was to develop a novel electrosprayed nanospherule providing the most optimized aqueous solubility and oral bioavailability for poorly water-soluble fenofibrate. Numerous fenofibrate-loaded electrosprayed nanospherules were prepared with polyvinylpyrrolidone (PVP) and Labrafil(®) M 2125 as carriers using the electrospray technique, and the effect of the carriers on drug solubility and solvation was assessed. The solid state characterization of an optimized formulation was conducted by scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopic analyses. Oral bioavailability in rats was also evaluated for the formulation of an optimized nanospherule in comparison with free drug and a conventional fenofibrate-loaded solid dispersion. All of the electrosprayed nanospherule formulations had remarkably enhanced aqueous solubility and dissolution compared with free drug. Moreover, Labrafil M 2125, a surfactant, had a positive influence on the solubility and dissolution of the drug in the electrosprayed nanospherule. Increases were observed as the PVP/drug ratio increased to 4:1, but higher ratios gave no significant increases. In particular, an electrosprayed nanospherule composed of fenofibrate, PVP, and Labrafil M 2125 at the weight ratio of 1:4:0.5 resulted in a particle size of <200 nm with the drug present in the amorphous state. It demonstrated the highest solubility (32.51±2.41 μg/mL), an excellent dissolution (~85% in 10 minutes), and an oral bioavailability ~2.5-fold better than that of the free drug. It showed similar oral bioavailability compared to the conventional solid dispersion. Electrosprayed nanospherules, which provide improved solubility and bioavailability, are promising drug delivery tools for oral administration of poorly water-soluble fenofibrate.

  11. [Application of the concetrations ratio of soluble receptor tyrosine kinase type 1, and placental growth factor for short-term prediction and diagnosis of preeclampsia].

    PubMed

    Bubeníková, Š; Cíchová, A; Roubalová, L; Durdová, V; Vlk, R

    Bring a comprehensive overview of the available information about applications of the concetration ratio of soluble receptor tyrosine kinase type 1 (sFlt-1), and placental growth factor for short-term prediction and diagnosis of preeclampsia. Overview study. Department of Midwifery, Faculty of Health Sciences, Olomouc; Department of Clinical Biochemistry, University Hospital Olomouc; Department of Obstetrics and Gynecology, University Hospital Olomouc; Department of Obstetrics and Gynecology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital. Analysis of literary sources and databases Ovid, Medline (2001-2016). Preeclampsia is a multisystem disease with not fully understood etiology. This disease occurs in 2-5% of pregnant women. Preeclampsia is one of the main causes of global maternal and perinatal morbidity and mortality. It manifests itself as a newborn hypertension and proteinuria after 20 weeks of pregnancy in previously normotensive women. The only effective treatment is the delivery of the child. Diagnosis of preeclampsia comprises measuring blood pressure and proteinuria. These indicators have low diagnostic sensitivity and specificity. In preeclampsia, there is a decrease of serum levels of placental growth factor (PlGF). Soluble receptor tyrosine kinase type 1 (sFlt-1) is an antagonist of PlGF. Increased levels of sFlt-1 in proportion to the reduced level of PlGF are associated with an increased risk of preeclampsia. The sFlt-1/PlGF ratio can be a better predictive marker in the diagnosis of pre-eclampsia after 20 weeks of gestation.

  12. The Significance of Interfacial Water Structure in Soluble Salt Flotation Systems.

    PubMed

    Hancer, M.; Celik, M. S.; Miller, J. D.

    2001-03-01

    Flotation of soluble salts with dodecyl amine hydrochloride (DAH) and sodium dodecyl sulfate (SDS) collectors has demonstrated that the interfacial water structure and hydration states of soluble salt surfaces together with the precipitation tendency of the corresponding collector salts are of considerable importance in explaining their flotation behavior. In particular, the high concentration of ions in these soluble salt brines and their hydration appear to modify the bulk and interfacial structure of water as revealed by contact angle measurements and this effect is shown to be an important feature in the flotation chemistry of soluble salt minerals including alkali halide and alkali oxyanion salts. Depending on characteristic chemical features (salt type), the salt can serve either as a structure maker, in which intermolecular hydrogen bonding between water molecules is facilitated, or as a structure breaker, in which intermolecular hydrogen bonding between water molecules is disrupted. For structure making salts the brine completely wets the salt surface and no contact angle can be measured. For structure breaking salts the brine does not completely wet the salt surface and a finite contact angle is measured. In this regard it has been found that soluble salt flotation either with the cationic DAH or anionic SDS collector is possible only if the salt is a structure breaker. Copyright 2001 Academic Press.

  13. IUPAC-NIST Solubility Data Series 70. The Solubility of Gases in Glassy Polymers

    NASA Astrophysics Data System (ADS)

    Paterson, Russell; Yampol'Skii, Yuri P.; Fogg, Peter G. T.; Bokarev, Alexandre; Bondar, Valerii; Ilinich, Oleg; Shishatskii, Sergey

    1999-09-01

    Solubility of gases in polymers is an important property of polymeric materials relevant to many practical applications. Sorption of small molecules in polymers is a fundamental concern in such areas as food packaging, beverage storage, and polymer processing. However, by far the main interest in the solubility of gases in polymers, and especially in glassy polymers, is related to development of novel advanced materials for gas separation membranes. This is because the concentration gradient of a dissolved gas is the driving force of membrane processes. Development of these novel separation methods resulted in a rapid accumulation, in the recent literature, of thermodynamic data related to the solubility of gases in polymers at different temperatures and pressures. Polymers can be regarded as special cases of media intermediate between liquids and solids. As a consequence, modeling of gas sorption in polymers is very difficult and presents a permanent challenge to theoreticians and experimenters. The collection and critical evaluation of solubility data for various gas-polymer systems is relevant to both practical aspects of polymer applications and to fundamental studies of polymer behavior. This volume of the IUPAC-NIST Solubility Data Series summarizes the compilations and critical evaluations of the data on solubility of gases in glassy polymers. It is implied in this edition that "gases" are the components that are either permanent gases (supercitical fluids) or have saturated vapor pressure more than 1 atm at ambient conditions (298 K). The polymeric components of compilations and critical evaluations are primarily high molecular mass, amorphous, linear (noncross-linked) compounds that have the glass transition temperatures above ambient temperature. The data for each gas-polymer system have been evaluated, if the results of at least three independent and reliable studies have been reported. Where the data of sufficient accuracy and reliability are available

  14. Applications of Solubility Data

    ERIC Educational Resources Information Center

    Tomkins, Reginald P. T.

    2008-01-01

    This article describes several applications of the use of solubility data. It is not meant to be exhaustive but rather to show that knowledge of solubility data is required in a variety of technical applications that assist in the design of chemical processes. (Contains 3 figures and 1 table.)

  15. Solubility of (+/-)-ibuprofen and S (+)-ibuprofen in the presence of cosolvents and cyclodextrins.

    PubMed

    Nerurkar, Jayanti; Beach, J W; Park, M O; Jun, H W

    2005-01-01

    Aqueous solubility is an important parameter for the development of liquid formulations and in the determination of bioavailability of oral dosage forms. Ibuprofen (IB), a nonsteroidal anti-inflammatory drug, is a chiral molecule and is currently used clinically as a racemate (racIB). However, the S form of ibuprofen or S(+)-ibuprofen (SIB) is the biologically active isomer and is primarily responsible for the antiinflammatory activity. Phase solubility studies were carried out to compare the saturation solubilities of racIB and SIB in the presence of common pharmaceutical solvents such as glycerol, sorbitol solution, propylene glycol (PG), and polyethylene glycol (PEG 300) over the range of 20% to 80% v/v in aqueous based systems. The solubilities of the two compounds were also compared in the presence of cyclodextrins such as beta cyclodextrin (CD), hydroxypropyl beta cyclodextrin (HPCD), and beta cyclodextrin sulfobutyl ether sodium salt (CDSB) over the range of 5% to 25% w/v. Solubility determinations were carried at 25 degrees C and 37 degrees C. Cosolvents exponentially increased the solubility of both SIB and racIB, especially in the presence of PG and PEG 300. Glycerol was not very effective in increasing the aqueous solubilities of both compounds, whereas sorbitol solution had a minimal effect on their solubility. PG and PEG 300 increased the solubility of SIB by 400-fold and 1500-fold, respectively, whereas the rise in solubility for racIB was 193-fold and 700-fold, respectively, at 25 degrees C for the highest concentration of the cosolvents used (80% v/v). Of the two compounds studied, higher equilibrium solubilities were observed for SIB as compared with racIB. The derivatized cyclodextrins increased the aqueous solubility of racIB and SIB in a concentration-dependent manner giving AL type of phase diagrams. The phase solubility diagrams indicated the formation of soluble inclusion complexes between the drugs and HPCD and CDSB, which was of 1

  16. Novel electrosprayed nanospherules for enhanced aqueous solubility and oral bioavailability of poorly water-soluble fenofibrate

    PubMed Central

    Yousaf, Abid Mehmood; Mustapha, Omer; Kim, Dong Wuk; Kim, Dong Shik; Kim, Kyeong Soo; Jin, Sung Giu; Yong, Chul Soon; Youn, Yu Seok; Oh, Yu-Kyoung; Kim, Jong Oh; Choi, Han-Gon

    2016-01-01

    Purpose The purpose of the present research was to develop a novel electrosprayed nanospherule providing the most optimized aqueous solubility and oral bioavailability for poorly water-soluble fenofibrate. Methods Numerous fenofibrate-loaded electrosprayed nanospherules were prepared with polyvinylpyrrolidone (PVP) and Labrafil® M 2125 as carriers using the electrospray technique, and the effect of the carriers on drug solubility and solvation was assessed. The solid state characterization of an optimized formulation was conducted by scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopic analyses. Oral bioavailability in rats was also evaluated for the formulation of an optimized nanospherule in comparison with free drug and a conventional fenofibrate-loaded solid dispersion. Results All of the electrosprayed nanospherule formulations had remarkably enhanced aqueous solubility and dissolution compared with free drug. Moreover, Labrafil M 2125, a surfactant, had a positive influence on the solubility and dissolution of the drug in the electrosprayed nanospherule. Increases were observed as the PVP/drug ratio increased to 4:1, but higher ratios gave no significant increases. In particular, an electrosprayed nanospherule composed of fenofibrate, PVP, and Labrafil M 2125 at the weight ratio of 1:4:0.5 resulted in a particle size of <200 nm with the drug present in the amorphous state. It demonstrated the highest solubility (32.51±2.41 μg/mL), an excellent dissolution (~85% in 10 minutes), and an oral bioavailability ~2.5-fold better than that of the free drug. It showed similar oral bioavailability compared to the conventional solid dispersion. Conclusion Electrosprayed nanospherules, which provide improved solubility and bioavailability, are promising drug delivery tools for oral administration of poorly water-soluble fenofibrate. PMID:26834471

  17. Drug Solubility: Importance and Enhancement Techniques

    PubMed Central

    Savjani, Ketan T.; Gajjar, Anuradha K.; Savjani, Jignasa K.

    2012-01-01

    Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and so forth. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics. PMID:22830056

  18. Macrophage uptake and accumulation of folates are polarization-dependent in vitro and in vivo and are regulated by activin A.

    PubMed

    Samaniego, Rafael; Palacios, Blanca Soler; Domiguez-Soto, Ángeles; Vidal, Carlos; Salas, Azucena; Matsuyama, Takami; Sánchez-Torres, Carmen; de la Torre, Inmaculada; Miranda-Carús, Maria Eugenia; Sánchez-Mateos, Paloma; Puig-Kröger, Amaya

    2014-05-01

    Vitamin B9, commonly known as folate, is an essential cofactor for one-carbon metabolism that enters cells through three major specialized transporter molecules (RFC, FR, and PCFT), which differ in expression pattern, affinity for substrate, and ligand-binding pH dependency. We now report that the expression of the folate transporters differs between macrophage subtypes and explains the higher accumulation of 5-MTHF-the major folate form found in serum-in M2 macrophages in vitro and in vivo. M1 macrophages display a higher expression of RFC, whereas FRβ and PCFT are preferentially expressed by anti-inflammatory and homeostatic M2 macrophages. These differences are also seen in macrophages from normal tissues involved in folate transit (placenta, liver, colon) and inflamed tissues (ulcerative colitis, RA), as M2-like macrophages from normal tissues express FRβ and PCFT, whereas TNF-α-expressing M1 macrophages from inflamed tissues are RFC+. Besides, we provide evidences that activin A is a critical factor controlling the set of folate transporters in macrophages, as it down-regulates FRβ, up-regulates RFC expression, and modulates 5-MTHF uptake. All of these experiments support the notion that folate handling is dependent on the stage of macrophage polarization. © 2014 Society for Leukocyte Biology.

  19. Molecularly designed water soluble, intelligent, nanosize polymeric carriers.

    PubMed

    Pişkin, Erhan

    2004-06-11

    Intelligent polymers, also referred as "stimuli-responsive polymers" undergo strong property changes (in shape, surface characteristics, solubility, etc.) when only small changes in their environment (changes in temperature, pH, ionic strength light, electrical and magnetic field, etc.). They have been used in several novel applications, drug delivery systems, tissue engineering scaffolds, bioseparation, biomimetic actuators, etc. The most popular member of these type of polymers is poly(N-isopropylacrylamide) (poly(NIPA)) which exhibits temperature-sensitive character, in which the polymer chains change from water-soluble coils to water-insoluble globules in aqueous solution as temperature increases above the lower critical solution temperature (LCST) of the polymer. Copolymerization of NIPA with acrylic acid (AAc) allows the synthesis of both pH and temperature-responsive copolymers. This paper summarizes some of our related studies in which NIPA and its copolymers were synthesized and used as intelligent carriers in diverse applications.

  20. Click strategy using disodium salts of amino acids improves the water solubility of plinabulin and KPU-300.

    PubMed

    Yakushiji, Fumika; Muguruma, Kyohei; Hayashi, Yoshiki; Shirasaka, Takuya; Kawamata, Ryosuke; Tanaka, Hironari; Yoshiwaka, Yushi; Taguchi, Akihiro; Takayama, Kentaro; Hayashi, Yoshio

    2017-07-15

    Plinabulin and KPU-300 are promising anti-microtubule agents; however, the low water solubility of these compounds (<0.1µg/mL) has limited their pharmaceutical advantages. Here, we developed five water-soluble derivatives of plinabulin and KPU-300 with a click strategy using disodium salts of amino acids. The mother skeleton, diketopiperazine (DKP), was transformed into a monolactim-type alkyne and a copper-catalyzed alkyne azide cycloaddition (CuAAC) combined azides that was derived from amino acids as a water-solubilizing moiety. The conversion of carboxyl groups into disodium salts greatly improved the water solubility by 0.8 million times compared to the solubility of the parent molecules. In addition, the α-amino acid side chains of the water-solubilizing moieties affected both the water solubility and the half-lives of the compounds during enzymatic hydrolysis. Our effort to develop a variety of water-soluble derivatives using the click strategy has revealed that the replaceable water-solubilizing moieties can alter molecular solubility and stability under enzymatic hydrolysis. With this flexibility, we are approaching to the in vivo study using water-soluble derivative. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Effect of composition of simulated intestinal media on the solubility of poorly soluble compounds investigated by design of experiments.

    PubMed

    Madsen, Cecilie Maria; Feng, Kung-I; Leithead, Andrew; Canfield, Nicole; Jørgensen, Søren Astrup; Müllertz, Anette; Rades, Thomas

    2018-01-01

    The composition of the human intestinal fluids varies both intra- and inter-individually. This will influence the solubility of orally administered drug compounds, and hence, the absorption and efficacy of compounds displaying solubility limited absorption. The purpose of this study was to assess the influence of simulated intestinal fluid (SIF) composition on the solubility of poorly soluble compounds. Using a Design of Experiments (DoE) approach, a set of 24 SIF was defined within the known compositions of human fasted state intestinal fluid. The SIF were composed of phospholipid, bile salt, and different pH, buffer capacities and osmolarities. On a small scale semi-robotic system, the solubility of 6 compounds (aprepitant, carvedilol, felodipine, fenofibrate, probucol, and zafirlukast) was determined in the 24 SIF. Compound specific models, describing key factors influencing the solubility of each compound, were identified. Although all models were different, the level of phospholipid and bile salt, the pH, and the interactions between these, had the biggest influences on solubility overall. Thus, a reduction of the DoE from five to three factors was possible (11-13 media), making DoE solubility studies feasible compared to single SIF solubility studies. Applying this DoE approach will lead to a better understanding of the impact of intestinal fluid composition on the solubility of a given drug compound. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Upregulation of contractile endothelin type B receptors by lipid-soluble cigarette smoking particles in rat cerebral arteries via activation of MAPK

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sandhu, Hardip, E-mail: sandhu.hardip@gmail.co; Xu, Cang Bao; Edvinsson, Lars

    2010-11-15

    Cigarette smoke exposure increases the risk of stroke. However, the underlying molecular mechanisms are poorly understood. Endothelin system plays key roles in the pathogenesis of stroke. The present study was designed to examine if lipid-soluble (dimethyl sulfoxide-soluble) cigarette smoke particles (DSP) induces upregulation of contractile endothelin type B (ET{sub B}) receptors in rat cerebral arteries and if activation of mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NF-{kappa}B) mediate the upregulation of contractile endothelin receptors in the cerebral arteries. Rat middle cerebral arteries were isolated and organ cultured in serum free medium for 24 h in the presence of DSPmore » with or without specific inhibitors: MEK specific (U0126), p38 specific (SB202190), JNK specific (SP600125), NF-{kappa}B specific (BMS-345541) or (IMD-0354), transcription inhibitor (actinomycin D), or translation blocker (cycloheximide). Contractile responses to the ET{sub B} receptor agonist sarafotoxin 6c were investigated by a sensitive myograph. The expression of the ET{sub B} receptors were studied at mRNA and protein levels using quantitative real time PCR and immunohistochemistry, respectively. Results show that organ culture per se induced transcriptional upregulation of contractile ET{sub B} receptors in the cerebral vascular smooth muscle cells. This upregulation was further increased at the translational level by addition of DSP to the organ culture, but this increase was not seen by addition of nicotine or water-soluble cigarette smoke particles to the organ culture. The increased upregulation of contractile ET{sub B} receptors by DSP was abrogated by U0126, SP600125, actinomycin D, and cycloheximide, suggesting that the underlying molecular mechanisms involved in this process include activation of MEK and JNK MAPK-mediated transcription and translation of new contractile ET{sub B} receptors. Thus, the MAPK-mediated upregulation of contractile ET

  3. Trade-off between soluble protein production and nutritional storage in Bromeliaceae

    PubMed Central

    Gonçalves, Ana Zangirolame; Mercier, Helenice; Oliveira, Rafael Silva; Romero, Gustavo Quevedo

    2016-01-01

    Background and Aims Bromeliads are able to occupy some of the most nutrient-poor environments especially because they possess absorptive leaf trichomes, leaves organized in rosettes, distinct photosynthetic pathways [C3, Crassulacean acid metabolism (CAM) or facultative C3–CAM], and may present an epiphytic habit. The more derived features related to these traits are described for the Tillandsioideae subfamily. In this context, the aims of this study were to evaluate how terrestrial predators contribute to the nutrition and performance of bromeliad species, subfamilies and ecophysiological types, whether these species differ in their ecophysiological traits and whether the physiological outcomes are consistent among subfamilies and types (e.g. presence/absence of tank, soil/tank/atmosphere source of nutrients, trichomes/roots access to nutrients). Methods Isotopic (15N-enriched predator faeces) and physiological methods (analyses of plant protein, amino acids, growth, leaf mass per area and total N incorporated) in greenhouse experiments were used to investigate the ecophysiological contrasts between Tillandsioideae and Bromelioideae, and among ecophysiological types when a predatory anuran contributes to their nutrition. Key Results It was observed that Bromelioideae had higher concentrations of soluble protein and only one species grew more (Ananas bracteatus), while Tillandsioideae showed higher concentrations of total amino acids, asparagine and did not grow. The ecophysiological types that showed similar protein contents also had similar growth. Additionally, an ordination analysis showed that the subfamilies and ecophysiological types were discrepant considering the results of the total nitrogen incorporated from predators, soluble protein and asparagine concentrations, relative growth rate and leaf mass per area. Conclusions Bromeliad subfamilies showed a trade-off between two strategies: Tillandsioideae stored nitrogen into amino acids possibly for

  4. Trade-off between soluble protein production and nutritional storage in Bromeliaceae.

    PubMed

    Gonçalves, Ana Zangirolame; Mercier, Helenice; Oliveira, Rafael Silva; Romero, Gustavo Quevedo

    2016-11-01

    Bromeliads are able to occupy some of the most nutrient-poor environments especially because they possess absorptive leaf trichomes, leaves organized in rosettes, distinct photosynthetic pathways [C 3 , Crassulacean acid metabolism (CAM) or facultative C 3 -CAM], and may present an epiphytic habit. The more derived features related to these traits are described for the Tillandsioideae subfamily. In this context, the aims of this study were to evaluate how terrestrial predators contribute to the nutrition and performance of bromeliad species, subfamilies and ecophysiological types, whether these species differ in their ecophysiological traits and whether the physiological outcomes are consistent among subfamilies and types (e.g. presence/absence of tank, soil/tank/atmosphere source of nutrients, trichomes/roots access to nutrients). Isotopic ( 15 N-enriched predator faeces) and physiological methods (analyses of plant protein, amino acids, growth, leaf mass per area and total N incorporated) in greenhouse experiments were used to investigate the ecophysiological contrasts between Tillandsioideae and Bromelioideae, and among ecophysiological types when a predatory anuran contributes to their nutrition. It was observed that Bromelioideae had higher concentrations of soluble protein and only one species grew more (Ananas bracteatus), while Tillandsioideae showed higher concentrations of total amino acids, asparagine and did not grow. The ecophysiological types that showed similar protein contents also had similar growth. Additionally, an ordination analysis showed that the subfamilies and ecophysiological types were discrepant considering the results of the total nitrogen incorporated from predators, soluble protein and asparagine concentrations, relative growth rate and leaf mass per area. Bromeliad subfamilies showed a trade-off between two strategies: Tillandsioideae stored nitrogen into amino acids possibly for transamination reactions during nutritional stress and

  5. Solubility of carbamazepine co-crystals in ethanolic solution

    NASA Astrophysics Data System (ADS)

    Ramle, Noor Ashila; Rahim, Syarifah Abd; Anuar, Nornizar; El-Hadad, Omar

    2017-08-01

    The study aimed to determine the solubility of carbamazepine (CBZ) co-crystals formed from co-crystal formers (CCFs) of nicotinamide (NIC), saccharin (SAC), succinic acid (SUC) and fumaric acid (FUM) at various temperatures (25-50°C). High Performance Liquid Chromatography (HPLC) was used to determine the solubility and the X-Ray Powder Diffraction was used to characterize the crystals. The solubility of CBZ-NIC and CBZ-FUM co-crystals were found to be higher than the solubility of the CBZ for the range of studied temperatures. However, opposite findings was obtained for CBZ-SUC co-crystal as its solubility is lower than the solubility of CBZ. Different trend was found for CBZ-SAC co-crystal in which for temperature lower than 40°C, the solubility of CBZ crystal is higher than the CBZ-SAC co-crystal. The solubility of CBZ-SAC co-crystal is higher than the solubility of CBZ at a temperature above 40°C. CBZ co-crystals with NIC and FUM have shown to increase the solubility of CBZ by solubility ratio of 1.95 and 1.24 respectively. However, the CBZ co-crystal with SAC was found to have similar solubility value as the CBZ.

  6. Vacuum-driven power-free microfluidics utilizing the gas solubility or permeability of polydimethylsiloxane (PDMS).

    PubMed

    Xu, Linfeng; Lee, Hun; Jetta, Deekshitha; Oh, Kwang W

    2015-10-21

    Suitable pumping methods for flow control remain a major technical hurdle in the path of biomedical microfluidic systems for point-of-care (POC) diagnostics. A vacuum-driven power-free micropumping method provides a promising solution to such a challenge. In this review, we focus on vacuum-driven power-free microfluidics based on the gas solubility or permeability of polydimethylsiloxane (PDMS); degassed PDMS can restore air inside itself due to its high gas solubility or gas permeable nature. PDMS allows the transfer of air into a vacuum through it due to its high gas permeability. Therefore, it is possible to store or transfer air into or through the gas soluble or permeable PDMS in order to withdraw liquids into the embedded dead-end microfluidic channels. This article provides a comprehensive look at the physics of the gas solubility and permeability of PDMS, a systematic review of different types of vacuum-driven power-free microfluidics, and guidelines for designing solubility-based or permeability-based PDMS devices, alongside existing applications. Advanced topics and the outlook in using micropumping that utilizes the gas solubility or permeability of PDMS will be also discussed. We strongly recommend that microfluidics and lab-on-chip (LOC) communities harness vacuum energy to develop smart vacuum-driven microfluidic systems.

  7. Derivation of Mesenchymal Stromal Cells from Canine Induced Pluripotent Stem Cells by Inhibition of the TGFβ/Activin Signaling Pathway

    PubMed Central

    Frith, Jessica E.; Frith, Thomas J.R.; Ovchinnikov, Dmitry A.; Cooper-White, Justin J.; Wolvetang, Ernst J.

    2014-01-01

    In this study we have generated canine mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, from canine induced pluripotent stem cells (ciPSCs) by small-molecule inhibition of the transforming growth factor beta (TGFβ)/activin signaling pathway. These ciPSC-derived MSCs (ciPSC-MSCs) express the MSC markers CD73, CD90, CD105, STRO1, cPDGFRβ and cKDR, in addition to the pluripotency factors OCT4, NANOG and REX1. ciPSC-MSCs lack immunostaining for H3K27me3, suggesting that they possess two active X chromosomes. ciPSC-MSCs are highly proliferative and undergo robust differentiation along the osteo-, chondro- and adipogenic pathways, but do not form teratoma-like tissues in vitro. Of further significance for the translational potential of ciPSC-MSCs, we show that these cells can be encapsulated and maintained within injectable hydrogel matrices that, when functionalized with bound pentosan polysulfate, dramatically enhance chondrogenesis and inhibit osteogenesis. The ability to efficiently derive large numbers of highly proliferative canine MSCs from ciPSCs that can be incorporated into injectable, functionalized hydrogels that enhance their differentiation along a desired lineage constitutes an important milestone towards developing an effective MSC-based therapy for osteoarthritis in dogs, but equally provides a model system for assessing the efficacy and safety of analogous approaches for treating human degenerative joint diseases. PMID:25055193

  8. Solubility of the sesquiterpene alcohol patchoulol in supercritical carbon dioxide

    PubMed Central

    Hybertson, Brooks M.

    2009-01-01

    The solubility of the sesquiterpene alcohol patchoulol in supercritical carbon dioxide was measured at P ranging from 10.0 MPa to 25.0 MPa and T of 40.0 and 50.0 °C using a simple microsampling type apparatus with a 100.5 µL sample loop to remove aliquots for off-line analysis. The system was first validated using vanillin with off-line spectrophotometric analysis, then utilized for patchoulol measurements with off-line GC-MS analysis. The measured solubility of patchoulol in supercritical CO2 ranged from mole fractions of 0.43 × 10−3 at 10.0 MPa and 50.0 °C to 9.45 × 10−3 at 25.0 MPa and 40.0 °C. PMID:19424449

  9. APPLICATION OF VARIOUS POLYMERS AND POLYMERS BASED TECHNIQUES USED TO IMPROVE SOLUBILITY OF POORLY WATER SOLUBLE DRUGS: A REVIEW.

    PubMed

    Muhammad Sarfraz, Rai; Bashir, Sajid; Mahmood, Asif; Ahsan, Haseeb; Riaz, Humayun; Raza, Hina; Rashid, Zermina; Atif Raza, Syed; Asad Abrar, Muhammad; Abbas, Khawar; Yasmeen, Tahira

    2017-03-01

    Solubility is concerned with solute and solvent to form a homogenous mixture. If solubility of a drug is low, then usually it is difficult to achieve desired therapeutic level of drug. Most of the newly developed entities have solubility problems and encounter difficulty in dissolution. Basic aim of solubility enhancement is to achieve desired therapeutic'level of drug to produce required pharmacological response. Different techniques are being used to enhance the solubility of water insoluble drugs. These techniques include particle size reduction, spray drying, kneading method, solvent evaporation method, salt formation, microemulsions, co-solven- cy, hydrosols, prodrug approach, supercritical fluid process, hydrogel micro particles etc. Selection of solubility improving method depends on drug properties, site of absorption, and required dosage form characteristics. Variety of polymers are also used to enhance solubility of these drugs like polyethylene glycol 300, polyvinyl pyrrolidone, chitosan, β-cyclodextrins etc.

  10. Compatibility Assessment of Fuel System Thermoplastics with Bio-Blendstock Fuel Candidates Using Hansen Solubility Analysis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kass, Michael D.; West, Brian H.

    The compatibility of key fuel system infrastructure plastics with 39 bio-blendstock fuel candidates was examined using Hansen solubility analysis. Fuel types included multiple alcohols, esters, ethers, ketones, alkenes and one alkane. These compounds were evaluated as neat molecules and as blends with the gasoline surrogate, dodecane, and a mix of dodecane and 10% ethanol (E10D). The plastics included polyphenylene sulfide (PPS), polyethylene terephthalate (PET), polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polyoxymethylene (POM), polybutylene terephthalate (PBT), polypropylene (PP), high density polyethylene (HDPE), along with several nylon grades. These materials have been rigorously studied with other fuel types, and their volume change resultsmore » were found to correspond well with their predicted solubility levels.The compatibility was assessed using Hansen solubility parameters and in many instances peak solubility occurred for blends rather than the neat fuel components. The results showed that good compatibilities can be expected for PPS, PVDF, PET, nylons, acetal, PEI, PVC, HDPE and PBT. PTFE showed potential incompatibilities at low blend concentrations, especially when E10D was used as the base fuel blend. Although, the nylons show good overall compatibility, the results do indicate that mid-range and high alcohol contents may not be suitable for Nylon 6 and Nylon 11 in applications requiring low volume swell. Poor potential compatibility was limited to two plastic types; PETG exposed to mid and high blend levels of the ethers and PP exposed to sabinene and the aromatics. In general, the data showed good compatibility for the majority of the candidate fuels and plastics.« less

  11. Compatibility Assessment of Fuel System Thermoplastics with Bio-Blendstock Fuel Candidates Using Hansen Solubility Analysis

    DOE PAGES

    Kass, Michael D.; West, Brian H.

    2018-01-03

    The compatibility of key fuel system infrastructure plastics with 39 bio-blendstock fuel candidates was examined using Hansen solubility analysis. Fuel types included multiple alcohols, esters, ethers, ketones, alkenes and one alkane. These compounds were evaluated as neat molecules and as blends with the gasoline surrogate, dodecane, and a mix of dodecane and 10% ethanol (E10D). The plastics included polyphenylene sulfide (PPS), polyethylene terephthalate (PET), polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polyoxymethylene (POM), polybutylene terephthalate (PBT), polypropylene (PP), high density polyethylene (HDPE), along with several nylon grades. These materials have been rigorously studied with other fuel types, and their volume change resultsmore » were found to correspond well with their predicted solubility levels.The compatibility was assessed using Hansen solubility parameters and in many instances peak solubility occurred for blends rather than the neat fuel components. The results showed that good compatibilities can be expected for PPS, PVDF, PET, nylons, acetal, PEI, PVC, HDPE and PBT. PTFE showed potential incompatibilities at low blend concentrations, especially when E10D was used as the base fuel blend. Although, the nylons show good overall compatibility, the results do indicate that mid-range and high alcohol contents may not be suitable for Nylon 6 and Nylon 11 in applications requiring low volume swell. Poor potential compatibility was limited to two plastic types; PETG exposed to mid and high blend levels of the ethers and PP exposed to sabinene and the aromatics. In general, the data showed good compatibility for the majority of the candidate fuels and plastics.« less

  12. Solubilities of selected organic electronic materials in pressurized hot water and estimations of aqueous solubilities at 298.15 K.

    PubMed

    Karásek, Pavel; Hohnová, Barbora; Planeta, Josef; Št'avíková, Lenka; Roth, Michal

    2013-02-01

    Increasing production and disposal of organic light-emitting diode (OLED) displays for smartphones and tablets may have impact on the environment depending on the aqueous solubility of the pertinent chemicals. Here, aqueous solubilities are presented for several compounds, mostly aromatic amines, used as hole transport materials in the OLED displays. Solute selection includes 1,4-bis(diphenylamino)benzene, tetra-N-phenylbenzidine, 4,4'-bis(N-carbazolyl)-1,1'-biphenyl, 1,3,5-tris(diphenylamino)benzene, and 9,10-bis(phenylethynyl)anthracene. The solubilities are those in pressurized hot water (PHW), i.e., measured at elevated temperature (up to 260 °C) and pressure. The semi-quantitative estimates of room-temperature solubilities of the solutes have been obtained from extrapolations of the solubilities in PHW. For the compounds studied, the estimated aqueous solubilities at room temperature do not exceed 2×10(-11) g of the solute per 1 kg of water. Aqueous solubilities of triphenylamine have also been measured and used to upgrade a recent group-contribution model of aqueous solubilities of organic nonelectrolytes with the parameters for the nitrogen atom in aromatic amines. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Soluble Urokinase-Type Plasminogen Activator Receptor in Black Americans with CKD.

    PubMed

    Luo, Shengyuan; Coresh, Josef; Tin, Adrienne; Rebholz, Casey M; Chen, Teresa K; Hayek, Salim S; Tracy, Melissa; Lipkowitz, Michael S; Appel, Lawrence J; Levey, Andrew S; Inker, Lesley A; Reiser, Jochen; Grams, Morgan Erika

    2018-06-14

    Black Americans with and without APOL1 kidney disease risk variants face high risk of ESKD. Soluble urokinase-type plasminogen activator receptor (suPAR), a circulating signaling protein and marker of immune activation, constitutes a promising biomarker of CKD-associated risks. We aimed to quantify the associations between serum suPAR concentration and adverse outcomes in Black Americans with and without APOL1 kidney disease risk variants, over and above iodine-125 iothalamate measured GFR and proteinuria. Using data from the African-American Study of Kidney Disease and Hypertension, a multicenter clinical trial followed by a cohort phase with a median total follow-up of 9.7 years (interquartile range, 6.5-10.9 years), we examined the associations of suPAR with CKD progression (defined as doubling of serum creatinine or ESKD), ESKD, worsening proteinuria (defined as pre-ESKD doubling of 24-hour urine protein-to-creatinine ratio to ≥220 mg/g), and all-cause death. At baseline, the median suPAR was 4462 pg/ml, mean measured GFR was 46 ml/min per 1.73 m 2 , and median 24-hour urine protein-to-creatinine ratio was 80 mg/g. After controlling for baseline demographics, randomization arm, GFR, proteinuria, APOL1 risk status, and clinical risk factors, there was a 1.26-times higher risk for CKD progression per SD higher baseline log-transformed suPAR (hazard ratio [HR], 1.26; 95% confidence interval [95% CI], 1.11 to 1.43; P <0.001). Higher suPAR was also independently associated with risk of ESKD (HR, 1.36; 95% CI, 1.17 to 1.58; P <0.001) and death (HR, 1.25; 95% CI, 1.08 to 1.45; P =0.003). suPAR was only associated with worsening proteinuria in patients with two APOLI risk alleles (HR, 1.46; 95% CI, 1.08 to 1.99; P =0.02). Higher suPAR was associated with various adverse outcomes in Black Americans with CKD, with and without APOL1 kidney disease risk variants, independently of proteinuria and GFR. Copyright © 2018 by the American Society of Nephrology.

  14. Novel Mitochondria-Targeted Heat-Soluble Proteins Identified in the Anhydrobiotic Tardigrade Improve Osmotic Tolerance of Human Cells

    PubMed Central

    Tanaka, Sae; Tanaka, Junko; Miwa, Yoshihiro; Horikawa, Daiki D.; Katayama, Toshiaki; Arakawa, Kazuharu; Toyoda, Atsushi; Kubo, Takeo; Kunieda, Takekazu

    2015-01-01

    Tardigrades are able to tolerate almost complete dehydration through transition to a metabolically inactive state, called “anhydrobiosis”. Late Embryogenesis Abundant (LEA) proteins are heat-soluble proteins involved in the desiccation tolerance of many anhydrobiotic organisms. Tardigrades, Ramazzottius varieornatus, however, express predominantly tardigrade-unique heat-soluble proteins: CAHS (Cytoplasmic Abundant Heat Soluble) and SAHS (Secretory Abundant Heat Soluble) proteins, which are secreted or localized in most intracellular compartments, except the mitochondria. Although mitochondrial integrity is crucial to ensure cellular survival, protective molecules for mitochondria have remained elusive. Here, we identified two novel mitochondrial heat-soluble proteins, RvLEAM and MAHS (Mitochondrial Abundant Heat Soluble), as potent mitochondrial protectants from Ramazzottius varieornatus. RvLEAM is a group3 LEA protein and immunohistochemistry confirmed its mitochondrial localization in tardigrade cells. MAHS-green fluorescent protein fusion protein localized in human mitochondria and was heat-soluble in vitro, though no sequence similarity with other known proteins was found, and one region was conserved among tardigrades. Furthermore, we demonstrated that RvLEAM protein as well as MAHS protein improved the hyperosmotic tolerance of human cells. The findings of the present study revealed that tardigrade mitochondria contain at least two types of heat-soluble proteins that might have protective roles in water-deficient environments. PMID:25675104

  15. Novel mitochondria-targeted heat-soluble proteins identified in the anhydrobiotic Tardigrade improve osmotic tolerance of human cells.

    PubMed

    Tanaka, Sae; Tanaka, Junko; Miwa, Yoshihiro; Horikawa, Daiki D; Katayama, Toshiaki; Arakawa, Kazuharu; Toyoda, Atsushi; Kubo, Takeo; Kunieda, Takekazu

    2015-01-01

    Tardigrades are able to tolerate almost complete dehydration through transition to a metabolically inactive state, called "anhydrobiosis". Late Embryogenesis Abundant (LEA) proteins are heat-soluble proteins involved in the desiccation tolerance of many anhydrobiotic organisms. Tardigrades, Ramazzottius varieornatus, however, express predominantly tardigrade-unique heat-soluble proteins: CAHS (Cytoplasmic Abundant Heat Soluble) and SAHS (Secretory Abundant Heat Soluble) proteins, which are secreted or localized in most intracellular compartments, except the mitochondria. Although mitochondrial integrity is crucial to ensure cellular survival, protective molecules for mitochondria have remained elusive. Here, we identified two novel mitochondrial heat-soluble proteins, RvLEAM and MAHS (Mitochondrial Abundant Heat Soluble), as potent mitochondrial protectants from Ramazzottius varieornatus. RvLEAM is a group3 LEA protein and immunohistochemistry confirmed its mitochondrial localization in tardigrade cells. MAHS-green fluorescent protein fusion protein localized in human mitochondria and was heat-soluble in vitro, though no sequence similarity with other known proteins was found, and one region was conserved among tardigrades. Furthermore, we demonstrated that RvLEAM protein as well as MAHS protein improved the hyperosmotic tolerance of human cells. The findings of the present study revealed that tardigrade mitochondria contain at least two types of heat-soluble proteins that might have protective roles in water-deficient environments.

  16. SiO2 Solubility in Rutile at High Pressure and Temperature

    NASA Astrophysics Data System (ADS)

    Ren, Y.; Fei, Y.; Yang, J.; Bai, W. J.; Xu, Z. Q.

    2005-12-01

    Silicon-bearing rutile has been found in nature. The extent of SiO2 solubility in rutile and the nature of its origin are still not clear. At high pressure, SiO2 takes rutile structure with 6-coordinated Si. The high-pressure phase of SiO2 may enhance its solubility in rutile because possible isovalent exchange in octahedral site. In this study, we report new experimental results on SiO2 solubility in rutile up to 23 GPa and 2273 K. Starting materials are mixtures of powdered TiO2 and SiO2, with compositions of (Ti0.5Si0.5)O2, (Ti0.93Si0.07)O2, and (Ti0.75Si0.25)O2. The mixtures were loaded into either a platinum capsules (for a 10/5 assembly) or a rhenium capsules (for an 8/3 assembly). The experiments were carried out using multi-anvil high-pressure apparatus with rhenium resistance heater. Sample temperatures were measured with a type-C thermocouple. The quenched samples were recovered and prepared for electron microprobe analyses. TiO2-rich and SiO2-rich phases are produced in all the quenched samples. The analyses showed that the solubility of SiO2 in rutile increases with increasing pressure, from 1.5 wt% SiO2 at 10 GPa to 3.8 wt% SiO2 at 23 GPa for a given temperature of 2073 K. The solubility also increases with increasing temperature, from 0.5 wt% SiO2 at 1773 K to 4.5 wt% SiO2 at 2273 K for a given pressure of 18 GPa. On the other hand, the solubility of TiO2 in coesite or stishovite is very limited, with an average of 0.6 wt% TiO2 over the experimental P-T ranges. Lower oxygen fugacity decreases the solubility of SiO2 in rutile, whereas water has little effect on the solubility of SiO2 in rutile. Our experimental data are extreme useful for determine the depth of origin for the SiO2-bearing rutile in nature.

  17. Pressurized capillary electrochromatographic analysis of water-soluble vitamins by combining with on-line concentration technique.

    PubMed

    Jia, Li; Liu, Yaling; Du, Yanyan; Xing, Da

    2007-06-22

    A pressurized capillary electrochromatography (pCEC) system was developed for the separation of water-soluble vitamins, in which UV absorbance was used as the detection method and a monolithic silica-ODS column as the separation column. The parameters (type and content of organic solvent in the mobile phase, type and concentration of electrolyte, pH of the electrolyte buffer, applied voltage and flow rate) affecting the separation resolution were evaluated. The combination of two on-line concentration techniques, namely, solvent gradient zone sharpening effect and field-enhanced sample stacking, was utilized to improve detection sensitivity, which proved to be beneficial to enhance the detection sensitivity by enabling the injection of large volumes of samples. Coupling electrokinetic injection with the on-line concentration techniques was much more beneficial for the concentration of positively charged vitamins. Comparing with the conventional injection mode, the enhancement in the detection sensitivities of water-soluble vitamins using the on-line concentration technique is in the range of 3 to 35-fold. The developed pCEC method was applied to evaluate water-soluble vitamins in corns.

  18. [Effects of snow cover on water soluble and organic solvent soluble components during foliar litter decomposition in an alpine forest].

    PubMed

    Xu, Li-Ya; Yang, Wan-Qin; Li, Han; Ni, Xiang-Yin; He, Jie; Wu, Fu-Zhong

    2014-11-01

    Seasonal snow cover may change the characteristics of freezing, leaching and freeze-thaw cycles in the scenario of climate change, and then play important roles in the dynamics of water soluble and organic solvent soluble components during foliar litter decomposition in the alpine forest. Therefore, a field litterbag experiment was conducted in an alpine forest in western Sichuan, China. The foliar litterbags of typical tree species (birch, cypress, larch and fir) and shrub species (willow and azalea) were placed on the forest floor under different snow cover thickness (deep snow, medium snow, thin snow and no snow). The litterbags were sampled at snow formation stage, snow cover stage and snow melting stage in winter. The results showed that the content of water soluble components from six foliar litters decreased at snow formation stage and snow melting stage, but increased at snow cover stage as litter decomposition proceeded in the winter. Besides the content of organic solvent soluble components from azalea foliar litter increased at snow cover stage, the content of organic solvent soluble components from the other five foliar litters kept a continue decreasing tendency in the winter. Compared with the content of organic solvent soluble components, the content of water soluble components was affected more strongly by snow cover thickness, especially at snow formation stage and snow cover stage. Compared with the thicker snow covers, the thin snow cover promoted the decrease of water soluble component contents from willow and azalea foliar litter and restrain the decrease of water soluble component content from cypress foliar litter. Few changes in the content of water soluble components from birch, fir and larch foliar litter were observed under the different thicknesses of snow cover. The results suggested that the effects of snow cover on the contents of water soluble and organic solvent soluble components during litter decomposition would be controlled by

  19. Effects of c-Jun N-terminal kinase on Activin A/Smads signaling in PC12 cell suffered from oxygen-glucose deprivation.

    PubMed

    Wang, J Q; Xu, Z H; Liang, W Z; He, J T; Cui, Y; Liu, H Y; Xue, L X; Shi, W; Shao, Y K; Mang, J; Xu, Z X

    2016-02-29

    Activin A (Act A), a member of transforming growth factor-β (TGF-β) superfamily, is an early gene in response to cerebral ischemia. Growing evidences confirm the neuroprotective effect of Act A in ischemic injury through Act A/Smads signal activation. In this process, regulation networks are involved in modulating the outcomes of Smads signaling. Among these regulators, crosstalk between c-Jun N-terminal kinase (JNK) and Smads signaling has been found in the TGF-β induced epithelial-mesenchymal transition. However, in neural ischemia, the speculative regulation between JNK and Act A/Smads signaling pathways has not been clarified. To explore this issue, an Oxygen Glucose Deprivation (OGD) model was introduced to nerve-like PC12 cells. We found that JNK signal activation occurred at the early time of OGD injury (1 h). Act A administration suppressed JNK phosphorylation. In addition, JNK inhibition could elevate the strength of Smads signaling and attenuate neural apoptosis after OGD injury. Our results indicated a negative regulation effect of JNK on Smads signaling in ischemic injury. Taken together, JNK, as a critical site for neural apoptosis and negative regulator for Act A/Smads signaling, was presumed to be a molecular therapeutic target for ischemia.

  20. Soluble proteins of chemical communication: an overview across arthropods

    PubMed Central

    Pelosi, Paolo; Iovinella, Immacolata; Felicioli, Antonio; Dani, Francesca R.

    2014-01-01

    Detection of chemical signals both in insects and in vertebrates is mediated by soluble proteins, highly concentrated in olfactory organs, which bind semiochemicals and activate, with still largely unknown mechanisms, specific chemoreceptors. The same proteins are often found in structures where pheromones are synthesized and released, where they likely perform a second role in solubilizing and delivering chemical messengers in the environment. A single class of soluble polypeptides, called Odorant-Binding Proteins (OBPs) is known in vertebrates, while two have been identified in insects, OBPs and CSPs (Chemosensory Proteins). Despite their common name, OBPs of vertebrates bear no structural similarity with those of insects. We observed that in arthropods OBPs are strictly limited to insects, while a few members of the CSP family have been found in crustacean and other arthropods, where however, based on their very limited numbers, a function in chemical communication seems unlikely. The question we address in this review is whether another class of soluble proteins may have been adopted by other arthropods to perform the role of OBPs and CSPs in insects. We propose that lipid-transporter proteins of the Niemann-Pick type C2 family could represent likely candidates and report the results of an analysis of their sequences in representative species of different arthropods. PMID:25221516

  1. Solubility of lysozyme in polyethylene glycol-electrolyte mixtures: the depletion interaction and ion-specific effects.

    PubMed

    Boncina, Matjaz; Rescic, Jurij; Vlachy, Vojko

    2008-08-01

    The solubility of aqueous solutions of lysozyme in the presence of polyethylene glycol and various alkaline salts was studied experimentally. The protein-electrolyte mixture was titrated with polyethylene glycol, and when precipitation of the protein occurred, a strong increase of the absorbance at 340 nm was observed. The solubility data were obtained as a function of experimental variables such as protein and electrolyte concentrations, electrolyte type, degree of polymerization of polyethylene glycol, and pH of the solution; the last defines the net charge of the lysozyme. The results indicate that the solubility of lysozyme decreases with the addition of polyethylene glycol; the solubility is lower for a polyethylene glycol with a higher degree of polymerization. Further, the logarithm of the protein solubility is a linear function of the polyethylene glycol concentration. The process is reversible and the protein remains in its native form. An increase of the electrolyte (NaCl) concentration decreases the solubility of lysozyme in the presence and absence of polyethylene glycol. The effect can be explained by the screening of the charged amino residues of the protein. The solubility experiments were performed at two different pH values (pH = 4.0 and 6.0), where the lysozyme net charge was +11 and +8, respectively. Ion-specific effects were systematically investigated. Anions such as Br(-), Cl(-), F(-), and H(2)PO(4)(-) (all in combination with Na(+)), when acting as counterions to a protein with positive net charge, exhibit a strong effect on the lysozyme solubility. The differences in protein solubility for chloride solutions with different cations Cs(+), K(+), and Na(+) (coions) were much smaller. The results at pH = 4.0 show that anions decrease the lysozyme solubility in the order F(-) < H(2)PO(4)(-) < Cl(-) < Br(-) (the inverse Hofmeister series), whereas cations follow the direct Hofmeister series (Cs(+) < K(+) < Na(+)) in this situation.

  2. Solubility of xenon in amino-acid solutions. II. Nine less-soluble amino acids

    NASA Astrophysics Data System (ADS)

    Kennan, Richard P.; Himm, Jeffrey F.; Pollack, Gerald L.

    1988-05-01

    Ostwald solubility (L) of xenon gas, as the radioisotope 133Xe, has been measured as a function of solute concentration, at 25.0 °C, in aqueous solutions of nine amino acids. The amino-acid concentrations investigated covered much of their solubility ranges in water, viz., asparagine monohydrate (0-0.19 M), cysteine (0-1.16 M), glutamine (0-0.22 M), histidine (0-0.26 M), isoleucine (0-0.19 M), methionine (0-0.22 M), serine (0-0.38 M), threonine (0-1.4 M), and valine (0-0.34 M). We have previously reported solubility results for aqueous solutions of six other, generally more soluble, amino acids (alanine, arginine, glycine, hydroxyproline, lysine, and proline), of sucrose and sodium chloride. In general, L decreases approximately linearly with increasing solute concentration in these solutions. If we postulate that the observed decreases in gas solubility are due to hydration, the results under some assumptions can be used to calculate hydration numbers (H), i.e., the number of H2O molecules associated with each amino-acid solute molecule. The average values of hydration number (H¯) obtained at 25.0 °C are 15.3±1.5 for asparagine, 6.8±0.3 for cysteine, 11.5±1.1 for glutamine, 7.3±0.7 for histidine, 5.9±0.4 for isoleucine, 10.6±0.8 for methionine, 11.2±1.3 for serine, 7.7± 1.0 for threonine, and 6.6±0.6 for valine. We have also measured the temperature dependence of solubility L(T) from 5-40 °C for arginine, glycine, and proline, and obtained hydration numbers H¯(T) in this range. Between 25-40 °C, arginine has an H¯ near zero. This may be evidence for an attractive interaction between xenon and arginine molecules in aqueous solution.

  3. Efficient osmolyte-based procedure to increase expression level and solubility of infectious hematopoietic necrosis virus (IHNV) nucleoprotein in E. coli.

    PubMed

    Mohammadinezhad, Rezvan; Farahmand, Hamid; Jalali, Seyed Amir Hossein; Mirvaghefi, Alireza

    2018-05-01

    The nucleoprotein of infectious hematopoietic necrosis virus (IHNV) is considered as the main target antigen for detection of IHNV infection in salmonid fish. This study aimed at improving the expression and solubility of IHNV nucleoprotein (IHNV-NP) in E. coli expression system. The effects of several expression strategies including host strain type, protein expression temperature, heat-shock treatment prior to protein induction, and additives in the growth medium and in the cell lysis buffer were examined. Results showed that bacterial strain type had a great impact on protein expression level, whereas it was not effective in preventing protein aggregation. Production of soluble IHNV-NP was proportionally increased with decreased incubation temperature. Heat-shock treatment prior to protein induction did not change the percent of solubility. For cells grown at low temperature, the presence of additives in the lysis buffer enhanced the solubility of IHNV-NP up to 24%. The highest yield of soluble protein was obtained via incorporation of osmolytes in the growth medium of cells exposed to a mild salt stress, in the following order: sucrose > sorbitol > glycerol > glycine. Soluble protein obtained by the optimized condition was efficiently purified in high yield and successfully detected by two monoclonal antibodies in a sandwich ELISA. Taken together, a combination of proper host strain, low-temperature expression, and timely application of osmolytes in the growth medium provided sufficient quantities of soluble recombinant IHNV-NP that has the potential to be used for diagnostic purposes.

  4. Solid-state characterization and solubility of a genistein-caffeine cocrystal

    NASA Astrophysics Data System (ADS)

    Sowa, Michał; Ślepokura, Katarzyna; Matczak-Jon, Ewa

    2014-11-01

    Combination of genistein and caffeine leads to a 1:1 cocrystalline phase, which was identified by means of a solvent-drop grinding experiment and isolated afterwards in a solution-evaporation approach. Obtained cocrystal was characterized by X-ray single-crystal and powder diffraction as well as investigated in terms of thermal stability and Hirshfeld surfaces. A scale-up procedure was provided by slurry technique, enabling solubility determination. Neutral forms of both compounds cocrystallize in a common P21/c space group of the monoclinic crystal system. Analysis of packing and interactions in the crystal lattice reveals formation of molecular layers, formed by O-H⋯O, O-H⋯N and C-H⋯O-type contacts between genistein and caffeine molecules, whereas stabilization of the three-dimensional crystal lattice is provided by π⋯π interactions. Dissolution studies in a 50:50 v/v ethanol-water medium revealed that the maximum solubility of the cocrystalline phase reached 0.861 mg/mL after 8 h, revealing some degree of enhancement as compared to parent genistein, maximum solubility of which was also reached after 8 h and equalled 0.588 mg/mL.

  5. Solubility from the Femtoscale to the Macroscale

    ERIC Educational Resources Information Center

    Pollock, David W.; Truong, Giovanna T.; Bonjour, Jessica L.; Frost, John A.

    2018-01-01

    Solubility is frequently introduced at the high school and introductory college levels through the symbolic domain using net ionic equations and solubility product constants. Students may become proficient with spectator ion cancellation and skilled with algorithmic mathematical applications of solubility without obtaining a deeper understanding…

  6. Solubility advantage of amorphous pharmaceuticals: II. Application of quantitative thermodynamic relationships for prediction of solubility enhancement in structurally diverse insoluble pharmaceuticals.

    PubMed

    Murdande, Sharad B; Pikal, Michael J; Shanker, Ravi M; Bogner, Robin H

    2010-12-01

    To quantitatively assess the solubility advantage of amorphous forms of nine insoluble drugs with a wide range of physico-chemical properties utilizing a previously reported thermodynamic approach. Thermal properties of amorphous and crystalline forms of drugs were measured using modulated differential calorimetry. Equilibrium moisture sorption uptake by amorphous drugs was measured by a gravimetric moisture sorption analyzer, and ionization constants were determined from the pH-solubility profiles. Solubilities of crystalline and amorphous forms of drugs were measured in de-ionized water at 25°C. Polarized microscopy was used to provide qualitative information about the crystallization of amorphous drug in solution during solubility measurement. For three out the nine compounds, the estimated solubility based on thermodynamic considerations was within two-fold of the experimental measurement. For one compound, estimated solubility enhancement was lower than experimental value, likely due to extensive ionization in solution and hence its sensitivity to error in pKa measurement. For the remaining five compounds, estimated solubility was about 4- to 53-fold higher than experimental results. In all cases where the theoretical solubility estimates were significantly higher, it was observed that the amorphous drug crystallized rapidly during the experimental determination of solubility, thus preventing an accurate experimental assessment of solubility advantage. It has been demonstrated that the theoretical approach does provide an accurate estimate of the maximum solubility enhancement by an amorphous drug relative to its crystalline form for structurally diverse insoluble drugs when recrystallization during dissolution is minimal.

  7. EGF-CFC proteins are essential coreceptors for the TGF-β signals Vg1 and GDF1

    PubMed Central

    Cheng, Simon K.; Olale, Felix; Bennett, James T.; Brivanlou, Ali H.; Schier, Alexander F.

    2003-01-01

    The TGF-β signals Nodal, Activin, GDF1, and Vg1 have been implicated in mesoderm induction and left-right patterning. Nodal and Activin both activate Activin receptors, but only Nodal requires EGF-CFC coreceptors for signaling. We report that Vg1 and GDF1 signaling in zebrafish also depends on EGF-CFC proteins, but not on Nodal signals. Correspondingly, we find that in Xenopus Vg1 and GDF1 bind to and signal through Activin receptors only in the presence of EGF-CFC proteins. These results establish that multiple TGF-β signals converge on Activin receptor/EGF-CFC complexes and suggest a more widespread requirement for coreceptors in TGF-β signaling than anticipated previously. PMID:12514096

  8. Sibutramine characterization and solubility, a theoretical study

    NASA Astrophysics Data System (ADS)

    Aceves-Hernández, Juan M.; Nicolás Vázquez, Inés; Hinojosa-Torres, Jaime; Penieres Carrillo, Guillermo; Arroyo Razo, Gabriel; Miranda Ruvalcaba, René

    2013-04-01

    Solubility data from sibutramine (SBA) in a family of alcohols were obtained at different temperatures. Sibutramine was characterized by using thermal analysis and X-ray diffraction technique. Solubility data were obtained by the saturation method. The van't Hoff equation was used to obtain the theoretical solubility values and the ideal solvent activity coefficient. No polymorphic phenomena were found from the X-ray diffraction analysis, even though this compound is a racemic mixture of (+) and (-) enantiomers. Theoretical calculations showed that the polarisable continuum model was able to reproduce the solubility and stability of sibutramine molecule in gas phase, water and a family of alcohols at B3LYP/6-311++G (d,p) level of theory. Dielectric constant, dipolar moment and solubility in water values as physical parameters were used in those theoretical calculations for explaining that behavior. Experimental and theoretical results were compared and good agreement was obtained. Sibutramine solubility increased from methanol to 1-octanol in theoretical and experimental results.

  9. Extended Hansen solubility approach: naphthalene in individual solvents.

    PubMed

    Martin, A; Wu, P L; Adjei, A; Beerbower, A; Prausnitz, J M

    1981-11-01

    A multiple regression method using Hansen partial solubility parameters, delta D, delta p, and delta H, was used to reproduce the solubilities of naphthalene in pure polar and nonpolar solvents and to predict its solubility in untested solvents. The method, called the extended Hansen approach, was compared with the extended Hildebrand solubility approach and the universal-functional-group-activity-coefficient (UNIFAC) method. The Hildebrand regular solution theory was also used to calculate naphthalene solubility. Naphthalene, an aromatic molecule having no side chains or functional groups, is "well-behaved', i.e., its solubility in active solvents known to interact with drug molecules is fairly regular. Because of its simplicity, naphthalene is a suitable solute with which to initiate the difficult study of solubility phenomena. The three methods tested (Hildebrand regular solution theory was introduced only for comparison of solubilities in regular solution) yielded similar results, reproducing naphthalene solubilities within approximately 30% of literature values. In some cases, however, the error was considerably greater. The UNIFAC calculation is superior in that it requires only the solute's heat of fusion, the melting point, and a knowledge of chemical structures of solute and solvent. The extended Hansen and extended Hildebrand methods need experimental solubility data on which to carry out regression analysis. The extended Hansen approach was the method of second choice because of its adaptability to solutes and solvents from various classes. Sample calculations are included to illustrate methods of predicting solubilities in untested solvents at various temperatures. The UNIFAC method was successful in this regard.

  10. Suppression of transient receptor potential melastatin 4 expression promotes conversion of endothelial cells into fibroblasts via transforming growth factor/activin receptor-like kinase 5 pathway.

    PubMed

    Echeverría, Cesar; Montorfano, Ignacio; Cabello-Verrugio, Claudio; Armisén, Ricardo; Varela, Diego; Simon, Felipe

    2015-05-01

    To study whether transient receptor potential melastatin 4 (TRPM4) participates in endothelial fibrosis and to investigate the underlying mechanism. Primary human endothelial cells were used and pharmacological and short interfering RNA-based approaches were used to test the transforming growth factor beta (TGF-β)/activin receptor-like kinase 5 (ALK5) pathway participation and contribution of TRPM7 ion channel. Suppression of TRPM4 expression leads to decreased endothelial protein expression and increased expression of fibrotic and extracellular matrix markers. Furthermore, TRPM4 downregulation increases intracellular Ca levels as a potential condition for fibrosis. The underlying mechanism of endothelial fibrosis shows that inhibition of TRPM4 expression induces TGF-β1 and TGF-β2 expression, which act through their receptor, ALK5, and the nuclear translocation of the profibrotic transcription factor smad4. TRPM4 acts to maintain endothelial features and its loss promotes fibrotic conversion via TGF-β production. The regulation of TRPM4 levels could be a target for preserving endothelial function during inflammatory diseases.

  11. Ideal gas solubilities and solubility selectivities in a binary mixture of room-temperature ionic liquids.

    PubMed

    Finotello, Alexia; Bara, Jason E; Narayan, Suguna; Camper, Dean; Noble, Richard D

    2008-02-28

    This study focuses on the solubility behaviors of CO2, CH4, and N2 gases in binary mixtures of imidazolium-based room-temperature ionic liquids (RTILs) using 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C2mim][Tf2N]) and 1-ethyl-3-methylimidazolium tetrafluoroborate ([C2mim][BF4]) at 40 degrees C and low pressures (approximately 1 atm). The mixtures tested were 0, 25, 50, 75, 90, 95, and 100 mol % [C2mim][BF4] in [C2mim][Tf2N]. Results show that regular solution theory (RST) can be used to describe the gas solubility and selectivity behaviors in RTIL mixtures using an average mixture solubility parameter or an average measured mixture molar volume. Interestingly, the solubility selectivity, defined as the ratio of gas mole fractions in the RTIL mixture, of CO2 with N2 or CH4 in pure [C2mim][BF4] can be enhanced by adding 5 mol % [C2mim][Tf2N].

  12. Understanding Solubility through Excel Spreadsheets

    NASA Astrophysics Data System (ADS)

    Brown, Pamela

    2001-02-01

    This article describes assignments related to the solubility of inorganic salts that can be given in an introductory general chemistry course. Le Châtelier's principle, solubility, unit conversion, and thermodynamics are tied together to calculate heats of solution by two methods: heats of formation and an application of the van't Hoff equation. These assignments address the need for math, graphing, and computer skills in the chemical technology program by developing skill in the use of Microsoft Excel to prepare spreadsheets and graphs and to perform linear and nonlinear curve-fitting. Background information on the value of understanding and predicting solubility is provided.

  13. Isolation and characterization of acid-soluble collagen from the scales of marine fishes from Japan and Vietnam.

    PubMed

    Minh Thuy, Le Thi; Okazaki, Emiko; Osako, Kazufumi

    2014-04-15

    Acid-soluble collagen (ASC) was successfully extracted from the scales of lizard fish (Saurida spp.) and horse mackerel (Trachurus japonicus) from Japan and Vietnam and grey mullet (Mugil cephalis), flying fish (Cypselurus melanurus) and yellowback seabream (Dentex tumifrons) from Japan. ASC yields were about 0.43-1.5% (on a dry weight basis), depending on the species. The SDS-PAGE profile showed that the ASCs were type I collagens, and consisted of two different α chains, α1 and α2, as well as a β component. ASC of horse mackerel from Vietnam contained a higher imino acid level than that from Japan. ASC denaturation temperature (Td) ranged from 26 to 29 °C, depending on fish species and imino acid content (p<0.01). Maximal solubility of individual collagens was observed at pHs 1-3. Collagen solubility decreased sharply at NaCl concentrations >0.4M, regardless of fish type. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Automated in Situ Measurement of Gas Solubility in Liquids with a Simple Tube-in-Tube Reactor.

    PubMed

    Zhang, Jisong; Teixeira, Andrew R; Zhang, Haomiao; Jensen, Klavs F

    2017-08-15

    Data on the solubilities of gases in liquids are foundational for assessing a variety of multiphase separations and gas-liquid reactions. Taking advantage of the tube-in-tube reactor design built with semipermeable Teflon AF-2400 tubes, liquids can be rapidly saturated without direct contacting of gas and liquid. The gas solubility can be determined by performing steady-state flux balances of both the gas and liquid flowing into the reactor system. Using this type of reactor, a fully automated strategy has been developed for the rapid in situ measurement of gas solubilities in liquids. The developed strategy enables precise gas solubility measurements within 2-5 min compared with 4-5 h using conventional methods. This technique can be extended to the discrete multipoint steady-state and continuous ramped-multipoint data acquisition methods. The accuracy of this method has been validated against several gas-liquid systems, showing less than 2% deviation from known values. Finally, this strategy has been extended to measure the temperature dependence of gas solubilities in situ and to estimate the local enthalpy of dissolution across a defined temperature range.

  15. The effect of relative solubility on crystal purity

    NASA Astrophysics Data System (ADS)

    Givand, Jeffrey Christopher

    This study establishes the relationship between impurity incorporation in a crystal by lattice substitution and the solubility of that impurity in solution. The model system studied was L-isoleucine crystals contaminated by the isomorphic impurity L-leucine. Upon crystallization from aqueous solution by cooling, leucine is concentrated in the isoleucine unit cell through lattice substitution mechanisms. Attempts to reduce the degree of leucine incorporation via adjustments of the rate at which supersaturation is generated yielded marginal success. This work demonstrates that incorporation of leucine in the crystal can be considerably suppressed by reducing the solubility of product relative to the solubility of impurity. Changes to the relative solubility of the impurity were accomplished by the addition of various electrolytes and organic co-solvents to the aqueous amino acid solutions. The solubilities of the two amino acids were measured and compared to their solubilities in pure water. Changes in the ratio of pure-component solubilities were directly related to changes in crystal purity. This thermodynamic quantity of relative solubility was shown to be a key factor in determining impurity uptake by lattice substitution. In addition to the experimental observations, a fundamental thermodynamic link between relative solubility and crystal purity is established through this research. First, the amino acid solubility data as a function of temperature in all solvent mixtures were accurately correlated using a thermodynamic model. The parameters from this model were then adapted to a novel solid-solution thermodynamic model to express the crystal purity in terms of equilibrium solution impurity concentration. After the determination of one system specific parameter, the model is able to predict the crystal purity in a new solvent in which the pure-component solubilities are known. The ability of an electrolyte or co-solvent to improve crystal purity from a given

  16. Solubility of carbohydrates in heavy water.

    PubMed

    Cardoso, Marcus V C; Carvalho, Larissa V C; Sabadini, Edvaldo

    2012-05-15

    The solubility of several mono-(glucose and xylose), di-(sucrose and maltose), tri-(raffinose) and cyclic (α-cyclodextrin) saccharides in H(2)O and in D(2)O were measured over a range of temperatures. The solution enthalpies for the different carbohydrates in the two solvents were determined using the vant' Hoff equation and the values in D(2)O are presented here for the first time. Our findings indicate that the replacement of H(2)O by D(2)O remarkably decreases the solubilities of the less soluble carbohydrates, such as maltose, raffinose and α-cyclodextrin. On the other hand, the more soluble saccharides, glucose, xylose, and sucrose, are practically insensitive to the H/D replacement in water. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Reinvestigation of the Steady-State Kinetics and Physiological Function of the Soluble NiFe-Hydrogenase I of Pyrococcus furiosus▿

    PubMed Central

    van Haaster, Daan J.; Silva, Pedro J.; Hagedoorn, Peter-Leon; Jongejan, Jaap A.; Hagen, Wilfred R.

    2008-01-01

    Pyrococcus furiosus has two types of NiFe-hydrogenases: a heterotetrameric soluble hydrogenase and a multimeric transmembrane hydrogenase. Originally, the soluble hydrogenase was proposed to be a new type of H2 evolution hydrogenase, because, in contrast to all of the then known NiFe-hydrogenases, the hydrogen production activity at 80°C was found to be higher than the hydrogen consumption activity and CO inhibition appeared to be absent. NADPH was proposed to be the electron donor. Later, it was found that the membrane-bound hydrogenase exhibits very high hydrogen production activity sufficient to explain cellular H2 production levels, and this seems to eliminate the need for a soluble hydrogen production activity and therefore leave the soluble hydrogenase without a physiological function. Therefore, the steady-state kinetics of the soluble hydrogenase were reinvestigated. In contrast to previous reports, a low Km for H2 (∼20 μM) was found, which suggests a relatively high affinity for hydrogen. Also, the hydrogen consumption activity was 1 order of magnitude higher than the hydrogen production activity, and CO inhibition was significant (50% inhibition with 20 μM dissolved CO). Since the Km for NADP+ is ∼37 μM, we concluded that the soluble hydrogenase from P. furiosus is likely to function in the regeneration of NADPH and thus reuses the hydrogen produced by the membrane-bound hydrogenase in proton respiration. PMID:18156274

  18. Multicharged and/or water-soluble fluorescent dendrimers: properties and uses.

    PubMed

    Caminade, Anne-Marie; Hameau, Aurélien; Majoral, Jean-Pierre

    2009-09-21

    The fluorescence of water-soluble dendritic compounds can be due to the whole structure or to fluorophores used as core, as peripheral groups, or as branches. Highly sophisticated precisely defined structures with other functional groups usable for material or biological purposes have been synthesised, but many recent examples have shown that dendrimers can be used as versatile platforms for statistically linking various types of functional groups.

  19. Partially soluble organics as cloud condensation nuclei: Role of trace soluble and surface active species

    NASA Astrophysics Data System (ADS)

    Broekhuizen, K.; Kumar, P. Pradeep; Abbatt, J. P. D.

    2004-01-01

    The ability of partially soluble organic species to act as cloud condensation nuclei (CCN) has been studied. A Köhler model incorporating solute solubility and droplet surface tension describes the behavior of solid adipic and succinic acid particles, whereas solid azelaic acid activates much more efficiently that predicted. In addition, it was shown that trace levels of either sulfate or surface active species have a dramatic effect on the activation of adipic acid, a moderately soluble organic, as predicted by the full Köhler model. For internally mixed particles in the atmosphere, these effects will greatly enhance the role of organic aerosols as CCN.

  20. Soluble asialoglycoprotein receptors reflect the apoptosis of hepatocytes.

    PubMed

    Kakegawa, Tetsuji; Ise, Hirohiko; Sugihara, Nobuhiro; Nikaido, Toshio; Negishi, Naoki; Akaike, Toshihiro; Tanaka, Eiji

    2002-01-01

    Cell death is thought to take place through at least two distinct processes: apoptosis and necrosis. There is increasing evidence that dysregulation of the apoptotic program is involved in liver diseases. However, there is no method to simply evaluate apoptosis in the liver tissue at present. It has been reported that the expression of asialoglycoprotein receptors (AGPRs) increases with apoptosis, but there is no report until now that investigates the influence of soluble AGPRs on apoptosis of hepatocytes. Soluble AGPRs have been reported to be present in human serum under physiological conditions. In the present study, in order to investigate the correlation between apoptosis of hepatocytes and soluble AGPR, mouse soluble AGPRs were detected using SDS-PAGE and Western blot analysis was conducted using anti-extracellular mouse hepatic lectin-1 (Ex-MHL-1) antiserum (polyclonal rabbit serum). The mouse soluble AGPRs were present in culture medium and mouse serum when hepatocytes were damaged. The soluble AGPRs increased proportionately, as the number of dead hepatocytes increased. In addition, soluble AGPRs existed more when apoptotic cell death was observed in in vitro and in vivo than when necrotic cell death was observed. The extracellular moiety of MHL-1 exists in the culture medium and mouse serum as a soluble AGPR, but the detailed mechanism of releasing soluble AGPR from hepatocytes has not been revealed yet. We described the first evidence for the relation between quantity of soluble AGPRs with two kinds of cell death: necrosis and apoptosis. Based on the results of our study, soluble AGPRs might become a new marker of apoptosis in the liver tissue and be useful for clinical diagnosis and treatment for liver diseases.

  1. Soluble urokinase-type plasminogen activator receptor (suPAR) and interleukin-6 levels in hyperemesis gravidarum.

    PubMed

    Desdicioglu, Raziye; Yildirim, Melahat; Kocaoglu, Gulcan; Demir Cendek, Busra; Avcioglu, Gamze; Tas, Emre Erdem; Sengul, Ozlem; Erel, Ozcan; Yavuz, Ayse Filiz

    2017-10-09

    The aim was to compare serum soluble urokinase-type plasminogen activator receptor (suPAR) levels as well as interleukin-6 levels (IL-6) in pregnant women with hyperemesis gravidarum (HG) and asymptomatic pregnant women. Our study population consists of voluntary first trimester-pregnant women who applied to the outpatient clinic of the department of obstetrics and gynecology of Ankara Ataturk Training and Research Hospital. Between February and May 2016, 60 pregnant women were included in our prospective study. Serum suPAR and IL-6 levels were evaluated with the ELISA method. Twenty-nine pregnant women with HG and 31 asymptomatic pregnant women were included in the study. Serum suPAR level in the HG group was measured as 0.36 ± 0.56 ng/ml, whereas this level in the healthy pregnant control group was measured as 0.15 ± 0.15 ng/ml (p < 0.05). The interleukin-6 level in the HG group was 5.69 ± 2.16 pg/ml, whereas in the control group it was measured as 3.88 ± 0.28 pg/ml (p < 0.05). Serum suPAR and IL-6 levels proved to be high in the HG group. It is likely that suPAR could play a role in the etiopathogenesis of hyperemesis gravidarum. Copyright © 2017. Published by Elsevier Taiwan LLC.

  2. Simultaneous Rapid Determination of the Solubility and Diffusion Coefficients of a Poorly Water-Soluble Drug Based on a Novel UV Imaging System.

    PubMed

    Lu, Yan; Li, Mingzhong

    2016-01-01

    The solubility and diffusion coefficient are two of the most important physicochemical properties of a drug compound. In practice, both have been measured separately, which is time consuming. This work utilizes a novel technique of UV imaging to determine the solubility and diffusion coefficients of poorly water-soluble drugs simultaneously. A 2-step optimal method is proposed to determine the solubility and diffusion coefficients of a poorly water-soluble pharmaceutical substance based on the Fick's second law of diffusion and UV imaging measurements. Experimental results demonstrate that the proposed method can be used to determine the solubility and diffusion coefficients of a drug with reasonable accuracy, indicating that UV imaging may provide a new opportunity to accurately measure the solubility and diffusion coefficients of a poorly water-soluble drug simultaneously and rapidly. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  3. Aluminum Solubility Mechanisms in Quartz: Implications for Al-in-Quartz Thermobarometry

    NASA Astrophysics Data System (ADS)

    Was, E.; Thomas, J. B.; Nachlas, W. O.

    2016-12-01

    Trace element thermobarometers in minerals are becoming increasingly important tools for studying geologic processes in many different geologic environments. The solubility of some trace-level (i.e. <1000 ppmw) components in minerals can be measured and used to estimate the pressure (P) and/or temperature (T) of mineral crystallization. To date, quartz has been useful for trace element thermobarometry (based on its Ti content) due to its common occurrence in many rock types and therefore can provide information on a wide range of petrologic processes. However, this technique relies on an independent constraint on T (or P) to calculate P (or T), which can be difficult to obtain in some rocks. To add to the utility of quartz as a thermobarometer, we have experimentally co-crystallized quartz and aluminosilicates at elevated P-T conditions to determine Al solubilities in quartz, which will allow use of the crossing isopleths method to determine a unique P and T solution from two independent techniques (using Ti and Al) in the same mineral. Preliminary experiments demonstrate that Al concentrations in quartz vary systematically with P and T, and also show that Al is soluble at greater levels than Ti. The success of an Al-in-quartz thermobarometer relies on determining both the variations in Al solubility across P-T space as well as the solubility mechanism for Al substitution into the quartz structure. To determine these parameters, we use Fourier transform infrared spectroscopy (FTIR) to quantify H+ contents as a charge-balancing ion for Al3+ to replace Si4+, electron microprobe (EPMA) to measure Al concentrations, and nuclear magnetic resonance spectroscopy (NMR) to determine the coordination environment of Al in quartz.

  4. Isothermal absorption of soluble gases by atmospheric nanoaerosols

    NASA Astrophysics Data System (ADS)

    Elperin, T.; Fominykh, A.; Krasovitov, B.; Lushnikov, A.

    2013-01-01

    We investigate mass transfer during the isothermal absorption of atmospheric trace soluble gases by a single droplet whose size is comparable to the molecular mean free path in air at normal conditions. It is assumed that the trace reactant diffuses to the droplet surface and then reacts with the substances inside the droplet according to the first-order rate law. Our analysis applies a flux-matching theory of transport processes in gases and assumes constant thermophysical properties of the gases and liquids. We derive an integral equation of Volterra type for the transient molecular flux density to a liquid droplet and solve it numerically. Numerical calculations are performed for absorption of sulfur dioxide (SO2), dinitrogen trioxide (N2O3), and chlorine (Cl2) by liquid nanoaerosols accompanied by chemical dissociation reaction. It is shown that during gas absorption by nanoaerosols, the kinetic effects play a significant role, and neglecting kinetic effects leads to a significant overestimation of the soluble gas flux into a droplet during the entire period of gas absorption.

  5. Isothermal absorption of soluble gases by atmospheric nanoaerosols.

    PubMed

    Elperin, T; Fominykh, A; Krasovitov, B; Lushnikov, A

    2013-01-01

    We investigate mass transfer during the isothermal absorption of atmospheric trace soluble gases by a single droplet whose size is comparable to the molecular mean free path in air at normal conditions. It is assumed that the trace reactant diffuses to the droplet surface and then reacts with the substances inside the droplet according to the first-order rate law. Our analysis applies a flux-matching theory of transport processes in gases and assumes constant thermophysical properties of the gases and liquids. We derive an integral equation of Volterra type for the transient molecular flux density to a liquid droplet and solve it numerically. Numerical calculations are performed for absorption of sulfur dioxide (SO(2)), dinitrogen trioxide (N(2)O(3)), and chlorine (Cl(2)) by liquid nanoaerosols accompanied by chemical dissociation reaction. It is shown that during gas absorption by nanoaerosols, the kinetic effects play a significant role, and neglecting kinetic effects leads to a significant overestimation of the soluble gas flux into a droplet during the entire period of gas absorption.

  6. Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes

    PubMed Central

    Yoon, Jeong-Hwan; Jung, Su Myung; Park, Seok Hee; Kato, Mitsuyasu; Yamashita, Tadashi; Lee, In-Kyu; Sudo, Katsuko; Nakae, Susumu; Han, Jin Soo; Kim, Ok-Hee; Oh, Byung-Chul; Sumida, Takayuki; Kuroda, Masahiko; Ju, Ji-Hyeon; Jung, Kyeong Cheon; Park, Seong Hoe; Kim, Dae-Kee; Mamura, Mizuko

    2013-01-01

    Varieties of transforming growth factor-β (TGF-β) antagonists have been developed to intervene with excessive TGF-β signalling activity in cancer. Activin receptor-like kinase5 (ALK5) inhibitors antagonize TGF-β signalling by blocking TGF-β receptor-activated Smad (R-Smad) phosphorylation. Here we report the novel mechanisms how ALK5 inhibitors exert a therapeutic effect on a mouse B16 melanoma model. Oral treatment with a novel ALK5 inhibitor, EW-7197 (2.5 mg/kg daily) or a representative ALK5 inhibitor, LY-2157299 (75 mg/kg bid) suppressed the progression of melanoma with enhanced cytotoxic T-lymphocyte (CTL) responses. Notably, ALK5 inhibitors not only blocked R-Smad phosphorylation, but also induced ubiquitin-mediated degradation of the common Smad, Smad4 mainly in CD8+ T cells in melanoma-bearing mice. Accordingly, T-cell-specific deletion of Smad4 was sufficient to suppress the progression of melanoma. We further identified eomesodermin (Eomes), the T-box transcription factor regulating CTL functions, as a specific target repressed by TGF-β via Smad4 and Smad3 in CD8+ T cells. Thus, ALK5 inhibition enhances anti-melanoma CTL responses through ubiquitin-mediated degradation of Smad4 in addition to the direct inhibitory effect on R-Smad phosphorylation. PMID:24127404

  7. Binding of Soluble Yeast β-Glucan to Human Neutrophils and Monocytes is Complement-Dependent

    PubMed Central

    Bose, Nandita; Chan, Anissa S. H.; Guerrero, Faimola; Maristany, Carolyn M.; Qiu, Xiaohong; Walsh, Richard M.; Ertelt, Kathleen E.; Jonas, Adria Bykowski; Gorden, Keith B.; Dudney, Christine M.; Wurst, Lindsay R.; Danielson, Michael E.; Elmasry, Natalie; Magee, Andrew S.; Patchen, Myra L.; Vasilakos, John P.

    2013-01-01

    The immunomodulatory properties of yeast β-1,3/1,6 glucans are mediated through their ability to be recognized by human innate immune cells. While several studies have investigated binding of opsonized and unopsonized particulate β-glucans to human immune cells mainly via complement receptor 3 (CR3) or Dectin-1, few have focused on understanding the binding characteristics of soluble β-glucans. Using a well-characterized, pharmaceutical-grade, soluble yeast β-glucan, this study evaluated and characterized the binding of soluble β-glucan to human neutrophils and monocytes. The results demonstrated that soluble β-glucan bound to both human neutrophils and monocytes in a concentration-dependent and receptor-specific manner. Antibodies blocking the CD11b and CD18 chains of CR3 significantly inhibited binding to both cell types, establishing CR3 as the key receptor recognizing the soluble β-glucan in these cells. Binding of soluble β-glucan to human neutrophils and monocytes required serum and was also dependent on incubation time and temperature, strongly suggesting that binding was complement-mediated. Indeed, binding was reduced in heat-inactivated serum, or in serum treated with methylamine or in serum reacted with the C3-specific inhibitor compstatin. Opsonization of soluble β-glucan was demonstrated by detection of iC3b, the complement opsonin on β-glucan-bound cells, as well as by the direct binding of iC3b to β-glucan in the absence of cells. Binding of β-glucan to cells was partially inhibited by blockade of the alternative pathway of complement, suggesting that the C3 activation amplification step mediated by this pathway also contributed to binding. PMID:23964276

  8. Preparations and properties of anti-corrosion additives of water-soluble metal working fluids for aluminum alloy materials.

    PubMed

    Watanabe, Shoji

    2008-01-01

    This short review describes various types of anti-corrosion additives of water-soluble metal working fluids for aluminum alloy materials. It is concerned with synthetic additives classified according to their functional groups; silicone compounds, carboxylic acids and dibasic acids, esters, Diels-Alder adducts, various polymers, nitrogen compounds, phosphoric esters, phosphonic acids, and others. Testing methods for water-soluble metal working fluids for aluminum alloy materials are described for a practical application in a laboratory.

  9. How Soluble GARP Enhances TGFβ Activation.

    PubMed

    Fridrich, Sven; Hahn, Susanne A; Linzmaier, Marion; Felten, Matthias; Zwarg, Jenny; Lennerz, Volker; Tuettenberg, Andrea; Stöcker, Walter

    2016-01-01

    GARP (glycoprotein A repetitions predominant) is a cell surface receptor on regulatory T-lymphocytes, platelets, hepatic stellate cells and certain cancer cells. Its described function is the binding and accommodation of latent TGFβ (transforming growth factor), before the activation and release of the mature cytokine. For regulatory T cells it was shown that a knockdown of GARP or a treatment with blocking antibodies dramatically decreases their immune suppressive capacity. This confirms a fundamental role of GARP in the basic function of regulatory T cells. Prerequisites postulated for physiological GARP function include membrane anchorage of GARP, disulfide bridges between the propeptide of TGFβ and GARP and connection of this propeptide to αvβ6 or αvβ8 integrins of target cells during mechanical TGFβ release. Other studies indicate the existence of soluble GARP complexes and a functionality of soluble GARP alone. In order to clarify the underlying molecular mechanism, we expressed and purified recombinant TGFβ and a soluble variant of GARP. Surprisingly, soluble GARP and TGFβ formed stable non-covalent complexes in addition to disulfide-coupled complexes, depending on the redox conditions of the microenvironment. We also show that soluble GARP alone and the two variants of complexes mediate different levels of TGFβ activity. TGFβ activation is enhanced by the non-covalent GARP-TGFβ complex already at low (nanomolar) concentrations, at which GARP alone does not show any effect. This supports the idea of soluble GARP acting as immune modulator in vivo.

  10. New recommendations for measuring collagen solubility.

    PubMed

    Latorre, María E; Lifschitz, Adrian L; Purslow, Peter P

    2016-08-01

    The heat-solubility of intramuscular collagen is usually conducted in 1/4 Ringer's solution at pH7.4, despite this ionic strength and pH being inappropriate for post-rigor meat. The current work studied the percentage of soluble collagen and hydrothermal isometric tension characteristics of perimysial strips on bovine semitendinosus muscles in either 1/4 Ringer's solution, distilled water, PBS, or a solution of the same salt concentration as 1/4 Ringer's but at pH5.6. Values of % soluble collagen were lower at pH7.4 than 5.6. Increasing ionic strength reduced % soluble collagen. The maximum perimysial isometric tension was independent of the bathing medium, but the percent relaxation was higher at pH7.4 than at pH5.6, and increased with ionic strength of the media. It is recommended that future measurements of collagen solubility and tests on connective tissue components of post-rigor meat should be carried out in a solution of concentrations NaCl and KCl equivalent to those in 1/4 Ringer's, but at pH5.6, a pH relevant to post-rigor meat. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Accumulation of a soluble form of human nectin-2 is required for exerting the resistance against herpes simplex virus type 2 infection in transfected cells.

    PubMed

    Fujimoto, Y; Ozaki, K; Iwamori, N; Takakuwa, H; Ono, E

    2016-03-01

    Cell entry of herpes simplex virus type 2 (HSV-2) requires the interaction of viral glycoprotein D (gD) with the receptor nectin-1 and herpesvirus entry mediator (HVEM). In addition, it is known that nectin-2 is also functional as a receptor for HSV-2, although the binding to the gD is weak. To examine an antiviral potential of a soluble form of human nectin-2 (hNectin-2Ig), transfected Vero cells expressing the entire ectodomain of nectin-2 fused to the Fc portion of human IgG were established. Specific binding of hNectin-2Ig to HSV-2 gD was confirmed by ELISA. Competitive ELISA demonstrated that accumulation of hNectin-2Ig in transfected cells increased significantly in a cell culture time dependent manner. Viral growth of several HSV-2 strains was significantly inhibited in the transfected cells that were cultured for 72 hr compared with control Vero cells, but not in cells that were cultured for 24 hr. These results indicate that accumulation of a soluble form of nectin-2 is required for exerting the resistance against HSV-2 infection.

  12. The Cardiovascular Effect of Single Injection and Toxicologic Effects of Repetitive 2-Week Intravenous Administration of Activin A/BMP-2 Chimera in Beagle Dog.

    PubMed

    Lee, Jae Hyup; Choe, Senyon; Han, Shihuan

    2018-02-01

    This study was performed for the purpose to evaluate the effect of activin A/BMP-2 chimera (AB204) on cardiovascular system and toxicological effect in beagle dogs. When administered AB204 at the dose of 0.32 mg/kg via intravenous injection in beagle dogs, there were no changes in systolic, diastolic and mean blood pressure as well as in pulse rate, in addition that there were no differences in ORS complex, PR interval, R-R interval, QT interval and QTcV interval on the electrocardiography. Also, when administered AB204 at the doses of 0.25 and 0.5 mg/kg/day via repetitive intravenous injection for 2 weeks, it did not cause any significant changes in general symptoms, weight, food intake, ophthalmologic abnormality, urine, hematology, serum biochemistry, organ weight and autopsy values. Therefore, AB204 did not affect cardiovascular functions including blood pressure, pulse rate and ECG, when administered at the dose of ≤0.32 mg/kg via single intravenous injection in male beagle dogs. When it was administered at the dose of 0.5 mg/kg repetitive intravenous injection for 2 weeks, it did not show any toxicity.

  13. Selective accumulation of langerhans-type dendritic cells in small airways of patients with COPD

    PubMed Central

    2010-01-01

    Background Dendritic cells (DC) linking innate and adaptive immune responses are present in human lungs, but the characterization of different subsets and their role in COPD pathogenesis remain to be elucidated. The aim of this study is to characterize and quantify pulmonary myeloid DC subsets in small airways of current and ex-smokers with or without COPD. Methods Myeloid DC were characterized using flowcytometry on single cell suspensions of digested human lung tissue. Immunohistochemical staining for langerin, BDCA-1, CD1a and DC-SIGN was performed on surgical resection specimens from 85 patients. Expression of factors inducing Langerhans-type DC (LDC) differentiation was evaluated by RT-PCR on total lung RNA. Results Two segregated subsets of tissue resident pulmonary myeloid DC were identified in single cell suspensions by flowcytometry: the langerin+ LDC and the DC-SIGN+ interstitial-type DC (intDC). LDC partially expressed the markers CD1a and BDCA-1, which are also present on their known blood precursors. In contrast, intDC did not express langerin, CD1a or BDCA-1, but were more closely related to monocytes. Quantification of DC in the small airways by immunohistochemistry revealed a higher number of LDC in current smokers without COPD and in COPD patients compared to never smokers and ex-smokers without COPD. Importantly, there was no difference in the number of LDC between current and ex-smoking COPD patients. In contrast, the number of intDC did not differ between study groups. Interestingly, the number of BDCA-1+ DC was significantly lower in COPD patients compared to never smokers and further decreased with the severity of the disease. In addition, the accumulation of LDC in the small airways significantly correlated with the expression of the LDC inducing differentiation factor activin-A. Conclusions Myeloid DC differentiation is altered in small airways of current smokers and COPD patients resulting in a selective accumulation of the LDC subset which

  14. Tough, soluble, aromatic, thermoplastic copolyimides

    NASA Technical Reports Server (NTRS)

    Bryant, Robert G. (Inventor)

    1994-01-01

    Tough, soluble, aromatic, thermoplastic copolyimides were prepared by reacting 4,4'-oxydiphthalic anhydride, 3,4,3',4'-biphenyltetracarboxylic dianhydride and 3,4'-oxydianiline. These copolyimides were found to be soluble in common amide solvents such as acetamide, Nmethylpyrrolidinone, and dimethylformamide allowing them to be applied as the fully imidized copolymer and to be used to prepare a wide range of articles.

  15. Exactly soluble local bosonic cocycle models, statistical transmutation, and simplest time-reversal symmetric topological orders in 3+1 dimensions

    NASA Astrophysics Data System (ADS)

    Wen, Xiao-Gang

    2017-05-01

    We propose a generic construction of exactly soluble local bosonic models that realize various topological orders with gappable boundaries. In particular, we construct an exactly soluble bosonic model that realizes a (3+1)-dimensional [(3+1)D] Z2-gauge theory with emergent fermionic Kramers doublet. We show that the emergence of such a fermion will cause the nucleation of certain topological excitations in space-time without pin+ structure. The exactly soluble model also leads to a statistical transmutation in (3+1)D. In addition, we construct exactly soluble bosonic models that realize 2 types of time-reversal symmetry-enriched Z2 topological orders in 2+1 dimensions, and 20 types of simplest time-reversal symmetry-enriched topological (SET) orders which have only one nontrivial pointlike and stringlike topological excitation. Many physical properties of those topological states are calculated using the exactly soluble models. We find that some time-reversal SET orders have pointlike excitations that carry Kramers doublet, a fractionalized time-reversal symmetry. We also find that some Z2 SET orders have stringlike excitations that carry anomalous (nononsite) Z2 symmetry, which can be viewed as a fractionalization of Z2 symmetry on strings. Our construction is based on cochains and cocycles in algebraic topology, which is very versatile. In principle, it can also realize emergent topological field theory beyond the twisted gauge theory.

  16. Active intestinal drug absorption and the solubility-permeability interplay.

    PubMed

    Porat, Daniel; Dahan, Arik

    2018-02-15

    The solubility-permeability interplay deals with the question: what is the concomitant effect on the drug's apparent permeability when increasing the apparent solubility with a solubility-enabling formulation? The solubility and the permeability are closely related, exhibit certain interplay between them, and ongoing research throughout the past decade shows that treating the one irrespectively of the other may be insufficient. The aim of this article is to provide an overview of the current knowledge on the solubility-permeability interplay when using solubility-enabling formulations for oral lipophilic drugs, highlighting active permeability aspects. A solubility-enabling formulation may affect the permeability in opposite directions; the passive permeability may decrease as a result of the apparent solubility increase, according to the solubility-permeability tradeoff, but at the same time, certain components of the formulation may inhibit/saturate efflux transporters (when relevant), resulting in significant apparent permeability increase. In these cases, excipients with both solubilizing and e.g. P-gp inhibitory properties may lead to concomitant increase of both the solubility and the permeability. Intelligent development of such formulation will account for the simultaneous effects of the excipients' nature/concentrations on the two arms composing the overall permeability: the passive and the active arms. Overall, thorough mechanistic understanding of the various factors involved in the solubility-permeability interplay may allow developing better solubility-enabling formulations, thereby exploiting the advantages analyzed in this article, offering oral delivery solution even for BCS class IV drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Soluble transition metals cause the pro-inflammatory effects of welding fumes in vitro.

    PubMed

    McNeilly, Jane D; Heal, Mathew R; Beverland, Iain J; Howe, Alan; Gibson, Mark D; Hibbs, Leon R; MacNee, William; Donaldson, Ken

    2004-04-01

    Epidemiological studies have consistently reported a higher incidence of respiratory illnesses such as bronchitis, metal fume fever (MFF), and chronic pneumonitis among welders exposed to high concentrations of metal-enriched welding fumes. Here, we studied the molecular toxicology of three different metal-rich welding fumes: NIMROD 182, NIMROD c276, and COBSTEL 6. Fume toxicity in vitro was determined by exposing human type II alveolar epithelial cell line (A549) to whole welding fume, a soluble extract of fume or the "washed" particulate. All whole fumes were significantly toxic to A549 cells at doses >63 microg ml(-1) (TD 50; 42, 25, and 12 microg ml(-1), respectively). NIMROD c276 and COBSTEL 6 fumes increased levels of IL-8 mRNA and protein at 6 h and protein at 24 h, as did the soluble fraction alone, whereas metal chelation of the soluble fraction using chelex beads attenuated the effect. The soluble fraction of all three fumes caused a rapid depletion in intracellular glutathione following 2-h exposure with a rebound increase by 24 h. In addition, both nickel based fumes, NIMROD 182 and NIMROD c276, induced significant reactive oxygen species (ROS) production in A549 cells after 2 h as determined by DCFH fluorescence. ICP analysis confirmed that transition metal concentrations were similar in the whole and soluble fractions of each fume (dominated by Cr), but significantly less in both the washed particles and chelated fractions. These results support the hypothesis that the enhanced pro-inflammatory responses of welding fume particulates are mediated by soluble transition metal components via an oxidative stress mechanism.

  18. Hydrocarbon-soluble low-melting corrosion inhibitor TAL-3

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nesterenko, S.A.; Sorokin, V.I.; Naumenko, O.V.

    1987-03-01

    The inhibitor TAL-3 is intended for the corrosion protection of metals that come into contact with two-phase systems of the hydrocarbon-water type. It is applicable to the service conditions of equipment and pipelines of the petroleum and petroleum refining industries. The purpose of this paper was to electrochemically assess its solubility in such systems and its inhibitory properties on samples of 08kp steel toward the effects of refinery and oil field waste water and process emulsions both on the laboratory scale and in field tests.

  19. In vitro and in vivo studies on the complexes of glipizide with water-soluble β-cyclodextrin-epichlorohydrin polymers.

    PubMed

    Nie, Shufang; Zhang, Shu; Pan, Weisan; Liu, Yanli

    2011-05-01

    The purpose of this study was to evaluate the potential of a newly modified cyclodextrin derivative, water-soluble β-cyclodextrin-epichlorohydrin polymer (β-CDP), as an effective drug carrier to enhance the dissolution rate and oral bioavailability of glipizide as a poorly water-soluble model drug. Inclusion complexes of glipizide with β-CDP were prepared by the co-evaporation method and characterized by phase solubility, dissolution, and differential scanning calorimetry. The solubility curve was classified as type A(L), which indicated the formation of 1:1 complex between glipizide and β-CDP. β-CDP had better properties of increasing the aqueous solubility of glipizide compared with HP-β-CD. The dissolution rate of drug from the β-CDP complexes was significantly greater than that of the corresponding physical mixtures indicating that the formation of amorphous complex increased the solubility of glipizide. Moreover, the increment in drug dissolution rate from the glipizide/β-CDP systems was higher than that from the corresponding ones with HP-β-CD, which indicated that β-CDP could provide greater capability of solubilization for poorly soluble drugs. Furthermore, in vivo study revealed that the bioavailability of glipizide was significantly improved by glipizide /β-CDP inclusion complex after oral administration to beagle dogs.

  20. Inverse gas chromatographic determination of solubility parameters of excipients.

    PubMed

    Adamska, Katarzyna; Voelkel, Adam

    2005-11-04

    The principle aim of this work was an application of inverse gas chromatography (IGC) for the estimation of solubility parameter for pharmaceutical excipients. The retention data of number of test solutes were used to calculate Flory-Huggins interaction parameter (chi1,2infinity) and than solubility parameter (delta2), corrected solubility parameter (deltaT) and its components (deltad, deltap, deltah) by using different procedures. The influence of different values of test solutes solubility parameter (delta1) over calculated values was estimated. The solubility parameter values obtained for all excipients from the slope, from Guillet and co-workers' procedure are higher than that obtained from components according Voelkel and Janas procedure. It was found that solubility parameter's value of the test solutes influences, but not significantly, values of solubility parameter of excipients.

  1. Aqueous solubility, effects of salts on aqueous solubility, and partitioning behavior of hexafluorobenzene: experimental results and COSMO-RS predictions.

    PubMed

    Schröder, Bernd; Freire, Mara G; Varanda, Fatima R; Marrucho, Isabel M; Santos, Luís M N B F; Coutinho, João A P

    2011-07-01

    The aqueous solubility of hexafluorobenzene has been determined, at 298.15K, using a shake-flask method with a spectrophotometric quantification technique. Furthermore, the solubility of hexafluorobenzene in saline aqueous solutions, at distinct salt concentrations, has been measured. Both salting-in and salting-out effects were observed and found to be dependent on the nature of the cationic/anionic composition of the salt. COSMO-RS, the Conductor-like Screening Model for Real Solvents, has been used to predict the corresponding aqueous solubilities at conditions similar to those used experimentally. The prediction results showed that the COSMO-RS approach is suitable for the prediction of salting-in/-out effects. The salting-in/-out phenomena have been rationalized with the support of COSMO-RS σ-profiles. The prediction potential of COSMO-RS regarding aqueous solubilities and octanol-water partition coefficients has been compared with typically used QSPR-based methods. Up to now, the absence of accurate solubility data for hexafluorobenzene hampered the calculation of the respective partition coefficients. Combining available accurate vapor pressure data with the experimentally determined water solubility, a novel air-water partition coefficient has been derived. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. Solubility of gases and liquids in glassy polymers.

    PubMed

    De Angelis, Maria Grazia; Sarti, Giulio C

    2011-01-01

    This review discusses a macroscopic thermodynamic procedure to calculate the solubility of gases, vapors, and liquids in glassy polymers that is based on the general procedure provided by the nonequilibrium thermodynamics for glassy polymers (NET-GP) method. Several examples are presented using various nonequilibrium (NE) models including lattice fluid (NELF), statistical associating fluid theory (NE-SAFT), and perturbed hard sphere chain (NE-PHSC). Particular applications illustrate the calculation of infinite-dilution solubility coefficients in different glassy polymers and the prediction of solubility isotherms for different gases and vapors in pure polymers as well as in polymer blends. The determination of model parameters is discussed, and the predictive abilities of the models are illustrated. Attention is also given to the solubility of gas mixtures and solubility isotherms in nanocomposite mixed matrices. The fractional free volume determined from solubility data can be used to correlate solute diffusivities in mixed matrices.

  3. Learning about Solubility

    ERIC Educational Resources Information Center

    Salinas, Dino G.; Reyes, Juan G.

    2015-01-01

    Qualitative questions are proposed to assess the understanding of solubility and some of its applications. To improve those results, a simple quantitative problem on the precipitation of proteins is proposed.

  4. Tough, Soluble, Aromatic, Thermoplastic Copolyimides

    NASA Technical Reports Server (NTRS)

    Bryant, Robert G. (Inventor)

    1998-01-01

    Tough, soluble, aromatic, thermoplastic copolyimides were prepared by reacting 4,4'-oxydiphthalic anhydride, 3,4,3',4'-biphenyltetracarboxylic dianhydride and 3,4'-oxydianiline. These copolyimides were found to be soluble in common amide solvents such as N,N'-dimethyl acetamide, N-methylpyrrolidinone, and dimethylformamide allowing them to be applied as the fully imidized copolymer and to be used to prepare a wide range of articles.

  5. An alanine residue in human parainfluenza virus type 3 phosphoprotein is critical for restricting excessive N0-P interaction and maintaining N solubility.

    PubMed

    Zhang, Shengwei; Cheng, Qi; Luo, Chenxi; Yin, Lei; Qin, Yali; Chen, Mingzhou

    2018-05-01

    The phosphoprotein (P) of human parainfluenza virus type 3 (HPIV3) plays a pivotal role in viral RNA synthesis, which interacts with the nucleoprotein (N) to form a soluble N 0 -P complex (N 0 , free of RNAs) to prevent the nonspecific RNA binding and illegitimate aggregation of N. Functional regions within P have been studied intensively. However, the precise site (s) within P directly involved in N 0 -P interaction still remains unclear. In this study, using a series of deleted and truncated mutants of P of HPIV3, we demonstrate that amino-terminal 40 amino acids (aa) of P restrict and regulate N 0 -P interaction. Furthermore, using in vivo HPIV3 minigenome replicon assay, we identify a critical P mutant (P A28P ) located in amino-terminal 40 aa, which fails to support RNA synthesis of HPIV3 minigenome replicon. Although P A28P maintains an enhanced N-P interaction, it is unable to form N 0 -P complex and keep N soluble, thus, resulting in aggregation and functional abolishment of N-P complex. Moreover, we found that recombinant HPIV3 with mutation of A28P in P failed to be rescued. Taken together, we identified a residue within the extreme amino-terminus of P, which plays a critical role in restricting the excessively N-P interaction and keeping a functional N 0 -P complex formation. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. The soluble leptin receptor.

    PubMed

    Schaab, Michael; Kratzsch, Juergen

    2015-10-01

    The adipokine leptin realizes signal transduction via four different leptin receptor (OB-R) isoforms. The amount of functionally active OB-R, however, is affected by constitutive shedding of the extracellular domain. The product of the cleavage process, the so-called soluble leptin receptor (sOB-R), is the main binding protein for leptin in human blood and modulates its bioavailability. Concentrations of sOB-R are differentially regulated in metabolic disorders, such as type 1 diabetes mellitus or obesity, and can, therefore, enhance or reduce leptin sensitivity. Lipotoxicity and apoptosis increase OB-R cleavage via ADAM10-dependent mechanisms. In contrast, although increased sOB-R concentrations seem to directly inhibit leptin effects, reduced amounts of sOB-R may reflect decreased membrane expression of OB-R. These findings, in part, explain alterations of leptin sensitivity that are associated with changes in serum sOB-R concentrations seen in metabolic disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Dual Activity of Hydroxypropyl-β-Cyclodextrin and Water-Soluble Carriers on the Solubility of Carvedilol.

    PubMed

    Zoghbi, Abdelmoumin; Geng, Tianjiao; Wang, Bo

    2017-11-01

    Carvedilol (CAR) is a non-selective α and β blocker categorized as class II drug with low water solubility. Several recent studies have investigated ways to overcome this problem. The aim of the present study was to combine two of these methods: the inclusion complex using hydroxypropyl-β-cyclodextrin (HPβCD) with solid dispersion using two carriers: Poloxamer 188 (PLX) and Polyvinylpyrrolidone K-30 (PVP) to enhance the solubility, bioavailability, and the stability of CAR. Kneading method was used to prepare CAR-HPβCD inclusion complex (KD). The action of different carriers separately and in combination on Carvedilol solubility was investigated in three series. CAR-carrier and KD-carrier solid dispersions were prepared by solvent evaporation method. In vitro dissolution test was conducted in three different media: double-distilled water (DDW), simulative gastric fluid (SGF), and PBS pH 6.8 (PBS). The interactions between CAR, HPβCD, and different carriers were explored by Fourier transform infrared spectroscopy (FTIR), powder X-ray diffractometry (XRD), and differential scanning colorimetry (DSC). The results showed higher solubility of CAR in KD-PVP solid dispersions up to 70, 25, and 22 fold compared to pure CAR in DDW, SGF, and PBS, respectively. DSC and XRD analyses indicated an improved degree of transformation of CAR in KD-PVP solid dispersion from crystalline to amorphous state. This study provides a new successful combination of two polymers with the dual action of HPβCD and PLX/PVP on water solubility and bioavailability of CAR.

  8. IUPAC-NIST Solubility Data Series. 95. Alkaline Earth Carbonates in Aqueous Systems. Part 2. Ca

    NASA Astrophysics Data System (ADS)

    Vanderdeelen, Jan

    2012-06-01

    The alkaline earth carbonates are an important class of minerals. This article is part of a volume in the IUPAC-NIST Solubility Data Series that compiles and critically evaluates solubility data of the alkaline earth carbonates in water and in simple aqueous electrolyte solutions. Part 1 outlined the procedure adopted in this volume, and presented the beryllium and magnesium carbonates. Part 2, the current paper, compiles and critically evaluates the solubility data of calcium carbonate. The chemical forms included are the anhydrous CaCO3 types calcite, aragonite, and vaterite, the monohydrate monohydrocalcite (CaCO3. H2O), the hexahydrate ikaite (CaCO3.6H2O), and an amorphous form. The data were analyzed with two model variants, and thermodynamic data of each form consistent with each of the models and with the CODATA key values for thermodynamics are presented.

  9. Using MD simulations to calculate how solvents modulate solubility

    PubMed Central

    Liu, Shuai; Cao, Shannon; Hoang, Kevin; Young, Kayla L.; Paluch, Andrew S.; Mobley, David L.

    2016-01-01

    Here, our interest is in predicting solubility in general, and we focus particularly on predicting how the solubility of particular solutes is modulated by the solvent environment. Solubility in general is extremely important, both for theoretical reasons – it provides an important probe of the balance between solute-solute and solute-solvent interactions – and for more practical reasons, such as how to control the solubility of a given solute via modulation of its environment, as in process chemistry and separations. Here, we study how the change of solvent affects the solubility of a given compound. That is, we calculate relative solubilities. We use MD simulations to calculate relative solubility and compare our calculated values with experiment as well as with results from several other methods, SMD and UNIFAC, the latter of which is commonly used in chemical engineering design. We find that straightforward solubility calculations based on molecular simulations using a general small-molecule force field outperform SMD and UNIFAC both in terms of accuracy and coverage of the relevant chemical space. PMID:26878198

  10. Water-soluble carbon nanotube compositions for drug delivery and medicinal applications

    DOEpatents

    Tour, James M.; Lucente-Schultz, Rebecca; Leonard, Ashley; Kosynkin, Dmitry V.; Price, Brandi Katherine; Hudson, Jared L.; Conyers, Jr., Jodie L.; Moore, Valerie C.; Casscells, S. Ward; Myers, Jeffrey N.; Milas, Zvonimir L.; Mason, Kathy A.; Milas, Luka

    2014-07-22

    Compositions comprising a plurality of functionalized carbon nanotubes and at least one type of payload molecule are provided herein. The compositions are soluble in water and PBS in some embodiments. In certain embodiments, the payload molecules are insoluble in water. Methods are described for making the compositions and administering the compositions. An extended release formulation for paclitaxel utilizing functionalized carbon nanotubes is also described.

  11. Lipid Lowering with Soluble Dietary Fiber.

    PubMed

    Surampudi, Prasanth; Enkhmaa, Byambaa; Anuurad, Erdembileg; Berglund, Lars

    2016-12-01

    Consumption of dietary soluble fibers has been associated with health benefits such as reduced lipid levels, lower blood pressure, improved blood glucose control, weight loss, improved immune function, and reduced inflammation. Many of these health benefits relate to a reduced risk of developing cardiovascular disease. In this paper, we have reviewed recent studies on the hypocholesterolemic effects of dietary soluble fibers as well as fiber-rich foods. Findings include the following: (a) consumption of water-soluble, viscous-forming fibers can reduce total and low-density lipoprotein cholesterol levels by about 5-10 %; (b) minimal changes of high-density lipoprotein cholesterol or triglyceride levels were observed; (c) cholesterol-lowering properties of soluble fibers depend on their physical and chemical properties; and (d) medium to high molecular weight fibers are more effective in reducing lipid levels. Hypocholesterolemic benefits were also observed with some fiber-rich foods, such as whole oats, whole barley, legumes, peas, beans, flax seeds, apples, and citrus foods.

  12. Comparison of the antiviral potential among soluble forms of herpes simplex virus type-2 glycoprotein D receptors, herpes virus entry mediator A, nectin-1 and nectin-2, in transgenic mice.

    PubMed

    Fujimoto, Yoshikazu; Tomioka, Yukiko; Ozaki, Kinuyo; Takeda, Keiko; Suyama, Haruka; Yamamoto, Sayo; Takakuwa, Hiroki; Morimatsu, Masami; Uede, Toshimitsu; Ono, Etsuro

    2017-07-01

    Herpesvirus entry mediator A (HVEM), nectin-1 and nectin-2 are cellular receptors of glycoprotein D (gD) of herpes simplex virus type-2 (HSV-2). It has been shown that soluble forms of HSV gD receptors have the antiviral potential in cultured cells and transgenic mice. Here, to compare antiviral potential of soluble forms of HVEM, nectin-1 and nectin-2 against HSV-2 infections in vivo, transgenic mice expressing fusion proteins consisting of the entire ectodomain of HVEM, nectin-1 or nectin-2 and the Fc portion of human IgG (HVEMIg, nectin-1Ig and nectin-2Ig, respectively) were intraperitoneally infected with HSV-2. In the infection with 3 MLD50 (50 % mouse lethal dose), effective resistance was not observed in transgenic mice expressing nectin-2Ig. In a transgenic mouse line with high expression of nectin-1Ig, significant protection from the infection with 30 and 300 MLD50 was observed (survival rate of 100 and 71 %, respectively). On the other hand, transgenic mice expressing HVEMIg showed a complete resistance to the lethal infection even with 300 MLD50 (survival rate of 100 %). These results demonstrated that HVEMIg could exert effective antiviral activities against HSV-2 infections in vivo as compared with other soluble forms of HSV gD receptors.

  13. Drug nanoparticles: formulating poorly water-soluble compounds.

    PubMed

    Merisko-Liversidge, Elaine M; Liversidge, Gary G

    2008-01-01

    More than 40% of compounds identified through combinatorial screening programs are poorly soluble in water. These molecules are difficult to formulate using conventional approaches and are associated with innumerable formulation-related performance issues. Formulating these compounds as pure drug nanoparticles is one of the newer drug-delivery strategies applied to this class of molecules. Nanoparticle dispersions are stable and have a mean diameter of less than 1 micron. The formulations consist of water, drug, and one or more generally regarded as safe excipients. These liquid dispersions exhibit an acceptable shelf-life and can be postprocessed into various types of solid dosage forms. Drug nanoparticles have been shown to improve bioavailability and enhance drug exposure for oral and parenteral dosage forms. Suitable formulations for the most commonly used routes of administration can be identified with milligram quantities of drug substance, providing the discovery scientist with an alternate avenue for screening and identifying superior analogs. For the toxicologist, the approach provides a means for dose escalation using a formulation that is commercially viable. In the past few years, formulating poorly water-soluble compounds using a nanoparticulate approach has evolved from a conception to a realization whose versatility and applicability are just beginning to be realized.

  14. Soluble ephrin a1 is necessary for the growth of HeLa and SK-BR3 cells

    PubMed Central

    2010-01-01

    Background Ephrin A1 (EFNA1) is a member of the A-type ephrin family of cell surface proteins that function as ligands for the A-type Eph receptor tyrosine kinase family. In malignancy, the precise role of EFNA1 and its preferred receptor, EPHA2, is controversial. Several studies have found that EFNA1 may suppress EPHA2-mediated oncogenesis, or enhance it, depending on cell type and context. However, little is known about the conditions that influence whether EFNA1 promotes or suppresses tumorigenicity. EFNA1 exists in a soluble form as well as a glycophosphatidylinositol (GPI) membrane attached form. We investigated whether the contradictory roles of EFNA1 in malignancy might in part be related to the existence of both soluble and membrane attached forms of EFNA1 and potential differences in the manner in which they interact with EPHA2. Results Using a RNAi strategy to reduce the expression of endogenous EFNA1 and EPHA2, we found that both EFNA1 and EPHA2 are required for growth of HeLa and SK-BR3 cells. The growth defects could be rescued by conditioned media from cells overexpressing soluble EFNA1. Interestingly, we found that overexpression of the membrane attached form of EFNA1 suppresses growth of HeLa cells in 3D but not 2D. Knockdown of endogenous EFNA1, or overexpression of full-length EFNA1, resulted in relocalization of EPHA2 from the cell surface to sites of cell-cell contact. Overexpression of soluble EFNA1 however resulted in more EPHA2 distributed on the cell surface, away from cell-cell contacts, and promoted the growth of HeLa cells. Conclusions We conclude that soluble EFNA1 is necessary for the transformation of HeLa and SK-BR3 cells and participates in the relocalization of EPHA2 away from sites of cell-cell contact during transformation. PMID:20979646

  15. Novel high/low solubility classification methods for new molecular entities.

    PubMed

    Dave, Rutwij A; Morris, Marilyn E

    2016-09-10

    This research describes a rapid solubility classification approach that could be used in the discovery and development of new molecular entities. Compounds (N=635) were divided into two groups based on information available in the literature: high solubility (BDDCS/BCS 1/3) and low solubility (BDDCS/BCS 2/4). We established decision rules for determining solubility classes using measured log solubility in molar units (MLogSM) or measured solubility (MSol) in mg/ml units. ROC curve analysis was applied to determine statistically significant threshold values of MSol and MLogSM. Results indicated that NMEs with MLogSM>-3.05 or MSol>0.30mg/mL will have ≥85% probability of being highly soluble and new molecular entities with MLogSM≤-3.05 or MSol≤0.30mg/mL will have ≥85% probability of being poorly soluble. When comparing solubility classification using the threshold values of MLogSM or MSol with BDDCS, we were able to correctly classify 85% of compounds. We also evaluated solubility classification of an independent set of 108 orally administered drugs using MSol (0.3mg/mL) and our method correctly classified 81% and 95% of compounds into high and low solubility classes, respectively. The high/low solubility classification using MLogSM or MSol is novel and independent of traditionally used dose number criteria. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Method of increasing biodegradation of sparingly soluble vapors

    DOEpatents

    Cherry, Robert S.

    2000-01-01

    A method for increasing biodegradation of sparingly soluble volatile organic compounds (VOCs) in a bioreactor is disclosed. The method comprises dissolving in the aqueous phase of the bioreactor a water soluble, nontoxic, non-biodegradable polymer having a molecular weight of at least 500 and operable for decreasing the distribution coefficient of the VOCs. Polyoxyalkylene alkanols are preferred polymers. A method of increasing the growth rate of VOC-degrading microorganisms in the bioreactor and a method of increasing the solubility of sparingly soluble VOCs in aqueous solution are also disclosed.

  17. Selection of solubility parameters for characterization of pharmaceutical excipients.

    PubMed

    Adamska, Katarzyna; Voelkel, Adam; Héberger, Károly

    2007-11-09

    The solubility parameter (delta(2)), corrected solubility parameter (delta(T)) and its components (delta(d), delta(p), delta(h)) were determined for series of pharmaceutical excipients by using inverse gas chromatography (IGC). Principal component analysis (PCA) was applied for the selection of the solubility parameters which assure the complete characterization of examined materials. Application of PCA suggests that complete description of examined materials is achieved with four solubility parameters, i.e. delta(2) and Hansen solubility parameters (delta(d), delta(p), delta(h)). Selection of the excipients through PCA of their solubility parameters data can be used for prediction of their behavior in a multi-component system, e.g. for selection of the best materials to form stable pharmaceutical liquid mixtures or stable coating formulation.

  18. Characterization and antioxidant activities of marine pepsin soluble collagen from the skin of yellow goosefish Lophius litulon

    NASA Astrophysics Data System (ADS)

    Zheng, Bin; Xiang, Xingwei; Zhou, Yufang; Yang, Huicheng; Luo, Hongyu; Liao, Miaofei; Wen, Zhengshun

    2017-05-01

    Characteristics and antioxidant activities of pepsin-soluble collagen (PSC) from yellow goosefish ( Lophius litulon) skins were investigated. PSC was characterized as a type I collagen, and its imino acid content was 193 residues/1 000 residues. PSC's denaturation temperature was 17.56°C and Fourier transform infrared spectra confirmed the presence of triple helices. Solubility analysis showed good solubility at acidic pH (1-6) or low NaCl concentrations (≤2%). PSC showed scavenging activity against hydroxyl radicals and superoxide anions in a concentration-dependent manner. Furthermore, PSC could protect D-galactose-induced skin aging by significantly controlling malondialdehyde formation and improving the activity of superoxide dismutase, glutathione peroxidase, catalase, glutathione, and hydroxyproline. PSC may be a promising antioxidant in appropriate applications.

  19. Sitagliptin but not alpha glucosidase inhibitor reduced the serum soluble CD163, a marker for activated macrophage, in individuals with type 2 diabetes mellitus.

    PubMed

    Hattori, Akiko; Takemoto, Minoru; Tokuyama, Hirotake; Koshizaka, Masaya; Yokote, Koutaro

    2017-04-01

    Dipeptidyl peptidase-4 inhibitor (DPP-4i) is commonly used worldwide for the treatment of type 2 diabetes mellitus. In addition to its hypoglycemic activity, DPP-4i might have anti-inflammatory effects. In this study we examined the effects of DPP-4i on the serum levels of soluble CD163 (sCD163), a marker for activated macrophages, in individuals with type 2 diabetes mellitus. We compared these anti-inflammatory effects with those of α glucosidase inhibitor (αGI). Japanese patients with type 2 diabetes mellitus who were stably maintained on ≤2mg/day glimepiride alone were recruited and randomly assigned to receive additional sitagliptin (n=37) or αGI (n=37). Levels of sCD163 were measured before the addition and after a 24-week treatment period. Addition of sitagliptin significantly reduced the serum sCD163 (632 vs. 575ng/mL, p<0.05), while αGI did not display this effect (624 vs. 607ng/mL). The changes in levels of sCD163 were not related to changes in either HbA1c or body mass index (BMI). Our results suggested that DPP-4i might exert anti-inflammatory effects in individuals with type 2 diabetes mellitus, which are independent of its effects on glycemia and BMI. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Water-soluble metal working fluids additives derived from the esters of acid anhydrides with higher alcohols for aluminum alloy materials.

    PubMed

    Yamamoto, Syutaro; Tomoda, Hideyuki; Watanabe, Shoji

    2007-01-01

    Water-soluble metal working fluids are used for processing of aluminum alloy materials. This short article describes properties of new additives in water-soluble metal working fluids for aluminum alloy materials. Many half esters or diesters were prepared from the reactions of higher alcohols with acid anhydrides. Interestingly, diesters of PTMG (tetrahydrofuran oligomer, MW = 650 and 1000) and polybutylene oxide (MW = 650) with maleic anhydride and succinic anhydride showed both of an excellent anti-corrosion property for aluminum alloy and a good hard water tolerance. The industrial soluble type processing oils including these additives also showed anti-corrosion property and hard water tolerance.

  1. Solubility and crystallization of xylose isomerase from Streptomyces rubiginosus

    NASA Astrophysics Data System (ADS)

    Vuolanto, Antti; Uotila, Sinikka; Leisola, Matti; Visuri, Kalevi

    2003-10-01

    We have studied the crystallization and crystal solubility of xylose isomerase (XI) from Streptomyces rubiginosus. In this paper, we show a rational approach for developing a large-scale crystallization process for XI. Firstly, we measured the crystal solubility in salt solutions with respect to salt concentration, temperature and pH. In ammonium sulfate the solubility of XI decreased logarithmically when increasing the salt concentration. Surprisingly, the XI crystals had a solubility minimum at low concentration of magnesium sulfate. The solubility of XI in 0.17 M magnesium sulfate was less than 0.5 g l -1. The solubility of XI increased logarithmically when increasing the temperature. We also found a solubility minimum around pH 7. This is far from the isoelectric point of XI (pH 3.95). Secondly, based on the solubility study, we developed a large-scale crystallization process for XI. In a simple and economical cooling crystallization of XI from 0.17 M magnesium sulfate solution, the recovery of crystalline active enzyme was over 95%. Moreover, we developed a process for production of uniform crystals and produced homogenous crystals with average crystal sizes between 12 and 360 μm.

  2. Determination of Solubility Parameters of Ibuprofen and Ibuprofen Lysinate.

    PubMed

    Kitak, Teja; Dumičić, Aleksandra; Planinšek, Odon; Šibanc, Rok; Srčič, Stanko

    2015-12-03

    In recent years there has been a growing interest in formulating solid dispersions, which purposes mainly include solubility enhancement, sustained drug release and taste masking. The most notable problem by these dispersions is drug-carrier (in)solubility. Here we focus on solubility parameters as a tool for predicting the solubility of a drug in certain carriers. Solubility parameters were determined in two different ways: solely by using calculation methods, and by experimental approaches. Six different calculation methods were applied in order to calculate the solubility parameters of the drug ibuprofen and several excipients. However, we were not able to do so in the case of ibuprofen lysinate, as calculation models for salts are still not defined. Therefore, the extended Hansen's approach and inverse gas chromatography (IGC) were used for evaluating of solubility parameters for ibuprofen lysinate. The obtained values of the total solubility parameter did not differ much between the two methods: by the extended Hansen's approach it was δt = 31.15 MPa(0.5) and with IGC it was δt = 35.17 MPa(0.5). However, the values of partial solubility parameters, i.e., δd, δp and δh, did differ from each other, what might be due to the complex behaviour of a salt in the presence of various solvents.

  3. Enhancing the solubility and bioavailability of poorly water-soluble drugs using supercritical antisolvent (SAS) process.

    PubMed

    Abuzar, Sharif Md; Hyun, Sang-Min; Kim, Jun-Hee; Park, Hee Jun; Kim, Min-Soo; Park, Jeong-Sook; Hwang, Sung-Joo

    2018-03-01

    Poor water solubility and poor bioavailability are problems with many pharmaceuticals. Increasing surface area by micronization is an effective strategy to overcome these problems, but conventional techniques often utilize solvents and harsh processing, which restricts their use. Newer, green technologies, such as supercritical fluid (SCF)-assisted particle formation, can produce solvent-free products under relatively mild conditions, offering many advantages over conventional methods. The antisolvent properties of the SCFs used for microparticle and nanoparticle formation have generated great interest in recent years, because the kinetics of the precipitation process and morphologies of the particles can be accurately controlled. The characteristics of the supercritical antisolvent (SAS) technique make it an ideal tool for enhancing the solubility and bioavailability of poorly water-soluble drugs. This review article focuses on SCFs and their properties, as well as the fundamentals of overcoming poorly water-soluble drug properties by micronization, crystal morphology control, and formation of composite solid dispersion nanoparticles with polymers and/or surfactants. This article also presents an overview of the main aspects of the SAS-assisted particle precipitation process, its mechanism, and parameters, as well as our own experiences, recent advances, and trends in development. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Impact of Dendrimers on Solubility of Hydrophobic Drug Molecules

    PubMed Central

    Choudhary, Sonam; Gupta, Lokesh; Rani, Sarita; Dave, Kaushalkumar; Gupta, Umesh

    2017-01-01

    Adequate aqueous solubility has been one of the desired properties while selecting drug molecules and other bio-actives for product development. Often solubility of a drug determines its pharmaceutical and therapeutic performance. Majority of newly synthesized drug molecules fail or are rejected during the early phases of drug discovery and development due to their limited solubility. Sufficient permeability, aqueous solubility and physicochemical stability of the drug are important for achieving adequate bioavailability and therapeutic outcome. A number of different approaches including co-solvency, micellar solubilization, micronization, pH adjustment, chemical modification, and solid dispersion have been explored toward improving the solubility of various poorly aqueous-soluble drugs. Dendrimers, a new class of polymers, possess great potential for drug solubility improvement, by virtue of their unique properties. These hyper-branched, mono-dispersed molecules have the distinct ability to bind the drug molecules on periphery as well as to encapsulate these molecules within the dendritic structure. There are numerous reported studies which have successfully used dendrimers to enhance the solubilization of poorly soluble drugs. These promising outcomes have encouraged the researchers to design, synthesize, and evaluate various dendritic polymers for their use in drug delivery and product development. This review will discuss the aspects and role of dendrimers in the solubility enhancement of poorly soluble drugs. The review will also highlight the important and relevant properties of dendrimers which contribute toward drug solubilization. Finally, hydrophobic drugs which have been explored for dendrimer assisted solubilization, and the current marketing status of dendrimers will be discussed. PMID:28559844

  5. The amorphous solid dispersion of the poorly soluble ABT-102 forms nano/microparticulate structures in aqueous medium: impact on solubility.

    PubMed

    Frank, Kerstin J; Westedt, Ulrich; Rosenblatt, Karin M; Hölig, Peter; Rosenberg, Jörg; Mägerlein, Markus; Fricker, Gert; Brandl, Martin

    2012-01-01

    Amorphous solid dispersions (ASDs) are a promising formulation approach for poorly soluble active pharmaceutical ingredients (APIs), because they ideally enhance both dissolution rate and solubility. However, the mechanism behind this is not understood in detail. In the present study, we investigated the supramolecular and the nano/microparticulate structures that emerge spontaneously upon dispersion of an ASD in aqueous medium and elucidated their influence on solubility. The ASD, prepared by hot melt extrusion, contained the poorly soluble ABT-102 (solubility in buffer, 0.05 μg/mL), a hydrophilic polymer, and three surfactants. The apparent solubility of ABT-102 from the ASD-formulation was enhanced up to 200 times in comparison to crystalline ABT-102. At the same time, the molecular solubility, as assessed by inverse equilibrium dialysis, was enhanced two times. Asymmetrical flow field-flow fractionation in combination with a multiangle light-scattering detector, an ultraviolet detector, and a refractometer enabled us to separate and identify the various supramolecular assemblies that were present in the aqueous dispersions of the API-free ASD (placebo) and of binary/ternary blends of the ingredients. Thus, the supramolecular assemblies with a molar mass between 20,000 and 90,000 could be assigned to the polyvinylpyrrolidone/vinyl acetate 64, while two other kinds of assemblies were assigned to different surfactant assemblies (micelles). The amount of ABT-102 remaining associated with each of the assemblies upon fractionation was quantified offline with high-performance liquid chromatography-ultraviolet-visible. The polymeric and the micellar fraction contributed to the substantial increase in apparent solubility of ABT-102. Furthermore, a microparticulate fraction was isolated by centrifugation and analyzed by scanning electron microscopy, X-ray scattering, and infrared spectroscopy. The microparticles were found to be amorphous and to contain two of the

  6. pH-metric solubility. 2: correlation between the acid-base titration and the saturation shake-flask solubility-pH methods.

    PubMed

    Avdeef, A; Berger, C M; Brownell, C

    2000-01-01

    The objective of this study was to compare the results of a normal saturation shake-flask method to a new potentiometric acid-base titration method for determining the intrinsic solubility and the solubility-pH profiles of ionizable molecules, and to report the solubility constants determined by the latter technique. The solubility-pH profiles of twelve generic drugs (atenolol, diclofenac.Na, famotidine, flurbiprofen, furosemide, hydrochlorothiazide, ibuprofen, ketoprofen, labetolol.HCl, naproxen, phenytoin, and propranolol.HCl), with solubilities spanning over six orders of magnitude, were determined both by the new pH-metric method and by a traditional approach (24 hr shaking of saturated solutions, followed by filtration, then HPLC assaying with UV detection). The 212 separate saturation shake-flask solubility measurements and those derived from 65 potentiometric titrations agreed well. The analysis produced the correlation equation: log(1/S)titration = -0.063(+/- 0.032) + 1.025(+/- 0.011) log(1/S)shake-flask, s = 0.20, r2 = 0.978. The potentiometrically-derived intrinsic solubilities of the drugs were: atenolol 13.5 mg/mL, diclofenac.Na 0.82 microg/mL, famotidine 1.1 mg/ mL, flurbiprofen 10.6 microg/mL, furosemide 5.9 microg/mL, hydrochlorothiazide 0.70 mg/mL, ibuprofen 49 microg/mL, ketoprofen 118 microg/mL, labetolol.HCl 128 microg/mL, naproxen 14 microg/mL, phenytoin 19 microg/mL, and propranolol.HCl 70 microg/mL. The new potentiometric method was shown to be reliable for determining the solubility-pH profiles of uncharged ionizable drug substances. Its speed compared to conventional equilibrium measurements, its sound theoretical basis, its ability to generate the full solubility-pH profile from a single titration, and its dynamic range (currently estimated to be seven orders of magnitude) make the new pH-metric method an attractive addition to traditional approaches used by preformulation and development scientists. It may be useful even to discovery

  7. A systematic evaluation of solubility enhancing excipients to enable the generation of permeability data for poorly soluble compounds in Caco-2 model.

    PubMed

    Shah, Devang; Paruchury, Sundeep; Matta, Muralikrishna; Chowan, Gajendra; Subramanian, Murali; Saxena, Ajay; Soars, Matthew G; Herbst, John; Haskell, Roy; Marathe, Punit; Mandlekar, Sandhya

    2014-01-01

    The study presented here identified and utilized a panel of solubility enhancing excipients to enable the generation of flux data in the Human colon carcinoma (Caco-2) system for compounds with poor solubility. Solubility enhancing excipients Dimethyl acetamide (DMA) 1 % v/v, polyethylene glycol (PEG) 400 1% v/v, povidone 1% w/v, poloxamer 188 2.5% w/v and bovine serum albumin (BSA) 4% w/v did not compromise Caco-2 monolayer integrity as assessed by trans-epithelial resistance measurement (TEER) and Lucifer yellow (LY) permeation. Further, these excipients did not affect P-glycoprotein (P-gp) mediated bidirectional transport of digoxin, permeabilities of high (propranolol) or low permeability (atenolol) compounds, and were found to be inert to Breast cancer resistant protein (BCRP) mediated transport of cladribine. This approach was validated further using poorly soluble tool compounds, atazanavir (poloxamer 188 2.5% w/v) and cyclosporine A (BSA 4% w/v) and also applied to new chemical entity (NCE) BMS-A in BSA 4% w/v, for which Caco-2 data could not be generated using the traditional methodology due to poor solubility (<1 µM) in conventional Hanks balanced salt solution (HBSS). Poloxamer 188 2.5% w/v increased solubility of atazanavir by >8 fold whereas BSA 4% w/v increased the solubility of cyclosporine A and BMS-A by >2-4 fold thereby enabling permeability as well as efflux liability estimation in the Caco-2 model with reasonable recovery values. To conclude, addition of excipients such as poloxamer 188 2.5% w/v and BSA 4% w/v to HBSS leads to a significant improvement in the solubility of the poorly soluble compounds resulting in enhanced recoveries without modulating transporter-mediated efflux, expanding the applicability of Caco-2 assays to poorly soluble compounds.

  8. Chemical characterization of extractable water soluble matter associated with PM10 from Mexico City during 2000.

    PubMed

    Gutiérrez-Castillo, M E; Olivos-Ortiz, M; De Vizcaya-Ruiz, A; Cebrián, M E

    2005-11-01

    We report the chemical composition of PM10-associated water-soluble species in Mexico City during the second semester of 2000. PM10 samples were collected at four ambient air quality monitoring sites in Mexico City. We determined soluble ions (chloride, nitrate, sulfate, ammonium, sodium, potassium), ionizable transition metals (Zn, Fe, Ti, Pb, Mn, V, Ni, Cr, Cu) and soluble protein. The higher PM(10) levels were observed in Xalostoc (45-174 microg m(-3)) and the lowest in Pedregal (19-54 microg m(-3)). The highest SO2 average concentrations were observed in Tlalnepantla, NO2 in Merced and O3 and NO(x) in Pedregal. The concentration range of soluble sulfate was 6.7-7.9 and 19-25.5 microg m(-3) for ammonium, and 14.8-29.19 for soluble V and 3.2-7.7 ng m(-3) for Ni, suggesting a higher contribution of combustion sources. PM-associated soluble protein levels varied between 0.038 and 0.169 mg m(-3), representing a readily inhalable constituent that could contribute to adverse outcomes. The higher levels for most parameters studied were observed during the cold dry season, particularly in December. A richer content of soluble metals was observed when they were expressed by mass/mass units rather than by air volume units. Significant correlations between Ni-V, Ni-SO4(-2), V-SO4(-2), V-SO2, Ni-SO2 suggest the same type of emission source. The variable soluble metal and ion concentrations were strongly influenced by the seasonal meteoclimatic conditions and the differential contribution of emission sources. Our data support the idea that PM10 mass concentration by itself does not provide a clear understanding of a local PM air pollution problem.

  9. Solid dispersions: a strategy for poorly aqueous soluble drugs and technology updates.

    PubMed

    Alam, Mohd Aftab; Ali, Raisuddin; Al-Jenoobi, Fahad Ibrahim; Al-Mohizea, Abdullah M

    2012-11-01

    Present article reviews solid dispersion (SD) technologies and other patented inventions in the area of pharmaceutical SDs, which provide stable amorphous SDs. The review briefly compiles different techniques for preparing SDs, their applications, characterization of SDs, types of SDs and also elaborates the carriers used to prepare SDs. The advantages of recently introduced SD technologies such as RightSize(™), closed-cycle spray drying (CSD), Lidose® are summarized. Stability-related issues like phase separation, re-crystallization and methods to curb these problems are also discussed. A patented carrier-screening tool for predicting physical stability of SDs on the basis of drug-carrier interaction is explained. Applications of SD technique in controlled drug delivery systems and cosmetics are explored. Review also summarizes the carriers such as Soluplus®, Neusilin®, Solumer(TM) used to prepare stable amorphous SD. Binary and ternary SDs are found to be more stable and provide better enhancement of solubility or dissolution of poorly water-soluble drugs. The use of surfactants in the carrier system of SD is a recent trend. Surfactants and polymers provide stability against re-crystallization of SDs, surfactants also improve solubility and dissolution of drug.

  10. Solubility of carbon dioxide and hydrogen sulfide in aqueous N-methyldiethanolamine solutions

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Huttenhuis, P.J.G.; Agrawal, N.J.; Versteeg, G.F.

    2009-04-15

    In this work, 72 new experimental solubility data points for H{sub 2}S and CO{sub 2} mixtures in aqueous N-methyldiethanol amine (MDEA) solutions at different methane partial pressures (up to 69 bara) are presented. They are correlated using an electrolyte equation of state (E-EOS) thermodynamic model. This model has already been used to estimate the CO{sub 2} solubility in aqueous MDEA (Huttenhuis et al. Fluid Phase Equilib. 2008, 264, 99-112) and the H{sub 2}S solubility in aqueous MDEA (Huttenhuis et al. Int. J. Oil, Gas Coal Technol. 2008, 1, 399-424). Here, the model is further extended to predict the behavior ofmore » CO{sub 2} and H{sub 2}S when they are present simultaneously in aqueous MDEA. The application of an equation of state is a new development for this type of system, i.e., of acid-gas-amine systems. The molecular interactions are described by Schwarzentruber et al.'s modification of the Redlich-Kwong-Soave equation of state, with terms added to account for ionic interactions in the liquid phase. The model is used to describe acid-gas solubility data for the CO{sub 2}-H{sub 2}S-MDEA-H{sub 2}O system reported in the open literature and experimental data reported here for the CO{sub 2}-H{sub 2}S-MDEA-H{sub 2}O-CH{sub 4} system.« less

  11. Neutralization of soluble, synaptotoxic amyloid β species by antibodies is epitope specific.

    PubMed

    Zago, Wagner; Buttini, Manuel; Comery, Thomas A; Nishioka, Christopher; Gardai, Shyra J; Seubert, Peter; Games, Dora; Bard, Frédérique; Schenk, Dale; Kinney, Gene G

    2012-02-22

    Several anti-amyloid β (Aβ) antibodies are under evaluation for the treatment of Alzheimer's disease (AD). Clinical studies using the N-terminal-directed anti-Aβ antibody bapineuzumab have demonstrated reduced brain PET-Pittsburg-B signals, suggesting the reduction of Aβ plaques, and reduced levels of total and phosphorylated tau protein in the CSF of treated AD patients. Preclinical studies using 3D6 (the murine form of bapineuzumab) have demonstrated resolution of Aβ plaque and vascular burdens, neuritic dystrophy, and preservation of synaptic density in the transgenic APP mouse models. In contrast, few studies have evaluated the direct interaction of this antibody with synaptotoxic soluble Aβ species. In the current report, we demonstrated that 3D6 binds to soluble, synaptotoxic assemblies of Aβ(1-42) and prevents multiple downstream functional consequences in rat hippocampal neurons including changes in glutamate AMPA receptor trafficking, AD-type tau phosphorylation, and loss of dendritic spines. In vivo, we further demonstrated that 3D6 prevents synaptic loss and acutely reverses the behavioral deficit in the contextual fear conditioning task in transgenic mouse models of AD, two endpoints thought to be linked to synaptotoxic soluble Aβ moieties. Importantly C-terminal anti-Aβ antibodies were ineffective on these endpoints. These results, taken with prior studies, suggest that N-terminal anti-Aβ antibodies effectively interact with both soluble and insoluble forms of Aβ and therefore appear particularly well suited for testing the Aβ hypothesis of AD.

  12. Investigation of soluble salts on Kentucky bridges

    DOT National Transportation Integrated Search

    2003-01-01

    Several state highway agencies are looking at ways to increase the durability of their bridge maintenance painting projects and are using/investigating various chemical neutralizers/soluble salt removers to preclude problems caused by soluble salts. ...

  13. An Improved Variant of Soybean Type 1 Diacylglycerol Acyltransferase Increases the Oil Content and Decreases the Soluble Carbohydrate Content of Soybeans.

    PubMed

    Roesler, Keith; Shen, Bo; Bermudez, Ericka; Li, Changjiang; Hunt, Joanne; Damude, Howard G; Ripp, Kevin G; Everard, John D; Booth, John R; Castaneda, Leandro; Feng, Lizhi; Meyer, Knut

    2016-06-01

    Kinetically improved diacylglycerol acyltransferase (DGAT) variants were created to favorably alter carbon partitioning in soybean (Glycine max) seeds. Initially, variants of a type 1 DGAT from a high-oil, high-oleic acid plant seed, Corylus americana, were screened for high oil content in Saccharomyces cerevisiae Nearly all DGAT variants examined from high-oil strains had increased affinity for oleoyl-CoA, with S0.5 values decreased as much as 4.7-fold compared with the wild-type value of 0.94 µm Improved soybean DGAT variants were then designed to include amino acid substitutions observed in promising C. americana DGAT variants. The expression of soybean and C. americana DGAT variants in soybean somatic embryos resulted in oil contents as high as 10% and 12%, respectively, compared with only 5% and 7.6% oil achieved by overexpressing the corresponding wild-type DGATs. The affinity for oleoyl-CoA correlated strongly with oil content. The soybean DGAT variant that gave the greatest oil increase contained 14 amino acid substitutions out of a total of 504 (97% sequence identity with native). Seed-preferred expression of this soybean DGAT1 variant increased oil content of soybean seeds by an average of 3% (16% relative increase) in highly replicated, single-location field trials. The DGAT transgenes significantly reduced the soluble carbohydrate content of mature seeds and increased the seed protein content of some events. This study demonstrated that engineering of the native DGAT enzyme is an effective strategy to improve the oil content and value of soybeans. © 2016 American Society of Plant Biologists. All Rights Reserved.

  14. Solubility advantage of amorphous pharmaceuticals: I. A thermodynamic analysis.

    PubMed

    Murdande, Sharad B; Pikal, Michael J; Shanker, Ravi M; Bogner, Robin H

    2010-03-01

    In recent years there has been growing interest in advancing amorphous pharmaceuticals as an approach for achieving adequate solubility. Due to difficulties in the experimental measurement of solubility, a reliable estimate of the solubility enhancement ratio of an amorphous form of a drug relative to its crystalline counterpart would be highly useful. We have developed a rigorous thermodynamic approach to estimate enhancement in solubility that can be achieved by conversion of a crystalline form to the amorphous form. We rigorously treat the three factors that contribute to differences in solubility between amorphous and crystalline forms. First, we calculate the free energy difference between amorphous and crystalline forms from thermal properties measured by modulated differential scanning calorimetry (MDSC). Secondly, since an amorphous solute can absorb significant amounts of water, which reduces its activity and solubility, a correction is made using water sorption isotherm data and the Gibbs-Duhem equation. Next, a correction is made for differences in the degree of ionization due to differences in solubilities of the two forms. Utilizing this approach the theoretically estimated solubility enhancement ratio of 7.0 for indomethacin (amorphous/gamma-crystal) was found to be in close agreement with the experimentally determined ratio of 4.9. 2009 Wiley-Liss, Inc. and the American Pharmacists Association

  15. Cloud condensation nuclei activation of limited solubility organic aerosol

    NASA Astrophysics Data System (ADS)

    Huff Hartz, Kara E.; Tischuk, Joshua E.; Chan, Man Nin; Chan, Chak K.; Donahue, Neil M.; Pandis, Spyros N.

    The cloud condensation nuclei (CCN) activation of 19 organic species with water solubilities ( Csat) ranging from 10 -4 to 10 2 g solute 100 g -1 H 2O was measured. The organic particles were generated by nebulization of an aqueous or an alcohol solution. Use of alcohols as solvents enables the measurement of low solubility, non-volatile organic CCN activity and reduces the likelihood of residual water in the aerosol. The activation diameter of organic species with very low solubility in water ( Csat<0.3 g 100 g -1 H 2O) is in agreement with Köhler theory using the bulk solubility (limited solubility case) of the organic in water. Many species, including 2-acetylbenzoic acid, aspartic acid, azelaic acid, glutamic acid, homophthalic acid, phthalic acid, cis-pinonic acid, and salicylic acid are highly CCN active in spite of their low solubility (0.3 g 100 g -1 H 2O< Csat<1 g 100 g -1 H 2O), and activate almost as if completely water soluble. The CCN activity of most species is reduced, if the particles are produced using non-aqueous solvents. The existence of the particles in a metastable state at low RH can explain the observed enhancement in CCN activity beyond the levels suggested by their solubility.

  16. The Comparison of Sorption and Solubility Behavior of Four Different Resin Luting Cements in Different Storage Media.

    PubMed

    Giti, Rashin; Vojdani, Mahroo; Abduo, Jaafar; Bagheri, Rafat

    2016-06-01

    Structural integrity and dimensional stability are the key factors that determine the clinical success and durability of luting cements in the oral cavity. Sorption and solubility of self-adhesive resin luting cements in food-simulating solutions has not been studied sufficiently. This study aimed to compare the sorption and solubility of 2 conventional and 2 self-adhesive resin-based luting cements immersed in four different storage media. A total of 32 disc-shaped specimens were prepared from each of four resin luting cements; seT (SDI), Panavia F (Kuraray), Clearfil SA Cement (Kuraray), and Choice 2 (Bisco). Eight specimens of each material were immersed in all tested solutions including n-heptane 97%, distilled water, apple juice, or Listerine mouth wash. Sorption and solubility were measured by weighing the specimens before and after immersion and desiccation. Data were analyzed by SPSS version 18, using two-way ANOVA and Tukey's HSD test with p≤ 0.05 set as the level of significance. There was a statistically significant interaction between the materials and solutions. The effect of media on the sorption and solubility was material-dependent. While seT showed the highest values of the sorption in almost all solutions, Choice 2 showed the least values of sorption and solubility. Immersion in apple juice caused more sorption than other solutions (p≤ 0.05). The sorption and solubility behavior of the studied cements were significantly affected by their composition and the storage media. The more hydrophobic materials with higher filler content like Choice 2 resin cement showed the least sorption and solubility. Due to their lower sorption and solubility, these types of resin-based luting cements are recommended to be used clinically.

  17. Solubilities of nitrogen and noble gases in basalt melt

    NASA Technical Reports Server (NTRS)

    Miyazaki, A.; Hiyagon, H.; Sugiura, N.

    1994-01-01

    Nitrogen and noble gases are important tracers in geochemistry and chosmochemistry. Compared to noble gases, however, physicochemical properties of nitrogen, such as solubility in melt or melt/silicate partition, are not well known. Solubility of nitrogen in basalt melt depends on redox condition of the atmosphere. For example, solubility of nitrogen in E chondrite melt under reducing conditions is as high as 2 mol percent at 1500 C, suggesting that nitrogen is chemically dissolved in silicate melts, i.e., being dissolved as free anions or replacing oxygen sites in silicate network. However, the solubility and the dissolution mechanism of nitrogen under oxidizing conditions are not well investigated. To obtain nitrogen solubility in silicate melts under various redox conditions and to understand its mechanism, we are conducting experiments by using (15)N(15)N-labeled nitrogen gas. This makes it easy to distinguish dissolved nitrogen from later contamination of atmospheric nitrogen, and hence enables us to measure the nitrogen solubility accurately. As a preliminary experiment, we have measured solubility of nitrogen in basalt melt under the atmospheric oxygen pressure.

  18. Uranium (VI) solubility in carbonate-free ERDA-6 brine

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lucchini, Jean-francois; Khaing, Hnin; Reed, Donald T

    2010-01-01

    When present, uranium is usually an element of importance in a nuclear waste repository. In the Waste Isolation Pilot Plant (WIPP), uranium is the most prevalent actinide component by mass, with about 647 metric tons to be placed in the repository. Therefore, the chemistry of uranium, and especially its solubility in the WIPP conditions, needs to be well determined. Long-term experiments were performed to measure the solubility of uranium (VI) in carbonate-free ERDA-6 brine, a simulated WIPP brine, at pC{sub H+} values between 8 and 12.5. These data, obtained from the over-saturation approach, were the first repository-relevant data for themore » VI actinide oxidation state. The solubility trends observed pointed towards low uranium solubility in WIPP brines and a lack of amphotericity. At the expected pC{sub H+} in the WIPP ({approx} 9.5), measured uranium solubility approached 10{sup -7} M. The objective of these experiments was to establish a baseline solubility to further investigate the effects of carbonate complexation on uranium solubility in WIPP brines.« less

  19. Polysaccharide components from the scape of Musa paradisiaca: main structural features of water-soluble polysaccharide component.

    PubMed

    Anjaneyalu, Y V; Jagadish, R L; Raju, T S

    1997-06-01

    Polysaccharide components present in the pseudo-stem (scape) of M. paradisiaca were purified from acetone powder of the scape by delignification followed by extraction with aqueous solvents into water soluble polysaccharide (WSP), EDTA-soluble polysaccharide (EDTA-SP), alkali-soluble polysaccharide (ASP) and alkali-insoluble polysaccharide (AISP) fractions. Sugar compositional analysis showed that WSP and EDTA-SP contained only D-Glc whereas ASP contained D-Glc, L-Ara and D-Xyl in approximately 1:1:10 ratio, respectively, and AISP contained D-Glc, L-Ara and D-Xyl in approximately 10:1:2 ratio, respectively. WSP was further purified by complexation with iso-amylalcohol and characterized by specific rotation, IR spectroscopy, Iodine affinity, ferricyanide number, blue value, hydrolysis with alpha-amylase and glucoamylase, and methylation linkage analysis, and shown to be a amylopectin type alpha-D-glucan.

  20. Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs.

    PubMed

    Lukyanov, Anatoly N; Torchilin, Vladimir P

    2004-05-07

    Polymeric micelles have a whole set of unique characteristics, which make them very promising drug carriers, in particular, for poorly soluble drugs. Our review article focuses on micelles prepared from conjugates of water-soluble polymers, such as polyethylene glycol (PEG) or polyvinyl pyrrolidone (PVP), with phospholipids or long-chain fatty acids. The preparation of micelles from certain polymer-lipid conjugates and the loading of these micelles with various poorly soluble anticancer agents are discussed. The data on the characterization of micellar preparations in terms of their morphology, stability, longevity in circulation, and ability to spontaneously accumulate in experimental tumors via the enhanced permeability and retention (EPR) effect are presented. The review also considers the preparation of targeted immunomicelles with specific antibodies attached to their surface. Available in vivo results on the efficiency of anticancer drugs incorporated into plain micelles and immunomicelles in animal models are also discussed.

  1. Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1).

    PubMed

    Brough, Chris; Miller, Dave A; Keen, Justin M; Kucera, Shawn A; Lubda, Dieter; Williams, Robert O

    2016-02-01

    Polyvinyl alcohol (PVAL) has not been investigated in a binary formulation as a concentration-enhancing polymer owing to its high melting point/high viscosity and poor organic solubility. Due to the unique attributes of the KinetiSol® dispersing (KSD) technology, PVAL has been enabled for this application and it is the aim of this paper to investigate various grades for improvement of the solubility and bioavailability of poorly water soluble active pharmaceutical ingredients. Solid amorphous dispersions were created with the model drug, itraconazole (ITZ), at a selected drug loading of 20%. Polymer grades were chosen with variation in molecular weight and degree of hydroxylation to determine the effects on performance. Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, size exclusion chromatography, and dissolution testing were used to characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also conducted to compare the selected formulation to current market formulations of ITZ. The 4-88 grade of PVAL was determined to be effective at enhancing solubility and bioavailability of itraconazole.

  2. GADOLINIUM OXALATE SOLUBILITY MEASUREMENTS IN NITRIC ACID SOLUTIONS

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pierce, R. A.

    2012-03-12

    HB-Line will begin processing Pu solutions during FY2012 that will involve the recovery of Pu using oxalate precipitation and filtration. After the precipitation and filtration processes, the filtrate solution will be transferred from HB-Line to H-Canyon. The presence of excess oxalate and unfiltered Pu oxalate solids in these solutions create a criticality safety issue if they are sent to H-Canyon without controls in H-Canyon. One approach involves H-Canyon receiving the filtrate solution into a tank that is poisoned with soluble gadolinium (Gd). Decomposition of the oxalate will occur within a subsequent H-Canyon vessel. The receipt of excess oxalate into themore » H-Canyon receipt tanks has the potential to precipitate a portion of the Gd poison in the receipt tanks. Because the amount of Gd in solution determines the maximum amount of Pu solids that H-Canyon can receive, H-Canyon Engineering requested that SRNL determine the solubility of Gd in aqueous solutions of 4-10 M nitric acid (HNO{sub 3}), 4-12 g/L Gd, and 0.15-0.25 M oxalic acid (H{sub 2}C{sub 2}O{sub 4}) at 25 °C. The target soluble Gd concentration is 6 g/L. The data indicate that the target can be achieved above 6 M HNO{sub 3} and below 0.25 M H{sub 2}C{sub 2}O{sub 4}. At 25 °C, for 6 M HNO{sub 3}, 11 g/L and 7 g/L Gd are soluble in 0.15 M and 0.25 M H{sub 2}C{sub 2}O{sub 4}, respectively. In 4 M HNO{sub 3}, the Gd solubility drops significantly to 2.5 g/L and 0.8 g/L in 0.15 M and 0.25 M H{sub 2}C{sub 2}O{sub 4}, respectively. The solubility of Gd at 8-10 M HNO{sub 3} exceeds the solubility at 6 M HNO{sub 3}. The data for 4 M HNO{sub 3} showed good agreement with data in the literature. To achieve a target of 6 g/L soluble Gd in solution in the presence of 0.15-0.25 M oxalate, the HNO{sub 3} concentration must be maintained at or above 6 M HNO{sub 3}. The solubility of Gd in 4 M HNO{sub 3} with 0.15 M oxalate at 10 °C is about 1.5 g/L. For 6 M HNO{sub 3} with 0.15 M oxalate, the solubility of

  3. Hansen solubility parameters for polyethylene glycols by inverse gas chromatography.

    PubMed

    Adamska, Katarzyna; Voelkel, Adam

    2006-11-03

    Inverse gas chromatography (IGC) has been applied to determine solubility parameter and its components for nonionic surfactants--polyethylene glycols (PEG) of different molecular weight. Flory-Huggins interaction parameter (chi) and solubility parameter (delta(2)) were calculated according to DiPaola-Baranyi and Guillet method from experimentally collected retention data for the series of carefully selected test solutes. The Hansen's three-dimensional solubility parameters concept was applied to determine components (delta(d), delta(p), delta(h)) of corrected solubility parameter (delta(T)). The molecular weight and temperature of measurement influence the solubility parameter data, estimated from the slope, intercept and total solubility parameter. The solubility parameters calculated from the intercept are lower than those calculated from the slope. Temperature and structural dependences of the entopic factor (chi(S)) are presented and discussed.

  4. HILIC separation and quantitation of water-soluble vitamins using diol column.

    PubMed

    Karatapanis, Andreas E; Fiamegos, Yiannis C; Stalikas, Constantine D

    2009-04-01

    Hydrophilic interaction liquid-chromatography (HILIC) in conjunction with diode array detection has been applied for the separation of selected-water-soluble vitamins using an end-capped HILIC-diol column. Vitamins with significant biological importance, such as thiamine (B(1)), riboflavin (B(2)), nicotinic acid (B(3)), nicotinamide (B(3)), pyridoxine (B(6)), folic acid (B(9)), cyanocobalamin (B(12)) and ascorbic acid (vitamin C) were simultaneously separated. Chromatographic conditions including type and percentage of organic modifier in the mobile phase, pH, type and concentration of buffer salt and flow rate were investigated. ACN was shown to offer superior separation for the compounds tested as compared to methanol, isopropanol and THF. Isocratic separation and analysis were achieved for six vitamins (B(1), B(2), nicotinic acid/nicotinamide, B(6) and C) at ACN-H(2)O 90:10, containing ammonium acetate 10 mM, triethylamine 20 mM, pH 5.0, using a flow rate of 0.8 mL/min, while a gradient was necessary to resolve a mixture of all eight water-soluble vitamins. The HILIC method was validated and successfully applied to the analysis of a pharmaceutical formulation and an energy drink negating the need for time consuming clean-up steps.

  5. Soluble Extract from Moringa oleifera Leaves with a New Anticancer Activity

    PubMed Central

    Jung, Il Lae

    2014-01-01

    Moringa oleifera has been regarded as a food substance since ancient times and has also been used as a treatment for many diseases. Recently, various therapeutic effects of M. oleifera such as antimicrobial, anticancer, anti-inflammatory, antidiabetic, and antioxidant effects have been investigated; however, most of these studies described only simple biological phenomena and their chemical compositions. Due to the increasing attention on natural products, such as those from plants, and the advantages of oral administration of anticancer drugs, soluble extracts from M. oleifera leaves (MOL) have been prepared and their potential as new anticancer drug candidates has been assessed in this study. Here, the soluble cold Distilled Water extract (4°C; concentration, 300 µg/mL) from MOL greatly induced apoptosis, inhibited tumor cell growth, and lowered the level of internal reactive oxygen species (ROS) in human lung cancer cells as well as other several types of cancer cells, suggesting that the treatment of cancer cells with MOL significantly reduced cancer cell proliferation and invasion. Moreover, over 90% of the genes tested were unexpectedly downregulated more than 2-fold, while just below 1% of the genes were upregulated more than 2-fold in MOL extract-treated cells, when compared with nontreated cells. Since severe dose-dependent rRNA degradation was observed, the abnormal downregulation of numerous genes was considered to be attributable to abnormal RNA formation caused by treatment with MOL extracts. Additionally, the MOL extract showed greater cytotoxicity for tumor cells than for normal cells, strongly suggesting that it could potentially be an ideal anticancer therapeutic candidate specific to cancer cells. These results suggest the potential therapeutic implications of the soluble extract from MOL in the treatment of various types of cancers. PMID:24748376

  6. Solubility enhancement of miconazole nitrate: binary and ternary mixture approach.

    PubMed

    Rai, Vineet Kumar; Dwivedi, Harinath; Yadav, Narayan Prasad; Chanotiya, Chandan Singh; Saraf, Shubhini A

    2014-08-01

    Enhancement of aqueous solubility of very slightly soluble Miconazole Nitrate (MN) is required to widen its application from topical formulation to oral/mucoadhesive formulations. Aim of the present investigation was to enhance the aqueous solubility of MN using binary and ternary mixture approach. Binary mixtures such as solvent deposition, inclusion complexation and solid dispersion were adopted to enhance solubility using different polymers like lactose, beta-cyclodextrin (β-CD) and polyethylene-glycol 6000 (PEG 6000), respectively. Batches of binary mixtures with highest solubility enhancement potentials were further mixed to form ternary mixture by a simple kneading method. Drug polymer interaction and mixture morphology was studied using the Fourier transform infrared spectroscopy and the scanning electron microscopy, respectively along with their saturation solubility studies and drug release. An excellent solubility enhancement, i.e. up to 72 folds and 316 folds of MN was seen by binary and ternary mixture, respectively. Up to 99.5% drug was released in 2 h from the mixtures of MN and polymers. RESULTS revealed that solubility enhancement by binary mixtures is achieved due to surface modification and by increasing wettability of MN. Tremendous increase in solubility of MN by ternary mixture could possibly be due to blending of water soluble polymers, i.e. lactose and PEG 6000 with β-CD which was found to enhance the solubilizing nature of β-CD. Owing to the excellent solubility enhancement potential of ternary mixtures in enhancing MN solubility from 110.4 μg/ml to 57640.0 μg/ml, ternary mixture approach could prove to be promising in the development of oral/mucoadhesive formulations.

  7. Structural hot spots for the solubility of globular proteins

    PubMed Central

    Ganesan, Ashok; Siekierska, Aleksandra; Beerten, Jacinte; Brams, Marijke; Van Durme, Joost; De Baets, Greet; Van der Kant, Rob; Gallardo, Rodrigo; Ramakers, Meine; Langenberg, Tobias; Wilkinson, Hannah; De Smet, Frederik; Ulens, Chris; Rousseau, Frederic; Schymkowitz, Joost

    2016-01-01

    Natural selection shapes protein solubility to physiological requirements and recombinant applications that require higher protein concentrations are often problematic. This raises the question whether the solubility of natural protein sequences can be improved. We here show an anti-correlation between the number of aggregation prone regions (APRs) in a protein sequence and its solubility, suggesting that mutational suppression of APRs provides a simple strategy to increase protein solubility. We show that mutations at specific positions within a protein structure can act as APR suppressors without affecting protein stability. These hot spots for protein solubility are both structure and sequence dependent but can be computationally predicted. We demonstrate this by reducing the aggregation of human α-galactosidase and protective antigen of Bacillus anthracis through mutation. Our results indicate that many proteins possess hot spots allowing to adapt protein solubility independently of structure and function. PMID:26905391

  8. Nickel, soluble salts

    Integrated Risk Information System (IRIS)

    Nickel , soluble salts ; CASRN Various Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic

  9. Uranium, soluble salts

    Integrated Risk Information System (IRIS)

    Uranium , soluble salts ; no CASRN Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic Eff

  10. IUPAC-NIST Solubility Data Series. 95. Alkaline Earth Carbonates in Aqueous Systems. Part 2. Ca

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    De Visscher, Alex; Vanderdeelen, Jan; Department of Applied Analytical and Physical Chemistry, Faculty of Bioscience Engineering, Ghent University, B-9000 Ghent

    The alkaline earth carbonates are an important class of minerals. This article is part of a volume in the IUPAC-NIST Solubility Data Series that compiles and critically evaluates solubility data of the alkaline earth carbonates in water and in simple aqueous electrolyte solutions. Part 1 outlined the procedure adopted in this volume, and presented the beryllium and magnesium carbonates. Part 2, the current paper, compiles and critically evaluates the solubility data of calcium carbonate. The chemical forms included are the anhydrous CaCO{sub 3} types calcite, aragonite, and vaterite, the monohydrate monohydrocalcite (CaCO{sub 3}{center_dot} H{sub 2}O), the hexahydrate ikaite (CaCO{sub 3}{center_dot}6H{submore » 2}O), and an amorphous form. The data were analyzed with two model variants, and thermodynamic data of each form consistent with each of the models and with the CODATA key values for thermodynamics are presented.« less

  11. Calculation of Drug Solubilities by Pharmacy Students.

    ERIC Educational Resources Information Center

    Cates, Lindley A.

    1981-01-01

    A method of estimating the solubilities of drugs in water is reported that is based on a principle applied in quantitative structure-activity relationships. This procedure involves correlation of partition coefficient values using the octanol/water system and aqueous solubility. (Author/MLW)

  12. Determination of water-soluble vitamins using a colorimetric microbial viability assay based on the reduction of water-soluble tetrazolium salts.

    PubMed

    Tsukatani, Tadayuki; Suenaga, Hikaru; Ishiyama, Munetaka; Ezoe, Takatoshi; Matsumoto, Kiyoshi

    2011-07-15

    A method for the determination of water-soluble vitamins using a colorimetric microbial viability assay based on the reduction of the tetrazolium salt {2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt (WST-8)} via 2-methyl-1,4-napthoquinone (NQ) was developed. Measurement conditions were optimized for the microbiological determination of water-soluble vitamins, such as vitamin B(6), biotin, folic acid, niacin, and pantothenic acid, using microorganisms that have a water-soluble vitamin requirement. A linear relationship between absorbance and water-soluble vitamin concentration was obtained. The proposed method was applied to determine the concentration of vitamin B(6) in various foodstuffs. There was good agreement between vitamin B(6) concentrations determined after 24h using the WST-8 colorimetric method and those obtained after 48h using a conventional method. The results suggest that the WST-8 colorimetric assay is a useful method for the rapid determination of water-soluble vitamins in a 96-well microtiter plate. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Surface shear inviscidity of soluble surfactants

    PubMed Central

    Zell, Zachary A.; Nowbahar, Arash; Mansard, Vincent; Leal, L. Gary; Deshmukh, Suraj S.; Mecca, Jodi M.; Tucker, Christopher J.; Squires, Todd M.

    2014-01-01

    Foam and emulsion stability has long been believed to correlate with the surface shear viscosity of the surfactant used to stabilize them. Many subtleties arise in interpreting surface shear viscosity measurements, however, and correlations do not necessarily indicate causation. Using a sensitive technique designed to excite purely surface shear deformations, we make the most sensitive and precise measurements to date of the surface shear viscosity of a variety of soluble surfactants, focusing on SDS in particular. Our measurements reveal the surface shear viscosity of SDS to be below the sensitivity limit of our technique, giving an upper bound of order 0.01 μN·s/m. This conflicts directly with almost all previous studies, which reported values up to 103–104 times higher. Multiple control and complementary measurements confirm this result, including direct visualization of monolayer deformation, for SDS and a wide variety of soluble polymeric, ionic, and nonionic surfactants of high- and low-foaming character. No soluble, small-molecule surfactant was found to have a measurable surface shear viscosity, which seriously undermines most support for any correlation between foam stability and surface shear rheology of soluble surfactants. PMID:24563383

  14. Respiratory carcinogenicity assessment of soluble nickel compounds.

    PubMed Central

    Oller, Adriana R

    2002-01-01

    The many chemical forms of nickel differ in physicochemical properties and biological effects. Health assessments for each main category of nickel species are needed. The carcinogenicity assessment of water-soluble nickel compounds has proven particularly difficult. Epidemiologic evidence indicates an association between inhalation exposures to nickel refinery dust containing soluble nickel compounds and increased risk of respiratory cancers. However, the nature of this association is unclear because of limitations of the exposure data, inconsistent results across cohorts, and the presence of mixed exposures to water-insoluble nickel compounds and other confounders that are known or suspected carcinogens. Moreover, well-conducted animal inhalation studies, where exposures were solely to soluble nickel, failed to demonstrate a carcinogenic potential. Similar negative results were seen in animal oral studies. A model exists that relates respiratory carcinogenic potential to the bioavailability of nickel ion at nuclear sites within respiratory target cells. This model helps reconcile human, animal, and mechanistic data for soluble nickel compounds. For inhalation exposures, the predicted lack of bioavailability of nickel ion at target sites suggests that water-soluble nickel compounds, by themselves, will not be complete human carcinogens. However, if inhaled at concentrations high enough to induce chronic lung inflammation, these compounds may enhance carcinogenic risks associated with inhalation exposure to other substances. Overall, the weight of evidence indicates that inhalation exposure to soluble nickel alone will not cause cancer; moreover, if exposures are kept below levels that cause chronic respiratory toxicity, any possible tumor-enhancing effects (particularly in smokers) would be avoided. PMID:12426143

  15. Fluorine (soluble fluoride)

    Integrated Risk Information System (IRIS)

    Fluorine ( soluble fluoride ) ; CASRN 7782 - 41 - 4 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for No

  16. In vitro dynamic solubility test: influence of various parameters.

    PubMed Central

    Thélohan, S; de Meringo, A

    1994-01-01

    This article discusses the dissolution of mineral fibers in simulated physiological fluids (SPF), and the parameters that affect the solubility measurement in a dynamic test where an SPF runs through a cell containing fibers (Scholze and Conradt test). Solutions simulate either the extracellular fluid (pH 7.6) or the intracellular fluid (pH 4.5). The fibers have various chemical compositions and are either continuously drawn or processed as wool. The fiber solubility is determined by the amount of SiO2 (and occasionally other ions) released in the solution. Results are stated as percentage of the initial silica content released or as dissolution rate v in nm/day. The reproducibility of the test is higher with the less soluble fibers (10% solubility), than with highly soluble fibers (20% solubility). The influence of test parameters, including SPF, test duration, and surface area/volume (SA/V), has been studied. The pH and the inorganic buffer salts have a major influence: industrial glasswool composition is soluble at pH 7.6 but not at pH 4.5. The opposite is true for rock- (basalt) wool composition. For slightly soluble fibers, the dissolution rate v remains constant with time, whereas for highly soluble fibers, the dissolution rate decreases rapidly. The dissolution rates believed to occur are v1, initial dissolution rate, and v2, dissolution rate of the residual fibers. The SA of fibers varies with the mass of the fibers tested, or with the fiber diameter at equal mass. Volume, V, is the chosen flow rate. An increase in the SA/V ratio leads to a decrease in the dissolution rate.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7882964

  17. In vitro dynamic solubility test: influence of various parameters.

    PubMed

    Thélohan, S; de Meringo, A

    1994-10-01

    This article discusses the dissolution of mineral fibers in simulated physiological fluids (SPF), and the parameters that affect the solubility measurement in a dynamic test where an SPF runs through a cell containing fibers (Scholze and Conradt test). Solutions simulate either the extracellular fluid (pH 7.6) or the intracellular fluid (pH 4.5). The fibers have various chemical compositions and are either continuously drawn or processed as wool. The fiber solubility is determined by the amount of SiO2 (and occasionally other ions) released in the solution. Results are stated as percentage of the initial silica content released or as dissolution rate v in nm/day. The reproducibility of the test is higher with the less soluble fibers (10% solubility), than with highly soluble fibers (20% solubility). The influence of test parameters, including SPF, test duration, and surface area/volume (SA/V), has been studied. The pH and the inorganic buffer salts have a major influence: industrial glasswool composition is soluble at pH 7.6 but not at pH 4.5. The opposite is true for rock- (basalt) wool composition. For slightly soluble fibers, the dissolution rate v remains constant with time, whereas for highly soluble fibers, the dissolution rate decreases rapidly. The dissolution rates believed to occur are v1, initial dissolution rate, and v2, dissolution rate of the residual fibers. The SA of fibers varies with the mass of the fibers tested, or with the fiber diameter at equal mass. Volume, V, is the chosen flow rate. An increase in the SA/V ratio leads to a decrease in the dissolution rate.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Low-solubility particles and a Trojan-horse type mechanism of toxicity: the case of cobalt oxide on human lung cells

    PubMed Central

    2014-01-01

    Background The mechanisms of toxicity of metal oxide particles towards lung cells are far from being understood. In particular, the relative contribution of intracellular particulate versus solubilized fractions is rarely considered as it is very challenging to assess, especially for low-solubility particles such as cobalt oxide (Co3O4). Methods This study was possible owing to two highly sensitive, independent, analytical techniques, based on single-cell analysis, using ion beam microanalysis, and on bulk analysis of cell lysates, using mass spectrometry. Results Our study shows that cobalt oxide particles, of very low solubility in the culture medium, are readily incorporated by BEAS-2B human lung cells through endocytosis via the clathrin-dependent pathway. They are partially solubilized at low pH within lysosomes, leading to cobalt ions release. Solubilized cobalt was detected within the cytoplasm and the nucleus. As expected from these low-solubility particles, the intracellular solubilized cobalt content is small compared with the intracellular particulate cobalt content, in the parts-per-thousand range or below. However, we were able to demonstrate that this minute fraction of intracellular solubilized cobalt is responsible for the overall toxicity. Conclusions Cobalt oxide particles are readily internalized by pulmonary cells via the endo-lysosomal pathway and can lead, through a Trojan-horse mechanism, to intracellular release of toxic metal ions over long periods of time, involving specific toxicity. PMID:24669904

  19. 21 CFR 520.1044c - Gentamicin sulfate soluble powder.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Gentamicin sulfate soluble powder. 520.1044c... Gentamicin sulfate soluble powder. (a) Specifications. Each gram of gentamicin sulfate soluble powder contains gentamicin sulfate equivalent to 16.7, 66.7, or 333.3 milligrams of gentamicin. (b) Sponsor. See...

  20. 21 CFR 520.1044c - Gentamicin sulfate soluble powder.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Gentamicin sulfate soluble powder. 520.1044c... Gentamicin sulfate soluble powder. (a) Specifications. Each gram of gentamicin sulfate soluble powder contains gentamicin sulfate equivalent to 16.7, 66.7, or 333.3 milligrams of gentamicin. (b) Sponsor. See...

  1. The solubility of metals in Pb17Li liquid alloy

    NASA Astrophysics Data System (ADS)

    Borgstedt, H. U.; Feuerstein, H.

    1992-09-01

    The solubility data of iron in the eutectic alloy Pb17Li which were evaluated from corrosion tests in a turbulent flow of the molten alloy are discussed in the frame of solubilities of the transition metals in liquid lead. It is shown that the solubility of iron in the alloy is close to that in lead. This is also the fact for several other alloying elements of steels.A comparison of all known data shows that they are in agreement with generally shown trends for the solubility of the transition metals in low melting metals. These trends indicate comparably high solubilities of nickel and manganese in the liquid metals, lower saturation concentrations of vanadium, chromium, iron, and cobalt, and extremely low solubility of molybdenum.

  2. Phosphate Solubilization and Gene Expression of Phosphate-Solubilizing Bacterium Burkholderia multivorans WS-FJ9 under Different Levels of Soluble Phosphate.

    PubMed

    Zeng, Qingwei; Wu, Xiaoqin; Wang, Jiangchuan; Ding, Xiaolei

    2017-04-28

    Phosphate-solubilizing bacteria (PSB) have the ability to dissolve insoluble phosphate and enhance soil fertility. However, the growth and mineral phosphate solubilization of PSB could be affected by exogenous soluble phosphate and the mechanism has not been fully understood. In the present study, the growth and mineral phosphate-solubilizing characteristics of PSB strain Burkholderia multivorans WS-FJ9 were investigated at six levels of exogenous soluble phosphate (0, 0.5, 1, 5, 10, and 20 mM). The WS-FJ9 strain showed better growth at high levels of soluble phosphate. The phosphate-solubilizing activity of WS-FJ9 was reduced as the soluble phosphate concentration increased, as well as the production of pyruvic acid. Transcriptome profiling of WS-FJ9 at three levels of exogenous soluble phosphate (0, 5, and 20 mM) identified 446 differentially expressed genes, among which 44 genes were continuously up-regulated when soluble phosphate concentration was increased and 81 genes were continuously down-regulated. Some genes related to cell growth were continuously up-regulated, which would account for the better growth of WS-FJ9 at high levels of soluble phosphate. Genes involved in glucose metabolism, including glycerate kinase, 2-oxoglutarate dehydrogenase, and sugar ABC-type transporter, were continuously down-regulated, which indicates that metabolic channeling of glucose towards the phosphorylative pathway was negatively regulated by soluble phosphate. These findings represent an important first step in understanding the molecular mechanisms of soluble phosphate effects on the growth and mineral phosphate solubilization of PSB.

  3. Characterization of the Water Soluble Component of Inedible Residue from Candidate CELSS Crops

    NASA Technical Reports Server (NTRS)

    Garland, Jay

    1992-01-01

    Recycling of inorganic nutrients required for plant growth will be a necessary component of a fully closed, bioregenerative life support system. This research characterized the recovery of plant nutrients from the inedible fraction of three crop types (wheat, potato, and soybean) by soaking, or leaching, in water. A considerable portion of the dry weight of the inedible biomass was readily soluble (29 percent for soybean, 43 percent for wheat, and 52 percent for potato). Greater weight loss from potato was a result of higher tissue concentrations of potassium, nitrate, and phosphate. Approximately 25 percent of the organic content of the biomass was water soluble, while the majority of most inorganic nutrients, except for calcium and iron, were recovered in the leachate. Direct use of the leachates in hydroponic media could provide between 40-90 percent of plant nutrient demands for wheat, and 20-50 percent of demand for soybean and potato. Further evaluation of leaching as a component of resource recovery scheme in a bioregenerative system requires study of (1) utilization of plant leachates in hydroponic plant culture; and (2) conversion of organic material (both soluble and insoluble) into edible, or other useful, products.

  4. Three new hydrochlorothiazide cocrystals: Structural analyses and solubility studies

    NASA Astrophysics Data System (ADS)

    Ranjan, Subham; Devarapalli, Ramesh; Kundu, Sudeshna; Vangala, Venu R.; Ghosh, Animesh; Reddy, C. Malla

    2017-04-01

    Hydrochlorothiazide (HCT) is a diuretic BCS class IV drug with poor aqueous solubility and low permeability leading to poor oral absorption. The present work explores the cocrystallization technique to enhance the aqueous solubility of HCT. Three new cocrystals of HCT with water soluble coformers phenazine (PHEN), 4-dimethylaminopyridine (DMAP) and picolinamide (PICA) were prepared successfully by solution crystallization method and characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), fourier transform -infraredspectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Structural characterization revealed that the cocrystals with PHEN, DMAP and PICA exists in P21/n, P21/c and P21/n space groups, respectively. The improved solubility of HCT-DMAP (4 fold) and HCT-PHEN (1.4 fold) cocrystals whereas decreased solubility of HCT-PICA (0.5 fold) as compared to the free drug were determined after 4 h in phosphate buffer, pH 7.4, at 25 °C by using shaking flask method. HCT-DMAP showed a significant increase in solubility than all previously reported cocrystals of HCT suggest the role of a coformer. The study demonstrates that the selection of coformer could have pronounced impact on the physicochemical properties of HCT and cocrystallization can be a promising approach to improve aqueous solubility of drugs.

  5. Solubility of NaCl in water by molecular simulation revisited.

    PubMed

    Aragones, J L; Sanz, E; Vega, C

    2012-06-28

    In this paper, the solubility of NaCl in water is evaluated by using computer simulations for three different force fields. The condition of chemical equilibrium (i.e., equal chemical potential of the salt in the solid and in the solution) is obtained at room temperature and pressure to determine the solubility of the salt. We used the same methodology that was described in our previous work [E. Sanz and C. Vega, J. Chem. Phys. 126, 014507 (2007)] although several modifications were introduced to improve the accuracy of the calculations. It is found that the predictions of the solubility are quite sensitive to the details of the force field used. Certain force fields underestimate the experimental solubility of NaCl in water by a factor of four, whereas the predictions of other force fields are within 20% of the experimental value. Direct coexistence molecular dynamic simulations were also performed to determine the solubility of the salt. Reasonable agreement was found between the solubility obtained from free energy calculations and that obtained from direct coexistence simulations. This work shows that the evaluation of the solubility of salts in water can now be performed in computer simulations. The solubility depends on the ion-ion, ion-water, and water-water interactions. For this reason, the prediction of the solubility can be quite useful in future work to develop force fields for ions in water.

  6. Dietary fiber content influences soluble carbohydrate levels in ruminal fluids.

    PubMed

    Pinder, R S; Patterson, J A; O'Bryan, C A; Crandall, P G; Ricke, S C

    2012-01-01

    The soluble carbohydrate concentration of ruminal fluid, as affected by dietary forage content (DFC) and/or ruminally undegradable intake protein content (UIPC), was determined. Four ruminally cannulated steers, in a 4 × 4 Latin square design, were offered diets containing high (75 % of DM) or low (25 % of DM) DFC and high (6 % of DM) or low (5 % of DM) UIPC, in a 2 × 2 factorial arrangement. Zinc-treated SBM was the primary UIP source. Soluble hexose concentration (145.1 μM) in ruminal fluid (RF) of steers fed low DFC diets exhibited a higher trend (P = 0.08) than that (124.5 μM) of steers fed high DFC diets. UIPC did not modulate (P = 0.54) ruminal soluble hexose concentrations. Regardless of diet, soluble hexose concentration declined immediately after feeding and did not rise until 3 h after feeding (P < 0.0001). Cellobiose (≈90 %) and glucose (≈10 %) were the major soluble hexoses present in RF. Maltose was not detected. Soluble glucose concentration (13.0 μM) was not modified by either UIPC (P = 0.40) nor DFC (P = 0.61). However, a DFC by post-prandial time interaction was detected (P = 0.02). Pentose concentrations were greater (P = 0.02) in RF of steers fed high DFC (100.2 μM) than steers fed low DFC (177.0 μM). UIPC did not influence (P = 0.35) soluble pentose concentration. The identity of soluble pentoses in ruminal fluid could not be determined. However, unsubstituted xylose and arabinose were excluded. These data indicate that: (i) soluble carbohydrate concentrations remain in ruminal fluid during digestion and fermentation; (ii) slight diurnal changes began after feeding; (iii) DFC influences the soluble carbohydrate concentration in RF; and (iv) UIPC of these diets does not affect the soluble carbohydrate concentration of RF.

  7. Determination of excipient based solubility increases using the CheqSol method.

    PubMed

    Etherson, Kelly; Halbert, Gavin; Elliott, Moira

    2014-04-25

    Aqueous solubility is an essential characteristic assessed during drug development to determine a compound's drug-likeness since solubility plays an important pharmaceutical role. However, nearly half of the drug candidates discovered today display poor water solubility; therefore methods have to be applied to increase solubility. Solubility determination using the CheqSol method is a novel rapid solubility screening technique for ionisable compounds. The aim of this study is to determine if the CheqSol method can be employed to determine solubility increases of four test drugs (ibuprofen, gliclazide, atenolol and propranolol) induced by non-ionising excipients such as hydroxypropyl-β-cyclodextrin and poloxamers 407 and 188. CheqSol assays were performed for the drugs alone or in combination with varying solubiliser concentrations. The measured intrinsic solubility of all four drugs increased with all the excipients tested in an excipient concentration dependent manner providing results consistent with previous literature. The results demonstrate that it may be possible to use this method to determine the solubility increases induced by non-ionic solubilising excipients with results that are comparable to standard equilibrium based solubility techniques. Since the technique is automated and requires only small drug quantities it may serve as a useful solubility or formulation screening tool providing more detailed physicochemical information than multiwell plate or similar visual systems. Copyright © 2014. Published by Elsevier B.V.

  8. The Hildebrand solubility parameters of ionic liquids-part 2.

    PubMed

    Marciniak, Andrzej

    2011-01-01

    The Hildebrand solubility parameters have been calculated for eight ionic liquids. Retention data from the inverse gas chromatography measurements of the activity coefficients at infinite dilution were used for the calculation. From the solubility parameters, the enthalpies of vaporization of ionic liquids were estimated. Results are compared with solubility parameters estimated by different methods.

  9. Prevention of obesity relatred metabolic diseases by processed foods containing soluble dietary fibers and flavonoids (abstract)

    USDA-ARS?s Scientific Manuscript database

    Asians and other non-caucasians are generally more susceptible to obesity related chronic diseases such as type 2 diabetes and cardiovascular disease. Viscous soluble dietary fibers such as cereal beta-glucans and psyllium reduce plasma cholesterol and postprandial glycemia in humans. We have stud...

  10. Increased expression of cytokines, soluble cytokine receptors, soluble apoptosis ligand and apoptosis in dengue.

    PubMed

    Arias, Julia; Valero, Nereida; Mosquera, Jesús; Montiel, Milagros; Reyes, Eduardo; Larreal, Yraima; Alvarez-Mon, Melchor

    2014-03-01

    Several studies have been performed to determine biomarkers that define the risk factors to developing severe forms of dengue. In this study, the levels of TNF-α, IL-6, IL-1, IL-17, soluble interleukin-1 receptor like 1 protein (sST2), soluble TNF-related apoptosis-inducing ligand (sTRAIL), IL-12 and soluble receptors for TNF (sTNF-RI and sTNF-RII) were determined by ELISA in dengue patients and monocyte/macrophage cultures. Dengue was classified as dengue without warning symptoms (DNWS), with warning symptoms (DWWS) and severe dengue (SD). High values of IL-6, sTNFRI, sTNFRII and sST2 were observed in DWWS and/or SD and IL-12 and sTRAIL in DNWS. TNF-α and IL-17 were increased not associated to the disease severity. High production of TNF-α, IL-1β, IL-12, IL-17, sST2 and sTRAIL and apoptosis expression were observed in dengue monocyte/macrophage cultures. This study shows that beneficial or deleterious biomarkers can be present in dengue regardless the disease severity and that monocytes may be in part the source of studied molecules. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. An Improved Variant of Soybean Type 1 Diacylglycerol Acyltransferase Increases the Oil Content and Decreases the Soluble Carbohydrate Content of Soybeans[OPEN

    PubMed Central

    Shen, Bo; Damude, Howard G.; Everard, John D.; Booth, John R.

    2016-01-01

    Kinetically improved diacylglycerol acyltransferase (DGAT) variants were created to favorably alter carbon partitioning in soybean (Glycine max) seeds. Initially, variants of a type 1 DGAT from a high-oil, high-oleic acid plant seed, Corylus americana, were screened for high oil content in Saccharomyces cerevisiae. Nearly all DGAT variants examined from high-oil strains had increased affinity for oleoyl-CoA, with S0.5 values decreased as much as 4.7-fold compared with the wild-type value of 0.94 µm. Improved soybean DGAT variants were then designed to include amino acid substitutions observed in promising C. americana DGAT variants. The expression of soybean and C. americana DGAT variants in soybean somatic embryos resulted in oil contents as high as 10% and 12%, respectively, compared with only 5% and 7.6% oil achieved by overexpressing the corresponding wild-type DGATs. The affinity for oleoyl-CoA correlated strongly with oil content. The soybean DGAT variant that gave the greatest oil increase contained 14 amino acid substitutions out of a total of 504 (97% sequence identity with native). Seed-preferred expression of this soybean DGAT1 variant increased oil content of soybean seeds by an average of 3% (16% relative increase) in highly replicated, single-location field trials. The DGAT transgenes significantly reduced the soluble carbohydrate content of mature seeds and increased the seed protein content of some events. This study demonstrated that engineering of the native DGAT enzyme is an effective strategy to improve the oil content and value of soybeans. PMID:27208257

  12. The solubility of hen egg-white lysozyme

    NASA Technical Reports Server (NTRS)

    Howard, Sandra B.; Twigg, Pamela J.; Baird, James K.; Meehan, Edward J.

    1988-01-01

    The equilibrium solubility of chicken egg-white lysozyme in the presence of crystalline solid state was determined as a function of NaCl concentration, pH, and temperature. The solubility curves obtained represent a region of the lysozyme phase diagram. This diagram makes it possible to determine the supersaturation of a given set of conditions or to achieve identical supersaturations by different combinations of parameters. The temperature dependence of the solubility permits the evaluation of Delta-H of crystallization. The data indicate a negative heat of crystallization for the tetragonal crystal form but a positive heat of crystallization for the high-temperature orthorhombic form.

  13. Synergistic Effect of Hydrotrope and Surfactant on Solubility and Dissolution of Atorvastatin Calcium: Screening Factorial Design Followed by Ratio Optimization

    PubMed Central

    Patel, V. F.; Sarai, J.

    2014-01-01

    The present study was aimed at investigating the effect of hydrotrope and surfactant on poor solubility of atorvastatin calcium. Excipients screening followed by factorial design was performed to study effect of excipients and manufacturing methods on solubility of drug. Three independent factors (carrier, surfactant and manufacturing method) were evaluated at two levels using solubility as a dependant variable. Solid-state characterisation was performed using Fourier transform infrared spectroscopy and differential scanning calorimetry. Optimised complex were incorporated into orally disintegrating micro tablets and in vitro dissolution test was performed. Nicotinamide, Plasdone and sodium dodecyl sulphate were emerged as promising excipients from excipient screening. General regression analysis revealed only the type of carrier has significantly enhanced (P<0.05) the solubility of drug while other factors were found to be nonsignificant. Ratio optimisation trial revealed that drug to nicotinamide ratio is more critical in enhancing the solubility of drug (40 fold increases in solubility compared to pure drug) in comparison to drug-surfactant ratio; however the presence of surfactant deemed essential. Significantly higher rate and extent of dissolution was observed from solid dispersion complex and tablets compared to dissolution of pure drug (P<0.05). Study revealed hydrotrope and surfactant have synergistic effect on solubility and dissolution of atorvastatin calcium and this can be explored further. PMID:25593381

  14. Biochemical Characterization of the Lactobacillus reuteri Glycoside Hydrolase Family 70 GTFB Type of 4,6-α-Glucanotransferase Enzymes That Synthesize Soluble Dietary Starch Fibers.

    PubMed

    Bai, Yuxiang; van der Kaaij, Rachel Maria; Leemhuis, Hans; Pijning, Tjaard; van Leeuwen, Sander Sebastiaan; Jin, Zhengyu; Dijkhuizen, Lubbert

    2015-10-01

    4,6-α-Glucanotransferase (4,6-α-GTase) enzymes, such as GTFB and GTFW of Lactobacillus reuteri strains, constitute a new reaction specificity in glycoside hydrolase family 70 (GH70) and are novel enzymes that convert starch or starch hydrolysates into isomalto/maltopolysaccharides (IMMPs). These IMMPs still have linear chains with some α1→4 linkages but mostly (relatively long) linear chains with α1→6 linkages and are soluble dietary starch fibers. 4,6-α-GTase enzymes and their products have significant potential for industrial applications. Here we report that an N-terminal truncation (amino acids 1 to 733) strongly enhances the soluble expression level of fully active GTFB-ΔN (approximately 75-fold compared to full-length wild type GTFB) in Escherichia coli. In addition, quantitative assays based on amylose V as the substrate are described; these assays allow accurate determination of both hydrolysis (minor) activity (glucose release, reducing power) and total activity (iodine staining) and calculation of the transferase (major) activity of these 4,6-α-GTase enzymes. The data show that GTFB-ΔN is clearly less hydrolytic than GTFW, which is also supported by nuclear magnetic resonance (NMR) analysis of their final products. From these assays, the biochemical properties of GTFB-ΔN were characterized in detail, including determination of kinetic parameters and acceptor substrate specificity. The GTFB enzyme displayed high conversion yields at relatively high substrate concentrations, a promising feature for industrial application. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  15. Solubility enhancement of a bisnaphthalimide tumoricidal agent, DMP 840, through complexation.

    PubMed

    Raghavan, K S; Nemeth, G A; Gray, D B; Hussain, M A

    1996-10-01

    The purpose of this research was to enhance the aqueous solubility of DMP 840 by complexation with water-soluble and nontoxic agents, and to understand the nature of the interactions involved in complex formation using nuclear magnetic resonance (1H-NMR). The solubility of DMP 840 in water, saline, acetate buffers, and cosolvent mixtures was determined by high-performance liquid chromatography, and the effect of nicotinamide and pyridoxine concentrations on the solubility of DMP 840 was examined by the phase solubility method. 1H-NMR spectra were acquired in deuterated acetate buffer at 400 MHz on a Varian Unity-400 spectrometer. The aqueous solubility of DMP 840 was sensitive to the presence of chloride and acetate anions in solution, and did not improve in the presence of cosolvents. The use of the nontoxic and water-soluble complex-forming agents nicotinamide and pyridoxine, however, resulted in a linear increase in the aqueous solubility of DMP 840 with both ligands. The solubilization appears to be due to formation of 1:1 complexes between DMP 840 and the bioorganic ligands. The complexation constants were 15.57 M-1 for the DMP 840:nicotinamide complex and 13.36 M-1 for the DMP 840:pyridoxine complex. The NMR results indicate that the interaction is a result of vertical or plane-to-plane stacking and the complexation constants were in agreement with that obtained by phase solubility. The results suggest that the aqueous solubility of a poorly water soluble drug substance such as DMP 840 can be significantly enhanced by its complexation with water-soluble and nontoxic agents.

  16. A Colorful Solubility Exercise for Organic Chemistry

    ERIC Educational Resources Information Center

    Shugrue, Christopher R.; Mentzen, Hans H., II; Linton, Brian R.

    2015-01-01

    A discovery chemistry laboratory has been developed for the introductory organic chemistry student to investigate the concepts of polarity, miscibility, solubility, and density. The simple procedure takes advantage of the solubility of two colored dyes in a series of solvents or solvent mixtures, and the diffusion of colors can be easily…

  17. The Hildebrand Solubility Parameters of Ionic Liquids—Part 2

    PubMed Central

    Marciniak, Andrzej

    2011-01-01

    The Hildebrand solubility parameters have been calculated for eight ionic liquids. Retention data from the inverse gas chromatography measurements of the activity coefficients at infinite dilution were used for the calculation. From the solubility parameters, the enthalpies of vaporization of ionic liquids were estimated. Results are compared with solubility parameters estimated by different methods. PMID:21747694

  18. Relationship of Soluble RAGE with Insulin Resistance and Beta Cell Function during Development of Type 2 Diabetes Mellitus

    PubMed Central

    Biswas, Subrata Kumar; Mohtarin, Sabreena; Mudi, Sonchita Rani; Anwar, Taznuva; Banu, Laila Anjuman; Alam, Sheikh Md. Khorshed; Fariduddin, Md.; Arslan, M. Iqbal

    2015-01-01

    This study examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE) alter in prediabetes and correlate with insulin resistance (IR) and beta cell function in prediabetes and newly diagnosed type 2 diabetes mellitus (T2DM). Subjects without previous history of diabetes were recruited and grouped as control, prediabetes, and newly diagnosed T2DM. The control subjects (n = 40) and people with prediabetes (n = 52) and diabetes (n = 66) were similar in terms of age, sex, BMI, systolic and diastolic BP, and fasting insulin level. HOMA-IR was found significantly higher in people with diabetes than control subjects (p < 0.001) and people with prediabetes (p = 0.005); and HOMA-%B was found significantly deteriorated in people with diabetes (p < 0.001) compared to control subjects and people with prediabetes. However, serum sRAGE levels did not show any significant alteration in people with prediabetes compared to control subjects. Moreover, univariate and multivariate analyses did not identify any significant correlation and statistical association of sRAGE with HOMA-IR and HOMA-%B in people with prediabetes and newly diagnosed T2DM. Our data suggest that serum sRAGE levels do not alter in people with prediabetes compared to control subjects and do not correlate or associate with IR and beta cell function during development of T2DM. PMID:26078977

  19. Relationship of Soluble RAGE with Insulin Resistance and Beta Cell Function during Development of Type 2 Diabetes Mellitus.

    PubMed

    Biswas, Subrata Kumar; Mohtarin, Sabreena; Mudi, Sonchita Rani; Anwar, Taznuva; Banu, Laila Anjuman; Alam, Sheikh Md Khorshed; Fariduddin, Md; Arslan, M Iqbal

    2015-01-01

    This study examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE) alter in prediabetes and correlate with insulin resistance (IR) and beta cell function in prediabetes and newly diagnosed type 2 diabetes mellitus (T2DM). Subjects without previous history of diabetes were recruited and grouped as control, prediabetes, and newly diagnosed T2DM. The control subjects (n = 40) and people with prediabetes (n = 52) and diabetes (n = 66) were similar in terms of age, sex, BMI, systolic and diastolic BP, and fasting insulin level. HOMA-IR was found significantly higher in people with diabetes than control subjects (p < 0.001) and people with prediabetes (p = 0.005); and HOMA-%B was found significantly deteriorated in people with diabetes (p < 0.001) compared to control subjects and people with prediabetes. However, serum sRAGE levels did not show any significant alteration in people with prediabetes compared to control subjects. Moreover, univariate and multivariate analyses did not identify any significant correlation and statistical association of sRAGE with HOMA-IR and HOMA-%B in people with prediabetes and newly diagnosed T2DM. Our data suggest that serum sRAGE levels do not alter in people with prediabetes compared to control subjects and do not correlate or associate with IR and beta cell function during development of T2DM.

  20. Soluble Molecularly Imprinted Nanorods for Homogeneous Molecular Recognition

    NASA Astrophysics Data System (ADS)

    Liang, Rongning; Wang, Tiantian; Zhang, Huan; Yao, Ruiqing; Qin, Wei

    2018-03-01

    Nowadays, it is still difficult for molecularly imprinted polymer (MIPs) to achieve homogeneous recognition since they cannot be easily dissolved in organic or aqueous phase. To address this issue, soluble molecularly imprinted nanorods have been synthesized by using soluble polyaniline doped with a functionalized organic protonic acid as the polymer matrix. By employing 1-naphthoic acid as a model, the proposed imprinted nanorods exhibit an excellent solubility and good homogeneous recognition ability. The imprinting factor for the soluble imprinted nanoroads is 6.8. The equilibrium dissociation constant and the apparent maximum number of the proposed imprinted nanorods are 248.5 μM and 22.1 μmol/g, respectively. We believe that such imprinted nanorods may provide an appealing substitute for natural receptors in homogeneous recognition related fields.

  1. Solubility Enhancement of Raloxifene Using Inclusion Complexes and Cogrinding Method

    PubMed Central

    Patil, Payal H.; Belgamwar, Veena S.; Patil, Pratibha R.; Surana, Sanjay J.

    2013-01-01

    The objective of the present work was to enhance the solubility and dissolution of practically water-insoluble drug raloxifene HCl (RLX), for the same two approaches that were used. In the first approach, drug was kneaded with hydroxypropyl-β-cyclodextrin (HPβCD), and in the second one drug was cogrinded with modified guar gum (MGG). The drug-cyclodextrin complex and drug-MGG cogrind mixtures were characterized by differential scanning calorimetry, X-ray diffraction studies, scanning electron microscopy, and Fourier transform infrared spectroscopy. The solubility and dissolution study reveals that solubility and dissolution rate of RLX remarkably increased in both methods. It was concluded that the prepared inclusion complex showed a remarkable increase in solubility and dissolution of poorly water-soluble drug raloxifene. In the cogrinding mixture, a natural modified gum is used as a surfactant and enhances the solubility and dissolution of RLX without requiring addition of organic solvent or high temperature for its preparation; thus, process is less cumbersome and cost effective. But when both methods were compared; HPβCD complexation method showed significant enhancement of drug solubility. PMID:26555984

  2. Soluble CD26 and CD30 plasma levels in HIV infected patients with and without GB virus type C coinfection.

    PubMed

    Mostafa, Haji-Molla-Hoseini; Ali-Akbar, Pourfathollah; Zahra, Soheili; Minoo, Mohraz; Sedigheh, Amini; Mahnaz, Aghaiepour; Shahram, Samiee; Mahin, Nikoogoftar; Mina, Moghtadaie

    2007-06-15

    GB virus type C (GBV-C) probably influences HIV infection associated disease by either directly inhibiting HIV replication or enhancing the immune competence to cope with HIV. Still the definitive mechanisms of this inhibitory effect need to be identified. To address the possibility of immune modulating effects of GBV-C coinfection in HIV patients we evaluated plasma levels of soluble (s) CD26 and CD30 in HIV infected patients with and without GBV-C. Cross-sectional comparison of sCD26 and sCD30 levels among 6 HIV/GBV-C coinfected, 11 HIV mono-infected and 13 healthy controls was carried out. We used a commercial EIA to evaluate sCD26 and scD30 and a RT-PCR assay to detect active GBV-C infection. The Mann-Whitney U test was used for statistical analysis. No statistically significant differences were observed in levels of sCD26 and sCD30 in plasma of HIV infected patients with and without GBV-C viremia. GBV-C infection does not appear to influence the sCD26 and sCD30 levels.

  3. Soluble HLA-G: Are They Clinically Relevant?

    PubMed Central

    Pistoia, Vito; Morandi, Fabio; Wang, Xinhui; Ferrone, Soldano

    2007-01-01

    HLA-G is a non-classical HLA-class Ib molecule with multiple immunoregulatory properties. Its main function in physiological conditions is to abrogate maternal NK cell activity against foetal tissue and to establish immune tolerance at maternal-foetal interface. HLA-G is expressed not only as a membrane bound molecule on the surface of cells, but also as a soluble moiety in body fluids. The major isoforms of HLA-G present in serum are soluble HLA-G1 and HLA-G5 which are generated by shedding or proteolytic cleavage of the membrane bound isoform and by secretion of a soluble isoform, respectively. Here we review the data about soluble HLA-G (sHLA-G) serum levels in different pathological conditions, including immune-mediated disorders, transplantation, and malignancies. In particular, we focus on sHLA-G expression and function in human neuroblastoma, a pediatric tumor, with special emphasis on a novel potential immuno escape mechanism utilized by NB to instruct monocytes to produce and release sHLA-G. Finally, the potential clinical relevance of sHLA-G serum levels is discussed. PMID:17825579

  4. Golden rule for buttressing vulnerable soluble proteins.

    PubMed

    Fernández, Ariel; Berry, R Stephen

    2010-05-07

    Local weaknesses in the structure of soluble proteins have received little attention. The structure may be inherently weak at sites where hydration of the protein backbone is locally hampered by formation of an intramolecular hydrogen bond which in turn is not fully stabilized through burial within a hydrophobic environment. The result is insufficient compensation for the thermodynamic cost of dehydrating the backbone polar groups. This work shows that these structural deficiencies, the unburied backbone hydrogen bonds, are compensated in natural proteins by disulfide bonds that are needed to maintain the structural integrity. Examination of all PDB-reported soluble structures reveals that, after suitable normalization, the number of disulfide bonds, X, correlates tightly with the number of unburied backbone hydrogen bonds, Y, beyond the baseline level Y = 20, revealing a simple balance relation: Y = 5X + 20. This equation introduces a 1:5 ratio associated with the buttressing of soluble proteins with structural deficiencies. The results are justified on thermodynamic grounds and have implications for biomolecular engineering as they introduce two constants of universal applicability determining the architecture of soluble proteins.

  5. Estimation of intragastric solubility of drugs: in what medium?

    PubMed

    Vertzoni, Maria; Pastelli, Eleni; Psachoulias, Dimitris; Kalantzi, Lida; Reppas, Christos

    2007-05-01

    To measure the solubility of four drugs in human gastric aspirates, canine gastric aspirates (CGF) and simulated gastric fluids in order to propose a medium for estimating intragastric drug solubility relevant to a bioavailability study in the fasted state. Intragastric environment after administration of water to healthy fasted adults and to healthy fasted dogs (this study) was initially characterized. Solubilities were then measured with the shake-flask method in gastric fluid aspirated after the administration of water to healthy fasted adults and to healthy fasted dogs, in various simulated gastric fluids, i.e. SGF(SLS), SGF(Triton), FaSSGF, FaSSGF(NaCl), and in various HCl solutions with pH values ranging from 1.2 to 2.9. In all cases, FaSSGF performed better than canine aspirates, SGF(SLS), SGF(Triton), or FaSSGF(NaCl) in predicting solubility in HGF. However, its superiority over HCl pH 1.6 was not clear. For ketoconazole, dipyridamole, miconazole, and felodipine deviations of solubility data in FaSSGF from solubility data in HGF were non-significant, 34, -39 and 252%, respectively, whereas the corresponding deviations of data in HCl pH 1.6 from data in HGF were non-significant, 24, 70, and 130%, respectively. Combining data in FaSSGF and HCl pH 1.6 is comparatively the most efficient way to get an estimate of drug solubility in the fasting gastric contents during a bioavailability study. However, accurate estimation of intragastric solubility is limited by the changing environment during intragastric residence of solid particles and the degree of simulation of intragastric composition.

  6. The Effects of Acetate Buffer Concentration on Lysozyme Solubility

    NASA Technical Reports Server (NTRS)

    Forsythe, Elizabeth L.; Pusey, Marc L.

    1996-01-01

    The micro-solubility column technique was employed to systematically investigate the effects of buffer concentration on tetragonal lysozyme solubility. While keeping the NaCl concentrations constant at 2%, 3%, 4%, 5% and 7%, and the pH at 4.0, we have studied the solubility of tetragonal lysozyme over an acetate buffer concentration range of 0.01M to 0.5M as a function of temperature. The lysozyme solubility decreased with increasing acetate concentration from 0.01M to 0.1M. This decrease may simply be due to the net increase in solvent ionic strength. Increasing the acetate concentration beyond 0.1M resulted in an increase in the lysozyme solubility, which reached a peak at - 0.3M acetate concentration. This increase was believed to be due to the increased binding of acetate to the anionic binding sites of lysozyme, preventing their occupation by chloride. In keeping with the previously observed reversal of the Hoffmeister series for effectiveness of anions in crystallizing lysozyme, acetate would be a less effective precipitant than chloride. Further increasing the acetate concentration beyond 0.3M resulted in a subsequent gradual decrease in the lysozyme solubility at all NaCl concentrations.

  7. Water-Soluble Polyphosphazenes and Their Hydrogels

    DTIC Science & Technology

    1994-05-18

    side groups, such as -OH, -COONa, -NH2, -NHCH3, -SO3", or -C=O, or amphiphilic units such as -OCH2CH20-, etc. High concentrations of hydrophilic side...soluble polymers since it allows a high degree of utilization of molecular design and either extensive or subtle structural manipulation. The third...advantages for development as water-soluble polymers or hydrogels. The backbone is hydrophilic, the chain structure has a high 3 degree of flexibility, and

  8. water-soluble fluorocarbon coating

    NASA Technical Reports Server (NTRS)

    Nanelli, P.

    1979-01-01

    Water-soluble fluorocarbon proves durable nonpolluting coating for variety of substrates. Coatings can be used on metals, masonry, textiles, paper, and glass, and have superior hardness and flexibility, strong resistance to chemicals fire, and weather.

  9. Enhancing the Solubility and Oral Bioavailability of Poorly Water-Soluble Drugs Using Monoolein Cubosomes.

    PubMed

    Ali, Md Ashraf; Kataoka, Noriko; Ranneh, Abdul-Hackam; Iwao, Yasunori; Noguchi, Shuji; Oka, Toshihiko; Itai, Shigeru

    2017-01-01

    Monoolein cubosomes containing either spironolactone (SPI) or nifedipine (NI) were prepared using a high-pressure homogenization technique and characterized in terms of their solubility and oral bioavailability. The mean particle size, polydispersity index (PDI), zeta potential, solubility and encapsulation efficiency (EE) values of the SPI- and NI-loaded cubosomes were determined to be 90.4 nm, 0.187, -13.4 mV, 163 µg/mL and 90.2%, and 91.3 nm, 0.168, -12.8 mV, 189 µg/mL and 93.0%, respectively, which were almost identical to those of the blank cubosome. Small-angle X-ray scattering analyses confirmed that the SPI-loaded, NI-loaded and blank cubosomes existed in the cubic space group Im3̄m. The lattice parameters of the SPI- and NI-loaded cubosomes were 147.6 and 151.6 Å, respectively, making them almost identical to that of blank cubosome (151.0 Å). The in vitro release profiles of the SPI- and NI-loaded cubosomes showed that they released less than 5% of the drugs into various media over 12-48 h, indicating that most of the drug remained encapsulated within the cubic phase of their lipid bilayer. Furthermore, the in vivo pharmacokinetic results suggested that these cubosomes led to a considerable increase in the systemic oral bioavailability of the drugs compared with pure dispersions of the same materials. Notably, the stability results indicated that the mean particle size and PDI values of these cubosomes were stable for at least 4 weeks. Taken together, these results demonstrate that monoolein cubosomes represent promising drug carriers for enhancing the solubility and oral bioavailability of poorly water-soluble drugs.

  10. Water and acid soluble trace metals in atmospheric particles

    NASA Technical Reports Server (NTRS)

    Lindberg, S. E.; Harriss, R. C.

    1983-01-01

    Continental aerosols are collected above a deciduous forest in eastern Tennessee and subjected to selective extractions to determine the water-soluble and acid-leachable concentrations of Cd, Mn, Pb, and Zn. The combined contributions of these metals to the total aerosol mass is 0.5 percent, with approximately 70 percent of this attributable to Pb alone. A substantial fraction (approximately 50 percent or more) of the acid-leachable metals is soluble in distilled water. In general, this water-soluble fraction increases with decreasing particle size and with increasing frequency of atmospheric water vapor saturation during the sampling period. The pattern of relative solubilities (Zn being greater than Mn, which is approximately equal to Cd, which is greater than Pb) is found to be similar to the general order of the thermodynamic solubilities of the most probable salts of these elements in continental aerosols with mixed fossil fuel and soil sources.

  11. Tetragonal Chicken Egg White Lysozyme Solubility in Sodium Chloride Solutions

    NASA Technical Reports Server (NTRS)

    Forsythe, Elizabeth L.; Judge, Russell A.; Pusey, Marc L.

    1998-01-01

    The solubility of chicken egg white lysozyme, crystallized in the tetragonal form was measured in sodium chloride solutions from 1.6 to 30.7 C, using a miniature column solubility apparatus. Sodium chloride solution concentrations ranged from 1 to 7% (w/v). The solutions were buffered with 0.1 M sodium acetate buffer with the solubility being measured at pH values in 0.2 pH unit increments in the range pH 4.0 to 5.4, with data also included at pH 4.5. Lysozyme solubility was found to increase with increases in temperature and decreasing salt concentration. Solution pH has a varied and unpredictable effect on solubility.

  12. Enhancement of carvedilol solubility by solid dispersion technique using cyclodextrins, water soluble polymers and hydroxyl acid.

    PubMed

    Yuvaraja, K; Khanam, Jasmina

    2014-08-05

    Aim of the present work is to enhance aqueous solubility of carvedilol (CV) by solid dispersion technique using wide variety of carriers such as: β-cyclodextrin (βCD), hydroxypropyl-β-cyclodextrin (HPβCD), tartaric acid (TA), polyvinyl pyrrolidone K-30 (PVP K-30) and poloxamer-407 (PLX-407). Various products of 'CV-solid dispersion' had been studied extensively in various pH conditions to check enhancement of solubility and dissolution characteristics of carvedilol. Any physical change upon interaction between CV and carriers was confirmed by instrumental analysis: XRD, DSC, FTIR and SEM. Negative change of Gibb's free energy and complexation constants (Kc, 75-240M(-1), for cyclodextrins and 1111-20,365M(-1), for PVP K-30 and PLX-407) were the evidence of stable nature of the binding between CV and carriers. 'Solubility enhancement factor' of ionized-CV was found high enough (340 times) with HPβCD in presence of TA. TA increases the binding efficiency of cyclodextrin and changing the pH of microenvironment in dissolution medium. In addition, ionization process was used to increase the apparent intrinsic solubility of drug. In vitro, dissolution time of CV was remarkably reduced in the solid dispersion system compared to that of pure drug. This may be attributed to increased wettability, dispersing ability and transformation of crystalline state of drug to amorphous one. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Soluble Antigen Fluorescent-Antibody Technique

    PubMed Central

    Toussaint, Andre J.; Anderson, Robert I.

    1965-01-01

    An indirect fluorescent-antibody (FA) procedure employing soluble antigen fixed onto an artificial matrix was developed, and a mechanical means for reading of test results was devised. The method employs two small cellulose acetate paper discs for each test. One disc contains soluble antigen diluted in 1% bovine serum albumin (BSA); the other contains only 1% BSA and serves as a control. After testing by the indirect FA procedure, the results of the tests are read on a fluorometer fitted with a paper chromatogram door. The instrument is set at zero with the control disc as a blank, and the specific fluorescence of the antigen disc is determined. Findings obtained with homologous and heterologous antisera indicated that the method yields excellent results. The soluble antigen fluorescent-antibody technique has definite advantages over the conventional indirect FA procedures. (i) The investigator may objectively select the antigen to be employed. (ii) It is possible to obtain objective mechanical reading of test results rather than the highly subjective readings required by conventional methods. (iii) The system compensates for any nonspecific fluorescence contributed either by the serum (e.g., drugs) or by free fluorescein in the conjugated antiserum. Images Fig. 1 PMID:14339261

  14. Solubility and dissolution improvement of ketoprofen by emulsification ionic gelation

    NASA Astrophysics Data System (ADS)

    Rachmaniar, Revika; Tristiyanti, Deby; Hamdani, Syarif; Afifah

    2018-02-01

    Ketoprofen or [2-(3-benzoylphenyl) propionic acid] is non-steroidal anti-inflammatory (NSAID) and an analgesic which has high permeability and low solubility. The purpose of this work was to improve the solubility and dissolution of poorly water-soluble ketoprofen prepared by emulsification ionic gelation method and utilizing polymer (chitosan) and cross linker (tripolyphosphate, TPP) for particles formulation. The results show that increasing pH value of TPP, higher solubility and dissolution of as-prepared ketoprofen-chitosan was obtained. The solubility in water of ketoprofen-chitosan with pH 6 for TPP increased 2.71-fold compared to untreated ketoprofen. While the dissolution of ketoprofen-chitosan with pH 6 of TPP in simulated gastric fluid without enzyme (0.1 N HCl), pH 4.5 buffer and simulated intestinal fluid without enzyme (phosphate buffer pH 6.8) was increased 1.9-fold, 1.6-fold and 1.2-fold compared to untreated ketoprofen for dissolution time of 30 minutes, respectively. It could be concluded that chitosan and TPP in the emulsification ionic gelation method for ketoprofen preparation effectively increases solubility and dissolution of poorly water-soluble ketoprofen.

  15. Hydrodistillation-adsorption method for the isolation of water-soluble, non-soluble and high volatile compounds from plant materials.

    PubMed

    Mastelić, J; Jerković, I; Blazević, I; Radonić, A; Krstulović, L

    2008-08-15

    Proposed method of hydrodistillation-adsorption (HDA) on activated carbon and hydrodistillation (HD) with solvent trap were compared for the isolation of water-soluble, non-soluble and high volatile compounds, such as acids, monoterpenes, isothiocyanates and others from carob (Certonia siliqua L.), rosemary (Rosmarinus officinalis L.) and rocket (Eruca sativa L.). Isolated volatiles were analyzed by GC and GC/MS. The main advantages of HDA method over ubiquitous HD method were higher yields of volatile compounds and their simultaneous separation in three fractions that enabled more detail analyses. This method is particularly suitable for the isolation and analysis of the plant volatiles with high amounts of water-soluble compounds. In distinction from previously published adsorption of remaining volatile compounds from distillation water on activated carbon, this method offers simultaneous hydrodistillation and adsorption in the same apparatus.

  16. Structure of myostatin·follistatin-like 3: N-terminal domains of follistatin-type molecules exhibit alternate modes of binding.

    PubMed

    Cash, Jennifer N; Angerman, Elizabeth B; Kattamuri, Chandramohan; Nolan, Kristof; Zhao, Huaying; Sidis, Yisrael; Keutmann, Henry T; Thompson, Thomas B

    2012-01-06

    TGF-β family ligands are involved in a variety of critical physiological processes. For instance, the TGF-β ligand myostatin is a staunch negative regulator of muscle growth and a therapeutic target for muscle-wasting disorders. Therefore, it is important to understand the molecular mechanisms of TGF-β family regulation. One form of regulation is through inhibition by extracellular antagonists such as the follistatin (Fst)-type proteins. Myostatin is tightly controlled by Fst-like 3 (Fstl3), which is the only Fst-type molecule that has been identified in the serum bound to myostatin. Here, we present the crystal structure of myostatin in complex with Fstl3. The structure reveals that the N-terminal domain (ND) of Fstl3 interacts uniquely with myostatin as compared with activin A, because it utilizes different surfaces on the ligand. This results in conformational differences in the ND of Fstl3 that alter its position in the type I receptor-binding site of the ligand. We also show that single point mutations in the ND of Fstl3 are detrimental to ligand binding, whereas corresponding mutations in Fst have little effect. Overall, we have shown that the NDs of Fst-type molecules exhibit distinctive modes of ligand binding, which may affect overall affinity of ligand·Fst-type protein complexes.

  17. Soluble Amyloid-beta Aggregates from Human Alzheimer’s Disease Brains

    PubMed Central

    Esparza, Thomas J.; Wildburger, Norelle C.; Jiang, Hao; Gangolli, Mihika; Cairns, Nigel J.; Bateman, Randall J.; Brody, David L.

    2016-01-01

    Soluble amyloid-beta (Aβ) aggregates likely contribute substantially to the dementia that characterizes Alzheimer’s disease. However, despite intensive study of in vitro preparations and animal models, little is known about the characteristics of soluble Aβ aggregates in the human Alzheimer’s disease brain. Here we present a new method for extracting soluble Aβ aggregates from human brains, separating them from insoluble aggregates and Aβ monomers using differential ultracentrifugation, and purifying them >6000 fold by dual antibody immunoprecipitation. The method resulted in <40% loss of starting material, no detectible ex vivo aggregation of monomeric Aβ, and no apparent ex vivo alterations in soluble aggregate sizes. By immunoelectron microscopy, soluble Aβ aggregates typically appear as clusters of 10–20 nanometer diameter ovoid structures with 2-3 amino-terminal Aβ antibody binding sites, distinct from previously characterized structures. This approach may facilitate investigation into the characteristics of native soluble Aβ aggregates, and deepen our understanding of Alzheimer’s dementia. PMID:27917876

  18. Solubilities of crystalline drugs in polymers: an improved analytical method and comparison of solubilities of indomethacin and nifedipine in PVP, PVP/VA, and PVAc.

    PubMed

    Sun, Ye; Tao, Jing; Zhang, Geoff G Z; Yu, Lian

    2010-09-01

    A previous method for measuring solubilities of crystalline drugs in polymers has been improved to enable longer equilibration and used to survey the solubilities of indomethacin (IMC) and nifedipine (NIF) in two homo-polymers [polyvinyl pyrrolidone (PVP) and polyvinyl acetate (PVAc)] and their co-polymer (PVP/VA). These data are important for understanding the stability of amorphous drug-polymer dispersions, a strategy actively explored for delivering poorly soluble drugs. Measuring solubilities in polymers is difficult because their high viscosities impede the attainment of solubility equilibrium. In this method, a drug-polymer mixture prepared by cryo-milling is annealed at different temperatures and analyzed by differential scanning calorimetry to determine whether undissolved crystals remain and thus the upper and lower bounds of the equilibrium solution temperature. The new annealing method yielded results consistent with those obtained with the previous scanning method at relatively high temperatures, but revised slightly the previous results at lower temperatures. It also lowered the temperature of measurement closer to the glass transition temperature. For D-mannitol and IMC dissolving in PVP, the polymer's molecular weight has little effect on the weight-based solubility. For IMC and NIF, the dissolving powers of the polymers follow the order PVP > PVP/VA > PVAc. In each polymer studied, NIF is less soluble than IMC. The activities of IMC and NIF dissolved in various polymers are reasonably well fitted to the Flory-Huggins model, yielding the relevant drug-polymer interaction parameters. The new annealing method yields more accurate data than the previous scanning method when solubility equilibrium is slow to achieve. In practice, these two methods can be combined for efficiency. The measured solubilities are not readily anticipated, which underscores the importance of accurate experimental data for developing predictive models.

  19. Characterisation, solubility and intrinsic dissolution behaviour of benzamide: dibenzyl sulfoxide cocrystal.

    PubMed

    Grossjohann, Christine; Eccles, Kevin S; Maguire, Anita R; Lawrence, Simon E; Tajber, Lidia; Corrigan, Owen I; Healy, Anne Marie

    2012-01-17

    This study examined the 1:1 cocrystal benzamide:dibenzyl sulfoxide, comprising the poorly water soluble dibenzyl sulfoxide (DBSO) and the more soluble benzamide (BA), to establish if this cocrystal shows advantages in terms of solubility and dissolution in comparison to its pure components and to a physical mixture. Solubility studies were performed by measuring DBSO solubility as a function of BA concentration, and a ternary phase diagram was constructed. Dissolution was examined through intrinsic dissolution studies. Solid-state characterisation was carried out by powder X-ray diffraction (PXRD), energy-dispersive X-ray diffraction (EDX), infra-red spectroscopy (ATR-FTIR) and thermal analysis. DBSO solubility was increased by means of complexation with BA. For the cocrystal, the solubility of both components was decreased in comparison to pure components. The cocrystal was identified as metastable and incongruently saturating. Dissolution studies revealed that dissolution of DBSO from the cocrystal was not enhanced in comparison to the pure compound or a physical mix, while BA release was retarded and followed square root of time kinetics. At the disk surface a layer of DBSO was found. The extent of complexation in solution can change the stability of the complex substantially. Incongruent solubility and dissolution behaviour of a cocrystal can result in no enhancement in the dissolution of the less soluble component and retardation of release of the more soluble component. Copyright © 2011 Elsevier B.V. All rights reserved.

  20. Total and soluble oxalate content of some Indian spices.

    PubMed

    Ghosh Das, Sumana; Savage, G P

    2012-06-01

    Spices, such as cinnamon, cloves, cardamom, garlic, ginger, cumin, coriander and turmeric are used all over the world as flavouring and colouring ingredients in Indian foods. Previous studies have shown that spices contain variable amounts of total oxalates but there are few reports of soluble oxalate contents. In this study, the total, soluble and insoluble oxalate contents of ten different spices commonly used in Indian cuisine were measured. Total oxalate content ranged from 194 (nutmeg) to 4,014 (green cardamom) mg/100 g DM, while the soluble oxalate contents ranged from 41 (nutmeg) to 3,977 (green cardamom) mg/100 g DM. Overall, the percentage of soluble oxalate content of the spices ranged from 4.7 to 99.1% of the total oxalate content which suggests that some spices present no risk to people liable to kidney stone formation, while other spices can supply significant amounts of soluble oxalates and therefore should be used in moderation.

  1. Amino acid contribution to protein solubility: Asp, Glu, and Ser contribute more favorably than the other hydrophilic amino acids in RNase Sa.

    PubMed

    Trevino, Saul R; Scholtz, J Martin; Pace, C Nick

    2007-02-16

    Poor protein solubility is a common problem in high-resolution structural studies, formulation of protein pharmaceuticals, and biochemical characterization of proteins. One popular strategy to improve protein solubility is to use site-directed mutagenesis to make hydrophobic to hydrophilic mutations on the protein surface. However, a systematic investigation of the relative contributions of all 20 amino acids to protein solubility has not been done. Here, 20 variants at the completely solvent-exposed position 76 of ribonuclease (RNase) Sa are made to compare the contributions of each amino acid. Stability measurements were also made for these variants, which occur at the i+1 position of a type II beta-turn. Solubility measurements in ammonium sulfate solutions were made at high positive net charge, low net charge, and high negative net charge. Surprisingly, there was a wide range of contributions to protein solubility even among the hydrophilic amino acids. The results suggest that aspartic acid, glutamic acid, and serine contribute significantly more favorably than the other hydrophilic amino acids especially at high net charge. Therefore, to increase protein solubility, asparagine, glutamine, or threonine should be replaced with aspartic acid, glutamic acid or serine.

  2. Amino acid contribution to protein solubility: Asp, Glu, and Ser contribute more favorably than the other hydrophilic amino acids in RNase Sa

    PubMed Central

    Trevino, Saul R.; Scholtz, J. Martin; Pace, C. Nick

    2009-01-01

    SUMMARY Poor protein solubility is a common problem in high resolution structural studies, formulation of protein pharmaceuticals, and biochemical characterization of proteins. One popular strategy to improve protein solubility is to use site-directed mutagenesis to make hydrophobic to hydrophilic mutations on the protein surface. However, a systematic investigation of the relative contributions of all twenty amino acids to protein solubility has not been done. Here, twenty variants at the completely solvent-exposed position 76 of Ribonuclease (RNase) Sa are made to compare the contributions of each amino acid. Stability measurements were also made for these variants, which occur at the i+1 position of a type II β-turn. Solubility measurements in ammonium sulfate solutions were made at high positive net charge, low net charge, and high negative net charge. Surprisingly, there was a wide range of contributions to protein solubility even among the hydrophilic amino acids. The results suggest that aspartic acid, glutamic acid, and serine contribute significantly more favorably than the other hydrophilic amino acids especially at high net charge. Therefore, to increase protein solubility, asparagine, glutamine, or threonine should be replaced with aspartic acid, glutamic acid or serine. PMID:17174328

  3. Increased soluble vascular cell adhesion molecule-1 plasma levels and soluble intercellular adhesion molecule-1 during antiretroviral therapy interruption and retention of elevated soluble vascular cellular adhesion molecule-1 levels following resumption of antiretroviral therapy.

    PubMed

    Papasavvas, Emmanouil; Azzoni, Livio; Pistilli, Maxwell; Hancock, Aidan; Reynolds, Griffin; Gallo, Cecile; Ondercin, Joe; Kostman, Jay R; Mounzer, Karam; Shull, Jane; Montaner, Luis J

    2008-06-19

    We investigated the effect of short viremic episodes on soluble markers associated with endothelial stress and cardiovascular disease risk in chronically HIV-1-infected patients followed during continuous antiretroviral therapy, antiretroviral therapy interruption and antiretroviral therapy resumption. We assessed changes in plasma levels of von Willebrand factor, soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 by enzyme-linked immunosorbent assay, as well as T-cell activation (CD8+/CD38+, CD8+/HLA-DR+ and CD3+/CD95+) by flow cytometry, in 36 chronically HIV-1-infected patients participating in a randomized study. Patients were divided into the following three groups: a, on continuous antiretroviral therapy; b, on a 6-week antiretroviral therapy interruption; or c, on antiretroviral therapy interruption extended to the achievement of viral set point. Although all measurements remained stable over a 40-week follow-up on antiretroviral therapy, plasma levels of soluble vascular cell adhesion molecule-1 (P < 0.0001) and soluble intercellular adhesion molecule-1 (P = 0.003) increased during treatment interruption in correlation with viral rebound and T-cell activation. No significant changes in von Willebrand factor were observed in any of the groups. After resuming antiretroviral therapy, soluble vascular cell adhesion molecule-1 levels remained elevated even after achievement of viral suppression to less than 50 copies/ml. The prompt rise in plasma soluble vascular cell adhesion molecule-1 and soluble intercellular adhesion molecule-1 upon viral rebound suggests an acute increase in endothelial stress upon treatment interruption, which may persists after viral resuppression of virus. Thus, viral replication during short-term treatment interruption may increase the overall cardiovascular risk during and beyond treatment interruption.

  4. Sorption, Solubility, Bond Strength and Hardness of Denture Soft Lining Incorporated with Silver Nanoparticles

    PubMed Central

    Chladek, Grzegorz; Kasperski, Jacek; Barszczewska-Rybarek, Izabela; Żmudzki, Jarosław

    2013-01-01

    The colonization of denture soft lining material by oral fungi can result in infections and stomatitis of oral tissues. In this study, 0 ppm to 200 ppm of silver nanoparticles was incorporated as an antimicrobial agent into composites to reduce the microbial colonization of lining materials. The effect of silver nanoparticle incorporation into a soft lining material on the sorption, solubility, hardness (on the Shore A scale) and tensile bond strength of the composites was investigated. The data were statistically analyzed using two-way ANOVA and Newman-Keuls post hoc tests or the chi-square Pearson test at the p < 0.05 level. An increase in the nanosilver concentration resulted in a decrease in hardness, an increase in sorption and solubility, a decrease in bond strength and a change in the failure type of the samples. The best combination of bond strength, sorption, solubility and hardness with antifungal efficacy was achieved for silver nanoparticle concentrations ranging from 20 ppm to 40 ppm. These composites did not show properties worse than those of the material without silver nanoparticles and exhibited enhanced in vitro antifungal efficiency. PMID:23271371

  5. Viscous versus nonviscous soluble fiber supplements: mechanisms and evidence for fiber-specific health benefits.

    PubMed

    Chutkan, Robynne; Fahey, George; Wright, Wendy L; McRorie, Johnson

    2012-08-01

    This review focuses on the health benefits of viscous versus nonviscous soluble fibers, why symptoms can occur with increased fiber consumption, and how to avoid symptoms to improve adherence with a high-fiber diet. Review of scientific literature as well as evidence-based guidelines and resources. While it is generally known that "fiber is good for you," it is less well known that specific health benefits are associated with specific fiber characteristics. Many of the health benefits of fiber can be directly correlated with the viscosity of soluble fibers when hydrated (i.e., gel-forming). A reduction in viscosity of a given fiber will attenuate these health benefits, and a nonviscous fiber does not exhibit these health benefits. Increasing the viscosity of chyme with a viscous soluble fiber has been shown clinically to lower cholesterol for cardiovascular health, improve glycemic control in type 2 diabetes, normalize stool form in both constipation (softens hard stool) and diarrhea (firms loose/liquid stool), and improve the objective clinical measures of metabolic syndrome (glycemic control, lipoprotein profile, body mass index/weight loss, and blood pressure). ©2012 The Author(s) Journal compilation ©2012 American Academy of Nurse Practitioners.

  6. Treating SCA1 Mice with Water-Soluble Compounds to Non-Specifically Boost Mitochondrial Function.

    PubMed

    Ferro, Austin; Carbone, Emily; Marzouk, Evan; Siegel, Asher; Nguyen, Donna; Polley, Kailen; Hartman, Jessilyn; Frederick, Kimberley; Ives, Stephen; Lagalwar, Sarita

    2017-01-22

    Mitochondrial dysfunction plays a significant role in the aging process and in neurodegenerative diseases including several hereditary spinocerebellar ataxias and other movement disorders marked by progressive degeneration of the cerebellum. The goal of this protocol is to assess mitochondrial dysfunction in Spinocerebellar ataxia type 1 (SCA1) and assess the efficacy of pharmacological targeting of metabolic respiration via the water-soluble compound succinic acid to slow disease progression. This approach is applicable to other cerebellar diseases and can be adapted to a host of water-soluble therapies. Ex vivo analysis of mitochondrial respiration is used to detect and quantify disease-related changes in mitochondrial function. With genetic evidence (unpublished data) and proteomic evidence of mitochondrial dysfunction in the SCA1 mouse model, we evaluate the efficacy of treatment with the water-soluble metabolic booster succinic acid by dissolving this compound directly into the home cage drinking water. The ability of the drug to pass the blood brain barrier can be deduced using high performance liquid chromatography (HPLC). The efficacy of these compounds can then be tested using multiple behavioral paradigms including the accelerating rotarod, balance beam test and footprint analysis. Cytoarchitectural integrity of the cerebellum can be assessed using immunofluorescence assays that detect Purkinje cell nuclei and Purkinje cell dendrites and soma. These methods are robust techniques for determining mitochondrial dysfunction and the efficacy of treatment with water-soluble compounds in cerebellar neurodegenerative disease.

  7. Efficient programming of human eye conjunctiva-derived induced pluripotent stem (ECiPS) cells into definitive endoderm-like cells.

    PubMed

    Massumi, Mohammad; Hoveizi, Elham; Baktash, Parvaneh; Hooti, Abdollah; Ghazizadeh, Leili; Nadri, Samad; Pourasgari, Farzaneh; Hajarizadeh, Athena; Soleimani, Masoud; Nabiuni, Mohammad; Khorramizadeh, Mohammad R

    2014-03-10

    Due to pluripotency of induced pluripotent stem (iPS) cells, and the lack of immunological incompatibility and ethical issues, iPS cells have been considered as an invaluable cell source for future cell replacement therapy. This study was aimed first at establishment of novel iPS cells, ECiPS, which directly reprogrammed from human Eye Conjunctiva-derived Mesenchymal Stem Cells (EC-MSCs); second, comparing the inductive effects of Wnt3a/Activin A biomolecules to IDE1 small molecule in derivation of definitive endoderm (DE) from the ECiPS cells. To that end, first, the EC-MSCs were transduced by SOKM-expressing lentiviruses and characterized for endogenous expression of embryonic markers Then the established ECiPS cells were induced to DE formation by Wnt3a/Activin A or IDE1. Quantification of GSC, Sox17 and Foxa2 expression, as DE-specific markers, in both mRNA and protein levels revealed that induction of ECiPS cells by either Wnt3a/Activin A or IDE1 could enhance the expression level of the genes; however the levels of increase were higher in Wnt3a/Activin A induced ECiPS-EBs than IDE1 induced cells. Furthermore, the flow cytometry analyses showed no synergistic effect between Activin A and Wnt3a to derive DE-like cells from ECiPS cells. The comparative findings suggest that although both Wnt3a/Activin A signaling and IDE1 molecule could be used for differentiation of iPS into DE cells, the DE-inducing effect of Wnt3a/Activin A was statistically higher than IDE1. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Measuring Soluble ICAM-1 in African Populations

    PubMed Central

    Abdi, Abdirahman I.; Muthui, Michelle; Kiragu, Esther; Bull, Peter C.

    2014-01-01

    The level of plasma soluble ICAM-1 (sICAM-1) has been associated with the pathogenesis of several diseases. Previously, a commercial antibody was reported not to recognize an ICAM-1 allele known as ICAM-1kilifi prevalent among African populations. However, that study was based on 19 samples from African Americans of whom 13 had the wild type allele, five heterozygotes and one homozygote. Here, we compare plasma sICAM-1 measures using three different commercial antibodies in samples from Kenyan children genotyped for ICAM-1kilifi allele. We show that two of these antibodies have some degree of deficiency in detecting the ICAM-1kilifi allele. Consideration of the antibody used to measure sICAM-1 is important as up to 30% of the populations in Africa harbour this allele. PMID:25289635

  9. Hypoxic Vasospasm Mediated by cIMP: When Soluble Guanylyl Cyclase Turns Bad.

    PubMed

    Gao, Yuansheng; Chen, Zhengju; Leung, Susan W S; Vanhoutte, Paul M

    2015-06-01

    In a number of isolated blood vessel types, hypoxia causes an acute contraction that is dependent on the presence of nitric oxide and activation of soluble guanylyl cyclase. It is more pronounced when the preparations are constricted and is therefore termed hypoxic augmentation of vasoconstriction. This hypoxic response is accompanied by increases in the intracellular level of inosine 5'-triphosphate and in the synthesis of inosine 3',5'-cyclic monophosphate (cIMP) by soluble guanylyl cyclase. The administration of exogenous cIMP or inosine 5'-triphosphate causes augmented vasoconstriction to hypoxia. Furthermore, the vasoconstriction evoked by hypoxia and cIMP is associated with increased activity of Rho kinase (ROCK), indicating that cIMP may mediate the hypoxic effect by sensitizing the myofilaments to Ca through ROCK. Hypoxia is implicated in exaggerated vasoconstriction in the pathogenesis of coronary artery disease, myocardial infarction, hypertension, and stroke. The newly found role of cIMP may help to identify unique therapeutic targets for certain cardiovascular disorders.

  10. Solubility of α-Tocopheryl Succinate in Supercritical Carbon Dioxide Using Offline HPLC-MS/MS Analysis

    PubMed Central

    Hybertson, Brooks M.

    2010-01-01

    The solubility of the vitamin E-related compound α-tocopheryl succinate in supercritical carbon dioxide was measured at pressures ranging from (15.0 to 30.0) MPa and temperatures of (40 and 50) °C using a simple microsampling type apparatus with a 100.5 μL sample loop to remove aliquots and collect them in ethanol for off line analysis. α-Tocopheryl succinate concentrations in the collected samples were measured using HPLC-MS/MS analysis. The solubility of α-tocopheryl succinate in supercritical carbon dioxide ranged from mole fractions of 0.28 × 10−5 at 15.0 MPa and 50 °C to 2.56 × 10−5 at 30.0 MPa and 50 °C. PMID:20953319

  11. Structural characterization of alkali-soluble polysaccharides from Panax ginseng C. A. Meyer

    PubMed Central

    Ji, Li; Jie, Zhenjing; Ying, Xin; Yue, Qi; Zhou, Yifa

    2018-01-01

    Panax ginseng C. A. Meyer (ginseng) has been widely used as a herb and functional food in the world. Polysaccharides are the main active components of ginseng. In this paper, the polysaccharides were sequentially extracted by 50 mM Na2CO3, 1 M KOH and 4 M KOH from ginseng roots treated sequentially with hot water, α-amylase and ethylenediaminetetraacetic acid extraction. Na2CO3-soluble ginseng polysaccharide (NGP) was fractionated into one neutral and three acidic fractions by anion exchange and gel permeation chromatography. Fourier transform infrared, NMR and methylation analysis indicated acidic fractions in NGP were highly branched rhamnogalacturonan-I domains, with  → 4)-α-GalpA-(1 → 2)-α-Rhap-(1 → disaccharide repeating units as backbone and β-1,4-galactan, α-1,5/1,3,5-arabinan and type II arabinogalactan as side chains. 1-KGP (1 M KOH-soluble ginseng polysaccharide) and 4-KGP (4 M KOH-soluble ginseng polysaccharide) were mainly composed of hemicellulose besides starch-like polysaccharides and minor pectin. Antibody detection, enzymic hydrolysis, high performance anion exchange chromatography and methylation analysis demonstrated xylan was the major component in 1-KGP, while xyloglucan was predominant in 4-KGP. Comparing the polysaccharides obtained by different solvent extractions, we have a comprehensive understanding about total ginseng polysaccharides. PMID:29657770

  12. Water-soluble derivatives of 25-OCH3-PPD and their anti-proliferative activities.

    PubMed

    Zhou, Wu-Xi; Sun, Yuan-Yuan; Yuan, Wei-Hui; Zhao, Yu-Qing

    2017-05-01

    (20R)-25-Methoxyl-dammarane-3β,12β,20-triol (25-OCH 3 -PPD, AD-1) is a dammarane-type sapogenin showing anti-tumor potential. In the search for new anti-tumor agents with higher potency than our previously identified compound 25-OCH 3 -PPD, 11 novel sulfamic acid and diacid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 25-OCH 3 -PPD, compounds 1, 4, and 5 exhibited higher cytotoxic activity on almost all cell lines, together with lower toxicity in the normal cell. In particular, compound 1 exhibited the best anti-tumor activity in the in vitro assays. The water solubility of 25-OCH 3 -PPD and its derivatives was tested and the results showed that the solubility of 25-OCH 3 -PPD sulfamic acid and diacid derivatives were better than that of 25-OCH 3 -PPD in water, which may provide valuable data for the research and development of new anti-tumor agents. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Synthetic Method for Oligonucleotide Block by Using Alkyl-Chain-Soluble Support.

    PubMed

    Matsuno, Yuki; Shoji, Takao; Kim, Shokaku; Chiba, Kazuhiro

    2016-02-19

    A straightforward method for the synthesis of oligonucleotide blocks using a Cbz-type alkyl-chain-soluble support (Z-ACSS) attached to the 3'-OH group of 3'-terminal nucleosides was developed. The Z-ACSS allowed for the preparation of fully protected deoxyribo- and ribo-oligonucleotides without chromatographic purification and released dimer- to tetramer-size oligonucleotide blocks via hydrogenation using a Pd/C catalyst without significant loss or migration of protective groups such as 5'-end 4,4'-dimethoxtrityl, 2-cyanoethyl on internucleotide bonds, or 2'-TBS.

  14. A possible water-soluble inducer for synthesis of cellulase in Aspergillus niger.

    PubMed

    Zhang, Jian-Guo; Li, Qi-Meng; Thakur, Kiran; Faisal, Shah; Wei, Zhao-Jun

    2017-02-01

    The synthesis of cellulase in filamentous fungi can be triggered by several inducers. In this study, a bamboo-shoot shell pretreated with Pleurotus ostreatus could promote the formation of cellulases in Aspergillus niger. Further identification, including UPLC-TOF-MS, ultrafiltration, and FT-IR, denoted that the soluble inducer was not a traditional disaccharide but a type of modified lignin polymer. This revelation may result in incipient strategies to ameliorate cellulase productivity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Lefty Blocks a Subset of TGFβ Signals by Antagonizing EGF-CFC Coreceptors

    PubMed Central

    Cheng, Simon K; Olale, Felix; Brivanlou, Ali H

    2004-01-01

    Members of the EGF-CFC family play essential roles in embryonic development and have been implicated in tumorigenesis. The TGFβ signals Nodal and Vg1/GDF1, but not Activin, require EGF-CFC coreceptors to activate Activin receptors. We report that the TGFβ signaling antagonist Lefty also acts through an EGF-CFC-dependent mechanism. Lefty inhibits Nodal and Vg1 signaling, but not Activin signaling. Lefty genetically interacts with EGF-CFC proteins and competes with Nodal for binding to these coreceptors. Chimeras between Activin and Nodal or Vg1 identify a 14 amino acid region that confers independence from EGF-CFC coreceptors and resistance to Lefty. These results indicate that coreceptors are targets for both TGFβ agonists and antagonists and suggest that subtle sequence variations in TGFβ signals result in greater ligand diversity. PMID:14966532

  16. Effect of particle size on solubility, dissolution rate, and oral bioavailability: evaluation using coenzyme Q10 as naked nanocrystals

    PubMed Central

    Sun, Jiao; Wang, Fan; Sui, Yue; She, Zhennan; Zhai, Wenjun; Wang, Chunling; Deng, Yihui

    2012-01-01

    In this paper work, four naked nanocrystals (size range 80–700 nm) were prepared without any surfactant or polymer using the solvent/nonsolvent method. The effects of particle size on their solubility, dissolution, and oral bioavailability were investigated. Solubility and dissolution testing were performed in three types of dissolution medium, and the studies demonstrated that the equilibrium solubilities of coenzyme Q10 nanocrystals and bulk drugs were not affected by the dissolution media but the kinetic solubilities were. Kinetic solubility curves and changes in particle size distribution were determined and well explained by the proposed solubilization model for the nanocrystals and bulk drugs. The particle size effect on dissolution was clearly influenced by the diffusion coefficients of the various dissolution media, and the dissolution velocity of coenzyme Q10 increased as particle size decreased. The bioavailability of coenzyme Q10 after oral administration in beagle dogs was improved by reducing the particle size. For 700 nm nanocrystals, the AUC0–48 was 4.4-fold greater than that for the coarse suspensions, but a further decrease in particle size from 700 nm to 120 nm did not contribute to improvement in bioavailability until the particle size was reduced to 80 nm, when bioavailability was increased by 7.3-fold. PMID:23166438

  17. Calcium carbonate solubility: a reappraisal of scale formation and inhibition.

    PubMed

    Gal, J Y; Bollinger, J C; Tolosa, H; Gache, N

    1996-09-01

    Considerable disparity exists in the published thermodynamic data for selected species in the Ca(2+) /CO(2)/H(2)O system near 25 degrees C and 1 atm pressure. Some authors doubt the significance of CaCO(3)(0)aq) complexes although there is experimental evidence of their occurrence. Evaluation of all the published experimental and estimated data for aqueous calcium carbonate species confirms that the consistent set of constants given by Plummer and Busenberg in 1982 is the best available, and suggests a formation constant log beta = 3.22 for CaCO(3)(0)(aq). This value was confirmed by additional experimental data and calculations using a specially developed computer program. The solubility s and solubility product K(s) are critically evaluated for each solid polymorph (amorphous CaCO(3), ikaite, vaterite, aragonite and calcite) using a hydrated ion pair model and we give coherent explanations for the calcium carbonate precipitation/dissolution process and the existence of supersaturated waters. The practical cases of scale formation and its inhibition by phosphonate-type compounds are discussed and explained with the same model, taking into account the CaCO(3)(0)(aq) species.

  18. Water-Soluble Vitamin E-Tocopheryl Phosphate.

    PubMed

    Zingg, Jean-Marc

    The hydrophobicity of vitamin E poses transport and metabolic challenges to regulate its bioavailability and to prevent its accumulation in lipid-rich tissues such as adipose tissue, brain, and liver. Water-soluble precursors of vitamin E (α-tocopherol, αT), such as its esters with acetate (αTA), succinate (αTS), or phosphate (αTP), have increased solubility in water and stability against reaction with free radicals, but they are rapidly converted during their uptake into the lipid-soluble vitamin E. Therefore, the bioavailability of these precursors as intact molecules is low; nevertheless, at least for αTS and αTP, the recent research has revealed unique regulatory effects on signal transduction and gene expression and the modulation of cellular events ranging from proliferation, survival/apoptosis, lipid uptake and metabolism, phagocytosis, long term potentiation, cell migration, telomere maintenance, and angiogenesis. Moreover, water-soluble derivatives of vitamin E including some based on αTP are increasingly used as components of nanocarriers for enhanced and targeted delivery of drugs and other molecules (vitamins, including αT and αTP itself, vitamin D3, carnosine, caffeine, docosahexaenoic acid (DHA), insulin) and cofactors such as coenzyme Q10. In this review, the chemical characteristics, transport, metabolic pathways, and molecular mechanisms of action of αTP in cells and tissues are summarized and put into perspective with its possible role in the prevention of a number of diseases. © 2018 Elsevier Inc. All rights reserved.

  19. Biofiltration of Volatile Pollutants: Solubility Effects

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Davison, Brian H.; Barton, John W.

    2001-06-15

    This project investigates and collects fundamental partitioning data for a variety of sparingly soluble subsurface contaminants (e.g., TCE, etc.) between vapor, aqueous phase, and matrices containing substantial quantities of biomass and biomass components. Due to the difficulty of obtaining these measurements, environmental models have generally used solubility constants of chemicals in pure water or, in a few rare cases, simple linear models. Our prior EMSP work has shown that the presence of biological material can increase effective solubilities by an order of magnitude for sparingly soluble organics; therefore, the previous simple approaches are not valid and are extremely poor predictorsmore » of actual bio-influenced partitioning. It is likely that environmental contaminants will partition in a similar manner into high-biomass phases (e.g. biobarriers and plants) or humic soils. Biological material in the subsurface can include lipids, fatty acids, humic materials, as well a s the lumped and difficult to estimate 'biomass'. Our measurements include partition into these biological materials to allow better estimation. Fundamental data collected will be used in mathematical models predicting transport and sorption in subsurface environments, with the impacts on bioremediation being evaluated based on this new information. Our 2-D Win95/98 software program, Biofilter 1.0, developed as a part of our prior EMSP efforts for describing biofiltration processes with consideration given to both kinetic and mass transfer factors, will be extended to incorporate and use this information.« less

  20. Biofiltration of Volatile Pollutants: Solubility Effects

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Davison, Brian H.; Barton, John W.

    2002-06-15

    This project investigates and collects fundamental partitioning data for a variety of sparingly soluble subsurface contaminants (e.g., TCE, etc.) between vapor, aqueous phase, and matrices containing substantial quantities of biomass and biomass components. Due to the difficulty of obtaining these measurements, environmental models have generally used solubility constants of chemicals in pure water or, in a few rare cases, simple linear models. Our prior EMSP work has shown that the presence of biological material can increase effective solubilities by an order of magnitude for sparingly soluble organics; therefore, the previous simple approaches are not valid and are extremely poor predictorsmore » of actual bio-influenced partitioning. It is likely that environmental contaminants will partition in a similar manner into high-biomass phases (e.g. biobarriers and plants) or humic soils. Biological material in the subsurface can include lipids, fatty acids, humic materials, as well as the lumped and difficult-to-estimate 'biomass'. Our measurements include partition into these biological materials to allow better estimation. Fundamental data collected will be used in mathematical models predicting transport and sorption in subsurface environments, with the impacts on bioremediation being evaluated based on this new information. Our 2-D Win95/98/XP software program, Biofilter 1.0, developed as a part of our prior EMSP efforts for describing biofiltration processes with consideration given to both kinetic and mass transfer factors, is being extended to incorporate and use this information.« less

  1. Tough soluble aromatic thermoplastic copolyimides

    NASA Technical Reports Server (NTRS)

    Bryant, Robert G. (Inventor)

    2000-01-01

    Tough, soluble, aromatic, thermoplastic copolyimides were prepared by reacting 4,4'-oxydiphthalic anhydride, 3,4,3',4'-biphenyltetracarboxylic dianhydride and 3,4'-oxydianiline. Alternatively, these copolyimides may be prepared by reacting 4,4'-oxydiphthalic anhydride with 3,4,3',4'-biphenyltetracarboxylic dianhydride and 3,4'-oxydiisocyanate. Also, the copolyimide may be prepared by reacting the corresponding tetra acid and ester precursors of 4,4'-oxydiphthalic anhydride and 3,4,3',4'-biphenyltetracarboxylic dianhydride with 3,4'-oxydianiline. These copolyimides were found to be soluble in common amide solvents such as N,N'-dimethyl acetamide, N-methylpyrrolidinone, and dimethylformamide allowing them to be applied as the fully imidized copolymer and to be used to prepare a wide range of articles.

  2. The contribution of water soluble and water insoluble organic fractions to oxygen uptake rate during high rate composting.

    PubMed

    Giuliana, D'Imporzano; Fabrizio, Adani

    2007-02-01

    This study aims to establish the contribution of the water soluble and water insoluble organic fractions to total oxygen uptake rate during high rate composting process of a mixture of organic fraction of municipal solid waste and lignocellulosic material. This mixture was composted using a 20 l self-heating pilot scale composter for 250 h. The composter was fully equipped to record both the biomass-temperature and oxygen uptake rate. Representative compost samples were taken at 0, 70, 100, 110, 160, and 250 h from starting time. Compost samples were fractionated in water soluble and water insoluble fractions. The water soluble fraction was then fractionated in hydrophilic, hydrophobic, and neutral hydrophobic fractions. Each fraction was then studied using quantitative (total organic carbon) and qualitative analysis (diffuse reflectance infrared spectroscopy and biodegradability test). Oxygen uptake rates were high during the initial stages of the process due to rapid degradation of the soluble degradable organic fraction (hydrophilic plus hydrophobic fractions). Once this fraction was depleted, polymer hydrolysis accounted for most of the oxygen uptake rate. Finally, oxygen uptake rate could be modeled using a two term kinetic. The first term provides the oxygen uptake rate resulting from the microbial growth kinetic type on easily available, no-limiting substrate (soluble fraction), while the second term considers the oxygen uptake rate caused by the degradation of substrate produced by polymer hydrolysis.

  3. AW-101 entrained solids - Solubility versus temperature

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    GJ Lumetta; RC Lettau; GF Piepel

    This report describes the results of a test conducted by Battelle to assess the solubility of the solids entrained in the diluted AW-101 low-activity waste (LAW) sample. BNFL requested Battelle to dilute the AW-1-1 sample using de-ionized water to mimic expected plant operating conditions. BNFL further requested Battelle to assess the solubility of the solids present in the diluted AW-101 sample versus temperature conditions of 30, 40, and 50 C. BNFL requested these tests to assess the composition of the LAW supernatant and solids versus expected plant-operating conditions. The work was conducted according to test plan BNFL-TP-29953-7, Rev. 0, Determinationmore » of the Solubility of LAW Entrained Solids. The test went according to plan, with no deviations from the test plan.« less

  4. Resveratrol cocrystals with enhanced solubility and tabletability.

    PubMed

    Zhou, Zhengzheng; Li, Wanying; Sun, Wei-Jhe; Lu, Tongbu; Tong, Henry H Y; Sun, Changquan Calvin; Zheng, Ying

    2016-07-25

    Two new 1:1 cocrystals of resveratrol (RES) with 4-aminobenzamide (RES-4ABZ) and isoniazid (RES-ISN) were synthesized by liquid assisted grinding (LAG) and rapid solvent removal (RSR) methods using ethanol as solvent. Their physiochemical properties were characterized using PXRD, DSC, solid state and solution NMR, FT-IR, and HPLC. Pharmaceutically relevant properties, including tabletability, solubility, intrinsic dissolution rate, and hygroscopicity, were evaluated. Temperature-composition phase diagram for RES-ISN cocrystal system was constructed from DSC data. Both cocrystals show higher solubility than resveratrol over a broad range of pH. They are phase stable and non-hygroscopic even under high humidity conditions. Importantly, both cocrystals exhibit improved solubility and tabletability compared with RES, which make them more suitable candidates for tablet formulation development. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Antibacterial activities of peptides from the water-soluble extracts of Italian cheese varieties.

    PubMed

    Rizzello, C G; Losito, I; Gobbetti, M; Carbonara, T; De Bari, M D; Zambonin, P G

    2005-07-01

    Water-soluble extracts of 9 Italian cheese varieties that differed mainly for type of cheese milk, starter, technology, and time of ripening were fractionated by reversed-phase fast protein liquid chromatography, and the antimicrobial activity of each fraction was first assayed toward Lactobacillus sakei A15 by well-diffusion assay. Active fractions were further analyzed by HPLC coupled to electrospray ionization-ion trap mass spectrometry, and peptide sequences were identified by comparison with a proteomic database. Parmigiano Reggiano, Fossa, and Gorgonzola water-soluble extracts did not show antibacterial peptides. Fractions of Pecorino Romano, Canestrato Pugliese, Crescenza, and Caprino del Piemonte contained a mixture of peptides with a high degree of homology. Pasta filata cheeses (Caciocavallo and Mozzarella) also had antibacterial peptides. Peptides showed high levels of homology with N-terminal, C-terminal, or whole fragments of well known antimicrobial or multifunctional peptides reported in the literature: alphaS1-casokinin (e.g., sheep alphaS1-casein (CN) f22-30 of Pecorino Romano and cow alphaS1-CN f24-33 of Canestrato Pugliese); isracidin (e.g., sheep alphaS1-CN f10-21 of Pecorino Romano); kappacin and casoplatelin (e.g., cow kappa-CN f106-115 of Canestrato Pugliese and Crescenza); and beta-casomorphin-11 (e.g., goat beta-CN f60-68 of Caprino del Piemonte). As shown by the broth microdilution technique, most of the water-soluble fractions had a large spectrum of inhibition (minimal inhibitory concentration of 20 to 200 microg/mL) toward gram-positive and gram-negative bacterial species, including potentially pathogenic bacteria of clinical interest. Cheeses manufactured from different types of cheese milk (cow, sheep, and goat) have the potential to generate similar peptides with antimicrobial activity.

  6. A literature review of interaction of oxidized uranium species and uranium complexes with soluble organic matter

    USGS Publications Warehouse

    Jennings, Joan K.; Leventhal, J.S.

    1978-01-01

    Organic material is commonly found associated with uranium ores in sandstone-type deposits. This review of the literature summarizes the classes and separations of naturally occurring organic material but the emphasis is on soluble organic species. The main class of materials of interest is humic substances which are high-molecular-weight complex molecules that are soluble in alkaline solution. These humic substances are able to solubilize (make soluble) minerals and also to complex [by ion exchange and (or) chelation] many cations. The natural process of soil formation results in both mineral decomposition and element complexing by organic species. Uranium in solution, such as ground water, can form many species with other elements or complexes present depending on Eh and pH. In natural systems (oxidizing Eh, pH 5-9) the uranium is usually present as a complex with hydroxide or carbonate. Thermodynamic data for these species are presented. Interacting metals and organic materials have been observed in nature and studied in the laboratory by many workers in diverse scientific disciplines. The results are not easily compared. Measurements of the degree of complexation are reported as equilibrium stability constant determinations. This type of research has been done for Mn, Fe, Cu, Zn, Pb, Ni, Co, Mg, Ca, Al, and to a limited degree for U. The use of Conditional Stability Constants has given quantitative results in some cases. The methods utilized in experiments and calculations are reviewed.

  7. A Lab Experiment to Introduce Gas/Liquid Solubility

    ERIC Educational Resources Information Center

    Fonsecaa, I. M. A.; Almeida, J. P. B.; Fachada, H. C.

    2008-01-01

    A simplified version of a volumetric apparatus for gas/liquid solubility measurements is proposed. The procedure familiarizes undergraduate students with the experimental study of the solubility of a gas in a liquid and contributes to the understanding of this important phase equilibrium concept. The experimental results report the determination…

  8. Phenol-Soluble Modulin Toxins of Staphylococcus haemolyticus.

    PubMed

    Da, Fei; Joo, Hwang-Soo; Cheung, Gordon Y C; Villaruz, Amer E; Rohde, Holger; Luo, Xiaoxing; Otto, Michael

    2017-01-01

    Coagulase-negative staphylococci (CoNS) are important nosocomial pathogens and the leading cause of sepsis. The second most frequently implicated species, after Staphylococcus epidermidis , is Staphylococcus haemolyticus . However, we have a significant lack of knowledge about what causes virulence of S. haemolyticus , as virulence factors of this pathogen have remained virtually unexplored. In contrast to the aggressive pathogen Staphylococcus aureus , toxin production has traditionally not been associated with CoNS. Recent findings have suggested that phenol-soluble modulins (PSMs), amphipathic peptide toxins with broad cytolytic activity, are widespread in staphylococci, but there has been no systematic assessment of PSM production in CoNS other than S. epidermidis . Here, we identified, purified, and characterized PSMs of S. haemolyticus . We found three PSMs of the β-type, which correspond to peptides that before were described to have anti-gonococcal activity. We also detected an α-type PSM that has not previously been described. Furthermore, we confirmed that S. haemolyticus does not produce a δ-toxin, as results from genome sequencing had indicated. All four S. haemolyticus PSMs had strong pro-inflammatory activity, promoting neutrophil chemotaxis. Notably, we identified in particular the novel α-type PSM, S. haemolyticus PSMα, as a potent hemolysin and leukocidin. For the first time, our study describes toxins of this important staphylococcal pathogen with the potential to have a significant impact on virulence during blood infection and sepsis.

  9. Level-set simulations of soluble surfactant driven flows

    NASA Astrophysics Data System (ADS)

    Cleret de Langavant, Charles; Guittet, Arthur; Theillard, Maxime; Temprano-Coleto, Fernando; Gibou, Frédéric

    2017-11-01

    We present an approach to simulate the diffusion, advection and adsorption-desorption of a material quantity defined on an interface in two and three spatial dimensions. We use a level-set approach to capture the interface motion and a Quad/Octree data structure to efficiently solve the equations describing the underlying physics. Coupling with a Navier-Stokes solver enables the study of the effect of soluble surfactants that locally modify the parameters of surface tension on different types of flows. The method is tested on several benchmarks and applied to three typical examples of flows in the presence of surfactant: a bubble in a shear flow, the well-known phenomenon of tears of wine, and the Landau-Levich coating problem.

  10. Design of Chitosan and Its Water Soluble Derivatives-Based Drug Carriers with Polyelectrolyte Complexes

    PubMed Central

    Wu, Qing-Xi; Lin, Dong-Qiang; Yao, Shan-Jing

    2014-01-01

    Chitosan, the cationic polysaccharide derived from the natural polysaccharide chitin, has been studied as a biomaterial for more than two decades. As a polycationic polymer with favorable properties, it has been widely used to form polyelectrolyte complexes with polyanions for various applications in drug delivery fields. In recent years, a growing number of studies have been focused on the preparation of polyelectrolyte complexes based on chitosan and its water soluble derivatives. They have been considered well-suited as biomaterials for a number of vital drug carriers with targeted/controlled release profiles, e.g., films, capsules, microcapsules. In this work, an overview highlights not only the favorable properties of chitosan and its water soluble derivatives but also the good performance of the polyelectrolyte complexes produced based on chitosan. Their various types of applications as drug carriers are reviewed in detail. PMID:25532565

  11. Design of chitosan and its water soluble derivatives-based drug carriers with polyelectrolyte complexes.

    PubMed

    Wu, Qing-Xi; Lin, Dong-Qiang; Yao, Shan-Jing

    2014-12-19

    Chitosan, the cationic polysaccharide derived from the natural polysaccharide chitin, has been studied as a biomaterial for more than two decades. As a polycationic polymer with favorable properties, it has been widely used to form polyelectrolyte complexes with polyanions for various applications in drug delivery fields. In recent years, a growing number of studies have been focused on the preparation of polyelectrolyte complexes based on chitosan and its water soluble derivatives. They have been considered well-suited as biomaterials for a number of vital drug carriers with targeted/controlled release profiles, e.g., films, capsules, microcapsules. In this work, an overview highlights not only the favorable properties of chitosan and its water soluble derivatives but also the good performance of the polyelectrolyte complexes produced based on chitosan. Their various types of applications as drug carriers are reviewed in detail.

  12. Influence of biopolymers on the solubility of branched-chain amino acids and stability of their solutions.

    PubMed

    Hong, Chi Rac; Lee, Gyu Whan; Paik, Hyun-Dong; Chang, Pahn-Shick; Choi, Seung Jun

    2018-01-15

    This study confirmed the possibility of biopolymer-type stabilizers to increase the saturation concentration of branched-chain amino acids by preventing their crystallization/precipitation. Although microfluidization increased the initial solubility, it failed to increase the saturation concentration of the branched-chain amino acids. The saturation concentration of the branched-chain amino acids increased from 3.81% to 4.42% and 4.85% after the incorporation of food hydrocolloids and proteins, respectively. However, the branched-chain amino acids:stabilizer ratio did not affect the solubility. In the case of food hydrocolloid-based solutions, crystal formation and growth of branched-chain amino acids occurred during storage, resulting in the precipitation of branched-chain amino acid crystals. However, food proteins effectively increased the stability of the solubilized branched-chain amino acids. The improved solubility and stability of the solubilized branched-chain amino acids could be attributed to interactions between the functional groups (carboxyl, amine, sulfate, aliphatic, aromatic, etc.) of the stabilizer and the branched-chain amino acid molecules. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Fabrication and notable optical nonlinearities of ultrathin composite films derived from water-soluble Keggin-type polyoxometalates and water-insoluble phthalocyanine.

    PubMed

    Shehzad, Farooq Khurum; Qu, Ningning; Zhou, Yunshan; Zhang, Lijuan; Ji, Huanyao; Shi, Zonghai; Li, Jiaqi; Hassan, Sadaf Ul

    2016-11-28

    Composite films with the general formula (POM/CuTAPc) n derived from water-soluble Keggin-type polyoxometalates (POMs = H 5 PMo 10 V 2 O 40 , H 4 SiW 12 O 40 , H 3 PMo 12 O 40 and H 3 PW 12 O 40 ) and water-insoluble 4,9,16,23-copper tetraaminophthalocyanine (denoted CuTAPc) are successfully fabricated by a layer-by-layer self-assembly technique and systematically characterized. The structure of the polyoxometalate anions in the multilayers is kept intact; the deposition amounts of POM and CuTAPc remain constant in every adsorption cycle of the composite film assembly process. The nonlinear optical properties of the composite films were studied by a Z-scan technique at a wavelength of 532 nm and a pulse width of 7 ns. The results not only show that the composite films exhibit notable optical nonlinear self-defocusing behavior and a saturated absorption effect with the nonlinear optical absorption co-efficient β, refractive index n 2 , and third-order NLO susceptibility χ (3) of the films increasing with the increase in number of layers of the films, but also reveal importantly that the discrepancy of LUMO levels between CuTAPc and POMs is proportional to their third-order NLO response.

  14. Solubility of non-polar gases in electrolyte solutions

    NASA Technical Reports Server (NTRS)

    Walker, R. L., Jr.

    1970-01-01

    Solubility theory describes the effects of both concentration and temperature on solute activity coefficients. It predicts the salting-out effect and the decrease in solubility of non-polar gases with increased electrolyte concentration, and can be used to calculate heats of solution, entropies, and partial molal volumes of dissolved gases

  15. 21 CFR 520.44 - Acetazolamide sodium soluble powder.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Acetazolamide sodium soluble powder. 520.44... Acetazolamide sodium soluble powder. (a) Specifications. The drug is in a powder form containing acetazolamide sodium, USP equivalent to 25 percent acetazolamide activity. (b) Sponsor. See No. 053501 in § 510.600(c...

  16. 21 CFR 520.44 - Acetazolamide sodium soluble powder.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Acetazolamide sodium soluble powder. 520.44... Acetazolamide sodium soluble powder. (a) Specifications. The drug is in a powder form containing acetazolamide sodium, USP equivalent to 25 percent acetazolamide activity. (b) Sponsor. See No. 053501 in § 510.600(c...

  17. 21 CFR 520.44 - Acetazolamide sodium soluble powder.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Acetazolamide sodium soluble powder. 520.44... Acetazolamide sodium soluble powder. (a) Specifications. The drug is in a powder form containing acetazolamide sodium, USP equivalent to 25 percent acetazolamide activity. (b) Sponsor. See No. 053501 in § 510.600(c...

  18. Solubility of small-chain carboxylic acids in supercritical carbon dioxide

    DOE PAGES

    Sparks, Darrell L.; Estevez, L. Antonio; Hernandez, Rafael; ...

    2010-07-08

    The solubility of heptanoic acid and octanoic acid in supercritical carbon dioxide has been determined at temperatures of (313.15, 323.15, and 333.15) K over a pressure range of (8.5 to 30.0) MPa, depending upon the solute. The solubility of heptanoic acid ranged from a solute concentration of (0.08 ± 0.03) kg • m -3 (T = 323.15 K, p = 8.5 MPa) to (147 ± 0.2) kg • m -3 (T = 323.15 K, p = 20.0 MPa). The lowest octanoic acid solubility obtained was a solute concentration of (0.40 ± 0.1) kg • m -3 (T = 333.15 K,more » p = 10.0 MPa), while the highest solute concentration was (151 ± 2) kg • m -3 (T = 333.15 K, p = 26.7 MPa). In addition, solubility experiments were performed for nonanoic acid in supercritical carbon dioxide at 323.15 K and pressures of (10.0 to 30.0) MPa to add to the solubility data previously published by the authors. In general, carboxylic acid solubility increased with increasing solvent density. The results also showed that the solubility of the solutes decreased with increasing molar mass at constant supercritical-fluid density. Additionally, the efficacy of Chrastil's equation and other density-based models was evaluated for each fatty acid.« less

  19. Solubility of Plutonium (IV) Oxalate During Americium/Curium Pretreatment

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Rudisill, T.S.

    1999-08-11

    Approximately 15,000 L of solution containing isotopes of americium and curium (Am/Cm) will undergo stabilization by vitrification at the Savannah River Site (SRS). Prior to vitrification, an in-tank pretreatment will be used to remove metal impurities from the solution using an oxalate precipitation process. Material balance calculations for this process, based on solubility data in pure nitric acid, predict approximately 80 percent of the plutonium in the solution will be lost to waste. Due to the uncertainty associated with the plutonium losses during processing, solubility experiments were performed to measure the recovery of plutonium during pretreatment and a subsequent precipitationmore » process to prepare a slurry feed for a batch melter. A good estimate of the plutonium content of the glass is required for planning the shipment of the vitrified Am/Cm product to Oak Ridge National Laboratory (ORNL).The plutonium solubility in the oxalate precipitation supernate during pretreatment was 10 mg/mL at 35 degrees C. In two subsequent washes with a 0.25M oxalic acid/0.5M nitric acid solution, the solubility dropped to less than 5 mg/mL. During the precipitation and washing steps, lanthanide fission products in the solution were mostly insoluble. Uranium, and alkali, alkaline earth, and transition metal impurities were soluble as expected. An elemental material balance for plutonium showed that greater than 94 percent of the plutonium was recovered in the dissolved precipitate. The recovery of the lanthanide elements was generally 94 percent or higher except for the more soluble lanthanum. The recovery of soluble metal impurities from the precipitate slurry ranged from 15 to 22 percent. Theoretically, 16 percent of the soluble oxalates should have been present in the dissolved slurry based on the dilution effects and volumes of supernate and wash solutions removed. A trace level material balance showed greater than 97 percent recovery of americium-241 (from the

  20. Redesigning the type II' β-turn in green fluorescent protein to type I': implications for folding kinetics and stability.

    PubMed

    Madan, Bharat; Sokalingam, Sriram; Raghunathan, Govindan; Lee, Sun-Gu

    2014-10-01

    Both Type I' and Type II' β-turns have the same sense of the β-turn twist that is compatible with the β-sheet twist. They occur predominantly in two residue β-hairpins, but the occurrence of Type I' β-turns is two times higher than Type II' β-turns. This suggests that Type I' β-turns may be more stable than Type II' β-turns, and Type I' β-turn sequence and structure can be more favorable for protein folding than Type II' β-turns. Here, we redesigned the native Type II' β-turn in GFP to Type I' β-turn, and investigated its effect on protein folding and stability. The Type I' β-turns were designed based on the statistical analysis of residues in natural Type I' β-turns. The substitution of the native "GD" sequence of i+1 and i+2 residues with Type I' preferred "(N/D)G" sequence motif increased the folding rate by 50% and slightly improved the thermodynamic stability. Despite the enhancement of in vitro refolding kinetics and stability of the redesigned mutants, they showed poor soluble expression level compared to wild type. To overcome this problem, i and i + 3 residues of the designed Type I' β-turn were further engineered. The mutation of Thr to Lys at i + 3 could restore the in vivo soluble expression of the Type I' mutant. This study indicates that Type II' β-turns in natural β-hairpins can be further optimized by converting the sequence to Type I'. © 2014 Wiley Periodicals, Inc.

  1. The role of growth factors in embryonic induction in Xenopus laevis.

    PubMed

    Dawid, I B; Taira, M; Good, P J; Rebagliati, M R

    1992-06-01

    Establishment of the body pattern in all animals, and especially in vertebrate embryos, depends on cell interactions. During the cleavage and blastula stages in amphibians, signal(s) from the vegetal region induce the equatorial region to become mesoderm. Two types of peptide growth factors have been shown by explant culture experiments to be active in mesoderm induction. First, there are several isoforms of fibroblast growth factor (FGF), including aFGF, bFGF, and hst/kFGF. FGF induces ventral, but not the most dorsal, levels of mesodermal tissue; bFGF and its mRNA, and an FGF receptor and its mRNA, are present in the embryo. Thus, FGF probably has a role in mesoderm induction, but is unlikely to be the sole inducing agent in vivo. Second, members of the transforming growth factor-beta (TGF-beta) family. TGF-beta 2 and TGF-beta 3 are active in induction, but the most powerful inducing factors are the distant relatives of TGF-beta named activin A and activin B, which are capable of inducing all types of mesoderm. An important question relates to the establishment of polarity during the induction of mesoderm. While all regions of the animal hemisphere of frog embryos are competent to respond to activins by mesoderm differentiation, only explants that include cells close to the equator form structures with some organization along dorsoventral and anteroposterior axes. These observations suggest that cells in the blastula animal hemisphere are already polarized to some extent, although inducers are required to make this polarity explicit.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. A Novel Soluble Immune-Type Receptor (SITR) in Teleost Fish: Carp SITR Is Involved in the Nitric Oxide-Mediated Response to a Protozoan Parasite

    PubMed Central

    Ribeiro, Carla M. S.; Bird, Steve; Raes, Geert; Ghassabeh, Gholamreza H.; Schijns, Virgil E. J. C.; Pontes, Maria J. S. L.; Savelkoul, Huub F. J.; Wiegertjes, Geert F.

    2011-01-01

    Background The innate immune system relies upon a wide range of germ-line encoded receptors including a large number of immunoglobulin superfamily (IgSF) receptors. Different Ig-like immune receptor families have been reported in mammals, birds, amphibians and fish. Most innate immune receptors of the IgSF are type I transmembrane proteins containing one or more extracellular Ig-like domains and their regulation of effector functions is mediated intracellularly by distinct stimulatory or inhibitory pathways. Methodology/Principal Findings Carp SITR was found in a substracted cDNA repertoire from carp macrophages, enriched for genes up-regulated in response to the protozoan parasite Trypanoplasma borreli. Carp SITR is a type I protein with two extracellular Ig domains in a unique organisation of a N-proximal V/C2 (or I-) type and a C-proximal V-type Ig domain, devoid of a transmembrane domain or any intracytoplasmic signalling motif. The carp SITR C-proximal V-type Ig domain, in particular, has a close sequence similarity and conserved structural characteristics to the mammalian CD300 molecules. By generating an anti-SITR antibody we could show that SITR protein expression was restricted to cells of the myeloid lineage. Carp SITR is abundantly expressed in macrophages and is secreted upon in vitro stimulation with the protozoan parasite T. borreli. Secretion of SITR protein during in vivo T. borreli infection suggests a role for this IgSF receptor in the host response to this protozoan parasite. Overexpression of carp SITR in mouse macrophages and knock-down of SITR protein expression in carp macrophages, using morpholino antisense technology, provided evidence for the involvement of carp SITR in the parasite-induced NO production. Conclusion/Significance We report the structural and functional characterization of a novel soluble immune-type receptor (SITR) in a teleost fish and propose a role for carp SITR in the NO-mediated response to a protozoan parasite. PMID

  3. Determination of soluble sugar profile in rice.

    PubMed

    Hu, Xianqiao; Fang, Changyun; Lu, Lin; Hu, Zhanqiang; Shao, Yafang; Zhu, Zhiwei

    2017-07-15

    Soluble sugars in rice are the main components affecting sweetness taste of rice. In this paper, an accurate, precise and rapid method for simultaneous determination of multi soluble sugars in rice by using ion chromatography equipped with pulsed amperometric detector was presented. Pretreatment and parameters of ion chromatography and pulsed amperometric detector were optimized. Regression coefficients (R) of 0.9998, 1.0000, 0.9979, 0.9998 and 0.9998 were obtained for glucose, fructose, sucrose, raffinose and maltose, respectively. The recovery ranges of five sugars were 92.9-112.0% for milled rice matrix. Repeatability and reproducibility of the method were 0.8-9.7% and 1.9-7.6%, respectively. Method LODs of 3.1-34.6μgg -1 were obtained for soluble sugars in milled rice matrix. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Spectroscopic and solubility characteristics of oxidized soots

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chughtai, A.R.; Jassim, J.A.; Peterson, J.H.

    1991-01-01

    Spectroscopic and solubility studies of reaction products of soot (black carbon) with O{sub 3}, NO{sub 2}/N{sub 2}O{sub 4}, and SO{sub 2} have revealed a relationship between reactivity and product solubility and structure. A remarkably high solubility of ozonated n-hexane soot has its origin in the formation of anhydride and lactone surface structures and their subsequent hydrolysis to carboxylic acid species. Calculations indicate that the rate of surface carboxylation of 0.1-{mu}m diameter spheroidal soot particles, in the presence of 50 ppbv ozone at ambient temperature, is such that solubilization may occur within a 30-minute time frame. Measurements on ambient air aerosolmore » samples in metropolitan Denver are consistent with these observations and demonstrate the high reactivity of soot with ozone even at very low levels in natural systems.« less

  5. Polymeric Micelles and Alternative Nanonized Delivery Vehicles for Poorly Soluble Drugs

    PubMed Central

    Lu, Ying; Park, Kinam

    2013-01-01

    Poorly soluble drugs often encounter low bioavailability and erratic absorption patterns in the clinical setting. Due to the rising number of compounds having solubility issues, finding ways to enhance the solubility of drugs is one of the major challenges in the pharmaceutical industry today. Polymeric micelles, which form upon self-assembly of amphiphilic macromolecules, can act as solubilizing agents for delivery of poorly soluble drugs. This manuscript examines the fundamentals of polymeric micelles through reviews of representative literature and demonstrates possible applications through recent examples of clinical trial developments. In particular, the potential of polymeric micelles for delivery of poorly water-soluble drugs, especially in the areas of oral delivery and in cancer therapy, is discussed. Key considerations in utilizing polymeric micelles’ advantages and overcoming potential disadvantages have been highlighted. Lastly, other possible strategies related to particle size reduction for enhancing solubilization of poorly water-soluble drugs are introduced. PMID:22944304

  6. The apparent solubility of aluminum (III) in Hanford high-level waste.

    PubMed

    Reynolds, Jacob G

    2012-01-01

    The solubility of aluminum in Hanford nuclear waste impacts on the processability of the waste by a number of proposed treatment options. For many years, Hanford staff has anecdotally noted that aluminum appears to be considerably more soluble in Hanford waste than the simpler electrolyte solutions used as analogues. There has been minimal scientific study to confirm these anecdotal observations, however. The present study determines the apparent solubility product for gibbsite in 50 tank samples. The ratio of hydroxide to aluminum in the liquid phase for the samples is calculated and plotted as a function of total sodium molarity. Total sodium molarity is used as a surrogate for ionic strength, because the relative ratios of mono-, di- and trivalent anions are not available for all of the samples. These results were compared to the simple NaOH-NaAl(OH)(4)-H(2)O system, and the NaOH-NaAl(OH)(4)-NaCl-H(2)O system data retrieved from the literature. The results show that gibbsite is apparently more soluble in the samples than in the simple systems whenever the sodium molarity is greater than 2M. This apparent enhanced solubility cannot be explained solely by differences in ionic strength. The change in solubility with ionic strength in simple systems is small compared to the difference between aluminum solubility in Hanford waste and the simple systems. The reason for the apparent enhanced solubility is unknown, but could include kinetic or thermodynamic factors that are not present in the simple electrolyte systems. Any kinetic explanation would have to explain why the samples are always supersaturated whenever the sodium molarity is above 2M. Real waste characterization data should not be used to validate thermodynamic solubility models until it can be confirmed that the apparent enhanced gibbsite solubility is a thermodynamic effect and not a kinetic effect.

  7. Ferricyanide-based analysis of aqueous lignin suspension revealed sequestration of water-soluble lignin moieties

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Joshua, C. J.; Simmons, B. A.; Singer, S. W.

    This study describes the application of a ferricyanide-based assay as a simple and inexpensive assay for rapid analysis of aqueous lignin samples. The assay measures the formation of Prussian blue from the redox reaction between a mixture of potassium ferricyanide and ferric chloride, and phenolic hydroxyl groups of lignin or lignin-derived phenolic moieties. This study revealed that soluble lignin moieties exhibited stronger ferricyanide reactivity than insoluble aggregates. The soluble lignin moieties exhibited higher ferricyanide reactivity because of increased access of the phenolic hydroxyl groups to the ferricyanide reagents. Ferricyanide reactivity of soluble lignin moieties correlated inversely with the molecular weightmore » distributions of the molecules, probably due to the involvement of phenolic hydroxyl groups in bond formation. The insoluble lignin aggregates exhibited low ferricyanide reactivity due to sequestration of the phenolic hydroxyl groups within the solid matrix. The study also highlighted the sequestration of polydispersed water-soluble lignin moieties by insoluble aggregates. The sequestered moieties were released by treatment with 0.01 M NaOH at 37 °C for 180 min. The redox assay was effective on different types of lignin extracts such as Klason lignin from switchgrass, ionic-liquid derived lignin from Eucalyptus and alkali lignin extracts. The assay generated a distinct profile for each lignin sample that was highly reproducible. The assay was also used to monitor consumption of syringic acid by Sphingobium sp. SYK-6. The simplicity and reproducibility of this assay makes it an excellent and versatile tool for qualitative and semi-quantitative characterization and comparative profiling of aqueous lignin samples.« less

  8. Ferricyanide-based analysis of aqueous lignin suspension revealed sequestration of water-soluble lignin moieties

    DOE PAGES

    Joshua, C. J.; Simmons, B. A.; Singer, S. W.

    2016-06-02

    This study describes the application of a ferricyanide-based assay as a simple and inexpensive assay for rapid analysis of aqueous lignin samples. The assay measures the formation of Prussian blue from the redox reaction between a mixture of potassium ferricyanide and ferric chloride, and phenolic hydroxyl groups of lignin or lignin-derived phenolic moieties. This study revealed that soluble lignin moieties exhibited stronger ferricyanide reactivity than insoluble aggregates. The soluble lignin moieties exhibited higher ferricyanide reactivity because of increased access of the phenolic hydroxyl groups to the ferricyanide reagents. Ferricyanide reactivity of soluble lignin moieties correlated inversely with the molecular weightmore » distributions of the molecules, probably due to the involvement of phenolic hydroxyl groups in bond formation. The insoluble lignin aggregates exhibited low ferricyanide reactivity due to sequestration of the phenolic hydroxyl groups within the solid matrix. The study also highlighted the sequestration of polydispersed water-soluble lignin moieties by insoluble aggregates. The sequestered moieties were released by treatment with 0.01 M NaOH at 37 °C for 180 min. The redox assay was effective on different types of lignin extracts such as Klason lignin from switchgrass, ionic-liquid derived lignin from Eucalyptus and alkali lignin extracts. The assay generated a distinct profile for each lignin sample that was highly reproducible. The assay was also used to monitor consumption of syringic acid by Sphingobium sp. SYK-6. The simplicity and reproducibility of this assay makes it an excellent and versatile tool for qualitative and semi-quantitative characterization and comparative profiling of aqueous lignin samples.« less

  9. Bioenergetics and the role of soluble cytochromes C for alkaline adaptation in gram-negative alkaliphilic Pseudomonas.

    PubMed

    Matsuno, T; Yumoto, I

    2015-01-01

    Very few studies have been conducted on alkaline adaptation of Gram-negative alkaliphiles. The reversed difference of H(+) concentration across the membrane will make energy production considerably difficult for Gram-negative as well as Gram-positive bacteria. Cells of the alkaliphilic Gram-negative bacterium Pseudomonas alcaliphila AL15-21(T) grown at pH 10 under low-aeration intensity have a soluble cytochrome c content that is 3.6-fold higher than that of the cells grown at pH 7 under high-aeration intensity. Cytochrome c-552 content was higher (64% in all soluble cytochromes c) than those of cytochrome c-554 and cytochrome c-551. In the cytochrome c-552-dificient mutant grown at pH 10 under low-aeration intensity showed a marked decrease in μ max⁡ [h(-1)] (40%) and maximum cell turbidity (25%) relative to those of the wild type. Considering the high electron-retaining abilities of the three soluble cytochromes c, the deteriorations in the growth of the cytochrome c-552-deficient mutant could be caused by the soluble cytochromes c acting as electron storages in the periplasmic space of the bacterium. These electron-retaining cytochromes c may play a role as electron and H(+) condenser, which facilitate terminal oxidation at high pH under air-limited conditions, which is difficult to respire owing to less oxygen and less H(+).

  10. Bioenergetics and the Role of Soluble Cytochromes c for Alkaline Adaptation in Gram-Negative Alkaliphilic Pseudomonas

    PubMed Central

    Matsuno, T.; Yumoto, I.

    2015-01-01

    Very few studies have been conducted on alkaline adaptation of Gram-negative alkaliphiles. The reversed difference of H+ concentration across the membrane will make energy production considerably difficult for Gram-negative as well as Gram-positive bacteria. Cells of the alkaliphilic Gram-negative bacterium Pseudomonas alcaliphila AL15-21T grown at pH 10 under low-aeration intensity have a soluble cytochrome c content that is 3.6-fold higher than that of the cells grown at pH 7 under high-aeration intensity. Cytochrome c-552 content was higher (64% in all soluble cytochromes c) than those of cytochrome c-554 and cytochrome c-551. In the cytochrome c-552-dificient mutant grown at pH 10 under low-aeration intensity showed a marked decrease in μ max⁡ [h−1] (40%) and maximum cell turbidity (25%) relative to those of the wild type. Considering the high electron-retaining abilities of the three soluble cytochromes c, the deteriorations in the growth of the cytochrome c-552-deficient mutant could be caused by the soluble cytochromes c acting as electron storages in the periplasmic space of the bacterium. These electron-retaining cytochromes c may play a role as electron and H+ condenser, which facilitate terminal oxidation at high pH under air-limited conditions, which is difficult to respire owing to less oxygen and less H+. PMID:25705691

  11. Increased serum soluble corin in dyslipidemia: A cross-sectional study.

    PubMed

    Wang, Xiaolei; Chen, Shi; Zhang, Qiu; Liu, Yan; Liu, Lu; Li, Huiling; Peng, Hao

    2015-10-23

    Natriuretic peptides have been associated with dyslipidemia. As a physiological activator of natriuretic peptides, corin might also be associated with dyslipidemia. However, this association has not yet been studied in Chinese populations. Serum soluble corin and blood lipid profiles were determined for 2496 participants aged above 30y. A logistic regression model was applied to evaluate the association between serum soluble corin and dyslipidemia. Serum soluble corin was significantly increased in participants with dyslipidemia in both men (P<0.001) and women (P<0.001). After controlling for the confounding factors, OR of dyslipidemia positively increased with increasing levels of serum soluble corin in men (P for trend=0.011) and women (P for trend=0.043). Participants with a high corin level were more likely to have dyslipidemia than those with a low corin level in men (OR, 95% CI: 1.45, 1.07-1.97) and women (OR, 95% CI: 1.33, 1.04-1.70). Serum soluble corin was significantly and positively associated with dyslipidemia. Our findings suggested that serum soluble corin may be a marker or risk factor for dyslipidemia. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Solubility and precipitation of nicotinic acid in supercritical carbon dioxide.

    PubMed

    Rehman, M; Shekunov, B Y; York, P; Colthorpe, P

    2001-10-01

    Solubilities of a model compound (nicotinic acid) in pure supercritical carbon dioxide (SC-CO(2)) and SC-CO(2) modified with methanol have been measured in the pressure range of 80-200 bar and between temperatures of 35 and 90 degrees C. On-line ultraviolet detection enabled a simple and relatively fast measurement of very low levels of solubility (10(-7) mol fraction) with good accuracy in pure and modified SC-CO(2). The solute solubility in both pure SC-CO(2) and SC-CO(2) modified with methanol increased with pressure at all investigated temperatures. A retrograde solubility behavior was observed in that, at pressures below 120 bar, a solubility decrease on temperature increase occurred. Solubility data were used to calculate supersaturation values and to define optimum operating conditions to obtain crystalline particles 1-5 microm in diameter using the solution-enhanced dispersion by supercritical fluids (SEDS) process, thereby demonstrating the feasibility of a one-step production process for particulate pharmaceuticals suitable for respiratory drug delivery. Copyright 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1570-1582, 2001

  13. Metal Oxide Solubility and Molten Salt Corrosion.

    DTIC Science & Technology

    1982-03-29

    METAL OXIDE SOLUBILITY AND MOLTEN SALT CORROSION .(U) MAR 82 K H STERN UNCLASSI E DL R L-4772NL EL .2. MICROCOPY RESOLUTION TEST CHART NATIONAL BURALU...21 l 7 3 ..... l DTIC NSPECT I" ’I cCPY INSECE( METAL OXIDE SOLUBILITY AND MOLTEN SALT CORROSION I. INTRODUCTION Molten ...discussed in terms of its importance to the understanding of molten salt corrosion . II. PROTECTIVE COATINGS Since most structural metals and alloys are

  14. The remedial effect of soluble interleukin-1 receptor type II on endometriosis in the nude mouse model.

    PubMed

    Gao, Liying; Sun, Liang; Cui, Yugui; Hou, Zhen; Gao, Li; Zhou, Jing; Mao, Yundong; Han, Suping; Liu, Jiayin

    2010-01-01

    Recent studies have shown that the local expression of soluble interleukin (IL) -1 receptor type II (sIL-1 RII) in endometrial tissue of women with endometriosis is decreased, and the depression of IL-1 RII was more significant in infertile women than that in fertile women with endometriosis. In this research, we investigated the remedial effect of sIL-1-RII administration on endometriosis in the nude mouse model. NINETEEN NUDE MODEL MICE WITH ENDOMETRIOSIS WERE RANDOMLY DIVIDED INTO THREE GROUPS: group A was treated by intraperitoneal administration with only sIL-1 RII for two weeks, group B was similarly treated with only IL-1, and group C (control) was administered saline . After 2 weeks, the size of the ectopic endometrial lesions was calculated, and the expression of vascular endothelial growth factor (VEGF) and B-cell lymphoma leukemia-2 (Bcl-2) were detected by immunohistochemistry. The IL-8 and VEGF levels in the peritoneal fluid (PF) and serum were also measured by enzyme-linked immunosorbent assay (ELISA). The mean size of ectopic endometrial lesion did not differ between the three groups (P > 0.05). Compared with the control, the expression of VEGF and Bcl-2 was significantly lower in group A, and higher in group B. In the three groups, the levels of IL-8 in the PF and serum were highest in group A, and lowest in group B. sIL-1 RII may suppresse hyperplasia of ectopic endometriosis, perhaps by reducing the expression of certain cytokines, such as VEGF, IL-8, and Bcl-2, which could provide a new clinical strategy for the treatment of endometriosis.

  15. Molecular Simulation of Gas Solubility in Nitrile Butadiene Rubber.

    PubMed

    Khawaja, M; Sutton, A P; Mostofi, A A

    2017-01-12

    Molecular simulation is used to compute the solubility of small gases in nitrile butadiene rubber (NBR) with a Widom particle-insertion technique biased by local free volume. The convergence of the method is examined as a function of the number of snapshots upon which the insertions are performed and the number of insertions per snapshot and is compared to the convergence of the unbiased Widom insertion technique. The effect of varying the definition of local free volume is also investigated. The acrylonitrile content of the polymer is altered to examine its influence on the solubility of helium, CO 2 , and H 2 O, and the solubilities of polar gases are found to be enhanced relative to those of nonpolar gases, in qualitative agreement with experiment. To probe this phenomenon further, the solubilities are decomposed into contributions from the neighborhoods of different atoms, using a Voronoi cell construction, and a strong bias is found for CO 2 and H 2 O in particular to be situated near nitrogen sites in the elastomer. Temperature is shown to suppress the solubility of CO 2 and H 2 O but to increase that of helium. Increasing pressure is found to suppress the solubility of all gases but at different rates, according to a balance between their molecular sizes and electrostatic interactions with the polymer. These results are relevant to the use of NBR seals at elevated temperatures and pressures, such as in oil and gas wells.

  16. Solubility behavior of lamivudine crystal forms in recrystallization solvents.

    PubMed

    Jozwiakowski, M J; Nguyen, N A; Sisco, J M; Spancake, C W

    1996-02-01

    Lamivudine can be obtained as acicular crystals (form I, 0.2 hydrate) from water or methanol and as bipyramidal crystals (form II, nonsolvated) from many nonaqueous solvents. Form II is thermodynamically favored in the solid state (higher melting point and greater density than form I) at ambient relative humidities. Solubility measurements on both forms versus solvent and temperature was used to determine whether entropy or enthalpy was the driving force for solubility. Solution calorimetry data indicated that form I is favored (less soluble) in all solvents studied on the basis of enthalpy alone. In higher alcohols and other organic solvents, form I has a larger entropy of solution than form II, which compensates for the enthalpic factors and results in physical stability for form II in these systems. The metastable crystal form solubility at 25 degrees C was estimated to be 1.2-2.3 times as high as the equilibrium solubility of the stable form, depending on the temperature, solvent, and crystal form. Binary solvent studies showed that > 18-20% water must be present in ethanol to convert the excess solid to form I at equilibrium.

  17. Soluble Endoglin (CD105) Serum Level as a Potential Marker in the Management of Head and Neck Paragangliomas.

    PubMed

    Litwiniuk, Małgorzata; Niemczyk, Kazimierz; Niderla-Bielińska, Justyna; Łukawska-Popieluch, Izabela; Grzela, Tomasz

    2017-10-01

    To assess the expression of endoglin in head and neck paragangliomas and the soluble endoglin level in serum of paraganglioma patients. Seven tumor samples of patients operated for cervical paraganglioma were assessed, as well as serum samples collected preoperatively, on days 4 and 28 postoperation. Serum level of endoglin in healthy controls was also determined. Tumor samples were subjected to immunofluorescent staining and examined with confocal microscope. The level of soluble endoglin in serum samples was examined using the immunoenzymatic assay (ELISA). Endoglin was highly expressed in all tumor samples. The level of soluble endoglin was significantly higher in paraganglioma patients compared to healthy controls and correlated with the tumor size. The serum level of s-endoglin was reduced after surgical excision of the tumor and remained stable after 4 weeks in all patients with complete resection of the tumor. Endoglin is an important factor in the pathophysiology of head and neck paragangliomas and may be a potential diagnostic and prognostic marker in these types of tumors.

  18. Curcumin loaded nano globules for solubility enhancement: preparation, characterization and ex vivo release study.

    PubMed

    Kumar, Anil; Ahuja, Alka; Ali, Javed; Baboota, Sanjula

    2012-11-01

    Curcumin in spite of being an effective chemotherapeutic agent against different type of cancer, suffer from the problem of low systemic bioavailability due to low aqueous solubility, extensive intestinal metabolism and first-pass metabolism when administered via the oral route. The aim of present investigation was to evaluate the potential of nano globules based nanoemulsion formulation for the solubility enhancement of curcumin. The nano globules based formulation was developed using Labrafac Lipophile WL 1349, Unitop FFT 40, PEG 400 and distilled water as an oil, surfactant, co-surfactant and aqueous phase respectively using aqueous titration method. Furthermore, different formulations were subjected to physical stability and consequently evaluated for ex vivo permeation using small intestine. The optimized formulation had small average globule diameter of 58 nm with zeta potential of -32 mv which indicated long-term dispersion stability. The globules were spherical in shape as observed by Transmission electron microscopy. During ex vivo study, the release of curcumin from nanoemulsion was 96.21% and 98.1% in 6 h and 12 h respectively whereas CU suspension was release up to 28.2% at the end of 12 h. This indicated the enhancement of solubility of curcumin in aqueous solution which is the rate limiting step in the absorption of curcumin in the intestine.

  19. The solubility of gold in silicate melts: First results

    NASA Technical Reports Server (NTRS)

    Borisov, A.; Palme, H.; Spettel, B.

    1993-01-01

    The effects of oxygen fugacity and temperature on the solubility of Au in silicate melts were determined. Pd-Au alloys were equilibrated with silicate of anorthite-diopside eutectic composition at different T-fO2 conditions. The behavior of Au was found to be similar to that of Pd reported recently. Au solubilities for alloys with 30 to 40 at. percent Au decrease at 1400 C from 12 ppm in air to 160 ppb at a log fO2 = -8.7. The slope of the log(Me-solubility) vs. log(fO2) curve is close to 1/4 for Au and the simultaneously determined Pd suggesting a formal valence of Au and Pd of 1+. Near the IW buffer Pd and Au solubilities become even less dependent on fO2 perhaps reflecting the presence of some metallic Au and Pd.

  20. The Evaluation of Water Sorption/Solubility on Various Acrylic Resins

    PubMed Central

    Tuna, Suleyman Hakan; Keyf, Filiz; Gumus, Hasan Onder; Uzun, Cengiz

    2008-01-01

    Objectives The absorption of water by acrylic resins is a phenomenon of considerable importance since it is accompanied by dimensional changes, a further undesirable effect of absorbed water in acrylic resins to reduce the tensile strength of the material. Solubility is also an important property because it represents the mass of soluble materials from the polymers. Methods Ten acrylic resin-based materials were evaluated: two heat cure acrylic resins (De Trey QC-20, Meliodent Heat Cure) and eight self cure acrylic resins (Meliodent Cold, Akrileks, Akribel, Akribel Transparent, Vertex Trayplast, Formatray, Dentalon Plus, Palavit G). To evaluate water sorption and water solubility, thirty square-shaped specimens (20×20×1.5 mm) were fabricated from the wax specimens. One way ANOVA test, Tukey test and Pearson correlation coefficient performed for data. Results Water sorption mean values varied from 11.33±0.33 to 30.46±0.55 μg/mm3. Water solubility mean values varied from −0.05±0.23 to 3.69±0.12 μg/mm3. There was statistically significant difference between mean values of the materials (P<.05). There was no linear correlation between sorption and solubility values. Conclusions The results of the water sorption and water solubility values of both self-cured and heat-cured acrylic resins were in accordance with the ISO specification. No correlation found between water sorption and water solubility values. PMID:19212546

  1. Update in pediatrics: focus on fat-soluble vitamins.

    PubMed

    Sathe, Meghana N; Patel, Ashish S

    2010-08-01

    This article provides an update on fat-soluble vitamins (A, D, E, and K) in the healthy pediatric population and in children with chronic disease states that commonly cause deficiencies, specifically cystic fibrosis and cholestatic liver disease. For each fat-soluble vitamin, the biological function, nutrition availability, absorption, deficiency, toxic states, and monitoring parameters are defined.

  2. Influence of mechanical and chemical polishing in the solubility of acrylic resins polymerized by microwave irradiation and conventional water bath.

    PubMed

    Machado, Cristiane; Rizzatti-Barbosa, Célia M; Gabriotti, Morgana N; Joia, Fábio A; Ribeiro, Margarete C; Sousa, Rodrigo L S

    2004-07-01

    The aim of this work was to evaluate the solubility of acrylic resin activated by microwave irradiation (MI) or water bath (WB), when submitted to chemical (CP) or mechanical (MP) polishing. Forty acrylic resin samples were made and processed either by water bath (74 +/- 1 degrees C, 9 h) or microwave irradiation (500 W, 3 min). After deflasking, the samples were finished with aluminum oxide sandpapers in decreasing granulations till reaching similar dimensions. The samples were divided into four groups according to the association between kind of polymerization and polishing: A (WB + CP), B (WB + MP), C (MI + CP) and D (MI + MP). Solubility test was performed for each group and percentile solubility was calculated. Data were statistically analyzed using variance analysis and Kruskal-Wallis. The average of percentile solubility (%) was obtained: A = 0.07, B = 0.02, C = 0.04, D = -0.14, however, no significant difference was found between types of polishing in the samples polymerized by water bath (A and B). When processed by microwave irradiation (C and D), there was significant difference between the applied methods of polishing, so that mechanical polishing lead to a lower solubility. Solubility is a property of acrylic resins, representing not reacted substances releasing that could promote tissular reactions in prosthesis users. The association between polymerization by microwave irradiation and mechanical polishing showed less residual substances releasing for heat-cured acrylic resins, reducing the probability of developing tissular reactions.

  3. Correlation of Helium Solubility in Liquid Nitrogen

    NASA Technical Reports Server (NTRS)

    VanDresar, Neil T.; Zimmerli, Gregory A.

    2012-01-01

    A correlation has been developed for the equilibrium mole fraction of soluble gaseous helium in liquid nitrogen as a function of temperature and pressure. Experimental solubility data was compiled and provided by National Institute of Standards and Technology (NIST). Data from six sources was used to develop a correlation within the range of 0.5 to 9.9 MPa and 72.0 to 119.6 K. The relative standard deviation of the correlation is 6.9 percent.

  4. Supercritical fluid particle design for poorly water-soluble drugs (review).

    PubMed

    Sun, Yongda

    2014-01-01

    Supercritical fluid particle design (SCF PD) offers a number of routes to improve solubility and dissolution rate for enhancing the bioavailability of poorly water-soluble drugs, which can be adopted through an in-depth knowledge of SCF PD processes and the molecular properties of active pharmaceutical ingredients (API) and drug delivery system (DDS). Combining with research experiences in our laboratory, this review focuses on the most recent development of different routes (nano-micron particles, polymorphic particles, composite particles and bio-drug particles) to improve solubility and dissolution rate of poorly water-soluble drugs, covering the fundamental concept of SCF and the principle of SCF PD processes which are typically used to control particle size, shape, morphology and particle form and hence enable notable improvement in the dissolution rate of the poorly water-soluble drugs. The progress of the industrialization of SCF PD processes in pharmaceutical manufacturing environment with scaled-up plant under current good manufacturing process (GMP) specification is also considered in this review.

  5. Gas solubility in dilute solutions: A novel molecular thermodynamic perspective

    NASA Astrophysics Data System (ADS)

    Chialvo, Ariel A.

    2018-05-01

    We present an explicit molecular-based interpretation of the thermodynamic phase equilibrium underlying gas solubility in liquids, through rigorous links between the microstructure of the dilute systems and the relevant macroscopic quantities that characterize their solution thermodynamics. We apply the formal analysis to unravel and highlight the molecular-level nature of the approximations behind the widely used Krichevsky-Kasarnovsky [J. Am. Chem. Soc. 57, 2168 (1935)] and Krichevsky-Ilinskaya [Acta Physicochim. 20, 327 (1945)] equations for the modeling of gas solubility. Then, we implement a general molecular-based approach to gas solubility and illustrate it by studying Lennard-Jones binary systems whose microstructure and thermodynamic properties were consistently generated via integral equation calculations. Furthermore, guided by the molecular-based analysis, we propose a novel macroscopic modeling approach to gas solubility, emphasize some usually overlook modeling subtleties, and identify novel interdependences among relevant solubility quantities that can be used as either handy modeling constraints or tools for consistency tests.

  6. Gas solubility in dilute solutions: A novel molecular thermodynamic perspective.

    PubMed

    Chialvo, Ariel A

    2018-05-07

    We present an explicit molecular-based interpretation of the thermodynamic phase equilibrium underlying gas solubility in liquids, through rigorous links between the microstructure of the dilute systems and the relevant macroscopic quantities that characterize their solution thermodynamics. We apply the formal analysis to unravel and highlight the molecular-level nature of the approximations behind the widely used Krichevsky-Kasarnovsky [J. Am. Chem. Soc. 57, 2168 (1935)] and Krichevsky-Ilinskaya [Acta Physicochim. 20, 327 (1945)] equations for the modeling of gas solubility. Then, we implement a general molecular-based approach to gas solubility and illustrate it by studying Lennard-Jones binary systems whose microstructure and thermodynamic properties were consistently generated via integral equation calculations. Furthermore, guided by the molecular-based analysis, we propose a novel macroscopic modeling approach to gas solubility, emphasize some usually overlook modeling subtleties, and identify novel interdependences among relevant solubility quantities that can be used as either handy modeling constraints or tools for consistency tests.

  7. The solubility parameter for biomedical polymers-Application of inverse gas chromatography.

    PubMed

    Adamska, K; Voelkel, A; Berlińska, A

    2016-08-05

    The solubility parameter seems to be a useful tool for thermodynamic characterisation of different materials. The solubility parameter concept can be used to predict sufficient miscibility or solubility between a solvent and a polymer, as well as components of co-polymer matrix in composite biomaterials. The values of solubility parameter were determined for polycaprolactone (PCL), polylactic acid (PLA) and polyethylene glycol (PEG) by using different procedures and experimental data, collected by means of inverse gas chromatography. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. High levels of the soluble form of CD30 molecule in rheumatoid arthritis (RA) are expression of CD30+ T cell involvement in the inflamed joints.

    PubMed Central

    Gerli, R; Muscat, C; Bistoni, O; Falini, B; Tomassini, C; Agea, E; Tognellini, R; Biagini, P; Bertotto, A

    1995-01-01

    The CD30 is a surface molecule expressed by Th2-type lymphokine-producing T cells upon activation. CD30-expressing activated T cells release a soluble form of the molecule, which can be detectable both in vitro and in vivo. In the present study, high levels of soluble CD30 were found in peripheral blood and synovial fluid from patients with RA. However, CD30+ CD3+ cells, either CD4+ or CD8+, were significantly present in synovial fluid, but not in peripheral blood, of RA patients. Serum values of soluble CD30 were higher in active than inactive RA patients and directly correlated with rheumatoid factor serum titres. These data strongly support an involvement of CD30+ T cells in the immune processes of rheumatoid synovitis, and may suggest a relationship between Th2-type cytokine-secreting T cells and the pathological response in RA. PMID:8536371

  9. Illustrating the Concept of Sparingly Soluble Salts Using Various Copper Compounds: A Classroom Demonstration

    ERIC Educational Resources Information Center

    O'Sullivan, Daniel W.; Crouch, Collier C.

    2009-01-01

    Many students in general and advanced chemistry courses have difficulty understanding differences in solubility by inspecting changing values of the solubility product constants for sparingly soluble salts. In this demonstration, the concepts involved in understanding the solubility of sparingly soluble salts are illustrated visually. Utilizing…

  10. Thermodynamic Solubility Profile of Carbamazepine-Cinnamic Acid Cocrystal at Different pH.

    PubMed

    Keramatnia, Fatemeh; Shayanfar, Ali; Jouyban, Abolghasem

    2015-08-01

    Pharmaceutical cocrystal formation is a direct way to dramatically influence physicochemical properties of drug substances, especially their solubility and dissolution rate. Because of their instability in the solution, thermodynamic solubility of cocrystals could not be determined in the common way like other compounds; therefore, the thermodynamic solubility is calculated through concentration of their components in the eutectic point. The objective of this study is to investigate the effect of an ionizable coformer in cocrystal with a nonionizable drug at different pH. Carbamazepine (CBZ), a nonionizable drug with cinnamic acid (CIN), which is an acidic coformer, was selected to prepare CBZ-CIN cocrystal and its thermodynamic solubility was studied in pH range 2-7. Instead of HPLC that is a costly and time-consuming method, a chemometric-based approach, net analyte signal standard addition method, was selected for simultaneous determination of CBZ and CIN in solution. The result showed that, as pH increases, CIN ionization leads to change in CBZ-CIN cocrystal solubility and stability in solution. In addition, the results of this study indicated that there is no significant difference between intrinsic solubility of CBZ and cocrystal despite the higher ideal solubility of cocrystal. This verifies that ideal solubility is not good parameter to predict cocrystal solubility. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  11. Human soluble phospholipase A2 receptor is an inhibitor of the integrin-mediated cell migratory response to collagen-I.

    PubMed

    Watanabe, Kazunori; Watanabe, Kazuhiro; Watanabe, Yosuke; Fujioka, Daisuke; Nakamura, Takamitsu; Nakamura, Kazuto; Obata, Jun-Ei; Kugiyama, Kiyotaka

    2018-05-23

    Murine membrane-bound phospholipase A 2 receptor 1 (PLA 2 R) is shed and released into plasma in a soluble form that retains all of the extracellular domains. Relatively little is known about human PLA 2 R. This study examined whether human soluble PLA 2 R may have biological functions and whether soluble PLA 2 R may exist in human plasma. Here, we showed that human recombinant soluble PLA 2 R (rsPLA 2 R) bound to collagen-I and inhibited interaction of collagen-I with the extracellular domain of integrin β1 on the cell surface of HEK293 cells. As a result, rsPLA 2 R suppressed integrin β1-mediated migratory responses of HEK293 cells to collagen-I in Boyden chamber experiments. Inhibition of phosphorylation of FAK Tyr397 was also observed. Similar results were obtained with experiments using soluble PLA 2 R released from HEK293 cells transfected with a construct encoding human soluble PLA 2 R. rsPLA 2 R lacking the fibronectin-like type II (FNII) domain had no inhibitory effects on cell responses to collagen-I, suggesting an important role of the FNII domain in the interaction of rsPLA 2 R with collagen-I. In addition, rsPLA 2 R suppressed the migratory response to collagen-IV and binding of collagen-IV to the cell surface of human podocytes that endogenously express membrane-bound full-length PLA 2 R. Immunoprecipitation and Western blotting showed the existence of immuno-reactive PLA 2 R in human plasma. In conclusion, human recombinant soluble PLA 2 R inhibits integrin β1-mediated cell responses to collagens. Further studies are warranted to elucidate whether immuno-reactive PLA 2 R in human plasma has the same properties as rsPLA 2 R.

  12. Diagnostic value of decoy receptor 3 combined with procalcitonin and soluble urokinase-type plasminogen activator receptor for sepsis.

    PubMed

    Zhao, Jing-Jing; Lou, Xiao-Li; Chen, Hong-Wei; Zhu, Feng-Ting; Hou, Yan-Qiang

    2018-01-01

    The levels of decoy receptor 3 (DcR3), soluble urokinase type plasminogen activator receptor (suPAR) and procalcitonin (PCT) are significantly increased in sepsis. We investigated the diagnostic value of DcR3 combined with suPAR and PCT in sepsis. Patients with sepsis, non-infectious systemic inflammatory response comprehensive syndrome (SIRS) and healthy controls were recruited according to the diagnostic standard. We measured DcR3, suPAR, PCT, interleukin-6 (IL-6) and C-reactive protein (CRP), and the diagnostic value was evaluated by receiver operating characteristics (ROC) curves. In our analysis, serum DcR3, suPAR and PCT levels of the sepsis group were significantly higher than those of the SIRS and control groups. However, IL-6, CRP and WBC showed no significant difference between the SIRS group and the sepsis group. The serum DcR3 level was positively correlated with the serum suPAR level ( r  = 0.37, p  = 0.0022) and PCT level ( r  = 0.37, p  = 0.0021). Using DcR3, suPAR and PCT to distinguish SIRS from sepsis, the area under the curve (AUC) values were 0.892, 0.778 and 0.692. When DcR3, suPAR and PCT combined were used for diagnosis of sepsis, the AUC was 0.933, at a cut-off point of 0.342. This combination improved the sensitivity and specificity of diagnosis of sepsis, suggesting that use of the combination of three indexes enhanced the efficiency of sepsis diagnosis.

  13. Statistical investigation of simulated intestinal fluid composition on the equilibrium solubility of biopharmaceutics classification system class II drugs.

    PubMed

    Khadra, Ibrahim; Zhou, Zhou; Dunn, Claire; Wilson, Clive G; Halbert, Gavin

    2015-01-25

    , with again drug specific effects evident. This indicates that a drug's equilibrium solubility in SIF is influenced depending upon drug type by between eight to fourteen individual or combinations of media components with some of these drug specific. This illustrates the complex nature of these fluids and provides for individual drugs a visualisation of the possible solubility envelope within the gastrointestinal tract, which may be of importance for modelling in vivo behaviour. In addition the results indicate that the design of experiment approach can be employed to provide greater detail of drug solubility behaviour, possible drug specific interactions and influence of variations in gastrointestinal media components due to disease. The approach is also feasible and amenable to adaptation for high throughput screening of drug candidates. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Identification of number and type of cations in water-soluble Cs+ and Na+ calix[4]arene-bis-crown-6 complexes by using ESI-TOF-MS.

    PubMed

    Kumagai, Shogo; Hayashi, Kotaro; Kameda, Tomohito; Morohashi, Naoya; Hattori, Tetsutaro; Yoshioka, Toshiaki

    2018-04-01

    The treatment of cesium-contaminated wastewater has become one of the biggest issues. The selective Cs + removal from wastewater containing competitive alkali metal ions such as Na + is desired to reduce the volume of sludge. Therefore, the present work focused on water-soluble calix[4]arene-bis-crown-6 (W-BisC6) to selectively capture Cs + . For characterization of the complex, UV-vis spectroscopy is commonly used, however, due to the limited availability of information it can be hard to quickly identify the specific structures of some complexes. In this work, the electrospray ionization time of flight spectrometry (ESI-TOF-MS) is successfully utilized to identify the number and type of cations in W-BisC6-cation complexes. ESI-TOF-MS accurately recognized 4 types of complex (W-BisC6-Na + , W-BisC6-Cs + , W-BisC6-2Na + , W-BisC6-Na + -Cs + ), and the experimental and simulated results were almost perfectly matched. It also revealed the difficulty of W-BisC6-2Cs + complex formation under the present conditions. Thus, this technique is significantly helpful for rapid identification of the specific structures of complexes during Cs + -contaminated wastewater treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.

  15. Heat-induced alterations in cashew allergen solubility and IgE binding.

    PubMed

    Mattison, Christopher P; Bren-Mattison, Yvette; Vant-Hull, Barry; Vargas, Aurora M; Wasserman, Richard L; Grimm, Casey C

    2016-01-01

    Cashew nuts are an increasingly common cause of food allergy. We compare the soluble protein profile of cashew nuts following heating. SDS-PAGE indicate that heating can alter the solubility of cashew nut proteins. The 11S legumin, Ana o 2, dominates the soluble protein content in ready to eat and mildly heated cashew nuts. However, we found that in dark-roasted cashew nuts, the soluble protein profile shifts and the 2S albumin Ana o 3 composes up to 40% of the soluble protein. Analysis of trypsin-treated extracts by LC/MS/MS indicate changes in the relative number and intensity of peptides. The relative cumulative intensity of the 5 most commonly observed Ana o 1 and 2 peptides are altered by heating, while those of the 5 most commonly observed Ana o 3 peptides remaine relatively constant. ELISA experiments indicate that there is a decrease in rabbit IgG and human serum IgE binding to soluble cashew proteins following heating. Our findings indicate that heating can alter the solubility of cashew allergens, resulting in altered IgE binding. Our results support the use of both Ana o 2 and Ana o 3 as potential cashew allergen diagnostic targets.

  16. "JCE" Classroom Activity #105. A Sticky Situation: Chewing Gum and Solubility

    ERIC Educational Resources Information Center

    Montes-Gonzalez, Ingrid; Cintron-Maldonado, Jose A.; Perez-Medina, Ilia E.; Montes-Berrios, Veronica; Roman-Lopez, Saurie N.

    2010-01-01

    In this Activity, students perform several solubility tests using common food items such as chocolate, chewing gum, water, sugar, and oil. From their observations during the Activity, students will initially classify the substances tested as soluble or insoluble. They will then use their understanding of the chemistry of solubility to classify the…

  17. Facilitating protein solubility by use of peptide extensions

    DOEpatents

    Freimuth, Paul I; Zhang, Yian-Biao; Howitt, Jason

    2013-09-17

    Expression vectors for expression of a protein or polypeptide of interest as a fusion product composed of the protein or polypeptide of interest fused at one terminus to a solubility enhancing peptide extension are provided. Sequences encoding the peptide extensions are provided. The invention further comprises antibodies which bind specifically to one or more of the solubility enhancing peptide extensions.

  18. The apparent solubility of aluminum (III) in Hanford high-level waste

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Reynolds, Jacob G.

    2012-12-01

    The solubility of aluminum in Hanford nuclear waste impacts on the process ability of the waste by a number of proposed treatment options. For many years, Hanford staff has anecdotally noted that aluminum appears to be considerably more soluble in Hanford waste than the simpler electrolyte solutions used as analogues. There has been minimal scientific study to confirm these anecdotal observations, however. The present study determines the apparent solubility product for gibbsite in 50 tank samples. The ratio of hydroxide to aluminum in the liquid phase for the samples is calculated and plotted as a function of total sodium molarity.more » Total sodium molarity is used as a surrogate for ionic strength, because the relative ratios of mono, di and trivalent anions are not available for all of the samples. These results were compared to the simple NaOH-NaAl(OH{sub 4})H{sub 2}O system, and the NaOH-NaAl(OH{sub 4})NaCl-H{sub 2}O system data retrieved from the literature. The results show that gibbsite is apparently more soluble in the samples than in the simple systems whenever the sodium molarity is greater than two. This apparent enhanced solubility cannot be explained solely by differences in ionic strength. The change in solubility with ionic strength in simple systems is small compared to the difference between aluminum solubility in Hanford waste and the simple systems. The reason for the apparent enhanced solubility is unknown, but could include. kinetic or thermodynamic factors that are not present in the simple electrolyte systems. Any kinetic explanation would have to explain why the samples are always supersaturated whenever the sodium molarity is above two. Real waste characterization data should not be used to validate thermodynamic solubility models until it can be confirmed that the apparent enhanced gibbsite solubility is a thermodynamic effect and not a kinetic effect.« less

  19. Bioinspired co-crystals of Imatinib providing enhanced kinetic solubility.

    PubMed

    Reggane, Maude; Wiest, Johannes; Saedtler, Marco; Harlacher, Cornelius; Gutmann, Marcus; Zottnick, Sven H; Piechon, Philippe; Dix, Ina; Müller-Buschbaum, Klaus; Holzgrabe, Ulrike; Meinel, Lorenz; Galli, Bruno

    2018-05-04

    Realizing the full potential of co-crystals enhanced kinetic solubility demands a comprehensive understanding of the mechanisms of dissolution, phase conversion, nucleation and crystal growth, and of the complex interplay between the active pharmaceutical ingredient (API), the coformer and co-existing forms in aqueous media. One blueprint provided by nature to keep poorly water-soluble bases in solution is the complexation with phenolic acids. Consequently, we followed a bioinspired strategy for the engineering of co-crystals of a poorly water-soluble molecule - Imatinib - with a phenolic acid, syringic acid (SYA). The dynamics of dissolution and solution-mediated phase transformations were monitored by Nuclear Magnetic Resonance (NMR) spectroscopy, providing mechanistic insights into the 60 fold-increased long lasting concentrations achieved by the syringate co-crystals as compared to Imatinib base and Imatinib mesylate. This lasting effect was linked to SYA's ability to delay the formation and nucleation of Imatinib hydrate - the thermodynamically stable form in aqueous media - through a metastable association of SYA with Imatinib in solution. Results from permeability studies evidenced that SYA did not impact Imatinib's permeability across membranes while suggesting improved bioavailability through higher kinetic solubility at the biological barriers. These results reflect that some degree of hydrophobicity of the coformer might be key to extend the kinetic solubility of co-crystals with hydrophobic APIs. Understanding how kinetic supersaturation can be shaped by the selection of an interactive coformer may help achieving the needed performance of new forms of poorly water-soluble, slowly dissolving APIs. Copyright © 2018. Published by Elsevier B.V.

  20. A soluble NADH-dependent fumarate reductase in the reductive tricarboxylic acid cycle of Hydrogenobacter thermophilus TK-6.

    PubMed

    Miura, Akane; Kameya, Masafumi; Arai, Hiroyuki; Ishii, Masaharu; Igarashi, Yasuo

    2008-11-01

    Fumarate reductase (FRD) is an enzyme that reduces fumarate to succinate. In many organisms, it is bound to the membrane and uses electron donors such as quinol. In this study, an FRD from a thermophilic chemolithoautotrophic bacterium, Hydrogenobacter thermophilus TK-6, was purified and characterized. FRD activity using NADH as an electron donor was not detected in the membrane fraction but was found in the soluble fraction. The purified enzyme was demonstrated to be a novel type of FRD, consisting of five subunits. One subunit showed high sequence identity to the catalytic subunits of known FRDs. Although the genes of typical FRDs are assembled in a cluster, the five genes encoding the H. thermophilus FRD were distant from each other in the genome. Furthermore, phylogenetic analysis showed that the H. thermophilus FRD was located in a distinct position from those of known soluble FRDs. This is the first report of a soluble NADH-dependent FRD in Bacteria and of the purification of a FRD that operates in the reductive tricarboxylic acid cycle.

  1. Solubility of glucose isomerase in ammonium sulphate solutions

    NASA Astrophysics Data System (ADS)

    Chayen, N.; Akins, J.; Campbell-Smith, S.; Blow, D. M.

    1988-07-01

    In order to quantify protein crystallization techniques, a method for measuring protein solubility in high salt concentration has been developed. It is based on a sensitive protein concentration assay, using binding to Coomassie blue dye. The protein concentration in a supernatant from which glucose isomerase is crystallising has been studied as a function of time. Equilibrium is established in 3-5 weeks, and the protein concentration remaining in solution is defined as the solubility of the protein. The solubility of glucose isomerase has been determined as a function of ammonium sulphate concentration; its variation with pH in 1.50M ammonium sulphate has also been studied. A remarkable dependence on pH over the range of 5.5 to 6.5 has been observed.

  2. Fat-Soluble Vitamins: Clinical Indications and Current Challenges for Chromatographic Measurement

    PubMed Central

    Albahrani, Ali A.; Greaves, Ronda F.

    2016-01-01

    Fat-soluble vitamins, including vitamins A, D and E, are required for a wide variety of physiological functions. Over the past two decades, deficiencies of these vitamins have been associated with increased risk of cancer, type II diabetes mellitus and a number of immune system disorders. In addition, there is increasing evidence of interactions between these vitamins, especially between vitamins A and D. As a result of this enhanced clinical association with disease, translational clinical research and laboratory requests for vitamin measurements have significantly increased. These laboratory requests include measurement of 25-OHD (vitamin D), retinol (vitamin A) and α-tocopherol (vitamin E); the most accepted blood indicators for the assessment of body fat-soluble vitamin (FSV) status. There are significant obstacles to precise FSV measurement in blood. These obstacles include their physical and chemical properties, incomplete standardisation of measurement and limitations in the techniques that are currently used for quantification. The aim of this review is to briefly outline the metabolism and interactions of FSV as a prelude to identifying the current challenges for the quantification of blood vitamins A, D and E. PMID:27057076

  3. Fat-Soluble Vitamins: Clinical Indications and Current Challenges for Chromatographic Measurement.

    PubMed

    Albahrani, Ali A; Greaves, Ronda F

    2016-02-01

    Fat-soluble vitamins, including vitamins A, D and E, are required for a wide variety of physiological functions. Over the past two decades, deficiencies of these vitamins have been associated with increased risk of cancer, type II diabetes mellitus and a number of immune system disorders. In addition, there is increasing evidence of interactions between these vitamins, especially between vitamins A and D. As a result of this enhanced clinical association with disease, translational clinical research and laboratory requests for vitamin measurements have significantly increased. These laboratory requests include measurement of 25-OHD (vitamin D), retinol (vitamin A) and α-tocopherol (vitamin E); the most accepted blood indicators for the assessment of body fat-soluble vitamin (FSV) status. There are significant obstacles to precise FSV measurement in blood. These obstacles include their physical and chemical properties, incomplete standardisation of measurement and limitations in the techniques that are currently used for quantification. The aim of this review is to briefly outline the metabolism and interactions of FSV as a prelude to identifying the current challenges for the quantification of blood vitamins A, D and E.

  4. Towards improved solubility of poorly water-soluble drugs: cryogenic co-grinding of piroxicam with carrier polymers.

    PubMed

    Penkina, Anna; Semjonov, Kristian; Hakola, Maija; Vuorinen, Sirpa; Repo, Timo; Yliruusi, Jouko; Aruväli, Jaan; Kogermann, Karin; Veski, Peep; Heinämäki, Jyrki

    2016-01-01

    Amorphous solid dispersions (SDs) open up exciting opportunities in formulating poorly water-soluble active pharmaceutical ingredients (APIs). In the present study, novel catalytic pretreated softwood cellulose (CPSC) and polyvinylpyrrolidone (PVP) were investigated as carrier polymers for preparing and stabilizing cryogenic co-ground SDs of poorly water-soluble piroxicam (PRX). CPSC was isolated from pine wood (Pinus sylvestris). Raman and Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) were used for characterizing the solid-state changes and drug-polymer interactions. High-resolution scanning electron microscope (SEM) was used to analyze the particle size and surface morphology of starting materials and final cryogenic co-ground SDs. In addition, the molecular aspects of drug-polymer interactions and stabilization mechanisms are presented. The results showed that the carrier polymer influenced both the degree of amorphization of PRX and stabilization against crystallization. The cryogenic co-ground SDs prepared from PVP showed an enhanced dissolution rate of PRX, while the corresponding SDs prepared from CPSC exhibited a clear sustained release behavior. In conclusion, cryogenic co-grinding provides a versatile method for preparing amorphous SDs of poorly water-soluble APIs. The solid-state stability and dissolution behavior of such co-ground SDs are to a great extent dependent on the carrier polymer used.

  5. On the solubility of gallium nitride in supercritical ammonia-sodium solutions

    NASA Astrophysics Data System (ADS)

    Griffiths, Steven; Pimputkar, Siddha; Speck, James S.; Nakamura, Shuji

    2016-12-01

    Due to the disparity between observed gallium nitride (GaN) growth under conditions for which literature reports normal solubility, GaN solubility in supercritical NH3-Na containing solutions was re-evaluated. Isothermal gravimetric experiments on polycrystalline GaN were performed in the temperature range (T =415-650 °C) for which retrograde growth of GaN routinely occurs (P ≈ 200 MPa, molar NH3:Na fill ratio =20:1). Two previously-unreported error contributions to the gravimetric determination of GaN solubility were identified: Ga-alloying of exposed Ni-containing components, and the presence of a dense, Ga-absorbing Na-rich, second phase under these conditions. Due to the inability to measure Ga-alloying of the exposed autoclave wall for each experiment, considerable scatter was introduced in the refined GaN solubility curve. No clear dependence of GaN solubility on temperature was resolvable, while most solubility values were determined to be within a band of 0.03-0.10 mol% GaN, normalized by fill NH3.

  6. Direct growth of high crystallinity graphene from water-soluble polymer powders

    NASA Astrophysics Data System (ADS)

    Chen, Qiao; Zhong, Yujia; Huang, Meirong; Zhao, Guoke; Zhen, Zhen; Zhu, Hongwei

    2018-07-01

    The use of solid-state carbon sources is effective to produce graphene by safe and low-cost chemical vapor deposition (CVD) process. Water-soluble polymers are generally environmentally friendly and have great potential on large-scale green production of graphene. Here, we systematically study the growth of graphene from water-soluble polymers on copper foils. Two different conversion ways are adopted to investigate the growth mechanism of graphene from water-soluble polymers. We find that the metal-binding functional group hydroxyl strongly influences the vaporization of water-soluble polymers on Cu foils, which hinders the formation of graphene films by rapid thermal treatment. In direct CVD process using water-soluble polymer powders as precursors, oxygenated functional groups in polymers can enhance the crystallinity of as-grown graphene in contrast to solid hydrocarbons without containing oxygen (e.g. polyethylene). Large and continuous graphene films of high quality are synthesized from polyvinyl alcohol and polyethylene glycol. Nitrogen doping in graphene can be easily realized by using nitrogen-containing water-soluble polymers (e.g. polyvinyl pyrrolidone).

  7. Buckminsterfullerene's (C60) octanol-water partition coefficient (Kow) and aqueous solubility.

    PubMed

    Jafvert, Chad T; Kulkarni, Pradnya P

    2008-08-15

    To assess the risk and fate of fullerene C60 in the environment, its water solubility and partition coefficients in various systems are useful. In this study, the log Kow of C60 was measured to be 6.67, and the toluene-water partition coefficient was measured at log Ktw = 8.44. From these values and the respective solubilities of C60 in water-saturated octanol and water-saturated toluene, C60's aqueous solubility was calculated at 7.96 ng/L(1.11 x 10(-11) M) for the organic solvent-saturated aqueous phase. Additionally, the solubility of C60 was measured in mixtures of ethanol-water and tetrahydrofuran-water and modeled with Wohl's equation to confirm the accuracy of the calculated solubility value. Results of a generator column experiment strongly support the hypothesis that clusters form at aqueous concentrations below or near this calculated solubility. The Kow value is compared to those of other hydrophobic organic compounds, and bioconcentration factors for C60 were estimated on the basis of Kow.

  8. Gaseous Sulfate Solubility in Glass: Experimental Method

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bliss, Mary

    2013-11-30

    Sulfate solubility in glass is a key parameter in many commercial glasses and nuclear waste glasses. This report summarizes key publications specific to sulfate solubility experimental methods and the underlying physical chemistry calculations. The published methods and experimental data are used to verify the calculations in this report and are expanded to a range of current technical interest. The calculations and experimental methods described in this report will guide several experiments on sulfate solubility and saturation for the Hanford Waste Treatment Plant Enhanced Waste Glass Models effort. There are several tables of sulfate gas equilibrium values at high temperature tomore » guide experimental gas mixing and to achieve desired SO3 levels. This report also describes the necessary equipment and best practices to perform sulfate saturation experiments for molten glasses. Results and findings will be published when experimental work is finished and this report is validated from the data obtained.« less

  9. Solubility limits in quaternary SnTe-based alloys [Metastability and solubility limits in quaternary SnTe-based alloys guided by combinatorial sputtering

    DOE PAGES

    Siol, Sebastian; Holder, Aaron; Ortiz, Brenden R.; ...

    2017-05-09

    Here, the controlled decomposition of metastable alloys is an attractive route to form nanostructured thermoelectric materials with reduced thermal conductivity. The ternary SnTe–MnTe and SnTe–SnSe heterostructural alloys have been demonstrated as promising materials for thermoelectric applications. In this work, the quaternary Sn 1–yMnyTe 1–xSe x phase space serves as a relevant model system to explore how a combination of computational and combinatorial-growth methods can be used to study equilibrium and non-equilibrium solubility limits. Results from first principle calculations indicate low equilibrium solubility for x,y < 0.05 that are in good agreement with results obtained from bulk equilibrium synthesis experiments andmore » predict significantly higher spinodal limits. An experimental screening using sputtered combinatorial thin film sample libraries showed a remarkable increase in non-equilibrium solubility for x,y > 0.2. These theoretical and experimental results were used to guide the bulk synthesis of metastable alloys. The ability to reproduce the non-equilibrium solubility levels in bulk materials indicates that such theoretical calculations and combinatorial growth can inform bulk synthetic routes. Further, the large difference between equilibrium and non-equilibrium solubility limits in Sn 1–yMn yTe 1–xSe x indicates these metastable alloys are attractive in terms of nano-precipitate formation for potential thermoelectric applications.« less

  10. Phenol-Soluble Modulin Toxins of Staphylococcus haemolyticus

    PubMed Central

    Da, Fei; Joo, Hwang-Soo; Cheung, Gordon Y. C.; Villaruz, Amer E.; Rohde, Holger; Luo, Xiaoxing; Otto, Michael

    2017-01-01

    Coagulase-negative staphylococci (CoNS) are important nosocomial pathogens and the leading cause of sepsis. The second most frequently implicated species, after Staphylococcus epidermidis, is Staphylococcus haemolyticus. However, we have a significant lack of knowledge about what causes virulence of S. haemolyticus, as virulence factors of this pathogen have remained virtually unexplored. In contrast to the aggressive pathogen Staphylococcus aureus, toxin production has traditionally not been associated with CoNS. Recent findings have suggested that phenol-soluble modulins (PSMs), amphipathic peptide toxins with broad cytolytic activity, are widespread in staphylococci, but there has been no systematic assessment of PSM production in CoNS other than S. epidermidis. Here, we identified, purified, and characterized PSMs of S. haemolyticus. We found three PSMs of the β-type, which correspond to peptides that before were described to have anti-gonococcal activity. We also detected an α-type PSM that has not previously been described. Furthermore, we confirmed that S. haemolyticus does not produce a δ-toxin, as results from genome sequencing had indicated. All four S. haemolyticus PSMs had strong pro-inflammatory activity, promoting neutrophil chemotaxis. Notably, we identified in particular the novel α-type PSM, S. haemolyticus PSMα, as a potent hemolysin and leukocidin. For the first time, our study describes toxins of this important staphylococcal pathogen with the potential to have a significant impact on virulence during blood infection and sepsis. PMID:28596942

  11. Aqueous solubility of calcium L-lactate, calcium D-gluconate, and calcium D-lactobionate: importance of complex formation for solubility increase by hydroxycarboxylate mixtures.

    PubMed

    Vavrusova, Martina; Munk, Merete Bøgelund; Skibsted, Leif H

    2013-08-28

    Among the calcium hydroxycarboxylates important for cheese quality, D-lactobionate [Ksp = (7.0 ± 0.3) × 10(-3) mol(3) L(-3)] and L-lactate [Ksp = (5.8 ± 0.2) × 10(-3) mol(3) L(-3)] were found more soluble than D-gluconate [Ksp = (7.1 ± 0.2) × 10(-4) mol(3) L(-3)], as indicated by the solubility products determined electrochemically for aqueous 1.0 M NaCl at 25.0 °C. Still, solubility of calcium L-lactate increases by 45% in the presence of 0.50 M sodium D-gluconate and by 37% in the presence of 0.50 M sodium D-lactobionate, while solubility of calcium D-gluconate increases by 66 and 85% in the presence of 0.50 M sodium L-lactate and 0.50 M sodium D-lactobionate, respectively, as determined by complexometric titration. Sodium L-lactate and sodium D-gluconate have only little influence on solubility of calcium D-lactobionate. The increased solubility is described quantitatively by calcium binding to D-gluconate (K1 = 14 ± 3 mol(-1) L) in 1.0 M NaCl at 25 °C, D-lactobionate (K1 = 11 ± 2 mol(-1) L), and L-lactate (K1 = 8 ± 2 mol(-1) L), as indicated by the association constants determined electrochemically. In mixed hydroxycarboxylate solutions, calcium binding is quantitatively described by the geometric mean of the individual association constants for both aqueous 1.0 and 0.20 M NaCl, indicating a 1:1 stoichiometry for complex formation.

  12. Data representing two separate LC-MS methods for detection and quantification of water-soluble and fat-soluble vitamins in tears and blood serum.

    PubMed

    Khaksari, Maryam; Mazzoleni, Lynn R; Ruan, Chunhai; Kennedy, Robert T; Minerick, Adrienne R

    2017-04-01

    Two separate liquid chromatography (LC)-mass spectrometry (MS) methods were developed for determination and quantification of water-soluble and fat-soluble vitamins in human tear and blood serum samples. The water-soluble vitamin method was originally developed to detect vitamins B 1 , B 2 , B 3 (nicotinamide), B 5 , B 6 (pyridoxine), B 7 , B 9 and B 12 while the fat-soluble vitamin method detected vitamins A, D 3 , 25(OH)D 3, E and K 1 . These methods were then validated with tear and blood serum samples. In this data in brief article, we provide details on the two LC-MS methods development, methods sensitivity, as well as precision and accuracy for determination of vitamins in human tears and blood serum. These methods were then used to determine the vitamin concentrations in infant and parent samples under a clinical study which were reported in "Determination of Water-Soluble and Fat-Soluble Vitamins in Tears and Blood Serum of Infants and Parents by Liquid Chromatography/Mass Spectrometry DOI:10.1016/j.exer.2016.12.007 [1]". This article provides more details on comparison of vitamin concentrations in the samples with the ranges reported in the literature along with the medically accepted normal ranges. The details on concentrations below the limits of detection (LOD) and limits of quantification (LOQ) are also discussed. Vitamin concentrations were also compared and cross-correlated with clinical data and nutritional information. Significant differences and strongly correlated data were reported in [1]. This article provides comprehensive details on the data with slight differences or slight correlations.

  13. Detection of colloidal silver chloride near solubility limit

    NASA Astrophysics Data System (ADS)

    Putri, K. Y.; Adawiah, R.

    2018-03-01

    Detection of nanoparticles in solution has been made possible by several means; one of them is laser-induced breakdown detection (LIBD). LIBD is able to distinguish colloids of various sizes and concentrations. This technique has been used in several solubility studies. In this study, the formation of colloids in a mixed system of silver nitrate and sodium chloride was observed by acoustic LIBD. Silver chloride has low solubility limit, therefore LIBD measurement is appropriate. Silver and chloride solutions with equal concentrations, set at below and above the solubility of silver chloride as the expected solid product, were mixed and the resulting colloids were observed. The result of LIBD measurement showed that larger particles were present as more silver and chloride introduced. However, once the concentrations exceeded the solubility limit of silver chloride, the detected particle size seemed to be decreasing, hence suggested the occurrence of coprecipitation process. This phenomenon indicated that the ability of LIBD to detect even small changes in colloid amounts might be a useful tool in study on formation and stability of colloids, i.e. to confirm whether nanoparticles synthesis has been successfully performed and whether the system is stable or not.

  14. Solubility of aluminum and silica in Spodic horizons as affected by drying and freezing

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Simonsson, M.; Berggren, D.; Gustafsson, J.P.

    The release of toxic Al{sup 3+} is one of the most serious consequences of anthropogenic soil acidification. Therefore, the mechanisms controlling Al solubility have been a topic of intense research for more than a decade. For convenience, soil samples are often dried before storage and experimental use. However, the literature offers examples of drying that results in changes in pH, solubility of organic matter, and dissolution rates of Al. In this study, the authors examined the solubility of Al and Si in fresh soil and in soil that had been dried or deep-frozen. Five Spodosol B horizon soils were subjectedmore » to batch titrations, where portions of each soil were equilibrated with solutions with varying concentrations of acid or base added. Extractions with acid oxalate and Na pyrophosphate indicated the presence of imogolite-type materials (ITM) in three of the soils. In the other two soils most secondary solid-phase Al was associated with humic substances. Deep-freezing did not significantly change pH nor the concentration of Al or Si as compared with fresh soil. Drying, on the other hand, yielded pH increases of up to 0.3 units at a given addition of acid or base, whereas Al{sup 3+} changed only slightly, implying a higher Al solubility in all of the soils. Furthermore, dissolved silica increased by up to 200% after drying, except in a soil that almost completely lacked oxalate-extractable Si. The authors suggest that drying enhanced the dissolution of ITM by disrupting soil organic matter, thus exposing formerly coated mineral surfaces. In the soil where dissolved Si did not change with drying, it has been demonstrated that Al-humus complexes controlled Al solubility. They suggest that fissures in the organic material caused by drying may have exposed formerly occluded binding sites that had a higher Al saturation than had sites at the surface of humus particles.« less

  15. Caffeine: a potential complexing agent for solubility and dissolution enhancement of celecoxib.

    PubMed

    Shakeel, Faiyaz; Faisal, Mohammed S

    2010-01-01

    Complexation of caffeine with the drug celecoxib was used to enhance its solubility as well as in vitro dissolution in the present investigation. Caffeine was extracted from tea leaves using the sublimation method. A molecular complex (1:1) of caffeine-celecoxib was prepared using the solubility method. The solubility of celecoxib in distilled water and the caffeine complex was determined using a HPLC method at a wavelength of 250 nm. Dissolution studies of pure celecoxib, a marketed capsule (Celebrex), and the complex were performed using USP dissolution apparatus I for pure celecoxib and the complex and apparatus II for the capsule in distilled water. The highest solubility (48.32 mg/mL) as well as percent dissolution (90.54%) of celecoxib was obtained with the caffeine-celecoxib complex. The results for solubility and dissolution were highly significant as compared to pure celecoxib and the marketed capsule (p < 0.01). These results suggest that caffeine is a promising complexing agent for solubility as well as dissolution enhancement of the poorly soluble drug celecoxib.

  16. Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction.

    PubMed

    Onda, Kenji; Tong, Stephen; Beard, Sally; Binder, Natalie; Muto, Masanaga; Senadheera, Sevvandi N; Parry, Laura; Dilworth, Mark; Renshall, Lewis; Brownfoot, Fiona; Hastie, Roxanne; Tuohey, Laura; Palmer, Kirsten; Hirano, Toshihiko; Ikawa, Masahito; Kaitu'u-Lino, Tu'uhevaha; Hannan, Natalie J

    2017-03-01

    Preeclampsia is a severe complication of pregnancy. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. Oxidative stress and vascular inflammation exacerbate the endothelial injury. A drug that can block these pathophysiological steps would be an attractive treatment option. Proton pump inhibitors (PPIs) are safe in pregnancy where they are prescribed for gastric reflux. We performed functional studies on primary human tissues and animal models to examine the effects of PPIs on sFlt-1 and soluble endoglin secretion, vessel dilatation, blood pressure, and endothelial dysfunction. PPIs decreased sFlt-1 and soluble endoglin secretion from trophoblast, placental explants from preeclamptic pregnancies, and endothelial cells. They also mitigated tumor necrosis factor-α-induced endothelial dysfunction: PPIs blocked endothelial vascular cell adhesion molecule-1 expression, leukocyte adhesion to endothelium, and disruption of endothelial tube formation. PPIs decreased endothelin-1 secretion and enhanced endothelial cell migration. Interestingly, the PPI esomeprazole vasodilated maternal blood vessels from normal pregnancies and cases of preterm preeclampsia, but its vasodilatory effects were lost when the vessels were denuded of their endothelium. Esomeprazole decreased blood pressure in a transgenic mouse model where human sFlt-1 was overexpressed in placenta. PPIs upregulated endogenous antioxidant defenses and decreased cytokine secretion from placental tissue and endothelial cells. We have found that PPIs decrease sFlt-1 and soluble endoglin secretion and endothelial dysfunction, dilate blood vessels, decrease blood pressure, and have antioxidant and anti-inflammatory properties. They have therapeutic potential for preeclampsia and other diseases where endothelial dysfunction is involved. © 2017 American Heart Association

  17. The solubility of rare gases in fused silica: A numerical evaluation

    NASA Astrophysics Data System (ADS)

    Guillot, Bertrand; Guissani, Yves

    1996-07-01

    The solubility of rare gases in a simulated model of fused silica is evaluated by the test particle method. It is shown that the order of magnitude of the rare gas solubility in liquid silica is mainly governed by the entropy of cavity formation and only marginally by the solvation energy of the solute in the melt. Hence, the hierarchy of solubilities is dictated by the size of the noble gases: The smaller the atom the higher the solubility. Moreover, the solubility exhibits only a moderate temperature dependence at fixed density. In silica glass the same solubility hierarchy is found (in agreement with the experimental data) although the energetic contribution to the absorption process may become significant, particularly when the temperature decreases. These results in silica are in strong contrast with those obtained in liquid water where the energetic contribution to the rare gas solubility is large enough to overcompensate the entropic loss of cavity formation, the net result being that light noble gases (e.g., He) are less soluble than heavier ones (e.g., Xe). These contrasting behaviors are explained by pointing out that the liquid phase occurs in very different temperature ranges for these two systems (SiO2 and H2O) while the rare gas-solvent interaction energy is essentially of the same order of magnitude. Finally, the structure of silica around helium and neon atoms is found to be interstitial (cristobalitelike) while in the case of heavier rare gases, the structure of cavities is more reminiscent of the polyhedral arrangement encountered with clathrasils.

  18. Iron (III) hydrolysis and solubility at 25 degrees C.

    PubMed

    Stefánsson, Andri

    2007-09-01

    UV-vis spectrophotometric measurements, potentiometric titrations, and solubility measurements were performed to evaluate the hydrolysis constants for aqueous Fe(III) and the solubility of 2-line ferrihydrite over a wide concentration range (0-3 M NaClO4 and p[H+] 1.54-11.23). From these measurements, Fe3+ was found to hydrolyze to form FeOH2+, Fe2(OH)24+, Fe(OH)2+, Fe(OH)3(0), and Fe(OH)4-. The hydrolysis and solubility constants of these species were determined together with their dependence on ionic strength. The iron (III) hydrolysis constants at infinity dilution were (logbeta(1,1) to logbeta(1,4) and logbeta(2,2))-2.19 +/- 0.02, -5.76 +/- 0.06, -14.30 +/- 0.32, -21.71 +/- 0.24, and -2.92 +/- 0.02, respectively. The solubility product for 2-line ferrihydrite was (logK(s,0)) +3.50 +/- 0.20. The results have been compared with literature values.

  19. Solubility correlation of anthraquinone derivatives in supercritical carbon dioxide

    NASA Astrophysics Data System (ADS)

    Alwi, Ratna Surya; Tamura, Kazuhiro; Tanaka, Tatsuro; Shimizu, Keisuke

    2017-05-01

    In this work, solubilites of anthraquinone dyestuffs in supercritical carbon dioxide (sc-CO2) were correlated by semiempirical models, expressed in terms of CO2 density. All solubility data used, experimentally measured by us, and were described in details elsewhere; namely, 1,4-diaminoanthraquinone and 1,4-bis(ethylamino)anthraquinone [J. Chem. Thermo-dyn. 74, 119-125 (2014)]; 1-amino-4-hydroxyanthraquinone and 1-hydroxy-4-nitroanthraquionone [Dyes Pigm.113, 351-356 (2015)]; 1,4-diamino-2,3-dichloroanthraquinone and 1,8-dihydroxy-4,5-dinitroanthraquinone [J. Chem. Eng. Data 60, 3046-3052 (2015)], and 1-aminoanthraquinone and 1-nitroanthraquinone [J. Chem. Thermodyn. 104, 162-168 (2017)]. It was found that 1-aminoanthraquinone shows the highest solubility at 383,15 K and pressure of 25 MPa, and the solubility of anthraquinone derivatives in sc-CO2 changed by the substituent groups. Satisfactory agreement between the experimental data used and calculated solubilities of the anthraquinone derivatives was obtained.

  20. Levels of soluble TREM-1 in children with newly diagnosed type 1 diabetes and their siblings without type 1 diabetes: a Danish case-control study.

    PubMed

    Thorsen, Steffen U; Pipper, Christian B; Mortensen, Henrik B; Skogstrand, Kristin; Pociot, Flemming; Johannesen, Jesper; Svensson, Jannet

    2017-12-01

    Type 1 diabetes (T1D) is an organ-specific autoimmune disease with an increase in incidence worldwide including Denmark. The triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory responses and has been linked to autoimmunity, severe psychiatric disorders, sepsis, and cancer. Our primary hypothesis was that levels of soluble TREM-1 (sTREM-1) differed between newly diagnosed children with T1D and their siblings without T1D. Since 1996, the Danish Childhood Diabetes Register has collected data on all patients who have developed T1D before the age of 18 years. Four hundred and eighty-one patients and 478 siblings with measurements of sTREM-1-blood samples were taken within 3 months after onset-were available for statistical analyses. Sample period was from 1997 through 2005. A robust log-normal regression model was used, which takes into account that measurements are left censored and accounts for correlation within siblings from the same family. In the multiple regression model (case status, gender, age, HLA-risk, season, and period of sampling), levels of sTREM-1 were found to be significantly higher in patients (relative change [95%CI], 1.5 [1.1; 2.2],P = 0.02), but after adjustment for multiple testing our result was no longer statistically significant (P adjust = 0.1). We observed a statistical significant temporal increase in levels of sTREM-1. Our results need to be replicated by independent studies, but our study suggests that the TREM-1 pathway may have a role in T1D pathogenesis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.