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Sample records for soluble activin type

  1. A Soluble Activin Receptor Type IIB Does Not Improve Blood Glucose in Streptozotocin-Treated Mice

    PubMed Central

    Wang, Qian; Guo, Tingqing; Portas, Jennifer; McPherron, Alexandra C.

    2015-01-01

    Type 1 diabetes mellitus (T1DM), or insulin dependent DM, is accompanied by decreased muscle mass. The growth factor myostatin (MSTN) is a negative regulator of muscle growth, and a loss of MSTN signaling has been shown to increase muscle mass and prevent the development of obesity, insulin resistance and lipodystrophic diabetes in mice. The effects of MSTN inhibition in a T1DM model on muscle mass and blood glucose are unknown. We asked whether MSTN inhibition would increase muscle mass and decrease hyperglycemia in mice treated with streptozotocin (STZ) to destroy pancreatic beta cells. After diabetes developed, mice were treated with a soluble MSTN/activin receptor fused to Fc (ACVR2B:Fc). ACVR2B:Fc increased body weight and muscle mass compared to vehicle treated mice. Unexpectedly, ACVR2B:Fc reproducibly exacerbated hyperglycemia within approximately one week of administration. ACVR2B:Fc treatment also elevated serum levels of the glucocorticoid corticosterone. These results suggest that although MSTN/activin inhibitors increased muscle mass, they may be counterproductive in improving health in patients with T1DM. PMID:25561902

  2. Development of Novel Activin-Targeted Therapeutics

    PubMed Central

    Chen, Justin L; Walton, Kelly L; Al-Musawi, Sara L; Kelly, Emily K; Qian, Hongwei; La, Mylinh; Lu, Louis; Lovrecz, George; Ziemann, Mark; Lazarus, Ross; El-Osta, Assam; Gregorevic, Paul; Harrison, Craig A

    2015-01-01

    Soluble activin type II receptors (ActRIIA/ActRIIB), via binding to diverse TGF-β proteins, can increase muscle and bone mass, correct anemia or protect against diet-induced obesity. While exciting, these multiple actions of soluble ActRIIA/IIB limit their therapeutic potential and highlight the need for new reagents that target specific ActRIIA/IIB ligands. Here, we modified the activin A and activin B prodomains, regions required for mature growth factor synthesis, to generate specific activin antagonists. Initially, the prodomains were fused to the Fc region of mouse IgG2A antibody and, subsequently, “fastener” residues (Lys45, Tyr96, His97, and Ala98; activin A numbering) that confer latency to other TGF-β proteins were incorporated. For the activin A prodomain, these modifications generated a reagent that potently (IC50 5 nmol/l) and specifically inhibited activin A signaling in vitro, and activin A-induced muscle wasting in vivo. Interestingly, the modified activin B prodomain inhibited both activin A and B signaling in vitro (IC50 ~2 nmol/l) and in vivo, suggesting it could serve as a general activin antagonist. Importantly, unlike soluble ActRIIA/IIB, the modified prodomains did not inhibit myostatin or GDF-11 activity. To underscore the therapeutic utility of specifically antagonising activin signaling, we demonstrate that the modified activin prodomains promote significant increases in muscle mass. PMID:25399825

  3. ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma

    PubMed Central

    Su, Gloria H.; Bansal, Ravi; Murphy, Kathleen M.; Montgomery, Elizabeth; Yeo, Charles J.; Hruban, Ralph H.; Kern, Scott E.

    2001-01-01

    DPC4 is known to mediate signals initiated by type β transforming growth factor (TGFβ) as well as by other TGFβ superfamily ligands such as activin and BMP (bone morphogenic proteins), but mutational surveys of such non-TGFβ receptors have been negative to date. Here we describe the gene structure and novel somatic mutations of the activin type I receptor, ACVR1B, in pancreatic cancer. ACVR1B has not been described previously as a mutated tumor-suppressor gene. PMID:11248065

  4. Characterization of Follistatin-Type Domains and Their Contribution to Myostatin and Activin A Antagonism

    PubMed Central

    Cash, Jennifer N.; Angerman, Elizabeth B.; Keutmann, Henry T.

    2012-01-01

    Follistatin (FST)-type proteins are important antagonists of some members of the large TGF-β family of cytokines. These include myostatin, an important negative regulator of muscle growth, and the closely related activin A, which is involved in many physiological functions, including maintenance of a normal reproductive axis. FST-type proteins, including FST and FST-like 3 (FSTL3), differentially inhibit various TGF-β family ligands by binding each ligand with two FST-type molecules. In this study, we sought to examine features that are important for ligand antagonism by FST-type proteins. Previous work has shown that a modified construct consisting of the FST N-terminal domain (ND) followed by two repeating follistatin domains (FSD), herein called FST ND-FSD1-FSD1, exhibits strong specificity for myostatin over activin A. Using cell-based assays, we show that FST ND-FSD1-FSD1 is unique in its specificity for myostatin as compared with similar constructs containing domains from FSTL3 and that the ND is critical to its activity. Furthermore, we demonstrate that FSD3 of FST provides affinity to ligand inhibition and confers resistance to perturbations in the ND and FSD2, likely through the interaction of FSD3 of one FST molecule with the ND of the other FST molecule. Additionally, our data suggest that this contact provides cooperativity to ligand antagonism. Cross-linking studies show that this interaction also potentiates formation of 1:2 ligand-FST complexes, whereas lack of FSD3 allows formation of 1:1 complexes. Altogether, these studies support that domain differences generate FST-type molecules that are each uniquely suited ligand antagonists. PMID:22593183

  5. A Soluble Activin Receptor IIB Fails to Prevent Muscle Atrophy in a Mouse Model of Spinal Cord Injury.

    PubMed

    Graham, Zachary A; Collier, Lauren; Peng, Yuanzhen; Saéz, Juan C; Bauman, William A; Qin, Weiping; Cardozo, Christopher P

    2016-06-15

    Myostatin (MST) is a potent regulator of muscle growth and size. Spinal cord injury (SCI) results in marked atrophy of muscle below the level of injury. Currently, there is no effective pharmaceutical treatment available to prevent sublesional muscle atrophy post-SCI. To determine whether inhibition of MST with a soluble activin IIB receptor (RAP-031) prevents sublesional SCI-induced muscle atrophy, mice were randomly assigned to the following groups: Sham-SCI; SCI+Vehicle group (SCI-VEH); and SCI+RAP-031 (SCI-RAP-031). SCI was induced by complete transection at thoracic level 10. Animals were euthanized at 56 days post-surgery. RAP-031 reduced, but did not prevent, body weight loss post-SCI. RAP-031 increased total lean tissue mass compared to SCI-VEH (14.8%). RAP-031 increased forelimb muscle mass post-SCI by 38% and 19% for biceps and triceps, respectively (p < 0.001). There were no differences in hindlimb muscle weights between the RAP-031 and SCI-VEH groups. In the gastrocnemius, messenger RNA (mRNA) expression was elevated for interleukin (IL)-6 (8-fold), IL-1β (3-fold), and tumor necrosis factor alpha (8-fold) in the SCI-VEH, compared to the Sham group. Muscle RING finger protein 1 mRNA was 2-fold greater in the RAP-031 group, compared to Sham-SCI. RAP-031 did not influence cytokine expression. Bone mineral density of the distal femur and proximal tibia were decreased post-SCI (-26% and -28%, respectively) and were not altered by RAP-031. In conclusion, MST inhibition increased supralesional muscle mass, but did not prevent sublesional muscle or bone loss, or the inflammation in paralyzed muscle.

  6. Activation of activin type IB receptor signals in pancreatic β cells leads to defective insulin secretion through the attenuation of ATP-sensitive K+ channel activity.

    PubMed

    Nomura, Masatoshi; Morinaga, Hidetaka; Zhu, Hai-Lei; Wang, Lixiang; Hasuzawa, Nao; Takayanagi, Ryoichi; Teramoto, Noriyoshi

    2014-07-18

    In studies of gene-ablated mice, activin signaling through activin type IIB receptors (ActRIIB) and Smad2 has been shown to regulate not only pancreatic β cell mass but also insulin secretion. However, it still remains unclear whether gain of function of activin signaling is involved in the modulation of pancreatic β cell mass and insulin secretion. To identify distinct roles of activin signaling in pancreatic β cells, the Cre-loxP system was used to activate signaling through activin type IB receptor (ActRIB) in pancreatic β cells. The resultant mice (pancreatic β cell-specific ActRIB transgenic (Tg) mice; ActRIBCAβTg) exhibited a defect in glucose-stimulated insulin secretion (GSIS) and a progressive impairment of glucose tolerance. Patch-clamp techniques revealed that the activity of ATP-sensitive K(+) channels (KATP channels) was decreased in mutant β cells. These results indicate that an appropriate level of activin signaling may be required for GSIS in pancreatic β cells, and that activin signaling involves modulation of KATP channel activity.

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

    SciTech Connect

    Nomura, Masatoshi; Tanaka, Kimitaka; Wang, Lixiang; Goto, Yutaka; Mukasa, Chizu; Ashida, Kenji; Takayanagi, Ryoichi

    2013-01-04

    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 cancer 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.

  8. 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

  9. Inhibition of activin receptor type IIB increases strength and lifespan in myotubularin-deficient mice.

    PubMed

    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

    2011-02-01

    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

  10. Mutant activin-like kinase 2 in fibrodysplasia ossificans progressiva are activated via T203 by BMP type II receptors.

    PubMed

    Fujimoto, Mai; Ohte, Satoshi; Osawa, Kenji; Miyamoto, Arei; Tsukamoto, Sho; Mizuta, Takato; Kokabu, Shoichiro; Suda, Naoto; Katagiri, Takenobu

    2015-01-01

    Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder characterized by progressive heterotopic ossification in soft tissues, such as the skeletal muscles. FOP has been shown to be caused by gain-of-function mutations in activin receptor-like kinase (ALK)-2, which is a type I receptor for bone morphogenetic proteins (BMPs). In the present study, we examined the molecular mechanisms that underlie the activation of intracellular signaling by mutant ALK2. Mutant ALK2 from FOP patients enhanced the activation of intracellular signaling by type II BMP receptors, such as BMPR-II and activin receptor, type II B, whereas that from heart disease patients did not. This enhancement was dependent on the kinase activity of the type II receptors. Substitution mutations at all nine serine and threonine residues in the ALK2 glycine- and serine-rich domain simultaneously inhibited this enhancement by the type II receptors. Of the nine serine and threonine residues in ALK2, T203 was found to be critical for the enhancement by type II receptors. The T203 residue was conserved in all of the BMP type I receptors, and these residues were essential for intracellular signal transduction in response to ligand stimulation. The phosphorylation levels of the mutant ALK2 related to FOP were higher than those of wild-type ALK2 and were further increased by the presence of type II receptors. The phosphorylation levels of ALK2 were greatly reduced in mutants carrying a mutation at T203, even in the presence of type II receptors. These findings suggest that the mutant ALK2 related to FOP is enhanced by BMP type II receptors via the T203-regulated phosphorylation of ALK2.

  11. Ligand trap for the activin type IIA receptor protects against vascular disease and renal fibrosis in mice with chronic kidney disease.

    PubMed

    Agapova, Olga A; Fang, Yifu; Sugatani, Toshifumi; Seifert, Michael E; Hruska, Keith A

    2016-06-01

    The causes of cardiovascular mortality associated with chronic kidney disease (CKD) are partly attributed to the CKD-mineral bone disorder (CKD-MBD). The causes of the early CKD-MBD are not well known. Our discovery of Wnt (portmanteau of wingless and int) inhibitors, especially Dickkopf 1, produced during renal repair as participating in the pathogenesis of the vascular and skeletal components of the CKD-MBD implied that additional pathogenic factors are critical. In the search for such factors, we studied the effects of activin receptor type IIA (ActRIIA) signaling by using a ligand trap for the receptor, RAP-011 (a soluble extracellular domain of ActRIIA fused to a murine IgG-Fc fragment). In a mouse model of CKD that stimulated atherosclerotic calcification, RAP-011 significantly increased aortic ActRIIA signaling assessed by the levels of phosphorylated Smad2/3. Furthermore, RAP-011 treatment significantly reversed CKD-induced vascular smooth muscle dedifferentiation as assessed by smooth muscle 22α levels, osteoblastic transition, and neointimal plaque calcification. In the diseased kidneys, RAP-011 significantly stimulated αklotho levels and it inhibited ActRIIA signaling and decreased renal fibrosis and proteinuria. RAP-011 treatment significantly decreased both renal and circulating Dickkopf 1 levels, showing that Wnt activation was downstream of ActRIIA. Thus, ActRIIA signaling in CKD contributes to the CKD-MBD and renal fibrosis. ActRIIA signaling may be a potential therapeutic target in CKD. PMID:27165838

  12. Activins and activin antagonists in hepatocellular carcinoma

    PubMed Central

    Deli, Alev; Kreidl, Emanuel; Santifaller, Stefan; Trotter, Barbara; Seir, Katja; Berger, Walter; Schulte-Hermann, Rolf; Rodgarkia-Dara, Chantal; Grusch, Michael

    2008-01-01

    In many parts of the world hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood. There is increasing evidence that activins, which are members of the transforming growth factor β (TGFβ) superfamily of growth and differentiation factors, could play important roles in liver carcinogenesis. Activins are disulphide-linked homo- or heterodimers formed from four different β subunits termed βA, βB, βC, and βE, respectively. Activin A, the dimer of two βA subunits, is critically involved in the regulation of cell growth, apoptosis, and tissue architecture in the liver, while the hepatic function of other activins is largely unexplored so far. Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG, and at the cell membrane antagonistic co-receptors like Cripto or BAMBI. Additionally, in the intracellular space inhibitory Smads can modulate and control activin activity. Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation, fibrosis and development of cancer. The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis. PMID:18350601

  13. Activin signaling as an emerging target for therapeutic interventions

    PubMed Central

    Tsuchida, Kunihiro; Nakatani, Masashi; Hitachi, Keisuke; Uezumi, Akiyoshi; Sunada, Yoshihide; Ageta, Hiroshi; Inokuchi, Kaoru

    2009-01-01

    After the initial discovery of activins as important regulators of reproduction, novel and diverse roles have been unraveled for them. Activins are expressed in various tissues and have a broad range of activities including the regulation of gonadal function, hormonal homeostasis, growth and differentiation of musculoskeletal tissues, regulation of growth and metastasis of cancer cells, proliferation and differentiation of embryonic stem cells, and even higher brain functions. Activins signal through a combination of type I and II transmembrane serine/threonine kinase receptors. Activin receptors are shared by multiple transforming growth factor-β (TGF-β) ligands such as myostatin, growth and differentiation factor-11 and nodal. Thus, although the activity of each ligand is distinct, they are also redundant, both physiologically and pathologically in vivo. Activin receptors activated by ligands phosphorylate the receptor-regulated Smads for TGF-β, Smad2 and 3. The Smad proteins then undergo multimerization with the co-mediator Smad4, and translocate into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. Signaling through receptors and Smads is controlled by multiple mechanisms including phosphorylation and other posttranslational modifications such as sumoylation, which affect potein localization, stability and transcriptional activity. Non-Smad signaling also plays an important role in activin signaling. Extracellularly, follistatin and related proteins bind to activins and related TGF-β ligands, and control the signaling and availability of ligands. The functions of activins through activin receptors are pleiotrophic, cell type-specific and contextual, and they are involved in the etiology and pathogenesis of a variety of diseases. Accordingly, activin signaling may be a target for therapeutic interventions. In this review, we summarize the current knowledge on activin signaling and discuss the potential roles of

  14. FOXL2-induced follistatin attenuates activin A-stimulated cell proliferation in human granulosa cell tumors

    SciTech Connect

    Cheng, Jung-Chien; Chang, Hsun-Ming; Qiu, Xin; Fang, Lanlan; Leung, Peter C.K.

    2014-01-10

    Highlights: •Activin A stimulates cell proliferation in KGN human granulosa cell tumor-derived cell line. •Cyclin D2 mediates activin A-induced KGN cell proliferation. •FOXL2 induces follistatin expression in KGN cells. •FOXL2-induced follistatin attenuates activin A-stimulated KGN cell proliferation. -- Abstract: Human granulosa cell tumors (GCTs) are rare, and their etiology remains largely unknown. Recently, the FOXL2 402C > G (C134W) mutation was found to be specifically expressed in human adult-type GCTs; however, its function in the development of human GCTs is not fully understood. Activins are members of the transforming growth factor-beta superfamily, which has been shown to stimulate normal granulosa cell proliferation; however, little is known regarding the function of activins in human GCTs. In this study, we examined the effect of activin A on cell proliferation in the human GCT-derived cell line KGN. We show that activin A treatment stimulates KGN cell proliferation. Treatment with the activin type I receptor inhibitor SB431542 blocks activin A-stimulated cell proliferation. In addition, our results show that cyclin D2 is induced by treatment with activin A and is involved in activin A-stimulated cell proliferation. Moreover, the activation of Smad signaling is required for activin A-induced cyclin D2 expression. Finally, we show that the overexpression of the wild-type FOXL2 but not the C134W mutant FOXL2 induced follistatin production. Treatment with exogenous follistatin blocks activin A-stimulated cell proliferation, and the overexpression of wild-type FOXL2 attenuates activin A-stimulated cell proliferation. These results suggest that FOXL2 may act as a tumor suppressor in human adult-type GCTs by inducing follistatin expression, which subsequently inhibits activin-stimulated cell proliferation.

  15. Intertwining of Activin A and TGFβ Signaling: Dual Roles in Cancer Progression and Cancer Cell Invasion

    PubMed Central

    Loomans, Holli A.; Andl, Claudia D.

    2014-01-01

    In recent years, a significant amount of research has examined the controversial role of activin A in cancer. Activin A, a member of the transforming growth factor β (TGFβ) superfamily, is best characterized for its function during embryogenesis in mesoderm cell fate differentiation and reproduction. During embryogenesis, TGFβ superfamily ligands, TGFβ, bone morphogenic proteins (BMPs) and activins, act as potent morphogens. Similar to TGFβs and BMPs, activin A is a protein that is highly systemically expressed during early embryogenesis; however, post-natal expression is overall reduced and remains under strict spatiotemporal regulation. Of importance, normal post-natal expression of activin A has been implicated in the migration and invasive properties of various immune cell types, as well as endometrial cells. Aberrant activin A signaling during development results in significant morphological defects and premature mortality. Interestingly, activin A has been found to have both oncogenic and tumor suppressor roles in cancer. Investigations into the role of activin A in prostate and breast cancer has demonstrated tumor suppressive effects, while in lung and head and neck squamous cell carcinoma, it has been consistently shown that activin A expression is correlated with increased proliferation, invasion and poor patient prognosis. Activin A signaling is highly context-dependent, which is demonstrated in studies of epithelial cell tumors and the microenvironment. This review discusses normal activin A signaling in comparison to TGFβ and highlights how its dysregulation contributes to cancer progression and cell invasion. PMID:25560921

  16. Seasonal changes in immunoreactivity of activin signaling component proteins in wild ground squirrel testes.

    PubMed

    Sheng, Xia; Zhang, Haolin; Zhang, Mengyuan; Zhang, Wei; Hu, Xiao; Song, Moshi; Zhou, Jiao; Xu, Meiyu; Weng, Qiang; Watanabe, Gen; Taya, Kazuyoshi

    2012-01-01

    The seasonal spermatogenesis and localization of inhibin/activin subunits (alpha, betaA, betaB) in the testes of wild ground squirrel has been previously described; however, the expression pattern of activin receptors and cytoplasmic signaling SMADs has not been detected in any seasonal breeders. The objective of this study was to investigate the abundance and cellular localization of activin signaling components in testes of the wild ground squirrel during the breeding and nonbreeding seasons. The immunolocalizations of ActRIIB (activin type II receptor B) and activin-related SMADs (phospho-SMAD2/3, SMAD4 and SMAD7) were observed by immunohistochemistry. Total proteins were extracted from testicular tissues in the breeding and nonbreeding seasons and were used for Western blotting analysis for ActRIIB and SMADs. Immunoreactivities of activin signaling components were greater in the testes of the breeding season, and then decreased to a relatively low level in the nonbreeding season. ActRIIB and related SMADs were widely spread in the active testes, while spermatogonia were the predominant cellular sites of activin signal transduction during arrested spermatogenesis. The dynamic regulation of activin type II receptor and SMADs indicated that the activin signal pathway played an important paracrine role in seasonal spermatogenesis of the wild ground squirrel. Furthermore, the distinct localizations and immunoreactivity of ActRIIB and SMADs might suggest different functions of activin in seasonal spermatogenesis.

  17. 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. PMID:26205544

  18. Transgenic models to study the roles of inhibins and activins in reproduction, oncogenesis, and development.

    PubMed

    Matzuk, M M; Kumar, T R; Shou, W; Coerver, K A; Lau, A L; Behringer, R R; Finegold, M J

    1996-01-01

    With the advent of gene targeting in pluripotent mouse embryonic stem cells, it is now possible to modify the mammalian genome to generate mutant strains of mice with precise genetic mutations. The major goal of my laboratory is to generate transgenic mice to use as physiologic models to study mammalian reproduction and development. The initial focus of our research has been to generate mice deficient in inhibins, activins, activin binding proteins (i.e., follistatin), and activin receptors (i.e., activin receptor type II) to understand their interactions and roles in the hypothalamic-pituitary-gonadal axis and mammalian development. Inhibins and activins, dimeric members of the TGF-beta superfamily, were discovered due to their role in pituitary follicle stimulating hormone homeostasis. However, these proteins have later been shown to have diverse endocrine, paracrine, and autocrine functions. Activins have been shown to mediate their signals through type I and type II serine/threonine kinase receptors. The high interspecies conservation of activins, inhibins, and activin receptors and the universal presence of activins in mammals, birds, amphibians, and fish suggest an evolutionarily conserved role of these proteins in animal development. Our initial studies have demonstrated a tumor suppressor role of inhibin in the gonads and adrenals and have also suggested a role of activins in cancer cachexia-like syndrome. To further study the gonadal tumor development and the cancer cachexia-like syndrome in these mice, we have begun to generate mice with multiple genetic alterations (e.g., mice deficient in both inhibin and Mullerian inhibiting substance). We have also generated mice deficient in other components of this complex system (e.g., activin beta A, activin receptor type II, follistatin). Analysis of these transgenic mutant models has aided our overall understanding of the critical roles these proteins play in the development of the reproductive system, in the

  19. Activin A regulation of gonadotropin-releasing hormone synthesis and release in vitro.

    PubMed

    MacConell, L A; Lawson, M A; Mellon, P L; Roberts, V J

    1999-10-01

    Activin is essential for the regulation of normal mammalian reproductive function at both the pituitary and gonadal levels. However, its central actions in the control of the hypothalamic-pituitary-gonadal axis remain largely unexplored. The present study aims to determine whether activin could regulate the reproductive axis at the level of the hypothalamus, through control of the GnRH neuroendocrine system. Using the GnRH-secreting GT1-7 neuronal cell line as a model system, we demonstrate expression of mRNAs encoding activin receptor types I, IB, and II. We examined the effects of activin A on GnRH protein secretion and mRNA levels in GT1-7 cells. Treatment with rh-activin A regulated both GnRH protein secretion and GnRH mRNA expression in the GT1-7 cells in a time-dependent fashion. Using transient transfection assays, we explored a potential transcriptional basis for these changes. Activin A increased reporter gene activity driven by minimal GnRH enhancer and promoter elements, suggesting that activin may regulate GnRH gene expression at the level of transcription. Lastly, activin A treatment of male rat hypothalami, in vitro, increased GnRH protein secretion. Collectively, molecular and physiological evidence support the presence of an activin system which might act at a hypothalamic site to regulate mammalian reproduction via activation of GnRH synthesis and release.

  20. 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

  1. Activins and inhibins: Novel regulators of thymocyte development

    SciTech Connect

    Licona-Limon, Paula; Aleman-Muench, German; Macias-Silva, Marina; Garcia-Zepeda, Eduardo A.; Fortoul, Teresa I.; Soldevila, Gloria

    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 and 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.

  2. Activins and Inhibins: novel regulators of thymocyte development

    PubMed Central

    Licona-Limón, Paula; Alemán-Muench, German; Chimal-Monroy, Jesus; Macías-Silva, Marina; García-Zepeda, Eduardo A.; Matzuk, Martin M.; Fortoul, Teresa I.; Soldevila, Gloria

    2009-01-01

    Activins and inhibins are members of the transforming growth factor β 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+CD24hiTCRβlo intermediate subpopulation, inhibin A promotes the differentiation of DN4 to DP. In addition, both activin A and inhibin A appear to promote CD8+SP differentiation Moreover, Inhibin α 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. PMID:19338778

  3. Activation of signalling by the activin receptor complex.

    PubMed Central

    Attisano, L; Wrana, J L; Montalvo, E; Massagué, J

    1996-01-01

    Activin exerts its effects by simultaneously binding to two types of p rotein serine/threonine kinase receptors, each type existing in various isoforms. Using the ActR-IB and ActR-IIB receptor isoforms, we have investigated the mechanism of activin receptor activation. ActR-IIB are phosphoproteins with demonstrable affinity for each other. However, activin addition strongly promotes an interaction between these two proteins. Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation, suggesting that this domain contains phosphorylation sites required for signalling. ActR-IB activation can be mimicked by mutation of Thr-206 to aspartic acid, which yields a construct, ActR-IB(T206D), that signals in the absence of ligand. Furthermore, the signalling activity of this mutant construct is undisturbed by overexpression of a dominant negative kinase-defective ActR-IIB construct, indicating that ActR-IB(T206D) can signal independently of ActR-IIB. The evidence suggests that ActR-IIB acts as a primary activin receptor and ActR-IB acts as a downstream transducer of activin signals. PMID:8622651

  4. ACTIVIN IIB RECEPTOR BLOCKADE ATTENUATES DYSTROPHIC PATHOLOGY IN A MOUSE MODEL OF DUCHENNE MUSCULAR DYSTROPHY

    PubMed Central

    Morine, Kevin J.; Bish, Lawrence T.; Selsby, Joshua T.; Gazzara, Jeffery A.; Pendrak, Klara; Sleeper, Meg M.; Barton, Elisabeth R.; Lee, Se-Jin; Sweeney, H. Lee

    2015-01-01

    Modulation of transforming growth factor-β (TGF-β) signaling to promote muscle growth holds tremendous promise for the muscular dystrophies and other disorders involving the loss of functional muscle mass. Previous studies have focused on the TGF-β family member myostatin and demonstrated that inhibition of myostatin leads to muscle growth in normal and dystrophic mice. We describe a unique method of systemic inhibition of activin IIB receptor signaling via adeno-associated virus (AAV)-mediated gene transfer of a soluble form of the extracellular domain of the activin IIB receptor to the liver. Treatment of mdx mice with activin IIB receptor blockade led to increased skeletal muscle mass, increased force production in the extensor digitorum longus (EDL), and reduced serum creatine kinase. No effect on heart mass or function was observed. Our results indicate that activin IIB receptor blockade represents a novel and effective therapeutic strategy for the muscular dystrophies. PMID:20730876

  5. Mutual effects of melatonin and activin on induction of aldosterone production by human adrenocortical cells.

    PubMed

    Hara, Takayuki; Otsuka, Fumio; Tsukamoto-Yamauchi, Naoko; Inagaki, Kenichi; Hosoya, Takeshi; Nakamura, Eri; Terasaka, Tomohiro; Komatsubara, Motoshi; Makino, Hirofumi

    2015-08-01

    Melatonin has been reported to suppress adrenocorticotropin (ACTH) secretion in the anterior pituitary and cortisol production in the adrenal by different mechanisms. However, the effect of melatonin on aldosterone production has remained unknown. In this study, we investigated the role of melatonin in the regulation of aldosterone production using human adrenocortical H295R cells by focusing on the activin system expressed in the adrenal. Melatonin receptor MT1 mRNA and protein were expressed in H295R cells and the expression levels of MT1 were increased by activin treatment. Activin increased ACTH-induced, but not angiotensin II (Ang II)-induced, aldosterone production. Melatonin alone did not affect basal synthesis of either aldosterone or cortisol. However, melatonin effectively enhanced aldosterone production induced by co-treatment with ACTH and activin, although melatonin had no effect on aldosterone production induced by Ang II in combination with activin. These changes in steroidogenesis became apparent when the steroid production was evaluated by the ratio of aldosterone/cortisol. Melatonin also enhanced dibutyryl-AMP-induced aldosterone/cortisol levels in the presence of activin, suggesting a functional link to the cAMP-PKA pathway for induction of aldosterone production by melatonin and activin. In accordance with the data for steroids, ACTH-induced, but not Ang II-induced, cAMP synthesis was also amplified by co-treatment with melatonin and activin. Furthermore, the ratio of ACTH-induced mRNA level of CYP11B2 compared with that of CYP17 was amplified in the condition of treatment with both melatonin and activin. In addition, melatonin increased expression of the activin type-I receptor ALK-4 but suppressed expression of inhibitory Smads6/7, leading to the enhancement of Smad2 phosphorylation. Collectively, the results showed that melatonin facilitated aldosterone production induced by ACTH and activin via the cAMP-PKA pathway. The results also

  6. The Biology Of Activin: Recent Advances In Structure, Regulation And Function

    PubMed Central

    Xia, Yin; Schneyer, Alan L.

    2009-01-01

    Activin was discovered in the 1980’s as a gonadal protein that stimulated FSH release from pituitary gonadotropes and was thought of as a reproductive hormone. In the ensuing decades many additional activities of activin were described and it was found to be produced in a wide variety of cell types at nearly all stages of development. Its signaling and actions are regulated intracellularly as well as by extracellular antagonists. Over the past 5 years a number of important advances have been made that clarify our understanding of the structural basis for signaling and regulation, as well as the biological roles of activin in stem cells, embryonic development, and in adults. These include the crystallization of activin in complex with the activin type II receptor ActRIIB, or with the binding proteins follistatin and follistatin-like 3 (FSTL3), and identification of the activin roles in gonadal sex development, follicle development and luteolysis, in β-cell proliferation and function in the islet, in stem cell self-renewal and differentiation into different cell types, and in immune cells. These advances are reviewed to provide perspective for future studies. PMID:19273500

  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

    2015-09-01

    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.

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

    SciTech Connect

    Tamminen, Jenni A.; Yin, Miao; Rönty, Mikko; Sutinen, Eva; Pasternack, Arja; Ritvos, Olli; Myllärniemi, Marjukka; Koli, Katri

    2015-03-01

    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 cells 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.

  9. Activin B promotes BMSC-mediated cutaneous wound healing by regulating cell migration via the JNK-ERK signaling pathway.

    PubMed

    Zhang, Min; Sun, Li; Wang, Xueer; Chen, Shixuan; Kong, Yanan; Liu, Nuyun; Chen, Yinghua; Jia, Qin; Zhang, Lu; Zhang, Lin

    2014-01-01

    Bone marrow-derived mesenchymal stem cells (BMSCs) are able to differentiate into various types of skin cells and participate in skin regeneration and repair. Activin signaling can regulate wound healing and reepithelialization. The present study assessed the impact of activin B on BMSC-mediated cutaneous wound healing in rats and explored the possible mechanism involved. We found that CFSE-labeled BMSCs participated in wound healing in vivo, and compared to administration with PBS, activin B, or BMSCs, activin B plus BMSCs significantly promoted wound healing and hair follicle regeneration. Activin B induced actin stress fiber formation and cell migration in BMSCs in vitro. Activation of JNK and ERK, but not p38, was required for activin B-induced actin stress fiber formation and BMSC migration. These results show that activin B may promote BMSC-mediated wound healing by inducing actin stress fiber formation and BMSC migration via the ERK and JNK signal pathways. Combined administration of BMSCs and cytokines may be a promising therapeutic strategy for the management of skin wounds.

  10. RAP-011, an activin receptor ligand trap, increases hemoglobin concentration in hepcidin transgenic mice.

    PubMed

    Langdon, Jacqueline M; Barkataki, Sangjucta; Berger, Alan E; Cheadle, Chris; Xue, Qian-Li; Sung, Victoria; Roy, Cindy N

    2015-01-01

    Over expression of hepcidin antimicrobial peptide is a common feature of iron-restricted anemia in humans. We investigated the erythroid response to either erythropoietin or RAP-011, a "murinized" ortholog of sotatercept, in C57BL/6 mice and in hepcidin antimicrobial peptide 1 over expressing mice. Sotatercept, a soluble, activin receptor type IIA ligand trap, is currently being evaluated for the treatment of anemias associated with chronic renal disease, myelodysplastic syndrome, β-thalassemia, and Diamond Blackfan anemia and acts by inhibiting signaling downstream of activin and other Transforming Growth Factor-β superfamily members. We found that erythropoietin and RAP-011 increased hemoglobin concentration in C57BL/6 mice and in hepcidin antimicrobial peptide 1 over expressing mice. While erythropoietin treatment depleted splenic iron stores in C57BL/6 mice, RAP-011 treatment did not deplete splenic iron stores in mice of either genotype. Bone marrow erythroid progenitors from erythropoietin-treated mice exhibited iron-restricted erythropoiesis, as indicated by increased median fluorescence intensity of transferrin receptor immunostaining by flow cytometry. In contrast, RAP-011-treated mice did not exhibit the same degree of iron-restricted erythropoiesis. In conclusion, we have demonstrated that RAP-011 can improve hemoglobin concentration in hepcidin antimicrobial peptide 1 transgenic mice. Our data support the hypothesis that RAP-011 has unique biologic effects which prevent or circumvent depletion of mouse splenic iron stores. RAP-011 may, therefore, be an appropriate therapeutic for trials in human anemias characterized by increased expression of hepcidin antimicrobial peptide and iron-restricted erythropoiesis.

  11. Activin-like factor from a Xenopus laevis cell line responsible for mesoderm induction.

    PubMed

    van den Eijnden-Van Raaij, A J; van Zoelent, E J; van Nimmen, K; Koster, C H; Snoek, G T; Durston, A J; Huylebroeck, D

    1990-06-21

    Induction of mesoderm during early amphibian embryogenesis can be mimicked in vitro by adding growth factors, including heparin-binding and type-beta transforming growth factors (TGF-beta), to isolated ectoderm explants from Xenopus laevis embryos. Although the mesoderm-inducing factor (MIF) from X. laevis XTC cells (XTC-MIF) has properties similar to TGF-beta, this factor is still unidentified. Recently, we obtained a number of homogeneous cell lines from the heterogeneous XTC population, which differ in their MIF production. Only one, XTC-GTX-11, produced MIF, although it was similar to the rest of the clones in its production of known growth factors, including TGF-beta activity. This observation, together with the identification of activin A as a potent MIF led us to study the parallel activities of MIF and activin. Here we report an analysis of activin-like activity from XTC cells and some of the XTC clones, including XTC-GTX-11. There is a clear consistent correlation between MIF activity and presence of activin activity, indicating that XTC-MIF is the Xenopus homologue of mammalian activin.

  12. Activins and inhibins in mammalian testis development: new models, new insights.

    PubMed

    Barakat, B; Itman, C; Mendis, S H; Loveland, K L

    2012-08-15

    The discovery of activin and inhibins as modulators of the hypothalamic-pituitary-gonadal axis has set the foundation for understanding their central importance to many facets of development and disease. This review contains an overview of the processes and cell types that are central to testis development and spermatogenesis and then provides an update focussed on information gathered over the past five years to address new concepts about how these proteins function to control testis development in fetal and juvenile life. Current knowledge about the interactive nature of the transforming growth factor-β (TGFβ) superfamily signalling network is applied to recent findings about activins and inhibins in the testis. Information about the regulated synthesis of signalling components and signalling regulators in the testis is integrated with new concepts that demonstrate their functional significance. The importance of activin bioactivity levels or dosage in controlling balanced growth of spermatogonial cells and their niche at different stages of testis development is highlighted.

  13. Isolation and characterization of Xenopus follistatin and activins.

    PubMed

    Fukui, A; Nakamura, T; Sugino, K; Takio, K; Uchiyama, H; Asashima, M; Sugino, H

    1993-09-01

    Xenopus follistatin and activins were purified from a Xenopus laevis cell line (XTC-F1) by four purification steps consisting of consecutive affinity chromatography on dextran sulfate-Sepharose and Sulfate Cellulofine, fast protein liquid chromatography gel permeation, and reverse-phase high performance liquid chromatography (HPLC). Our results thus obtained indicated that almost equimolar amounts of activins A, AB, and B were found to be present as a complex with follistatin (activin-binding protein) in the conditioned medium of XTC-F1 cells. Reverse-phase HPLC of the complex gave Xenopus follistatin and activins A, AB, and B. The purified Xenopus follistatin showed four major bands in a molecular mass range from 34 to 39 kDa by SDS-polyacrylamide gel electrophoresis under nonreducing conditions. The ability of each form of the protein to specifically bind activin was determined by activin-binding assay and ligand blotting analysis. Each protein was found to have the same NH2-terminus and its sequence was very homologous to that of mammalian follistatin. Several criteria including immunoblotting analysis and various functional assays revealed the existence of three isoforms of activins A, AB, and B in Xenopus, as in mammals. Xenopus activins significantly induced both ventral and dorsal mesoderm in explants of Xenopus blastula cells that would otherwise form epidermis. In a dose-dependent manner of each isoform of activin, the induced explants were able to differentiate into blood-like cells, coelomic epithelium, mesenchyme, muscle, and notochord. The induction patterns of three Xenopus activins were essentially the same. The mesoderm induction by the purified Xenopus activins was shown to be inhibited stoichiometrically by the purified Xenopus follistatin. These results indicate that Xenopus XTC-F1 cells secrete several molecular forms of follistatin/activin-binding protein and three isoforms of activins AB and B in addition to activin A.

  14. BAFF and APRIL from Activin A-Treated Dendritic Cells Upregulate the Antitumor Efficacy of Dendritic Cells In Vivo.

    PubMed

    Shurin, Michael R; Ma, Yang; Keskinov, Anton A; Zhao, Ruijing; Lokshin, Anna; Agassandian, Marianna; Shurin, Galina V

    2016-09-01

    The members of the TGFβ superfamily play a key role in regulating developmental and homeostasis programs by controlling differentiation, proliferation, polarization, and survival of different cell types. Although the role of TGFβ1 in inflammation and immunity is well evident, the contribution of other TGFβ family cytokines in the modulation of the antitumor immune response remains less documented. Here we show that activin A triggers SMAD2 and ERK1/2 pathways in dendritic cells (DC) expressing type I and II activin receptors, and upregulates production of the TNFα family cytokines BAFF (TALL-1, TNFSF13B) and APRIL (TALL-2, TNFSF13A), which is blocked by SMAD2 and ERK1/2 inhibitors, respectively. BAFF and APRIL derived from activin A-treated DCs upregulate proliferation and survival of T cells expressing the corresponding receptors, BAFF-R and TACI. In vivo, activin A-stimulated DCs demonstrate a significantly increased ability to induce tumor-specific CTLs and inhibit the growth of melanoma and lung carcinoma, which relies on DC-derived BAFF and APRIL, as knockdown of the BAFF and APRIL gene expression in activin A-treated DCs blocks augmentation of their antitumor potential. Although systemic administration of activin A, BAFF, or APRIL for the therapeutic purposes is not likely due to the pluripotent effects on malignant and nonmalignant cells, our data open a novel opportunity for improving the efficacy of DC vaccines. In fact, a significant augmentation of the antitumor activity of DC pretreated with activin A and the proven role of DC-derived BAFF and APRIL in the induction of antitumor immunity in vivo support this direction. Cancer Res; 76(17); 4959-69. ©2016 AACR. PMID:27364554

  15. 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

  16. Vascular Endothelial Growth Factor-A (VEGF-A) Mediates Activin A-Induced Human Trophoblast Endothelial-Like Tube Formation.

    PubMed

    Li, Yan; Zhu, Hua; Klausen, Christian; Peng, Bo; Leung, Peter C K

    2015-11-01

    Remodeling of maternal spiral arteries during pregnancy requires a subpopulation of extravillous cytotrophoblasts (EVTs) to differentiate into endovascular EVTs. Activin A, which is abundantly expressed at the maternal-fetal interface, has been shown to promote trophoblast invasion, but its role in endovascular differentiation remains unknown. Vascular endothelial growth factor-A (VEGF-A) is well recognized as a key regulator in trophoblast endovascular differentiation. Whether and how activin A might regulate VEGF-A production in human trophoblasts and its relationship to endovascular differentiation have yet to be determined. In the present study, we found that activin A increased VEGF-A production in primary and immortalized (HTR8/SVneo) human EVT cells. In addition, activin A enhanced HTR8/SVneo endothelial-like tube formation, and these effects were attenuated by pretreatment with small interfering RNA targeting VEGF-A or the VEGF receptor 1/2 inhibitor SU4312. Pretreatment with the activin/TGF-β type 1 receptor (ALK4/5/7) inhibitor SB431542 abolished the stimulatory effects of activin A on phosphorylated mothers against decapentaplegic (SMAD)-2/3 phosphorylation, VEGF-A production, and endothelial-like tube formation. Moreover, small interfering RNA-mediated down-regulation of SMAD2, SMAD3, or common SMAD4 abolished the effects of activin A on VEGF-A production and endothelial-like tube formation. In conclusion, activin A may promote human trophoblast cell endothelial-like tube formation by up-regulating VEGF-A production in an SMAD2/3-SMAD4-dependent manner. These findings provide insight into the cellular and molecular events regulated by activin A during human implantation. PMID:26327470

  17. Activin A-induced increase in LOX activity in human granulosa-lutein cells is mediated by CTGF.

    PubMed

    Chang, Hsun-Ming; Cheng, Jung-Chien; Liu, Yingtao; Klausen, Christian; Xu, Congjian; Leung, Peter C K

    2016-10-01

    Lysyl oxidase (LOX) is the key enzyme involved in the crosslinking of collagen and elastin that is essential for the formation of extracellular matrix (ECM). LOX-mediated ECM remodeling plays a critical role in follicle development, oocyte maturation and corpus luteum formation. To date, the regulation of LOX in human ovary has never been elucidated. Activin A and its functional receptors are highly expressed in ovarian follicles from an early developmental stage. They locally regulate follicle progression. The aim of this study was to investigate the effects of activin A on the expression of LOX and its extracellular enzyme activity in primary and immortalized human granulosa-lutein cells obtained from patients undergoing an in vitro fertilization procedure. We demonstrated that activin A significantly upregulated the expression of connective tissue growth factor (CTGF) and LOX via an activin/TGF-β type I receptor mediated-signaling pathway. Using a target depletion small interfering RNA knockdown approach, we further confirmed that the upregulation of CTGF expression resulted in an activin-A-induced increases in LOX expression and activity. These findings may provide insight into the mechanisms by which intrafollicular growth factors regulate the expression of LOX for ECM formation and tissue remodeling in the human ovary. PMID:27530347

  18. Seasonal changes in spermatogenesis and immunolocalization of inhibin/activin subunits in the wild male ground squirrel (Citellus dauricus Brandt).

    PubMed

    Sheng, Xia; Zhang, Haolin; Zhang, Wei; Song, Moshi; Zhang, Mengyuan; Li, Ben; Weng, Qiang; Watanabe, Gen; Taya, Kazuyoshi

    2008-12-01

    The objective of this study was to investigate the seasonal changes in spermatogenesis and the immunolocalization of the inhibin alpha and inhibin/activin (betaA and betaB) subunits during the breeding and non-breeding seasons in the wild male ground squirrel. The testicular weight and size and seminiferous tubule diameter were measured, and histological observations of testes were performed. The sections of the testes were immunostained by the avidin-biotin-peroxidase complex method (ABC) using polyclonal antisera raised against porcine inhibin alpha, inhibin/activin betaA and inhibin/activin betaB during the breeding and non-breeding seasons. There were marked variations in testicular weight and size and seminiferous tubule diameter between the breeding and non-breeding seasons, and all types of spermatogenic cells, including spermatozoa, were found in the breeding season. In addition, immunoreactivity was also detected for the inhibin alpha, betaA and betaB subunits in Sertoli and Leydig cells during the breeding season, but immunostaining was only present for the inhibin alpha and inhibin/activin betaB subunits in Sertoli cells during the non-breeding season. These results suggest that seasonal changes in testicular weight and size and seminiferous tubule diameter of wild ground squirrels are correlated with changes in spermatogenesis, and the cellular localization of the inhibin/activin subunits showed season related changes in the breeding and non-breeding seasons.

  19. The role of activin in mammary gland development and oncogenesis.

    PubMed

    Dunphy, Karen A; Schneyer, Alan L; Hagen, Mary J; Jerry, D Joseph

    2011-06-01

    TGFβ contributes to mammary gland development and has paradoxical roles in breast cancer because it has both tumor suppressor and tumor promoter activity. Another member of the TGFβ superfamily, activin, also has roles in the developing mammary gland, but these functions, and the role of activin in breast cancer, are not well characterized. TGFβ and activin share the same intracellular signaling pathways, but divergence in their signaling pathways are suggested. The purpose of this review is to compare the spatial and temporal expression of TGFβ and activin during mammary gland development, with consideration given to their functions during each developmental period. We also review the contributions of TGFβ and activin to breast cancer resistance and susceptibility. Finally, we consider the systemic contributions of activin in regulating obesity and diabetes; and the impact this regulation has on breast cancer. Elevated levels of activin in serum during pregnancy and its influence on pregnancy associated breast cancer are also considered. We conclude that evidence demonstrates that activin has tumor suppressing potential, without definitive indication of tumor promoting activity in the mammary gland, making it a good target for development of therapeutics.

  20. Uric acid: a modulator of prostate cells and activin sensitivity.

    PubMed

    Sangkop, Febbie; Singh, Geeta; Rodrigues, Ely; Gold, Elspeth; Bahn, Andrew

    2016-03-01

    Elevated serum uric acid (SUA) or urate is associated with inflammation and gout. Recent evidence has linked urate to cancers, but little is known about urate effects in prostate cancer. Activins are inflammatory cytokines and negative growth regulators in the prostate. A hallmark of prostate cancer progression is activin insensitivity; however, mechanisms underlying this are unclear. We propose that elevated SUA is associated with prostate cancer counteracting the growth inhibitory effects of activins. The expression of activins A and B, urate transporter GLUT9 and tissue urate levels were examined in human prostate disease. Intracellular and secreted urate and GLUT9 expression were assessed in human prostate cancer cell lines. Furthermore, the effects of urate and probenecid, a known urate transport inhibitor, were determined in combination with activin A. Activin A expression was increased in low-grade prostate cancer, whereas activin B expression was reduced in high-grade prostate cancer. Intracellular urate levels decreased in all prostate pathologies, while GLUT9 expression decreased in benign prostatic hyperplasia, prostatitis and high-grade prostate cancer. Activin responsive LNCaP cells had higher intracellular and lower secreted urate levels than activin-insensitive PC3 cells. GLUT9 expression in prostate cancer cells was progressively lower than in prostate epithelial cells. Elevated extracellular urate was growth promoting in vitro, which was abolished by the gout medication probenecid, and it antagonized the growth inhibitory effects of activins. This study shows for the first time that a change in plasma or intracellular urate levels, possibly involving GLUT9 and a urate efflux transporter, has an impact on prostate cancer cell growth, and that lowering SUA levels in prostate cancer is likely to be therapeutically beneficial. PMID:26910779

  1. Identification of a potent Xenopus mesoderm-inducing factor as a homologue of activin A.

    PubMed

    Smith, J C; Price, B M; Van Nimmen, K; Huylebroeck, D

    1990-06-21

    The first inductive interaction in amphibian development is mesoderm induction, when a signal from the vegetal hemisphere of the blastula induces mesoderm from overlying equatorial cells. Recently, several 'mesoderm-inducing factors' (MIFs) have been discovered. These cause isolated Xenopus animal caps to form mesodermal cell types such as muscle, instead of their normal fate of epidermis. The MIFs fall into two classes. One comprises members of the fibroblast growth factor (FGF) family, and the other members of the transforming growth factor type beta (TGF-beta) family. Of the latter group, the most potent is XTC-MIF, a protein produced by Xenopus XTC cells. Here we show that XTC-MIF is the homologue of mammalian activin A. Activins modulate the release of follicle-stimulating hormone from cultured anterior pituitary cells and cause the differentiation of two erythroleukaemia cell lines. Our results indicate that these molecules may also act in early development during formation of the mesoderm.

  2. Activin A balance regulates epithelial invasiveness and tumorigenesis

    PubMed Central

    Le Bras, Grégoire F.; Loomans, Holli A.; Taylor, Chase; Revetta, Frank; Andl, Claudia D.

    2015-01-01

    Activin A is a member of the TGFβ superfamily. Activin A and TGFβ have multiple common downstream targets and have been described to merge in their intracellular signaling cascades and function. We have previously demonstrated that coordinated loss of E-cadherin and TGFβ receptor II results in epithelial cell invasion. When grown in three-dimensional organotypic reconstruct cultures, esophageal keratinocytes expressing dominant-negative mutants of E-cadherin and TGFβ receptor II showed activated Smad2 in the absence of functional TGFβ receptor II. However, we could show increased levels of Activin A secretion, and Activin A was able to induce Smad2 phosphorylation. Growth factor secretion can activate autocrine and paracrine signaling, which affects crosstalk between the epithelial compartment and the surrounding microenvironment. We show that treatment with the Act A antagonist Follistatin or with a neutralizing Activin A antibody can increase cell invasion in organotypic cultures in a fibroblast- and MMP-dependent manner. Similarly, suppression of Activin A with shRNA increases cell invasion and tumorigenesis in vivo. Therefore, we conclude that maintaining a delicate balance of Activin A expression is critical for homeostasis in the esophageal microenvironment. PMID:25068654

  3. Activin Signaling in the Pathogenesis and Therapy of Neuropsychiatric Diseases

    PubMed Central

    Link, Andrea S.; Zheng, Fang; Alzheimer, Christian

    2016-01-01

    Activins are members of the transforming growth factor β (TGFβ) family and serve as multifunctional regulatory proteins in many tissues and organs. In the brain, activin A, which is formed by two disulfide-linked βA subunits, is recognized as the predominant player in activin signaling. Over the last years, considerable progress has been made in elucidating novel and unexpected functions of activin in the normal and diseased brain and in deciphering the underlying molecular mechanisms. Initially identified as a neurotrophic and protective factor during development and in several forms of acute injury, the scope of effects of activin A in the adult central nervous system (CNS) has been considerably broadened by now. Here, we will highlight recent findings that bear significance for a better understanding of the pathogenesis of various neuropsychiatric diseases and might hold promise for novel therapeutic strategies. While the basal level of activin A in the adult brain is low, significant short-term up-regulation occurs in response to increased neuronal activity. In fact, brief exposure to an enriched environment (EE) is already sufficient to considerably strengthen activin signaling. Enhancement of this pathway tunes the performance of glutamatergic and GABAergic synapses in a fashion that impacts on cognitive functions and affective behavior, counteracts death-inducing signals through extrasynaptic NMDA receptors (NMDARs), and stimulates adult neurogenesis in the hippocampus. We will discuss how impaired activin signaling is involved in anxiety disorders, depression, drug dependence, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s, and how reinforcement of activin signaling might be exploited for therapeutic interventions. PMID:27242425

  4. Activin A is essential for neurogenesis following neurodegeneration.

    PubMed

    Abdipranoto-Cowley, Andrea; Park, Jin Sung; Croucher, David; Daniel, James; Henshall, Susan; Galbraith, Sally; Mervin, Kyle; Vissel, Bryce

    2009-06-01

    It has long been proposed that excitotoxicity contributes to nerve cell death in neurodegenerative diseases. Activin A, a member of the transforming growth factor-beta superfamily, is expressed by neurons following excitotoxicity. We show for the first time that this activin A expression is essential for neurogenesis to proceed following neurodegeneration. We found that intraventricular infusion of activin A increased the number of newborn neurons in the dentate gyrus, CA3, and CA1 layers of the normal adult hippocampus and also, following lipopolysaccharide administration, had a potent inhibitory effect on gliosis in vivo and on microglial proliferation in vivo and in vitro. Consistent with the role of activin A in regulating central nervous system inflammation and neurogenesis, intraventricular infusion of follistatin, an activin A antagonist, profoundly impaired neurogenesis and increased the number of microglia and reactive astrocytes following onset of kainic acid-induced neurodegeneration. These results show that inhibiting endogenous activin A is permissive for a potent underlying inflammatory response to neurodegeneration. We demonstrate that the anti-inflammatory actions of activin A account for its neurogenic effects following neurodegeneration because co-administration of nonsteroidal anti-inflammatory drugs reversed follistatin's inhibitory effects on neurogenesis in vivo. Our work indicates that activin A, perhaps working in conjunction with other transforming growth factor-beta superfamily molecules, is essential for neurogenesis in the adult central nervous system following excitotoxic neurodegeneration and suggests that neurons can regulate regeneration by suppressing the inflammatory response, a finding with implications for understanding and treating acute and chronic neurodegenerative diseases. PMID:19489097

  5. An activin A/BMP2 chimera, AB204, displays bone-healing properties superior to those of BMP2.

    PubMed

    Yoon, Byung-Hak; Esquivies, Luis; Ahn, Chihoon; Gray, Peter C; Ye, Sang-Kyu; Kwiatkowski, Witek; Choe, Senyon

    2014-09-01

    Recombinant bone morphogenetic protein 2 (rhBMP2) has been used clinically to treat bone fractures in human patients. However, the high doses of rhBMP2 required for a therapeutic response can cause undesirable side effects. Here, we demonstrate that a novel Activin A/BMP2 (AB2) chimera, AB204, promotes osteogenesis and bone healing much more potently and effectively than rhBMP2. Remarkably, 1 month of AB204 treatment completely heals tibial and calvarial defects of critical size in mice at a concentration 10-fold lower than a dose of rhBMP2 that only partially heals the defect. We determine the structure of AB204 to 2.3 Å that reveals a distinct BMP2-like fold in which the Activin A sequence segments confer insensitivity to the BMP2 antagonist Noggin and an affinity for the Activin/BMP type II receptor ActRII that is 100-fold greater than that of BMP2. The structure also led to our identification of a single Activin A-derived amino acid residue, which, when mutated to the corresponding BMP2 residue, resulted in a significant increase in the affinity of AB204 for its type I receptor BMPRIa and a further enhancement in AB204's osteogenic potency. Together, these findings demonstrate that rationally designed AB2 chimeras can provide BMP2 substitutes with enhanced potency for treating non-union bone fractures.

  6. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A.

    PubMed

    Hatsell, Sarah J; Idone, Vincent; Wolken, Dana M Alessi; Huang, Lily; Kim, Hyon J; Wang, Lili; Wen, Xialing; Nannuru, Kalyan C; Jimenez, Johanna; Xie, Liqin; Das, Nanditha; Makhoul, Genevieve; Chernomorsky, Rostislav; D'Ambrosio, David; Corpina, Richard A; Schoenherr, Christopher J; Feeley, Kieran; Yu, Paul B; Yancopoulos, George D; Murphy, Andrew J; Economides, Aris N

    2015-09-01

    Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodically exuberant heterotopic ossification (HO), whereby skeletal muscle is abnormally converted into misplaced, but histologically normal bone. This HO leads to progressive immobility with catastrophic consequences, including death by asphyxiation. FOP results from mutations in the intracellular domain of the type I BMP (bone morphogenetic protein) receptor ACVR1; the most common mutation alters arginine 206 to histidine (ACVR1(R206H)) and has been thought to drive inappropriate bone formation as a result of receptor hyperactivity. We unexpectedly found that this mutation rendered ACVR1 responsive to the activin family of ligands, which generally antagonize BMP signaling through ACVR1 but cannot normally induce bone formation. To test the implications of this finding in vivo, we engineered mice to carry the Acvr1(R206H) mutation. Because mice that constitutively express Acvr1[R206H] die perinatally, we generated a genetically humanized conditional-on knock-in model for this mutation. When Acvr1[R206H] expression was induced, mice developed HO resembling that of FOP; HO could also be triggered by activin A administration in this mouse model of FOP but not in wild-type controls. Finally, HO was blocked by broad-acting BMP blockers, as well as by a fully human antibody specific to activin A. Our results suggest that ACVR1(R206H) causes FOP by gaining responsiveness to the normally antagonistic ligand activin A, demonstrating that this ligand is necessary and sufficient for driving HO in a genetically accurate model of FOP; hence, our human antibody to activin A represents a potential therapeutic approach for FOP.

  7. Therapeutic effects of soluble dietary fiber consumption on type 2 diabetes mellitus

    PubMed Central

    Chen, Chunye; Zeng, Yuan; Xu, Jing; Zheng, Hongting; Liu, Jun; Fan, Rong; Zhu, Wenyi; Yuan, Lijia; Qin, Yu; Chen, Shihui; Zhou, Yong; Wu, Ying; Wan, Jing; Mi, Mantian; Wang, Jian

    2016-01-01

    Soluble dietary fiber (DF) reduces the risk of developing diabetes and may have therapeutic effects in patients with type 2 diabetes mellitus (DM2). The present study aimed to investigate the effect of soluble DF on metabolic control in patients with DM2. A total of 117 patients with DM2 between the ages of 40 and 70 were assessed. Patients were randomly assigned to one of two groups, and administered extra soluble DF (10 or 20 g/day), or to a control group (0 g/day) for one month. Blood glucose, serum insulin and connecting peptide (C-peptide) levels, and the insulin resistance index, as determined using the homeostatic model assessment method, were measured during fasting and up to 2-h postprandially prior to and following one month of treatment. Other measurements included serum levels of glycated albumin (GA), blood lipid profiles, and an analysis of the blood pressure, body weight and waist/hip ratio of all patients. Following intervention, the levels of 2-h blood glucose, fasting insulin and lipoprotein(a), and the insulin resistance index, were significantly improved in all groups. Furthermore, the fasting blood glucose, 2-h insulin, fasting C-peptide, 2-h C-peptide, GA and triglyceride (TG) levels were significantly improved in the soluble DF groups. The 20 g/day soluble DF group exhibited significantly improved fasting blood glucose and low-density lipoprotein levels, as well as a significantly improved insulin resistance index. In addition, 10 and 20 g/day soluble DF significantly improved the waist and hip circumferences and levels of TGs and apolipoprotein A. The results of the present study suggested that increased and regular consumption of soluble DF led to significant improvements in blood glucose levels, insulin resistance and metabolic profiles, without improving the secretory function of the islets of Langerhans, over a short-term intervention period in patients with DM2. PMID:27446349

  8. Inhibins and activins in human ovulation, conception and pregnancy.

    PubMed

    Lockwood, G M; Muttukrishna, S; Ledger, W L

    1998-01-01

    The activins and inhibins are glycoproteins that belong to the transforming growth factor-beta superfamily and, as such, have diverse effects at many stages during growth and development. Originally identified by their effects on follicle stimulating hormone in males and females, the recent development of specific and sensitive assays for this group of polypeptides has permitted the elucidation of their role in 'fine-tuning' the hypothalamic-pituitary-gonadal axis. This review article focuses on the roles of inhibin and activin in female reproductive physiology with reference to possible future clinical applications in the investigation of infertility and abnormal pregnancy.

  9. Activin Enhances α- to β-Cell Transdifferentiation as a Source For β-Cells In Male FSTL3 Knockout Mice.

    PubMed

    Brown, Melissa L; Andrzejewski, Danielle; Burnside, Amy; Schneyer, Alan L

    2016-03-01

    Diabetes results from inadequate β-cell number and/or function to control serum glucose concentrations so that replacement of lost β-cells could become a viable therapy for diabetes. In addition to embryonic stem cell sources for new β-cells, evidence for transdifferentiation/reprogramming of non-β-cells to functional β-cells is accumulating. In addition, de-differentiation of β-cells observed in diabetes and their subsequent conversion to α-cells raises the possibility that adult islet cell fate is malleable and controlled by local hormonal and/or environmental cues. We previously demonstrated that inactivation of the activin antagonist, follistatin-like 3 (FSTL3) resulted in β-cell expansion and improved glucose homeostasis in the absence of β-cell proliferation. We recently reported that activin directly suppressed expression of critical α-cell genes while increasing expression of β-cell genes, supporting the hypothesis that activin is one of the local hormones controlling islet cell fate and that increased activin signaling accelerates α- to β-cell transdifferentiation. We tested this hypothesis using Gluc-Cre/yellow fluorescent protein (YFP) α-cell lineage tracing technology combined with FSTL3 knockout (KO) mice to label α-cells with YFP. Flow cytometry was used to quantify unlabeled and labeled α- and β-cells. We found that Ins+/YFP+ cells were significantly increased in FSTL3 KO mice compared with wild type littermates. Labeled Ins+/YFP+ cells increased significantly with age in FSTL3 KO mice but not wild type littermates. Sorting results were substantiated by counting fluorescently labeled cells in pancreatic sections. Activin treatment of isolated islets significantly increased the number of YFP+/Ins+ cells. These results suggest that α- to β-cell transdifferentiation is influenced by activin signaling and may contribute substantially to β-cell mass.

  10. A drug delivery hydrogel system based on activin B for Parkinson's disease.

    PubMed

    Li, Juan; Darabi, Mohammadali; Gu, Jingjing; Shi, Junbin; Xue, Jinhua; Huang, Lu; Liu, Yutong; Zhang, Lei; Liu, N; Zhong, Wen; Zhang, Lin; Xing, Malcolm; Zhang, Lu

    2016-09-01

    Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Activins are members of the superfamily of transforming growth factors and have many potential neuroprotective effects. Herein, at the first place, we verified activin B's neuroprotective role in a PD model, and revealed that activin B's fast release has limited function in the PD therapy. To this end, we developed a multi-functional crosslinker based thermosensitive injectable hydrogels to deliver activin B, and stereotactically injected the activin B-loaded hydrogel into the striatum of a mouse model of PD. The histological evaluation showed that activin B can be detected even 5 weeks post-surgery in PD mice implanted with activin B-loaded hydrogels, and activin B-loaded hydrogels can significantly increase the density of tyrosine hydroxylase positive (TH(+)) nerve fibers and reduce inflammatory responses. The behavioral evaluation demonstrated that activin B-loaded hydrogels significantly improved the performance of the mice in the PD model. Meanwhile, we found that hydrogels can slightly induce the activation of microglia cells and astrocytes, while cannot induce apoptosis in the striatum. Overall, our data demonstrated that the developed activin B-loaded hydrogels provide sustained release of activin B for over 5 weeks and contribute to substantial cellular protection and behavioral improvement, suggesting their potential as a therapeutic strategy for PD.

  11. XSmad2 directly activates the activin-inducible, dorsal mesoderm gene XFKH1 in Xenopus embryos.

    PubMed Central

    Howell, M; Hill, C S

    1997-01-01

    Transforming growth factor (TGF)-beta family members play a central role in mesoderm induction during early embryogenesis in Xenopus. Although a number of target genes induced as an immediate-early response to activin-like members of the family have been described, little is known about the molecular mechanisms involved. Our systematic analysis of the activin induction of the target gene XFKH1 reveals two regions that mediate activin-responsive transcription: one, in the first intron, is targeted directly by the activin-signalling pathway; the other, in the 5' flanking sequences, responds to activin indirectly, possibly being required for maintenance of gene expression. We demonstrate that a 107 bp region of the XFKH1 first intron acts as an enhancer and confers activin inducibility onto a minimal uninducible promoter in the absence of new protein synthesis. It bears little sequence similarity to other activin responsive sequences. We further demonstrate that overexpression of a constitutively active derivative of Xenopus Smad2 (XSmad2), which has been implicated as a component of the activin signalling pathway, is sufficient for direct activation of transcription via this enhancer. Moreover, we show that XSmad2 acts indirectly on the proximal promoter element induced by activin via an indirect mechanism. These results establish the XFKH1 intron enhancer as a direct nuclear target of the activin signalling pathway in Xenopus embryos, and provide strong new evidence that XSmad2 is a transducer of activin signals. PMID:9405370

  12. X-ray structure of a soluble Rieske-type ferredoxin from Mus musculus

    SciTech Connect

    Levin, Elena J.; Elsen, Nathaniel L.; Seder, Kory D.; McCoy, Jason G.; Fox, Brian G; Phillips, Jr., George N.

    2009-03-11

    The 2.07 {angstrom} resolution X-ray crystal structure of a soluble Rieske-type ferredoxin from Mus musculus encoded by the gene Mm.266515 is reported. Although they are present as covalent domains in eukaryotic membrane oxidase complexes, soluble Rieske-type ferredoxins have not previously been observed in eukaryotes. The overall structure of the mouse Rieske-type ferredoxin is typical of this class of iron-sulfur proteins and consists of a larger partial {beta}-barrel domain and a smaller domain containing Cys57, His59, Cys80 and His83 that binds the [2Fe-2S] cluster. The S atoms of the cluster are hydrogen-bonded by six backbone amide N atoms in a pattern typical of membrane-bound high-potential eukaryotic respiratory Rieske ferredoxins. However, phylogenetic analysis suggested that the mouse Rieske-type ferredoxin was more closely related to bacterial Rieske-type ferredoxins. Correspondingly, the structure revealed an extended loop most similar to that seen in Rieske-type ferredoxin subunits of bacterial aromatic dioxygenases, including the positioning of an aromatic side chain (Tyr85) between this loop and the [2Fe-2S] cluster. The mouse Rieske-type ferredoxin was shown to be capable of accepting electrons from both eukaryotic and prokaryotic oxidoreductases, although it was unable to serve as an electron donor for a bacterial monooxygenase complex. The human homolog of mouse Rieske-type ferredoxin was also cloned and purified. It behaved identically to mouse Rieske-type ferredoxin in all biochemical characterizations but did not crystallize. Based on its high sequence identity, the structure of the human homolog is likely to be modeled well by the mouse Rieske-type ferredoxin structure.

  13. X-ray structure of a soluble Rieske-type ferredoxin from Mus musculus

    SciTech Connect

    Levin, Elena J.; Elsen, Nathaniel L.; Seder, Kory D.; McCoy, Jason G.; Fox, Brian G.; Phillips Jr, George N.

    2008-09-01

    The X-ray crystal structure of a soluble Rieske ferredoxin from M. musculus was solved at 2.07 Å resolution, revealing an iron–sulfur cluster-binding domain with similar architecture to the Rieske-type domains of bacterial aromatic dioxygenases. The ferredoxin was also shown to be capable of accepting electrons from both eukaryotic and prokaryotic oxidoreductases. The 2.07 Å resolution X-ray crystal structure of a soluble Rieske-type ferredoxin from Mus musculus encoded by the gene Mm.266515 is reported. Although they are present as covalent domains in eukaryotic membrane oxidase complexes, soluble Rieske-type ferredoxins have not previously been observed in eukaryotes. The overall structure of the mouse Rieske-type ferredoxin is typical of this class of iron–sulfur proteins and consists of a larger partial β-barrel domain and a smaller domain containing Cys57, His59, Cys80 and His83 that binds the [2Fe–2S] cluster. The S atoms of the cluster are hydrogen-bonded by six backbone amide N atoms in a pattern typical of membrane-bound high-potential eukaryotic respiratory Rieske ferredoxins. However, phylogenetic analysis suggested that the mouse Rieske-type ferredoxin was more closely related to bacterial Rieske-type ferredoxins. Correspondingly, the structure revealed an extended loop most similar to that seen in Rieske-type ferredoxin subunits of bacterial aromatic dioxygenases, including the positioning of an aromatic side chain (Tyr85) between this loop and the [2Fe–2S] cluster. The mouse Rieske-type ferredoxin was shown to be capable of accepting electrons from both eukaryotic and prokaryotic oxidoreductases, although it was unable to serve as an electron donor for a bacterial monooxygenase complex. The human homolog of mouse Rieske-type ferredoxin was also cloned and purified. It behaved identically to mouse Rieske-type ferredoxin in all biochemical characterizations but did not crystallize. Based on its high sequence identity, the structure of the

  14. 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

  15. Structure and activation of pro-activin A.

    PubMed

    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

  16. IMMUNOLOCALIZATION OF INHIBIN/ACTIVIN SUBUNITS AND STEROIDOGENIC ENZYMES IN THE TESTES OF AN ADULT AFRICAN ELEPHANT (LOXODONTA AFRICANA).

    PubMed

    Li, Qinglin; Lu, Lu; Weng, Qiang; Kawakami, Shigehisa; Saito, Eriko; Yamamoto, Tatsuya; Yamamoto, Yuki; Kaewmanee, Saroch; Nagaoka, Kentaro; Watanabe, Gen; Taya, Kazuyoshi

    2016-06-01

    In this case report, the authors investigated immunolocalization of inhibin α and inhibin/activin βA and βB subunits, as well as steroidogenic enzymes, in the testes of an African elephant. Testes were collected from a reproductively active male African elephant (24 yr old) at autopsy. Histologically, all types of spermatogenic cells including mature-phase spermatozoa were found in the seminiferous tubules. Positive immunostaining for inhibin α and inhibin/activin βA and βB subunits was observed in Sertoli and Leydig cells. In addition, P450scc, 3βHSD, P450c17, and P450arom were also detected in the cytoplasm of Leydig cells. These results suggested that Leydig cells of adult African elephant testes have the ability to synthesize progestin, androgen, and estrogen, whereas both Sertoli and Leydig cells appear as a major source of inhibin secretion in the male African elephant.

  17. Replica exchange molecular dynamics simulations of an α/β-type small acid soluble protein (SASP).

    PubMed

    Ojeda-May, P; Pu, Jingzhi

    2013-12-31

    Small acid soluble proteins (SASPs) of α/β-type play a major role in the resistance of spore DNAs to external assaults. It has been found that α/β-type SASP exhibits intrinsic disorder on isolation, but it acquires a defined native state upon binding to DNA. This disorder to order transition is not yet understood. Other questions related to the role of the thermodynamics and structure of the individual protein in the complex formation remain elusive. Characterization of the unbound state of α/β-type SASP in experiments could be a challenging problem because of the heterogeneous nature of the ensemble. Here, computer simulations can help gain more insights into the unbound state of α/β-type SASP. In the present work, by using replica exchange molecular dynamics (REMD), we simulated an α/β-type SASP on isolation with an implicit solvent. We found that α/β-type SASP undergoes a continuous phase transition with a small free energy barrier, a common feature of intrinsically disordered proteins (IDPs). Additionally, we detected the presence of residual α-helical structures at local level and a high degree of plasticity in the chain which can contribute to the fast disorder to order transition by reducing the fly-casting mechanism.

  18. Activin A and follistatin during the oestrous cycle and early pregnancy in ewes.

    PubMed

    O'Connell, Anne R; McNatty, Kenneth P; Hurst, Peter R; Spencer, Thomas E; Bazer, Fuller W; Reader, Karen L; Johnstone, Peter D; Davis, George H; Juengel, Jennifer L

    2016-03-01

    The activin pathway has been postulated to be involved in regulation of multiple reproductive processes important for survival of the conceptus. These processes include luteinisation of the follicular cells and thus function of the corpus luteum, early embryo development and uterine function including implantation of the conceptus. Therefore, the aim of the current study was to determine whether the concentrations of activin A and follistatin (FST), an activin-binding protein, differed between ewes with a lifetime history of enhanced or reduced embryonic survival (ES). The mRNAs encoding FST and activin A (inhibin beta A subunit; INHBA) were present in the uterus and abundant in the uterine luminal or glandular epithelia by day 18 of gestation. A peak of activin A was observed in the systemic circulation around the time of oestrus, and activin A concentrations were elevated in animals with reduced ES during the oestrous cycle and early gestation. Concentrations of activin A in uterine fluid were approximately twofold greater on day 16 of gestation in ewes with reduced ES compared to those with enhanced ES. No consistent differences in FST were observed between these groups. Treatment of luteinising ovine granulosa cells with activin A in vitro suppressed progesterone secretion providing evidence of a potential pathway whereby increased concentrations of activin A may decrease ES. PMID:26733604

  19. Novel ovarian regulatory peptides: inhibin, activin, and follistatin.

    PubMed

    Ling, N; DePaolo, L V; Bicsak, T A; Shimasaki, S

    1990-09-01

    Based on the extensive amount of research on inhibin and related polypeptides accomplished during the past 5 years, the inhibin concept put forth more than 50 years ago has not only become well established but also more complex than originally imagined. The closed-loop feedback mechanism of ovarian inhibin and pituitary FSH has been joined by possible "inhibin-like" actions of follistatin and FSH-stimulatory effects of activin. In addition, in vitro experiments suggest possible autocrine and paracrine functions for the gonadal polypeptide hormones. Figure 3 shows a simplistic diagram summarizing our current understanding of inhibin/activin and follistatin action along the hypothalamic-pituitary-gonadal axis. Hopefully, research in the coming years will allow us to remove the many question marks still remaining but will undoubtedly add others.

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

    SciTech Connect

    Tsvitov, Marianna; Frampton, Arthur R.; Shah, Waris A.; Wendell, Steven K.; Ozuer, Ali; Kapacee, Zoher; Goins, William F.; Cohen, Justus B.; Glorioso, Joseph C. . E-mail: glorioso@pitt.edu

    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 and 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.

  1. Primary focal and segmental glomerulosclerosis and soluble factor urokinase-type plasminogen activator receptor.

    PubMed

    Trimarchi, Hernán

    2013-11-01

    Primary focal and segmental glomerulosclerosis (FSGS) may be due to genetic or acquired etiologies and is a common cause of nephrotic syndrome with high morbidity that often leads to end-stage renal failure. The different available therapeutic approaches are unsuccessful, in part due to partially deciphered heterogeneous and complex pathophysiological mechanisms. Moreover, the term FSGS, even in its primary form, comprises a histological description shared by a number of different causes with completely different molecular pathways of disease. This review focuses on the latest developments regarding the pathophysiology of primary acquired FSGS caused by soluble factor urokinase type plasminogen activator receptor, a circulating permeability factor involved in proteinuria and edema formation, and describes recent advances with potential success in therapy.

  2. 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

  3. A novel method for the purification of low soluble recombinant C-type lectin proteins.

    PubMed

    Yin, Chunhui; Jia, Ying; Garcia, Carlos A

    2012-08-31

    Snake venoms contain a complex mixture of many biological molecules including proteins. The purification of recombinant proteins is a key step in studying their function and structure with affinity chromatography as the common method used in their purification. In bacterial expression systems, hydrophobic recombinant proteins are usually precipitated into inclusion bodies, and contaminants are typically associated with tagged proteins after purification. The purpose of this study was to develop a procedure to purify hydrophobic recombinant proteins without an affinity tag. Snake venom mature C-type lectin-like proteins (CLPs) with a tag were cloned, expressed, and purified by repeated sonication and wash steps. The effects of the signal peptide on the expression and solubility of the recombinant protein were investigated. The CLPs in washed inclusion bodies were solubilized and refolded by dialysis. The CLPs without a tag were successfully purified with a yield 38 times higher than the traditional method, and inhibited blood platelet aggregation with an IC(50) of 100.57 μM in whole blood. This novel procedure is a rapid, and inexpensive method to purify functional recombinant hydrophobic CLPs from snake venoms useful in the development of drug therapies. PMID:22867876

  4. 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

  5. Soluble Urokinase-Type Plasminogen Activator Receptor Levels in Patients With Schizophrenia

    PubMed Central

    Nielsen, Jimmi; Røge, Rasmus; Pristed, Sofie Gry; Viuff, Anne Grethe; Ullum, Henrik; Thørner, Lise Wegner; Werge, Thomas; Vang, Torkel

    2015-01-01

    Background: The etiology of schizophrenia remains largely unknown but alterations in the immune system may be involved. In addition to the psychiatric symptoms, schizophrenia is also associated with up to 20 years reduction in life span. Soluble urokinase-type plasminogen activator receptor (suPAR) is a protein that can be measured in blood samples and reflects the levels of inflammatory activity. It has been associated with mortality and the development of type 2 diabetes and cardiovascular disease. Methods: suPAR levels in patients with schizophrenia were compared to healthy controls from the Danish Blood Donor Study. SuPAR levels were dichotomized at >4.0 ng/ml, which is considered the threshold for low grade inflammation. A multiple logistic regression model was used and adjusted for age, sex, and current smoking. Results: In total we included 1009 subjects, 105 cases with schizophrenia (10.4%) and 904 controls (89.6%). The mean suPAR values were 4.01 ng/ml (SD = 1.43) for the cases vs 1.91 ng/ml (SD = 1.35) for the controls (P < .001). Multiple logistic regression with odds ratio (OR) for suPAR levels >4.0 ng/ml yielded: schizophrenia, OR: 46.15 95% CI 22.69–93.87, P < .001; age, OR: 1.02 95% CI 0.99–1.02, P = .15; male sex, OR: 0.70 95% CI 0.35–1.36, P = .29; and current smoking, OR: 3.51 95% CI 1.78–6.94, P < .001. Conclusions: Patients with schizophrenia had significantly higher suPAR levels than healthy controls. Further studies are warranted to clarify if elevated suPAR levels are involved in the pathophysiology of schizophrenia and/or the increased mortality found in patients with schizophrenia. PMID:25154621

  6. Activin A Predicts Left Ventricular Remodeling and Mortality in Patients with ST-Elevation Myocardial Infarction

    PubMed Central

    Lin, Jeng-Feng; Hsu, Shun-Yi; Teng, Ming-Sheng; Wu, Semon; Hsieh, Chien-An; Jang, Shih-Jung; Liu, Chih-Jen; Huang, Hsuan-Li; Ko, Yu-Lin

    2016-01-01

    Background Activin A levels increase in a variety of heart diseases including ST-elevation myocardial infarction (STEMI). The aim of this study is to investigate whether the level of activin A can be beneficial in predicting left ventricular remodeling, heart failure, and death in patients with ST-elevation myocardial infarction (STEMI). Methods We enrolled 278 patients with STEMI who had their activin A levels measured on day 2 of hospitalization. Echocardiographic studies were performed at baseline and were repeated 6 months later. Thereafter, the clinical events of these patients were followed for a maximum of 3 years, including all-cause death and readmission for heart failure. Results During hospitalization, higher activin A level was associated with higher triglyceride level, lower left ventricular ejection fraction (LVEF), and lower left ventricular end diastolic ventricular volume index (LVEDVI) in multivariable linear regression model. During follow-up, patients with activin A levels > 129 pg/ml had significantly lower LVEF, and higher LVEDVI at 6 months. Kaplan-Meier survival curves showed that activin A level > 129 pg/ml was a predictor of all-cause death (p = 0.022), but not a predictor of heart failure (p = 0.767). Conclusions Activin A level > 129 pg/ml predicts worse left ventricular remodeling and all-cause death in STEMI. PMID:27471355

  7. Constitutively active FOXO1 diminishes activin induction of Fshb transcription in immortalized gonadotropes.

    PubMed

    Park, Chung Hyun; Skarra, Danalea V; Rivera, Alissa J; Arriola, David J; Thackray, Varykina G

    2014-01-01

    In the present study, we investigate whether the FOXO1 transcription factor modulates activin signaling in pituitary gonadotropes. Our studies show that overexpression of constitutively active FOXO1 decreases activin induction of murine Fshb gene expression in immortalized LβT2 cells. We demonstrate that FOXO1 suppression of activin induction maps to the -304/-95 region of the Fshb promoter containing multiple activin response elements and that the suppression requires the FOXO1 DNA-binding domain (DBD). FOXO1 binds weakly to the -125/-91 region of the Fshb promoter in a gel-shift assay. Since this region of the promoter contains a composite SMAD/FOXL2 binding element necessary for activin induction of Fshb transcription, it is possible that FOXO1 DNA binding interferes with SMAD and/or FOXL2 function. In addition, our studies demonstrate that FOXO1 directly interacts with SMAD3/4 but not SMAD2 in a FOXO1 DBD-dependent manner. Moreover, we show that SMAD3/4 induction of Fshb-luc and activin induction of a multimerized SMAD-binding element-luc are suppressed by FOXO1 in a DBD-dependent manner. These results suggest that FOXO1 binding to the proximal Fshb promoter as well as FOXO1 interaction with SMAD3/4 proteins may result in decreased activin induction of Fshb in gonadotropes.

  8. Upregulation of activin A gene by butyrate in human colon cancer cell lines.

    PubMed

    Sonoyama, Kei; Pholnukulkit, Pimara; Toyoda, Masahiko; Rutatip, Suriya; Kasai, Takanori

    2003-06-01

    Activin A has been reported to play a role in the progression of colorectal cancer. Because dietary fiber protects against colorectal cancer, we hypothesized that butyrate, a fermentation product of dietary fiber, may affect the expression of activin A in colon cancer cells. Semiquantitative RT-PCR demonstrated that the activin A gene was upregulated by sodium butyrate in the human colon cancer cell lines HT-29 and Caco-2 in a concentration- and time-dependent manner. However, the activin A gene did not respond to sodium butyrate in the human normal colonic cell line FHC, rat normal intestinal epithelial cell (IEC) line IEC-6, and the explant of rat colon. Flow cytometry and agarose gel electrophoresis of genomic DNA revealed that cell cycle arrest and apoptosis were induced by sodium butyrate but not exogenous activin A in HT-29 cells, indicating that activin A could not act as an autocrine factor in colon cancer cells. By assuming that activin A promotes colorectal cancer spread as a paracrine factor, our findings suggest that butyrate could act as a tumor promoter in some circumstances.

  9. Effects of Activin A on the phenotypic properties of human periodontal ligament cells.

    PubMed

    Sugii, Hideki; Maeda, Hidefumi; Tomokiyo, Atsushi; Yamamoto, Naohide; Wada, Naohisa; Koori, Katsuaki; Hasegawa, Daigaku; Hamano, Sayuri; Yuda, Asuka; Monnouchi, Satoshi; Akamine, Akifumi

    2014-09-01

    Periodontal ligament (PDL) tissue plays an important role in tooth preservation by structurally maintaining the connection between the tooth root and the bone. The mechanisms involved in the healing and regeneration of damaged PDL tissue, caused by bacterial infection, caries and trauma, have been explored. Accumulating evidence suggests that Activin A, a member of the transforming growth factor-β (TGF-β) superfamily and a dimer of inhibinβa, contributes to tissue healing through cell proliferation, migration, and differentiation of various target cells. In bone, Activin A has been shown to exert an inhibitory effect on osteoblast maturation and mineralization. However, there have been no reports examining the expression and function of Activin A in human PDL cells (HPDLCs). Thus, we aimed to investigate the biological effects of Activin A on HPDLCs. Activin A was observed to be localized in HPDLCs and rat PDL tissue. When PDL tissue was surgically damaged, Activin A and IL-1β expression increased and the two proteins were shown to be co-localized around the lesion. HPDLCs treated with IL-1β or TNF-α also up-regulated the expression of the gene encoding inhibinβa. Activin A promoted chemotaxis, migration and proliferation of HPDLCs, and caused an increase in fibroblastic differentiation of these cells while down-regulating their osteoblastic differentiation. These osteoblastic inhibitory effects of Activin A, however, were only noted during the early phase of HPDLC osteoblastic differentiation, with later exposures having no effect on differentiation. Collectively, our results suggest that Activin A could be used as a therapeutic agent for healing and regenerating PDL tissue in response to disease, trauma or surgical reconstruction. PMID:24928494

  10. Effects of Activin A on the phenotypic properties of human periodontal ligament cells.

    PubMed

    Sugii, Hideki; Maeda, Hidefumi; Tomokiyo, Atsushi; Yamamoto, Naohide; Wada, Naohisa; Koori, Katsuaki; Hasegawa, Daigaku; Hamano, Sayuri; Yuda, Asuka; Monnouchi, Satoshi; Akamine, Akifumi

    2014-09-01

    Periodontal ligament (PDL) tissue plays an important role in tooth preservation by structurally maintaining the connection between the tooth root and the bone. The mechanisms involved in the healing and regeneration of damaged PDL tissue, caused by bacterial infection, caries and trauma, have been explored. Accumulating evidence suggests that Activin A, a member of the transforming growth factor-β (TGF-β) superfamily and a dimer of inhibinβa, contributes to tissue healing through cell proliferation, migration, and differentiation of various target cells. In bone, Activin A has been shown to exert an inhibitory effect on osteoblast maturation and mineralization. However, there have been no reports examining the expression and function of Activin A in human PDL cells (HPDLCs). Thus, we aimed to investigate the biological effects of Activin A on HPDLCs. Activin A was observed to be localized in HPDLCs and rat PDL tissue. When PDL tissue was surgically damaged, Activin A and IL-1β expression increased and the two proteins were shown to be co-localized around the lesion. HPDLCs treated with IL-1β or TNF-α also up-regulated the expression of the gene encoding inhibinβa. Activin A promoted chemotaxis, migration and proliferation of HPDLCs, and caused an increase in fibroblastic differentiation of these cells while down-regulating their osteoblastic differentiation. These osteoblastic inhibitory effects of Activin A, however, were only noted during the early phase of HPDLC osteoblastic differentiation, with later exposures having no effect on differentiation. Collectively, our results suggest that Activin A could be used as a therapeutic agent for healing and regenerating PDL tissue in response to disease, trauma or surgical reconstruction.

  11. The potential role of activin and follistatin in lung transplant dysfunction.

    PubMed

    Snell, James N; Westall, Glen P; Snell, Gregory I

    2015-01-01

    Activin A, a member of the transforming growth factor β super-family, is a key regulator of multiple biological pathways including the physiological processes of organ development and homeostasis; as well as the pathological processes of inflammation, remodelling and fibrosis. Dysregulation of activin A and its naturally occurring antagonist follistatin, contribute to the development of disease in multiple organ systems. In this review, we summarize the regulation of activin A, its dysregulated expression in a number of respiratory diseases and postulate its potential role in contributing to allograft dysfunction following lung transplantation.

  12. An Activin Receptor IA/Activin-Like Kinase-2 (R206H) Mutation in Fibrodysplasia Ossificans Progressiva.

    PubMed

    Herrera-Esparza, Rafael; Pacheco-Tovar, Deyanira; Bollain-Y-Goytia, Juan José; Torres Del Muro, Felipe; Ramírez-Sandoval, Roxana; Pacheco-Tovar, María Guadalupe; Castañeda-Ureña, María; Avalos-Díaz, Esperanza

    2013-01-01

    Fibrodysplasia ossificans progressiva (FOP) is an exceptionally rare genetic disease that is characterised by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomical areas. This disease is caused by a mutation in activin receptor IA/activin-like kinase-2 (ACVR1/ALK2). A Mexican family with one member affected by FOP was studied. The patient is a 19-year-old female who first presented with symptoms of FOP at 8 years old; she developed spontaneous and painful swelling of the right scapular area accompanied by functional limitation of movement. Mutation analysis was performed in which genomic DNA as PCR amplified using primers flanking exons 4 and 6, and PCR products were digested with Cac8I and HphI restriction enzymes. The most informative results were obtained with the exon 4 flanking primers and the Cac8I restriction enzyme, which generated a 253 bp product that carries the ACVR1 617G>A mutation, which causes an amino acid substitution of histidine for arginine at position 206 of the glycine-serine (GS) domain, and its mutation results in the dysregulation of bone morphogenetic protein (BMP) signalling that causes FOP. PMID:23653868

  13. Abnormal concentration of maternal serum activin-A in gestational diseases.

    PubMed

    Petraglia, F; De Vita, D; Gallinelli, A; Aguzzoli, L; Genazzani, A R; Romero, R; Woodruff, T K

    1995-02-01

    Serum plasma activin-A is measurable in the maternal circulation of healthy pregnant women, increases in specimens collected during the third trimester of gestation, and is highest at parturition. Hormone abnormalities are known to be associated with preterm labor or diabetes in pregnancy. Therefore, in the present study serum activin-A levels in normal controls were compared to those in pregnant women with preterm labor or gestational diabetes. In some cases, values were obtained before and after insulin therapy. In other controls and patients with preterm labor, the activin-A concentration in cord serum was also studied. A newly developed two-site immunotest was used to determine activin-A levels. Subjects included normal controls (n = 7), who were sampled throughout gestation every 5 weeks; pregnant women at term (38-40 weeks) not in labor (n = 22); pregnant women at term in spontaneous labor (< 3.0 cm dilated; n = 42); women in preterm labor (25-35 weeks; n = 38); and women with gestational diabetes (20-39 weeks; n = 9). In control women, serum activin-A levels increased from 4.8 +/- 5.5 micrograms/L (mean +/- SD) at 20 weeks to 25.4 +/- 27.8 micrograms/L at 40 weeks (P < 0.01), and values correlated with gestational age. Pregnant women in preterm labor had serum activin-A concentrations (89.04 +/- 173.31 micrograms/L) higher than those in normal controls (P < 0.01), and no significant correlation to gestational age was found in this group of pregnant women. Healthy women in labor showed serum activin-A concentrations higher than those in women at term but not in labor (P < 0.01). Diabetic patients had serum activin-A concentrations (52.39 +/- 23.32 micrograms/L) significantly higher than those in normal controls. In these patients, maternal serum activin-A concentrations significantly decreased to the range in healthy controls at the same gestational age after insulin therapy (9.48 +/- 3.82 micrograms/L). The present study shows that preterm labor is

  14. 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.

  15. Change in the Gastro-Intestinal Tract by Overexpressed Activin Beta A

    PubMed Central

    Kim, Mi-Nyeu; Kim, Young Il; Cho, Chunghee; Mayo, Kelly E.; Cho, Byung-Nam

    2015-01-01

    Originally, activins were identified as stimulators of FSH release in reproduction. Other activities, including secondary axis formation in development, have since been revealed. Here, we investigated the influence of activin βA on the body, including the gastro-intestinal (GI) tract. Initially, the activin βA protein was detected in the serum proportional to the amount of pCMV-rAct plasmid injected. The induced level of activin βA in muscle was higher in female than male mice. Subsequent results revealed that stomach and intestine were severely damaged in pCMV-rAct-injected mice. At the cellular level, loss of parietal cells was observed, resulting in increased pH within the stomach. This phenomenon was more severe in male than female mice. Consistent with damage of the stomach and intestine, activin βA often led to necrosis in the tip of the tail or foot, and loss of body weight was observed in pCMV-rAct-injected male but not female mice. Finally, in pCMV-rAct-injected mice, circulating activin βA led to death at supraphysiological doses, and this was dependent on the strain of mice used. Taken together, these results indicate that activin βA has an important role outside of reproduction and development, specifically in digestion. These data also indicate that activin βA must be controlled within a narrow range because of latent lethal activity. In addition, our approach can be used effectively for functional analysis of secreted proteins. PMID:26608361

  16. Activin A is associated with asthma in underweight and overweight patients.

    PubMed

    Zhang, L L; Liu, C T

    2015-01-01

    There are limited data regarding the effects of activin A on underweight, normal weight, and overweight patients with asthma. We determined serum levels of activin A in asthmatic patients in relation to body mass index. The study protocol included questionnaires, measurement of exhaled nitric oxide, blood sampling for inflammatory biomarkers, and high-resolution computed tomography of the lungs to identify bronchial wall thickening. Serum and sputum activin A levels were measured using an enzyme-linked immunosorbent assay in 94 asthmatic patients. Mean serum levels of activin A were significantly (P = 0.001) higher in underweight (1781 ± 327.3 pg/mL) than in normal weight and overweight asthmatic patients, regardless of gender. After stratification by gender, significantly higher mean values of activin A were observed in females compared to males in the normal and underweight groups (P = 0.003 and P = 0.0002, respectively). Significant differences between groups were found in airway wall area (%) (P < 0.0001). We also observed a much higher percentage of sputum lymphocytes in the underweight group compared to the other groups (P < 0.0001). Correlations between bronchial wall thickness and activin A were found in the underweight (r = 0.67, P = 0.48) and normal weight groups (r = 0.51, P = 0.042). Correlations between fractional of exhaled nitric oxide, forced expiratory volume in 1 s, delayed treatment years, and activin A in different groups were also observed. Increased serum level of activin A indicates its role in the pathogenesis of asthma, particularly in underweight and overweight patients.

  17. Activin a signaling regulates cell invasion and proliferation in esophageal adenocarcinoma

    PubMed Central

    Le Bras, Gregoire F.; Koumangoye, Rainelli B.; Romero-Morales, Alejandra I.; Quast, Laura L.; Zaika, Alexander I.; El-Rifai, Wael; Andl, Thomas; Andl, Claudia D.

    2015-01-01

    TGFβ signaling has been implicated in the metaplasia from squamous epithelia to Barrett's esophagus and, ultimately, esophageal adenocarcinoma. The role of the family member Activin A in Barrett's tumorigenesis is less well established. As tumorigenesis is influenced by factors in the tumor microenvironment, such as fibroblasts and the extracellular matrix, we aimed to determine if epithelial cell-derived Activin affects initiation and progression differently than Activin signaling stimulation from a mimicked stromal source. Using Barrett's esophagus cells, CPB, and the esophageal adenocarcinoma cell lines OE33 and FLO-1, we showed that Activin reduces colony formation only in CPB cells. Epithelial cell overexpression of Activin increased cell migration and invasion in Boyden chamber assays in CPB and FLO-1 cells, which exhibited mesenchymal features such as the expression of the CD44 standard form, vimentin, and MT1-MMP. When grown in organotypic reconstructs, OE33 cells expressed E-cadherin and Keratin 8. As mesenchymal characteristics have been associated with the acquisition of stem cell-like features, we analyzed the expression and localization of SOX9, showing nuclear localization of SOX9 in esophageal CPB and FLO-1 cells. In conclusion, we show a role for autocrine Activin signaling in the regulation of colony formation, cell migration and invasion in Barrett's tumorigenesis. PMID:26447543

  18. Immunohistochemical localization of inhibin/activin subunits in the wild ground squirrel (Citellus dauricus Brandt) ovary.

    PubMed

    Sheng, Xia; Weng, Jiaju; Zhang, Haolin; Li, Xiaonan; Zhang, Mengyuan; Xu, Meiyu; Weng, Qiang; Watanabe, Gen; Taya, Kazuyoshi

    2012-01-01

    The intraovarian function of gonadally produced inhibin and activin has been extensively studied in experimental models for decades, yet their presence and function have been rarely reported in wild rodents. With our seasonal breeding model, the wild ground squirrel, we aimed to investigate the possible roles of these peptides in the seasonal folliculogenesis. Immunohistochemical staining and Western blotting have been used to detect the cellular localization and expression patterns of inhibin/activin subunits (α, β(A) and β(B)). In the breeding season ovary, all three subunits were present in granulosa cells, theca cells of antral follicles and interstitial cells, with the strongest immunostaining in granulosa cells. Following ovulation, the corpora lutea become a major site of inhibin/activin synthesis. In the nonbreeding season ovary, inhibin/activin α and β(A) subunits were weakly immunopositive in granulosa cells of early stage follicles, while β(B) subunit was undetectable. The expression level of inhibin/activin subunit proteins were generally higher in the ovaries of the breeding season, and then decreased to a relatively low level during the nonbreeding season. The dynamic expression of inhibin/activin subunits indicated that they might play important paracrine and/or autocrine roles during the seasonal folliculogenesis of the wild ground squirrel.

  19. 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.

  20. 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.

  1. Serum soluble urokinase-type plasminogen activator receptor levels in male patients with acute exacerbation of schizophrenia.

    PubMed

    Genc, Abdullah; Kalelioglu, Tevfik; Karamustafalioglu, Nesrin; Tasdemir, Akif; Genc, Esra Sena; Akkus, Mustafa; Emul, Murat

    2016-02-28

    Inflammatory abnormalities have been shown in the pathogenesis of schizophrenia. Soluble urokinase-type plasminogen activator receptor (suPAR) is a protein that is measurable in the circulating blood and reflects the inflammation in the body. We aimed to investigate serum suPAR levels in patients with schizophrenia who were in acute state and to compare with healthy controls. Forty five patients and 43 healthy controls were included in the study. We found no significant difference in suPAR levels between patients and controls, suggesting that suPAR as an inflammatory marker does not have a role in the inflammatory process of acute schizophrenia.

  2. Serum activin A and B, and follistatin in critically ill patients with influenza A(H1N1) infection

    PubMed Central

    2014-01-01

    Background Activin A and its binding protein follistatin (FS) are increased in inflammatory disorders and sepsis. Overexpression of activin A in the lung causes similar histopathological changes as acute respiratory distress syndrome (ARDS). ARDS and severe respiratory failure are complications of influenza A(H1N1) infection. Interleukin 6 (IL-6), which in experimental studies increases after activin A release, is known to be related to the severity of H1N1 infection. Our aim was to evaluate the levels of activin A, activin B, FS, IL-6 and IL-10 and their association with the severity of respiratory failure in critically ill H1N1 patients. Methods A substudy of a prospective, observational cohort of H1N1 patients in Finnish intensive care units (ICU). Clinical information was recorded during ICU treatment, and serum activin A, activin B, FS, IL-6 and IL-10 were measured at admission to ICU and on days 2 and 7. Results Blood samples from 29 patients were analysed. At the time of admission to intensive care unit, elevated serum levels above the normal range for respective age group and sex were observed in 44% for activin A, 57% for activin B, and 39% for FS. In 13 of the 29 patients, serial samples at all time points were available and in these the highest activin A, activin B and FS were above the normal range in 85%, 100% and 46% of the patients, respectively. No difference in baseline or highest activin A or activin B was found in patients with or without acute lung injury (ALI) or ARDS (P > 0.05 for all). Peak levels of IL-6 were significantly elevated in ALI/ARDS patients. Peak activin A and activin A/FS were associated with ventilatory support free-days, severity of acute illness and length of ICU stay (P < 0.05 for all). Conclusions Higher than normal values of these proteins were common in patients with H1N1 infection but we found no association with the severity of their respiratory failure. PMID:24885241

  3. 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

  4. 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

  5. The immunoregulatory and fibrotic roles of activin A in allergic asthma

    PubMed Central

    Hardy, C L; Rolland, J M; O'Hehir, R E

    2015-01-01

    Activin A, a member of the TGF-β superfamily of cytokines, was originally identified as an inducer of follicle stimulating hormone release, but has since been ascribed roles in normal physiological processes, as an immunoregulatory cytokine and as a driver of fibrosis. In the last 10–15 years, it has also become abundantly clear that activin A plays an important role in the regulation of asthmatic inflammation and airway remodelling. This review provides a brief introduction to the activin A/TGF-β superfamily, focussing on the regulation of receptors and signalling pathways. We examine the contradictory evidence for generalized pro- vs. anti-inflammatory effects of activin A in inflammation, before appraising its role in asthmatic inflammation and airway remodelling specifically by evaluating data from both murine models and clinical studies. We identify key issues to be addressed, paving the way for safe exploitation of modulation of activin A function for treatment of allergic asthma and other inflammatory lung diseases. PMID:25962695

  6. Xenopus axis formation: induction of goosecoid by injected Xwnt-8 and activin mRNAs.

    PubMed

    Steinbeisser, H; De Robertis, E M; Ku, M; Kessler, D S; Melton, D A

    1993-06-01

    In this study, we compare the effects of three mRNAs-goosecoid, activin and Xwnt-8- that are able to induce partial or complete secondary axes when injected into Xenopus embryos. Xwnt-8 injection produces complete secondary axes including head structures whereas activin and goosecoid injection produce partial secondary axes at high frequency that lack head structures anterior to the auditory vesicle and often lack notochord. Xwnt-8 can activate goosecoid only in the deep marginal zone, i.e., in the region in which this organizer-specific homeobox gene is normally expressed on the dorsal side. Activin B mRNA, however, can turn on goosecoid in all regions of the embryo. We also tested the capacity of these gene products to restore axis formation in embryos in which the cortical rotation was blocked by UV irradiation. Whereas Xwnt-8 gives complete rescue of anterior structures, both goosecoid and activin give partial rescue. Rescued axes including hindbrain structures up to level of the auditory vesicle can be obtained at high frequency even in the absence of notochord structures. The possible functions of Wnt-like and activin-like signals and of the goosecoid homeobox gene, and their order of action in the formation of Spemann's organizer are discussed. PMID:7900991

  7. Targeting tumour vasculature by inhibiting activin receptor-like kinase (ALK)1 function.

    PubMed

    de Vinuesa, Amaya García; Bocci, Matteo; Pietras, Kristian; Ten Dijke, Peter

    2016-08-15

    Angiogenesis is a hallmark of cancer and is now a validated therapeutic target in the clinical setting. Despite the initial success, anti-angiogenic compounds impinging on the vascular endothelial growth factor (VEGF) pathway display limited survival benefits in patients and resistance often develops due to activation of alternative pathways. Thus, finding and validating new targets is highly warranted. Activin receptor-like kinase (ALK)1 is a transforming growth factor beta (TGF-β) type I receptor predominantly expressed in actively proliferating endothelial cells (ECs). ALK1 has been shown to play a pivotal role in regulating angiogenesis by binding to bone morphogenetic protein (BMP)9 and 10. Two main pharmacological inhibitors, an ALK1-Fc fusion protein (Dalantercept/ACE-041) and a fully human antibody against the extracellular domain of ALK1 (PF-03446962) are currently under clinical development. Herein, we briefly recapitulate the role of ALK1 in blood vessel formation and the current status of the preclinical and clinical studies on inhibition of ALK1 signalling as an anti-angiogenic strategy. Future directions in terms of new combination regimens will also be presented. PMID:27528762

  8. Soluble and insoluble fiber (image)

    MedlinePlus

    ... stool. There are two types of dietary fiber, soluble and insoluble. Soluble fiber retains water and turns to gel during ... and nutrient absorption from the stomach and intestine. Soluble fiber is found in foods such as oat ...

  9. Activin/Nodal signalling before implantation: setting the stage for embryo patterning

    PubMed Central

    Papanayotou, Costis; Collignon, Jérôme

    2014-01-01

    Activins and Nodal are members of the transforming growth factor beta (TGF-β) family of growth factors. Their Smad2/3-dependent signalling pathway is well known for its implication in the patterning of the embryo after implantation. Although this pathway is active early on at preimplantation stages, embryonic phenotypes for loss-of-function mutations of prominent components of the pathway are not detected before implantation. It is only fairly recently that an understanding of the role of the Activin/Nodal signalling pathway at these stages has started to emerge, notably from studies detailing how it controls the expression of target genes in embryonic stem cells. We review here what is currently known of the TGF-β-related ligands that determine the activity of Activin/Nodal signalling at preimplantation stages, and recent advances in the elucidation of the Smad2/3-dependent mechanisms underlying developmental progression. PMID:25349448

  10. Activin/Nodal signalling before implantation: setting the stage for embryo patterning.

    PubMed

    Papanayotou, Costis; Collignon, Jérôme

    2014-12-01

    Activins and Nodal are members of the transforming growth factor beta (TGF-β) family of growth factors. Their Smad2/3-dependent signalling pathway is well known for its implication in the patterning of the embryo after implantation. Although this pathway is active early on at preimplantation stages, embryonic phenotypes for loss-of-function mutations of prominent components of the pathway are not detected before implantation. It is only fairly recently that an understanding of the role of the Activin/Nodal signalling pathway at these stages has started to emerge, notably from studies detailing how it controls the expression of target genes in embryonic stem cells. We review here what is currently known of the TGF-β-related ligands that determine the activity of Activin/Nodal signalling at preimplantation stages, and recent advances in the elucidation of the Smad2/3-dependent mechanisms underlying developmental progression.

  11. Low miR-143/miR-145 Cluster Levels Induce Activin A Overexpression in Oral Squamous Cell Carcinomas, Which Contributes to Poor Prognosis

    PubMed Central

    Bufalino, Andreia; Cervigne, Nilva K.; de Oliveira, Carine Ervolino; Fonseca, Felipe Paiva; Rodrigues, Priscila Campioni; Macedo, Carolina Carneiro Soares; Sobral, Lays Martin; Miguel, Marcia Costa; Lopes, Marcio Ajudarte; Leme, Adriana Franco Paes; Lambert, Daniel W.; Salo, Tuula A.; Kowalski, Luiz Paulo; Graner, Edgard; Coletta, Ricardo D.

    2015-01-01

    Deregulated expression of activin A is reported in several tumors, but its biological functions in oral squamous cell carcinoma (OSCC) are unknown. Here, we investigate whether activin A can play a causal role in OSCCs. Activin A expression was assessed by qPCR and immunohistochemistry in OSCC tissues. Low activin A-expressing cells were treated with recombinant activin A and assessed for apoptosis, proliferation, adhesion, migration, invasion and epithelial-mesenchymal transition (EMT). Those phenotypes were also evaluated in high activin A-expressing cells treated with follistatin (an activin A antagonist) or stably expressing shRNA targeting activin A. Transfections of microRNA mimics were performed to determine whether the overexpression of activin A is regulated by miR-143/miR-145 cluster. Activin A was overexpressed in OSCCs in comparison with normal oral mucosa, and high activin A levels were significantly associated with lymph node metastasis, tumor differentiation and poor survival. High activin A levels promoted multiple properties associated with malignant transformation, including decreased apoptosis and increased proliferation, migration, invasion and EMT. Both miR-143 and miR-145 were markedly downregulated in OSCC cell lines and in clinical specimens, and inversely correlated to activin A levels. Forced expression of miR-143 and miR-145 in OSCC cells significantly decreased the expression of activin A. Overexpression of activin A in OSCCs, which is controlled by downregulation of miR-143/miR-145 cluster, regulates apoptosis, proliferation and invasiveness, and it is clinically correlated with lymph node metastasis and poor survival. PMID:26317418

  12. Regulation of FSHbeta and GnRH receptor gene expression in activin receptor II knockout male mice.

    PubMed

    Kumar, T Rajendra; Agno, Julio; Janovick, Jo Ann; Conn, P Michael; Matzuk, Martin M

    2003-12-30

    To examine in vivo, the local effects of inhibins and activins within the anterior pituitary, independent of their endocrine effects exerted from the gonad, in mediating FSH homeostasis, we used castrated knockout mice lacking either inhibin alpha or activin receptor II (ACVR2) alone or in combination. Compared to castrated wild-type (WT) mice, FSHbeta mRNA levels in the pituitaries of Acvr2 null mice were significantly downregulated in the absence of gonadal feedback. FSHbeta mRNA levels were not significantly higher in the pituitaries of castrated inhibin alpha null mice compared to those in Acvr2 null mice and remained the same in the pituitaries of castrated double mutant mice lacking both inhibin and ACVR2. In contrast to FSHbeta mRNA expression changes, pituitary FSH content was significantly reduced in Acvr2 null mice whereas it was only slightly upregulated in inhibin alpha null mice. Combined absence of both ACVR2 signaling and inhibins caused a decrease in FSH content compared to that in the absence of inhibins alone. These changes in pituitary content were in parallel to those in serum FSH levels in these three groups of castrated mice, suggesting that the unopposed actions of locally produced inhibins are dominant over those effects mediated by ACVR2 signaling to regulate FSH biosynthesis and secretion. Thus, our in vivo results demonstrate that within the pituitary, locally produced activins and inhibins exert their actions at distinct phases of FSH homeostasis. In an independent set of experiments, we tested whether in vivo signaling via ACVR2 is necessary for hypothalamic GnRH biosynthesis and for GnRH receptor expression. Our results demonstrate that in contrast to previous in vitro studies, signaling through ACVR2 is neither required for hypothalamic synthesis of GnRH peptide nor for expression of GnRH receptors in the anterior pituitary. We conclude that within the hypothalamic-pituitary short loop, ACVR2 signaling is critical only for FSH

  13. Diagnostic accuracy of serum activin A in detection of ectopic pregnancy

    PubMed Central

    Roghaei, Mohammad Ali; Sabet, Fahimeh; Mohamadi, Keivan

    2012-01-01

    Background: Ectopic pregnancy (EP) still remains a main cause of maternal mortalities. This study is designed to evaluate the accuracy of serum Activin A in detection of ectopic pregnancy. Methods: This prospective observational study was conducted from 2009 to 2010 at two main referral university hospitals, Isfahan University of Medical Sciences, Isfahan, Iran. Two hundred subjects who were under 10 week's pregnancy with clinical presentations of abdominal pain and vaginal bleeding were enrolled. After sampling serum Activin A, patients underwent ultrasonography, titer of B-HCG and surgery (if indicated) and were divided into two groups: EP (n = 100) and intrauterine pregnancy (IUP) (n = 100). The mean of Activin A was compared between groups and by ROC curve, the optimal cut off with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were determined. Results: The mean age of women with IUP was 25.4 ± 4.3 years (15-40 years) compared with 25.9 ± 4.1 years in women in EP group (P = 0.448). Statistical difference was not found between EP versus IUP groups in gestational age (6.32 ± 1.03 vs. 6.85 ± 1.82 weeks, P = 0.124). The mean of serum Activin A in EP group was 0.264 ± 0.0703 ng/ml versus 0.949 ± 0.5283 ng/ml in IUP group (P < 0.05). According to ROC curve (area under the curve = 0.981, P < 0.05, confidence interval: 0.961-1.000), the optimal cut off was estimated as 0.504 ng/ml with sensitivity of 97% and specificity of 93.5%. Conclusion: This study indicated that the mean of serum Activin A is lower in EP compared with IUP. The serum Activin A has a fair accuracy in detecting EP. PMID:23267401

  14. Brugia malayi soluble and excretory-secretory proteins attenuate development of streptozotocin-induced type 1 diabetes in mice.

    PubMed

    Amdare, N; Khatri, V; Yadav, R S P; Tarnekar, A; Goswami, K; Reddy, M V R

    2015-12-01

    Understanding the modulation of the host-immune system by pathogens-like filarial parasites offers an alternate approach to prevent autoimmune diseases. In this study, we have shown that treatment with filarial proteins prior to or after the clinical onset of streptozotocin-induced type-1 diabetes (T1D) can ameliorate the severity of disease in BALB/c mice. Pre-treatment with Brugia malayi adult soluble (Bm A S) or microfilarial excretory-secretory (Bm mf ES) or microfilarial soluble (Bm mf S) antigens followed by induction of diabetes led to lowering of fasting blood glucose levels with as many as 57.5-62.5% of mice remaining nondiabetic. These proteins were more effective when they were used to treat the mice with established T1D as 62.5-71.5% of the mice turned to be nondiabetic. Histopathological examination of pancreas of treated mice showed minor inflammatory changes in pancreatic islet cell architecture. The therapeutic effect was found to be associated with the decreased production of cytokines TNF-α & IFN-γ and increased production of IL-10 in the culture supernatants of splenocytes of treated mice. A switch in the production of anti-insulin antibodies from IgG2a to IgG1 isotype was also seen. Together these results provide a proof towards utilizing the filarial derived proteins as novel anti-diabetic therapeutics.

  15. Activin-receptor signaling regulates cocaine-primed behavioral and morphological plasticity

    PubMed Central

    Gancarz, Amy M.; Wang, Zi-Jun; Schroeder, Gabrielle L.; Damez-Werno, Diane; Braunscheidel, Kevin; Mueller, Lauren E.; Humby, Monica S.; Caccamise, Aaron; Martin, Jennifer A.; Dietz, Karen C.; Neve, Rachael L.; Dietz, David M.

    2015-01-01

    Cocaine addiction is a life-long relapsing disorder that results from long-term adaptations within the brain. We find that Activin-receptor signaling, including the transcription factor Smad3, is upregulated in the rat nucleus accumbens shell following withdrawal from cocaine. Direct genetic and pharmacological manipulations of this pathway bidirectionally alter cocaine seeking, while governing morphological plasticity in nucleus accumbens neurons. These findings reveal that Activin/Smad3 signaling is induced following withdrawal from cocaine, and such regulation may be a key molecular mechanism underlying behavioral and cellular plasticity in the brain following cocaine self-administration. PMID:26030849

  16. Regulation of the activin-inhibin-follistatin system by bone morphogenetic proteins in the zebrafish ovary.

    PubMed

    Li, Cheuk Wun; Ge, Wei

    2013-09-01

    In the zebrafish, the dynamic expression of the activin-inhibin-follistatin system during folliculogenesis and its exclusive localization (except follistatin) in follicle cells suggests that the system plays important roles in follicle development and that its expression is subject to tight controls, probably by external factors including those derived from the oocyte. We have previously identified zebrafish bone morphogenetic proteins (BMPs) as oocyte factors that may act on follicle cells; however, the targets of BMPs in the follicle cells remain unknown. Considering their spatiotemporal expression in the follicle, we hypothesized that members of the activin-inhibin-follistatin system in follicle cells could be potential target genes of BMPs. In the present study, we developed a novel coculture system to co-incubate zebrafish bone morphogenetic protein 2b or 4 (zfBMP2b/4)-producing Chinese hamster ovary (CHO) cells with zebrafish follicle cells. During incubation, the zfBMPs secreted from the CHO cells would act directly on the follicle cells in a paracrine manner. Our results showed that all activin beta subunits (inhbaa, inhbab, and inhbb) were down-regulated by both zfBMP2b and zfBMP4, while follistatin (fst, an activin-binding protein) and inhibin alpha (inha, an activin antagonist) were significantly up-regulated. The specificity of bone morphogenetic protein (BMP) actions was confirmed by short interfering RNA knockdown of zfBMP4 expression in the CHO cells. The robust response of inha to zfBMPs, together with our previous observation that inha expression surged at the full-grown stage prior to oocyte maturation, led us to hypothesize that the full-grown oocyte may signal upper levels of the hypothalamic-pituitary-gonadal axis its readiness to mature by releasing BMPs, which in turn stimulate inhibin production. As an ovarian hormone and activin antagonist, inhibin may suppress the action of activin in the pituitary to reduce follicle-stimulating hormone

  17. 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.

  18. Pegylated Interferon-α Modulates Liver Concentrations of Activin-A and Its Related Proteins in Normal Wistar Rat

    PubMed Central

    Refaat, Bassem; El-Shemi, Adel Galal; Ashshi, Ahmed Mohamed; Mahamid, Elaf Wael; Al-Qadi, Noha Mohammed

    2015-01-01

    Aims. To measure the expression of activin βA-subunit, activin IIA and IIB receptors, Smad4, Smad7, and follistatin in the liver and the liver and serum concentrations of mature activin-A and follistatin in normal rat following treatment with pegylated interferon-α (Peg-INF-α) and ribavirin (RBV). Materials and Methods. 40 male Wistar rats were divided equally into 4 groups: “control,” “Peg-only” receiving 4 injections of Peg-INF-α (6 µg/rat/week), “RBV-only” receiving ribavirin (4 mg/rat/day) orally, and “Peg & RBV” group receiving both drugs. The expression of candidate molecules in liver was measured by immunohistochemistry and quantitative PCR. The concentrations of mature proteins in serum and liver homogenate samples were measured using ELISA. Results. Peg-INF-α  ± RBV altered the expression of all candidate molecules in the liver at the gene and protein levels (P < 0.05) and decreased activin-A and increased follistatin in serum and liver homogenates compared with the other groups (P < 0.05). There were also significant correlations between serum and liver activin-A and follistatin. Conclusion. Peg-INF-α modulates the hepatic production of activin-A and follistatin, which can be detected in serum. Further studies are needed to explore the role of Peg-INF-α on the production of activins and follistatin by the liver and immune cells. PMID:26236109

  19. 1α,25-dihydroxyvitamin D3 stimulates activin A production to fine-tune osteoblast-induced mineralization.

    PubMed

    Woeckel, V J; van der Eerden, B C J; Schreuders-Koedam, M; Eijken, M; Van Leeuwen, J P T M

    2013-11-01

    In healthy bones, mineralization has to be tightly controlled to avoid pathological phenotypes. In this study, we investigated interactions between 1α,25(OH)2 D3 (1,25D3) and activin A in the regulation of osteoblast induced mineralization. In human osteoblast cultures, we demonstrated that besides stimulation of mineralization, 1,25D3 also induced activin A, a strong inhibitor of mineralization. Simultaneously, follistatin (FST), the natural antagonist of activin A, was down-regulated by1,25D3. This resulted in an increase in activin A activity during 1,25D3 treatment. We also showed that in 1,25D3-treated osteoblasts, mineralization can be further increased when activin A activity was abrogated by adding exogenous FST. This observation implies that, besides stimulation of mineralization, 1,25D3 also controls activin A-mediated inhibition of mineralization. Besides activin A, 1,25D3 also induces osteocalcin (BGLAP), another inhibitor of mineralization. Warfarin, which has been shown to inactivate osteocalcin, increased 1,25D3-induced mineralization. Interaction between these two systems became evident from the synergistic increase in BGLAP expression upon blocking activin activity in 1,25D3-treated cultures. In conclusion, we demonstrate that 1,25D3 stimulation of mineralization by human osteoblasts is suppressed by concomitant induction of inhibitors of mineralization. Mineralization induction by 1,25D3 may actually be controlled via interplay with activin A and osteocalcin. Finally, this complex regulation of mineralization substantiates the significance of tight control of mineralization to prevent excessive mineralization and consequently reduction in bone quality and strength.

  20. Serum Activin A and Follistatin Levels in Gestational Diabetes and the Association of the Activin A-Follistatin System with Anthropometric Parameters in Offspring

    PubMed Central

    Näf, Silvia; Escote, Xavier; Ballesteros, Mónica; Yañez, Rosa Elena; Simón-Muela, Inmaculada; Gil, Pilar; Albaiges, Gerard

    2014-01-01

    Context The Activin A-Follistatin system has emerged as an important regulator of lipid and glucose metabolism with possible repercussions on fetal growth. Objective To analyze circulating activin A, follistatin and follistatin-like-3 (FSTL3) levels and their relationship with glucose metabolism in pregnant women and their influence on fetal growth and neonatal adiposity. Design and methods A prospective cohort was studied comprising 207 pregnant women, 129 with normal glucose tolerance (NGT) and 78 with gestational diabetes mellitus (GDM) and their offspring. Activin A, follistatin and FSTL3 levels were measured in maternal serum collected in the early third trimester of pregnancy. Serial fetal ultrasounds were performed during the third trimester to evaluate fetal growth. Neonatal anthropometry was measured to assess neonatal adiposity. Results Serum follistatin levels were significantly lower in GDM than in NGT pregnant women (8.21±2.32 ng/mL vs 9.22±3.41, P = 0.012) whereas serum FSTL3 and activin A levels were comparable between the two groups. Serum follistatin concentrations were negatively correlated with HOMA-IR and positively with ultrasound growth parameters such as fractional thigh volume estimation in the middle of the third trimester and percent fat mass at birth. Also, in the stepwise multiple linear regression analysis serum follistatin levels were negatively associated with HOMA-IR (β = −0.199, P = 0.008) and the diagnosis of gestational diabetes (β = −0.138, P = 0.049). Likewise, fractional thigh volume estimation in the middle of third trimester and percent fat mass at birth were positively determined by serum follistatin levels (β = 0.214, P = 0.005 and β = 0.231, P = 0.002, respectively). Conclusions Circulating follistatin levels are reduced in GDM compared with NGT pregnant women and they are positively associated with fetal growth and neonatal adiposity. These data suggest a role of the Activin

  1. Soluble CD40L in children and adolescents with type 1 diabetes: relation to microvascular complications and glycemic control.

    PubMed

    El-Asrar, Mohamed A; Adly, Amira Am; Ismail, Eman A

    2012-12-01

    CD40-soluble CD40 ligand (sCD40L) interactions might constitute an important mediator for vascular inflammation that initiates diabetic microangiopathy. Little is known about the relation between sCD40L and glycemic control. Therefore, this study aimed to evaluate sCD40L levels in patients with type 1 diabetes and its relation to microvascular complications and metabolic control. Sixty patients with type 1 diabetes were compared with 30 healthy control subjects. Detailed medical history, thorough clinical examination, and laboratory assessment of high-sensitivity C-reactive protein, glycemic control, and the presence of microvascular complications were performed. Measurement of serum sCD40L levels was done using enzyme-linked immunosorbent assay. Patients were divided into two groups according to the presence of microvascular complications. Serum sCD40L levels were significantly elevated in patients with type 1 diabetes in both groups compared with healthy controls (p < 0.001). Patients with microvascular complications had higher serum sCD40L concentrations than non-complicated cases (median, 13 000 vs. 450 pg/mL; p < 0.001). Serum sCD40L cutoff value of 530 pg/mL was able to differentiate complicated from non-complicated cases (p < 0.001). Patients with microalbuminuria or peripheral neuropathy showed higher levels of sCD40L when compared with patients without these complications (p < 0.05). Serum sCD40L levels were positively correlated with hemoglobin A1c and urinary albumin excretion (p < 0.001). We suggest that serum sCD40L levels are elevated in type 1 diabetes, particularly in patients with microvascular complications and a significant correlation with glycemic control exists. Therefore, measurement of serum sCD40L levels in poorly controlled patients would help to identify those at high risk of developing microvascular complications.

  2. The prolyl hydroxylase PHD3 identifies proinflammatory macrophages and its expression is regulated by activin A.

    PubMed

    Escribese, María M; Sierra-Filardi, Elena; Nieto, Concha; Samaniego, Rafael; Sánchez-Torres, Carmen; Matsuyama, Takami; Calderon-Gómez, Elisabeth; Vega, Miguel A; Salas, Azucena; Sánchez-Mateos, Paloma; Corbí, Angel L

    2012-08-15

    Modulation of macrophage polarization underlies the onset and resolution of inflammatory processes, with polarization-specific molecules being actively sought as potential diagnostic and therapeutic tools. Based on their cytokine profile upon exposure to pathogenic stimuli, human monocyte-derived macrophages generated in the presence of GM-CSF or M-CSF are considered as proinflammatory (M1) or anti-inflammatory (M2) macrophages, respectively. We report in this study that the prolyl hydroxylase PHD3-encoding EGLN3 gene is specifically expressed by in vitro-generated proinflammatory M1(GM-CSF) human macrophages at the mRNA and protein level. Immunohistochemical analysis revealed the expression of PHD3 in CD163(+) lung macrophages under basal homeostatic conditions, whereas PHD3(+) macrophages were abundantly found in tissues undergoing inflammatory responses (e.g., Crohn's disease and ulcerative colitis) and in tumors. In the case of melanoma, PHD3 expression marked a subset of tumor-associated macrophages that exhibit a weak (e.g., CD163) or absent (e.g., FOLR2) expression of typical M2-polarization markers. EGLN3 gene expression in proinflammatory M1(GM-CSF) macrophages was found to be activin A dependent and could be prevented in the presence of an anti-activin A-blocking Ab or inhibitors of activin receptor-like kinase receptors. Moreover, EGLN3 gene expression was upregulated in response to hypoxia only in M2(M-CSF) macrophages, and the hypoxia-mediated upregulation of EGLN3 expression was significantly impaired by activin A neutralization. These results indicate that EGLN3 gene expression in macrophages is dependent on activin A both under basal and hypoxic conditions and that the expression of the EGLN3-encoded PHD3 prolyl hydroxylase identifies proinflammatory macrophages in vivo and in vitro. PMID:22778395

  3. 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.

  4. 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. PMID:27495231

  5. Activin-Like Kinase 2 Functions in Peri-implantation Uterine Signaling in Mice and Humans

    PubMed Central

    Clementi, Caterina; Tripurani, Swamy K.; Large, Michael J.; Edson, Mark A.; Creighton, Chad J.; Hawkins, Shannon M.; Kovanci, Ertug; Kaartinen, Vesa; Lydon, John P.; Pangas, Stephanie A.; DeMayo, Francesco J.; Matzuk, Martin M.

    2013-01-01

    Implantation of a blastocyst in the uterus is a multistep process tightly controlled by an intricate regulatory network of interconnected ovarian, uterine, and embryonic factors. Bone morphogenetic protein (BMP) ligands and receptors are expressed in the uterus of pregnant mice, and BMP2 has been shown to be a key regulator of implantation. In this study, we investigated the roles of the BMP type 1 receptor, activin-like kinase 2 (ALK2), during mouse pregnancy by producing mice carrying a conditional ablation of Alk2 in the uterus (Alk2 cKO mice). In the absence of ALK2, embryos demonstrate delayed invasion into the uterine epithelium and stroma, and upon implantation, stromal cells fail to undergo uterine decidualization, resulting in sterility. Mechanistically, microarray analysis revealed that CCAAT/enhancer-binding protein β (Cebpb) expression is suppressed during decidualization in Alk2 cKO females. These findings and the similar phenotypes of Cebpb cKO and Alk2 cKO mice lead to the hypothesis that BMPs act upstream of CEBPB in the stroma to regulate decidualization. To test this hypothesis, we knocked down ALK2 in human uterine stromal cells (hESC) and discovered that ablation of ALK2 alters hESC decidualization and suppresses CEBPB mRNA and protein levels. Chromatin immunoprecipitation (ChIP) analysis of decidualizing hESC confirmed that BMP signaling proteins, SMAD1/5, directly regulate expression of CEBPB by binding a distinct regulatory sequence in the 3′ UTR of this gene; CEBPB, in turn, regulates the expression of progesterone receptor (PGR). Our work clarifies the conserved mechanisms through which BMPs regulate peri-implantation in rodents and primates and, for the first time, uncovers a linear pathway of BMP signaling through ALK2 to regulate CEBPB and, subsequently, PGR during decidualization. PMID:24244176

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

    PubMed

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

    2015-09-01

    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

  7. 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

  8. Induction of tolerance against the arthritogenic antigen with type-II collagen peptide-linked soluble MHC class II molecules

    PubMed Central

    Park, Yoon-Kyung; Jung, Sundo; Park, Se-Ho

    2016-01-01

    In murine collagen-induced arthritis (CIA), self-reactive T cells can recognize peptide antigens derived from type-II collagen (CII). Activation of T cells is an important mediator of autoimmune diseases. Thus, T cells have become a focal point of study to treat autoimmune diseases. In this study, we evaluated the efficacy of recombinant MHC class II molecules in the regulation of antigen-specific T cells by using a self peptide derived from CII (CII260-274; IAGFKGEQGPKGEPG) linked to mouseI-Aq in a murine CIA model. We found that recombinant I-Aq/CII260-274 molecules could be recognized by CII-specific T cells and inhibit the same T cells in vitro. Furthermore, the development of CIA in mice was successfully prevented by in vivo injection of recombinant I-Aq/CII260-274 molecules. Thus, treatment with recombinant soluble MHC class II molecules in complex with an immunodominant self-peptide might offer a potential therapeutic for chronic inflammation in autoimmune disease such as rheumatoid arthritis. [BMB Reports 2016; 49(6): 331-336 PMID:26779996

  9. Hydrothermal synthesis of brookite-type titanium dioxide with snowflake-like nanostructures using a water-soluble citratoperoxotitanate complex

    NASA Astrophysics Data System (ADS)

    Kobayashi, Makoto; Petrykin, Valery; Tomita, Koji; Kakihana, Masato

    2011-12-01

    Hydrothermal synthesis of brookite-type titanium dioxide was performed with excellent reproducibility using an aqueous NH 3 solution of a water-soluble citratoperoxotitanate (CPT) complex. X-ray diffraction confirmed that the brookite phase was formed by hydrothermal treatment of the CPT complex in NH 3 solution with a concentration of more than 6.5 wt%, whereas single phase anatase was obtained when distilled water without any additives was applied as the solvent. The aspect ratios of the obtained rod-like brookite particles increased from 5 up to 20 with an increase of the NH 3 concentration. Transmission electron microscopy and selected area electron diffraction measurements provided evidence that the growth of the brookite particles is along the c-axis. Hydrothermal treatment of the CPT complex at high NH 3 concentrations resulted in the formation of agglomerated brookite particles with unusual shapes, where many rod-like particles were branched around a somewhat longer central particle, and the side view of the agglomerated particles revealed two-dimensional crystal growth within a given restricted plane. The multi-needle agglomerate of particles was snowflake shaped. The reason for the formation of brookite with this unique morphology may be attributed to an intrinsic character of the CPT complex itself, although the mechanism is yet to be clarified.

  10. Collaboration between a soluble C-type lectin and calreticulin facilitates white spot syndrome virus infection in shrimp.

    PubMed

    Wang, Xian-Wei; Xu, Yi-Hui; Xu, Ji-Dong; Zhao, Xiao-Fan; Wang, Jin-Xing

    2014-09-01

    White spot syndrome virus (WSSV) mainly infects crustaceans through the digestive tract. Whether C-type lectins (CLs), which are important receptors for many viruses, participate in WSSV infection in the shrimp stomach remains unknown. In this study, we orally infected kuruma shrimp Marsupenaeus japonicus to model the natural transmission of WSSV and identified a CL (designated as M. japonicus stomach virus-associated CL [MjsvCL]) that was significantly induced by virus infection in the stomach. Knockdown of MjsvCL expression by RNA interference suppressed the virus replication, whereas exogenous MjsvCL enhanced it. Further analysis by GST pull-down and coimmunoprecipitation showed that MjsvCL could bind to viral protein 28, the most abundant and functionally relevant envelope protein of WSSV. Furthermore, cell-surface calreticulin was identified as a receptor of MjsvCL, and the interaction between these proteins was a determinant for the viral infection-promoting activity of MjsvCL. The MjsvCL-calreticulin pathway facilitated virus entry likely in a cholesterol-dependent manner. This study provides insights into a mechanism by which soluble CLs capture and present virions to the cell-surface receptor to facilitate viral infection. PMID:25070855

  11. [Molecular cloning of activin betaA subunit mature peptide from peafowl and its application in taxonomy and phylogeny].

    PubMed

    Zou, Fang-Dong; Tong, Xin-Xin; Yue, Bi-Song

    2005-03-01

    The sequences of activin gene betaA subunit mature peptide have been amplified from white peafowl, blue peafowl (pavo cristatus) and green peafowl (pavo muticus) genomic DNA by polymerase chain reaction (PCR) with a pair of degenerate primers. The target fragments were cloned into the vector pMD18-T and sequenced. The length of activin gene betaA subunit mature peptide is 345bp, which encoded a peptide of 115 amino acid residues. Sequence analysis of activin gene betaA subunit mature peptide demonstrated that the identity of nucleotide is 98.0% between blue peaflowl and green peafowl, and the identity of that is 98.8% between blue peaflowl and white peafow. Sequences comparison in NCBI revealed that the sequences of activin gene betaA subunit mature peptides of different species are highly conserved during evolution process. In addition, the restriction enzyme map of activins is high similar between white peafowl and blue peafowl. Phylogenetic tree was constructed with Mega 2 and Clustalxldx software. The result showed that white peafowl has a closer relationship to blue peafowl than to green peafowl. Considered the nucleotide differences of peafowls' activin gene betaA subunit mature peptides, a highly conserved region, we supported that white peafowl was derived from blue peafowl, and it is more possible the hybrid but just the product of color mutation, or maybe as a subspecies of Pavo genus.

  12. Blood cell induction in Xenopus animal cap explants: effects of fibroblast growth factor, bone morphogenetic proteins, and activin.

    PubMed

    Miyanaga, Y; Shiurba, R; Asashima, M

    1999-02-01

    Cultures of Xenopus blastula animal caps were used to explore the haematopoietic effects of three candidate inducers of mesoderm: basic fibroblast growth factor (bFGF), bone morphogenetic proteins (BMPs) and activin A. In response to either bFGF or activin A, explants expanded into egg-shaped structures, and beneath an outer layer of epidermis, a ventral mesodermal lining surrounded a fluid-filled cavity containing "blood-like cells". Immunocytochemistry identified some of these cells as early leukocytes, but erythrocytes were rare. BMP-2 or BMP-4 induced primitive erythrocytes as well as leukocytes, and a high concentration was required for these cells to differentiate in only a small proportion of explants. BMP-2 but not BMP-4 induced ventral mesoderm concomitantly. High concentrations of activin A dorsalized explants, which contained infrequent leukocytes, and an optimal combination of activin A and bFGF caused differentiation of muscle with few blood cells. By contrast, BMP-2 or BMP-4 plus activin A synergistically increased the numbers of both leukocytes and erythrocytes. Explants treated with BMPs plus activin contained a well organized cell mass in which yolk-rich cells mixed with blood cells and pigmented cells did not. BMP-2 plus bFGF also induced numerous leukocytes and fewer erythrocytes, but BMP-4 antagonized the leukopoietic effect of bFGF. The data suggest that the signalling pathways these three factors use to induce leukopoiesis overlap and that erythropoiesis may be activated when inducers are present in combination.

  13. [Molecular cloning of activin betaA subunit mature peptide from peafowl and its application in taxonomy and phylogeny].

    PubMed

    Zou, Fang-Dong; Tong, Xin-Xin; Yue, Bi-Song

    2005-03-01

    The sequences of activin gene betaA subunit mature peptide have been amplified from white peafowl, blue peafowl (pavo cristatus) and green peafowl (pavo muticus) genomic DNA by polymerase chain reaction (PCR) with a pair of degenerate primers. The target fragments were cloned into the vector pMD18-T and sequenced. The length of activin gene betaA subunit mature peptide is 345bp, which encoded a peptide of 115 amino acid residues. Sequence analysis of activin gene betaA subunit mature peptide demonstrated that the identity of nucleotide is 98.0% between blue peaflowl and green peafowl, and the identity of that is 98.8% between blue peaflowl and white peafow. Sequences comparison in NCBI revealed that the sequences of activin gene betaA subunit mature peptides of different species are highly conserved during evolution process. In addition, the restriction enzyme map of activins is high similar between white peafowl and blue peafowl. Phylogenetic tree was constructed with Mega 2 and Clustalxldx software. The result showed that white peafowl has a closer relationship to blue peafowl than to green peafowl. Considered the nucleotide differences of peafowls' activin gene betaA subunit mature peptides, a highly conserved region, we supported that white peafowl was derived from blue peafowl, and it is more possible the hybrid but just the product of color mutation, or maybe as a subspecies of Pavo genus. PMID:15843351

  14. The biological function of type I receptors of bone morphogenetic protein in bone

    PubMed Central

    Lin, Shuxian; Svoboda, Kathy K H; Feng, Jian Q; Jiang, Xinquan

    2016-01-01

    Bone morphogenetic proteins (BMPs) have multiple roles in skeletal development, homeostasis and regeneration. BMPs signal via type I and type II serine/threonine kinase receptors (BMPRI and BMPRII). In recent decades, genetic studies in humans and mice have demonstrated that perturbations in BMP signaling via BMPRI resulted in various diseases in bone, cartilage, and muscles. In this review, we focus on all three types of BMPRI, which consist of activin-like kinase 2 (ALK2, also called type IA activin receptor), activin-like kinase 3 (ALK3, also called BMPRIA), and activin-like kinase 6 (ALK6, also called BMPRIB). The research areas covered include the current progress regarding the roles of these receptors during myogenesis, chondrogenesis, and osteogenesis. Understanding the physiological and pathological functions of these receptors at the cellular and molecular levels will advance drug development and tissue regeneration for treating musculoskeletal diseases and bone defects in the future. PMID:27088043

  15. Serum activin A and B levels predict outcome in patients with acute respiratory failure: a prospective cohort study

    PubMed Central

    2013-01-01

    Introduction 30 day mortality in patients with Acute Respiratory Failure (ARF) is approximately 30%, defined as patients requiring ventilator support for more than 6 hours. Novel biomarkers are needed to predict patient outcomes and to guide potential future therapies. The activins A and B, members of the Transforming Growth Factor β family of proteins, and their binding protein, follistatin, have recently been shown to be important regulators of inflammation and fibrosis but no substantial data are available concerning their roles in ARF. Our objectives were to evaluate whether the serum levels of activin A, B and follistatin are elevated in 518 patients with ARF from the FINNALI study compared the concentrations in 138 normal subjects that form a reference range. Methods Specific assays for activin A, B and follistatin were used and the results analyzed according to diagnostic groups as well as according to standard measures in intensive care. Multivariable logistic regression was used to create a model to predict death at 90 days and 12 months from the onset of the ARF. Results Serum activin A and B were significantly elevated in most patients and in most of the diagnostic groups. Patients who had activin A and/or B concentrations above the reference maximum were significantly more likely to die in the 12 months following admission [either activin A or B above reference maximum: Positive Likelihood Ratio [LR+] 1.65 [95% CI 1.28-2.12, P = 0.00013]; both activin A and B above reference maximum: LR + 2.78 [95% CI 1.96-3.95, P < 0.00001]. The predictive model at 12 months had an overall accuracy of 80.2% [95% CI 76.6-83.3%]. Conclusions The measurement of activin A and B levels in these patients with ARF would have assisted in predicting those at greatest risk of death. Given the existing data from animal studies linking high activin A levels to significant inflammatory challenges, the results from this study suggest that approaches to modulate

  16. Activin A accelerates the progression of fetal oocytes throughout meiosis and early oogenesis in the mouse.

    PubMed

    Liang, Gui-Jin; Zhang, Xi-Feng; Wang, Jun-Jie; Sun, Yuan-Chao; Sun, Xiao-Feng; Cheng, Shun-Feng; Li, Lan; De Felici, Massimo; Shen, Wei

    2015-10-15

    Activins can exert several roles in ovary development. However, little is known about their involvement in early mammalian oogenesis. In this study, we reported that activin receptors (including ActRIA, ActRIB, ActRIIA, and ActRIIB) are expressed throughout the development of the mouse ovaries from 12.5 days postcoitum (dpc) to 21 days postparturition (dpp). Moreover, we found that in vitro, the addition of activin A (ActA) to the culture medium of 12.5 dpc ovarian tissues accelerated the progression of oocytes throughout meiotic prophase I stages. This result was reproduced in vivo following administration of ActA to pregnant mice. The in vitro effect of ActA was associated with increased expression of premeiotic and meiotic genes (including Dazl, Spo11, Stra8, Scp3, and Rec8) in the ovarian tissues. Mechanistically, ActA-dependent SMAD3 signaling modulated the expression of members of the retinoic acid (RA) system, including the RA degradation CYP26B1 enzyme and the RA receptors. Finally, ActA promoted the survival and growth of fetal and early postnatal oocytes and primordial follicle assembly both in vitro and in vivo. In conclusion, the present study identifies new roles of ActA in early oogenesis and suggested that ActA and RA might cooperate in promoting meiosis in female germ cells.

  17. Soluble Forms of Intercellular and Vascular Cell Adhesion Molecules Independently Predict Progression to Type 2 Diabetes in Mexican American Families

    PubMed Central

    Kulkarni, Hemant; Mamtani, Manju; Peralta, Juan; Almeida, Marcio; Dyer, Thomas D.; Goring, Harald H.; Johnson, Matthew P.; Duggirala, Ravindranath; Mahaney, Michael C.; Olvera, Rene L.; Almasy, Laura; Glahn, David C.; Williams-Blangero, Sarah; Curran, Joanne E.; Blangero, John

    2016-01-01

    Objective While the role of type 2 diabetes (T2D) in inducing endothelial dysfunction is fairly well-established the etiological role of endothelial dysfunction in the onset of T2D is still a matter of debate. In the light of conflicting evidence in this regard, we conducted a prospective study to determine the association of circulating levels of soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vessel cell adhesion molecule 1 (sVCAM-1) with incident T2D. Methods Data from this study came from 1,269 Mexican Americans of whom 821 initially T2D-free individuals were longitudinally followed up in the San Antonio Family Heart Study. These individuals were followed for 9752.95 person-years for development of T2D. Prospective association of sICAM-1 and sVCAM-1 with incident T2D was studied using Kaplan-Meier survival plots and mixed effects Cox proportional hazards modeling to account for relatedness among study participants. Incremental value of adhesion molecule biomarkers was studied using integrated discrimination improvement (IDI) and net reclassification improvement (NRI) indexes. Results Decreasing median values for serum concentrations of sICAM-1 and sVCAM-1 were observed in the following groups in this order: individuals with T2D at baseline, individuals who developed T2D during follow-up, individuals with prediabetes at baseline and normal glucose tolerant (NGT) individuals who remained T2D-free during follow-up. Top quartiles for sICAM-1 and sVCAM-1 were strongly and significantly associated with homeostatic model of assessment—insulin resistance (HOMA-IR). Mixed effects Cox proportional hazards modeling revealed that after correcting for important clinical confounders, high sICAM-1 and sVCAM-1 concentrations were associated with 2.52 and 1.99 times faster progression to T2D as compared to low concentrations, respectively. Individuals with high concentrations for both sICAM-1 and sVCAM-1 progressed to T2D 3.42 times faster than those with low

  18. Effect of type of fiber, site of fermentation, and method of analysis on digestibility of soluble and insoluble fiber in rabbits.

    PubMed

    Abad-Guamán, R; Carabaño, R; Gómez-Conde, M S; García, J

    2015-06-01

    The effect of type of fiber, site of fermentation, method for quantifying insoluble and soluble dietary fiber, and their correction for intestinal mucin on fiber digestibility were examined in rabbits. Three diets differing in soluble fiber were formulated (8.5% soluble fiber, on DM basis, in the low soluble fiber [LSF] diet; 10.2% in the medium soluble fiber [MSF] diet; and 14.5% in the high soluble fiber [HSF] diet). They were obtained by replacing half of the dehydrated alfalfa in the MSF diet with a mixture of beet and apple pulp (HSF diet) or with a mix of oat hulls and soybean protein (LSF diet). Thirty rabbits with ileal T-cannulas were used to determine ileal and fecal digestibility. Cecal digestibility was determined by difference between fecal and ileal digestibility. Insoluble fiber was measured as NDF, insoluble dietary fiber (IDF), and in vitro insoluble fiber, whereas soluble fiber was calculated as the difference between total dietary fiber (TDF) and NDF (TDF-NDF), IDF (TDF-IDF), and in vitro insoluble fiber (TDF-in vitro insoluble fiber). The intestinal mucin content was used to correct the TDF and soluble fiber digestibility. Ileal and fecal concentration of mucin increased from the LSF to the HSF diet group (P < 0.01). Once corrected for intestinal mucin, ileal and fecal digestibility of TDF and soluble fiber increased whereas cecal digestibility decreased (P < 0.01). Ileal digestibility of TDF increased from the LSF to the HSF diet group (12.0 vs. 28.1%; P < 0.01), with no difference in the cecum (26.4%), resulting in a higher fecal digestibility from the LSF to the HSF diet group (P < 0.01). Ileal digestibility of insoluble fiber increased from the LSF to the HSF diet group (11.3 vs. 21.0%; P < 0.01), with no difference in the cecum (13.9%) and no effect of fiber method, resulting in a higher fecal digestibility for rabbits fed the HSF diet compared with the MSF and LSF diet groups (P < 0.01). Fecal digestibility of NDF was higher compared with

  19. Effect of type of fiber, site of fermentation, and method of analysis on digestibility of soluble and insoluble fiber in rabbits.

    PubMed

    Abad-Guamán, R; Carabaño, R; Gómez-Conde, M S; García, J

    2015-06-01

    The effect of type of fiber, site of fermentation, method for quantifying insoluble and soluble dietary fiber, and their correction for intestinal mucin on fiber digestibility were examined in rabbits. Three diets differing in soluble fiber were formulated (8.5% soluble fiber, on DM basis, in the low soluble fiber [LSF] diet; 10.2% in the medium soluble fiber [MSF] diet; and 14.5% in the high soluble fiber [HSF] diet). They were obtained by replacing half of the dehydrated alfalfa in the MSF diet with a mixture of beet and apple pulp (HSF diet) or with a mix of oat hulls and soybean protein (LSF diet). Thirty rabbits with ileal T-cannulas were used to determine ileal and fecal digestibility. Cecal digestibility was determined by difference between fecal and ileal digestibility. Insoluble fiber was measured as NDF, insoluble dietary fiber (IDF), and in vitro insoluble fiber, whereas soluble fiber was calculated as the difference between total dietary fiber (TDF) and NDF (TDF-NDF), IDF (TDF-IDF), and in vitro insoluble fiber (TDF-in vitro insoluble fiber). The intestinal mucin content was used to correct the TDF and soluble fiber digestibility. Ileal and fecal concentration of mucin increased from the LSF to the HSF diet group (P < 0.01). Once corrected for intestinal mucin, ileal and fecal digestibility of TDF and soluble fiber increased whereas cecal digestibility decreased (P < 0.01). Ileal digestibility of TDF increased from the LSF to the HSF diet group (12.0 vs. 28.1%; P < 0.01), with no difference in the cecum (26.4%), resulting in a higher fecal digestibility from the LSF to the HSF diet group (P < 0.01). Ileal digestibility of insoluble fiber increased from the LSF to the HSF diet group (11.3 vs. 21.0%; P < 0.01), with no difference in the cecum (13.9%) and no effect of fiber method, resulting in a higher fecal digestibility for rabbits fed the HSF diet compared with the MSF and LSF diet groups (P < 0.01). Fecal digestibility of NDF was higher compared with

  20. High circulating activin A level is associated with tumor progression and predicts poor prognosis in lung adenocarcinoma

    PubMed Central

    Hoda, Mir Alireza; Rozsas, Anita; Lang, Elisabeth; Klikovits, Thomas; Lohinai, Zoltan; Torok, Szilvia; Berta, Judit; Bendek, Matyas; Berger, Walter; Hegedus, Balazs; Klepetko, Walter; Renyi-Vamos, Ferenc; Grusch, Michael; Dome, Balazs; Laszlo, Viktoria

    2016-01-01

    Activin A (ActA)/follistatin (FST) signaling has been shown to be deregulated in different tumor types including lung adenocarcinoma (LADC). Here, we report that serum ActA protein levels are significantly elevated in LADC patients (n=64) as compared to controls (n=46, p=0.015). ActA levels also correlated with more advanced disease stage (p<0.0001) and T (p=0.0035) and N (p=0.0002) factors. M1 patients had significantly higher ActA levels than M0 patients (p<0.001). High serum ActA level was associated with poor overall survival (p<0.0001) and was confirmed as an independent prognostic factor (p=0.004). Serum FST levels were increased only in female LADC patients (vs. female controls, p=0.031). Two out of five LADC cell lines secreted biologically active ActA, while FST was produced in all of them. Transcripts of both type I and II ActA receptors were detected in all five LADC cell lines. In conclusion, our study does not only suggest that measuring blood ActA levels in LADC patients might improve the prediction of prognosis, but also indicates that this parameter might be a novel non-invasive biomarker for identifying LADC patients with organ metastases. PMID:26950277

  1. Soluble Urokinase-Type Plasminogen Activator Receptor Plasma Concentration May Predict Susceptibility to High Altitude Pulmonary Edema.

    PubMed

    Hilty, Matthias Peter; Zügel, Stefanie; Schoeb, Michele; Auinger, Katja; Dehnert, Christoph; Maggiorini, Marco

    2016-01-01

    Introduction. Acute exposure to high altitude induces inflammation. However, the relationship between inflammation and high altitude related illness such as high altitude pulmonary edema (HAPE) and acute mountain sickness (AMS) is poorly understood. We tested if soluble urokinase-type plasminogen activator receptor (suPAR) plasma concentration, a prognostic factor for cardiovascular disease and marker for low grade activation of leukocytes, will predict susceptibility to HAPE and AMS. Methods. 41 healthy mountaineers were examined at sea level (SL, 446 m) and 24 h after rapid ascent to 4559 m (HA). 24/41 subjects had a history of HAPE and were thus considered HAPE-susceptible (HAPE-s). Out of the latter, 10/24 HAPE-s subjects were randomly chosen to suppress the inflammatory cascade with dexamethasone 8 mg bid 24 h prior to ascent. Results. Acute hypoxic exposure led to an acute inflammatory reaction represented by an increase in suPAR (1.9 ± 0.4 at SL versus 2.3 ± 0.5 at HA, p < 0.01), CRP (0.7 ± 0.5 at SL versus 3.6 ± 4.6 at HA, p < 0.01), and IL-6 (0.8 ± 0.4 at SL versus 3.3 ± 4.9 at HA, p < 0.01) in all subjects except those receiving dexamethasone. The ascent associated decrease in PaO2 correlated with the increase in IL-6 (r = 0.46, p < 0.001), but not suPAR (r = 0.27, p = 0.08); the increase in IL-6 was not correlated with suPAR (r = 0.16, p = 0.24). Baseline suPAR plasma concentration was higher in the HAPE-s group (2.0 ± 0.4 versus 1.8 ± 0.4, p = 0.04); no difference was found for CRP and IL-6 and for subjects developing AMS. Conclusion. High altitude exposure leads to an increase in suPAR plasma concentration, with the missing correlation between suPAR and IL-6 suggesting a cytokine independent, leukocyte mediated mechanism of low grade inflammation. The correlation between IL-6 and PaO2 suggests a direct effect of hypoxia, which is not the case for suPAR. However, suPAR plasma concentration measured before hypoxic exposure may predict

  2. n-Type Water/Alcohol-Soluble Naphthalene Diimide-Based Conjugated Polymers for High-Performance Polymer Solar Cells.

    PubMed

    Wu, Zhihong; Sun, Chen; Dong, Sheng; Jiang, Xiao-Fang; Wu, Siping; Wu, Hongbin; Yip, Hin-Lap; Huang, Fei; Cao, Yong

    2016-02-17

    With the demonstration of small-area, single-junction polymer solar cells (PSCs) with power conversion efficiencies (PCEs) over the 10% performance milestone, the manufacturing of high-performance large-area PSC modules is becoming the most critical issue for commercial applications. However, materials and processes that are optimized for fabricating small-area devices may not be applicable for the production of high-performance large-area PSC modules. One of the challenges is to develop new conductive interfacial materials that can be easily processed with a wide range of thicknesses without significantly affecting the performance of the PSCs. Toward this goal, we report two novel naphthalene diimide-based, self-doped, n-type water/alcohol-soluble conjugated polymers (WSCPs) that can be processed with a broad thickness range of 5 to 100 nm as efficient electron transporting layers (ETLs) for high-performance PSCs. Space charge limited current and electron spin resonance spectroscopy studies confirm that the presence of amine or ammonium bromide groups on the side chains of the WSCP can n-dope PC71BM at the bulk heterojunction (BHJ)/ETL interface, which improves the electron extraction properties at the cathode. In addition, both amino functional groups can induce self-doping to the WSCPs, although by different doping mechanisms, which leads to highly conductive ETLs with reduced ohmic loss for electron transport and extraction. Ultimately, PSCs based on the self-doped WSCP ETLs exhibit significantly improved device performance, yielding PCEs as high as 9.7% and 10.11% for PTB7-Th/PC71BM and PffBT4T-2OD/PC71BM systems, respectively. More importantly, with PffBT4T-2OD/PC71BM BHJ as an active layer, a prominent PCE of over 8% was achieved even when a thick ETL of 100 nm was used. To the best of our knowledge, this is the highest efficiency demonstrated for PSCs with a thick interlayer and light-harvesting layer, which are important criteria for eventually making

  3. n-Type Water/Alcohol-Soluble Naphthalene Diimide-Based Conjugated Polymers for High-Performance Polymer Solar Cells.

    PubMed

    Wu, Zhihong; Sun, Chen; Dong, Sheng; Jiang, Xiao-Fang; Wu, Siping; Wu, Hongbin; Yip, Hin-Lap; Huang, Fei; Cao, Yong

    2016-02-17

    With the demonstration of small-area, single-junction polymer solar cells (PSCs) with power conversion efficiencies (PCEs) over the 10% performance milestone, the manufacturing of high-performance large-area PSC modules is becoming the most critical issue for commercial applications. However, materials and processes that are optimized for fabricating small-area devices may not be applicable for the production of high-performance large-area PSC modules. One of the challenges is to develop new conductive interfacial materials that can be easily processed with a wide range of thicknesses without significantly affecting the performance of the PSCs. Toward this goal, we report two novel naphthalene diimide-based, self-doped, n-type water/alcohol-soluble conjugated polymers (WSCPs) that can be processed with a broad thickness range of 5 to 100 nm as efficient electron transporting layers (ETLs) for high-performance PSCs. Space charge limited current and electron spin resonance spectroscopy studies confirm that the presence of amine or ammonium bromide groups on the side chains of the WSCP can n-dope PC71BM at the bulk heterojunction (BHJ)/ETL interface, which improves the electron extraction properties at the cathode. In addition, both amino functional groups can induce self-doping to the WSCPs, although by different doping mechanisms, which leads to highly conductive ETLs with reduced ohmic loss for electron transport and extraction. Ultimately, PSCs based on the self-doped WSCP ETLs exhibit significantly improved device performance, yielding PCEs as high as 9.7% and 10.11% for PTB7-Th/PC71BM and PffBT4T-2OD/PC71BM systems, respectively. More importantly, with PffBT4T-2OD/PC71BM BHJ as an active layer, a prominent PCE of over 8% was achieved even when a thick ETL of 100 nm was used. To the best of our knowledge, this is the highest efficiency demonstrated for PSCs with a thick interlayer and light-harvesting layer, which are important criteria for eventually making

  4. Soluble Urokinase-Type Plasminogen Activator Receptor Plasma Concentration May Predict Susceptibility to High Altitude Pulmonary Edema

    PubMed Central

    Zügel, Stefanie; Schoeb, Michele; Auinger, Katja; Dehnert, Christoph; Maggiorini, Marco

    2016-01-01

    Introduction. Acute exposure to high altitude induces inflammation. However, the relationship between inflammation and high altitude related illness such as high altitude pulmonary edema (HAPE) and acute mountain sickness (AMS) is poorly understood. We tested if soluble urokinase-type plasminogen activator receptor (suPAR) plasma concentration, a prognostic factor for cardiovascular disease and marker for low grade activation of leukocytes, will predict susceptibility to HAPE and AMS. Methods. 41 healthy mountaineers were examined at sea level (SL, 446 m) and 24 h after rapid ascent to 4559 m (HA). 24/41 subjects had a history of HAPE and were thus considered HAPE-susceptible (HAPE-s). Out of the latter, 10/24 HAPE-s subjects were randomly chosen to suppress the inflammatory cascade with dexamethasone 8 mg bid 24 h prior to ascent. Results. Acute hypoxic exposure led to an acute inflammatory reaction represented by an increase in suPAR (1.9 ± 0.4 at SL versus 2.3 ± 0.5 at HA, p < 0.01), CRP (0.7 ± 0.5 at SL versus 3.6 ± 4.6 at HA, p < 0.01), and IL-6 (0.8 ± 0.4 at SL versus 3.3 ± 4.9 at HA, p < 0.01) in all subjects except those receiving dexamethasone. The ascent associated decrease in PaO2 correlated with the increase in IL-6 (r = 0.46, p < 0.001), but not suPAR (r = 0.27, p = 0.08); the increase in IL-6 was not correlated with suPAR (r = 0.16, p = 0.24). Baseline suPAR plasma concentration was higher in the HAPE-s group (2.0 ± 0.4 versus 1.8 ± 0.4, p = 0.04); no difference was found for CRP and IL-6 and for subjects developing AMS. Conclusion. High altitude exposure leads to an increase in suPAR plasma concentration, with the missing correlation between suPAR and IL-6 suggesting a cytokine independent, leukocyte mediated mechanism of low grade inflammation. The correlation between IL-6 and PaO2 suggests a direct effect of hypoxia, which is not the case for suPAR. However, suPAR plasma concentration measured before hypoxic exposure may predict

  5. Activin Regulates Self-renewal and Differentiation of Trophoblast Stem Cells by Down-regulating the X Chromosome Gene Bcor*

    PubMed Central

    Zhu, Gaoyang; Fei, Teng; Li, Zhongwei; Yan, Xiaohua; Chen, Ye-Guang

    2015-01-01

    The development of a functional placenta is largely dependent upon proper proliferation and differentiation of trophoblast stem cells (TSCs). Activin signaling has long been regarded to play important roles during this process, but the exact mechanism is largely unknown. Here, we demonstrate that the X chromosome gene BCL-6 corepressor (Bcor) is a critical downstream effector of activin to fine-tune mouse TSC fate decision. Bcor was specifically down-regulated by activin A in TSCs in a dose-dependent manner, and immediately up-regulated upon TSC differentiation. Knockdown of Bcor partially compensated for the absence of activin A in maintaining the self-renewal of TSCs together with FGF4, while promoting syncytiotrophoblast differentiation in the absence of FGF4. Moreover, the impaired trophoblast giant cell and spongiotrophoblast differentiation upon Bcor knockdown also resembled the function of activin. Reporter analysis showed that BCOR inhibited the expression of the key trophoblast regulator genes Eomes and Cebpa by binding to their promoter regions. Our findings provide us with a better understanding of placental development and placenta-related diseases. PMID:26221038

  6. Graded changes in dose of a Xenopus activin A homologue elicit stepwise transitions in embryonic cell fate.

    PubMed

    Green, J B; Smith, J C

    1990-09-27

    The protein XTC-MIF, a Xenopus homologue of activin A and a potent mesoderm-inducing factor, can induce responding animal pole explants to form several different cell types in a dose-dependent manner, higher doses eliciting more dorso-anterior tissues. This graded response, characteristic of classically postulated morphogens, may underlie pattern formation, but the response of intact animal caps to XTC-MIF provides only a crude indication of trends. Here we report the effects of XTC-MIF on dispersed blastomeres rather than intact animal caps. Under these conditions, responding cells distinguish sharply between doses of pure XTC-MIF differing by less than 1.5-fold. Two different response thresholds have been found, defining three cell states. This suggests that XTC-MIF has an instructive effect. Notochord and muscle are both induced in the same narrow dose-range. Mixing treated with untreated cells does not seem to shift the dose thresholds, showing that at least some cells can stably record the received dose of inducing factor.

  7. 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.

  8. [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. PMID:22946180

  9. Solubility of {sup 238}U radionuclide from various types of soil in synthetic gastrointestinal fluids using “US in vitro” digestion method

    SciTech Connect

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

    2015-04-29

    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.

  10. Antisense-oligonucleotide mediated exon skipping in activin-receptor-like kinase 2: inhibiting the receptor that is overactive in fibrodysplasia ossificans progressiva.

    PubMed

    Shi, Songting; Cai, Jie; de Gorter, David J J; Sanchez-Duffhues, Gonzalo; Kemaladewi, Dwi U; Hoogaars, Willem M H; Aartsma-Rus, Annemieke; 't Hoen, Peter A C; ten Dijke, Peter

    2013-01-01

    Fibrodysplasia ossificans progressiva (FOP) is a rare heritable disease characterized by progressive heterotopic ossification of connective tissues, for which there is presently no definite treatment. A recurrent activating mutation (c.617G→A; R206H) of activin receptor-like kinase 2 (ACVR1/ALK2), a BMP type I receptor, has been shown as the main cause of FOP. This mutation constitutively activates the BMP signaling pathway and initiates the formation of heterotopic bone. In this study, we have designed antisense oligonucleotides (AONs) to knockdown mouse ALK2 expression by means of exon skipping. The ALK2 AON could induce exon skipping in cells, which was accompanied by decreased ALK2 mRNA levels and impaired BMP signaling. In addition, the ALK2 AON potentiated muscle differentiation and repressed BMP6-induced osteoblast differentiation. Our results therefore provide a potential therapeutic approach for the treatment of FOP disease by reducing the excessive ALK2 activity in FOP patients.

  11. Activin signaling balances proliferation and differentiation of ovarian niche precursors and enables adjustment of niche numbers.

    PubMed

    Lengil, Tamar; Gancz, Dana; Gilboa, Lilach

    2015-03-01

    How the numbers of niches and resident stem cells within a particular organ are determined during development and how they may be modulated or corrected is a question with significant medical implications. In the larval ovary of Drosophila melanogaster, somatic precursors for niches, and germ cells that will become germline stem cells, co-develop. Somatic precursors proliferate during the first 3 days of larval development. By mid-third instar, adult terminal filament (TF) (part of the germline stem cell niche) cells first appear, and differentiation terminates 24 h later when 16-20 TFs fully form. The developmental sequence responsible for TF cell determination and final TF numbers is only partially understood. We show that TF formation proceeds through several, hitherto uncharacterized stages, which include an early exit from the cell cycle to form TF precursors and two steps of cell shape change to form the mature TF cells. The Activin receptor Baboon (Babo) is required for somatic precursor cell proliferation and therefore determines the pool of TF precursors available for TF differentiation. During the final differentiation stage, Babo facilitates TF and germ cell differentiation, and promotes the accumulation of Broad-Z1, which is also a target of the steroid hormone ecdysone. Epistasis analysis shows that Activin controls cell proliferation in an ecdysone-independent manner and TF differentiation by affecting ecdysone targets. We propose that this mode of function allows Activin to balance proliferation and differentiation, and to equilibrate niche numbers. These results suggest a novel model for how niche numbers are corrected during development.

  12. Mechanical properties and solubility in water of corn starch-collagen composite films: Effect of starch type and concentrations.

    PubMed

    Wang, Kun; Wang, Wenhang; Ye, Ran; Liu, Anjun; Xiao, Jingdong; Liu, Yaowei; Zhao, Yana

    2017-02-01

    This study investigated the possibility of enhancing the properties of collagen with three different maize starches: waxy maize starch, normal starch, and high amylose starch. Scanning electron microscopy images revealed that starch-collagen films had a rougher surface compared to pure collagen films which became smoother upon heating. Amylose starch and normal starch increased the tensile strength of unheated collagen films in both dry and wet states, while all starches increased tensile strength of collagen film by heating. Depending upon the amylose content and starch concentrations, film solubility in water decreased with the addition of starch. DSC thermograms demonstrated that addition of all starches improved the thermal stability of the collagen film. Moreover, X-ray diffraction results indicated that except for high amylose starch, the crystallinity of both starch and collagen was significantly decreased when subject to heating. FTIR spectra indicated that intermolecular interactions between starch and collagen were enhanced upon heating. PMID:27596411

  13. Neuropoietic cytokines and activin A differentially regulate the phenotype of cultured sympathetic neurons.

    PubMed Central

    Fann, M J; Patterson, P H

    1994-01-01

    A number of cytokines sharing limited sequence homology have been grouped as a family because of partially overlapping biological activities, receptor subunit promiscuity, and the prediction of a shared secondary structure. Since several of these cytokines regulate gene expression and cell number in the nervous and hematopoietic systems, this specific group is termed the neuropoietic cytokine family. Using a reverse transcription-polymerase chain reaction-based assay system for monitoring the expression of multiple phenotypic markers in cultured sympathetic neurons, we present further evidence that, in addition to cholinergic differentiation factor/leukemia inhibitory factor and ciliary neurotrophic factor, oncostatin M, growth promoting activity, interleukin 6, and interleukin 11 belong in this family. In addition, one member of the transforming growth factor beta superfamily, activin A, shares a selective overlap with the neuropoietic family in the spectrum of neuropeptides that it induces in sympathetic neurons. The particular neuropeptides induced by activin A, however, demonstrate that the activity of this cytokine is distinct from that of the neuropoietic family. Twenty-six other cytokines and growth factors were without detectable activity in this assay. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:7904069

  14. Clinical Relevance and Mechanisms of Antagonism Between the BMP and Activin/TGF-β Signaling Pathways.

    PubMed

    Hudnall, Aaron M; Arthur, Jon W; Lowery, Jonathan W

    2016-07-01

    The transforming growth factor β (TGF-β) superfamily is a large group of signaling molecules that participate in embryogenesis, organogenesis, and tissue homeostasis. These molecules are present in all animal genomes. Dysfunction in the regulation or activity of this superfamily's components underlies numerous human diseases and developmental defects. There are 2 distinct arms downstream of the TGF-β superfamily ligands-the bone morphogenetic protein (BMP) and activin/TGF-β signaling pathways-and these 2 responses can oppose one another's effects, most notably in disease states. However, studies have commonly focused on a single arm of the TGF-β superfamily, and the antagonism between these pathways is unknown in most physiologic and pathologic contexts. In this review, the authors summarize the clinically relevant scenarios in which the BMP and activin/TGF-β pathways reportedly oppose one another and identify several molecular mechanisms proposed to mediate this interaction. Particular attention is paid to experimental findings that may be informative to human pathology to highlight potential therapeutic approaches for future investigation. PMID:27367950

  15. Graded Nodal/Activin Signaling Titrates Conversion of Quantitative Phospho-Smad2 Levels into Qualitative Embryonic Stem Cell Fate Decisions

    PubMed Central

    Orlov, Yuriy Lvovich; Yit, Le Yau; Yang, Henry; Ang, Lay Teng; Poellinger, Lorenz; Lim, Bing

    2011-01-01

    Nodal and Activin are morphogens of the TGFbeta superfamily of signaling molecules that direct differential cell fate decisions in a dose- and distance-dependent manner. During early embryonic development the Nodal/Activin pathway is responsible for the specification of mesoderm, endoderm, node, and mesendoderm. In contradiction to this drive towards cellular differentiation, the pathway also plays important roles in the maintenance of self-renewal and pluripotency in embryonic and epiblast stem cells. The molecular basis behind stem cell interpretation of Nodal/Activin signaling gradients and the undertaking of disparate cell fate decisions remains poorly understood. Here, we show that any perturbation of endogenous signaling levels in mouse embryonic stem cells leads to their exit from self-renewal towards divergent differentiation programs. Increasing Nodal signals above basal levels by direct stimulation with Activin promotes differentiation towards the mesendodermal lineages while repression of signaling with the specific Nodal/Activin receptor inhibitor SB431542 induces trophectodermal differentiation. To address how quantitative Nodal/Activin signals are translated qualitatively into distinct cell fates decisions, we performed chromatin immunoprecipitation of phospho-Smad2, the primary downstream transcriptional factor of the Nodal/Activin pathway, followed by massively parallel sequencing, and show that phospho-Smad2 binds to and regulates distinct subsets of target genes in a dose-dependent manner. Crucially, Nodal/Activin signaling directly controls the Oct4 master regulator of pluripotency by graded phospho-Smad2 binding in the promoter region. Hence stem cells interpret and carry out differential Nodal/Activin signaling instructions via a corresponding gradient of Smad2 phosphorylation that selectively titrates self-renewal against alternative differentiation programs by direct regulation of distinct target gene subsets and Oct4 expression. PMID

  16. Controls on iron distributions in the deep water column of the North Pacific Ocean: Iron(III) hydroxide solubility and marine humic-type dissolved organic matter

    NASA Astrophysics Data System (ADS)

    Kitayama, Saori; Kuma, Kenshi; Manabe, Eri; Sugie, Koji; Takata, Hyoe; Isoda, Yutaka; Toya, Kenji; Saitoh, Sei-Ichi; Takagi, Shohgo; Kamei, Yoshihiko; Sakaoka, Keiichiro

    2009-08-01

    Dissolved Fe in the western and central North Pacific Ocean was characterized by surface depletion, middepth maxima and, below that, a slight decrease with depth similar to the vertical distributions of nutrients, apparent oxygen utilization, Fe(III) hydroxide solubility, and humic-type fluorescence (H-flu) intensity. Dissolved Fe concentrations ([D-Fe], <0.22-μm fraction) in the deep water column were one-half lower in the central region (0.3-0.6 nM) than the western region (0.5-1.2 nM) although the Fe(III) solubility ([Fe(III)sol], <0.025-μm fraction) levels and distributions in deep waters were almost the same between both regions with middepth maxima (˜0.6 nM) at 500-1500-m depth range and then a gradual decrease to ˜0.3 nM at 5000-m depth. Higher [D-Fe] than [Fe(III)sol] in the deep water column of the western region results from the higher production of dissolved Fe from the decomposition of sinking particulate organic matter in the western region than the central region because of the high atmospheric and/or lateral Fe inputs in the western region. Similarity between [D-Fe] level and [Fe(III)sol] value at each deep water depth in the central region may be attributed to [D-Fe] being nearly in the solubility equilibrium with Fe(III) hydroxide in seawater. Strong linear correlation between [D-Fe] and H-flu intensity in the central region and relatively similar linear relationships between [Fe(III)sol] and H-flu intensity in the western and central regions are the first confirmation that humic-type fluorescent dissolved organic matter may be responsible for [D-Fe] in the deep water column as natural organic ligands complexing with Fe(III).

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  18. Molecular and cellular mechanisms of bone morphogenetic proteins and activins in the skin: potential benefits for wound healing.

    PubMed

    Moura, J; da Silva, L; Cruz, M T; Carvalho, E

    2013-09-01

    Bone morphogenetic proteins (BMPs) and activins are phylogenetically conserved proteins, belonging to the transforming growth factor-β superfamily, that signal through the phosphorylation of receptor-regulated Smad proteins, activating different cell responses. They are involved in various steps of skin morphogenesis and wound repair, as can be evidenced by the fact that their expression is increased in skin injuries. BMPs play not only a role in bone regeneration but are also involved in cartilage, tendon-like tissue and epithelial regeneration, maintain vascular integrity, capillary sprouting, proliferation/migration of endothelial cells and angiogenesis, promote neuron and dendrite formation, alter neuropeptide levels and are involved in immune response modulation, at least in animal models. On the other hand, activins are involved in wound repair through the regulation of skin and immune cell migration and differentiation, re-epithelialization and granulation tissue formation, and also promote the expression of collagens by fibroblasts and modulate scar formation. This review aims at enunciating the effects of BMPs and activins in the skin, namely in skin development, as well as in crucial phases of skin wound healing, such as inflammation, angiogenesis and repair, and will focus on the effects of these proteins on skin cells and their signaling pathways, exploring the potential therapeutic approach of the application of BMP-2, BMP-6 and activin A in chronic wounds, particularly diabetic foot ulcerations.

  19. 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…

  20. The stability of water- and fat-soluble vitamin in dentifrices according to pH level and storage type.

    PubMed

    Park, Jung-Eun; Kim, Ki-Eun; Choi, Yong-Jun; Park, Yong-Duk; Kwon, Ha-Jeong

    2016-02-01

    The purpose of this study is to evaluate the vitamin stabilities in dentifrices by analyzing various vitamins according to the level and storage temperature. The stabilities of water- and fat-soluble vitamins were investigated in buffer solution at different pH values (4, 7, 8, 10 and 11) for 14 days and in dentifrices at different pH (7 and 10) for 5 months at two temperature conditions (room and refrigeration temperature) by analyzing the remaining amounts using HPLC methods. In the buffer solution, the stability of vitamins B1 , B6 and C was increased as the pH values increased. Vitamins E and K showed poor stability at pH 4, and vitamin B3 showed poor stability at pH 11. In dentifrices, the storage temperature highly influenced vitamin stability, especially vitamins C and E, but the stabilities of vitamins B1 and C according to pH values did not correspond to the buffer solution tests. Vitamin B group was relatively stable in dentifrices, but vitamin C completely disappeared after 5 months. Vitamin K showed the least initial preservation rates. Vitamins were not detected in commercial dentifrices for adults and detected amounts were less than the advertised contents in dentifrices for children.

  1. Cilostazol attenuates the severity of peripheral arterial occlusive disease in patients with type 2 diabetes: the role of plasma soluble receptor for advanced glycation end-products.

    PubMed

    Liu, Jhih-Syuan; Chuang, Tsung-Ju; Chen, Jui-Hung; Lee, Chien-Hsing; Hsieh, Chang-Hsun; Lin, Tsung-Kun; Hsiao, Fone-Ching; Hung, Yi-Jen

    2015-08-01

    Recent studies have demonstrated that the plasma soluble receptor for advanced glycation end-products (sRAGE) play a major role in developing macrovascular complications of type 2 diabetes, including peripheral arterial occlusion disease (PAOD). Cilostazol is an antiplatelet, antithrombotic agent, which has been used for the treatment of PAOD. We hypothesized that cilostazol attenuates the severity of PAOD in patients with type 2 diabetes through the augmentation of plasma sRAGE. Ninety type 2 diabetic patients with PAOD defined as intermittent claudication with ankle-brachial index (ABI) ≦0.9 were recruited for an open-labeled, placebo-controlled study for 52 weeks with oral cilostazol 100 mg twice daily (n = 45) or placebo (n = 45). Fasting plasma sRAGE, endothelial variables of E-selectin, soluble vascular cell adhesion molecule-1 (sVCAM-1), and inflammatory markers of high-sensitivity C-reactive protein (hsCRP) and tumor necrosis factor-α (TNF-α) were determined. After completely the 52-week treatment program, the ABI values were elevated in cilostazol group (P < 0.001). The plasma sRAGE was significantly increased (P = 0.007), and hsCRP, sVCAM, and E-selectin concentrations were significantly decreased (P = 0.028, <0.001 and <0.001, respectively) with cilostazol treatment. In a partial correlation analysis with adjustments for sex and age, the net change of sRAGE significantly correlated with the change of ABI in the cilostazol group (P = 0.043). In a stepwise multiple regression model, only the change with regards to sRAGE was significantly associated with the change of ABI (P = 0.046). Our results suggest that cilostazol may effectively attenuate the severity of PAOD in patients with type 2 diabetes. Plasma sRAGE plays a role as an independent predictor for improving the index of PAOD.

  2. Cilostazol attenuates the severity of peripheral arterial occlusive disease in patients with type 2 diabetes: the role of plasma soluble receptor for advanced glycation end-products.

    PubMed

    Liu, Jhih-Syuan; Chuang, Tsung-Ju; Chen, Jui-Hung; Lee, Chien-Hsing; Hsieh, Chang-Hsun; Lin, Tsung-Kun; Hsiao, Fone-Ching; Hung, Yi-Jen

    2015-08-01

    Recent studies have demonstrated that the plasma soluble receptor for advanced glycation end-products (sRAGE) play a major role in developing macrovascular complications of type 2 diabetes, including peripheral arterial occlusion disease (PAOD). Cilostazol is an antiplatelet, antithrombotic agent, which has been used for the treatment of PAOD. We hypothesized that cilostazol attenuates the severity of PAOD in patients with type 2 diabetes through the augmentation of plasma sRAGE. Ninety type 2 diabetic patients with PAOD defined as intermittent claudication with ankle-brachial index (ABI) ≦0.9 were recruited for an open-labeled, placebo-controlled study for 52 weeks with oral cilostazol 100 mg twice daily (n = 45) or placebo (n = 45). Fasting plasma sRAGE, endothelial variables of E-selectin, soluble vascular cell adhesion molecule-1 (sVCAM-1), and inflammatory markers of high-sensitivity C-reactive protein (hsCRP) and tumor necrosis factor-α (TNF-α) were determined. After completely the 52-week treatment program, the ABI values were elevated in cilostazol group (P < 0.001). The plasma sRAGE was significantly increased (P = 0.007), and hsCRP, sVCAM, and E-selectin concentrations were significantly decreased (P = 0.028, <0.001 and <0.001, respectively) with cilostazol treatment. In a partial correlation analysis with adjustments for sex and age, the net change of sRAGE significantly correlated with the change of ABI in the cilostazol group (P = 0.043). In a stepwise multiple regression model, only the change with regards to sRAGE was significantly associated with the change of ABI (P = 0.046). Our results suggest that cilostazol may effectively attenuate the severity of PAOD in patients with type 2 diabetes. Plasma sRAGE plays a role as an independent predictor for improving the index of PAOD. PMID:25666934

  3. 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

  4. Fibrodysplasia ossificans progressiva-related activated activin-like kinase signaling enhances osteoclast formation during heterotopic ossification in muscle tissues.

    PubMed

    Yano, Masato; Kawao, Naoyuki; Okumoto, Katsumi; Tamura, Yukinori; Okada, Kiyotaka; Kaji, Hiroshi

    2014-06-13

    Fibrodysplasia ossificans progressiva is characterized by extensive ossification within muscle tissues, and its molecular pathogenesis is responsible for the constitutively activating mutation (R206H) of the bone morphogenetic protein type 1 receptor, activin-like kinase 2 (ALK2). In this study, we investigated the effects of implanting ALK2 (R206H)-transfected myoblastic C2C12 cells into nude mice on osteoclast formation during heterotopic ossification in muscle and subcutaneous tissues. The implantation of ALK2 (R206H)-transfected C2C12 cells with BMP-2 in nude mice induced robust heterotopic ossification with an increase in the formation of osteoclasts in muscle tissues but not in subcutaneous tissues. The implantation of ALK2 (R206H)-transfected C2C12 cells in muscle induced heterotopic ossification more effectively than that of empty vector-transfected cells. A co-culture of ALK2 (R206H)-transfected C2C12 cells as well as the conditioned medium from ALK2 (R206H)-transfected C2C12 cells enhanced osteoclast formation in Raw264.7 cells more effectively than those with empty vector-transfected cells. The transfection of ALK2 (R206H) into C2C12 cells elevated the expression of transforming growth factor (TGF)-β, whereas the inhibition of TGF-β signaling suppressed the enhanced formation of osteoclasts in the co-culture with ALK2 (R206H)-transfected C2C12 cells and their conditioned medium. In conclusion, this study demonstrated that the causal mutation transfection of fibrodysplasia ossificans progressiva in myoblasts enhanced the formation of osteoclasts from its precursor through TGF-β in muscle tissues.

  5. Trpc2-expressing sensory neurons in the mouse main olfactory epithelium of type B express the soluble guanylate cyclase Gucy1b2

    PubMed Central

    Omura, Masayo; Mombaerts, Peter

    2015-01-01

    Chemoreception in the mouse olfactory system occurs primarily at two chemosensory epithelia in the nasal cavity: the main olfactory epithelium (MOE) and the vomeronasal epithelium. The canonical chemosensory neurons in the MOE, the olfactory sensory neurons (OSNs), express the odorant receptor (OR) gene repertoire, and depend on Adcy3 and Cnga2 for chemosensory signal transduction. The canonical chemosensory neurons in the vomeronasal epithelium, the vomeronasal sensory neurons (VSNs), express two unrelated vomeronasal receptor (VR) gene repertoires, and involve Trpc2 for chemosensory signal transduction. Recently we reported the discovery of two types of neurons in the mouse MOE that express Trcp2 in addition to Cnga2. These cell types can be distinguished at the single-cell level by expression of Adcy3: positive, type A and negative, type B. Some type A cells express OR genes. Thus far there is no specific gene or marker for type B cells, hampering further analyses such as physiological recordings. Here, we show that among MOE cells, type B cells are unique in their expression of the soluble guanylate cyclase Gucy1b2. We came across Gucy1b2 in an explorative approach based on Long Serial Analysis of Gene Expression (LongSAGE) that we applied to single red-fluorescent cells isolated from whole olfactory mucosa and vomeronasal organ of mice of a novel Trcp2-IRES-taumCherry gene-targeted strain. The generation of a novel Gucy1b2-IRES-tauGFP gene-targeted strain enabled us to visualize coalescence of axons of type B cells into glomeruli in the main olfactory bulb. Our molecular and anatomical analyses define Gucy1b2 as a marker for type B cells within the MOE. The Gucy1b2-IRES-tauGFP strain will be useful for physiological, molecular, cellular, and anatomical studies of this newly described chemosensory subsystem. PMID:25701815

  6. Lectin-dependent enhancement of Ebola virus infection via soluble and transmembrane C-type lectin receptors.

    PubMed

    Brudner, Matthew; Karpel, Marshall; Lear, Calli; Chen, Li; Yantosca, L Michael; Scully, Corinne; Sarraju, Ashish; Sokolovska, Anna; Zariffard, M Reza; Eisen, Damon P; Mungall, Bruce A; Kotton, Darrell N; Omari, Amel; Huang, I-Chueh; Farzan, Michael; Takahashi, Kazue; Stuart, Lynda; Stahl, Gregory L; Ezekowitz, Alan B; Spear, Gregory T; Olinger, Gene G; Schmidt, Emmett V; Michelow, Ian C

    2013-01-01

    Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active

  7. 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.

  8. 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. PMID:8811044

  9. Seminal fluid factors regulate activin A and follistatin synthesis in female cervical epithelial cells.

    PubMed

    Sharkey, David J; Schjenken, John E; Mottershead, David G; Robertson, Sarah A

    2015-12-01

    Seminal fluid induces pro-inflammatory cytokines and elicits an inflammation-like response in the cervix. Here, Affymetrix microarray and qPCR was utilised to identify activin A (INHBA) and its inhibitor follistatin (FST) amongst the cytokines induced by seminal plasma in Ect1 ectocervical epithelial cells, and a similar response was confirmed in primary ectocervical epithelial cells. TGFB is abundant in seminal plasma and all three TGFB isoforms induced INHBA in Ect1 and primary cells, and neutralisation of TGFB in seminal plasma suppressed the INHBA response. Bacterial lipopolysaccharide in seminal plasma also elicited INHBA, but potently suppressed FST production. There was moderate reciprocal inhibition between FST and INHBA, and cross-attenuating effects were seen. These data identify TGFB and potentially LPS as factors mediating seminal plasma-induced INHBA synthesis in cervical cells. INHBA and FST induced by seminal fluid in cervical tissues may thus contribute to regulation of the post-coital response in women.

  10. Multiple roles of Activin/Nodal, bone morphogenetic protein, fibroblast growth factor and Wnt/β-catenin signalling in the anterior neural patterning of adherent human embryonic stem cell cultures

    PubMed Central

    Lupo, Giuseppe; Novorol, Claire; Smith, Joseph R.; Vallier, Ludovic; Miranda, Elena; Alexander, Morgan; Biagioni, Stefano; Pedersen, Roger A.; Harris, William A.

    2013-01-01

    Several studies have successfully produced a variety of neural cell types from human embryonic stem cells (hESCs), but there has been limited systematic analysis of how different regional identities are established using well-defined differentiation conditions. We have used adherent, chemically defined cultures to analyse the roles of Activin/Nodal, bone morphogenetic protein (BMP), fibroblast growth factor (FGF) and Wnt/β-catenin signalling in neural induction, anteroposterior patterning and eye field specification in hESCs. We show that either BMP inhibition or activation of FGF signalling is required for effective neural induction, but these two pathways have distinct outcomes on rostrocaudal patterning. While BMP inhibition leads to specification of forebrain/midbrain positional identities, FGF-dependent neural induction is associated with strong posteriorization towards hindbrain/spinal cord fates. We also demonstrate that Wnt/β-catenin signalling is activated during neural induction and promotes acquisition of neural fates posterior to forebrain. Therefore, inhibition of this pathway is needed for efficient forebrain specification. Finally, we provide evidence that the levels of Activin/Nodal and BMP signalling have a marked influence on further forebrain patterning and that constitutive inhibition of these pathways represses expression of eye field genes. These results show that the key mechanisms controlling neural patterning in model vertebrate species are preserved in adherent, chemically defined hESC cultures and reveal new insights into the signals regulating eye field specification. PMID:23576785

  11. Multiple roles of Activin/Nodal, bone morphogenetic protein, fibroblast growth factor and Wnt/β-catenin signalling in the anterior neural patterning of adherent human embryonic stem cell cultures.

    PubMed

    Lupo, Giuseppe; Novorol, Claire; Smith, Joseph R; Vallier, Ludovic; Miranda, Elena; Alexander, Morgan; Biagioni, Stefano; Pedersen, Roger A; Harris, William A

    2013-04-01

    Several studies have successfully produced a variety of neural cell types from human embryonic stem cells (hESCs), but there has been limited systematic analysis of how different regional identities are established using well-defined differentiation conditions. We have used adherent, chemically defined cultures to analyse the roles of Activin/Nodal, bone morphogenetic protein (BMP), fibroblast growth factor (FGF) and Wnt/β-catenin signalling in neural induction, anteroposterior patterning and eye field specification in hESCs. We show that either BMP inhibition or activation of FGF signalling is required for effective neural induction, but these two pathways have distinct outcomes on rostrocaudal patterning. While BMP inhibition leads to specification of forebrain/midbrain positional identities, FGF-dependent neural induction is associated with strong posteriorization towards hindbrain/spinal cord fates. We also demonstrate that Wnt/β-catenin signalling is activated during neural induction and promotes acquisition of neural fates posterior to forebrain. Therefore, inhibition of this pathway is needed for efficient forebrain specification. Finally, we provide evidence that the levels of Activin/Nodal and BMP signalling have a marked influence on further forebrain patterning and that constitutive inhibition of these pathways represses expression of eye field genes. These results show that the key mechanisms controlling neural patterning in model vertebrate species are preserved in adherent, chemically defined hESC cultures and reveal new insights into the signals regulating eye field specification. PMID:23576785

  12. Accurate, quantitative assays for the hydrolysis of soluble type I, II, and III /sup 3/H-acetylated collagens by bacterial and tissue collagenases

    SciTech Connect

    Mallya, S.K.; Mookhtiar, K.A.; Van Wart, H.E.

    1986-11-01

    Accurate and quantitative assays for the hydrolysis of soluble /sup 3/H-acetylated rat tendon type I, bovine cartilage type II, and human amnion type III collagens by both bacterial and tissue collagenases have been developed. The assays are carried out at any temperature in the 1-30/sup 0/C range in a single reaction tube and the progress of the reaction is monitored by withdrawing aliquots as a function of time, quenching with 1,10-phenanthroline, and quantitation of the concentration of hydrolysis fragments. The latter is achieved by selective denaturation of these fragments by incubation under conditions described in the previous paper of this issue. The assays give percentages of hydrolysis of all three collagen types by neutrophil collagenase that agree well with the results of gel electrophoresis experiments. The initial rates of hydrolysis of all three collagens are proportional to the concentration of both neutrophil or Clostridial collagenases over a 10-fold range of enzyme concentrations. All three assays can be carried out at collagen concentrations that range from 0.06 to 2 mg/ml and give linear double reciprocal plots for both tissue and bacterial collagenases that can be used to evaluate the kinetic parameters K/sub m/ and k/sub cat/ or V/sub max/. The assay developed for the hydrolysis of rat type I collagen by neutrophil collagenase is shown to be more sensitive by at least one order of magnitude than comparable assays that use rat type I collagen fibrils or gels as substrate.

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

    SciTech Connect

    Sandhu, Hardip; 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 DSP 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{sub B

  14. Activin-A stimulates hypothalamic gonadotropin-releasing hormone release by the explanted male rat hypothalamus: interaction with inhibin and androgens.

    PubMed

    Calogero, A E; Burrello, N; Ossino, A M; Polosa, P; D'Agata, R

    1998-02-01

    The presence of activins in those hypothalamic regions containing gonadotropin-releasing hormone (GnRH)-secreting neurons suggests that these peptides may regulate the reproductive function modulating not only pituitary FSH release and biosynthesis, but also hypothalamic GnRH release. The purpose of this study was to evaluate the effects of activin-A, a homodimer of inhibin beta A subunit, on hypothalamic GnRH release in vitro and, because of their well known antithetical effects, to evaluate its interaction with inhibin. In addition, since androgens modulate the release of GnRH from male rat hypothalami, we thought it of interest to study the possible interplay between these steroids and activin on GnRH release. To accomplish this, we employed a hypothalamic organ culture system which enabled us to evaluate GnRH release from individually incubated hemi-hypothalami explanted from male rats. Activin-A stimulated GnRH release in a biphasic manner. The maximal effect was reached at a concentration of 10 ng/ml which increased GnRH output by about 75%. Inhibin abolished the stimulatory effect of a maximally effective concentration of activin-A in a dose-dependent manner, whereas alone it had no effect on GnRH output. As previously shown, testosterone (1 nmol/l) and dihydrotestosterone (DHT, 0.1 nmol/l) suppressed basal GnRH release, but only testosterone was able to inhibit the release of GnRH stimulated by activin-A. Since DHT is a non-aromatizable androgen, we evaluated whether the inhibitory effect of testosterone was due to its in vitro conversion into 17 beta-estradiol. The addition of 4-hydroxyandrostenedione, a steroidal aromatase inhibitor, did not influence the suppressive effect of testosterone on GnRH release stimulated by activin-A. In conclusion, activin-A stimulated hypothalamic GnRH release in vitro and this effect was abolished by inhibin and was blunted by testosterone. These findings suggest that activins may participate in the regulation of the

  15. Human Lipocalin-Type Prostaglandin D Synthase-Based Drug Delivery System for Poorly Water-Soluble Anti-Cancer Drug SN-38.

    PubMed

    Nakatsuji, Masatoshi; Inoue, Haruka; Kohno, Masaki; Saito, Mayu; Tsuge, Syogo; Shimizu, Shota; Ishida, Atsuko; Ishibashi, Osamu; Inui, Takashi

    2015-01-01

    Lipocalin-type prostaglandin D synthase (L-PGDS) is a member of the lipocalin superfamily, which is composed of secretory transporter proteins, and binds a wide variety of small hydrophobic molecules. Using this function, we have reported the feasibility of using L-PGDS as a novel drug delivery vehicle for poorly water-soluble drugs. In this study, we show the development of a drug delivery system using L-PGDS, one that enables the direct clinical use of 7-ethyl-10-hydroxy-camptothecin (SN-38), a poorly water-soluble anti-cancer drug. In the presence of 2 mM L-PGDS, the concentration of SN-38 in PBS increased 1,130-fold as compared with that in PBS. Calorimetric experiments revealed that L-PGDS bound SN-38 at a molecular ratio of 1:3 with a dissociation constant value of 60 μM. The results of an in vitro growth inhibition assay revealed that the SN-38/L-PGDS complexes showed high anti-tumor activity against 3 human cancer cell lines, i.e., Colo201, MDA-MB-231, and PC-3 with a potency similar to that of SN-38 used alone. The intravenous administration of SN-38/L-PGDS complexes to mice bearing Colo201 tumors showed a pronounced anti-tumor effect. Intestinal mucositis, which is one of the side effects of this drug, was not observed in mice administered SN-38/L-PGDS complexes. Taken together, L-PGDS enables the direct usage of SN-38 with reduced side effects.

  16. 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 Central

    Bai, Yuxiang; van der Kaaij, Rachel Maria; Leemhuis, Hans; Pijning, Tjaard; van Leeuwen, Sander Sebastiaan; Jin, Zhengyu

    2015-01-01

    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. PMID:26253678

  17. An activin receptor IIA ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin

    PubMed Central

    Carrancio, Soraya; Markovics, Jennifer; Wong, Piu; Leisten, Jim; Castiglioni, Paola; Groza, Matthew C; Raymon, Heather K; Heise, Carla; Daniel, Tom; Chopra, Rajesh; Sung, Victoria

    2014-01-01

    Sotatercept (ACE-011), a recombinant human fusion protein containing the extracellular domain of the human Activin receptor IIA, binds to and inhibits activin and other members of the transforming growth factor -β (TGF-β) superfamily. Administration of sotatercept led to a rapid and sustained increase in red blood cell (RBC) count and haemoglobin (Hb) in healthy volunteers (phase I clinical trials), but the mechanism is not fully understood. Mice treated with RAP-011 (murine ortholog of ACE-011) respond with a rapid (within 24 h) increase in haematocrit, Hb, and RBC count. These effects are accompanied by an equally rapid stimulation of late-stage erythroid precursors in the bone marrow (BM). RAP-011 also induces a significant increase in erythroid burst-forming units and erythropoietin, which could contribute to additional, sustained effects on RBC production. Further in vitro co-culture studies demonstrate that BM accessory cells are required for RAP-011 effects. To better understand which TGF-β family ligand(s) mediate RAP-011 effects, we evaluated the impact of several of these ligands on erythroid differentiation. Our data suggest that RAP-011 may act to rescue growth differentiation factor 11/Activin A-induced inhibition of late-stage erythropoiesis. These data define the mechanism of action of a novel agent that regulates RBC differentiation and provide the rationale to develop sotatercept for the treatment of anaemia and ineffective erythropoiesis. PMID:24635723

  18. Splitting placodes: effects of bone morphogenetic protein and Activin on the patterning and identity of mouse incisors.

    PubMed

    Munne, Pauliina M; Felszeghy, Szabolcs; Jussila, Maria; Suomalainen, Marika; Thesleff, Irma; Jernvall, Jukka

    2010-01-01

    The single large rodent incisor in each jaw quadrant is evolutionarily derived from a mammalian ancestor with many small incisors. The embryonic placode giving rise to the mouse incisor is considerably larger than the molar placode, and the question remains whether this large incisor placode is a developmental requisite to make a thick incisor. Here we used in vitro culture system to experiment with the molecular mechanism regulating tooth placode development and how mice have thick incisors. We found that large placodes are prone to disintegration and formation of two to three small incisor placodes. The balance between one large or multiple small placodes was altered through the regulation of bone morphogenetic protein (BMP) and Activin signaling. Exogenous Noggin, which inhibits BMP signaling, or exogenous Activin cause the development of two to three incisors. These incisors were more slender than normal incisors. Additionally, two inhibitor molecules, Sostdc1 and Follistatin, which regulate the effects of BMPs and Activin and have opposite expression patterns, are likely to be involved in the incisor placode regulation in vivo. Furthermore, inhibition of BMPs by recombinant Noggin has been previously suggested to cause a change in the tooth identity from the incisor to the molar. This evidence has been used to support a homeobox code in determining tooth identity. Our work provides an alternative interpretation, where the inhibition of BMP signaling can lead to splitting of the large incisor placode and the formation of partly separate incisors, thereby acquiring molar-like morphology without a change in tooth identity.

  19. Interstitial Perfusion Culture with Specific Soluble Factors Inhibits Type I Collagen Production from Human Osteoarthritic Chondrocytes in Clinical-Grade Collagen Sponges

    PubMed Central

    Talò, Giuseppe; Lovati, Arianna B.; Pasdeloup, Marielle; Riboldi, Stefania A.; Moretti, Matteo; Mallein-Gerin, Frédéric

    2016-01-01

    Articular cartilage has poor healing ability and cartilage injuries often evolve to osteoarthritis. Cell-based strategies aiming to engineer cartilaginous tissue through the combination of biocompatible scaffolds and articular chondrocytes represent an alternative to standard surgical techniques. In this context, perfusion bioreactors have been introduced to enhance cellular access to oxygen and nutrients, hence overcoming the limitations of static culture and improving matrix deposition. Here, we combined an optimized cocktail of soluble factors, the BIT (BMP-2, Insulin, Thyroxin), and clinical-grade collagen sponges with a bidirectional perfusion bioreactor, namely the oscillating perfusion bioreactor (OPB), to engineer in vitro articular cartilage by human articular chondrocytes (HACs) obtained from osteoarthritic patients. After amplification, HACs were seeded and cultivated in collagen sponges either in static or dynamic conditions. Chondrocyte phenotype and the nature of the matrix synthesized by HACs were assessed using western blotting and immunohistochemistry analyses. Finally, the stability of the cartilaginous tissue produced by HACs was evaluated in vivo by subcutaneous implantation in nude mice. Our results showed that perfusion improved the distribution and quality of cartilaginous matrix deposited within the sponges, compared to static conditions. Specifically, dynamic culture in the OPB, in combination with the BIT cocktail, resulted in the homogeneous production of extracellular matrix rich in type II collagen. Remarkably, the production of type I collagen, a marker of fibrous tissues, was also inhibited, indicating that the association of the OPB with the BIT cocktail limits fibrocartilage formation, favoring the reconstruction of hyaline cartilage. PMID:27584727

  20. Interstitial Perfusion Culture with Specific Soluble Factors Inhibits Type I Collagen Production from Human Osteoarthritic Chondrocytes in Clinical-Grade Collagen Sponges.

    PubMed

    Mayer, Nathalie; Lopa, Silvia; Talò, Giuseppe; Lovati, Arianna B; Pasdeloup, Marielle; Riboldi, Stefania A; Moretti, Matteo; Mallein-Gerin, Frédéric

    2016-01-01

    Articular cartilage has poor healing ability and cartilage injuries often evolve to osteoarthritis. Cell-based strategies aiming to engineer cartilaginous tissue through the combination of biocompatible scaffolds and articular chondrocytes represent an alternative to standard surgical techniques. In this context, perfusion bioreactors have been introduced to enhance cellular access to oxygen and nutrients, hence overcoming the limitations of static culture and improving matrix deposition. Here, we combined an optimized cocktail of soluble factors, the BIT (BMP-2, Insulin, Thyroxin), and clinical-grade collagen sponges with a bidirectional perfusion bioreactor, namely the oscillating perfusion bioreactor (OPB), to engineer in vitro articular cartilage by human articular chondrocytes (HACs) obtained from osteoarthritic patients. After amplification, HACs were seeded and cultivated in collagen sponges either in static or dynamic conditions. Chondrocyte phenotype and the nature of the matrix synthesized by HACs were assessed using western blotting and immunohistochemistry analyses. Finally, the stability of the cartilaginous tissue produced by HACs was evaluated in vivo by subcutaneous implantation in nude mice. Our results showed that perfusion improved the distribution and quality of cartilaginous matrix deposited within the sponges, compared to static conditions. Specifically, dynamic culture in the OPB, in combination with the BIT cocktail, resulted in the homogeneous production of extracellular matrix rich in type II collagen. Remarkably, the production of type I collagen, a marker of fibrous tissues, was also inhibited, indicating that the association of the OPB with the BIT cocktail limits fibrocartilage formation, favoring the reconstruction of hyaline cartilage. PMID:27584727

  1. Effect of repeated activin-A treatment on the activity of the hypothalamic-pituitary-gonadal axis of the adult male rat.

    PubMed

    Lee, S; Rivier, C

    1997-04-01

    The present study was undertaken to determine whether recombinant activin-A increases mRNA levels of the peptide GnRH, and whether this phenomenon correlates with increased FSH and/or LH release. One acute s.c. injection of activin-A (120 micrograms/kg body weight) to adult male rats was found to significantly (P < 0.01) increase plasma FSH levels, with no detectable changes in LH or testosterone (T) release. Similarly, there were no significant differences between GnRH mRNA values measured in the medial preoptic area of the hypothalamus. When activin-A was administered s.c. every 8 h for seven consecutive treatments, similar results were obtained for gonadotropin release; in addition, we observed a significant (p < 0.01) up-regulation of hypothalamic GnRH mRNA levels. The administration of activin-A intracerebroventricularly (i.c.v., 6 micrograms/rat) according to the same chronic schedule also produced a significant (p < 0.01) increase in FSH levels, as well as a modest, but detectable, elevation in LH concentrations, and a large augmentation of T secretion. In contrast, there were no changes in steady-state GnRH mRNA concentrations. Collectively, these results show that both the systemic (s.c.) and the central (i.c.v.) injection of activin-A stimulates FSH secretion. While we had originally thought that the lack of response of hypothalamic GnRH neurons to i.c.v. activin injections might have been due to increased steroid feedback, the observation that comparable results were obtained in both intact and castrated rats does not support this hypothesis. One possibility is that the previously reported stimulatory influence of i.c.v. activin-A treatment on neurons that manufacture corticotropin-releasing factor, and consequently on circulating catecholamine concentrations, may have increased testicular activity independently of changes in pituitary function.

  2. Soluble mimetics of human immunodeficiency virus type 1 viral spikes produced by replacement of the native trimerization domain with a heterologous trimerization motif: characterization and ligand binding analysis.

    PubMed

    Pancera, Marie; Lebowitz, Jacob; Schön, Arne; Zhu, Ping; Freire, Ernesto; Kwong, Peter D; Roux, Kenneth H; Sodroski, Joseph; Wyatt, Richard

    2005-08-01

    The human immunodeficiency virus type 1 (HIV-1) exterior envelope glycoprotein, gp120, mediates binding to the viral receptors and, along with the transmembrane glycoprotein gp41, is a major target for neutralizing antibodies. We asked whether replacing the gp41 fusion/trimerization domain with a stable trimerization motif might lead to a more stable gp120 trimer that would be amenable to structural and immunologic analysis. To obtain stable gp120 trimers, a heterologous trimerization motif, GCN4, was appended to the C terminus of YU2gp120. Biochemical analysis indicated that the gp120-GCN4 trimers were superior to gp140 molecules in their initial homogeneity, and trilobed structures were observable by electron microscopy. Biophysical analysis of gp120-GCN4 trimers by isothermal titration calorimetry (ITC) and ultracentrifugation analyses indicated that most likely two molecules of soluble CD4 could bind to one gp120-GCN4 trimer. To further examine restricted CD4 stoichiometric binding to the gp120-GCN4 trimers, we generated a low-affinity CD4 binding trimer by introducing a D457V change in the CD4 binding site of each gp120 monomeric subunit. The mutant trimers could definitively bind only one soluble CD4 molecule, as determined by ITC and sedimentation equilibrium centrifugation. These data indicate that there are weak interactions between the gp120 monomeric subunits of the GCN4-stabilized trimers that can be detected by low-affinity ligand sensing. By similar analysis, we also determined that removal of the variable loops V1, V2, and V3 in the context of the gp120-GCN4 proteins allowed the binding of three CD4 molecules per trimer. Interestingly, both the gp120-GCN4 variants displayed a restricted stoichiometry for the CD4-induced antibody 17b of one antibody molecule binding per trimer. This restriction was not evident upon removal of the variable loops V1 and V2 loops, consistent with conformational constraints in the wild-type gp120 trimers and similar to

  3. Total Soluble and Endogenous Secretory Receptor for Advanced Glycation End Products as Predictive Biomarkers of Coronary Heart Disease Risk in Patients With Type 2 Diabetes

    PubMed Central

    Colhoun, Helen M.; Betteridge, D. John; Durrington, Paul; Hitman, Graham; Neil, Andrew; Livingstone, Shona; Charlton-Menys, Valentine; Bao, Weihang; DeMicco, David A.; Preston, Gregory M.; Deshmukh, Harshal; Tan, Kathryn; Fuller, John H.

    2011-01-01

    OBJECTIVE Circulating levels of soluble receptor for advanced glycation end products (sRAGE) likely comprise both a secreted isoform (esRAGE) and wild-type RAGE cleaved from the cell membrane. Both sRAGE and esRAGE have been proposed as biomarkers of cardiovascular disease (CVD), but prospective data are limited. We examined the relationship of sRAGE and esRAGE to incident coronary heart disease (CHD) and stroke in type 2 diabetic patients followed for 3.9 years in a trial of atorvastatin: the Collaborative Atorvastatin Diabetes Study (CARDS). RESEARCH DESIGN AND METHODS We used a nested case-control design sampling all incident cases of CVD with available plasma and randomly selecting three control subjects, who were free of CVD throughout follow-up, per case. Analysis was by Cox regression with adjustment for treatment allocation and relevant covariates. RESULTS sRAGE and esRAGE were strongly correlated (ρ = 0.88) and were both higher in those with lower BMI (P < 0.001), higher adiponectin (P < 0.001), lower estimated glomerular filtration rate (P = 0.009), and white ethnicity (P < 0.001). Both sRAGE and esRAGE were associated with incident CHD events, independently of treatment allocation and the above factors; hazard ratio (HR) = 1.74 (95% CI 1.25–2.41; P = 0.002) for a doubling of the sRAGE level; HR = 1.45 (1.11–1.89; P = 0.006) for a doubling of the esRAGE level. There was no significant association with stroke; HR for sRAGE = 0.66 (0.38–1.14). Atorvastatin, 10 mg daily, did not alter sRAGE. CONCLUSIONS Higher levels of sRAGE and esRAGE are associated with incident CHD but not stroke in type 2 diabetes. PMID:21771973

  4. Soluble IL-6 Receptor and IL-27 Subunit p28 Protein Complex Mediate the Antiviral Response through the Type III IFN Pathway.

    PubMed

    Yang, Xiaodan; Hao, Hua; Xia, Zhangchuan; Xu, Gang; Cao, Zhongying; Chen, Xueyuan; Liu, Shi; Zhu, Ying

    2016-09-15

    Previously, we demonstrated that the soluble IL-6R (sIL-6R) plays an important role in the host antiviral response through induction of type I IFN and sIL-6R-mediated antiviral action via the IL-27 subunit p28; however, the mechanism that underlies sIL-6R and p28 antiviral action and whether type III IFN is involved remain unknown. In this study, we constructed a sIL-6R and p28 fusion protein (sIL-6R/p28 FP) and demonstrated that the fusion protein has stronger antiviral activity than sIL-6R alone. Consequently, knockout of sIL-6R inhibited virus-triggered IFN-λ1 expression. In addition, sIL-6R/p28 FP associated with mitochondrial antiviral signaling protein and TNFR-associated factor 6, the retinoic acid-inducible gene I adapter complex, and the antiviral activity mediated by sIL-6R/p28 FP was dependent on mitochondrial antiviral signaling protein. Furthermore, significantly reduced binding of p50/p65 and IFN regulatory factor 3 to the IFN-λ1 promoter was observed in sIL-6R knockout cells compared with the control cells. Interestingly, a novel heterodimer of c-Fos and activating transcription factor 1 was identified as a crucial transcriptional activator of IFN-λ1 The sIL-6R/p28 FP upregulated IFN-λ1 expression by increasing the binding abilities of c-Fos and activating transcription factor 1 to the IFN-λ1 promoter via the p38 MAPK signaling pathway. In conclusion, these results demonstrate the important role of sIL-6R/p28 FP in mediating virus-induced type III IFN production. PMID:27527594

  5. 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.

  6. 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

  7. 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. PMID:27208257

  8. Quantitative model of antibody- and soluble CD4-mediated neutralization of primary isolates and T-cell line-adapted strains of human immunodeficiency virus type 1.

    PubMed Central

    Klasse, P J; Moore, J P

    1996-01-01

    Primary isolates (PI) of human immunodeficiency virus type 1 (HIV-1) are considerably less sensitive than T-cell line-adapted strains to neutralization by soluble CD4 and by most cross-reactive monoclonal antibodies to the viral envelope (Env) glycoprotein, as well as by postinfection and postvaccination sera (J. P. Moore and D. D. Ho, AIDS 9 [suppl. A]:5117-5136, 1995). We developed a quantitative model to explain the neutralization resistance of PI. The factors incorporated into the model are the dissociation constants for the binding of the neutralizing agent to native Env oligomers, the number of outer Env molecules on the viral surface (which decreases by shedding), and the minimum number of Env molecules required for attachment and fusion. We conclude that modest differences in all these factors can, when combined, explain a relative neutralization resistance of PI versus T-cell line-adapted strains that sometimes amounts to several orders of magnitude. The hypothesis that neutralization of HIV is due to the reduction below a minimum number of the Env molecules on a virion available for attachment and fusion is at odds with single- and few-hit neutralization theories. Our analysis of these ideas favors the hypothesis that neutralization of HIV is instead a competitive blocking of interactions with cellular factors, including adsorption receptors. PMID:8648701

  9. Plasma levels of tumor necrosis factor-alpha (TNF-α), TNF-α soluble receptor type 1 (sTNFR I) and IL-22 in human leishmaniasis.

    PubMed

    Nateghi Rostami, M; Seyyedan Jasbi, E; Khamesipour, A; Miramin Mohammadi, A

    2015-09-01

    The role of pro-inammatory cytokine tumor necrosis factor-alpha (TNF-α) in human leishmaniasis is not fully understood. We analyzed the alterations in the plasma levels of TNF- α, soluble TNF receptor type 1 (sTNFR I), IL-17 and IL-22 in the volunteers with leishmaniasis. Blood samples were collected from patients with active cutaneous leishmaniasis (CL), the same CL patients after standard antimonial therapy as healed CL, active visceral leishmaniasis (VL) and healed VL volunteers. Levels of the cytokines were titrated on plasma samples by sandwich ELISA method. The mean level of TNF-α was significantly higher in active CL patients than healthy controls (P<0.001) and significantly reduced after treatment in the same volunteers (P<0.001). The mean level of sTNFR I was significantly higher in active CL patients than healthy controls (P<0.05). The mean level of IL-22 in plasma of the AVL patients was significantly higher than that of healthy control group (P<0.05). There is a negative correlation between the levels of TNF-α and sTNFR I and healing of CL. Measurement of cytokines in plasma samples is more feasible than cell culture in evaluation of immune response in human leishmaniasis.

  10. Effect of physical training on liver expression of activin A and follistatin in a nonalcoholic fatty liver disease model in rats.

    PubMed

    Silva, R N; Bueno, P G; Avó, L R S; Nonaka, K O; Selistre-Araújo, H S; Leal, A M O

    2014-09-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in the liver and is associated with obesity and insulin resistance. Activin A is a member of the transforming growth factor beta (TGF)-β superfamily and inhibits hepatocyte growth. Follistatin antagonizes the biological actions of activin. Exercise is an important therapeutic strategy to reduce the metabolic effects of obesity. We evaluated the pattern of activin A and follistatin liver expression in obese rats subjected to swimming exercise. Control rats (C) and high-fat (HF) diet-fed rats were randomly assigned to a swimming training group (C-Swim and HF-Swim) or a sedentary group (C-Sed and HF-Sed). Activin βA subunit mRNA expression was significantly higher in HF-Swim than in HF-Sed rats. Follistatin mRNA expression was significantly lower in C-Swim and HF-Swim than in either C-Sed or HF-Sed animals. There was no evidence of steatosis or inflammation in C rats. In contrast, in HF animals the severity of steatosis ranged from grade 1 to grade 3. The extent of liver parenchyma damage was less in HF-Swim animals, with the severity of steatosis ranging from grade 0 to grade 1. These data showed that exercise may reduce the deleterious effects of a high-fat diet on the liver, suggesting that the local expression of activin-follistatin may be involved.

  11. Effect of physical training on liver expression of activin A and follistatin in a nonalcoholic fatty liver disease model in rats

    PubMed Central

    Silva, R.N.; Bueno, P.G.; Avó, L.R.S.; Nonaka, K.O.; Selistre-Araújo, H.S.; Leal, A.M.O.

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in the liver and is associated with obesity and insulin resistance. Activin A is a member of the transforming growth factor beta (TGF)-β superfamily and inhibits hepatocyte growth. Follistatin antagonizes the biological actions of activin. Exercise is an important therapeutic strategy to reduce the metabolic effects of obesity. We evaluated the pattern of activin A and follistatin liver expression in obese rats subjected to swimming exercise. Control rats (C) and high-fat (HF) diet-fed rats were randomly assigned to a swimming training group (C-Swim and HF-Swim) or a sedentary group (C-Sed and HF-Sed). Activin βA subunit mRNA expression was significantly higher in HF-Swim than in HF-Sed rats. Follistatin mRNA expression was significantly lower in C-Swim and HF-Swim than in either C-Sed or HF-Sed animals. There was no evidence of steatosis or inflammation in C rats. In contrast, in HF animals the severity of steatosis ranged from grade 1 to grade 3. The extent of liver parenchyma damage was less in HF-Swim animals, with the severity of steatosis ranging from grade 0 to grade 1. These data showed that exercise may reduce the deleterious effects of a high-fat diet on the liver, suggesting that the local expression of activin-follistatin may be involved. PMID:25075578

  12. The Notch ligand Delta-like 1 integrates inputs from TGFbeta/Activin and Wnt pathways

    SciTech Connect

    Bordonaro, Michael Tewari, Shruti Atamna, Wafa Lazarova, Darina L.

    2011-06-10

    Unlike the well-characterized nuclear function of the Notch intracellular domain, it has been difficult to identify a nuclear role for the ligands of Notch. Here we provide evidence for the nuclear function of the Notch ligand Delta-like 1 in colon cancer (CC) cells exposed to butyrate. We demonstrate that the intracellular domain of Delta-like 1 (Dll1icd) augments the activity of Wnt signaling-dependent reporters and that of the promoter of the connective tissue growth factor (CTGF) gene. Data suggest that Dll1icd upregulates CTGF promoter activity through both direct and indirect mechanisms. The direct mechanism is supported by co-immunoprecipitation of endogenous Smad2/3 proteins and Dll1 and by chromatin immunoprecipitation analyses that revealed the occupancy of Dll1icd on CTGF promoter sequences containing a Smad binding element. The indirect upregulation of CTGF expression by Dll1 is likely due to the ability of Dll1icd to increase Wnt signaling, a pathway that targets CTGF. CTGF expression is induced in butyrate-treated CC cells and results from clonal growth assays support a role for CTGF in the cell growth-suppressive role of butyrate. In conclusion, integration of the Notch, Wnt, and TGFbeta/Activin signaling pathways is in part mediated by the interactions of Dll1 with Smad2/3 and Tcf4.

  13. Beneficial effect of the soluble guanylyl cyclase stimulator BAY 41-2272 on impaired penile erection in db/db-/- type II diabetic and obese mice.

    PubMed

    Nunes, Kenia Pedrosa; Teixeira, Cleber E; Priviero, Fernanda B M; Toque, Haroldo A; Webb, R Clinton

    2015-05-01

    Type 2 diabetes mellitus (DM2) and obesity are major risk factors for erectile dysfunction (ED). In diabetes, increased oxidative stress leads to decreased nitric oxide (NO) bioavailability, and diabetic patients appear to be less responsive to conventional therapy with phosphodiesterase type 5 inhibitors. We investigated whether the soluble guanylyl cyclase stimulator BAY 41-2272 (5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4ylamine) is effective in improving impaired corpus cavernosum (CC) relaxation in obese DM2 mice by reducing oxidative stress. Adult db/db(-/-) mice or their lean db(/+) littermates were used to assess vascular function, cGMP levels, antioxidant status, NADPH oxidase expression, and superoxide formation in the absence or presence of BAY 41-2272. Results showed that BAY 41-2272 (10(-8) to 10(-5) M) potently relaxed CC from db(/+) or db/db(-/-) mice in a similar manner. BAY 41-2272 significantly enhanced both endothelium-dependent and nitrergic relaxation induced by electrical field stimulation (EFS), and improved the impaired relaxation to acetylcholine and EFS in the diabetic animals in a concentration-dependent manner (10(-8) to 10(-7) M). BAY 41-2272 increased cGMP levels and potentiated relaxation responses to exogenous NO in CC. Total antioxidant status was reduced in plasma and urine whereas expression of vascular NADPH oxidase subunits (gp91phox, p22phox, and p47phox) was increased in the CC of db/db(-/-) mice, suggesting a state of oxidative stress. These effects were prevented by BAY 41-2272 in a concentration-dependent manner. These results suggest that BAY 41-2272 improves CC relaxation in db/db(-/-) mice by increasing cGMP and augmenting antioxidant status, making this drug is a potential novel candidate to treat ED.

  14. 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. PMID:26729812

  15. Specific activin receptor-like kinase 3 inhibitors enhance liver regeneration.

    PubMed

    Tsugawa, Daisuke; Oya, Yuki; Masuzaki, Ryota; Ray, Kevin; Engers, Darren W; Dib, Martin; Do, Nhue; Kuramitsu, Kaori; Ho, Karen; Frist, Audrey; Yu, Paul B; Bloch, Kenneth D; Lindsley, Craig W; Hopkins, Corey R; Hong, Charles C; Karp, Seth J

    2014-12-01

    Pharmacologic agents to enhance liver regeneration after injury would have wide therapeutic application. Based on previous work suggesting inhibition of bone morphogenetic protein (BMP) signaling stimulates liver regeneration, we tested known and novel BMP inhibitors for their ability to accelerate regeneration in a partial hepatectomy (PH) model. Compounds were produced based on the 3,6-disubstituted pyrazolo[1,5-a] pyrimidine core of the BMP antagonist dorsomorphin and evaluated for their ability to inhibit BMP signaling and enhance liver regeneration. Antagonists of the BMP receptor activin receptor-like kinase 3 (ALK3), including LDN-193189 (LDN; 4-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-quinoline), DMH2 (4-(2-(4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)ethyl)morpholine; VU0364849), and the novel compound VU0465350 (7-(4-isopropoxyphenyl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine; VU5350), blocked SMAD phosphorylation in vitro and in vivo, and enhanced liver regeneration after PH. In contrast, an antagonist of the BMP receptor ALK2, VU0469381 (5-(6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinolone; 1LWY), did not affect liver regeneration. LDN did not affect liver synthetic or metabolic function. Mechanistically, LDN increased serum interleukin-6 levels and signal transducer and activator of transcription 3 phosphorylation in the liver, and modulated other factors known to be important for liver regeneration, including suppressor of cytokine signaling 3 and p53. These findings suggest that inhibition of ALK3 may be part of a therapeutic strategy for treating human liver disease.

  16. Specific activin receptor-like kinase 3 inhibitors enhance liver regeneration.

    PubMed

    Tsugawa, Daisuke; Oya, Yuki; Masuzaki, Ryota; Ray, Kevin; Engers, Darren W; Dib, Martin; Do, Nhue; Kuramitsu, Kaori; Ho, Karen; Frist, Audrey; Yu, Paul B; Bloch, Kenneth D; Lindsley, Craig W; Hopkins, Corey R; Hong, Charles C; Karp, Seth J

    2014-12-01

    Pharmacologic agents to enhance liver regeneration after injury would have wide therapeutic application. Based on previous work suggesting inhibition of bone morphogenetic protein (BMP) signaling stimulates liver regeneration, we tested known and novel BMP inhibitors for their ability to accelerate regeneration in a partial hepatectomy (PH) model. Compounds were produced based on the 3,6-disubstituted pyrazolo[1,5-a] pyrimidine core of the BMP antagonist dorsomorphin and evaluated for their ability to inhibit BMP signaling and enhance liver regeneration. Antagonists of the BMP receptor activin receptor-like kinase 3 (ALK3), including LDN-193189 (LDN; 4-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-quinoline), DMH2 (4-(2-(4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)ethyl)morpholine; VU0364849), and the novel compound VU0465350 (7-(4-isopropoxyphenyl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine; VU5350), blocked SMAD phosphorylation in vitro and in vivo, and enhanced liver regeneration after PH. In contrast, an antagonist of the BMP receptor ALK2, VU0469381 (5-(6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinolone; 1LWY), did not affect liver regeneration. LDN did not affect liver synthetic or metabolic function. Mechanistically, LDN increased serum interleukin-6 levels and signal transducer and activator of transcription 3 phosphorylation in the liver, and modulated other factors known to be important for liver regeneration, including suppressor of cytokine signaling 3 and p53. These findings suggest that inhibition of ALK3 may be part of a therapeutic strategy for treating human liver disease. PMID:25271257

  17. The glycoprotein-hormones activin A and inhibin A interfere with dendritic cell maturation

    PubMed Central

    Segerer, Sabine E; Müller, Nora; Brandt, Jens van den; Kapp, Michaela; Dietl, Johannes; Reichardt, Holger M; Rieger, Lorenz; Kämmerer, Ulrike

    2008-01-01

    Background Pregnancy represents an exclusive situation in which the immune and the endocrine system cooperate to prevent rejection of the embryo by the maternal immune system. While immature dendritic cells (iDC) in the early pregnancy decidua presumably contribute to the establishment of peripheral tolerance, glycoprotein-hormones of the transforming growth factor beta (TGF-beta) family including activin A (ActA) and inhibin A (InA) are candidates that could direct the differentiation of DCs into a tolerance-inducing phenotype. Methods To test this hypothesis we generated iDCs from peripheral-blood-monocytes and exposed them to TGF-beta1, ActA, as well as InA and Dexamethasone (Dex) as controls. Results Both glycoprotein-hormones prevented up-regulation of HLA-DR during cytokine-induced DC maturation similar to Dex but did not influence the expression of CD 40, CD 83 and CD 86. Visualization of the F-actin cytoskeleton confirmed that the DCs retained a partially immature phenotype under these conditions. The T-cell stimulatory capacity of DCs was reduced after ActA and InA exposure while the secretion of cytokines and chemokines was unaffected. Conclusion These findings suggest that ActA and InA interfere with selected aspects of DC maturation and may thereby help preventing activation of allogenic T-cells by the embryo. Thus, we have identified two novel members of the TGF-beta superfamily that could promote the generation of tolerance-inducing DCs. PMID:18460206

  18. 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 ...

  19. Role of osteoclasts in heterotopic ossification enhanced by fibrodysplasia ossificans progressiva-related activin-like kinase 2 mutation in mice.

    PubMed

    Kawao, Naoyuki; Yano, Masato; Tamura, Yukinori; Okumoto, Katsumi; Okada, Kiyotaka; Kaji, Hiroshi

    2016-09-01

    Fibrodysplasia ossificans progressiva (FOP) is a disorder of skeletal malformations and progressive heterotopic ossification. The constitutively activating mutation (R206H) of the bone morphogenetic protein type 1 receptor, activin-like kinase 2 (ALK2), is responsible for the pathogenesis of FOP. Although transfection of the causal mutation of FOP into myoblasts enhances osteoclast formation by transforming growth factor-β (TGF-β), the role of osteoclasts in heterotopic ossification is unknown. We therefore examined the effects of alendronate, SB431542 and SB203580 on heterotopic ossification induced by the causal mutation of FOP. Total bone mineral content as well as numbers of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated and alkaline phosphatase (ALP)-positive cells in heterotopic bone were significantly higher in muscle tissues implanted with ALK2 (R206H)-transfected mouse myoblastic C2C12 cells than in the tissues implanted with empty vector-transfected cells in nude mice. Alendronate, an aminobisphosphonate, did not affect total mineral content or numbers of TRAP-positive multinucleated and ALP-positive cells in heterotopic bone, which were enhanced by the implantation of ALK2 (R206H)-transfected C2C12 cells, although it significantly decreased serum levels of cross-linked C-telopeptide of type I collagen, a bone resorption index. Moreover, neither SB431542, an inhibitor of TGF-β receptor type I kinase, nor SB203580, an inhibitor of p38 mitogen-activated protein kinase, affected the increase in heterotopic ossification due to the implantation of ALK2 (R206H)-transfected C2C12 cells. In conclusion, the present study indicates that osteoclast inhibition does not affect heterotopic ossification enhanced by FOP-related mutation.

  20. 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. PMID:24333131

  1. Fibroblast growth factor, but not activin, is a potent activator of mitogen-activated protein kinase in Xenopus explants.

    PubMed Central

    Graves, L M; Northrop, J L; Potts, B C; Krebs, E G; Kimelman, D

    1994-01-01

    Isolated explants from the animal hemisphere of Xenopus embryos were incubated with Xenopus basic fibroblast growth factor (XbFGF) or human activin A. XbFGF incubation resulted in the rapid activation of mitogen-activated protein kinase (MAPK) and ribosomal S6 protein kinase (pp90rsk) in a dose-dependent manner with the highest levels of activation occurring at 50 ng/ml. Maximal activation occurred within 6-10 min after the addition of growth factor, and the activity of both kinases declined to unstimulated levels after 30 min. Activin was unable to activate either MAPK or pp90rsk in the Xenopus explants to a substantial level, although it induced dorsal mesoderm better than XbFGF under the same experimental conditions. The regulatory protein Xwnt-8 did not activate MAPK, nor did it enhance the activation of MAPK by XbFGF. XbFGF was able to activate MAPK through at least the midgastrula stage, suggesting that this family of growth factors may have a role in gastrula-stage events. Images PMID:7510404

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

    SciTech Connect

    Sui, Lina; Mfopou, Josue K.; Geens, Mieke; Sermon, Karen; Bouwens, Luc

    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, 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.

  3. Exogenous supplementation of Activin A enhances germ cell differentiation of human embryonic stem cells.

    PubMed

    Duggal, Galbha; Heindryckx, Björn; Warrier, Sharat; Taelman, Jasin; Van der Jeught, Margot; Deforce, Dieter; Chuva de Sousa Lopes, Susana; De Sutter, Petra

    2015-05-01

    Human embryonic stem cells (hESCs) derived in the presence of Activin A (ActA) demonstrate an increased differentiation propensity toward the germ cell lineage. In addition, mouse epiblast stem cells and mouse epiblast-like cells are poised toward germ cell differentiation and are derived in the presence of ActA. We therefore investigated whether supplementation with ActA enhances in vitro hESC differentiation toward germ cell lineage. ActA up-regulated early primordial germ cell (PGC) genes STELLA/DPPA3 (developmental pluripotency associated 3) and tyrosine kinase receptor cKIT in both ActA-derived and standard-derived hESCs indicating its role in priming hESCs toward the PGC lineage. Indeed, ActA plus bone morphogenic protein 4 (BMP4) strongly increased germ cell differentiation potential of hESCs based on the high expression of late PGC markers DAZL (deleted in azoospermia-like) and VASA/DDX4 (DEAD-box polypeptide 4) at mRNA and protein level. Hence, the combination of ActA with BMP4 provides an additional boost for hESCs to develop into postmigratory germ cells. Together with increased VASA expression in the presence of ActA and BMP4, we also observed up-regulation of endoderm-specific genes GATA4 (GATA binding protein 4) and GATA6. Finally, we were able to further mature these in vitro-derived PGC-like cells (PGCLCs) by culturing them in in vitro maturation (IVM) medium, resulting in the formation of germ cell-like clusters and induction of meiotic gene expression. In conclusion, we demonstrate for the first time a synergism between ActA and BMP4 in facilitating germ cell-directed differentiation of hESCs, which is enhanced by extended culture in IVM medium, as shown by cytoplasmic VASA-expressing PGCLCs. We propose a novel relationship between the endoderm and germ cell lineage during hESC differentiation.

  4. Stimulation of activin A expression in rat aortic smooth muscle cells by thrombin and angiotensin II correlates with neointimal formation in vivo.

    PubMed Central

    Pawlowski, J E; Taylor, D S; Valentine, M; Hail, M E; Ferrer, P; Kowala, M C; Molloy, C J

    1997-01-01

    Vasoactive GTP-binding protein-coupled receptor agonists (e.g., angiotensin II [AII] and alpha-thrombin) stimulate the production of mitogenic factors from vascular smooth muscle cells. In experiments to identify mitogens secreted from AII- or alpha-thrombin-stimulated rat aortic smooth muscle (RASM) cells, neutralizing antibodies directed against several growth factors (e.g., PDGF and basic fibroblast growth factor [basic FGF]) failed to inhibit the mitogenic activity of conditioned media samples derived from the cells. In this report, we found that polyclonal neutralizing antibodies directed against purified human placental basic FGF reduced the mitogenic activity of AII-stimulated RASM cell-conditioned media and in immunoblot experiments identified a 26-kD protein (14 kD under reducing conditions) that was distinct from basic FGF. After purification from RASM cell-conditioned medium, amino acid sequence analysis identified the protein as activin A, a member of the TGF-beta superfamily. Increased activin A expression was observed after treatment of the RASM cells with AII, alpha-thrombin, and the protein kinase C agonist PMA. In contrast, PDGF-BB or serum caused only a minor induction of this protein. Although activin A alone only weakly stimulated RASM cell DNA synthesis, it demonstrated a potent comitogenic effect in combination with either EGF or heparin-binding EGF-like growth factor in the RASM cells, increasing DNA synthesis by up to fourfold. Furthermore, in a rat carotid injury model, activin A mRNA was upregulated within 6 h after injury followed by increases in immunoreactive protein detected in the expanding neointima 7 and 14 d later. Taken together, these results indicate that activin A is a vascular smooth muscle cell-derived factor induced by vasoactive agonists that may, either alone or in combination with other vascular derived growth factors, have a role in neointimal formation after arterial injury. PMID:9239411

  5. 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

  6. TAK-1/p38/nNFκB signaling inhibits myoblast differentiation by increasing levels of Activin A

    PubMed Central

    2012-01-01

    Background Skeletal-muscle differentiation is required for the regeneration of myofibers after injury. The differentiation capacity of satellite cells is impaired in settings of old age, which is at least one factor in the onset of sarcopenia, the age-related loss of skeletal-muscle mass and major cause of frailty. One important cause of impaired regeneration is increased levels of transforming growth factor (TGF)-β accompanied by reduced Notch signaling. Pro-inflammatory cytokines are also upregulated in aging, which led us hypothesize that they might potentially contribute to impaired regeneration in sarcopenia. Thus, in this study, we further analyzed the muscle differentiation-inhibition pathway mediated by pro-inflammatory cytokines in human skeletal muscle cells (HuSKMCs). Methods We studied the modulation of HuSKMC differentiation by the pro-inflammatory cytokines interleukin (IL)-1α and tumor necrosis factor (TNF)-α The grade of differentiation was determined by either imaging (fusion index) or creatine kinase (CK) activity, a marker of muscle differentiation. Secretion of TGF-β proteins during differentiation was assessed by using a TGF-β-responsive reporter-gene assay and further identified by means of pharmacological and genetic inhibitors. In addition, signaling events were monitored by western blotting and reverse transcription PCR, both in HuSKMC cultures and in samples from a rat sarcopenia study. Results The pro-inflammatory cytokines IL-1α and TNF-α block differentiation of human myoblasts into myotubes. This anti-differentiation effect requires activation of TGF-β-activated kinase (TAK)-1. Using pharmacological and genetic inhibitors, the TAK-1 pathway could be traced to p38 and NFκB. Surprisingly, the anti-differentiation effect of the cytokines required the transcriptional upregulation of Activin A, which in turn acted through its established signaling pathway: ActRII/ALK/SMAD. Inhibition of Activin A signaling was able to rescue human

  7. 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

    SciTech Connect

    Nissen, Silke; Liu, Xiaoxin; Chourey, Karuna; Hettich, Robert {Bob} L; Wagner, Darlene D; Pffifner, Susan; Loeffler, Frank E

    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 grown 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.

  8. Amyloid Fibril Solubility.

    PubMed

    Rizzi, L G; Auer, S

    2015-11-19

    It is well established that amyloid fibril solubility is protein specific, but how solubility depends on the interactions between the fibril building blocks is not clear. Here we use a simple protein model and perform Monte Carlo simulations to directly measure the solubility of amyloid fibrils as a function of the interaction between the fibril building blocks. Our simulations confirms that the fibril solubility depends on the fibril thickness and that the relationship between the interactions and the solubility can be described by a simple analytical formula. The results presented in this study reveal general rules how side-chain-side-chain interactions, backbone hydrogen bonding, and temperature affect amyloid fibril solubility, which might prove to be a powerful tool to design protein fibrils with desired solubility and aggregation properties in general. PMID:26496385

  9. Amyloid Fibril Solubility.

    PubMed

    Rizzi, L G; Auer, S

    2015-11-19

    It is well established that amyloid fibril solubility is protein specific, but how solubility depends on the interactions between the fibril building blocks is not clear. Here we use a simple protein model and perform Monte Carlo simulations to directly measure the solubility of amyloid fibrils as a function of the interaction between the fibril building blocks. Our simulations confirms that the fibril solubility depends on the fibril thickness and that the relationship between the interactions and the solubility can be described by a simple analytical formula. The results presented in this study reveal general rules how side-chain-side-chain interactions, backbone hydrogen bonding, and temperature affect amyloid fibril solubility, which might prove to be a powerful tool to design protein fibrils with desired solubility and aggregation properties in general.

  10. Stimulation of circus movement by activin, bFGF and TGF-beta 2 in isolated animal cap cells of Xenopus laevis.

    PubMed

    Minoura, I; Nakamura, H; Tashiro, K; Shiokawa, K

    1995-01-01

    Lobopodium is a hyaline cytoplasmic protrusion which rotates circumferencially around a cell. This movement is called circus movement, which is seen in dissociated cells of amphibian embryos. Relative abundance of the lobopodia-forming cells changes temporally and spatially within Xenopus embryos, reflecting stage-dependent difference of morphogenetic movements. The lobopodia-forming activity of dissociated animal cap cells was stimulated strongly by activin and bFGF, and weakly by TGF-beta 2. In addition, activin A was found to stimulate cellular attachment to the substratum when the cultivation lasted long. Thus, mesoderm-inducing growth factors stimulate lobopodia formation and cellular movements which may be necessary for gastrulation and neurulation in Xenopus early embryos.

  11. Tiling of R7 Axons in the Drosophila Visual System is Mediated Both by Transduction of an Activin Signal to the Nucleus and by Mutual Repulsion

    PubMed Central

    Ting, Chun-Yuan; Herman, Tory; Yonekura, Shinichi; Gao, Shuying; Wang, Jian; Serpe, Mihaela; O’Connor, Michael B.; Zipursky, S. Lawrence; Lee, Chi-Hon

    2009-01-01

    Summary The organization of neuronal wiring into layers and columns is a common feature of both vertebrate and invertebrate brains. In the Drosophila visual system, each R7 photoreceptor axon projects within a single column to a specific layer of the optic lobe. We refer to the restriction of terminals to single columns as tiling. In a genetic screen based on an R7-dependent behavior, we identified the Activin receptor Baboon and the nuclear import adaptor Importin-α3 as being required to prevent R7 axon terminals from overlapping with the terminals of R7s in neighboring columns. This tiling function requires the Baboon ligand, dActivin, the transcription factor, dSmad2, and retrograde transport from the growth cone to the R7 nucleus. We propose that dActivin is an autocrine signal that restricts R7 growth cone motility, and we demonstrate that it acts in parallel with a paracrine signal that mediates repulsion between R7 terminals. PMID:18054857

  12. Induction of autoantibodies against mouse soluble proteins after immunization with living cells presenting the autoantigen at the cell surface in fusion with a human type 2 transmembrane protein.

    PubMed

    Lemaire, Muriel M; Vanhaudenarde, Aurélie; Nizet, Yannick; Dumoutier, Laure; Renauld, Jean-Christophe

    2011-03-31

    Induction of autoantibodies towards immune regulatory proteins, such as cytokines or their receptors, is a powerful strategy for functional studies on the role of these factors in vivo. Here we describe a new procedure to elicit autoantibodies by taking advantage of tumor cells as a vaccine against peptides presented at their surface in fusion with the human CD134L transmembrane protein. P1.HTR, an immunogenic variant of the P815 mastocytoma cell line, was used to generate stably transfected cell clones with expression vectors encoding the human CD134L transmembrane protein fused with either mouse IL-22BP or IL-9. Following repeated injections of living tumor cells expressing the mIL-22BP construct, mice developed autoantibodies that bind to mIL-22BP and inhibit its interaction with IL-22 in vitro. Mice similarly immunized against mIL-9 produced high titers of autoantibodies that block the activity of this cytokine in the TS1 bioassay. This procedure also inhibits IL-9 activity in vivo as no increase of serum MMCP-1 mast cell protease concentration was observed following IL-9 administration to immunized mice. As an alternative to the injection of living tumor cells expressing the CD134L-antigen fusion protein, intramuscular electrotransfer of the corresponding DNA construct also induced autoantibodies. These results validate this method as a simple and convenient approach to knock down the in vivo activity of soluble regulatory proteins, including cytokines and their receptors.

  13. Serum erythropoietin and its relation with soluble transferrin receptor in patients with different types of anaemia in a locally defined reference population.

    PubMed

    Roque, M E; Sandoval, M J; Aggio, M C

    2001-10-01

    Serum erythropoietin (Epo) and soluble transferrin receptor (sTR) were measured in a locally defined reference population (n=100): healthy volunteers (n=50); iron- deficiency anaemia (n=41) and haemolytic anaemia (n=9) (beta-thalassaemia, n = 4; autoimmune, n=5). Our data demonstrated an inverse relationship between erythroid activity and Epo levels. The regression line between Ln Epo and haemoglobin (Hb) was highly significant: P < 0.0001, r2=0.8275, Ln Epo=8.5346-0.04275 Hb, confidence limit 95%. The mean observed/predicted (O/P) ratio of Ln (Epo) was 1.01 +/- 0.11. We demonstrated that the serum Epo concentration in this particular population correlated consistently with clinical measures of erythropoietic activity. sTR, a new index of erythropoiesis, varied from 16.1 to 148 nmol/l, mean 62.0 nmol/l in the anaemic patients' group. The relationship between Ln Epo and Ln sTR was highly significant: P < 0.0001. We conclude that locally defined regression analyses are crucial for correct data interpretation and can indicate whether or not Epo production is appropriate or inappropriate. Serial determinations of sTR could help in the assessment of response to therapeutic doses of Epo. PMID:11703410

  14. Serum erythropoietin and its relation with soluble transferrin receptor in patients with different types of anaemia in a locally defined reference population.

    PubMed

    Roque, M E; Sandoval, M J; Aggio, M C

    2001-10-01

    Serum erythropoietin (Epo) and soluble transferrin receptor (sTR) were measured in a locally defined reference population (n=100): healthy volunteers (n=50); iron- deficiency anaemia (n=41) and haemolytic anaemia (n=9) (beta-thalassaemia, n = 4; autoimmune, n=5). Our data demonstrated an inverse relationship between erythroid activity and Epo levels. The regression line between Ln Epo and haemoglobin (Hb) was highly significant: P < 0.0001, r2=0.8275, Ln Epo=8.5346-0.04275 Hb, confidence limit 95%. The mean observed/predicted (O/P) ratio of Ln (Epo) was 1.01 +/- 0.11. We demonstrated that the serum Epo concentration in this particular population correlated consistently with clinical measures of erythropoietic activity. sTR, a new index of erythropoiesis, varied from 16.1 to 148 nmol/l, mean 62.0 nmol/l in the anaemic patients' group. The relationship between Ln Epo and Ln sTR was highly significant: P < 0.0001. We conclude that locally defined regression analyses are crucial for correct data interpretation and can indicate whether or not Epo production is appropriate or inappropriate. Serial determinations of sTR could help in the assessment of response to therapeutic doses of Epo.

  15. Recombinant soluble, multimeric HA and NA exhibit distinctive types of protection against pandemic swine-origin 2009 A(H1N1) influenza virus infection in ferrets.

    PubMed

    Bosch, Berend Jan; Bodewes, Rogier; de Vries, Robert P; Kreijtz, Joost H C M; Bartelink, Willem; van Amerongen, Geert; Rimmelzwaan, Guus F; de Haan, Cornelis A M; Osterhaus, Albert D M E; Rottier, Peter J M

    2010-10-01

    The emergence and subsequent swift and global spread of the swine-origin influenza virus A(H1N1) in 2009 once again emphasizes the strong need for effective vaccines that can be developed rapidly and applied safely. With this aim, we produced soluble, multimeric forms of the 2009 A(H1N1) HA (sHA(3)) and NA (sNA(4)) surface glycoproteins using a virus-free mammalian expression system and evaluated their efficacy as vaccines in ferrets. Immunization twice with 3.75-microg doses of these antigens elicited strong antibody responses, which were adjuvant dependent. Interestingly, coadministration of both antigens strongly enhanced the HA-specific but not the NA-specific responses. Distinct patterns of protection were observed upon challenge inoculation with the homologous H1N1 virus. Whereas vaccination with sHA(3) dramatically reduced virus replication (e.g., by lowering pulmonary titers by about 5 log(10) units), immunization with sNA(4) markedly decreased the clinical effects of infection, such as body weight loss and lung pathology. Clearly, optimal protection was achieved by the combination of the two antigens. Our observations demonstrate the great vaccine potential of multimeric HA and NA ectodomains, as these can be easily, rapidly, flexibly, and safely produced in high quantities. In particular, our study underscores the underrated importance of NA in influenza vaccination, which we found to profoundly and specifically contribute to protection by HA. Its inclusion in a vaccine is likely to reduce the HA dose required and to broaden the protective immunity.

  16. What Variables Affect Solubility?

    ERIC Educational Resources Information Center

    Baker, William P.; Leyva, Kathryn

    2003-01-01

    Helps middle school students understand the concept of solubility through hands-on experience with a variety of liquids and solids. As they explore factors that affect solubility and saturation, students gain content mastery and an understanding of the inquiry process. Also enables teachers to authentically assess student performance on several…

  17. 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.)

  18. Peptide length and folding state govern the capacity of staphylococcal β-type phenol-soluble modulins to activate human formyl-peptide receptors 1 or 2.

    PubMed

    Kretschmer, Dorothee; Rautenberg, Maren; Linke, Dirk; Peschel, Andreas

    2015-04-01

    Most staphylococci produce short α-type PSMs and about twice as long β-type PSMs that are potent leukocyte attractants and toxins. PSMs are usually secreted with the N-terminal formyl group but are only weak agonists for the leukocyte FPR1. Instead, the FPR1-related FPR2 senses PSMs efficiently and is crucial for leukocyte recruitment in infection. Which structural features distinguish FPR1 from FPR2 ligands has remained elusive. To analyze which peptide properties may govern the capacities of β-type PSMs to activate FPRs, full-length and truncated variants of such peptides from Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus lugdunensis were synthesized. FPR2 activation was observed even for short N- or C-terminal β-type PSM variants once they were longer than 18 aa, and this activity increased with length. In contrast, the shortest tested peptides were potent FPR1 agonists, and this property declined with increasing peptide length. Whereas full-length β-type PSMs formed α-helices and exhibited no FPR1-specific activity, the truncated peptides had less-stable secondary structures, were weak agonists for FPR1, and required N-terminal formyl-methionine residues to be FPR2 agonists. Together, these data suggest that FPR1 and FPR2 have opposed ligand preferences. Short, flexible PSM structures may favor FPR1 but not FPR2 activation, whereas longer peptides with α-helical, amphipathic properties are strong FPR2 but only weak FPR1 agonists. These findings should help to unravel the ligand specificities of 2 critical human PRRs, and they may be important for new, anti-infective and anti-inflammatory strategies.

  19. Thermoreversible gel for delivery of activin receptor-like kinase 5 inhibitor SB-505124 for glaucoma filtration surgery.

    PubMed

    Sutariya, Vijaykumar; Miladore, Nicholas; Geldenhuys, Werner; Bhatia, Deepak; Wehrung, Daniel; Nakamura, Hiroshi

    2013-01-01

    The purpose of this study is to investigate a thermoreversible gel using Pluronic F-127 to deliver an activin receptor-like kinase 5 (ALK-5) inhibitor SB-505124 in glaucoma filtration surgery (GFS). The gel was characterized for in vitro drug release and viscosity studies. Cytotoxicity of Pluronic F-127 was examined by MTT assay using cultured rabbit subconjunctival fibroblasts. In addition, Pluronic F-127 gel (18% w/v) containing 5 mg of SB-505124 was applied at the surgical site in an in vivo rabbit GFS model. In the in vitro viscosity study, the gel showed a change in viscosity (from 1000 cps to 45,000 cps) from low temperature (10°C) to body temperature (37°C). The in vitro drug release study demonstrated 100% drug release within 12 h. The gel did not show cytotoxicity to the cultured rabbit subconjunctival cells by MTT assay. In the in vivo rabbit GFS model, the drug was successfully delivered by injection and no severe post-surgical complications were observed. A thermoreversible gel system with SB-505124 was successfully prepared and delivered for the rabbit GFS model, and it may provide a novel delivery system in GFS.

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

    PubMed Central

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

    2015-01-01

    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. PMID:26563344

  1. Blockade of the activin receptor IIb activates functional brown adipogenesis and thermogenesis by inducing mitochondrial oxidative metabolism.

    PubMed

    Fournier, Brigitte; Murray, Ben; Gutzwiller, Sabine; Marcaletti, Stefan; Marcellin, David; Bergling, Sebastian; Brachat, Sophie; Persohn, Elke; Pierrel, Eliane; Bombard, Florian; Hatakeyama, Shinji; Trendelenburg, Anne-Ulrike; Morvan, Frederic; Richardson, Brian; Glass, David J; Lach-Trifilieff, Estelle; Feige, Jerome N

    2012-07-01

    Brown adipose tissue (BAT) is a key tissue for energy expenditure via fat and glucose oxidation for thermogenesis. In this study, we demonstrate that the myostatin/activin receptor IIB (ActRIIB) pathway, which serves as an important negative regulator of muscle growth, is also a negative regulator of brown adipocyte differentiation. In parallel to the anticipated hypertrophy of skeletal muscle, the pharmacological inhibition of ActRIIB in mice, using a neutralizing antibody, increases the amount of BAT without directly affecting white adipose tissue. Mechanistically, inhibition of ActRIIB inhibits Smad3 signaling and activates the expression of myoglobin and PGC-1 coregulators in brown adipocytes. Consequently, ActRIIB blockade in brown adipose tissue enhances mitochondrial function and uncoupled respiration, translating into beneficial functional consequences, including enhanced cold tolerance and increased energy expenditure. Importantly, ActRIIB inhibition enhanced energy expenditure only at ambient temperature or in the cold and not at thermoneutrality, where nonshivering thermogenesis is minimal, strongly suggesting that brown fat activation plays a prominent role in the metabolic actions of ActRIIB inhibition.

  2. Derivation of mesenchymal stromal cells from canine induced pluripotent stem cells by inhibition of the TGFβ/activin signaling pathway.

    PubMed

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

    2014-12-15

    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

  3. 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

  4. Nanoemulsion delivery systems for oil-soluble vitamins: Influence of carrier oil type on lipid digestion and vitamin D3 bioaccessibility.

    PubMed

    Ozturk, Bengu; Argin, Sanem; Ozilgen, Mustafa; McClements, David Julian

    2015-11-15

    The influence of carrier oil type on the bioaccessibility of vitamin D3 encapsulated within oil-in-water nanoemulsions prepared using a natural surfactant (quillaja saponin) was studied using a simulated gastrointestinal tract (GIT) model: mouth; stomach; small intestine. The rate of free fatty acid release during lipid digestion decreased in the following order: medium chain triglycerides (MCT) > corn oil ≈ fish oil > orange oil > mineral oil. Conversely, the measured bioaccessibility of vitamin D3 decreased in the following order: corn oil ≈ fish oil > orange oil > mineral oil > MCT. These results show that carrier oil type has a considerable impact on lipid digestion and vitamin bioaccessibility, which was attributed to differences in the release of bioactives from lipid droplets, and their solubilization in mixed micelles. Nanoemulsions prepared using long chain triglycerides (corn or fish oil) were most effective at increasing vitamin bioaccessibility. PMID:25977056

  5. Nanoemulsion delivery systems for oil-soluble vitamins: Influence of carrier oil type on lipid digestion and vitamin D3 bioaccessibility.

    PubMed

    Ozturk, Bengu; Argin, Sanem; Ozilgen, Mustafa; McClements, David Julian

    2015-11-15

    The influence of carrier oil type on the bioaccessibility of vitamin D3 encapsulated within oil-in-water nanoemulsions prepared using a natural surfactant (quillaja saponin) was studied using a simulated gastrointestinal tract (GIT) model: mouth; stomach; small intestine. The rate of free fatty acid release during lipid digestion decreased in the following order: medium chain triglycerides (MCT) > corn oil ≈ fish oil > orange oil > mineral oil. Conversely, the measured bioaccessibility of vitamin D3 decreased in the following order: corn oil ≈ fish oil > orange oil > mineral oil > MCT. These results show that carrier oil type has a considerable impact on lipid digestion and vitamin bioaccessibility, which was attributed to differences in the release of bioactives from lipid droplets, and their solubilization in mixed micelles. Nanoemulsions prepared using long chain triglycerides (corn or fish oil) were most effective at increasing vitamin bioaccessibility.

  6. Crystal Structure of a Soluble Fragment of the Membrane Fusion Protein HlyD in a Type I Secretion System of Gram-Negative Bacteria.

    PubMed

    Kim, Jin-Sik; Song, Saemee; Lee, Minho; Lee, Seunghwa; Lee, Kangseok; Ha, Nam-Chul

    2016-03-01

    The protein toxin HlyA of Escherichia coli is exported without a periplasmic intermediate by the type I secretion system (T1SS). The T1SS is composed of an inner membrane ABC transporter HlyB, an outer-membrane channel protein TolC, and a membrane fusion protein HlyD. However, the assembly of the T1SS remains to be elucidated. In this study, we determine the crystal structure of a part of the C-terminal periplasmic domain of HlyD. The long α-helical domain consisting of three α helices and a lipoyl domain was identified in the crystal structure. Based on the HlyD structure, we modeled the hexameric assembly of HlyD with a long α-helical barrel, which formed a complex with TolC in an intermeshing cogwheel-to-cogwheel manner, as observed in tripartite RND-type drug efflux pumps. These observations provide a structural blueprint for understanding the type I secretion system in pathogenic Gram-negative bacteria.

  7. Chronic Treatment with a Water-Soluble Extract from the Culture Medium of Ganoderma lucidum Mycelia Prevents Apoptosis and Necroptosis in Hypoxia/Ischemia-Induced Injury of Type 2 Diabetic Mouse Brain.

    PubMed

    Xuan, Meiyan; Okazaki, Mari; Iwata, Naohiro; Asano, Satoshi; Kamiuchi, Shinya; Matsuzaki, Hirokazu; Sakamoto, Takeshi; Miyano, Yoshiyuki; Iizuka, Hiroshi; Hibino, Yasuhide

    2015-01-01

    Type 2 diabetes mellitus has been known to increase systemic oxidative stress by chronic hyperglycemia and visceral obesity and aggravate cerebral ischemic injury. On the basis of our previous study regarding a water-soluble extract from the culture medium of Ganoderma lucidum mycelia (designed as MAK), which exerts antioxidative and neuroprotective effects, the present study was conducted to evaluate the preventive effects of MAK on apoptosis and necroptosis (a programmed necrosis) induced by hypoxia/ischemia (H/I) in type 2 diabetic KKAy mice. H/I was induced by a combination of unilateral common carotid artery ligation with hypoxia (8% O2 for 20 min) and subsequent reoxygenation. Pretreatment with MAK (1 g/kg, p.o.) for a week significantly reduced H/I-induced neurological deficits and brain infarction volume assessed at 24 h of reoxygenation. Histochemical analysis showed that MAK significantly suppressed superoxide production, neuronal cell death, and vacuolation in the ischemic penumbra, which was accompanied by a decrease in the numbers of TUNEL- or cleaved caspase-3-positive cells. Furthermore, MAK decreased the expression of receptor-interacting protein kinase 3 mRNA and protein, a key molecule for necroptosis. These results suggest that MAK confers resistance to apoptotic and necroptotic cell death and relieves H/I-induced cerebral ischemic injury in type 2 diabetic mice.

  8. What Should We Teach Beginners about Solubility and Solubility Products?

    ERIC Educational Resources Information Center

    Hawkes, Stephen J.

    1998-01-01

    Argues that consideration should be given to whether teaching solubility product calculations is at all useful. Claims that experienced teachers seriously misunderstand and misuse solubility product calculations. (DDR)

  9. 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.

  10. Solubility of Organic Compounds

    ERIC Educational Resources Information Center

    James, K. C.

    1972-01-01

    Outlines factors to be considered in choosing suitable solvents for non-electrolytes and salts of weak acids and bases. Describes how, in some simple situation, the degree of solubility can be estimated. (Author/DF)

  11. 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.

  12. A comparative immunogenicity study in rabbits of disulfide-stabilized, proteolytically cleaved, soluble trimeric human immunodeficiency virus type 1 gp140, trimeric cleavage-defective gp140 and monomeric gp120

    SciTech Connect

    Beddows, Simon; Franti, Michael; Dey, Antu K.; Kirschner, Marc; Iyer, Sai Prasad N.; Fisch, Danielle C.; Ketas, Thomas; Yuste, Eloisa; Desrosiers, Ronald C.; Klasse, Per Johan; Maddon, Paul J.; Olson, William C.; Moore, John P. . E-mail: jpm2003@med.cornell.edu

    2007-04-10

    The human immunodeficiency virus type 1 (HIV-1) surface envelope glycoprotein (Env) complex, a homotrimer containing gp120 surface glycoprotein and gp41 transmembrane glycoprotein subunits, mediates the binding and fusion of the virus with susceptible target cells. The Env complex is the target for neutralizing antibodies (NAbs) and is the basis for vaccines intended to induce NAbs. Early generation vaccines based on monomeric gp120 subunits did not confer protection from infection; one alternative approach is therefore to make and evaluate soluble forms of the trimeric Env complex. We have directly compared the immunogenicity in rabbits of two forms of soluble trimeric Env and monomeric gp120 based on the sequence of HIV-1{sub JR-FL}. Both protein-only and DNA-prime, protein-boost immunization formats were evaluated, DNA-priming having little or no influence on the outcome. One form of trimeric Env was made by disrupting the gp120-gp41 cleavage site by mutagenesis (gp140{sub UNC}), the other contains an intramolecular disulfide bond to stabilize the cleaved gp120 and gp41 moieties (SOSIP.R6 gp140). Among the three immunogens, SOSIP.R6 gp140 most frequently elicited neutralizing antibodies against the homologous, neutralization-resistant strain, HIV-1{sub JR-FL}. All three proteins induced NAbs against more sensitive strains, but the breadth of activity against heterologous primary isolates was limited. When antibodies able to neutralize HIV-1{sub JR-FL} were detected, antigen depletion studies showed they were not directed at the V3 region but were targeted at other, undefined gp120 and also non-gp120 epitopes.

  13. Virions of primary human immunodeficiency virus type 1 isolates resistant to soluble CD4 (sCD4) neutralization differ in sCD4 binding and glycoprotein gp120 retention from sCD4-sensitive isolates.

    PubMed Central

    Moore, J P; McKeating, J A; Huang, Y X; Ashkenazi, A; Ho, D D

    1992-01-01

    Primary isolates of human immunodeficiency virus type 1 (HIV-1) are much less sensitive to neutralization by soluble CD4 (sCD4) and sCD4-immunoglobulin (Ig) chimeras (CD4-IgG) than are HIV-1 strains adapted to growth in cell culture. We demonstrated that there are significant reductions (10- to 30-fold) in the binding of sCD4 and CD4-IgG to intact virions of five primary isolates compared with sCD4-sensitive, cell culture-adapted isolates RF and IIIB. However, soluble envelope glycoproteins (gp120) derived from the primary isolate virions, directly by detergent solubilization or indirectly by recombinant DNA technology, differed in affinity from RF and IIIB gp120 by only one- to threefold. The reduced binding of sCD4 to these primary isolate virions must therefore be a consequence of the tertiary or quaternary structure of the envelope glycoproteins in their native, oligomeric form on the viral surface. In addition, the rate and extent of sCD4-induced gp120 shedding from these primary isolates was lower than that from RF. We suggest that reduced sCD4 binding and increased gp120 retention together account for the relative resistance of these primary isolates to neutralization by sCD4 and CD4-IgG and that virions of different HIV-1 isolates vary both in the mechanism of sCD4 binding and in subsequent conformational changes in their envelope glycoproteins. PMID:1727487

  14. DEVELOPMENT OF SOLUBILITY PRODUCT VISUALIZATION TOOLS

    SciTech Connect

    T.F. Turner; A.T. Pauli; J.F. Schabron

    2004-05-01

    Western Research Institute (WRI) has developed software for the visualization of data acquired from solubility tests. The work was performed in conjunction with AB Nynas Petroleum, Nynashamn, Sweden who participated as the corporate cosponsor for this Jointly Sponsored Research (JSR) task. Efforts in this project were split between software development and solubility test development. The Microsoft Windows-compatible software developed inputs up to three solubility data sets, calculates the parameters for six solid body types to fit the data, and interactively displays the results in three dimensions. Several infrared spectroscopy techniques have been examined for potential use in determining bitumen solubility in various solvents. Reflectance, time-averaged absorbance, and transmittance techniques were applied to bitumen samples in single and binary solvent systems. None of the techniques were found to have wide applicability.

  15. Solubility and secretability.

    PubMed

    Schein, C H

    1993-08-01

    The solubility and secretability of proteins can often be affected by extremely small changes in their primary structure. Attempts to determine empirical rules for the alteration of protein structure to improve either of these characteristics have met with only partial success. Those (mostly serendipitous) improvements in solubility that have been obtained via mutagenesis cannot be considered to be 'protein engineering'. The most successful examples where directed mutagenesis has been used to alter protein solubility, hemoglobin and insulin, have relied on established crystal structures and a wealth of data about the relationship between sequence and structure of the targeted protein. Currently, optimizing culture growth conditions by trial and error remains the fastest way to improve expression.

  16. Ramipril attenuates left ventricular remodeling by regulating the expression of activin A-follistatin in a rat model of heart failure

    PubMed Central

    Wei, Qun; Liu, Haiyan; Liu, Miao; Yang, Chunyan; Yang, Jie; Liu, Zhonghui; Yang, Ping

    2016-01-01

    Prior studies have shown that overexpression of ACT A can lead to ventricular remodeling in rat models of heart failure. Furthermore, recently work studying demonstrated that stimulation of activin An expression in rat aortic smooth muscle (RASM) cells by angiotensin II (Ang II). Ramipril is a recently developed angiotensin converting enzyme (ACE) inhibitor. To investigate the effects of Ramipril on expression of ACT A-FS, we established the rat model of heart failure after myocardial infarction (MI), and divided into either a sham operation (SO), MI, or MI-Ramipril group. We found that Ramipril significantly attenuates collagen-I and III deposition (col-I and III). Notably, we determined that expression of ACT A and II activin receptor (ActRII) were significantly down-regulated in the non-infarcted area of the left ventricle in the Ramipril group, whereas the mRNA and protein levels of FS were markedly up-regulated. Our data suggested that Ramipril benefited left ventricular remodeling by reducing fibrosis and collagen accumulation in the left ventricle of rats after myocardial infarction. This observation was also associated with down-regulation of ACT A expression. This study elucidated a new protective mechanism of Ramipril and suggests a novel strategy for treatment of post-infarct remodeling and subsequent heart failure. PMID:27642098

  17. Ramipril attenuates left ventricular remodeling by regulating the expression of activin A-follistatin in a rat model of heart failure.

    PubMed

    Wei, Qun; Liu, Haiyan; Liu, Miao; Yang, Chunyan; Yang, Jie; Liu, Zhonghui; Yang, Ping

    2016-01-01

    Prior studies have shown that overexpression of ACT A can lead to ventricular remodeling in rat models of heart failure. Furthermore, recently work studying demonstrated that stimulation of activin An expression in rat aortic smooth muscle (RASM) cells by angiotensin II (Ang II). Ramipril is a recently developed angiotensin converting enzyme (ACE) inhibitor. To investigate the effects of Ramipril on expression of ACT A-FS, we established the rat model of heart failure after myocardial infarction (MI), and divided into either a sham operation (SO), MI, or MI-Ramipril group. We found that Ramipril significantly attenuates collagen-I and III deposition (col-I and III). Notably, we determined that expression of ACT A and II activin receptor (ActRII) were significantly down-regulated in the non-infarcted area of the left ventricle in the Ramipril group, whereas the mRNA and protein levels of FS were markedly up-regulated. Our data suggested that Ramipril benefited left ventricular remodeling by reducing fibrosis and collagen accumulation in the left ventricle of rats after myocardial infarction. This observation was also associated with down-regulation of ACT A expression. This study elucidated a new protective mechanism of Ramipril and suggests a novel strategy for treatment of post-infarct remodeling and subsequent heart failure. PMID:27642098

  18. Exogenous GDF9 but not Activin A, BMP15 or TGFβ alters tight junction protein transcript abundance in zebrafish ovarian follicles.

    PubMed

    Clelland, Eric S; Kelly, Scott P

    2011-04-01

    The tight junction (TJ) complex plays an important role in regulating paracellular permeability and provides mechanical stability in vertebrate epithelia and endothelia. In zebrafish ovarian follicles, TJ complexes in the follicular envelope degenerate as the follicles develop towards maturation. In the current study, transcript abundance of claudins (cldn d, g, h, 1, and 12) and occludins (ocln, and ocln b) were assessed in mid-vitellogenic follicles in response to treatment with exogenous growth factors that are reported to be involved in zebrafish follicle development (i.e. Activin A, BMP15, GDF9 and TGFβ). Exogenous GDF9 reduced the transcript abundance of cldn g, ocln and ocln b in mid-vitellogenic follicles, whereas Activin A, BMP15, and TGFβ had no effect. Subsequent studies with GDF9 revealed that this factor did not alter TJ protein transcript abundance in pre-vitellogenic follicles but did increase the abundance of ocln b in fully grown (maturing) follicles. GDF9 was also seen to increase the abundance of StAR mRNA in all but primary stage follicles. These data suggest a role for GDF9 in the regulation of TJ integrity in zebrafish ovarian follicles, perhaps in the facilitation of ovulation, and support a previously postulated role for GDF9 in zebrafish ovarian follicle development. In addition, data also support the idea that endocrine factors play an important role in the regulation of TJ proteins during ovarian follicle development.

  19. Elimination of soluble sup 123 I-labeled aggregates of IgG in patients with systemic lupus erythematosus. Effect of serum IgG and numbers of erythrocyte complement receptor type 1

    SciTech Connect

    Halma, C.; Breedveld, F.C.; Daha, M.R.; Blok, D.; Evers-Schouten, J.H.; Hermans, J.; Pauwels, E.K.; van Es, L.A. )

    1991-04-01

    Using soluble {sup 123}I-labeled aggregates of human IgG ({sup 123}I-AHIgG) as a probe, we examined the function of the mononuclear phagocyte system in 22 patients with systemic lupus erythematosus (SLE) and 12 healthy controls. In SLE patients, a decreased number of erythrocyte complement receptor type 1 was associated with less binding of {sup 123}I-AHIgG to erythrocytes and a faster initial rate of elimination of {sup 123}I-AHIgG (mean +/- SEM half-maximal clearance time 5.23 +/- 0.2 minutes, versus 6.58 +/- 0.2 minutes in the controls), with possible spillover of the material outside the mononuclear phagocyte system of the liver and spleen. However, multiple regression analysis showed that serum concentrations of IgG were the most important factor predicting the rate of {sup 123}I-AHIgG elimination. IgG concentration may thus reflect immune complex clearance, which in turn, would influence the inflammatory reaction, in SLE.

  20. Intraperitoneal immunization with oligomannose-coated liposome-entrapped soluble leishmanial antigen induces antigen-specific T-helper type immune response in BALB/c mice through uptake by peritoneal macrophages.

    PubMed

    Shimizu, Y; Takagi, H; Nakayama, T; Yamakami, K; Tadakuma, T; Yokoyama, N; Kojima, N

    2007-05-01

    The present study demonstrates that the intraperitoneal administration of soluble leishmanial antigen (SLA) entrapped in liposomes coated with neoglycolipids containing oligomannose residues (mannopentaose or mannotriose) strongly induces an antigen-specific T-helper type 1 (Th1) immune response in BALB/c mice. In response to in vitro stimulation with SLA, spleen cells from mice that had received oligomannose-coated liposomes encasing SLA (SLA-OML) displayed greater interferon (IFN)-gamma and interleukin (IL)-2 production and lower IL-4 and IL-5 production than spleen cells from mice that had received SLA alone, indicating that the SLA-specific Th1 immune response had predominantly been induced in the mice that had received SLA-OML. After subsequent infection with Leishmania major, mice that had received SLA-OML were effectively protected against the disease, with a predominant production of IFN-gamma. OML were preferentially and rapidly incorporated into peritoneal macrophages, and the transplantation of macrophages containing SLA-OML into the peritoneal cavity also induced protection against L. major infection. Thus, SLA-OML were shown to successfully induce a specific Th1 immune response capable of controlling L. major infection in BALB/c mice through the effective uptake of OML by peritoneal macrophages.

  1. 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. PMID:27238488

  2. The maturation-inducing hormone 17a-20b-dihydroxy-4pregnen-3-one regulates gene expression of inhibin A and bambi (bone morphogenetic protein and activin membrane bound inhibitor) in the rainbow trout ovary

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Transforming growth factor-beta (TGFb) superfamily members are important paracrine and autocrine regulators of ovarian development and steroidogenesis in mammals and birds, but their reproductive roles in fish are not well understood. The activin system, Tgfb, and bone morphogenetic protein 15 (Bmp...

  3. 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

  4. Thallium (I), soluble salts

    Integrated Risk Information System (IRIS)

    Thallium ( I ) , 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 Noncarc

  5. 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

  6. 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

  7. Changes in intrafollicular concentrations of free IGF-1, activin A, inhibin A, VEGF, estradiol, and prolactin before ovulation in mares.

    PubMed

    Bashir, S T; Ishak, G M; Gastal, M O; Roser, J F; Gastal, E L

    2016-05-01

    Changes in intrafollicular growth factors and hormones were evaluated in vivo in postdeviation and impending ovulation follicles. Mares (n = 30) were randomly assigned to five experimental groups based on target diameters of 25, 30, 35, 40 mm, and impending signs of ovulation. Furthermore, data belonging to two or more proximal diameter groups that were not different were combined and regrouped for each factor separately. Follicular fluid-free insulin-like growth factor 1 was highest (P < 0.003) in 35-mm follicles, followed by the 40-mm and impending ovulation follicle group, and the 25- to 30-mm follicle group. However, concentrations of insulin-like growth factor binding protein 2 in follicular fluid did not differ (P > 0.05) among groups. Additionally, follicular fluid activin A tended (P < 0.06) to be higher in impending ovulation follicles when compared with the 25- to 40-mm follicle group. Concentrations of intrafollicular estradiol were higher (P < 0.0001) in 40-mm and impending ovulation follicles than in the other follicle groups. Follicular fluid concentrations of inhibin A and vascular endothelial growth factor were lower (P < 0.05) in the 40-mm and the impending ovulation follicle group when compared with the 25- to 35-mm follicle group. Systemic and intrafollicular prolactin levels were lower (P < 0.05) in the impending ovulation group when compared with the 25- to 40-mm follicle group. Prolactin concentrations were higher (P < 0.05) in the follicular fluid than in the plasma. The novel findings of this study, a decrease in intrafollicular-free insulin-like growth factor 1, inhibin A, vascular endothelial growth factor, and prolactin during the final stages of follicular growth, document for the first time the occurrence of dynamic changes among intrafollicular factors and hormones during the stages of follicle dominance and as ovulation approaches. PMID:26895618

  8. Enhancing Dopant Solubility via Epitaxial Surfactant Growth

    SciTech Connect

    Zhang, L.; Yan, Y.; Wei, S.-H.

    2009-01-01

    A general concept for enhancing dopant solubility via epitaxial surfactant growth is proposed. The key of the concept is to find the appropriate surfactants that generate high (low) levels that can transfer electrons (holes) to dopant acceptor (donor) levels in p-type (n-type) doping, thus significantly lowering the formation energy of dopants. Using first-principles density-functional calculations, our concept explains excellently the recently discovered dual-surfactant effect of Sb and H on enhancing Zn doping in epitaxially grown GaP(100) thin film and suggests that sole surfactant Te can also induce enhancement of N solubility in ZnSe(100) film. We also proposed the surfactants for enhancing p-type doing of ZnO with epitaxial growth with (000{bar 1}) surface. General rules for selecting surfactants for enhancing both p-type and n-type dopings are provided.

  9. P7170: A Novel Molecule with Unique Profile of mTORC1/C2 and Activin Receptor-like Kinase 1 Inhibition Leading to Antitumor and Antiangiogenic Activity.

    PubMed

    Jalota-Badhwar, Archana; Bhatia, Dimple R; Boreddy, Srinivas; Joshi, Asavari; Venkatraman, Magesh; Desai, Nikesh; Chaudhari, Sarika; Bose, Julie; Kolla, Lakshmi S; Deore, Vijaykumar; Yewalkar, Nilambari; Kumar, Sanjay; Sharma, Rajiv; Damre, Anagha; More, Avinash; Sharma, Somesh; Agarwal, Veena R

    2015-05-01

    The mTOR pathway is often upregulated in cancer and thus intensively pursued as a target to design novel anticancer therapies. Approved and emerging drugs targeting the mTOR pathway have positively affected the clinical landscape. Recently, activin receptor-like kinase 1 (ALK1), belonging to the TGFβ receptor family, has been reported as an emerging target for antiangiogenic cancer therapy. Here, we describe a novel orally efficacious compound, P7170, that inhibits mTORC1/mTORC2/ALK1 activity with a potent cell growth inhibition. In cell-based assays, P7170 strongly inhibited (IC50 < 10 nmol/L) the phosphorylation of p70S6K (T389) and pAKT (S473). In many cancer cell lines, such as prostate, ovarian, colon, and renal, P7170 treatment resulted in marked cell growth inhibition. Furthermore, it induced G1-S cell-cycle arrest and autophagy. In vitro HUVEC tube formation, in vivo Matrigel plug, and rat aorta ring assays demonstrated that P7170 exhibited significant antiangiogenic activity. In addition, ALK1 knockdown studies in HUVEC confirmed that the antiangiogenic activity of P7170 was primarily due to ALK1 inhibition. Strong inhibition of ALK1 in addition to mTORC1/mTORC2 differentiates P7170 in its mechanism of action in comparison with existing inhibitors. In vivo mouse xenograft studies revealed P7170 to exhibit a significant dose-dependent tumor growth inhibition in a broad range of human tumor types when administered orally at 10 to 20 mg/kg doses. The distinctive pharmacological profile with favorable pharmacokinetic parameters and in vivo efficacy makes P7170 an attractive candidate for clinical development. It is currently being tested in phase I clinical studies.

  10. Modeling aqueous solubility.

    PubMed

    Butina, Darko; Gola, Joelle M R

    2003-01-01

    This paper describes the development of an aqueous solubility model based on solubility data from the Syracuse database, calculated octanol-water partition coefficient, and 51 2D molecular descriptors. Two different statistical packages, SIMCA and Cubist, were used and the results were compared. The Cubist model, which comprises a collection of rules, each of which has an associated Multiple Linear Regression model (MLR), gave better overall results on a test set of 640 compounds with an overall squared correlation coefficient of 0.74 and an absolute average error of 0.68 log units. Both training and independent test sets had similar distributions of structures in terms of the different functionalities present-60% neutral, 14% acidic, 8% phenolic, 11% monobasic, 4% polybasic, and 3% zwitterionic molecules. Sets were designed by random selection, with 2688 (81%) and 640 (19%) molecules, respectively, forming the training and the test sets.

  11. A Perspective on Solubility Rules.

    ERIC Educational Resources Information Center

    Monroe, Manus; Abrams, Karl

    1984-01-01

    Presents four generalizations about solubilities. These generalizations (rules), are useful in introducing the dynamic topics of solubility and in helping high school and introductory college chemistry students make some order out of the tremendous number of facts available. (JN)

  12. Acyclic cucurbit[n]uril molecular containers enhance the solubility and bioactivity of poorly soluble pharmaceuticals

    NASA Astrophysics Data System (ADS)

    Ma, Da; Hettiarachchi, Gaya; Nguyen, Duc; Zhang, Ben; Wittenberg, James B.; Zavalij, Peter Y.; Briken, Volker; Isaacs, Lyle

    2012-06-01

    The solubility characteristics of 40-70% of new drug candidates are so poor that they cannot be formulated on their own, so new methods for increasing drug solubility are highly prized. Here, we describe a new class of general-purpose solubilizing agents—acyclic cucurbituril-type containers—which increase the solubility of ten insoluble drugs by a factor of between 23 and 2,750 by forming container-drug complexes. The containers exhibit low in vitro toxicity in human liver, kidney and monocyte cell lines, and outbred Swiss Webster mice tolerate high doses of the container without sickness or weight loss. Paclitaxel solubilized by the acyclic cucurbituril-type containers kills cervical and ovarian cancer cells more efficiently than paclitaxel alone. The acyclic cucurbituril-type containers preferentially bind cationic and aromatic drugs, but also solubilize neutral drugs such as paclitaxel, and represent an attractive extension of cyclodextrin-based technology for drug solubilization and delivery.

  13. Experimental measurement of solid solutes solubility in nanofluids

    NASA Astrophysics Data System (ADS)

    Fard, Manouchehr Manouchehrian; Beiki, Hossein

    2016-08-01

    The solubility of benzoic and salicylic acids was measured at a temperature range from 293 to 333 K in two types of water based nanofluids employed as the solvent. Silica and γ-alumina nanoparticles with volume concentrations of 0.025, 0.05, 0.1, 0.2 and 0.4 % were dispersed into de-ionized water as the based fluid. The results revealed that the solubility of nanofluid followed the same trend as pure water solubility with increasing temperature. At low temperatures, below 330 K for γ-Al2O3 nanofluids and 323 K for SiO2 nanofluids, nanoparticles had no effect on solubility, but by increasing the temperature, nanofluid solubility decreased. The maximum reduction in the solubility of compounds was observed at the temperature of 333 K and in 0.1 % γ-Alumina nanofluid and 0.025 % Silica nanofluids. Nanofluids solubility decreased up to a critical nanoparticles concentration while increased by increasing nanoparticles concentration further. The maximum reduction of nanofluids solubility at critical concentration was about 12.43 % for salicylic acid and 10.24 % for benzoic acid in 0.025 % SiO2 nanofluid. Nanofluids solubility was found to be strongly dependent on nanoparticles size. Bigger nanoparticles were more effective than smaller ones on nanofluids solubility.

  14. Hormonal and photoperiodic modulation of testicular mRNAs coding for inhibin/activin subunits and follistatin in Clethrionomys glareolus, Schreber.

    PubMed

    Tähkä, K M; Kaipia, A; Toppari, J; Tähkä, S; Tuuri, T; Tuohimaa, P

    1998-07-01

    Photoperiodic and hormonal modulation of mRNAs for testicular inhibin/activin subunits and follistatin were studied in a seasonally breeding rodent, the bank vole (Clethrionomys glareolus). Photoperiod-induced testicular regression had no effect on the relatively low steady-state levels of follistatin mRNA. Inhibin alpha (I alpha) and beta B (I beta B) mRNA levels were significantly higher in regressed than in active gonads, but inhibin beta A was undetectable. The effect of gonadotropin administration on testicular weight and mRNA concentrations differed between the sexually active and quiescent voles. Neither FSH (1.2 U/kg; s.c. for 5 days) nor hCG (600 IU/kg; s.c. for 5 days) affected testicular weight in sexually active voles, whereas both gonadotropins significantly increased testicular weight in photo-regressed individuals. FSH had no effect on I alpha or I beta B mRNA concentrations in the active testes, whereas excessive hCG challenge induced a decrease in the steady-state levels of these mRNAs. FSH induced an increase in I alpha mRNA concentrations in the regressed gonad, whereas both gonadotropins concomitantly down-regulated I beta B mRNA levels. In conclusion, the high expression of I alpha and I beta B mRNA in the regressed testis imply autocrine and paracrine roles for inhibin/activin in the quiescent gonad of seasonal breeders. Inhibin alpha-subunit expression is at least partly under the control of FSH in the bank vole testis.

  15. 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…

  16. Soluble porphyrin polymers

    SciTech Connect

    Gust, Jr., John Devens; Liddell, Paul Anthony

    2015-07-07

    Porphyrin polymers of Structure 1, where n is an integer (e.g., 1, 2, 3, 4, 5, or greater) ##STR00001## are synthesized by the method shown in FIGS. 2A and 2B. The porphyrin polymers of Structure 1 are soluble in organic solvents such as 2-MeTHF and the like, and can be synthesized in bulk (i.e., in processes other than electropolymerization). These porphyrin polymers have long excited state lifetimes, making the material suitable as an organic semiconductor for organic electronic devices including transistors and memories, as well as solar cells, sensors, light-emitting devices, and other opto-electronic devices.

  17. Serum Levels of Soluble CD26/Dipeptidyl Peptidase-IV in Type 2 Diabetes Mellitus and Its Association with Metabolic Syndrome and Therapy with Antidiabetic Agents in Malaysian Subjects

    PubMed Central

    Ahmed, Radwan H.; Huri, Hasniza Zaman; Al-Hamodi, Zaid; Salem, Sameer D.; Muniandy, Sekaran

    2015-01-01

    Background A soluble form of CD26/dipeptidyl peptidase-IV (sCD26/DPP-IV) induces DPP-IV enzymatic activity that degrades incretin. We investigated fasting serum levels of sCD26/DPP-IV and active glucagon-like peptide-1 (GLP-1) in Malaysian patients with type 2 diabetes mellitus (T2DM) with and without metabolic syndrome (MetS), as well as the associations between sCD26/DPP-IV levels, MetS, and antidiabetic therapy. Methods We assessed sCD26/DPP-IV levels, active GLP-1 levels, body mass index (BMI), glucose, insulin, A1c, glucose homeostasis indices, and lipid profiles in 549 Malaysian subjects (including 257 T2DM patients with MetS, 57 T2DM patients without MetS, 71 non-diabetics with MetS, and 164 control subjects without diabetes or metabolic syndrome). Results Fasting serum levels of sCD26/DPP-IV were significantly higher in T2DM patients with and without MetS than in normal subjects. Likewise, sCD26/DPP-IV levels were significantly higher in patients with T2DM and MetS than in non-diabetic patients with MetS. However, active GLP-1 levels were significantly lower in T2DM patients both with and without MetS than in normal subjects. In T2DM subjects, sCD26/DPP-IV levels were associated with significantly higher A1c levels, but were significantly lower in patients using monotherapy with metformin. In addition, no significant differences in sCD26/DPP-IV levels were found between diabetic subjects with and without MetS. Furthermore, sCD26/DPP-IV levels were negatively correlated with active GLP-1 levels in T2DM patients both with and without MetS. In normal subjects, sCD26/DPP-IV levels were associated with increased BMI, cholesterol, and LDL-cholesterol (LDL-c) levels. Conclusion Serum sCD26/DPP-IV levels increased in T2DM subjects with and without MetS. Active GLP-1 levels decreased in T2DM patients both with and without MetS. In addition, sCD26/DPP-IV levels were associated with Alc levels and negatively correlated with active GLP-1 levels. Moreover, metformin

  18. Water soluble laser dyes

    DOEpatents

    Hammond, Peter R.; Feeman, James F.; Field, George F.

    1998-01-01

    Novel water soluble dyes of the formula I are provided ##STR1## wherein R.sup.1 and R.sup.4 are alkyl of 1 to 4 carbon atoms or hydrogen; or R.sup.1 -R.sup.2 or R.sup.2 -R.sup.4 form part of aliphatic heterocyclic rings; R.sup.2 is hydrogen or joined with R.sup.1 or R.sup.4 as described above; R.sup.3 is --(CH.sub.2).sub.m --SO.sub.3.sup.-, where m is 1 to 6; X is N, CH or ##STR2## where Y is 2 --SO.sub.3.sup.- ; Z is 3, 4, 5 or 6 --SO.sub.3.sup.-. The novel dyes are particularly useful as the active media in water solution dye lasers.

  19. Water soluble laser dyes

    DOEpatents

    Hammond, P.R.; Feeman, J.F.; Field, G.F.

    1998-08-11

    Novel water soluble dyes of the formula 1 are provided by the formula described in the paper wherein R{sup 1} and R{sup 4} are alkyl of 1 to 4 carbon atoms or hydrogen; or R{sup 1}--R{sup 2} or R{sup 2}--R{sup 4} form part of aliphatic heterocyclic rings; R{sup 2} is hydrogen or joined with R{sup 1} or R{sup 4} as described above; R{sup 3} is --(CH{sub 2}){sub m}--SO{sub 3}{sup {minus}}, where m is 1 to 6; X is N, CH or formula 2 given in paper where Y is 2 --SO{sub 3}{sup {minus}} ; Z is 3, 4, 5 or 6 --SO{sub 3}{sup {minus}}. The novel dyes are particularly useful as the active media in water solution dye lasers.

  20. Discovery of 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole (TASP0382088): a potent and selective transforming growth factor-β type I receptor inhibitor as a topical drug for alopecia.

    PubMed

    Amada, Hideaki; Asanuma, Hajime; Koami, Takeshi; Okada, Atsushi; Endo, Mayumi; Ueda, Yasuji; Naruse, Takumi; Ikeda, Akiko

    2013-01-01

    7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 11 (TASP0382088) was synthesized and evaluated as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitor. Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals).

  1. [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).

  2. Activin Receptor-Like Kinase Receptors ALK5 and ALK1 Are Both Required for TGFβ-Induced Chondrogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells

    PubMed Central

    de Kroon, Laurie M. G.; Narcisi, Roberto; Blaney Davidson, Esmeralda N.; Cleary, Mairéad A.; van Beuningen, Henk M.; Koevoet, Wendy J. L. M.; van Osch, Gerjo J. V. M.; van der Kraan, Peter M.

    2015-01-01

    Introduction Bone marrow-derived mesenchymal stem cells (BMSCs) are promising for cartilage regeneration because BMSCs can differentiate into cartilage tissue-producing chondrocytes. Transforming Growth Factor β (TGFβ) is crucial for inducing chondrogenic differentiation of BMSCs and is known to signal via Activin receptor-Like Kinase (ALK) receptors ALK5 and ALK1. Since the specific role of these two TGFβ receptors in chondrogenesis is unknown, we investigated whether ALK5 and ALK1 are expressed in BMSCs and whether both receptors are required for chondrogenic differentiation of BMSCs. Materials & Methods ALK5 and ALK1 gene expression in human BMSCs was determined with RT-qPCR. To induce chondrogenesis, human BMSCs were pellet-cultured in serum-free chondrogenic medium containing TGFβ1. Chondrogenesis was evaluated by aggrecan and collagen type IIα1 RT-qPCR analysis, and histological stainings of proteoglycans and collagen type II. To overexpress constitutively active (ca) receptors, BMSCs were transduced either with caALK5 or caALK1. Expression of ALK5 and ALK1 was downregulated by transducing BMSCs with shRNA against ALK5 or ALK1. Results ALK5 and ALK1 were expressed in in vitro-expanded as well as in pellet-cultured BMSCs from five donors, but mRNA levels of both TGFβ receptors did not clearly associate with chondrogenic induction. TGFβ increased ALK5 and decreased ALK1 gene expression in chondrogenically differentiating BMSC pellets. Neither caALK5 nor caALK1 overexpression induced cartilage matrix formation as efficient as that induced by TGFβ. Moreover, short hairpin-mediated downregulation of either ALK5 or ALK1 resulted in a strong inhibition of TGFβ-induced chondrogenesis. Conclusion ALK5 as well as ALK1 are required for TGFβ-induced chondrogenic differentiation of BMSCs, and TGFβ not only directly induces chondrogenesis, but also modulates ALK5 and ALK1 receptor signaling in BMSCs. These results imply that optimizing cartilage formation by

  3. The Ksp-Solubility Conundrum.

    ERIC Educational Resources Information Center

    Clark, Roy W.; Bonicamp, Judith M.

    1998-01-01

    Argues that there are only a few cases in which solubility and Ksp are related in a simple way. States that illustrations of the solubility product principle for one-to-one salts are adequate for students. Contains 23 references. (DDR)

  4. Recombinant soluble adenovirus receptor

    DOEpatents

    Freimuth, Paul I.

    2002-01-01

    Disclosed are isolated polypeptides from human CAR (coxsackievirus and adenovirus receptor) protein which bind adenovirus. Specifically disclosed are amino acid sequences which corresponds to adenovirus binding domain D1 and the entire extracellular domain of human CAR protein comprising D1 and D2. In other aspects, the disclosure relates to nucleic acid sequences encoding these domains as well as expression vectors which encode the domains and bacterial cells containing such vectors. Also disclosed is an isolated fusion protein comprised of the D1 polypeptide sequence fused to a polypeptide sequence which facilitates folding of D1 into a functional, soluble domain when expressed in bacteria. The functional D1 domain finds application for example in a therapeutic method for treating a patient infected with a virus which binds to D1, and also in a method for identifying an antiviral compound which interferes with viral attachment. Also included is a method for specifically targeting a cell for infection by a virus which binds to D1.

  5. Intestinal solubility and absorption of poorly water soluble compounds: predictions, challenges and solutions.

    PubMed

    Fagerberg, Jonas H; Bergström, Christel A S

    2015-01-01

    We have explored for which type of compounds biorelevant dissolution profiling in simulated intestinal fluids would accurately predict solubility in human intestinal fluid. In total, 460 solubility values in simulated and aspirated human intestinal fluid for 78 drugs were compiled and analyzed. Significant solubilization in the colloidal structures was obtained in fasted and fed state fluids for drug compounds with a logD(oct)>3. Highly lipophilic compounds with high melting points (Tm > 200 °C) could also be significantly solubilized, but typically such compounds had solubility values in the lower µg/ml range also in the presence of the colloidal structures. On the basis of our analysis, compounds with a logD(oct)>3 should be explored in biorelevant dissolution media to better predict in vivo performance after oral dosing.

  6. Comparative Calculations of Solubility Equilibria

    SciTech Connect

    Beahm, E.C.

    2000-07-25

    The uncertainties in calculated solubilities in the Na-F-PO{sub 4}-HPO{sub 4}-OH system. at 25 C for NaOH concentrations up to 5 mol/kg were assessed. These uncertainties were based on an evaluation of the range of values for the Gibbs energies of the solids. Comparative calculations using the Environmental Simulation Program (ESP) and SOLGASMIX indicated that the variation in activity coefficients with NaOH concentration is much greater in the ESP code than in SOLGASMIX. This resulted in ESP calculating a higher solubility in water and a lower solubility in NaOH concentrations above 1 mol/kg: There was a marked discrepancy in the solubilities of the pure components sodium fluoride and trisodium phosphate predicted by ESP and SOLGASMIX. In addition, different solubilities for these components were obtained using different options in ESP. Because of these observations, a Best Practices Guide for ESP will be assembled.

  7. Scoring function to predict solubility mutagenesis

    PubMed Central

    2010-01-01

    Background Mutagenesis is commonly used to engineer proteins with desirable properties not present in the wild type (WT) protein, such as increased or decreased stability, reactivity, or solubility. Experimentalists often have to choose a small subset of mutations from a large number of candidates to obtain the desired change, and computational techniques are invaluable to make the choices. While several such methods have been proposed to predict stability and reactivity mutagenesis, solubility has not received much attention. Results We use concepts from computational geometry to define a three body scoring function that predicts the change in protein solubility due to mutations. The scoring function captures both sequence and structure information. By exploring the literature, we have assembled a substantial database of 137 single- and multiple-point solubility mutations. Our database is the largest such collection with structural information known so far. We optimize the scoring function using linear programming (LP) methods to derive its weights based on training. Starting with default values of 1, we find weights in the range [0,2] so that predictions of increase or decrease in solubility are optimized. We compare the LP method to the standard machine learning techniques of support vector machines (SVM) and the Lasso. Using statistics for leave-one-out (LOO), 10-fold, and 3-fold cross validations (CV) for training and prediction, we demonstrate that the LP method performs the best overall. For the LOOCV, the LP method has an overall accuracy of 81%. Availability Executables of programs, tables of weights, and datasets of mutants are available from the following web page: http://www.wsu.edu/~kbala/OptSolMut.html. PMID:20929563

  8. Adulteration of soluble coffee with coffee husks and parchments.

    PubMed

    Prodolliet, J; Bruelhart, M; Blanc, M B; Leloup, V; Cherix, G; Donnelly, C M; Viani, R

    1995-01-01

    Commercial soluble coffee can be adulterated with coffee husks or parchments. Xylose is a good tracer for this type of mispractice. The analysis of total xylose in a wide selection of green beans and the assessment of its fate during processing allowed the derivation of a maximum total xylose limit of 0.40%, above which a soluble coffee should be considered as adulterated. Out of the 700 commercial soluble coffees analyzed, 81 exhibited a total xylose level above this limit. Of the samples with total xylose level lower than the limit, 99% displayed concentrations in free mannitol and total glucose below 0.30 and 2.10%, respectively.

  9. Phenylated Polyimides With Greater Solubility

    NASA Technical Reports Server (NTRS)

    Harris, Frank W.

    1991-01-01

    In experiments, 3,6-diphenylpyromellitic dianhydride monomer prepared and polymerized with several different diamines. Polyimides with pendent phenyl groups along polymer backbones considerably more soluble than PMDA-based materials. Increased solubility eases processing, providing increased potential use in variety of applications. Because most polymers soluble in organic solvents, usable in microelectronics applications. Excellent thermal stabilities and high transition temperatures make them ideally suited. Many polymers extremely rigid and useful as reinforcing polymers in molecular composites. More flexible compositions useful as matrix resins in carbon-reinforced composites.

  10. 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.

  11. Water-soluble vitamins.

    PubMed

    Konings, Erik J M

    2006-01-01

    Simultaneous Determination of Vitamins.--Klejdus et al. described a simultaneous determination of 10 water- and 10 fat-soluble vitamins in pharmaceutical preparations by liquid chromatography-diode-array detection (LC-DAD). A combined isocratic and linear gradient allowed separation of vitamins in 3 distinct groups: polar, low-polar, and nonpolar. The method was applied to pharmaceutical preparations, fortified powdered drinks, and food samples, for which results were in good agreement with values claimed. Heudi et al. described a separation of 9 water-soluble vitamins by LC-UV. The method was applied for the quantification of vitamins in polyvitaminated premixes used for the fortification of infant nutrition products. The repeatability of the method was evaluated at different concentration levels and coefficients of variation were <6.5%. The concentrations of vitamins found in premixes with the method were comparable to the values declared. A disadvantage of the methods mentioned above is that sample composition has to be known in advance. According to European legislation, for example, foods might be fortified with riboflavin phosphate or thiamin phosphate, vitamers which are not included in the simultaneous separations described. Vitamin B2.--Viñas et al. elaborated an LC analysis of riboflavin vitamers in foods. Vitamin B2 can be found in nature as the free riboflavin, but in most biological materials it occurs predominantly in the form of 2 coenzymes, flavin mononucleotide (FMN) and flavin-adenine dinucleotide (FAD). Several methods usually involve the conversion of these coenzymes into free riboflavin before quantification of total riboflavin. According to the authors, there is growing interest to know flavin composition of foods. The described method separates the individual vitamers isocratically. Accuracy of the method is tested with 2 certified reference materials (CRMs). Vitamin B5.-Methods for the determination of vitamin B5 in foods are limited

  12. Dual Inhibition of Activin/Nodal/TGF-β and BMP Signaling Pathways by SB431542 and Dorsomorphin Induces Neuronal Differentiation of Human Adipose Derived Stem Cells

    PubMed Central

    Madhu, Vedavathi; Dighe, Abhijit S.; Cui, Quanjun; Deal, D. Nicole

    2016-01-01

    Damage to the nervous system can cause devastating diseases or musculoskeletal dysfunctions and transplantation of progenitor stem cells can be an excellent treatment option in this regard. Preclinical studies demonstrate that untreated stem cells, unlike stem cells activated to differentiate into neuronal lineage, do not survive in the neuronal tissues. Conventional methods of inducing neuronal differentiation of stem cells are complex and expensive. We therefore sought to determine if a simple, one-step, and cost effective method, previously reported to induce neuronal differentiation of embryonic stem cells and induced-pluripotent stem cells, can be applied to adult stem cells. Indeed, dual inhibition of activin/nodal/TGF-β and BMP pathways using SB431542 and dorsomorphin, respectively, induced neuronal differentiation of human adipose derived stem cells (hADSCs) as evidenced by formation of neurite extensions, protein expression of neuron-specific gamma enolase, and mRNA expression of neuron-specific transcription factors Sox1 and Pax6 and matured neuronal marker NF200. This process correlated with enhanced phosphorylation of p38, Erk1/2, PI3K, and Akt1/3. Additionally, in vitro subcutaneous implants of SB431542 and dorsomorphin treated hADSCs displayed significantly higher expression of active-axonal-growth-specific marker GAP43. Our data offers novel insights into cell-based therapies for the nervous system repair. PMID:26798350

  13. Expression and distribution of forkhead activin signal transducer 2 (FAST2) during follicle development in mouse ovaries and pre-implantation embryos.

    PubMed

    Wang, Guiping; Liu, Linlin; Guo, Shujuan; Zhang, Cong

    2016-07-01

    Xenopus forkhead activin signal transducer 1 (xFAST 1) was first characterized in Xenopus as the transcriptional partner for Smad proteins. FAST2, which is the xFAST 1 homologues in mouse, is expressed during early developmental stages of the organism. However, the function of FAST2 in mouse ovaries and pre-implantation embryos is unclear. Therefore, we investigated its expression during these processes. In postnatal mice, FAST2 was expressed in oocytes and thecal cells from postnatal day (PD) 1 to PD 21. In gonadotropin-induced immature mice, FAST2 was expressed in oocytes, thecal cells and newly formed corpora lutea (CLs), but was expressed at a lower level in degenerated CLs. Similar results were observed upon western blot analyses. In meloxicam-treated immature mice, ovulation was inhibited and FAST2 was expressed in thecal cells, luteinized granulosa cells and entrapped oocytes. Immunofluorescence results showed that FAST2 was expressed in the cytoplasm and nucleus but not the nucleolus from the zygote to 8-cell embryo stage, after which it was localized to the cytoplasm of the morulae and inner cell mass of the blastocysts. Taken together, these observations suggest that FAST2 is expressed in a cell-specific manner during ovarian follicle development, ovulation, luteinization and early embryonic development, and that FAST2 might play important roles in these physiological processes. PMID:27432806

  14. Th2 lymphocytes migrating to the bone marrow under high-altitude hypoxia promote erythropoiesis via activin A and interleukin-9.

    PubMed

    Li, Peng; Zheng, Shan-jun; Jiang, Chun-hua; Zhou, Si-min; Tian, Huai-jun; Zhang, Gang; Gao, Yu-qi

    2014-09-01

    The mechanism of accelerated erythropoiesis under the hypoxic conditions of high altitude (HA) remains largely obscure. Here, we investigated the potential role of bone marrow (BM) T cells in the increased production of erythrocytes at HA. We found that mice exposed to a simulated altitude of 6,000 m for 1-3 weeks exhibited a significant expansion of BM CD4+ cells, mainly caused by increasing T helper 2 (Th2) cells. Using a coculture model of BM T cells and hematopoietic stem/progenitor cells, we observed that BM CD4+ cells from hypoxic mice induced erythroid output more easily, in agreement with the erythroid-enhancing effect observed for Th2-condition-cultured BM CD4+ cells. It was further demonstrated that elevated secretion of activin A and interleukin-9 by BM Th2 cells of hypoxic mice promoted erythroid differentiation of hematopoietic stem/progenitor cells and the growth of erythroblasts, respectively. Our study also provided evidence that the CXCL12-CXCR4 interaction played an important role in Th2 cell trafficking to the BM under HA conditions. These results collectively suggest that Th2 cells migrating to the BM during HA exposure have a regulatory role in erythropoiesis, which provides new insight into the mechanism of high altitude polycythemia.

  15. Method for estimating solubility parameter

    NASA Technical Reports Server (NTRS)

    Lawson, D. D.; Ingham, J. D.

    1973-01-01

    Semiempirical correlations have been developed between solubility parameters and refractive indices for series of model hydrocarbon compounds and organic polymers. Measurement of intermolecular forces is useful for assessment of material compatibility, glass-transition temperature, and transport properties.

  16. Mineral oil soluble borate compositions

    SciTech Connect

    Dulat, J.

    1981-09-15

    Alkali metal borates are reacted with fatty acids or oils in the presence of a low hlb value surfactant to give a stable mineral oil-soluble product. Mineral oil containing the borate can be used as a cutting fluid.

  17. 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.

  18. 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.

  19. Pure Phase Solubility Limits: LANL

    SciTech Connect

    C. Stockman

    2001-01-26

    The natural and engineered system at Yucca Mountain (YM) defines the site-specific conditions under which one must determine to what extent the engineered and the natural geochemical barriers will prevent the release of radioactive material from the repository. Most important mechanisms for retention or enhancement of radionuclide transport include precipitation or co-precipitation of radionuclide-bearing solid phases (solubility limits), complexation in solution, sorption onto surfaces, colloid formation, and diffusion. There may be many scenarios that could affect the near-field environment, creating chemical conditions more aggressive than the conditions presented by the unperturbed system (such as pH changes beyond the range of 6 to 9 or significant changes in the ionic strength of infiltrated waters). For an extended period of time, the near-field water composition may be quite different and more extreme in pH, ionic strength, and CO{sub 2} partial pressure (or carbonate concentration) than waters at some distance from the repository. Reducing conditions, high pH (up to 11), and low carbonate concentration may be present in the near-field after reaction of infiltrating groundwater with engineered barrier systems, such as cementitious materials. In the far-field, conditions are controlled by the rock-mass buffer providing a near-neutral, oxidizing, low-ionic-strength environment that controls radionuclide solubility limits and sorption capacities. There is the need for characterization of variable chemical conditions that affect solubility, speciation, and sorption reactions. Modeling of the groundwater chemistry is required and leads to an understanding of solubility and speciation of the important radionuclides. Because experimental studies cannot be performed under the numerous potential chemical conditions, solubility limitations must rely on geochemical modeling of the radionuclide's chemistry. Fundamental thermodynamic properties, such as solubility

  20. Comparative evaluation of various solubility enhancement strategies for furosemide.

    PubMed

    Murtaza, Ghulam; Khan, Shujaat Ali; Najam-ul-Haq, Muhammad; Hussain, Izhar

    2014-07-01

    Drugs with good solubility exhibit good oral absorption, and subsequently good bioavailability. Thus, most exigent phase of drug development practice particularly for oral dosage forms is the enhancement of drug solubility. This review describes various traditional and novel methodologies proposed for the solubility enhancement of furosemide. For furosemide, solubility and permeability are crucial rate limiting factors to achieve its desired level in systemic circulation for pharmacological response. Thus, problematic solubility of furosemide is one of the main challenges for dosage form developing researchers. Various procedures, illustrated in this review, have been successfully employed to improve the furosemide solubility; however successful improvement essentially depends on the assortment of technique. It is concluded from the results that dissolution rate of drug increases by increasing the quantity of solubility enhancer. Dissolution rate also depends upon the type of enhancer and dissolution medium. In order to achieve relatively enhanced percentage drug release after 30 min (DP30), complexation by solvent evaporation using β-cyclodextrin is the best method. Solid dispersion is found the best if polyethylene glycol is used as enhancer along with microcrystalline cellulose as hydrophilic adsorbent. All the approaches narrated in this article possess good perceptions for additional research i.e. in-vivo studies should be carried out focusing on delivery system development.

  1. Synthesis and structure of a water-soluble hexanuclear silver(I) nicotinate cluster comprised of a "cyclohexane-chair"-type of framework, showing effective antibacterial and antifungal activities: use of "sparse matrix" techniques for growing crystals of water-soluble inorganic complexes.

    PubMed

    Tsyba, Irina; Mui, Becky Bun-Kit; Bau, Robert; Noguchi, Ryusuke; Nomiya, Kenji

    2003-12-01

    The synthesis of a water-soluble anionic silver 2-mercaptonicotinate complex having effective antibacterial and antifungal properties is described. Its structure has been confirmed to be a hexameric cluster by an X-ray diffraction analysis of a mixed Na(+)/Tris(+) salt (Tris(+) = tris(hydroxymethyl)methylammonium cation). The [Ag(mna)](6)(6-) cluster has a Ag(6)S(6) core and an overall shape of twisted hexagonal cylinder with six sulfur atoms and six silver atoms alternating on a puckered drum-like surface. Each Ag atom is trigonally coordinated by one N and two S ligands. The overall [Ag(mna)](6)(6-).4Na(+).2[(HOCH(2))(3)CNH(3)](+).10H(2)O complex has a layered appearance in the crystal packing diagram, with a [Ag(mna)](6)(-) cluster layer alternating with a solvent layer consisting of sodium atoms, Tris buffer cations, and water molecules. The structure is almost identical to that of a neutral [Ag(Hmna)](6) complex reported earlier. The neutral and charged complexes are both known to possess antimicrobial activities, and some biological properties of these and related compounds are briefly discussed in this paper.

  2. The interactive effect of dietary fat-soluble vitamin levels on the depression of gonadal development in growing male rats kept under disturbed daily rhythm. Investigations based on the L₁₆(2¹⁵) type orthogonal array.

    PubMed

    Hanai, Miho; Esashi, Takatoshi

    2011-01-01

    The purpose of this study was to clarify the effects of nutrients on the gonadal development of male rats kept under constant darkness as a model of disturbed daily rhythm. In the present study we examined fat-soluble vitamins and their interactions in this test population. Four fat-soluble vitamins (vitamin A (V.A), vitamin D (V.D), vitamin E (V.E) and vitamin K (V.K)) were selected as experimental factors, and the dietary content of these vitamins was normal (AIN-93G) or three times the normal content. Lighting conditions (constant darkness or normal lighting) were also added as a factor. Four-week-old rats (Fischer 344 strain) were kept under constant darkness or normal lighting (12-h light/dark cycle) for 4 wk. The lighting condition and V.E, and the interactions between the lighting condition and V.E and between V.A and V.D were observed to affect the testes and epididymides weights. There was an influence of the lighting condition only on the seminal vesicles and prostate weights and the serum testosterone concentration. Among the constant darkness groups (D-groups), the highest value for testes weight was observed under the normal-V.A, normal-V.D and high-V.E diet. The interaction between lighting condition and V.E showed the testes weight increased slightly in response to changing to a high-V.E diet from a normal-V.E diet under normal lighting (N-group) but was greatly increased in response to this change in the D-group. It became clear that the amount of dietary V.E necessary for the gonadal development of rats increases when rats are kept under constant darkness.

  3. 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%.

  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. 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%.

  6. 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.

  7. Phenol-soluble modulins.

    PubMed

    Otto, Michael

    2014-03-01

    PSMs are a recently discovered family of short, amphipathic, α-helical peptides in staphylococci. Several PSMs are key virulence determinants, particularly in highly virulent Staphylococcus aureus strains. PSMα peptides of S. aureus facilitate neutrophil lysis after phagocytosis, and are key contributors to several infection types, including skin infection and bacteremia. Furthermore, all PSMs contribute to biofilm structuring and the dissemination of biofilm-associated infection. Cytolytic PSMs as produced by S. aureus appear to have evolved from original functions in the non-infectious lifestyle of staphylococci. The surfactant properties of PSMs, which they all share, are believed to facilitate growth on epithelial surfaces. The basic role of PSMs in staphylococcal physiology is underscored, for example, by their exceptionally strict and direct control by quorum-sensing and the presence of a dedicated secretion system. Targeting PSMs for anti-staphylococcal drug development may be a promising approach to overcome the problems associated with widespread antibiotic resistance in staphylococci.

  8. 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. PMID:26713784

  9. 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.

  10. Transcutaneous auricular vagus nerve stimulation regulates expression of growth differentiation factor 11 and activin-like kinase 5 in cerebral ischemia/reperfusion rats.

    PubMed

    Ma, Jingxi; Zhang, Lina; He, Guoqian; Tan, Xiaodan; Jin, Xinhao; Li, Changqing

    2016-10-15

    Growth differentiation factor 11 (GDF11), as a rejuvenation factor in heterochronic parabiosis, can increase proliferation of primary brain capillary endothelial cells (ECs). However, the angiogenic role of GDF11 in ischemia-induced brain injury is still unclear. There are no previous reports on the spatiotemporal expression of GDF11 in cerebral ischemia/reperfusion (I/R) rats. Our recent work has strongly suggested that transcutaneous auricular vagus nerve stimulation (ta-VNS) reduces infarct size and induces angiogenesis in focal cerebral I/R rats. This study focused on expression of GDF11 and activin-like kinase 5 (ALK5) and the effects of ta-VNS in a rat cerebral I/R model. For ta-VNS, electrical stimulation of the left cavum concha (1h duration) using percutaneous needles was initiated 30min after induction of ischemia. Expression of GDF11 was analyzed by enzyme-linked immunosorbent assay, immunohistochemistry, real-time polymerase chain reaction, and western blot 24h, 3d, and 7d after reperfusion. In addition, neurobehavioral function, EC proliferation, and expression of ALK5 in ECs in the peri-infarct cortex were measured. Results showed that levels of GDF11 were significantly elevated after cerebral I/R, both in plasma and the peri-infarct cerebral cortex. Interestingly, splenic GDF11 levels decreased after ischemia. ALK5 was expressed in ECs in the peri-infarct cerebral cortex where active vessel remodeling was noted. ta-VNS improved neurobehavioral recovery, upregulated cerebral GDF11 and downregulated splenic GDF11, indicating a brain-spleen communication during stroke. ta-VNS also increased expression of ALK5 in ECs and stimulated proliferation of ECs. These results suggest that, after cerebral ischemia, GDF11 redistributes and participates in angiogenesis as an angiogenic factor that acts at least in part through ALK5. GDF11/ALK5 may represent a new potential therapy target for stroke. PMID:27653860

  11. Activin A and equine chorionic gonadotropin recover reproductive dysfunction induced by neonatal exposure to an estrogenic endocrine disruptor in adult male mice.

    PubMed

    Warita, Katsuhiko; Okamoto, Kazutaka; Mutoh, Ken-Ichiro; Hasegawa, Yoshihisa; Yue, Zhan-Peng; Yokoyama, Toshifumi; Matsumoto, Yoshiki; Miki, Takanori; Takeuchi, Yoshiki; Kitagawa, Hiroshi; Sugawara, Teruo; Hoshi, Nobuhiko

    2008-01-01

    We aimed to elucidate the mechanism of action of estrogenic endocrine disruptors and the rescue of reproductive function, particularly the responsiveness of testes to eCG and/or activin A (ACT) after establishing reproductive disorders. Newborn male mice (n = 29) were randomly divided into an untreated group and three treatment groups that received diethylstilbestrol (DES; 100 mug per animal) subcutaneously on Postnatal Day 3 to establish reproductive disorders and daily treatment with PBS (controls: DES + PBS), eCG (eCG group: DES + eCG), or eCG + ACT (eCG + ACT group: DES + eCG + ACT) at 6-8 wk of age prior to mating. After treatment, the controls showed diminished Leydig cells in the testes and thin germ cell layers containing pyknotic germ cells and multinucleated cells. In the eCG and eCG + ACT groups, spermatids and Leydig cells increased markedly. The immunoexpression of androgen receptors in the eCG group and steroidogenic acute regulatory (STAR) protein in the eCG and eCG + ACT groups recovered to approximately the levels in the untreated group; plasma LH and testosterone levels also increased relative to those in the controls. In addition, the cell proliferation index, which is estimated from 5-bromo-2'-deoxyuridine immunoexpression in spermatogonia, increased significantly under eCG treatment, and even more with eCG + ACT. However, the numbers of germ and Leydig cells decreased at 12 wk of age. Thus, ACT and eCG help the testes to recover from the dysfunction induced by neonatal DES administration. Furthermore, the permanent male reproductive disorder induced by neonatal exposure to estrogenic agents may be more likely to result from dysfunction of the hypothalamic-pituitary axis than from dysfunction of the lower reproductive organs.

  12. Modulation of Th1/Th2 immune responses by killed Propionibacterium acnes and its soluble polysaccharide fraction in a type I hypersensitivity murine model: induction of different activation status of antigen-presenting cells.

    PubMed

    Squaiella-Baptistão, Carla Cristina; Teixeira, Daniela; Mussalem, Juliana Sekeres; Ishimura, Mayari Eika; Longo-Maugéri, Ieda Maria

    2015-01-01

    Propionibacterium acnes (P. acnes) is a gram-positive anaerobic bacillus present in normal human skin microbiota, which exerts important immunomodulatory effects, when used as heat- or phenol-killed suspensions. We previously demonstrated that heat-killed P. acnes or its soluble polysaccharide (PS), extracted from the bacterium cell wall, suppressed or potentiated the Th2 response to ovalbumin (OVA) in an immediate hypersensitivity model, depending on the treatment protocol. Herein, we investigated the mechanisms responsible for these effects, using the same model and focusing on the activation status of antigen-presenting cells (APCs). We verified that higher numbers of APCs expressing costimulatory molecules and higher expression levels of these molecules are probably related to potentiation of the Th2 response to OVA induced by P. acnes or PS, while higher expression of toll-like receptors (TLRs) seems to be related to Th2 suppression. In vitro cytokines production in cocultures of dendritic cells and T lymphocytes indicated that P. acnes and PS seem to perform their effects by acting directly on APCs. Our data suggest that P. acnes and PS directly act on APCs, modulating the expression of costimulatory molecules and TLRs, and these differently activated APCs drive distinct T helper patterns to OVA in our model. PMID:25973430

  13. Modulation of Th1/Th2 Immune Responses by Killed Propionibacterium acnes and Its Soluble Polysaccharide Fraction in a Type I Hypersensitivity Murine Model: Induction of Different Activation Status of Antigen-Presenting Cells

    PubMed Central

    Mussalem, Juliana Sekeres; Ishimura, Mayari Eika; Longo-Maugéri, Ieda Maria

    2015-01-01

    Propionibacterium acnes (P. acnes) is a gram-positive anaerobic bacillus present in normal human skin microbiota, which exerts important immunomodulatory effects, when used as heat- or phenol-killed suspensions. We previously demonstrated that heat-killed P. acnes or its soluble polysaccharide (PS), extracted from the bacterium cell wall, suppressed or potentiated the Th2 response to ovalbumin (OVA) in an immediate hypersensitivity model, depending on the treatment protocol. Herein, we investigated the mechanisms responsible for these effects, using the same model and focusing on the activation status of antigen-presenting cells (APCs). We verified that higher numbers of APCs expressing costimulatory molecules and higher expression levels of these molecules are probably related to potentiation of the Th2 response to OVA induced by P. acnes or PS, while higher expression of toll-like receptors (TLRs) seems to be related to Th2 suppression. In vitro cytokines production in cocultures of dendritic cells and T lymphocytes indicated that P. acnes and PS seem to perform their effects by acting directly on APCs. Our data suggest that P. acnes and PS directly act on APCs, modulating the expression of costimulatory molecules and TLRs, and these differently activated APCs drive distinct T helper patterns to OVA in our model. PMID:25973430

  14. Solubility of Nd in brine

    SciTech Connect

    Khalili, F.; Symeopoulos, V.; Chen, J.F.; Choppin, G.R.

    1993-12-31

    The solubility of Nd(III) has been measured in a synthetic brine at pcH 6.4, 8.4, 10.4 and 12.4. The brine consisted predominantly of (Na+K)Cl and MgCl{sub 2}, with an ionic strength of 7.8M (9.4m). The experimental solubility is much less than that estimated from modeling of the species in solution in equilibrium with the Nd solid using S.I.T. The predominant solid compound of Nd (III) at each pcH was determined from X-ray diffraction patterns.

  15. Preliminary considerations concerning actinide solubilities

    SciTech Connect

    Newton, T.W.; Bayhurst, B.P.; Daniels, W.R.; Erdal, B.R.; Ogard, A.E.

    1980-01-01

    Work at the Los Alamos Scientific Laboratory on the fundamental solution chemistry of the actinides has thus far been confined to preliminary considerations of the problems involved in developing an understanding of the precipitation and dissolution behavior of actinide compounds under environmental conditions. Attempts have been made to calculate solubility as a function of Eh and pH using the appropriate thermodynamic data; results have been presented in terms of contour maps showing lines of constant solubility as a function of Eh and pH. Possible methods of control of the redox potential of rock-groundwater systems by the use of Eh buffers (redox couples) is presented.

  16. Formulation of soluble oils with synthetic and petroleum sulfonates

    SciTech Connect

    Eckard, A.; Riff, I.; Weaver, J.

    1997-06-01

    Metalworking fluids for metal removal are formulated to provide cooling, lubrication, and rust protection when cutting and machining metals. There are basically four types of cutting fluids: straight oils, synthetics, semisynthetic fluids and soluble oils. The last type is the most widely used for metal removal operations such as cutting, drilling and grinding. Soluble oils used for metalworking operations are normally the oil-in-water type, with oil as the internal phase and water as the external phase. The soluble oils can have rather complex compositions, usually containing two or more emulsifiers and coupling agents, as well as additives to provide rust inhibition, lubricity, detergency, resistance to bacterial attack and foam control. The dominant emulsifier in a soluble oil is usually sodium sulfonate which also has the secondary benefit of being a rust inhibitor. Soluble oil emulsions based on petroleum or synthetic sulfonates have been found to improve lubrication and cleaning of metal parts and equipment. As has been done previously, a series of emulsification studies were conducted using petroleum and synthetic sulfonates. Emulsifier level, coemulsifiers and minor formulation adjustments were made to optimize each system. This study was made using naphthenic oil basestock. Formulations were evaluated using criteria including concentrate stability, hard and soft water emulsion stability, emulsibility, foaming tendency and response to defoamers, antirust properties and cost effectiveness of individual formulations. The results of these evaluations are presented in the present paper.

  17. Dissolution and precipitation of fractures in soluble rock

    NASA Astrophysics Data System (ADS)

    Kaufmann, Georg; Gabrovšek, Franci; Romanov, Douchko

    2016-04-01

    Soluble rocks such as limestone, anhydrite, and gypsum are characterised by their large secondary permeability, which results from the interaction of water circulating through the rock and dissolving the soluble fracture walls. This highly selective dissolution process enlarges the fractures to voids and eventually cavities, which then carry the majority of flow through an aquifer along preferential flow pathes. We employ a numerical model describing the evolution of secondary porosity in a soluble rock to discuss the evolution of single fractures in different rock types. Our main focus is three-fold: The distinction of shallow versus deep flow pathes and their evolution on the one hand; the effect of precipitation of the dissolved material in the fracture, and finally the complication of fracture enlargement in fractures composed of several different soluble materials. We observe a similar evolution of void space for fractures composed of limestone and gypsum, but on different time scales. For anhydrite, owing to its difference in the kinetical rate law describing the removal of soluble rock, when compared to limestone and anhydrite, the evolution is even faster. Precipitation of the dissolved rock due to changes in the hydrochemical conditions can clog fractures fairly fast, thus changing the pattern of preferential pathways in the soluble aquifer, especially with depth. Finally, limestone fractures coated with gypsum, as frequently observed in caves, will result in a substantial acceleration of fracture enlargement with time, thus giving these fractures a hydraulical advantage over pure limestone fractures in their competition for capturing flow.

  18. Strategies to address low drug solubility in discovery and development.

    PubMed

    Williams, Hywel D; Trevaskis, Natalie L; Charman, Susan A; Shanker, Ravi M; Charman, William N; Pouton, Colin W; Porter, Christopher J H

    2013-01-01

    Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

  19. Solubility limits on radionuclide dissolution

    SciTech Connect

    Kerrisk, J.F.

    1984-12-31

    This paper examines the effects of solubility in limiting dissolution rates of a number of important radionuclides from spent fuel and high-level waste. Two simple dissolution models were used for calculations that would be characteristics of a Yucca Mountain repository. A saturation-limited dissolution model, in which the water flowing through the repository is assumed to be saturated with each waste element, is very conservative in that it overestimates dissolution rates. A diffusion-limited dissolution model, in which element-dissolution rates are limited by diffusion of waste elements into water flowing past the waste, is more realistic, but it is subject to some uncertainty at this time. Dissolution rates of some elements (Pu, Am, Sn, Th, Zr, Sm) are always limited by solubility. Dissolution rates of other elements (Cs, Tc, Np, Sr, C, I) are never solubility limited; their release would be limited by dissolution of the bulk waste form. Still other elements (U, Cm, Ni, Ra) show solubility-limited dissolution under some conditions. 9 references, 3 tables.

  20. Nanoemulsion: a promising tool for solubility and dissolution enhancement of celecoxib.

    PubMed

    Shakeel, Faiyaz; Faisal, Mohammed S

    2010-01-01

    The solubility and dissolution of the poorly soluble drug celecoxib (CXB) was enhanced using many techniques like nanoemulsion, solid lipid nanoparticle and solid dispersion in the present investigation. The solubility of CXB in each formulation was determined using the reported HPLC method at the wavelength of 250 nm. Dissolution studies of pure CXB and its formulations were performed using USP dissolution apparatus in distilled water. The highest solubility (228. 24 mg/mL) as well as % dissolution (99.9) of CXB was obtained with nanoemulsion technique. The results of solubility and dissolution were highly significant using the nanoemulsion technique as compared to other techniques (P < 0.01). All three formulations showed a sustained type of drug release. The best sustained type drug release was obtained with nanoemulsion. This indicated that nanoemulsion can be successfully used for sustained and controlled drug delivery of CXB. Overall these findings suggested that nanoemulsion is a promising vehicle for solubility and dissolution enhancement of CXB.

  1. Solubility enhancement studies on lurasidone hydrochloride using mixed hydrotropy

    PubMed Central

    Madan, Jyotsana R.; Pawar, Kiran T.; Dua, Kamal

    2015-01-01

    Low aqueous solubility is a major problem faced during formulation development of new drug molecules. Lurasidone HCl (LRD) is an antipsychotic agent specially used in the treatments of schizophrenia and is a good example of the problems associated with low aqueous solubility. Lurasidone is practically insoluble in water, has poor bioavailability and slow onset of action and therefore cannot be given in emergency clinical situations like schizophrenia. Hence, purpose of this research was to provide a fast dissolving oral dosage form of Lurasidone. This dosage form can provide quick onset of action by using the concept of mixed hydrotropy. Initially, solubility of LRD was determined individually in nicotinamide, sodium citrate, urea and sodium benzoate at concentration of 10, 20, 30 and 40% w/v solutions using purified water as a solvent. Highest solubility was obtained in 40% sodium benzoate solution. In order to decrease the individual hydrotrope concentration mixed hydrotropic agents were used. Highest solubility was obtained in 15:20:5 ratio of Nicotinamide + sodium benzoate + sodium citrate. This optimized combination was utilized in the preparation of solid dispersions by using distilled water as a solvent. Solid dispersions were evaluated for X-ray diffraction, differential scanning calorimetry and Fourier-transform infrared to show no drug-hydrotropes interaction has occurred. This solid dispersion was compressed to form fast dissolving tablets. Dissolution studies of prepared tablets were done using USP Type II apparatus. The batch L3 tablets show 88% cumulative drug release within 14 min and in vitro dispersion time was 32 min. It was concluded that the concept of mixed hydrotropic solid dispersion is novel, safe and cost-effective technique for enhancing the bioavailability of poorly water-soluble drugs. The miraculous enhancement in solubility and bioavailability of Lurasidone is clear indication of the potential of mixed hydrotropy to be used in future

  2. The Expression of Human Cytomegalovirus MicroRNA MiR-UL148D during Latent Infection in Primary Myeloid Cells Inhibits Activin A-triggered Secretion of IL-6.

    PubMed

    Lau, Betty; Poole, Emma; Krishna, Benjamin; Sellart, Immaculada; Wills, Mark R; Murphy, Eain; Sinclair, John

    2016-08-05

    The successful establishment and maintenance of human cytomegalovirus (HCMV) latency is dependent on the expression of a subset of viral genes. Whilst the exact spectrum and functions of these genes are far from clear, inroads have been made for protein-coding genes. In contrast, little is known about the expression of non-coding RNAs. Here we show that HCMV encoded miRNAs are expressed de novo during latent infection of primary myeloid cells. Furthermore, we demonstrate that miR-UL148D, one of the most highly expressed viral miRNAs during latent infection, directly targets the cellular receptor ACVR1B of the activin signalling axis. Consistent with this, we observed upregulation of ACVR1B expression during latent infection with a miR-UL148D deletion virus (ΔmiR-UL148D). Importantly, we observed that monocytes latently infected with ΔmiR-UL148D are more responsive to activin A stimulation, as demonstrated by their increased secretion of IL-6. Collectively, our data indicates miR-UL148D inhibits ACVR1B expression in latently infected cells to limit proinflammatory cytokine secretion, perhaps as an immune evasion strategy or to postpone cytokine-induced reactivation until conditions are more favourable. This is the first demonstration of an HCMV miRNA function during latency in primary myeloid cells, implicating that small RNA species may contribute significantly to latent infection.

  3. The Expression of Human Cytomegalovirus MicroRNA MiR-UL148D during Latent Infection in Primary Myeloid Cells Inhibits Activin A-triggered Secretion of IL-6

    PubMed Central

    Lau, Betty; Poole, Emma; Krishna, Benjamin; Sellart, Immaculada; Wills, Mark R.; Murphy, Eain; Sinclair, John

    2016-01-01

    The successful establishment and maintenance of human cytomegalovirus (HCMV) latency is dependent on the expression of a subset of viral genes. Whilst the exact spectrum and functions of these genes are far from clear, inroads have been made for protein-coding genes. In contrast, little is known about the expression of non-coding RNAs. Here we show that HCMV encoded miRNAs are expressed de novo during latent infection of primary myeloid cells. Furthermore, we demonstrate that miR-UL148D, one of the most highly expressed viral miRNAs during latent infection, directly targets the cellular receptor ACVR1B of the activin signalling axis. Consistent with this, we observed upregulation of ACVR1B expression during latent infection with a miR-UL148D deletion virus (ΔmiR-UL148D). Importantly, we observed that monocytes latently infected with ΔmiR-UL148D are more responsive to activin A stimulation, as demonstrated by their increased secretion of IL-6. Collectively, our data indicates miR-UL148D inhibits ACVR1B expression in latently infected cells to limit proinflammatory cytokine secretion, perhaps as an immune evasion strategy or to postpone cytokine-induced reactivation until conditions are more favourable. This is the first demonstration of an HCMV miRNA function during latency in primary myeloid cells, implicating that small RNA species may contribute significantly to latent infection. PMID:27491954

  4. The Expression of Human Cytomegalovirus MicroRNA MiR-UL148D during Latent Infection in Primary Myeloid Cells Inhibits Activin A-triggered Secretion of IL-6.

    PubMed

    Lau, Betty; Poole, Emma; Krishna, Benjamin; Sellart, Immaculada; Wills, Mark R; Murphy, Eain; Sinclair, John

    2016-01-01

    The successful establishment and maintenance of human cytomegalovirus (HCMV) latency is dependent on the expression of a subset of viral genes. Whilst the exact spectrum and functions of these genes are far from clear, inroads have been made for protein-coding genes. In contrast, little is known about the expression of non-coding RNAs. Here we show that HCMV encoded miRNAs are expressed de novo during latent infection of primary myeloid cells. Furthermore, we demonstrate that miR-UL148D, one of the most highly expressed viral miRNAs during latent infection, directly targets the cellular receptor ACVR1B of the activin signalling axis. Consistent with this, we observed upregulation of ACVR1B expression during latent infection with a miR-UL148D deletion virus (ΔmiR-UL148D). Importantly, we observed that monocytes latently infected with ΔmiR-UL148D are more responsive to activin A stimulation, as demonstrated by their increased secretion of IL-6. Collectively, our data indicates miR-UL148D inhibits ACVR1B expression in latently infected cells to limit proinflammatory cytokine secretion, perhaps as an immune evasion strategy or to postpone cytokine-induced reactivation until conditions are more favourable. This is the first demonstration of an HCMV miRNA function during latency in primary myeloid cells, implicating that small RNA species may contribute significantly to latent infection. PMID:27491954

  5. New ideas about the solubility of drugs.

    PubMed

    Box, Karl; Comer, John E; Gravestock, Tom; Stuart, Martin

    2009-11-01

    Methods are described for detecting precipitation of ionisable drugs under conditions of changing pH, estimating kinetic solubility from the onset of precipitation, and measuring solubility by chasing equilibrium. Definitions are presented for kinetic, equilibrium, and intrinsic solubility of ionisable drugs, supersaturation and subsaturation, and for chasers and non-chasers, which are two classes of ionisable drug with significantly different solubility properties. The use of Bjerrum Curves and Neutral-Species Concentration Profiles to depict solubility properties are described and illustrated with case studies showing super-dissolving behaviour, conversion between crystalline forms and enhancement of solubility through supersaturation, and the use of additives and simulated gastrointestinal fluids. PMID:19937815

  6. Phase II Evaluation of Dalantercept, a Soluble Recombinant Activin Receptor-Like Kinase 1 (ALK1) Receptor Fusion Protein, for the Treatment of Recurrent or Persistent Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study 0229N

    PubMed Central

    Makker, Vicky; Filiaci, Virginia L.; Chen, Lee-may; Darus, Christopher J.; Kendrick, James E.; Sutton, Gregory; Moxley, Katherine; Aghajanian, Carol

    2015-01-01

    Objective This two-stage phase II study assessed activity of single agent dalantercept in patients with recurrent/persistent endometrial carcinoma (EMC). Methods Eligible patients had persistent/recurrent EMC after 1–2 prior cytotoxic regimens, measurable disease (RECIST 1.1), and GOG performance ≤ 2. Dalantercept 1.2 mg/kg subcutaneous was administered once every 3 weeks until disease progression (PD)/development of prohibitory toxicity. Primary objectives were to estimate the proportion of patients with persistent/recurrent EMC, who survive progression-free without receiving non-protocol therapy (TPFS) for at least 6 months and to estimate the proportion having objective tumor response. Results All 28 enrolled patients were eligible and evaluable. Median age: 62 years. Most common histologies: 32% Grade 1/2 endometrioid and 54% serous tumors. Prior treatment: 1 or 2 regimens in 82% and 18% of patients, respectively. Eighteen patients received prior radiation therapy. Patients received 1–12 cycles of dalantercept, and 46% of patients received ≤2 cycles. The most common adverse events (AE) were fatigue, anemia, constipation and peripheral edema. Grade 3/4 AEs occurred in 39% and 4% of patients. One grade 5 gastric hemorrhage in a patient with a history of radiation fibrosis/small bowel obstruction was deemed possibly dalantercept-related. All patients are off study: 86% for PD. No ORs were observed; 57% had stable disease and 11% had TPFS ≥ 6 mos. Median progression-free and overall survival: 2.1 months (90% CI: 1.4–3.2) and 14.5 months (90% CI: 7.0–17.5), respectively. Conclusions Dalantercept has insufficient single agent activity in recurrent EMC to warrant further investigation at this dose level and schedule. PMID:25888978

  7. Overexpression of Soluble Recombinant Human Lysyl Oxidase by Using Solubility Tags: Effects on Activity and Solubility.

    PubMed

    Smith, Madison A; Gonzalez, Jesica; Hussain, Anjum; Oldfield, Rachel N; Johnston, Kathryn A; Lopez, Karlo M

    2016-01-01

    Lysyl oxidase is an important extracellular matrix enzyme that has not been fully characterized due to its low solubility. In order to circumvent the low solubility of this enzyme, three solubility tags (Nus-A, Thioredoxin (Trx), and Glutathione-S-Transferase (GST)) were engineered on the N-terminus of mature lysyl oxidase. Total enzyme yields were determined to be 1.5 mg for the Nus-A tagged enzyme (0.75 mg/L of media), 7.84 mg for the Trx tagged enzyme (3.92 mg/L of media), and 9.33 mg for the GST tagged enzyme (4.67 mg/L of media). Enzymatic activity was calculated to be 0.11 U/mg for the Nus-A tagged enzyme and 0.032 U/mg for the Trx tagged enzyme, and no enzymatic activity was detected for the GST tagged enzyme. All three solubility-tagged forms of the enzyme incorporated copper; however, the GST tagged enzyme appears to bind adventitious copper with greater affinity than the other two forms. The catalytic cofactor, lysyl tyrosyl quinone (LTQ), was determined to be 92% for the Nus-A and Trx tagged lysyl oxidase using the previously reported extinction coefficient of 15.4 mM(-1 )cm(-1). No LTQ was detected for the GST tagged lysyl oxidase. Given these data, it appears that Nus-A is the most suitable tag for obtaining soluble and active recombinant lysyl oxidase from E. coli culture. PMID:26942005

  8. Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling

    PubMed Central

    Hay, David C.; Fletcher, Judy; Payne, Catherine; Terrace, John D.; Gallagher, Ronald C. J.; Snoeys, Jan; Black, James R.; Wojtacha, Davina; Samuel, Kay; Hannoun, Zara; Pryde, Anne; Filippi, Celine; Currie, Ian S.; Forbes, Stuart J.; Ross, James A.; Newsome, Philip N.; Iredale, John P.

    2008-01-01

    Human embryonic stem cells (hESCs) are a valuable source of pluripotential primary cells. To date, however, their homogeneous cellular differentiation to specific cell types in vitro has proven difficult. Wnt signaling has been shown to play important roles in coordinating development, and we demonstrate that Wnt3a is differentially expressed at critical stages of human liver development in vivo. The essential role of Wnt3a in hepatocyte differentiation from hESCs is paralleled by our in vitro model, demonstrating the importance of a physiologic approach to cellular differentiation. Our studies provide compelling evidence that Wnt3a signaling is important for coordinated hepatocellular function in vitro and in vivo. In addition, we demonstrate that Wnt3a facilitates clonal plating of hESCs exhibiting functional hepatic differentiation. These studies represent an important step toward the use of hESC-derived hepatocytes in high-throughput metabolic analysis of human liver function. PMID:18719101

  9. 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.

  10. Matrigel and Activin A promote cell-cell contact and anti-apoptotic activity in cultured human retinal pigment epithelium cells.

    PubMed

    Guo, Xiaoling; Zhu, Deliang; Lian, Ruiling; Han, Yuting; Guo, Yonglong; Li, Zhijie; Tang, Shibo; Chen, Jiansu

    2016-06-01

    Age-related macular degeneration (AMD) is a leading cause of blindness among the aging population. Currently, replacement of diseased retinal pigment epithelium (RPE) cells with transplanted healthy RPE cells could be a feasible approach for AMD therapy. However, maintaining cell-cell contact and good viability of RPE cells cultured in vitro is difficult and fundamentally determines the success of RPE cell transplantation. This study was conducted to examine the role of Matrigel and Activin A (MA) in regulating cell-cell contact and anti-apoptotic activity in human RPE (hRPE) cells, as assessed by atomic force microscopy (AFM), scanning electron microscope (SEM), immunofluorescence staining, quantitative polymerase chain reaction (qPCR) analysis, Annexin V/propidium iodide (PI) analysis, mitochondrial membrane potential (△Ψ m) assays, intracellular reactive oxygen species (ROS) assays and Western blotting. hRPE cells cultured in vitro could maintain their epithelioid morphology after MA treatment over at least 4 passages. The contact of N-cadherin to the lateral cell border was promoted in hRPE cells at P2 by MA. MA treatment also enhanced the expression of tight junction-associated genes and proteins, such as Claudin-1, Claudin-3, Occludin and ZO-1, as well as polarized ZO-1 protein distribution and barrier function, in cultured hRPE cells. Moreover, MA treatment decreased apoptotic cells, ROS and Bax and increased △Ψ m and Bcl2 in hRPE cells under serum withdrawal-induced apoptosis. In addition, MA treatment elevated the protein expression levels of β-catenin and its target proteins, including Cyclin D1, c-Myc and Survivin, as well as the gene expression levels of ZO-1, β-catenin, Survivin and TCF-4, all of which could be down-regulated by the Wnt/β-catenin pathway inhibitor XAV-939. Taken together, MA treatment could effectively promote cell-cell contact and anti-apoptotic activity in hRPE cells, partly involving the Wnt/β-catenin pathway. This study

  11. Preparation of soluble and insoluble polymer supported IBX reagents.

    PubMed

    Reed, Neal N; Delgado, Mercedes; Hereford, Kristina; Clapham, Bruce; Janda, Kim D

    2002-08-01

    A series of soluble and insoluble polymer supported versions of the versatile oxidizing reagent IBX has been prepared. Each of the reagents were evaluated for their efficiency in the conversion of benzyl alcohol to benzaldehyde. Results from this study were that the soluble, non-crosslinked polystyrene supported IBX reagent gave the best rate of conversion to benzaldehyde, while the macroporous polymer supported IBX resin provided a superior rate of conversion to benzaldehyde when compared with a gel type resin. The macroporous IBX reagent was also shown to convert a series of alcohols to the corresponding aldehydes and ketones.

  12. Characterization of Soluble Organics in Produced Water

    SciTech Connect

    Bostick, D.T.

    2002-01-16

    Soluble organics in produced water and refinery effluents represent treatment problems for the petroleum industry. Neither the chemistry involved in the production of soluble organics nor the impact of these chemicals on total effluent toxicity is well understood. The U.S. Department of Energy provides funding for Oak Ridge National Laboratory (ORNL) to support a collaborative project with Shell, Chevron, Phillips, and Statoil entitled ''Petroleum and Environmental Research Forum project (PERF 9844: Manage Water-Soluble Organics in Produced Water''). The goal of this project, which involves characterization and evaluation of these water-soluble compounds, is aimed at reducing the future production of such contaminants. To determine the effect that various drilling conditions might have on water-soluble organics (WSO) content in produced water, a simulated brine water containing the principal inorganic components normally found in Gulf of Mexico (GOM) brine sources was prepared. The GOM simulant was then contacted with as-received crude oil from a deep well site to study the effects of water cut, produced-water pH, salinity, pressure, temperature, and crude oil sources on the type and content of the WSO in produced water. The identities of individual semivolatile organic compounds (SVOCs) were determined in all as-received crude and actual produced water samples using standard USEPA Method (8270C) protocol. These analyses were supplemented with the more general measurements of total petroleum hydrocarbon (TPH) content in the gas (C{sub 6}-C{sub 10}), diesel (C{sub 10}-C{sub 20}), and oil (C{sub 20}-C{sub 28}) carbon ranges as determined by both gas chromatographic (GC) and infrared (IR) analyses. An open liquid chromatographic procedure was also used to differentiate the saturated hydrocarbon, aromatic hydrocarbon, and polar components within the extractable TPH. Inorganic constituents in the produced water were analyzed by ion-selective electrodes and inductively

  13. [Soluble of Metals within TSP in Shanghai].

    PubMed

    Chang, Yan; Feng, Chong; Qu, Jian-guo; Zhang, Jing

    2015-04-01

    The dissolution of metals within aerosol particles is meaningful to evaluate the bioavailability and mobility of metals. Total suspended particles (TSP) samples were collected in Shanghai. We extracted the water soluble and acid soluble (pH = 2) metals by the mini-recirculation-leach-system and measured their concentrations by the high resolution inductively coupled plasma mass spectrometry. The dissolution kinetics were rapid, the maximum solubility of metals could be reached in a few minutes. Overall, the average water-soluble concentrations were low for Co, Cr, Cd, V and Ni, median for Cu, Pb and Mn and high for Fe, Al, Zn and Mg. Combine the soluble metal concentrations with the back trajectory, the original air mass had significant impacts on water soluble metal concentrations. The water solubility and acid solubility were different for various metals, the water solubility of Fe was the lowest (2.0%), others followed an order: Al, Cr, V, Pb, Co, Ni, Cu, Cd, Mn, Mg, Zn. The metals' solubility was increased with the decrease of the solvent pH value. While the chemical speciation of metals was the internal cause of metals' solubility, the metals' ionic potential and the water solubility was negatively correlated.

  14. Bridging solubility between drug discovery and development.

    PubMed

    Di, Li; Fish, Paul V; Mano, Takashi

    2012-05-01

    Solubility has a crucial role in the success of a drug candidate. Compounds with low solubility not only cause problems for in vitro and in vivo assays, but also add significant burdens to drug development. Drug discovery and drug development often have different solubility screening requirements and methodologies have been developed to meet the needs of these different stages.

  15. Diameter-dependent solubility of single-walled carbon nanotubes.

    PubMed

    Duque, Juan G; Parra-Vasquez, A Nicholas G; Behabtu, Natnael; Green, Micah J; Higginbotham, Amanda L; Price, B Katherine; Leonard, Ashley D; Schmidt, Howard K; Lounis, Brahim; Tour, James M; Doorn, Stephen K; Cognet, Laurent; Pasquali, Matteo

    2010-06-22

    We study the solubility and dispersibility of as-produced and purified HiPco single-walled carbon nanotubes (SWNTs). Variation in specific operating conditions of the HiPco process are found to lead to significant differences in the respective SWNT solubilities in oleum and surfactant suspensions. The diameter distributions of SWNTs dispersed in surfactant solutions are batch-dependent, as evidenced by luminescence and Raman spectroscopies, but are identical for metallic and semiconducting SWNTs within a batch. We thus find that small diameter SWNTs disperse at higher concentration in aqueous surfactants and dissolve at higher concentration in oleum than do large-diameter SWNTs. These results highlight the importance of controlling SWNT synthesis methods in order to optimize processes dependent on solubility, including macroscopic processing such as fiber spinning, material reinforcement, and films production, as well as for fundamental research in type selective chemistry, optoelectronics, and nanophotonics. PMID:20521799

  16. 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.

  17. Fosinopril-cyclodextrin inclusion complexes: phase solubility and physicochemical analysis.

    PubMed

    Sbârcea, L; Udrescu, L; Drăgan, L; Trandafirescu, C; Szabadai, Z; Bojiţă, M

    2011-08-01

    Fosinopril is one of the most hydrophobic substances among the angiotensin-converting enzyme inhibitors, exhibiting low water solubility and poor bioavailability following oral administration. Inclusion complexes between the drug substance and cyclodextrins (CDs) were obtained in order to improve its solubility. The purpose of this study was to investigate the guest-host interaction of fosinopril sodium (FOS) with beta-cyclodextrin (beta-CD) and its derivative, randomly methylated beta-cyclodextrin (RAMEB) in solution by phase solubility diagrams (PSD) and in solid state by using thermal analysis, powder X-ray diffractometry (PXRD) and Fourier transform infrared spectroscopy (FTIR). The phase solubility analysis indicated that the solubility of FOS in simulated gastric fluid was increased in the presence of CDs and revealed for RAMEB an A(L)-type diagram, suggesting the formation of a 1:1 inclusion complex, and for beta-CD a B(s)-type phase diagram. The estimated apparent stability constant (K1:1), according to the Higuchi and Connors method, is 3209.99 M(-1) and 1770.34 M(-1) for RAMEB and beta-CD complexes respectively. The binary systems FOS/CDs were prepared using the kneading method in the molar ratio 1:1. The PXRD patterns and the thermograms indicated a drug amorphization process, higher for FOS/RAMEB binary system and the FTIR analysis suggested that the ester group of FOS is probably enclosed in the CD's cavity. The results of this study confirm the formation of inclusion complexes both in solution and in solid state and suggest that the complexes formation between FOS and CDs could improve the bioavailability of the drug due to the enhancing absorption expected from increased drug solubility.

  18. Marangoni Flow of Soluble Amphiphiles

    NASA Astrophysics Data System (ADS)

    Roché, Matthieu; Li, Zhenzhen; Griffiths, Ian M.; Le Roux, Sébastien; Cantat, Isabelle; Saint-Jalmes, Arnaud; Stone, Howard A.

    2014-05-01

    Surfactant distribution heterogeneities at a fluid-fluid interface trigger the Marangoni effect, i.e., a bulk flow due to a surface tension gradient. The influence of surfactant solubility in the bulk on these flows remains incompletely characterized. Here we study Marangoni flows sustained by injection of hydrosoluble surfactants at the air-water interface. We show that these flows have a finite size that increases with a decrease of the critical micelle concentration of the surfactants. We document the universality of the surface velocity field of these finite flows and predict scaling laws based on hydrodynamics and surfactant physical chemistry that capture the flow features.

  19. Beneficial effects of soluble dietary Jerusalem artichoke (Helianthus tuberosus) in the prevention of the onset of type 2 diabetes and non-alcoholic fatty liver disease in high-fructose diet-fed rats.

    PubMed

    Chang, Wan-Ching; Jia, Huijuan; Aw, Wanping; Saito, Kenji; Hasegawa, Sumio; Kato, Hisanori

    2014-09-14

    Jerusalem artichoke (JA) has the potential to attenuate lipid disturbances and insulin resistance (IR), but the underlying mechanisms are not well understood. In the present study, we elucidated the physiological responses and mechanisms of JA intervention with a comprehensive transcriptome analysis. Wistar rats were fed a control diet, a 60 % fructose-enriched diet (FRU), or a FRU with 10 % JA (n 6-7) for 4 weeks. An oral glucose tolerance test was carried out on day 21. Liver samples were collected for biochemical and global gene expression analyses (GeneChip® Rat Genome 230 2.0 Array, Affymetrix). Fructose feeding resulted in IR and hepatic TAG accumulation; dietary JA supplementation significantly improved these changes. Transcriptomic profiling revealed that the expression of malic enzyme 1 (Me1), associated with fatty acid synthesis; decorin (Dcn), related to fibrosis; and cytochrome P450, family 1, subfamily a, polypeptide 2 (Cyp1a2) and nicotinamide phosphoribosyltransferase (Nampt), associated with inflammation, was differentially altered by the FRU, whereas dietary JA supplementation significantly improved the expression of these genes. We established for the first time the molecular mechanisms driving the beneficial effects of JA in the prevention of type 2 diabetes and non-alcoholic fatty liver disease. We propose that 10 % JA supplementation may be beneficial for the prevention of the onset of these diseases.

  20. Genotoxicity of poorly soluble particles.

    PubMed

    Schins, Roel P F; Knaapen, Ad M

    2007-01-01

    Poorly soluble particles such as TiO2, carbon black, and diesel exhaust particles have been evaluated for their genotoxicity using both in vitro and in vivo assays, since inhalation of these compounds by rats at high concentrations has been found to lead to tumor formation. Two principle modes of genotoxic action can be considered for particles, referred to as primary and secondary genotoxicity. Primary genotoxicity is defined as genetic damage elicited by particles in the absence of pulmonary inflammation, whereas secondary genotoxicity implies a pathway of genetic damage resulting from the oxidative DNA attack by reactive oxygen/nitrogen species (ROS/RNS), generated during particle-elicited inflammation. Conceptually, primary genotoxicity might operate via various mechanisms, such as the actions of ROS (e.g., as generated from reactive particle surfaces), or DNA-adduct formation by reactive metabolites of particle-associated organic compounds (e.g., polycyclic aromatic hydrocarbons). Currently available literature data, however, merely indicate that the tumorigenesis of poorly soluble particles involves a mechanism of secondary genotoxicity. However, further research is urgently required, since (1) causality between pulmonary inflammation and genotoxicity has not yet been established, and (2) effects of inflammation on fundamental DNA damage responses that orchestrate mutagenesis and carcinogenic outcome,that is, cell cycle arrest, DNA repair, proliferation, and apoptosis, are currently poorly understood. PMID:17886067

  1. Soluble fiber dextrin enhances the satiating power of beverages.

    PubMed

    Monsivais, Pablo; Carter, Brett E; Christiansen, Matthew; Perrigue, Martine M; Drewnowski, Adam

    2011-02-01

    This study compared the effects of four types of fiber on satiety and energy intakes at the next meal using a standard double-blinded preload study design. Study participants (14 men and 22 women) each took part in 6 study sessions. Study preloads were a combination of a solid snack and a liquid beverage (energy range 0.78-0.83 MJ) containing four different types of fiber: soluble fiber dextrin (12 g), soluble corn fiber (11.8 g), polydextrose (11.8 g), and resistant starch (11.2g). All four fibers were compared to two control conditions of equal volume: an isoenergetic, low-fiber preload and a lower-energy, low-fiber preload. All preloads were presented twice for a total of 0.35-1.65 MJ and 1-24 g fiber. Satiety ratings were collected for 20 min intervals for 220 min during the morning testing session. A test meal was served at 1200 h and plate waste measured. The five higher-energy preloads led to higher fullness and lower hunger ratings compared to the low-energy control but were not significantly different from each other. Relative to the isoenergetic control, only soluble fiber dextrin significantly suppressed energy intakes (p=0.023). Supplementing beverages with soluble fiber dextrin affects short term energy intake and may have implications for weight control.

  2. 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. PMID:17597370

  3. Ice nucleation by water-soluble macromolecules

    NASA Astrophysics Data System (ADS)

    Pummer, B. G.; Budke, C.; Augustin-Bauditz, S.; Niedermeier, D.; Felgitsch, L.; Kampf, C. J.; Huber, R. G.; Liedl, K. R.; Loerting, T.; Moschen, T.; Schauperl, M.; Tollinger, M.; Morris, C. E.; Wex, H.; Grothe, H.; Pöschl, U.; Koop, T.; Fröhlich-Nowoisky, J.

    2015-04-01

    Cloud glaciation is critically important for the global radiation budget (albedo) and for initiation of precipitation. But the freezing of pure water droplets requires cooling to temperatures as low as 235 K. Freezing at higher temperatures requires the presence of an ice nucleator, which serves as a template for arranging water molecules in an ice-like manner. It is often assumed that these ice nucleators have to be insoluble particles. We point out that also free macromolecules which are dissolved in water can efficiently induce ice nucleation: the size of such ice nucleating macromolecules (INMs) is in the range of nanometers, corresponding to the size of the critical ice embryo. As the latter is temperature-dependent, we see a correlation between the size of INMs and the ice nucleation temperature as predicted by classical nucleation theory. Different types of INMs have been found in a wide range of biological species and comprise a variety of chemical structures including proteins, saccharides, and lipids. Our investigation of the fungal species Acremonium implicatum, Isaria farinosa, and Mortierella alpina shows that their ice nucleation activity is caused by proteinaceous water-soluble INMs. We combine these new results and literature data on INMs from fungi, bacteria, and pollen with theoretical calculations to develop a chemical interpretation of ice nucleation and water-soluble INMs. This has atmospheric implications since many of these INMs can be released by fragmentation of the carrier cell and subsequently may be distributed independently. Up to now, this process has not been accounted for in atmospheric models.

  4. 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. PMID:27129443

  5. 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

  6. Determination of solubility parameters of ionic liquids and ionic liquid/solvent mixtures from intrinsic viscosity.

    PubMed

    Weerachanchai, Piyarat; Wong, Yuewen; Lim, Kok Hwa; Tan, Timothy Thatt Yang; Lee, Jong-Min

    2014-11-10

    The total and partial solubility parameters (dispersion, polar and hydrogen-bonding solubility parameters) of ten ionic liquids were determined. Intrinsic viscosity approaches were used that encompassed a one-dimensional method (1D-Method), and two different three-dimensional methods (3D-Method1 and 3D-Method2). The effect of solvent type, the dimethylacetamide (DMA) fraction in the ionic liquid, and dissolution temperature on solubility parameters were also investigated. For all types of effect, both the 1D-Method and 3D-Method2 present the same trend in the total solubility parameter. The partial solubility parameters are influenced by the cation and anion of the ionic liquid. Considering the effect on partial solubility parameters of the solvent type in the ionic liquid, it was observed that in both 3D methods, the dispersion and polar parameters of a 1-ethyl-3-methylimidazolium acetate/solvent (60:40 vol %) mixture tend to increase as the total solubility parameter of the solvent increases. PMID:25145759

  7. 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)

  8. Spreadsheet Techniques for Evaluating the Solubility of Sparingly Soluble Salts of Weak Acids

    NASA Astrophysics Data System (ADS)

    Guinón, José L.; García-Antón, José; Pérez-Herranz, Valentín

    1999-08-01

    A spreadsheet of Microsoft Excel for determining the solubility of sparingly soluble salts is described. The chart and worksheet are shown simultaneously on the screen. The worksheet can be used for any salt by merely changing the data for the solubility product constant and ionization constants. Practical examples of calculations are given and discussed.

  9. 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…

  10. 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)

  11. Acid-Soluble Material of Adenovirus

    PubMed Central

    Boulanger, P. A.; Jaume, F.; Flamencourt, P.; Biserte, G.

    1970-01-01

    Two methods are described for adenovirus capsid disruption and extraction of acid-soluble proteins from the viral core. The acid-soluble material of adenovirus consisted of three major proteins, one of them being selectively extracted after mild disruption of the virus particle. Some chemical properties of these proteins are reported. Images PMID:4986288

  12. Water-soluble conductive polymers

    DOEpatents

    Aldissi, Mahmoud

    1989-01-01

    Polymers which are soluble in water and are electrically conductive. The monomer repeat unit is a thiophene or pyrrole molecule having an alkyl group substituted for the hydrogen atom located in the beta position of the thiophene or pyrrole ring and having a surfactant molecule at the end of the alkyl chain. Polymers of this class having 8 or more carbon atoms in the alkyl chain exhibit liquid crystalline behavior, resulting in high electrical anisotropy. The monomer-to-monomer bonds are located between the carbon atoms which are adjacent to the sulfur or nitrogen atoms. The number of carbon atoms in the alkyl group may vary from 1 to 20 carbon atoms. The surfactant molecule consists of a sulfonate group, or a sulfate group, or a carboxylate group, and hydrogen or an alkali metal. Negative ions from a supporting electrolyte which may be used in the electrochemical synthesis of a polymer may be incorporated into the polymer during the synthesis and serve as a dopant to increase the conductivity.

  13. Water-soluble conductive polymers

    DOEpatents

    Aldissi, Mahmoud

    1990-01-01

    Polymers which are soluble in water and are electrically conductive. The monomer repeat unit is a thiophene or pyrrole molecule having an alkyl group substituted for the hydrogen atom located in the beta position of the thiophene or pyrrole ring and having a surfactant molecule at the end of the alkyl chain. Polymers of this class having 8 or more carbon atoms in the alkyl chain exhibit liquid crystalline behavior, resulting in high electrical anisotropy. The monomer-to-monomer bonds are located between the carbon atoms which are adjacent to the sulfur or nitrogen atoms. The number of carbon atoms in the alkyl group may vary from 1 to 20 carbon atoms. The surfactant molecule consists of a sulfonate group, or a sulfate group, or a carboxylate group, and hydrogen or an alkali metal. Negative ions from a supporting electrolyte which may be used in the electrochemical synthesis of a polymer may be incorporated into the polymer during the synthesis and serve as a dopant to increase the conductivity.

  14. Water-soluble conductive polymers

    DOEpatents

    Aldissi, M.

    1988-02-12

    Polymers which are soluble in water and are electrically conductive. The monomer repeat unit is a thiophene or pyrrole molecule having an alkyl group substituted for the hydrogen atom located in the beta position of the thiophene or pyrrole ring and having a surfactant molecule at the end of the alkyl chain. Polymers of this class having 8 or more carbon atoms in the alkyl chain exhibit liquid crystalline behavior, resulting in high electrical anisotropy. The monomer-to-monomer bonds are located between the carbon atoms which are adjacent to the sulfur or nitrogen atoms. The number of carbon atoms in the alkyl group may vary from 1 to 20 carbon atoms. The surfactant molecule consists of a sulfonate group, or a sulfate group, or a carboxylate group, and hydrogen or an alkali metal. Negative ions from a supporting electrolyte which may be used in the electrochemical synthesis of a polymer may be incorporated into the polymer during the synthesis and serve as a dopant to increase the conductivity.

  15. Barium solubility in colquiriite fluorides

    SciTech Connect

    Yaobo Yin; Keszler, D.A. )

    1993-12-01

    Several crystals in the family of Colquiriite fluorides LiAEMF[sub 6] (AE = Ca, Sr; M = Al, Ga, Cr) have been reported to function as efficient, broadly tunable laser materials when doped with the ion Cr[sup 3+]. The optical characteristics of the Cr[sup 3+] ion are considerably affected by the specific AE atom in the crystal. In this paper the systems LiSr[sub 1[minus]x]Ba[sub x]MF[sub 6](M = Al, Ga) have been studied by powder and single-crystal X-ray diffraction methods. Solubility limits of x = 0.06 for the Al compound and x = 0.20 for the Ga compound have been established. The structures of LiSr[sub 0.94(1)]Ba[sub 0.06]AlF[sub 6] and LiSr[sub 0.80(1)]Ba[sub 0.20]GaF[sub 6] corresponding to these limits are isotypic to the mineral Colquiriite. Each crystallizes in space group P[bar 3]1c: LiSr[sub 0.94]Ba[sub 0.06]AlF[sub 6]: a = 5.096(1) [angstrom], c = 10.269(2) [angstrom], R = 0.034, R[sub w] = 0.041; and LiSr[sub 0.80]Ba[sub 0.20]GaF[sub 6]: a = 5.173(1) [angstrom], c = 10.415(1) [angstrom], R = 0.028, R[sub w] = 0.033. The trigonal F planes about the Al and Ga atoms are rotated, one relative to the other, by 68.0 and 69.0[degrees], respectively.

  16. OZONE TREATMENT OF SOLUBLE ORGANICS IN PRODUCED WATER

    SciTech Connect

    Klasson, KT

    2002-03-14

    This project was an extension of previous research to improve the applicability of ozonation and will help address the petroleum-industry problem of treating produced water containing soluble organics. The goal of this project was to maximize oxidation of hexane-extractable organics during a single-pass operation. The project investigated: (1) oxidant production by electrochemical and sonochemical methods, (2) increasing the mass transfer rate in the reactor by forming microbubbles during ozone injection into the produced water, and (3) using ultraviolet irradiation to enhance the reaction if needed. Several types of methodologies for treatment of soluble organics in synthetic and actual produced waters have been performed. The technologies tested may be categorized as follows: (1) Destruction via sonochemical oxidation at different pH, salt concentration, ultraviolet irradiation, and ferrous iron concentrations. (2) Destruction via ozonation at different pH, salt concentration, hydrogen peroxide concentrations, ultraviolet irradiation, temperature, and reactor configurations.

  17. Regulation of the neural niche by the soluble molecule Akhirin.

    PubMed

    Acharjee, Uzzal Kumar; Felemban, Athary Abdulhaleem; Riyadh, Asrafuzzaman M; Ohta, Kunimasa

    2016-06-01

    Though the adult central nervous system has been considered a comparatively static tissue with little turnover, it is well established today that new neural cells are generated throughout life. Neural stem/progenitor cells (NS/PCs) can self-renew and generate all types of neural cells. The proliferation of NS/PCs, and differentiation and fate determination of PCs are regulated by extrinsic factors such as growth factors, neurotrophins, and morphogens. Although several extrinsic factors that influence neurogenesis have already been reported, little is known about the role of soluble molecules in neural niche regulation. In this review, we will introduce the soluble molecule Akhirin and discuss its role in the eye and spinal cord during development.

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

    PubMed

    Hybertson, Brooks M

    2007-01-01

    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 CO(2) 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.

  19. 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

  20. Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility.

    PubMed

    Bollini, Mariela; Cisneros, José A; Spasov, Krasimir A; Anderson, Karen S; Jorgensen, William L

    2013-09-15

    Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.

  1. Oxygen solubility and permeability of carbohydrates.

    PubMed

    Whitcombe, Michael J; Parker, Roger; Ring, Stephen G

    2005-06-13

    The saturated oxygen concentration in a series of aqueous solutions of sorbitol (up to 35% w/w) and maltitol (up to 50% w/w) was measured using colorimetric reagent vials based on Rhodazine D. The results indicate that the solubility of oxygen in low-water carbohydrates is considerably lower than its solubility in pure water. It was concluded that the low-oxygen solubility is a major factor contributing to the barrier properties of low-water content carbohydrates used in the encapsulation of flavours, lipids, peptides and other oxidisable species.

  2. Solubility prediction of satranidazole in propylene glycol-water mixtures using extended hildebrand solubility approach.

    PubMed

    Rathi, P B

    2011-11-01

    Extended Hildebrand solubility approach is used to estimate the solubility of satranidazole in binary solvent systems. The solubility of satranidazole in various propylene glycol-water mixtures was analyzed in terms of solute-solvent interactions using a modified version of Hildebrand-Scatchard treatment for regular solutions. The solubility equation employs term interaction energy (W) to replace the geometric mean (δ(1)δ(2)), where δ(1) and δ(2) are the cohesive energy densities for the solvent and solute, respectively. The new equation provides an accurate prediction of solubility once the interaction energy, W, is obtained. In this case, the energy term is regressed against a polynomial in δ(1) of the binary mixture. A quartic expression of W in terms of solvent solubility parameter was found for predicting the solubility of satranidazole in propylene glycol-water mixtures. The expression yields an error in mole fraction solubility of ~3.74%, a value approximating that of the experimentally determined solubility. The method has potential usefulness in preformulation and formulation studies during which solubility prediction is important for drug design. PMID:23112403

  3. Solubility of drugs in aqueous solutions. Part 5. Thermodynamic consistency test for the solubility data.

    PubMed

    Ruckenstein, E; Shulgin, I

    2005-03-23

    This paper is devoted to the verification of the quality of experimental data regarding the solubility of sparingly soluble solids, such as drugs, environmentally important substances, etc. in mixed solvents. A thermodynamic consistency test based on the Gibbs-Duhem equation for ternary mixtures is suggested. This test has the form of an equation, which connects the solubilities of the solid, and the activity coefficients of the constituents of the solute-free mixed solvent in two mixed solvents of close compositions. The experimental data regarding the solubility of sparingly soluble substances can be verified with the suggested test if accurate data for the activity coefficients of the constituents of the solute-free mixed solvent are available. The test was applied to a number of systems representing the solubilities of sparingly soluble substances in mixed solvents. First, the test was scrutinized for four nonaqueous systems for which accurate solubility data were available. Second, the suggested test was applied to a number of systems representing experimental data regarding the solubility of sparingly soluble substances in aqueous mixed solvents.

  4. Soluble endoglin, hypercholesterolemia and endothelial dysfunction.

    PubMed

    Rathouska, Jana; Jezkova, Katerina; Nemeckova, Ivana; Nachtigal, Petr

    2015-12-01

    A soluble form of endoglin (sEng) is known to be an extracellular domain of the full-length membrane endoglin, which is elevated during various pathological conditions related to vascular endothelium. In the current review, we tried to summarize a possible role of soluble endoglin in cardiovascular pathologies, focusing on its relation to endothelial dysfunction and cholesterol levels. We discussed sEng as a proposed biomarker of cardiovascular disease progression, cardiovascular disease treatment and endothelial dysfunction. We also addressed a potential interaction of sEng with TGF-β/eNOS or BMP-9 signaling. We suggest soluble endoglin levels to be monitored, because they reflect the progression/treatment efficacy of cardiovascular diseases related to endothelial dysfunction and hypercholesterolemia. A possible role of soluble endoglin as an inducer of endothelial dysfunction however remains to be elucidated. PMID:26520890

  5. Soluble high molecular weight polyimide resins

    NASA Technical Reports Server (NTRS)

    Jones, R. J.; Lubowitz, H. R.

    1970-01-01

    High molecular weight polyimide resins have greater than 20 percent /by weight/ solubility in polar organic solvents. They permit fabrication into films, fibers, coatings, reinforced composite, and adhesive product forms. Characterization properties for one typical polyimide resin are given.

  6. An Introduction to the Understanding of Solubility.

    ERIC Educational Resources Information Center

    Letcher, Trevor M.; Battino, Rubin

    2001-01-01

    Explores different solubility processes and related issues, including the second law of thermodynamics and ideal mixtures, real liquids, intermolecular forces, and solids in liquids or gases in liquids. (Contains 22 references.) (ASK)

  7. Predicting the octanol solubility of organic compounds.

    PubMed

    Admire, Brittany; Yalkowsky, Samuel H

    2013-07-01

    The molar octanol solubility of an organic nonelectrolytes can be reasonably predicted solely from its melting point provided that its liquid (or a hypothetical super-cooled liquid) form is miscible with octanol. The aim of this work is to develop criteria to determine if the real or hypothetical liquid form of a given compound will be miscible with octanol based on its molar volume and solubility parameter. Fortunately, most organic compounds (including most drugs) conform to the criteria for complete liquid miscibility, and therefore have solubilities that are proportional to their melting points. The results show that more than 95% of the octanol solubilities studied are predicted with an error of less than 1 logarithmic unit.

  8. 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. PMID:22480785

  9. The Solubility of Phenylborate Compounds in Benzene

    SciTech Connect

    Eibling, R.E.

    1998-04-01

    The original goal of this scoping study was to determine if the solubility of sodium and potassium tetraphenylborates in benzene was sufficiently large to justify designing and performing kinetic studies on a benzene-phase catalytic reaction.

  10. Acid soluble, pepsin resistant platelet aggregating material

    SciTech Connect

    Schneider, M.D.

    1982-08-31

    Disclosed is an acid soluble, pepsin resistant, platelet aggregating material isolated from equine arterial tissue by extraction with dilute aqueous acid. The method of isolation and use to control bleeding are described. 4 figs.

  11. 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.

  12. GADOLINIUM SOLUBILITY AND VOLATILITY DURING DWPF PROCESSING

    SciTech Connect

    Reboul, S

    2008-01-30

    Understanding of gadolinium behavior, as it relates to potential neutron poisoning applications at the DWPF, has increased over the past several years as process specific data have been generated. Of primary importance are phenomena related to gadolinium solubility and volatility, which introduce the potential for gadolinium to be separated from fissile materials during Chemical Process Cell (CPC) and Melter operations. Existing data indicate that gadolinium solubilities under moderately low pH conditions can vary over several orders of magnitude, depending on the quantities of other constituents that are present. With respect to sludge batching processes, the gadolinium solubility appears to be highly affected by iron. In cases where the mass ratio of Fe:Gd is 300 or more, the gadolinium solubility has been observed to be low, one milligram per liter or less. In contrast, when the ratio of Fe:Gd is 20 or less, the gadolinium solubility has been found to be relatively high, several thousands of milligrams per liter. For gadolinium to serve as an effective neutron poison in CPC operations, the solubility needs to be limited to approximately 100 mg/L. Unfortunately, the Fe:Gd ratio that corresponds to this solubility limit has not been identified. Existing data suggest gadolinium and plutonium are not volatile during melter operations. However, the data are subject to inherent uncertainties preventing definitive conclusions on this matter. In order to determine if gadolinium offers a practical means of poisoning waste in DWPF operations, generation of additional data is recommended. This includes: Gd solubility testing under conditions where the Fe:Gd ratio varies from 50 to 150; and Gd and Pu volatility studies tailored to quantifying high temperature partitioning. Additional tests focusing on crystal aging of Gd/Pu precipitates should be pursued if receipt of gadolinium-poisoned waste into the Tank Farm becomes routine.

  13. Correlation of Catalytic Rates With Solubility Parameters

    NASA Technical Reports Server (NTRS)

    Lawson, Daniel D.; England, Christopher

    1987-01-01

    Catalyst maximizes activity when its solubility parameter equals that of reactive species. Catalytic activities of some binary metal alloys at maximum when alloy compositions correspond to Hildebrand solubility parameters equal to those of reactive atomic species on catalyst. If this suggestive correlation proves to be general, applied to formulation of other mixed-metal catalysts. Also used to identify reactive species in certain catalytic reactions.

  14. How Soluble GARP Enhances TGFβ Activation

    PubMed Central

    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. PMID:27054568

  15. 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.

  16. 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. PMID:27054568

  17. Ammonia Solubility in High Concentration Salt Solutions

    SciTech Connect

    HEDENGREN, D.C.

    2000-02-01

    Solubility data for ammonia in water and various dilute solutions are abundant in the literature. However, there is a noticeable lack of ammonia solubility data for high salt, basic solutions of various mixtures of salts including those found in many of the Hanford Washington underground waste tanks. As a result, models based on solubility data for dilute salt solutions have been used to extrapolate to high salt solutions. These significant extrapolations need to be checked against actual laboratory data. Some indirect vapor measurements have been made. A more direct approach is to determine the ratio of solubility of ammonia in water to its solubility in high salt solutions. In various experiments, pairs of solutions, one of which is water and the other a high salt solution, are allowed to come to equilibrium with a common ammonia vapor pressure. The ratio of concentrations of ammonia in the two solutions is equal to the ratio of the respective ammonia solubilities (Henry's Law constants) at a given temperature. This information can then be used to refine the models that predict vapor space compositions of ammonia. Ammonia at Hanford is of concern because of its toxicity in the environment and its contribution to the flammability of vapor space gas mixtures in waste tanks.

  18. Dermal nanocrystals from medium soluble actives - physical stability and stability affecting parameters.

    PubMed

    Zhai, Xuezhen; Lademann, Jürgen; Keck, Cornelia M; Müller, Rainer H

    2014-09-01

    Nanocrystals are meanwhile applied to increase the dermal penetration of drugs, but were applied by now only to poorly soluble drugs (e.g. 1-10 μg/ml). As a new concept nanocrystals from medium soluble actives were produced, using caffeine as model compound (solubility 16 mg/ml at 20 °C). Penetration should be increased by (a) further increase in solubility and (b) mainly by increased hair follicle targeting of nanocrystals compared to pure solution. Caffeine nanocrystal production in water lead to pronounced crystal growth. Therefore the stability of nanocrystals in water-ethanol (1:9) and ethanol-propylene glycol (3:7) mixtures with lower dielectric constant D was investigated, using various stabilizers. Both mixtures in combination with Carbopol 981 (non-neutralized) yielded stable nanosuspensions over 2 months at 4 °C and room temperature. Storage at 40 °C lead to crystal growth, attributed to too strong solubility increase, supersaturation and Ostwald ripening effects. Stability of caffeine nanocrystals at lower temperatures could not only be attributed to lower solubility, because the solubilities of caffeine in mixtures and in water are not that much different. Other effects such as quantified by reduced dielectric constant D, and specific interactions between dispersion medium and crystal surface seem to play a role. With the 2 mixtures and Carbopol 981, a basic formulation composition for this type of nanocrystals has been established, to be used in the in vivo proof of principle of the new concept.

  19. Dermal nanocrystals from medium soluble actives - physical stability and stability affecting parameters.

    PubMed

    Zhai, Xuezhen; Lademann, Jürgen; Keck, Cornelia M; Müller, Rainer H

    2014-09-01

    Nanocrystals are meanwhile applied to increase the dermal penetration of drugs, but were applied by now only to poorly soluble drugs (e.g. 1-10 μg/ml). As a new concept nanocrystals from medium soluble actives were produced, using caffeine as model compound (solubility 16 mg/ml at 20 °C). Penetration should be increased by (a) further increase in solubility and (b) mainly by increased hair follicle targeting of nanocrystals compared to pure solution. Caffeine nanocrystal production in water lead to pronounced crystal growth. Therefore the stability of nanocrystals in water-ethanol (1:9) and ethanol-propylene glycol (3:7) mixtures with lower dielectric constant D was investigated, using various stabilizers. Both mixtures in combination with Carbopol 981 (non-neutralized) yielded stable nanosuspensions over 2 months at 4 °C and room temperature. Storage at 40 °C lead to crystal growth, attributed to too strong solubility increase, supersaturation and Ostwald ripening effects. Stability of caffeine nanocrystals at lower temperatures could not only be attributed to lower solubility, because the solubilities of caffeine in mixtures and in water are not that much different. Other effects such as quantified by reduced dielectric constant D, and specific interactions between dispersion medium and crystal surface seem to play a role. With the 2 mixtures and Carbopol 981, a basic formulation composition for this type of nanocrystals has been established, to be used in the in vivo proof of principle of the new concept. PMID:25016978

  20. Controlled porosity solubility modulated osmotic pump tablets of gliclazide.

    PubMed

    Banerjee, Arti; Verma, P R P; Gore, Subhash

    2015-06-01

    A system that can deliver drug at a controlled rate is very important for the treatment of various chronic diseases such as diabetes, asthma, and heart disease. Poorly water-soluble drug with pH-dependent solubility such as gliclazide (GLZ) offers challenges in the controlled-release formulation because of low dissolution rate and poor bioavailability. Solid dispersion (SD) of GLZ consisted of hydroxypropyl cellulose (HPC-SSL) as a polymeric solubilizer was manufactured by hot melt extrusion (HME) technology. Then, controlled porosity osmotic pump (CPOP) tablet of gliclazide was designed to deliver drug in a controlled manner up to 16 h. The developed formulation was optimized for type and level of pore former and coating weight gain. The optimized formulation was found to exhibit zero order kinetics independent of pH and agitation speed but depends on osmotic pressure of dissolution media indicated that mechanism of drug release was osmotic pressure. The in vivo performance prediction of developed formulation using convolution approach revealed that the developed formulation was superior to the existing marketed extended-release formulation in terms of attaining steady state plasma levels and indicated adequate exposure in translating hypoglycemic response. The prototype solubilization method combined with controlled porosity osmotic pump based technique could provide a unique way to increase dissolution rate and bioavailability of many poorly water-soluble, narrow therapeutic index drugs used in diabetes, cardiovascular diseases, etc.

  1. Soluble levels of cytosolic tubulin regulate ciliary length control

    PubMed Central

    Sharma, Neeraj; Kosan, Zachary A.; Stallworth, Jannese E.; Berbari, Nicolas F.; Yoder, Bradley K.

    2011-01-01

    The primary cilium is an evolutionarily conserved dynamic organelle important for regulating numerous signaling pathways, and, as such, mutations disrupting ciliogenesis result in a variety of developmental abnormalities and postnatal disorders. The length of the cilium is regulated by the cell through largely unknown mechanisms. Normal cilia length is important, as either shortened or elongated cilia have been associated with disease and developmental defects. Here we explore the importance of cytoskeletal dynamics in regulating cilia length. Using pharmacological approaches in different cell types, we demonstrate that actin depolymerization or stabilization and protein kinase A activation result in a rapid elongation of the primary cilium. The effects of pharmacological agents on cilia length are associated with a subsequent increase in soluble tubulin levels and can be impaired by depletion of soluble tubulin with taxol. In addition, subtle nocodazole treatment was able to induce ciliogenesis under conditions in which cilia are not normally formed and also increases cilia length on cells that have already established cilia. Together these data indicate that cilia length can be regulated through changes in either the actin or microtubule network and implicate a possible role for soluble tubulin levels in cilia length control. PMID:21270438

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

    PubMed

    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

  3. 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

  4. Knowledge-based design of a soluble bacteriorhodopsin.

    PubMed

    Gibas, C; Subramaniam, S

    1997-10-01

    Much knowledge has been accrued from high resolution protein structures. This knowledge provides rules and guidelines for the rational design of soluble proteins. We have extracted these rules and applied them to redesigning the structure of bacteriorhodopsin and to creating blueprints for a monomeric, soluble seven-helix bundle protein. Such a protein is likely to have desirable properties, such as ready crystallization, which membrane proteins lack and an internal structure similar to that of the native protein. While preserving residues shown to be necessary for protein function, we made modifications to the rest of the sequence, distributing polar and charged residues over the surface of the protein to achieve an amino acid composition as akin to that of soluble helical proteins as possible. A secondary goal was to increase apolar contacts in the helix intercalation regions of the protein. The scheme used to design the model sequences requires knowledge of the number and orientation of helices and some information about interior contacts, but detailed structural knowledge is not required to use a scheme of this type.

  5. Redefining solubility parameters: the partial solvation parameters.

    PubMed

    Panayiotou, Costas

    2012-03-21

    The present work reconsiders a classical and universally accepted concept of physical chemistry, the solubility parameter. Based on the insight derived from modern quantum chemical calculations, a new definition of solubility parameter is proposed, which overcomes some of the inherent restrictions of the original definition and expands its range of applications. The original single solubility parameter is replaced by four partial solvation parameters reflecting the dispersion, the polar, the acidic and the basic character of the chemical compounds as expressed either in their pure state or in mixtures. Simple rules are adopted for the definition and calculation of these four parameters and their values are tabulated for a variety of common substances. In contrast, however, to the well known Hansen solubility parameters, their design and evaluation does not rely exclusively on the basic rule of "similarity matching" for solubility but it makes also use of the other basic rule of compatibility, namely, the rule of "complementarity matching". This complementarity matching becomes particularly operational with the sound definition of the acidic and basic components of the solvation parameter based on the third σ-moments of the screening charge distributions of the quantum mechanics-based COSMO-RS theory. The new definitions are made in a simple and straightforward manner, thus, preserving the strength and appeal of solubility parameter stemming from its simplicity. The new predictive method has been applied to a variety of solubility data for systems of pharmaceuticals and polymers. The results from quantum mechanics calculations are critically compared with the results from Abraham's acid/base descriptors. PMID:22327537

  6. Redefining solubility parameters: the partial solvation parameters.

    PubMed

    Panayiotou, Costas

    2012-03-21

    The present work reconsiders a classical and universally accepted concept of physical chemistry, the solubility parameter. Based on the insight derived from modern quantum chemical calculations, a new definition of solubility parameter is proposed, which overcomes some of the inherent restrictions of the original definition and expands its range of applications. The original single solubility parameter is replaced by four partial solvation parameters reflecting the dispersion, the polar, the acidic and the basic character of the chemical compounds as expressed either in their pure state or in mixtures. Simple rules are adopted for the definition and calculation of these four parameters and their values are tabulated for a variety of common substances. In contrast, however, to the well known Hansen solubility parameters, their design and evaluation does not rely exclusively on the basic rule of "similarity matching" for solubility but it makes also use of the other basic rule of compatibility, namely, the rule of "complementarity matching". This complementarity matching becomes particularly operational with the sound definition of the acidic and basic components of the solvation parameter based on the third σ-moments of the screening charge distributions of the quantum mechanics-based COSMO-RS theory. The new definitions are made in a simple and straightforward manner, thus, preserving the strength and appeal of solubility parameter stemming from its simplicity. The new predictive method has been applied to a variety of solubility data for systems of pharmaceuticals and polymers. The results from quantum mechanics calculations are critically compared with the results from Abraham's acid/base descriptors.

  7. Low Soluble Syndecan-1 Precedes Preeclampsia

    PubMed Central

    Gandley, Robin E.; Althouse, Andrew; Jeyabalan, Arundhathi; Bregand-White, Julia M.; McGonigal, Stacy; Myerski, Ashley C.; Gallaher, Marcia; Powers, Robert W.; Hubel, Carl A.

    2016-01-01

    Introduction Syndecan-1 (Sdc1; CD138) is a major transmembrane heparan sulfate proteoglycan expressed on the extracellular, luminal surface of epithelial cells and syncytiotrophoblast, thus comprising a major component of the glycocalyx of these cells. The “soluble” (shed) form of Sdc1 has paracrine and autocrine functions and is normally produced in a regulated fashion. We compared plasma soluble Sdc1 concentrations, in relation to placental Sdc1 expression, in uncomplicated (control) and preeclamptic pregnancies. Methods We evaluated soluble Sdc1 across uncomplicated pregnancy, and between preeclamptic, gestational hypertensive and control patients at mid-pregnancy (20 weeks) and 3rd trimester by ELISA. Placental expression level of Sdc1 was compared between groups in relation to pre-delivery plasma soluble Sdc1. Participants were recruited from Magee-Womens Hospital. Results In uncomplicated pregnancy, plasma soluble Sdc1 rose significantly in the 1st trimester, and reached an approximate 50-fold increase at term compared to post pregnancy levels. Soluble Sdc1 was lower at mid-pregnancy in women who later developed preeclampsia (P<0.05), but not gestational hypertension, compared to controls, and remained lower at late pregnancy in preeclampsia (P<0.01) compared to controls. Sdc1 was prominently expressed on syncytiotrophoblast of microvilli. Syncytiotrophoblast Sdc1 immunostaining intensities, and mRNA content in villous homogenates, were lower in preeclampsia vs. controls (P<0.05). Soluble Sdc1 and Sdc1 immunostaining scores were inversely associated with systolic blood pressures, and positively correlated with infant birth weight percentile. Conclusion Soluble Sdc1 is significantly lower before the clinical onset of preeclampsia, with reduced expression of Sdc1 in the delivered placenta, suggesting a role for glycocalyx disturbance in preeclampsia pathophysiology. PMID:27299886

  8. Formation of water-soluble soybean polysaccharides from spent flakes by hydrogen peroxide treatment.

    PubMed

    Pierce, Brian C; Wichmann, Jesper; Tran, Tam H; Cheetamun, Roshan; Bacic, Antony; Meyer, Anne S

    2016-06-25

    In this paper we propose a novel chemical process for the generation of water-soluble polysaccharides from soy spent flake, a by-product of the soy food industry. This process entails treatment of spent flake with hydrogen peroxide at an elevated temperature, resulting in the release of more than 70% of the original insoluble material as high molar mass soluble polysaccharides. A design of experiment was used to quantify the effects of pH, reaction time, and hydrogen peroxide concentration on the reaction yield, average molar mass, and free monosaccharides generated. The resulting product is low in protein, fat, and minerals and contains predominantly water-soluble polysaccharides of high molar mass, including arabinan, type I arabinogalactan, homogalacturonan, xyloglucan, rhamnogalacturonan, and (glucurono)arabinoxylan. This treatment provides a straightforward approach for generation of soluble soy polysaccharides and opens a new range of opportunities for this abundant and underutilized material in future research and industrial applications. PMID:27083842

  9. Preparation, characterization and solubility product constant of AmOHCO/sub 3/

    SciTech Connect

    Silva, R.J.

    1985-01-12

    An investigation into the nature and solubility of a stable solid phase formed by a trivalent actinide, /sup 243/Am/sup 3 +/, in dilute aqueous carbonate solutions was conducted. The compound exhibited an x-ray powder diffraction pattern which was nearly identical to that reported for NdOHCO/sub 3/ - type A. The pattern could be indexed in the orthorhombic system with unit cell parameters a = 4.958, b = 8.487, and c = 7.215 A. The steady-state solubility of the compound was determined from the results of both dissolution and precipitation experiments. The average solubility product quotient for 0.1M ionic strength, 25 +- 1/sup 0/C and 1 atmosphere pressure was found to be 583 +- 206. The solubility product constant for zero ionic strength was estimated to be 335 +- 120. 22 references, 3 tables.

  10. Ultrasound influence on the solubility of solid dispersions prepared for a poorly soluble drug.

    PubMed

    Pereira, Simone Vieira; Colombo, Fábio Belotti; de Freitas, Luis Alexandre Pedro

    2016-03-01

    Solid dispersions have been successfully used to enhance the solubility of several poorly water soluble drugs. Solid dispersions are produced by melting hydrophilic carriers and mixing in the poorly water soluble drug. Supersaturation is obtained by quickly cooling the mixture until it solidifies, thereby entrapping the drug. The effects of using ultrasound to homogenize the molten carrier and drug mixture were studied. In particular, the increase in drug solubility for the resulting solid dispersions was analyzed. Piroxicam, which has very low water solubility, was used as a model drug. A full factorial design was used to analyze how sonication parameters affected the solubility and in vitro release of the drug. The results show that the use of ultrasound can significantly increase the solubility and dissolution rate of the piroxicam solid dispersion. Pure piroxicam presented a solubility of 13.3 μg/mL. A maximum fourfold increase in solubility, reaching 53.8 μg/mL, was observed for a solid dispersion sonicated at 19 kHz for 10 min and 475 W. The in vitro dissolution rate test showed the sonicated solid dispersion reached a maximum rate of 18%/min, a sixfold increase over the piroxicam rate of 2.9%/min. Further solid state characterization by thermal, X-ray diffraction and Fourier transform infrared analyses also showed that the sonication process, in the described conditions, did not adversely alter the drug or significantly change its polymorphic form. Ultrasound is therefore an interesting technique to homogenize drug/carrier mixtures with the objective of increasing the solubility of drugs with poor water solubility. PMID:26548840

  11. Ultrasound influence on the solubility of solid dispersions prepared for a poorly soluble drug.

    PubMed

    Pereira, Simone Vieira; Colombo, Fábio Belotti; de Freitas, Luis Alexandre Pedro

    2016-03-01

    Solid dispersions have been successfully used to enhance the solubility of several poorly water soluble drugs. Solid dispersions are produced by melting hydrophilic carriers and mixing in the poorly water soluble drug. Supersaturation is obtained by quickly cooling the mixture until it solidifies, thereby entrapping the drug. The effects of using ultrasound to homogenize the molten carrier and drug mixture were studied. In particular, the increase in drug solubility for the resulting solid dispersions was analyzed. Piroxicam, which has very low water solubility, was used as a model drug. A full factorial design was used to analyze how sonication parameters affected the solubility and in vitro release of the drug. The results show that the use of ultrasound can significantly increase the solubility and dissolution rate of the piroxicam solid dispersion. Pure piroxicam presented a solubility of 13.3 μg/mL. A maximum fourfold increase in solubility, reaching 53.8 μg/mL, was observed for a solid dispersion sonicated at 19 kHz for 10 min and 475 W. The in vitro dissolution rate test showed the sonicated solid dispersion reached a maximum rate of 18%/min, a sixfold increase over the piroxicam rate of 2.9%/min. Further solid state characterization by thermal, X-ray diffraction and Fourier transform infrared analyses also showed that the sonication process, in the described conditions, did not adversely alter the drug or significantly change its polymorphic form. Ultrasound is therefore an interesting technique to homogenize drug/carrier mixtures with the objective of increasing the solubility of drugs with poor water solubility.

  12. Celestite (SrSO 4(s)) solubility in water, seawater and NaCl solution

    NASA Astrophysics Data System (ADS)

    Reardon, E. J.; Armstrong, D. K.

    1987-01-01

    Celestite solubility measurements have been conducted in pure water at temperatures from 10 to 90°C. Equilibrium was achieved with respect to a crystalline solid phase from both undersaturated and supersaturated solutions. The measurements show that the solubility undergoes a maximum near 20°C. LogK values for the solubility reaction are adequately described by the following expression over the temperature range 283.15 to 363.15 K: - logK= -35.3106+0.00422837 T+318312/ T2+14.99586 logT. The following thennodynamic values for the dissolution reaction of SrSO 4(s), at 25°C have been derived: ΔGR0 = 37852 ± 30 Jmol -1ΔHR0 = -1668±920 Jmol -1ΔSR0= -132.6±3.2 JK-1mol -1 Celestite solubility measurements were also determined in NaCl solutions up to 5 m concentration and from 10 to 40°C. These data are in good agreement with the work of StrÜbel (1966), who reports solubility measurements to temperatures of 100°C. The application of the Pitzer relations and the solubility constants determined in this study to calculate celestite solubility in NaCl solutions yields excellent agreement between predicted values and experimental measurements over the entire range of temperature and NaCl concentration conditions. For the limited number of solubility measurements in seawater-type solutions and mixed-salt brines, the agreement using the Pitzer relations is within three percent of the measured solubility.

  13. Biological activities of water-soluble fullerene derivatives

    NASA Astrophysics Data System (ADS)

    Nakamura, S.; Mashino, T.

    2009-04-01

    Three types of water-soluble fullerene derivatives were synthesized and their biological activities were investigated. C60-dimalonic acid, an anionic fullerene derivative, showed antioxidant activity such as quenching of superoxide and relief from growth inhibition of E. coli by paraquat. C60-bis(7V,7V-dimethylpyrrolidinium iodide), a cationic fullerene derivative, has antibacterial activity and antiproliferative effect on cancer cell lines. The mechanism is suggested to be respiratory chain inhibition by reactive oxygen species produced by the cationic fullerene derivative. Proline-type fullerene derivatives showed strong inhibition activities on HIV-reverse transcriptase. The IC50 values were remarkably lower than nevirapine, a clinically used anti-HIV drug. Fullerene derivatives have a big potential for a new type of lead compound to be used as medicine.

  14. 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. PMID:27057755

  15. Solubility of pllutonium in alkaline salt solutions

    SciTech Connect

    Hobbs, D.T.; Edwards, T.B.

    1993-02-26

    Plutonium solubility data from several studies have been evaluated. For each data set, a predictive model has been developed where appropriate. In addition, a statistical model and corresponding prediction intervals for plutonium solubility as a quadratic function of the hydroxide concentration have been developed. Because of the wide range of solution compositions, the solubility of plutonium can vary by as much as three orders of magnitude for any given hydroxide concentration and still remain within the prediction interval. Any nuclear safety assessments that depend on the maximum amount of plutonium dissolved in alkaline salt solutions should use concentrations at least as great as the upper prediction limits developed in this study. To increase the confidence in the prediction model, it is recommended that additional solubility tests be conducted at low hydroxide concentrations and with all of the other solution components involved. To validate the model for application to actual waste solutions, it is recommended that the plutonium solubilities in actual waste solutions be determined and compared to the values predicted by the quadratic model.

  16. 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.

  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. Development of self-nanoemulsifying drug delivery systems for the enhancement of solubility and oral bioavailability of fenofibrate, a poorly water-soluble drug

    PubMed Central

    Mohsin, Kazi; Alamri, Rayan; Ahmad, Ajaz; Raish, Mohammad; Alanazi, Fars K; Hussain, Muhammad Delwar

    2016-01-01

    Background Self-nanoemulsifying drug delivery systems (SNEDDS) have become a popular formulation option as nanocarriers for poorly water-soluble drugs. The objective of this study was to investigate the factor that can influence the design of successful lipid formulation classification system (LFCS) Type III SNEDDS formulation and improve the oral bioavailability (BA) of fenofibrate. Materials and methods LFCS Type III SNEDDS were designed using various oils, water-soluble surfactants, and/or cosolvents (in considering the polarity of the lipids) for the model anticholesterol drug, fenofibrate. The developed SNEDDS were assessed visually and by measurement of the droplet size. Equilibrium solubility of fenofibrate in the SNEDDS was conducted to find out the maximum drug loading. Dynamic dispersion studies were carried out (1/100 dilution) in water to investigate how much drug stays in solution after aqueous dispersion of the formulation. The BA of SNEDDS formulation was evaluated in the rat. Results The results from the characterization and solubility studies showed that formulations containing mixed glycerides were highly efficient SNEDDS as they had higher solubility of the drug and produced nanosized droplets. The dispersion studies confirmed that SNEDDS (containing polar mixed glycerides) can retain >98% drug in solution for >24 hours in aqueous media. The in vivo pharmacokinetics parameters of SNEDDS formulation in comparison with pure drug showed significant increase in Cmax and AUC0–t, ~78% and 67%, respectively. The oral BA of fenofibrate from SNEDDS in rats was ~1.7-fold enhanced as compared with the BA from pure drug. Conclusion Fenofibrate-loaded LFCS Type III SNEDDS formulations could be a potential oral pharmaceutical product for administering the poorly water-soluble drug, fenofibrate, with an enhanced oral BA. PMID:27366063

  19. 40 CFR Table 7 to Subpart Vvvvvv... - Partially Soluble HAP

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 15 2014-07-01 2014-07-01 false Partially Soluble HAP 7 Table 7 to... Pt. 63, Subpt. VVVVVV, Table 7 Table 7 to Subpart VVVVVV of Part 63—Partially Soluble HAP As required... partially soluble HAP listed in the following table. Partially soluble HAP name CAS No. 1....

  20. 40 CFR Table 7 to Subpart Vvvvvv... - Partially Soluble HAP

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 15 2013-07-01 2013-07-01 false Partially Soluble HAP 7 Table 7 to... Pt. 63, Subpt. VVVVVV, Table 7 Table 7 to Subpart VVVVVV of Part 63—Partially Soluble HAP As required... partially soluble HAP listed in the following table. Partially soluble HAP name CAS No. 1....

  1. 40 CFR Table 7 to Subpart Vvvvvv... - Partially Soluble HAP

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 15 2012-07-01 2012-07-01 false Partially Soluble HAP 7 Table 7 to... Pt. 63, Subpt. VVVVVV, Table 7 Table 7 to Subpart VVVVVV of Part 63—Partially Soluble HAP As required... partially soluble HAP listed in the following table. Partially soluble HAP name CAS No. 1....

  2. Improvement in solubility of poor water-soluble drugs by solid dispersion

    PubMed Central

    Sareen, Swati; Mathew, George; Joseph, Lincy

    2012-01-01

    This article is intended to combine recent literature on solid dispersion technology for solubility enhancement with special emphasis on mechanism responsible for the same by solid dispersion, various preparation methods, and evaluation parameters. Solubility behavior is the most challenging aspect for various new chemical entities as 60% of the new potential products possess solubility problems. This is the biggest reason for new drug molecules not reaching to the market or not reaches to full potential. There are various techniques to enhance the drug solubility such as particle size reduction, nanosuspension, use of surfactants, salt formation, solid dispersion, etc. From this article it may be concluded that solid dispersion is an important approach for improvement of bioavailability of poor water-soluble drugs. PMID:23071955

  3. Diffusion and solubility of oxygen in silver

    NASA Technical Reports Server (NTRS)

    Eichenauer, W.; Miller, G.

    1985-01-01

    The diffusion and solubility of oxygen in Ag in the temperature range between 412 and 862 C was determined. The following interpolation formula was found for the solubility: L = 8.19.1/100.exp(-11 860/RT)Mol O2/g.At.Ag.at 1/.5. The process obeys the Sieverts square root law within the limits of error. The dissolution of oxygen in Ag may be accompanied by the dissociation of the oxygen molecules into atoms. The tests on Ag-foils reveal that below a temperature of about 500 C a higher solubility is simulated by the adsorption of oxygen. The diffusion coefficient of oxygen in silver obeys the following equation: D = 2.72.1/100.exp(-11 000/RT)sq cm/s. The relatively low activation energy of 11 kcal/g.At suggests that the diffusion of oxygen takes places over interstitial sites.

  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. PMID:27282539

  5. Gaseous Sulfate Solubility in Glass: Experimental Method

    SciTech Connect

    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 to 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.

  6. Soluble proteins in insect chemical communication.

    PubMed

    Pelosi, P; Zhou, J-J; Ban, L P; Calvello, M

    2006-07-01

    Our understanding of the biochemical mechanisms that mediate chemoreception in insects has been greatly improved after the discovery of olfactory and taste receptor proteins. However, the presence of soluble polypeptides in high concentration around the dendrites of sensory neurons still poses unanswered questions. More than 2 decades after their discovery and despite the wealth of structural information available, the physiological function of odorant-binding proteins is not well understood. More recently, members of a second family of soluble polypeptides, the chemosensory proteins, were also discovered in the lymph of chemosensilla. Here we review the structural properties of both classes of soluble proteins, their affinity to small ligands, and their expression in the different parts of the insect body and subcellular localisation. Finally, we discuss current ideas and models of the role of such proteins in insect chemoreception.

  7. AW-101 entrained solids - Solubility versus temperature

    SciTech Connect

    GJ Lumetta; RC Lettau; GF Piepel

    2000-03-31

    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, Determination of the Solubility of LAW Entrained Solids. The test went according to plan, with no deviations from the test plan.

  8. Influence of Polymer Molecular Weight on Drug-Polymer Solubility: A Comparison between Experimentally Determined Solubility in PVP and Prediction Derived from Solubility in Monomer.

    PubMed

    Knopp, Matthias Manne; Olesen, Niels Erik; Holm, Per; Langguth, Peter; Holm, René; Rades, Thomas

    2015-09-01

    In this study, the influence of polymer molecular weight on drug-polymer solubility was investigated using binary systems containing indomethacin (IMC) and polyvinylpyrrolidone (PVP) of different molecular weights. The experimental solubility in PVP, measured using a differential scanning calorimetry annealing method, was compared with the solubility calculated from the solubility of the drug in the liquid analogue N-vinylpyrrolidone (NVP). The experimental solubility of IMC in the low-molecular-weight PVP K12 was not significantly different from that in the higher molecular weight PVPs (K25, K30, and K90). The calculated solubilities derived from the solubility in NVP (0.31-0.32 g/g) were found to be lower than those experimentally determined in PVP (0.38-0.40 g/g). Nevertheless, the similarity between the values indicates that the analogue solubility can provide valuable indications on the solubility in the polymer. Hence, if a drug is soluble in an analogue of the polymer, it is most likely also soluble in the polymer. In conclusion, the solubility of a given drug-polymer system is determined by the strength of the drug-polymer interactions rather than the molecular weight of the polymer. Therefore, during the first screenings for drug solubility in polymers, only one representative molecular weight per polymer is needed.

  9. [Soluble nitrogen and soluble phosphorus dynamics during foliar litter decomposition in winter in alinine forest streams].

    PubMed

    Zhang, Chuan; Yang, Wan-qin; Yue, Kai; Huang, Chun-ping; Peng, Yan; Wu, Fu-zhong

    2015-06-01

    In order to understand the dynamic pattern of soluble nitrogen and soluble phosphorus in the headwater streams during the process of litter decomposition in winter, a field experiment using litterbag method was conducted in an alpine forest in Western Sichuan, China. The foliar litter of two dominant canopy trees (Sabina saltuaria, and Larix mastersiana) and two shrubs (Salix paraplesia and Rhododendron lapponicum) were selected. The litterbags were placed in a headwater stream, river, riparian zone and closed canopy, and sampled in different freezing-thawing periods of winter (pre-freezing period, freezing period and thawing period). The results indicated that the soluble nitrogen content of foliar litter showed little changes over a whole winter decomposition regardless of species. In contrast, the soluble phosphorus content displayed the order as river < stream < riparian zone < closed canopy, and showed a decrease tendency in stream, river and riparian, although little changes under closed canopy over a whole winter decomposition. Correlation analysis suggested that the dynamics of soluble phosphorus content significantly correlated to the average temperature, positive accumulated temperature, negative accumulated temperature and flow velocity during the decomposition in winter. The dynamics of soluble nitrogen content only exhibited significant correlations with positive accumulated temperature. Additionally, litter quality (species) also controlled the dynamics of soluble nitrogen and soluble phosphorus content as litter decomposition proceeded. The results implied that soluble phosphorus could be more liable to loss in streams and rivers during litter decomposition compared with soluble nitrogen, which could further provide some new ideas in understanding nitrogen and phosphorus cycling in this alpine forest.

  10. [Soluble nitrogen and soluble phosphorus dynamics during foliar litter decomposition in winter in alinine forest streams].

    PubMed

    Zhang, Chuan; Yang, Wan-qin; Yue, Kai; Huang, Chun-ping; Peng, Yan; Wu, Fu-zhong

    2015-06-01

    In order to understand the dynamic pattern of soluble nitrogen and soluble phosphorus in the headwater streams during the process of litter decomposition in winter, a field experiment using litterbag method was conducted in an alpine forest in Western Sichuan, China. The foliar litter of two dominant canopy trees (Sabina saltuaria, and Larix mastersiana) and two shrubs (Salix paraplesia and Rhododendron lapponicum) were selected. The litterbags were placed in a headwater stream, river, riparian zone and closed canopy, and sampled in different freezing-thawing periods of winter (pre-freezing period, freezing period and thawing period). The results indicated that the soluble nitrogen content of foliar litter showed little changes over a whole winter decomposition regardless of species. In contrast, the soluble phosphorus content displayed the order as river < stream < riparian zone < closed canopy, and showed a decrease tendency in stream, river and riparian, although little changes under closed canopy over a whole winter decomposition. Correlation analysis suggested that the dynamics of soluble phosphorus content significantly correlated to the average temperature, positive accumulated temperature, negative accumulated temperature and flow velocity during the decomposition in winter. The dynamics of soluble nitrogen content only exhibited significant correlations with positive accumulated temperature. Additionally, litter quality (species) also controlled the dynamics of soluble nitrogen and soluble phosphorus content as litter decomposition proceeded. The results implied that soluble phosphorus could be more liable to loss in streams and rivers during litter decomposition compared with soluble nitrogen, which could further provide some new ideas in understanding nitrogen and phosphorus cycling in this alpine forest. PMID:26572009

  11. Respiratory carcinogenicity assessment of soluble nickel compounds.

    PubMed

    Oller, Adriana R

    2002-10-01

    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

  12. Solubilities of krypton and xenon in dichlorodifluoromethane

    SciTech Connect

    Shaffer, J.H.; Shockley, W.E.; Greene, C.W.

    1984-07-01

    The solubility behavior of krypton and xenon in dichlorodifluoromethane was investigated for the Consolidated Fuel Reprocessing Program (CFRP) in support of the fluorocarbon absorption process. The solubility data derived from solute radioisotopes had uncertainties of approx. 0.1%. Values for Henry's law constants were initially determined under equilibrium conditions at infinite solute dilution. Based on these results, the study was extended to finite solute concentrations. Nonidealities in the two binary systems were expressed as gas phase fugacity coefficients for each solute at 10/sup 0/ intervals over the range -30 to +50/sup 0/C. 22 references, 4 figures, 2 tables.

  13. Water sorption and solubility of glass fiber-reinforced denture polymethyl methacrylate resin.

    PubMed

    Miettinen, V M; Vallittu, P K; Docent, D T

    1997-05-01

    Polymethyl methacrylate (PMMA) absorbs water slowly over a period of time, primarily because of the polar properties of the resin molecules. The aim of this study was to determine the water sorption and solubility of heat-cured and chemical-cured glass fiber (GF) PMMA composite used in dentures. The test specimens (n = 5) were fabricated from experimental, unidirectional, continuous GF reinforcement; the GF concentration of the test specimens was approximately 11% by weight. Water sorption and solubility were tested in accordance with International Standards Organization specification No. 1567. The results revealed that the type of acrylate had more of an effect on water sorption than did the presence of GF reinforcement in the test specimen (p = 0.001 and p = 0.049, respectively). In the GF-reinforced test specimens the type of PMMA also affected the water sorption values (p = 0.006). GF reinforcement affected the solubility values of the test specimen (p = 0.002), but the type of acrylate had no effect on solubility (p = 0.585). The results of this study suggest that the water sorption and solubility of unreinforced PMMA and PMMA reinforced with GF are in accordance with International Standards Organization specification No. 1567.

  14. Water solubility measurements in supercritical fluids and high-pressure liquids using near-infrared spectroscopy

    SciTech Connect

    Jackson, K.; Bowman, L.E.; Fulton, J.L.

    1995-07-15

    A small amount of water added to a supercritical fluid can greatly increase the solubility of polar species in nonpolar fluids. These modified supercritical solutions significantly expand the use of the fluids in separations and reactions. In order to successfully utilize these systems, information on the miscibility or solubility of water in the fluid is required. Often solubility data are not available for water in a supercritical fluid under a given set of temperature and pressure conditions, and a costly set of equipment must be assembled in order to make these measurements. A relatively fast and inexpensive technique to measure water solubilities using a simple long path length optical cell in an FT-IR spectrometer is described. This technique is also applicable to common and newly developed refrigerants where water solubilities are often unknown at temperatures much above ambient. In this paper, water solubility data in carbon dioxide and two types of refrigerants (chlorodifluoromethane, R22; 1,1,1,2-tetrafluoroethane, R134a) are presented for temperatures from approximately 40 to 110{degree}C and pressures from approximately 10 to 344.8 bar. 26 refs., 6 figs., 4 tabs.

  15. 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.

  16. Optimization of single-walled carbon nanotube solubility by noncovalent PEGylation using experimental design methods.

    PubMed

    Hadidi, Naghmeh; Kobarfard, Farzad; Nafissi-Varcheh, Nastaran; Aboofazeli, Reza

    2011-01-01

    In this study, noncovalent functionalization of single-walled carbon nanotubes (SWCNTs) with phospholipid-polyethylene glycols (Pl-PEGs) was performed to improve the solubility of SWCNTs in aqueous solution. Two kinds of PEG derivatives, ie, Pl-PEG 2000 and Pl-PEG 5000, were used for the PEGylation process. An experimental design technique (D-optimal design and second-order polynomial equations) was applied to investigate the effect of variables on PEGylation and the solubility of SWCNTs. The type of PEG derivative was selected as a qualitative parameter, and the PEG/SWCNT weight ratio and sonication time were applied as quantitative variables for the experimental design. Optimization was performed for two responses, aqueous solubility and loading efficiency. The grafting of PEG to the carbon nanostructure was determined by thermogravimetric analysis, Raman spectroscopy, and scanning electron microscopy. Aqueous solubility and loading efficiency were determined by ultraviolet-visible spectrophotometry and measurement of free amine groups, respectively. Results showed that Pl-PEGs were grafted onto SWCNTs. Aqueous solubility of 0.84 mg/mL and loading efficiency of nearly 98% were achieved for the prepared Pl-PEG 5000-SWCNT conjugates. Evaluation of functionalized SWCNTs showed that our noncovalent functionalization protocol could considerably increase aqueous solubility, which is an essential criterion in the design of a carbon nanotube-based drug delivery system and its biodistribution.

  17. Encapsulation and Delivery of Crystalline Hydrophobic Nutraceuticals using Nanoemulsions: Factors Affecting Polymethoxyflavone Solubility.

    PubMed

    Li, Yan; Xiao, Hang; McClements, David Julian

    2012-12-01

    Polymethoxyflavones (PMF) isolated from citrus peel have potent anti-cancer activity, however their utilization as functional ingredients in foods is currently limited because of their high melting point and poor water-solubility. The influence of oil type and concentration, hydrophilic polymer addition, and simulated intestinal conditions on PMF (5-hydroxytangeretin) solubility in solutions and nanoemulsions was examined. The saturation concentration of PMF in water was relatively low (0.93 µM), but could be increased appreciably by adding certain hydrophilic polymers: polyethylene glycol (PEG) and β-cyclodextrin (CD) were ineffective at increasing solubility, but poly(vinyl alcohol) (PVA) and hydroxypropyl methylcellulose (HPMC) greatly enhanced solubility (e.g., > 6 µM for 0.5 % polymer). PMF was more soluble in medium chain triglycerides (MCT, 6.1 mM) than long chain triglycerides (LCT, 4.2 mM). The encapsulation efficiency of PMF in oil-in-water nanoemulsions was higher when MCT was used as the oil phase rather than LCT, and could be increased by increasing the oil droplet content. The solubility of PMF in simulated small intestinal fluids was increased by solubilization in bile micelles and mixed micelles formed during lipid digestion. These results have important implications for the development of functional foods fortified with bioactive hydrophobic components aimed at improving human health and wellness. PMID:23646037

  18. Solubility of drugs in aqueous solutions. Part 4. Drug solubility by the dilute approximation.

    PubMed

    Ruckenstein, E; Shulgin, I

    2004-07-01

    As in our previous publications in this journal [Int. J. Pharm. 258 (2003a) 193; Int. J. Pharm. 260 (2003b) 283; Int. J. Pharm. 267 (2003c) 121], this paper is concerned with the solubility of poorly soluble drugs in aqueous mixed solvents. In the previous publications, the solubilities of drugs were assumed to be low enough for the so-called infinite dilution approximation to be applicable. In contrast, in the present paper, the solubilities are considered to be finite and the dilute solution approximation is employed. As before, the fluctuation theory of solutions is used to express the derivatives of the activity coefficient of a solute in a ternary solution (dilute solute concentrations in a binary solvent) with respect to the concentrations of the solvent and cosolvent. The expressions obtained are combined with a theoretical equation for the activity coefficient of the solute. As a result, the activity coefficient of the solute was expressed through the activity coefficients of the solute at infinite dilution, solute mole fraction, some properties of the binary solvent (composition, molar volume and activity coefficients of the components) and parameters reflecting the nonidealities of binary species. The expression thus obtained was used to derive an equation for the solubility of poorly soluble drugs in aqueous binary solvents which was applied in two different ways. First, the nonideality parameters were considered as adjustable parameters, determined from experimental solubility data. Second, the obtained equation was used to correct the solubilities of drugs calculated via the infinite dilution approximation. It was shown that both procedures provide accurate correlations for the drug solubility.

  19. Water-soluble polymers and compositions thereof

    DOEpatents

    Smith, Barbara F.; Robison, Thomas W.; Gohdes, Joel W.

    2002-01-01

    Water-soluble polymers including functionalization from the group of amino groups, carboxylic acid groups, phosphonic acid groups, phosphonic ester groups, acylpyrazolone groups, hydroxamic acid groups, aza crown ether groups, oxy crown ethers groups, guanidinium groups, amide groups, ester groups, aminodicarboxylic groups, permethylated polvinylpyridine groups, permethylated amine groups, mercaptosuccinic acid groups, alkyl thiol groups, and N-alkylthiourea groups are disclosed.

  20. Water-soluble polymers and compositions thereof

    DOEpatents

    Smith, Barbara F.; Robison, Thomas W.; Gohdes, Joel W.

    1999-01-01

    Water-soluble polymers including functionalization from the group of amino groups, carboxylic acid groups, phosphonic acid groups, phosphonic ester groups, acylpyrazolone groups, hydroxamic acid groups, aza crown ether groups, oxy crown ethers groups, guanidinium groups, amide groups, ester groups, aminodicarboxylic groups, permethylated polyvinylpyridine groups, permethylated amine groups, mercaptosuccinic acid groups, alkyl thiol groups, and N-alkylthiourea groups are disclosed.

  1. Assessing Students' Conceptual Understanding of Solubility Equilibrium.

    ERIC Educational Resources Information Center

    Raviolo, Andres

    2001-01-01

    Presents a problem on solubility equilibrium which involves macroscopic, microscopic, and symbolic levels of representation as a resource for the evaluation of students, and allows for assessment as to whether students have acquired an adequate conceptual understanding of the phenomenon. Also diagnoses difficulties with regard to previous…

  2. Substrate stiffness regulates solubility of cellular vimentin

    PubMed Central

    Murray, Maria E.; Mendez, Melissa G.; Janmey, Paul A.

    2014-01-01

    The intermediate filament protein vimentin is involved in the regulation of cell behavior, morphology, and mechanical properties. Previous studies using cells cultured on glass or plastic substrates showed that vimentin is largely insoluble. Although substrate stiffness was shown to alter many aspects of cell behavior, changes in vimentin organization were not reported. Our results show for the first time that mesenchymal stem cells (hMSCs), endothelial cells, and fibroblasts cultured on different-stiffness substrates exhibit biphasic changes in vimentin detergent solubility, which increases from nearly 0 to 67% in hMSCs coincident with increases in cell spreading and membrane ruffling. When imaged, the detergent-soluble vimentin appears to consist of small fragments the length of one or several unit-length filaments. Vimentin detergent solubility decreases when these cells are subjected to serum starvation, allowed to form cell–cell contacts, after microtubule disruption, or inhibition of Rac1, Rho-activated kinase, or p21-activated kinase. Inhibiting myosin or actin assembly increases vimentin solubility on rigid substrates. These data suggest that in the mechanical environment in vivo, vimentin is more dynamic than previously reported and its assembly state is sensitive to stimuli that alter cellular tension and morphology. PMID:24173714

  3. Soluble arsenic removal at water treatment plants

    SciTech Connect

    McNeill, L.S.; Edwards, M.

    1995-04-01

    Arsenic profiles were obtained from full-scale conventional treatment (coagulation, Fe-Mn oxidation, or softening) plants, facilitating testing of theories regarding arsenic removal. Soluble As(V) removal efficiency was controlled primarily by pH during coagulation, be Fe{sup +2} oxidation and Fe(OH){sub 3} precipitation during Fe-Mn oxidation, and by Mg(OH){sub 2} formation during softening. Insignificant soluble As(V) removal occurred during calcite precipitation at softening plants or during Mn{sup +2} oxidation-precipitation at Fe-Mn oxidation plants. The extent of soluble As(V) removal during coagulation and softening treatments was lower than expected. Somewhat surprisingly, during coagulation As(V) removal efficiencies were limited by particulate aluminum formation and removal, because much of the added coagulant was not removed by 0.45-{mu}m-pore-size filters. At one utility, reducing the coagulation pH from 7.4 to 6.8 (at constant alum dose) improved removal of particulate aluminum, thereby enhancing soluble As(V) removal during treatment.

  4. Water-soluble polymers and compositions thereof

    DOEpatents

    Smith, B.F.; Robison, T.W.; Gohdes, J.W.

    1999-04-06

    Water-soluble polymers including functionalization from the group of amino groups, carboxylic acid groups, phosphonic acid groups, phosphonic ester groups, acylpyrazolone groups, hydroxamic acid groups, aza crown ether groups, oxy crown ethers groups, guanidinium groups, amide groups, ester groups, aminodicarboxylic groups, permethylated polyvinylpyridine groups, permethylated amine groups, mercaptosuccinic acid groups, alkyl thiol groups, and N-alkylthiourea groups are disclosed.

  5. 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.

  6. Anhydrite solubility in differentiated arc magmas

    NASA Astrophysics Data System (ADS)

    Masotta, M.; Keppler, H.

    2015-06-01

    The solubility of anhydrite in differentiated arc magmas was experimentally studied at 200 MPa and 800-1000 °C over a range of oxygen fugacities, from 0.5 log units above the Ni-NiO buffer to the hematite-magnetite buffer. Anhydrite is stable only at oxidizing conditions (fO2 ⩾ Re-ReO2), whereas sulfides only form under reducing conditions. The solubility of anhydrite in the melt ultimately regulates the amount of sulfur available to partition between melt and fluid phase during the eruption. At oxidizing conditions, the solubility product of anhydrite increases with temperature, nbo/t and melt water content. We provide a new calibration of the anhydrite solubility product (KSP = XCaO * XSO3), which reproduces all available experimental data with greatly improved accuracy: In this equation, the molar fractions XCaO and XSO3 in the melt as well as the number of non-bridging oxygen atoms per tetrahedron (nbo/t) are calculated on an anhydrous basis (H2O refers to the melt water content, T is temperature in Kelvin). We apply our model to estimate the sulfur yield of some recent volcanic eruptions and we show that the sulfur yield of the 1991 Mt. Pinatubo dacite eruption was unusually large, because only a small fraction of the sulfur was locked up in anhydrite. In general, high sulfur yields are expected when anhydrite solubility in the melt is high, i.e. for somewhat depolymerized melts. For rhyolitic systems, most of the available sulfur will be locked up in anhydrite, so that even very large eruptions may only have a small effect on global surface temperatures. Our model therefore allows improved predictions of the environmental impact of explosive volcanic eruptions.

  7. Shewanella oneidensis MR-1 mutants selected for their inability to produce soluble organic-Fe(III) complexes are unable to respire Fe(III) as anaerobic electron acceptor.

    PubMed

    Jones, Morris E; Fennessey, Christine M; DiChristina, Thomas J; Taillefert, Martial

    2010-04-01

    Recent voltammetric analyses indicate that Shewanella putrefaciens strain 200 produces soluble organic-Fe(III) complexes during anaerobic respiration of sparingly soluble Fe(III) oxides. Results of the present study expand the range of Shewanella species capable of producing soluble organic-Fe(III) complexes to include Shewanella oneidensis MR-1. Soluble organic-Fe(III) was produced by S. oneidensis cultures incubated anaerobically with Fe(III) oxides, or with Fe(III) oxides and the alternate electron acceptor fumarate, but not in the presence of O(2), nitrate or trimethylamine-N-oxide. Chemical mutagenesis procedures were combined with a novel MicroElectrode Screening Array (MESA) to identify four (designated Sol) mutants with impaired ability to produce soluble organic-Fe(III) during anaerobic respiration of Fe(III) oxides. Two of the Sol mutants were deficient in anaerobic growth on both soluble Fe(III)-citrate and Fe(III) oxide, yet retained the ability to grow on a suite of seven alternate electron acceptors. The rates of soluble organic-Fe(III) production were proportional to the rates of iron reduction by the S. oneidensis wild-type and Sol mutant strains, and all four Sol mutants retained wild-type siderophore production capability. Results of this study indicate that the production of soluble organic-Fe(III) may be an important intermediate step in the anaerobic respiration of both soluble and sparingly soluble forms of Fe(III) by S. oneidensis.

  8. Recombinant soluble betaglycan is a potent and isoform-selective transforming growth factor-beta neutralizing agent.

    PubMed Central

    Vilchis-Landeros, M M; Montiel, J L; Mendoza, V; Mendoza-Hernández, G; López-Casillas, F

    2001-01-01

    Betaglycan is an accessory receptor of members of the transforming growth factor-beta (TGF-beta) superfamily, which regulates their actions through ligand-dependent interactions with type II receptors. A natural soluble form of betaglycan is found in serum and extracellular matrices. Soluble betaglycan, prepared as a recombinant protein using the baculoviral expression system, inhibits the actions of TGF-beta. Because of its potential use as an anti-TGF-beta therapeutic agent, we have purified and characterized baculoviral recombinant soluble betaglycan. Baculoviral soluble betaglycan is a homodimer formed by two 110 kDa monomers associated by non-covalent interactions. This protein is devoid of glycosaminoglycan chains, although it contains the serine residues, which, in vertebrate cells, are modified by these carbohydrates. On the other hand, mannose-rich carbohydrates account for approximately 20 kDa of the mass of the monomer. End-terminal sequence analysis of the soluble betaglycan showed that Gly(24) is the first residue of the mature protein. Similarly to the natural soluble betaglycan, baculoviral soluble betaglycan has an equilibrium dissociation constant (K(d)) of 3.5 nM for TGF-beta1. Ligand competition assays indicate that the relative affinities of recombinant soluble betaglycan for the TGF-beta isoforms are TGF-beta2>TGF-beta3>TGF-beta1. The anti-TGF-beta potency of recombinant soluble betaglycan in vitro is 10-fold higher for TGF-beta2 than for TGF-beta1. Compared with a commercial pan-specific anti-TGF-beta neutralizing antibody, recombinant soluble betaglycan is more potent against TGF-beta2 and similar against TGF-beta1. These results indicate that baculoviral soluble betaglycan has the biochemical and functional properties that would make it a suitable agent for the treatment of the diseases in which excess TGF-beta plays a central physiopathological role. PMID:11256966

  9. Solubilities of significant compounds in HLW tank supernate solutions - FY 1996 progress report

    SciTech Connect

    Barney, G.S.

    1996-09-30

    The solubilities of two sodium salts of organic acids that are thought to exist in high-level waste at the Hanford Site were measured in tank supernate simulant solutions during FY1996 This solubility information will be used to determine if these organic salts could exist in solid phases (saltcake or sludges) in the waste where they might react violently with the nitrate or nitrite salts present in the tanks. Solubilities of sodium butyrate and trisodium N-(2-hydroxyethyl)ethylenediaminetriacetate were measured in simulated waste supernate solutions at 25 {degrees}C, 30 {degrees}C, 40 {degrees}C, and 50 {degrees}C. The organic compounds were selected because they are expected to exist in relatively high concentrations in the tanks. Two types of tank supernate simulants were used - a 4.O M sodium nitrate - 0.97 M sodium nitrite solution with sodium hydroxide concentrations ranging from O.00003 M to 2.O M and a 2.O M sodium nitrite solution saturated with crystalline sodium nitrate with sodium hydroxide concentrations ranging from 0.1 M to 2. 0 M. The solubilities of sodium butyrate and trisodium N-(2-hydroxyethyl)ethylene- diaminetriacetate in both types of HLW tank supernate solutions were high over the temperature and sodium hydroxide concentration ranges expected in the tanks. The solubilities of these compounds are similar (in terms of total organic carbon) to sodium glycolate, succinate, caproate, dibutylphosphate, citrate, formate, ethylenediaminetetraacetate, and nitrilotriacetate which were measured previously. High solubilities will prevent solid sodium salts of these organic acids from precipitating from tank supernate solutions. The total organic carbon concentrations (TOC) of actual tank supernates are generaly much lower than the TOC ranges for the simulated supernate solutions saturated (at the solubility limit) with the organic salts. This is true even if all the dissolved carbon in a given tank supernate is due to only one of these eight soluble

  10. 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

  11. 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.

  12. 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. PMID:25675104

  13. 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

  14. 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

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

    PubMed

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

    2012-11-01

    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.

  16. 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.

  17. Water solubility in pyrope at high pressures

    NASA Astrophysics Data System (ADS)

    Mookherjee, M.; Karato, S.-

    2006-12-01

    To address how much water is stored within the Earth's mantle, we need to understand the water solubility in the nominally anhydrous minerals. Much is known about olivine and pyroxene. Garnet is another important component, approaching 40% by volume in the transition zone. Only two studies on water solubility in pyrope at high-pressures exist which contradict each other. Lu and Keppler (1997) observed increase in water solubility in a natural pyrope up to 200 ppm wt of water, till 10 GPa. They concluded that the proton is located in the interstitial site. Withers et al. (1998) on the contrary, observed increasing water content in Mg-rich pyrope till 6 GPa, then sudden decrease of water, beyond detection, at 7 GPa. Based on infrared spectra, Withers et al. (1998), concluded hydrogarnet (Si^{4+} replaced by 4H+ to form O4H4) substitution in synthetic magnesium rich pyrope. They argued that at high pressure owing to larger volume, hydrogarnet substitution is unstable and water is expelled out of garnet. In transition zone conditions, however, majorite garnet seems to contain around 600-700 ppm wt of water (Bolfan-Casanova et al. 2000; Katayama et al. 2003). The cause for such discrepancy is not clear and whether garnet could store a significant amount of water at mantle condition is unconstrained. In order to understand the solubility mechanism of water in pyrope at high-pressure, we have conducted high- pressure experiments on naturally occurring single crystals of pyrope garnet (from Arizona, Aines and Rossman, 1984). To ascertain water-saturated conditions, we use olivine single-crystal as an internal standard. Preliminary results indicate that natural pyrope is capable of dissolving water at high-pressures, however, water preferentially enters olivine than in pyrope. We are undertaking systematic study to estimate the solubility of water in pyrope as a function of pressure. This will enable us to develop solubility models to understand the defect mechanisms

  18. 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.

  19. Prevention of obesity relatred metabolic diseases by processed foods containing soluble dietary fibers and flavonoids (abstract)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  20. Soluble catalysts for improved Pschorr cyclizations

    SciTech Connect

    Wassmundt, F.W.; Kiesman, W.F.

    1995-01-13

    Several improved catalysts for the Pschorr phenanthrene synthesis have been discovered; all are soluble substances which initiate free-radical reactions by electron donation and thereby shorten the reaction time and increase the yield. One technique with K{sub 4}Fe(CN){sub 6} in water produced phenanthrene-9-carboxylic acid (6a) in 87% yield, but its application did not extend to substituted examples where the diazonium salt is less soluble in water. A more general procedure with ferrocene in acetone produced not only 6a but also substituted examples 6b-f in yields of 88-94%. A modification which avoids the isolation of diazonium salts was developed for occasional synthetic use. 3 tabs.

  1. Preparation of Soluble Proteins from Escherichia coli

    PubMed Central

    Wingfield, Paul T.

    2014-01-01

    Purification of human IL-1β is used in this unit as an example of the preparation of soluble proteins from E. coli. Bacteria containing IL-1β are lysed, and IL-1 β in the resulting supernatant is purified by anion-exchange chromatography, salt precipitation and cation-exchange chromatography, and then concentrated. Finally, the IL-1 β protein is applied to a gel-filtration column to separate it from remaining higher- and lower-molecular-weight contaminants, the purified protein is stored frozen or is lyophilized. The purification protocol described is typical for a protein that is expressed in fairly high abundance (i.e., >5% total protein) and accumulates in a soluble state. Also, the purification procedure serves as an example of how use classical protein purifications methods which may also be used in conjunction with the affinity-based methods now more commonly used. PMID:25367009

  2. Biochemical synthesis of water soluble conducting polymers

    NASA Astrophysics Data System (ADS)

    Bruno, Ferdinando F.; Bernabei, Manuele

    2016-05-01

    An efficient biomimetic route for the synthesis of conducting polymers/copolymers complexed with lignin sulfonate and sodium (polystyrenesulfonate) (SPS) will be presented. This polyelectrolyte assisted PEG-hematin or horseradish peroxidase catalyzed polymerization of pyrrole (PYR), 3,4 ethyldioxithiophene (EDOT) and aniline has provided a route to synthesize water-soluble conducting polymers/copolymers under acidic conditions. The UV-vis, FTIR, conductivity and cyclic voltammetry studies for the polymers/copolymer complex indicated the presence of a thermally stable and electroactive polymers. Moreover, the use of water-soluble templates, used as well as dopants, provided a unique combination of properties such as high electronic conductivity, and processability. These polymers/copolymers are nowadays tested/evaluated for antirust features on airplanes and helicopters. However, other electronic applications, such as photovoltaics, for transparent conductive polyaniline, actuators, for polypyrrole, and antistatic films, for polyEDOT, will be proposed.

  3. Preparation of Hydrochlorothiazide Nanoparticles for Solubility Enhancement.

    PubMed

    Vaculikova, Eliska; Cernikova, Aneta; Placha, Daniela; Pisarcik, Martin; Peikertova, Pavlina; Dedkova, Katerina; Devinsky, Ferdinand; Jampilek, Josef

    2016-01-01

    Nanoparticles can be considered as a useful tool for improving properties of poorly soluble active ingredients. Hydrochlorothiazide (Class IV of the Biopharmaceutical Classification System) was chosen as a model compound. Antisolvent precipitation-solvent evaporation and emulsion solvent evaporation methods were used for preparation of 18 samples containing hydrochlorothiazide nanoparticles. Water solutions of surfactants sodium dodecyl sulfate, Tween 80 and carboxymethyl dextran were used in mass concentrations of 1%, 3% and 5%. Acetone and dichloromethane were used as solvents of the model compound. The particle size of the prepared samples was measured by dynamic light scattering. The selected sample of hydrochlorothiazide nanoparticles stabilized with carboxymethyl dextran sodium salt with particle size 2.6 nm was characterized additionally by Fourier transform mid-infrared spectroscopy and scanning electron microscopy. It was found that the solubility of this sample was 6.5-fold higher than that of bulk hydrochlorothiazide. PMID:27490530

  4. Soluble Aβ oligomer production and toxicity.

    PubMed

    Larson, Megan E; Lesné, Sylvain E

    2012-01-01

    For nearly 100 years following the first description of this neurological disorder by Dr Alois Alzheimer, amyloid plaques and neurofibrillary tangles have been hypothesized to cause neuronal loss. With evidence that the extent of insoluble, deposited amyloid poorly correlated with cognitive impairment, research efforts focused on soluble forms of Aβ, also referred as Aβ oligomers. Following a decade of studies, soluble oligomeric forms of Aβ are now believed to induce the deleterious cascade(s) involved in the pathophysiology of Alzheimer's disease. In this review, we will discuss our current understanding about endogenous oligomeric Aβ production, their relative toxicity in vivo and in vitro, and explore the potential future directions needed for the field.

  5. Co-solubility in binary phospholipid crystals.

    PubMed

    Dorset, D L; Massalski, A K

    1987-10-01

    Crystalline binary solid solutions of phosphatidylethanolamines are obtained when various fractions of compounds with different chain lengths are dissolved in chloroform and allowed to evaporate to dryness. Phase diagrams and electron diffraction measurements on chain mixtures with a difference of two or four methylene groups indicate that solubility is continuous, although non-ideal. Average molecular volume appears to increase according to Vegard's rule although deviations are noted. These deviations are similar to those observed for binary paraffin solids. Substitution of ether-links for ester-links in one component does not alter solubility behavior. In general the rules of solid solution formation appear to conform to those originally proposed by Kitaigorodskii [1961) Organic Chemical Crystallography, pp. 231-240, Consultants Bureau, New York).

  6. Nomenclature for mammalian soluble glutathione transferases.

    PubMed

    Mannervik, Bengt; Board, Philip G; Hayes, John D; Listowsky, Irving; Pearson, William R

    2005-01-01

    The nomenclature for human soluble glutathione transferases (GSTs) is extended to include new members of the GST superfamily that have been discovered, sequenced, and shown to be expressed. The GST nomenclature is based on primary structure similarities and the division of GSTs into classes of more closely related sequences. The classes are designated by the names of the Greek letters: Alpha, Mu, Pi, etc., abbreviated in Roman capitals: A, M, P, and so on. (The Greek characters should not be used.) Class members are distinguished by Arabic numerals and the native dimeric protein structures are named according to their subunit composition (e.g., GST A1-2 is the enzyme composed of subunits 1 and 2 in the Alpha class). Soluble GSTs from other mammalian species can be classified in the same manner as the human enzymes, and this chapter presents the application of the nomenclature to the rat and mouse GSTs. PMID:16399376

  7. Preparation of Soluble Proteins from Escherichia coli.

    PubMed

    Wingfield, Paul T

    2014-01-01

    Purification of human IL-1β is used in this unit as an example of the preparation of a soluble protein from E. coli. Bacteria containing IL-1β are lysed, and IL-1 β in the resulting supernatant is purified by anion-exchange chromatography, salt precipitation, and cation-exchange chromatography, and then concentrated. Finally, the IL-1 β protein is applied to a gel-filtration column to separate it from remaining higher- and lower-molecular-weight contaminants, the purified protein is stored frozen or is lyophilized. The purification protocol described is typical for a protein that is expressed in fairly high abundance (i.e., >5% total protein) and accumulates in a soluble state. In addition, the purification procedure serves as an example of how to use classical protein purifications methods, which may also be used in conjunction with the affinity-based methods now more commonly used. PMID:25367009

  8. Soluble organic nanotubes for catalytic systems.

    PubMed

    Xiong, Linfeng; Yang, Kunran; Zhang, Hui; Liao, Xiaojuan; Huang, Kun

    2016-03-18

    In this paper, we report a novel method for constructing a soluble organic nanotube supported catalyst system based on single-molecule templating of core–shell bottlebrush copolymers. Various organic or metal catalysts, such as sodium prop-2-yne-1-sulfonate (SPS), 1-(2-(prop-2-yn-1-yloxy)ethyl)-1H-imidazole (PEI) and Pd(OAc)2 were anchored onto the tube walls to functionalize the organic nanotubes via copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Depending on the 'confined effect' and the accessible cavity microenvironments of tubular structures, the organic nanotube catalysts showed high catalytic efficiency and site-isolation features. We believe that the soluble organic nanotubes will be very useful for the development of high performance catalyst systems due to their high stability of support, facile functionalization and attractive textural properties. PMID:27308672

  9. Nomenclature for mammalian soluble glutathione transferases.

    PubMed

    Mannervik, Bengt; Board, Philip G; Hayes, John D; Listowsky, Irving; Pearson, William R

    2005-01-01

    The nomenclature for human soluble glutathione transferases (GSTs) is extended to include new members of the GST superfamily that have been discovered, sequenced, and shown to be expressed. The GST nomenclature is based on primary structure similarities and the division of GSTs into classes of more closely related sequences. The classes are designated by the names of the Greek letters: Alpha, Mu, Pi, etc., abbreviated in Roman capitals: A, M, P, and so on. (The Greek characters should not be used.) Class members are distinguished by Arabic numerals and the native dimeric protein structures are named according to their subunit composition (e.g., GST A1-2 is the enzyme composed of subunits 1 and 2 in the Alpha class). Soluble GSTs from other mammalian species can be classified in the same manner as the human enzymes, and this chapter presents the application of the nomenclature to the rat and mouse GSTs.

  10. Best-basis estimates of solubility of selected radionuclides in sludges in Hanford single-shell tanks

    SciTech Connect

    HARMSEN, R.W.

    1999-02-24

    The Hanford Defined Waste (HDW) model (Rev. 4) (Agnew et al. 1997) projects inventories (as of January 1, 1994) of 46 radionuclides in the Hanford Site underground waste storage tanks. To model the distribution of the 46 radionuclides among the 177 tanks, it was necessary for Agnew et al. to estimate the solubility of each radionuclide in the various waste types originally added to the single-shell tanks. Previous editions of the HDW model used single-point solubility estimates. The work described in this report was undertaken to provide more accurate estimates of the solubility of all 46 radionuclides in the various wastes.

  11. Wormhole growth in soluble porous materials

    SciTech Connect

    Nilson, R.H.; Griffiths, S.K. )

    1990-09-24

    Analytical solutions are derived for the quasisteady shape and speed of a single wormhole resulting from the coupled processes of Darcian fluid motion and chemical dissolution in a soluble permeable material. For an initially unsaturated medium, two-dimensional solutions are obtained by addressing an inverted free-boundary problem in which the spatial coordinates are treated as dependent variables on the plane of a complex potential. For initially saturated materials, solutions are obtained by analogy to Ivantsov's problem of dendrite growth.

  12. Murine lung immunity to a soluble antigen

    SciTech Connect

    Weissman, D.N.; Bice, D.E.; Siegel, D.W.; Schuyler, M.R. Lovelace Biomedical and Environmental Research Inst., Albuquerque, NM )

    1990-01-01

    To test the hypothesis that soluble antigen triggers antigen-specific immunity in the respiratory tract in a fashion similar to that reported for particulate antigen, the authors examined the development of local and systemic immunity in C57BL/6 mice after intratracheal (i.t.) instillation of a soluble, large molecular weight protein neoantigen, keyhole limpet hemocyanin (KLH). Specific anti-KLH IgG and IgM first appeared in the sera of mice on day 7 after primary immunization by i.t. instillation of KLH, with specific serum antibody concentrations remaining elevated at day 11. Cultured spleen cells obtained from mice after primary immunization released only low levels of specific IgM, and no specific IgG. No specific antibody was released by cell populations derived from the lungs of animals undergoing primary immunization. When presensitized mice were given an i.t. challenge with KLH, responses differed markedly from those following primary immunization. Lung-associated lymph node cell populations from challenged mice released greater amounts of specific antibody earlier than did cell populations, which after primary immunization had not released detectable amounts of specific antibody in vitro, released easily detectable amounts of specific antibody after challenge. Thus, i.t. instillation of soluble KLH generates specific immunity in mice in a fashion similar to that reported for particulate antigen. Specific responses following primary immunization occur largely within draining lung-associated lymph nodes. In contrast, presensitized animals challenged i.t. with soluble KLH mount secondary antibody responses in both lung and lung-associated lymph nodes.

  13. Evaluation of soluble cell adhesion molecules in atopic dermatitis.

    PubMed

    Koide, M; Furukawa, F; Tokura, Y; Shirahama, S; Takigawa, M

    1997-02-01

    Recent studies have indicated the importance of cell adhesion molecules (CAMs) between the vascular endothelium and activated leukocytes in various inflammatory skin diseases. Soluble forms of CAMs (sCAMs) have also been detected in sera from such diseases. In order to elucidate the role of the soluble forms in skin inflammation, we determined the serum levels of E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) in patients with atopic dermatitis (AD). Using an enzyme-linked immunosorbent assay, we quantified sCAMs levels in 21 patients with atopic dermatitis and in 16 healthy controls. In severe AD patients, levels of these three types of sCAMs were markedly elevated. sE-selectin was significantly elevated in severe AD over the levels in mild AD. A positive correlation with individual clinical activity was found for changes in the sE-selectin and sVCAM-1 levels. sE-selectin levels were correlated with the serum IgE levels and the number of eosinophils. The sVCAM-1 level was also significantly correlated with the number of monocytes. Among these three molecules, sE-selectin appeared to be the most sensitive clinical parameter in monitoring the clinical course of AD patients.

  14. Theory Of Salt Effects On Protein Solubility

    NASA Astrophysics Data System (ADS)

    Dahal, Yuba; Schmit, Jeremy

    Salt is one of the major factors that effects protein solubility. Often, at low salt concentration regime, protein solubility increases with the salt concentration(salting in) whereas at high salt concentration regime, solubility decreases with the increase in salt concentration(salting out). There are no quantitative theories to explain salting in and salting out. We have developed a model to describe the salting in and salting out. Our model accounts for the electrostatic Coulomb energy, salt entropy and non-electrostatic interaction between proteins. We analytically solve the linearized Poisson Boltzmann equation modelling the protein charge by a first order multipole expansion. In our model, protein charges are modulated by the anion binding. Consideration of only the zeroth order term in protein charge doesn't help to describe salting in phenomenon because of the repulsive interaction. To capture the salting in behaviour, it requires an attractive electrostatic interaction in low salt regime. Our work shows that at low salt concentration, dipole interaction is the cause for salting in and at high salt concentration a salt-dependent depletion interaction dominates and gives the salting out. Our theoretical result is consistent with the experimental result for Chymosin protein NIH Grant No R01GM107487.

  15. Aluminum Solubility in Complex Electrolytes - 13011

    SciTech Connect

    Agnew, S.F.; Johnston, C.T.

    2013-07-01

    Predicting aluminum solubility for Hanford and Savannah River waste liquids is very important for their disposition. It is a key mission goal at each Site to leach as much aluminum as practical from sludges in order to minimize the amount of vitrified high level waste. And it is correspondingly important to assure that any soluble aluminum does not precipitate during subsequent decontamination of the liquid leachates with ion exchange. This report shows a very simple and yet thermodynamic model for aluminum solubility that is consistent with a wide range of Al liquors, from simple mixtures of hydroxide and aluminate to over 300 Hanford concentrates and to a set of 19 Bayer liquors for temperatures from 20-100 deg. C. This dimer-dS{sub mix} (DDS) model incorporates an ideal entropy of mixing along with previous reports for the Al dimer, water activities, gibbsite, and bayerite thermodynamics. We expect this model will have broad application for nuclear wastes as well as the Bayer gibbsite process industry. (authors)

  16. Skin protection, Viton, and solubility parameters.

    PubMed

    Perkins, J L; Ridge, M C; Holcombe, A B; Wang, M K; Nonidez, W E

    1986-12-01

    Permeation is a function of diffusion and solubility of the solvent/polymer system. A physical-chemical constant that has been used previously to predict solubility is the three-dimensional solubility parameter (3-DSP). This paper reports a method for calculating the 3-DSP for the polymer Viton, new permeation data for Viton and 14 solvents, and the application of the 3-DSP to a model for predicting permeation parameters. The 3-DSP values for Viton (J/cc)1/2 were dispersion = 17.0, polar = 10.6, and hydrogen bonding = 6.1. A correlation coefficient of 0.65 was obtained when the natural log of breakthrough time for 19 solvents was regressed against the differences of the 3-DSP's for these 19 solvents and Viton. A value of 0.69 was obtained for the natural log of the permeation rate vs 16 solvent-Viton 3-DSP differences. While the variance unaccounted for in these regression tests does not allow quantitative prediction of permeation parameters, qualitative prediction of polymer suitability is possible. PMID:3799483

  17. Fluorite solubility equilibria in selected geothermal waters

    USGS Publications Warehouse

    Nordstrom, D.K.; Jenne, E.A.

    1977-01-01

    Calculation of chemical equilibria in 351 hot springs and surface waters from selected geothermal areas in the western United States indicate that the solubility of the mineral fluorite, CaF2, provides an equilibrium control on dissolved fluoride activity. Waters that are undersaturated have undergone dilution by non-thermal waters as shown by decreased conductivity and temperature values, and only 2% of the samples are supersaturated by more than the expected error. Calculations also demonstrate that simultaneous chemical equilibria between the thermal waters and calcite as well as fluorite minerals exist under a variety of conditions. Testing for fluorite solubility required a critical review of the thermodynamic data for fluorite. By applying multiple regression of a mathematical model to selected published data we have obtained revised estimates of the pK (10,96), ??Gof (-280.08 kcal/mole), ??Hof (-292.59 kcal/mole), S?? (16.39 cal/deg/mole) and CoP (16.16 cal/deg/mole) for CaF2 at 25??C and 1 atm. Association constants and reaction enthalpies for fluoride complexes with boron, calcium and iron are included in this review. The excellent agreement between the computer-based activity products and the revised pK suggests that the chemistry of geothermal waters may also be a guide to evaluating mineral solubility data where major discrepancies are evident. ?? 1977.

  18. Structure and Aqueous Solubility of Sodium Isosaccharinate

    SciTech Connect

    Bontchev, Ranko P.; Moore, Robert; Tucker, Mark; Holt, Kathleen

    2004-03-29

    It has been recently shown that isosaccharinic acid, C6H12O6 (ISA), and its derivative salts have a great potential for practical application in the area of nuclear waste treatment and disposal sites management. Several studies demonstrated the effect of ISA complexation on radionuclide solubility and sorptive properties, especially on actinides in (+4) oxidation state like Np(IV) and Th(IV). The presence of ISA and/or its derivatives strongly affects the migration of radionuclides by increasing their solubility in water by several orders of magnitude and Na-ISA has been proposed as a component of decontamination formulations for actinide-contaminated surfaces. Here we report the synthesis, crystal's structure and characterization (FTIR, TGA) of sodium isosaccharate, NaC6H11O6-H2O (Na-ISA). The structure has been solved by single crystal X-ray diffraction methods. The solubility of Na-ISA has been evaluated and compared to that of Ca-ISA based on the structural features of both compounds.

  19. Solubility of nitrous oxide in amine solutions

    SciTech Connect

    Bensetiti, Z.; Iliuta, I.; Larachi, F.; Grandjean, B.P.A.

    1999-01-01

    The solubility of nitrous oxide (N{sub 2}O) in 13 amine solvents and solutions was correlated to amine mole fractions and temperature using feedforward neural networks. This general correlation, using a massive database, predicted N{sub 2}O solubility at temperatures between 283 and 398 K in pure solvents [H{sub 2}O, monoethanolamine (MEA), diethanolamine (DEA), methyldiethanolamine (MDEA), and 2-amino-2-methyl-1-propanolamine (AMP)], in binary aqueous amine solutions [H{sub 2}O/MEA, H{sub 2}O/DEA, H{sub 2}O/MDEA, and H{sub 2}O/AMP], and in ternary aqueous amine blends [AMP/MDEA/H{sub 2}O, AMP/DEA/H{sub 2}O, DEA/MDEA/H{sub 2}O, MDEA/MEA/H{sub 2}O, and AMP/MEA/H{sub 2}O]. Combined with the N{sub 2}O analogy, this present improved correlation can be advantageously implemented in amine plant design software and procedures for the prediction of CO{sub 2} solubility in amine blend solutions over wide temperature and concentration ranges.

  20. Determining silica solubility in bayer process liquor

    NASA Astrophysics Data System (ADS)

    Müller-Steinhagen, H.

    1998-11-01

    The efficient precipitation of dissolved silica from Bayer process liquor is essential for the production of high-quality alumina and the reduction of excessive scaling in the heat exchangers in the evaporation building of Bayer processes. The accurate prediction of silica solubility in Bayer liquor is one of the key parameters in improving the design and operation of the desilication process. Previous findings, particularly with respect to the influence of temperature and concentrations of caustic soda and alumina on the solubility of silica, are inconclusive. In this article, experimental results are presented over a wide range of temperature and alumina and caustic soda concentrations. Attempts are made to utilize artificial neural networks for identifying the process variables and modeling. The radial basis function neural network architecture was used successfully to generate a nonlinear correlation for the prediction of the solubility of silica in Bayer process liquor. The resulting correlation can predict the present data and the control data of other investigators with good accuracy.

  1. Chemiluminescent nitrogen detection (CLND) to measure kinetic aqueous solubility.

    PubMed

    Kestranek, Aimee; Chervenak, Andrew; Longenberger, Justin; Placko, Steven

    2013-01-01

    Solubility is the dose-limiting property for in vitro studies, and therefore is a critical physicochemical property to measure in drug discovery. Solubility data can be used to guide lead optimization, troubleshoot erratic bioassay results, and identify potential downstream liabilities such as insufficient solubility for bioassays or oral bioavailability. Typically, early in vitro studies are performed using library compounds prepared as dimethylsulfoxide (DMSO) stock solutions, resulting in in vitro test solutions containing DMSO at low concentration (<5% v/v). Since DMSO can affect the apparent solubility, it is desirable to obtain solubility data under conditions mimicking the in vitro study. Kinetic solubility (from DMSO stock solutions) is often preferred over thermodynamic solubility (from dry powder) in early drug discovery. The protocols in this article describe a general procedure for assessing kinetic aqueous solubility of early drug discovery compounds using a miniaturized shake flask method with chemiluminescent nitrogen detection (CLND).

  2. The removal of kaolinite suspensions by acid-soluble and water-soluble chitosans.

    PubMed

    Chung, Ying-Chien; Wu, Li-Chun; Chen, Chih-Yu

    2013-01-01

    Chitosan is a potential substitute for traditional aluminium salts in water treatment systems. This research compared the coagulant performance of acid-soluble chitosan with water-soluble chitosan and with coagulant mixtures of chitosan and aluminium sulfate (alum). We also assessed the coagulant performance of chitosan and poly-aluminium chloride (PAC) to remove kaolinite from turbid water. In addition, we evaluated their respective coagulation efficiencies under different coagulant concentrations, degrees of turbidity (NTU) and pH levels. Furthermore, we determined the size and settling velocity of flocs formed by these coagulants in order to illustrate major factors affecting kaolinite coagulation. The optimal concentrations of acid- versus water- soluble chitosan required to remove kaolinite from a 300 NTU suspension were 4.0 and 10.0 mg/l, respectively-with individual efficiencies of 79.3 and 92.4%, in that order. Optimum concentrations ofwater-soluble chitosan demonstrated a broader range than that of acid-soluble chitosan. In addition, it is of note that chitosan/alum and chitosan/PAC water-soluble coagulant mixtures demonstrated much wider ranges of optimal concentrations for turbidity reduction than either alum or PAC alone. Moreover, our water-soluble chitosan coagulant mixtures produced denser floc with elevated settling velocities that favour cost savings relevant to both installation and operational expenses. Based on our observations of these noteworthy performances, we confidently propose that a coagulant mixture with a 1:1 mass ratio of chitosan and alum presents a remarkably more cost-effective alternative to the use of chitosan alone in water treatment systems. PMID:23530342

  3. Solubilities of stearic acid, stearyl alcohol, and arachidyl alcohol in supercritical carbon dioxide at 35[degree]C

    SciTech Connect

    Iwai, Yoshio; Koga, Yoshio; Maruyama, Hironori; Arai, Yasuhiko . Dept. of Chemical Engineering)

    1993-10-01

    The solubilities of stearic acid (octadecanoic acid), stearyl alcohol (1-octadecanol), and arachidyl alcohol (1-eicosanol) in supercritical carbon dioxide were measured by using a flow-type apparatus at 35 C up to 23.7 MPa. The solubilities of those substances and other fatty acids and higher alcohols in supercritical carbon dioxide at 35 C were correlated by a solution model based on the regular solution model coupled with the Flory-Huggins theory.

  4. Solubility of fluoranthene, chrysene, and triphenylene in supercritical carbon dioxide

    SciTech Connect

    Barna, L.; Blanchard, J.M.; Rauzy, E.; Berro, C.

    1996-11-01

    The solubility of polycyclic aromatic hydrocarbons in supercritical carbon dioxide is very low, and very little experimental data exist. A method has been developed for the measurement of such low solubilities, and the solubilities of fluoranthene, chrysene, and triphenylene in a temperature range 308.15 K to 328.15 K and in a pressure range 84 bar to 251 bar have been determined. The solubilities have been fitted to the excess function-equation of state model.

  5. Mirabilite solubility in equilibrium sea ice brines

    NASA Astrophysics Data System (ADS)

    Butler, Benjamin Miles; Papadimitriou, Stathys; Santoro, Anna; Kennedy, Hilary

    2016-06-01

    The sea ice microstructure is permeated by brine channels and pockets that contain concentrated seawater-derived brine. Cooling the sea ice results in further formation of pure ice within these pockets as thermal equilibrium is attained, resulting in a smaller volume of increasingly concentrated residual brine. The coupled changes in temperature and ionic composition result in supersaturation of the brine with respect to mirabilite (Na2SO4·10H2O) at temperatures below -6.38 °C, which consequently precipitates within the sea ice microstructure. Here, mirabilite solubility in natural and synthetic seawater derived brines, representative of sea ice at thermal equilibrium, has been measured in laboratory experiments between 0.2 and -20.6 °C, and hence we present a detailed examination of mirabilite dynamics within the sea ice system. Below -6.38 °C mirabilite displays particularly large changes in solubility as the temperature decreases, and by -20.6 °C its precipitation results in 12.90% and 91.97% reductions in the total dissolved Na+ and SO42- concentrations respectively, compared to that of conservative seawater concentration. Such large non-conservative changes in brine composition could potentially impact upon the measurement of sea ice brine salinity and pH, whilst the altered osmotic conditions may create additional challenges for the sympagic organisms that inhabit the sea ice system. At temperatures above -6.38 °C, mirabilite again displays large changes in solubility that likely aid in impeding its identification in field samples of sea ice. Our solubility measurements display excellent agreement with that of the FREZCHEM model, which was therefore used to supplement our measurements to colder temperatures. Measured and modelled solubility data were incorporated into a 1D model for the growth of first-year Arctic sea ice. Model results ultimately suggest that mirabilite has a near ubiquitous presence in much of the sea ice on Earth, and illustrate the

  6. 21 CFR 524.1580c - Nitrofurazone soluble powder.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Nitrofurazone soluble powder. 524.1580c Section... § 524.1580c Nitrofurazone soluble powder. (a) Specifications. The drug contains 0.2 percent nitrofurazone in a water-soluble base. (b) Sponsor. See Nos. 000010, 000069, and 050749 in § 510.600(c) of...

  7. 21 CFR 524.1580c - Nitrofurazone soluble powder.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Nitrofurazone soluble powder. 524.1580c Section... § 524.1580c Nitrofurazone soluble powder. (a) Specifications. The drug contains 0.2 percent nitrofurazone in a water-soluble base. (b) Sponsor. See Nos. 000010 and 000069 in § 510.600(c) of this...

  8. 21 CFR 524.1580c - Nitrofurazone soluble powder.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Nitrofurazone soluble powder. 524.1580c Section... § 524.1580c Nitrofurazone soluble powder. (a) Specifications. The drug contains 0.2 percent nitrofurazone in a water-soluble base. (b) Sponsor. See Nos. 000010 and 000069 in § 510.600(c) of this...

  9. Solubility data are compiled for metals in liquid zinc

    NASA Technical Reports Server (NTRS)

    Dillon, I. G.; Johnson, I.

    1967-01-01

    Available data is compiled on the solubilities of various metals in liquid zinc. The temperature dependence of the solubility data is expressed using the empirical straight line relationship existing between the logarithm of the solubility and the reciprocal of the absolute temperature.

  10. 21 CFR 520.1263c - Lincomycin hydrochloride soluble powder.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Lincomycin hydrochloride soluble powder. 520.1263c... Lincomycin hydrochloride soluble powder. (a) Specifications. Each gram of soluble powder contains lincomycin... water containing lincomycin. Not for use in layer and breeder chickens....

  11. 21 CFR 520.1263c - Lincomycin hydrochloride soluble powder.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Lincomycin hydrochloride soluble powder. 520.1263c... Lincomycin hydrochloride soluble powder. (a) Specifications. Each gram of soluble powder contains lincomycin... water containing lincomycin. Not for use in layer and breeder chickens....

  12. 21 CFR 520.1263c - Lincomycin hydrochloride soluble powder.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Lincomycin hydrochloride soluble powder. 520.1263c... Lincomycin hydrochloride soluble powder. (a) Specifications. Each gram of soluble powder contains lincomycin... water containing lincomycin. Not for use in layer and breeder chickens....

  13. Role of hydrogen bonding in solubility of poly(N-isopropylacrylamide) brushes in sodium halide solutions

    NASA Astrophysics Data System (ADS)

    Xin-Jun, Zhao; Zhi-Fu, Gao

    2016-07-01

    By employing molecular theory, we systematically investigate the shift of solubility of poly(N-isopropylacrylamide) (PNIPAM) brushes in sodium halide solutions. After considering PNIPAM–water hydrogen bonds, water–anion hydrogen bonds, and PNIPAM–anion bonds and their explicit coupling to the PNIPAM conformations, we find that increasing temperature lowers the solubility of PNIPAM, and results in a collapse of the layer at high enough temperatures. The combination of the three types of bonds would yield a decrease in the solubility of PNIPAM following the Hofmeister series: NaCl>NaBr>NaI. PNIPAM–water hydrogen bonds are affected by water–anion hydrogen bonds and PNIPAM–anion bonds. The coupling of polymer conformations and the competition among the three types of bonds are essential for describing correctly a decrease in the solubility of PNIPAM brushes, which is determined by the free energy associated with the formation of the three types of bonds. Our results agree well with the experimental observations, and would be very important for understanding the shift of the lower critical solution temperature of PNIPAM brushes following the Hofmeister series. Project supported by the National Natural Science Foundation of China (Grant Nos. 21264016, 11464047, and 21364016) and the Joint Funds of Xinjiang Natural Science Foundation, China (Grant No. 2015211C298).

  14. 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

  15. Solubility Behavior and Phase Stability of Transition Metal Oxides in Alkaline Hydrothermal Environments

    SciTech Connect

    S.E. Ziemniak

    2000-05-18

    The solubility behavior of transition metal oxides in high temperature water is interpreted by recognizing three types of chemical reaction equilibria: metal oxide hydration/dehydration, metal oxide dissolution and metal ion hydroxocomplex formation. The equilibria are quantified using thermodynamic concepts and the thermochemical properties of the metal oxides/ions representative of the most common constituents of construction metal alloys, i.e., element shaving atomic numbers between Z = 22 (Ti) and Z = 30 (Zn), are summarized on the basis of metal oxide solubility studies conducted in the laboratory. Particular attention is devoted to the uncharged metal ion hydrocomplex, M{sup Z}(OH){sub Z}(aq), since its thermochemical properties define minimum solubilities of the metal oxide at a given temperature. Experimentally-extracted values of standard partial molal entropy (S{sup 0}) for the transition metal ion neutral hydroxocomplex are shown to be influenced by ligand field stabilization energies and complex symmetry.

  16. IUPAC-NIST Solubility Data Series. 95. Alkaline Earth Carbonates in Aqueous Systems. Part 2. Ca

    SciTech Connect

    De Visscher, Alex; Vanderdeelen, Jan

    2012-06-15

    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{sub 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.

  17. Predicting Melting Points of Organic Molecules: Applications to Aqueous Solubility Prediction Using the General Solubility Equation.

    PubMed

    McDonagh, J L; van Mourik, T; Mitchell, J B O

    2015-11-01

    In this work we make predictions of several important molecular properties of academic and industrial importance to seek answers to two questions: 1) Can we apply efficient machine learning techniques, using inexpensive descriptors, to predict melting points to a reasonable level of accuracy? 2) Can values of this level of accuracy be usefully applied to predicting aqueous solubility? We present predictions of melting points made by several novel machine learning models, previously applied to solubility prediction. Additionally, we make predictions of solubility via the General Solubility Equation (GSE) and monitor the impact of varying the logP prediction model (AlogP and XlogP) on the GSE. We note that the machine learning models presented, using a modest number of 2D descriptors, can make melting point predictions in line with the current state of the art prediction methods (RMSE≥40 °C). We also find that predicted melting points, with an RMSE of tens of degrees Celsius, can be usefully applied to the GSE to yield accurate solubility predictions (log10 S RMSE<1) over a small dataset of drug-like molecules. PMID:27491032

  18. Predicting Melting Points of Organic Molecules: Applications to Aqueous Solubility Prediction Using the General Solubility Equation.

    PubMed

    McDonagh, J L; van Mourik, T; Mitchell, J B O

    2015-11-01

    In this work we make predictions of several important molecular properties of academic and industrial importance to seek answers to two questions: 1) Can we apply efficient machine learning techniques, using inexpensive descriptors, to predict melting points to a reasonable level of accuracy? 2) Can values of this level of accuracy be usefully applied to predicting aqueous solubility? We present predictions of melting points made by several novel machine learning models, previously applied to solubility prediction. Additionally, we make predictions of solubility via the General Solubility Equation (GSE) and monitor the impact of varying the logP prediction model (AlogP and XlogP) on the GSE. We note that the machine learning models presented, using a modest number of 2D descriptors, can make melting point predictions in line with the current state of the art prediction methods (RMSE≥40 °C). We also find that predicted melting points, with an RMSE of tens of degrees Celsius, can be usefully applied to the GSE to yield accurate solubility predictions (log10 S RMSE<1) over a small dataset of drug-like molecules.

  19. Phenol-soluble modulins – critical determinants of staphylococcal virulence

    PubMed Central

    Cheung, Gordon Y. C.; Joo, Hwang-Soo; Chatterjee, Som S.; Otto, Michael

    2014-01-01

    Phenol-soluble modulins (PSMs) are a recently discovered family of amphipathic, alpha-helical peptides that have multiple roles in staphylococcal pathogenesis and contribute to a large extent to the pathogenic success of virulent staphylococci, such as Staphylococcus aureus. PSMs may cause lysis of many human cell types including leukocytes and erythrocytes, stimulate inflammatory responses, and contribute to biofilm development. PSMs appear to have an original role in the commensal lifestyle of staphylococci, where they facilitate growth and spreading on epithelial surfaces. Aggressive, cytolytic PSMs seem to have evolved from that original role and are mainly expressed in highly virulent S. aureus. Here we will review the biochemistry, genetics and role of PSMs in the commensal and pathogenic lifestyles of staphylococci, discuss how diversification of PSMs defines the aggressiveness of staphylococcal species, and evaluate potential avenues to target PSMs for drug development against staphylococcal infections. PMID:24372362

  20. Illinois basin coal fly ashes. 1. Chemical characterization and solubility

    USGS Publications Warehouse

    Roy, W.R.; Griffin, R.A.; Dickerson, D.R.; Schuller, R.M.; Martin, S.M.C.

    1984-01-01

    Twelve precipitator-collected fly ash samples (nine derived from high-sulfur Illinois Basin coals and three from Western U.S. coals) were found to contain a variety of paraffins, aryl esters, phenols, and polynuclear aromatic hydrocarbons including phenanthrene, pyrene, and chrysene but all at very low concentrations. Less than 1% of the organic carbon in the samples was extractable into benzene. Solubility studies with a short-term (24-h) extraction procedure and a long-term (20-week) procedure indicate that the inorganic chemical composition of some types of fly ash effluent is time dependent and may be most toxic to aquatic ecosystems when initially mixed with water and pumped to disposal ponds. Some acidic, high-Cd fly ashes would be classified as hazardous wastes if coal ash was included in this waste category by future RCRA revisions. ?? 1984 American Chemical Society.

  1. Scavenging of soluble organic matter from the prebiotic oceans.

    PubMed

    Nissenbaum, A

    1976-12-01

    The existence of hot or cold "nutrient broth" or "primeval soup" is challenged on the basis of the recent geochemistry of soluble organic carbon in the oceans. Most of the dissolved organic carbon is recycled quickly by organisms, but the residual, biologically refractive, organic matter is efficiently scavenged from the oceans (residence time of 1000 to 3500 years) by nonbiologically mediated chemical and physical processes, such as adsorption on sinking minerals, polymerization and aggregation to humic type polymers or by aggregation to particulate matter through bubbling and sinking of this material to the ocean bottom. Since there is no reason to believe that such nonbiological scavenging was not operative in the prebiotic oceans as well, then the prolonged existence of "organic soup" is very doubtful. The question of the origin of life is thus assumed to be related to solid-liquid interfacial activity, and the answer may be associated with sediment-water interaction rather than with solution chemistry.

  2. Reactivity of Metal Ions Bound to Water-Soluble Polymers

    SciTech Connect

    Sauer, N.N.; Watkins, J.G.; Lin, M.; Birnbaum, E.R.; Robison, T.W.; Smith, B.F.; Gohdes, J.W.; McDonald, J.G.

    1999-06-29

    The intent of this work is to determine the effectiveness of catalysts covalently bound to polymers and to understand the consequences of supporting the catalysts on catalyst efficiency and selectivity. Rhodium phosphine complexes with functional groups for coupling to polymers were prepared. These catalyst precursors were characterized using standard techniques including IR, NMR, and elemental analysis. Studies on the modified catalysts showed that they were still active hydrogenation catalysts. However, tethering of the catalysts to polyamines gave systems with low hydrogenation activity. Analogous biphasic systems were also explored. Phosphine ligands with a surfactant-like structure have been synthesized and used to prepare catalytically active complexes of palladium. The palladium complexes were utilized in Heck-type coupling reactions (e.g. coupling of iodobenzene and ethyl acrylate to produce ethyl cinnamate) under vigorously stirred biphasic reaction conditions, and were found to offer superior performance over a standard water-soluble palladium catalyst under analogous conditions.

  3. Comparative expression study to increase the solubility of cold adapted Vibrio proteins in Escherichia coli.

    PubMed

    Niiranen, Laila; Espelid, Sigrun; Karlsen, Christian R; Mustonen, Milla; Paulsen, Steinar M; Heikinheimo, Pirkko; Willassen, Nils P

    2007-03-01

    Functional and structural studies require gene overexpression and purification of soluble proteins. We wanted to express proteins from the psychrophilic bacterium Vibrio salmonicida in Escherichia coli, but encountered solubility problems. To improve the solubility of the proteins, we compared the effects of six N-terminal fusion proteins (Gb1, Z, thioredoxin, GST, MBP and NusA) and an N-terminal His6-tag. The selected test set included five proteins from the fish pathogen V. salmonicida and two related products from the mesophilic human pathogen Vibrio cholerae. We tested the expression in two different expression strains and at three different temperatures (16, 23 and 37 degrees C). His6-tag was the least effective tag, and these vector constructs were also difficult to transform. MBP and NusA performed best, expressing soluble proteins with all fusion partners in at least one of the cell types. In some cases MBP, GST and thioredoxin fusions resulted in products of incorrect size. The effect of temperature is complex: in most cases level of expression increased with temperature, whereas the effect on solubility was opposite. We found no clear connection between the preferred expression temperature of the protein and the temperature of the original host organism's natural habitat.

  4. Effects of solubility properties of solvents and biomass on biomass pretreatment.

    PubMed

    Weerachanchai, Piyarat; Kwak, Sang Kyu; Lee, Jong-Min

    2014-10-01

    Hildebrand solubility parameters of biomasses and pretreatment solvents were examined by a method of intrinsic viscosity. This is to be used as basic information in selecting a suitable solvent for biomass pretreatment processes. The effects of mixing1-ethyl-3-methylimidazolium acetate (EMIM-AC) and different solvents, lignin content in a pretreatment solvent, and biomass type on the Hildebrand solubility parameter and thermodynamic properties were carried out and calculated in this work. The Hildebrand solubility parameters of the mixtures are according to those of organic solvents: δH[EMIM-AC/DMA]=25.07<δH[EMIM-AC/DMF]=25.48<δH[EMIM-AC/DMSO]=26.10<δH[EMIM-AC/Ethanolamine]=26.95. The Hildebrand solubility parameters of biomass compositions (microcrystalline cellulose, xylan and alkali lignin) and biomasses (cassava pulp residue and rice straw) vary in the ranges of 25.14-26.13. The increases of lignin content in the pretreatment solvents lead to the Hildebrand solubility parameter becoming closer to that of lignin. PMID:25129231

  5. Pretreatment with soluble ST2 reduces warm hepatic ischemia/reperfusion injury

    SciTech Connect

    Yin Hui; Huang Baojun; Yang Heng; Huang Yafei; Xiong Ping; Zheng Fang; Chen Xiaoping; Chen Yifa . E-mail: yfchen@tjh.tjmu.edu.cn; Gong Feili . E-mail: flgong@163.com

    2006-12-29

    The interleukin-1 receptor-like protein ST2 exists in both membrane-bound (ST2L) and soluble form (sST2). ST2L has been found to play an important regulatory role in Th2-type immune response, but the function of soluble form of ST2 remains to be elucidated. In this study, we report the protective effect of soluble ST2 on warm hepatic ischemia/reperfusion injury. We constructed a eukaryotic expression plasmid, psST2-Fc, which expresses functional murine soluble ST2-human IgG1 Fc (sST2-Fc) fusion protein. The liver damage after ischemia/reperfusion was significantly attenuated by the expression of this plasmid in vivo. sST2-Fc remarkably inhibited the activation of Kupffer cells and the production of proinflammatory mediators TNF-{alpha} and IL-6. Furthermore, the levels of TLR4 mRNA and the nuclear translocation of NF-{kappa}B were also suppressed by pretreatment with sST2-Fc. These results thus identified soluble ST2 as a negative regulator in hepatic I/R injury, possibly via ST2-TLR4 pathway.

  6. 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.

  7. 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.

  8. Development of soluble ester-linked aldehyde polymers for proteomics.

    PubMed

    Beaudette, Patrick; Rossi, Nicholas A A; Huesgen, Pitter F; Yu, Xifei; Shenoi, Rajesh A; Doucet, Alain; Overall, Christopher M; Kizhakkedathu, Jayachandran N

    2011-09-01

    High molecular weight hyperbranched polyglycerol (HPG) was selected for development as a soluble polymer support for the targeted selection and release of primary-amine containing peptides from a complex mixture. HPG has been functionalized with ester-linked aldehyde groups that can bind primary-amine containing peptides via a reductive alkylation reaction. Once bound, the high molecular weight of the polymer facilitates separation from a complex peptide mixture by employing either a 30 kDa molecular weight cutoff membrane or precipitation in acetonitrile. Following the removal of unbound peptides and reagents, subsequent hydrolysis of the ester linker releases the bound peptide into solution for analysis by mass spectrometry. Released peptides retain the linker moiety and are therefore characteristically mass-shifted. Four water-soluble cleavable aldehyde polymers (CAP1, CAP2, CAP3, and CAP4) ranging in types of linker groups, length of the linker groups, have been prepared and characterized, each demonstrating the ability to selectively enrich and sequence primary-amine peptides from a complex human proteome containing blocked (dimethylated amine) and unblocked (primary amine) peptides. The polymers have very low nonspecific peptide-binding properties while possessing significantly more reactive groups per milligram of the support than commercially available resins. The polymers exhibit a range of reactivities and binding capacities that depend on the type of linker group between the aldehyde group and the polymer. Using various linker structures, we also probed the mechanism of the observed dehydration of hydrolyzed peptides during matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis.

  9. Ionizing radiation induces a motile phenotype in human carcinoma cells in vitro through hyperactivation of the TGF-beta signaling pathway.

    PubMed

    Carl, Cedric; Flindt, Anne; Hartmann, Julian; Dahlke, Markus; Rades, Dirk; Dunst, Jürgen; Lehnert, Hendrik; Gieseler, Frank; Ungefroren, Hendrik

    2016-01-01

    Radiotherapy, a major treatment modality against cancer, can lead to secondary malignancies but it is uncertain as to whether tumor cells that survive ionizing radiation (IR) treatment undergo epithelial-mesenchymal transition (EMT) and eventually become invasive or metastatic. Here, we have tested the hypothesis that the application of IR (10 MeV photon beams, 2-20 Gy) to lung and pancreatic carcinoma cells induces a migratory/invasive phenotype in these cells by hyperactivation of TGF-β and/or activin signaling. In accordance with this assumption, IR induced gene expression patterns and migratory responses consistent with an EMT phenotype. Moreover, in A549 cells, IR triggered the synthesis and secretion of both TGF-β1 and activin A as well as activation of intracellular TGF-β/activin signaling as evidenced by Smad phosphorylation and transcriptional activation of a TGF-β-responsive reporter gene. These responses were sensitive to SB431542, an inhibitor of type I receptors for TGF-β and activin. Likewise, specific antibody-mediated neutralization of soluble TGF-β, or dominant-negative inhibition of the TGF-β receptors, but not the activin type I receptor, alleviated IR-induced cell migration. Moreover, the TGF-β-specific approaches also blocked IR-dependent TGF-β1 secretion, Smad phosphorylation, and reporter gene activity, collectively indicating that autocrine production of TGF-β(s) and subsequent activation of TGF-β rather than activin signaling drives these changes. IR strongly sensitized cells to further increase their migration in response to recombinant TGF-β1 and this was accompanied by upregulation of TGF-β receptor expression. Our data raise the possibility that hyperactivation of TGF-β signaling during radiotherapy contributes to EMT-associated changes like metastasis, cancer stem cell formation and chemoresistance of tumor cells.

  10. Experimental data of solubility at different temperatures: a simple technique

    NASA Astrophysics Data System (ADS)

    Burghoff, J.; Nolte, S.; Tünnermann, A.

    2007-10-01

    This article describes a simple and inexpensive experimental technique, easy to set-up in a laboratory, for the measurement of solute solubilities in liquids (or gases). Experimental values of solubility were determined for the dissolution of benzoic acid in water, at 293 338 K, of 2-naphthol in water, at 293 373 K, and of salicylic acid in water, at 293 343 K. The experimental results obtained are in good agreement with the theoretical values of solubilities presented in literature. Empirical correlations are presented for the prediction of solubility over the entire range of temperatures studied, and they are shown to give the solubility value with very good accuracy.

  11. IUPAC-NIST Solubility Data Series. 84. Solubility of Inorganic Actinide Compounds

    NASA Astrophysics Data System (ADS)

    Hála, Jiri

    2007-12-01

    This volume presents the solubility of inorganic compounds of actinides except for carbonates, which are included in Volume 74 of this series, and nitrates, which are covered in Volume 55. Also included are solubility data of compounds such as organosulfates, phosphates, and arsenates, which are not covered in Volume 74. The predominant part of this volume covers solubility data of thorium, uranium, neptunium, and plutonium compounds. Fewer data have been published for americium compounds and very few for compounds of actinium, protactinium, and transamericium elements. The literature has been covered up to the end of 2004. Documents which remained unavailable to the editor, and could not be included in the volume are listed in the Appendix. For some compounds it was not possible to show the Chemical Abstracts registry numbers since these have not been assigned.

  12. Carbollide solubility and chemical compatibility summary

    SciTech Connect

    McCabe, D.J.

    1993-08-17

    This report examines the value of the cobalt dicarbollide anion as an effective form of in-tank precipitation. The cobalt dicarbollide anion (CDC) has been investigated for the possible replacement of tetraphenyl borate anion (TPB) for precipitation of cesium in SRS High Level Waste (HLW). The solubility of the cesium CDC in 5 M salt solutions and the reactivity with caustic have been studied extensively. The solubility of CSCDC in a mixture of 4 M sodium nitrate and 1 m sodium hydroxide is {approximately}2 {times} 10{sup {minus}3} M at 40{degrees}C. Furthermore, the CDC decomposes in 1 M sodium hydroxide solution with apparent first order kinetics with a half-life of 7.3 days at 60 {degrees}C and 94 days at 40{degrees}C. Tank temperatures are currently estimated to approach 60{degrees}C during the ITP filtration cycle. This solubility and rapid decomposition of the CDC under highly alkaline conditions and high temperature would require increasing the quantity of CDC and nonradioactive cesium which must be added, increasing the cost of production. Increasing the quantity of CDC would necessitate recovery of the material, probably using a solvent extraction system. Due to the large amount of nonradioactive cesium which must be added, the total amount of precipitate formed exceeds that for TPB precipitation. Also, formation of sodium and/or potassium precipitates compete with cesium salt precipitation in 5 M salt solutions at lower temperature (<30{degrees}C). Decomposition generates hydrogen, which may lead to process complications.

  13. Solubility of Sulfur Dioxide in Sulfuric Acid

    NASA Technical Reports Server (NTRS)

    Chang, K. K.; Compton, L. E.; Lawson, D. D.

    1982-01-01

    The solubility of sulfur dioxide in 50% (wt./wt.) sulfuric acid was evaluated by regular solution theory, and the results verified by experimental measurements in the temperature range of 25 C to 70 C at pressures of 60 to 200 PSIA. The percent (wt./wt.) of sulfur dioxide in 50% (wt./wt.) sulfuric acid is given by the equation %SO2 = 2.2350 + 0.0903P - 0.00026P 10 to the 2nd power with P in PSIA.

  14. Exactly soluble quantum wormhole in two dimensions

    SciTech Connect

    Kim, Won Tae; Son, Edwin J.; Yoon, Myung Seok

    2004-11-15

    We are presenting a quantum traversable wormhole in an exactly soluble two-dimensional model. This is different from previous works since the exotic negative energy that supports the wormhole is generated from the quantization of classical energy-momentum tensors. This explicit illustration shows the quantum-mechanical energy can be used as a candidate for the exotic source. As for the traversability, after a particle travels through the wormhole, the static initial wormhole geometry gets a back reaction which spoils the wormhole structure. However, it may still maintain the initial structure along with the appropriate boundary condition.

  15. Sulfide solubilities in Alteration-controlled Systems

    USGS Publications Warehouse

    Hemley, J.J.; Meyer, C.; Hodgson, C.J.; Thatcher, A.B.

    1967-01-01

    Solubilities of sphalerite (ZnS) and galena (PbS) were determined at 300?? to 500??C and 1000 bars total pressure in a chemical environment buffered by silicate mineral equilibria. Chloride solutions and muscovite-bearing assemblages characteristic of hydrothermal wall-rock alteration were used; weak acidities at temperature were therefore involved. The metal concentrations encountered tended to be higher than those observed in high bisulfide-H2S systems at neutral to weakly basic pH used in most previous experimentation; the chemical conditions of the work, although not completely satisfactory, are geologically more realistic than previous experimentation done in the basic-pH region.

  16. Water-soluble titanium alkoxide material

    SciTech Connect

    Boyle, Timothy J.

    2010-06-22

    A water soluble, water stable, titanium alkoxide composition represented by the chemical formula (OC.sub.6H.sub.6N).sub.2Ti(OC.sub.6H.sub.2(CH.sub.2N(CH.sub.3).sub.2).sub- .3-2,4,6).sub.2 with a theoretical molecular weight of 792.8 and an elemental composition of 63.6% C, 8.1% H, 14.1% N, 8.1% O and 6.0% Ti.

  17. Solubilities of tetracosane, octacosane, and dotriacontane in supercritical ethane

    SciTech Connect

    Kalaga, A.; Trebble, M.

    1997-03-01

    The solubilities of tetracosane, octacosane, and dotriacontane in ethane were determined at a temperature of 308.15 K and at pressures ranging from 50 bar to 200 bar. A dynamic single-pass flow system was used for this purpose. The extracted solute was dissolved in toluene after depressurizing the supercritical mixture. This method of measuring the solubilities facilitates the collection of dynamic solubility data since the concentration of solute in toluene can be determined as the experiment proceeds. Dynamic sampling provides more reliable and accurate solubility information compared to the conventional methods based on the weight of solute extracted. The experimental solubilities measured in this work are in agreement with most of the previously published data.The solubilities obtained in this work were modeled using the translated Trebble-Bishnoi-Salim (TBS) EOS which correlated the solubility data successfully to within an average error of 6% for all the systems studied.

  18. 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

  19. Activin/Nodal signaling and NANOG orchestrate human embryonic stem cell fate decisions by controlling the H3K4me3 chromatin mark

    PubMed Central

    Bertero, Alessandro; Madrigal, Pedro; Galli, Antonella; Hubner, Nina C.; Moreno, Inmaculada; Burks, Deborah; Brown, Stephanie; Pedersen, Roger A.; Gaffney, Daniel; Mendjan, Sasha; Pauklin, Siim

    2015-01-01

    Stem cells can self-renew and differentiate into multiple cell types. These characteristics are maintained by the combination of specific signaling pathways and transcription factors that cooperate to establish a unique epigenetic state. Despite the broad interest of these mechanisms, the precise molecular controls by which extracellular signals organize epigenetic marks to confer multipotency remain to be uncovered. Here, we use human embryonic stem cells (hESCs) to show that the Activin–SMAD2/3 signaling pathway cooperates with the core pluripotency factor NANOG to recruit the DPY30-COMPASS histone modifiers onto key developmental genes. Functional studies demonstrate the importance of these interactions for correct histone 3 Lys4 trimethylation and also self-renewal and differentiation. Finally, genetic studies in mice show that Dpy30 is also necessary to maintain pluripotency in the pregastrulation embryo, thereby confirming the existence of similar regulations in vivo during early embryonic development. Our results reveal the mechanisms by which extracellular factors coordinate chromatin status and cell fate decisions in hESCs. PMID:25805847

  20. The levels of water-soluble and triton-soluble Aβ are increased in Alzheimer's disease brain

    PubMed Central

    Mc Donald, Jessica M.; Cairns, Nigel J.; Taylor-Reinwald, Lisa; Holtzman, David; Walsh, Dominic M.

    2012-01-01

    Although plaques composed of the amyloid β-protein (Aβ) are considered a defining feature of Alzheimer's disease (AD), they are also found in cognitively normal individuals and extensive evidence suggests that non-plaque, water-soluble forms of Aβ may play a role in AD pathogenesis. However, the relationship between the levels of water-soluble Aβ and the clinical severity of disease has never been investigated. Here, we present results of a pilot study designed to examine the levels of water-soluble forms of Aβ in brains of individuals who died at clinically distinct stages of AD. Using a serial extraction method, we also investigated the levels of triton-soluble and formic acid-soluble Aβ. We found that water-soluble and detergent-soluble Aβ monomer and SDS-stable dimer were elevated in AD and that the levels of water soluble Aβ did not increase with plaque pathology. These results support the notion that both water- and detergent-soluble Aβ are important in AD and are not simply released from plaques by mechanical disruption. Moreover, the fact that the levels of water- and triton-soluble Aβ were similar in very mild/mild AD and moderate/severe AD suggests that once a certain level of these species is attained, further accumulation is not necessary for the disease to progress. Consequently, therapeutic targeting of water-soluble Aβ should best benefit individuals in earliest phases of the disease process. PMID:22440675

  1. The Soluble Proteome of the Drosophila Antenna

    PubMed Central

    Williams, Taufika Islam

    2010-01-01

    The olfactory system of Drosophila melanogaster is one of the best characterized chemosensory systems. Identification of proteins contained in the third antennal segment, the main olfactory organ, has previously relied primarily on immunohistochemistry, and although such studies and in situ hybridization studies are informative, they focus generally on one or few gene products at a time, and quantification is difficult. In addition, purification of native proteins from the antenna is challenging because it is small and encased in a hard cuticle. Here, we describe a simple method for the large-scale detection of soluble proteins from the Drosophila antenna by chromatographic separation of tryptic peptides followed by tandem mass spectrometry with femtomole detection sensitivities. Examination of the identities of these proteins indicates that they originate both from the extracellular perilymph and from the cytoplasm of disrupted cells. We identified enzymes involved with intermediary metabolism, proteins associated with regulation of gene expression, nucleic acid metabolism and protein metabolism, proteins associated with microtubular transport, 8 odorant-binding proteins, protective enzymes associated with antibacterial defense and defense against oxidative damage, cuticular proteins, and proteins of unknown function, which represented about one-third of all soluble proteins. The procedure described here opens the way for precise quantification of any target protein in the Drosophila antenna and should be readily applicable to antennae from other insects. PMID:19917591

  2. Actinide Solubility and Speciation in the WIPP

    SciTech Connect

    Reed, Donald T.

    2015-11-02

    The presentation begins with the role and need for nuclear repositories (overall concept, international updates (Sweden, Finland, France, China), US approach and current status), then moves on to the WIPP TRU repository concept (design, current status--safety incidents of February 5 and 14, 2014, path forward), and finally considers the WIPP safety case: dissolved actinide concentrations (overall approach, oxidation state distribution and redox control, solubility of actinides, colloidal contribution and microbial effects). The following conclusions are set forth: (1) International programs are moving forward, but at a very slow and somewhat sporadic pace. (2) In the United States, the Salt repository concept, from the perspective of the long-term safety case, remains a viable option for nuclear waste management despite the current operational issues/concerns. (3) Current model/PA prediction (WIPP example) are built on redundant conservatisms. These conservatisms are being addressed in the ongoing and future research to fill existing data gaps--redox control of plutonium by Fe(0, II), thorium (analog) solubility studies in simulated brine, contribution of intrinsic and biocolloids to the mobile concentration, and clarification of microbial ecology and effects.

  3. Selective Water-Soluble Gelatinase Inhibitor Prodrugs

    PubMed Central

    Gooyit, Major; Lee, Mijoon; Schroeder, Valerie A.; Ikejiri, Masahiro; Suckow, Mark A.; Mobashery, Shahriar; Chang, Mayland

    2011-01-01

    SB-3CT (1), a selective and potent thiirane-based gelatinase inhibitor, is effective in animal models of cancer metastasis and stroke; however, it is limited by poor aqueous solubility and extensive metabolism. We addressed these issues by blocking the primary site of metabolism and capitalizing on a prodrug strategy to achieve >5000-fold increased solubility. The amide prodrugs were quantitatively hydrolyzed in human blood to a potent gelatinase inhibitor, ND-322 (3). The arginyl amide prodrug (ND-478, 5d) was metabolically stable in mouse, rat, and human liver microsomes. Both 5d and 3 were non-mutagenic in the Ames II mutagenicity assay. The prodrug 5d showed moderate clearance of 0.0582 L/min/kg, remained mostly in the extracellular fluid compartment (Vd = 0.0978 L/kg), and had a terminal half-life of >4 h. The prodrug 5d had superior pharmacokinetic properties than 3, making the thiirane class of selective gelatinase inhibitors suitable for intravenous administration in treatment of acute gelatinase-dependent diseases. PMID:21866961

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

    SciTech Connect

    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 methods 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 that occur

  5. Drum drying performance of condensed distillers solubles and comparison to performance of modified condensed distillers solubles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Condensed distillers solubles (CDS) is a viscous, syrupy co-product of ethanol production from corn; CDS exhibits strong recalcitrance to drying due to its chemical composition, which includes a substantial amount of glycerol. The objectives of this study were to determine the drum drying performan...

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

    SciTech Connect

    Finotello Alexia; Bara Jason E.; Narayan Suguna; Campder Dean; Noble Richard D.

    2008-07-01

    This study focuses on the solubility behaviors of CO{sub 2}, CH{sub 4}, and N{sub 2} gases in binary mixtures of imidazolium-based room-temperature ionic liquids (RTILs) using l-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)-imide ((C{sub 2}mim)(Tf{sub 2}N)) and l-ethyl-3-methylimidazolium tetrafluoroborate ((C{sub 2}mim)(BF{sub 4})) at 40{sup o}C and low pressures (about 1 atm). The mixtures tested were 0, 25, 50, 75, 90, 95, and 100 mol % (C{sub 2}mim)(BF{sub 4}) in (C{sub 2}-mim)(Tf2{sub N}). 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 CO{sub 2} with N{sub 2} or CH{sub 4} in pure (C{sub 2}mim)(BF4) can be enhanced by adding 5 mol% (C{sub 2}-mim)(Tf{sub 2}N).

  7. Enhancement of carvedilol solubility by solid dispersion technique using cyclodextrins, water soluble polymers and hydroxyl acid.

    PubMed

    Yuvaraja, K; Khanam, Jasmina

    2014-08-01

    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.

  8. Controls on Calcite Solubility in Metamorphic and Magmatic Fluids

    NASA Astrophysics Data System (ADS)

    Manning, C. E.; Eguchi, J.; Galvez, M.

    2015-12-01

    Calcite is an important hydrothermal alteration product in a wide range of environments. The role of calcite in hydrothermal alteration depends on its solubility in geologic fluids, especially H2O. At ambient T and P, calcite solubility is low and it exhibits well-known declining, or "reverse", solubility with rising T. However, experimental and theoretical studies show that increasing P yields higher solubility and restricts the region of reverse solubility behavior to higher temperature. At 0.2 GPa the reverse solubility region lies at T>600°C; at 0.5 GPa, >800°C. Thus, whereas calcite possesses relatively low solubility in pure H2O in shallow hydrothermal systems (typically <10 ppm C), it is substantially more soluble at conditions of middle and lower crustal metamorphism and magmatism, reaching concentrations ≥1000 ppm. At the higher P of subduction zones, aragonite solubility in H2O is even greater. Thus, neglecting other solubility controls, calcite precipitation is favored as crustal fluids cool and/or decompress. However, the solubility of calcite in H2O also depends strongly on other solutes, pH, and fO2. Sources of alkalinity decrease calcite solubility. In contrast, sources of acidity such as CO2 and Cl increase solubility. Crustal fluids can be enriched in alkali halides such as NaCl. Calcite solubility increases with increasing salt content at a given P and T. From approximately seawater salinity to salt saturation, the fluid behaves as a dilute molten salt and calcite solubility increases as the square of the salt mole fraction regardless of the alkali (Li, Na, K, Cs) or halogen (F, Cl, Br, I) considered. Similar behavior is seen in mixed salt solutions. At lower salinities, solubility behavior is as expected in dilute electrolyte solutions. The transition from dilute electrolyte to molten salt is fundamental to the properties of crustal fluids. Reduction of carbonate species or CO2 in the fluid to CH4, which is common during serpentinization of

  9. Dry season aerosol iron solubility in tropical northern Australia

    NASA Astrophysics Data System (ADS)

    Winton, V. Holly L.; Edwards, Ross; Bowie, Andrew R.; Keywood, Melita; Williams, Alistair G.; Chambers, Scott D.; Selleck, Paul W.; Desservettaz, Maximilien; Mallet, Marc D.; Paton-Walsh, Clare

    2016-10-01

    Marine nitrogen fixation is co-limited by the supply of iron (Fe) and phosphorus in large regions of the global ocean. The deposition of soluble aerosol Fe can initiate nitrogen fixation and trigger toxic algal blooms in nitrate-poor tropical waters. We present dry season soluble Fe data from the Savannah Fires in the Early Dry Season (SAFIRED) campaign in northern Australia that reflects coincident dust and biomass burning sources of soluble aerosol Fe. The mean soluble and total aerosol Fe concentrations were 40 and 500 ng m-3 respectively. Our results show that while biomass burning species may not be a direct source of soluble Fe, biomass burning may substantially enhance the solubility of mineral dust. We observed fractional Fe solubility up to 12 % in mixed aerosols. Thus, Fe in dust may be more soluble in the tropics compared to higher latitudes due to higher concentrations of biomass-burning-derived reactive organic species in the atmosphere. In addition, biomass-burning-derived particles can act as a surface for aerosol Fe to bind during atmospheric transport and subsequently be released to the ocean upon deposition. As the aerosol loading is dominated by biomass burning emissions over the tropical waters in the dry season, additions of biomass-burning-derived soluble Fe could have harmful consequences for initiating nitrogen-fixing toxic algal blooms. Future research is required to quantify biomass-burning-derived particle sources of soluble Fe over tropical waters.

  10. Dispelling some myths about the CO2 solubility in ionic liquids.

    PubMed

    Carvalho, P J; Kurnia, K A; Coutinho, J A P

    2016-06-01

    Ionic liquids have been objects of extensive research for physical sorption of CO2 and a number of myths have been perpetuated in the literature, for lack of a critical analysis, concerning their potential for CO2 capture. This study carries a critical analysis of a number of widely accepted ideas and others not so well accepted that have been repeatedly expressed in the literature concerning the CO2 physical sorption in ionic liquids. Using the CO2 solubility in eicosane as benchmark, it will be shown that there is no evidence that ILs display a physical sorption of CO2 larger than n-alkanes when analyzed in adequate concentration units; the fluorination of the ions has no impact on the CO2 solubility and the oxygenation will marginally contribute to a decrease of the solubility. Ionic liquid-based deep eutectic systems are also shown to have a poor CO2 solubility. Although these widely used approaches to physically enhance the CO2 solubility in ILs do not seem to have any positive influence, this does not mean that other types of interaction cannot provide enhanced CO2 solubility as in the case of the anion [B(CN)4] confirmed here by a critical analysis of the published data. The mechanism of CO2 physical sorption in ionic liquids is discussed based on the results analyzed, supported by spectroscopic measurements and molecular simulations previously reported and further suggestions of possibilities for enhanced physical sorption based on fluorinated aromatic rings, other cyano based anions, mixtures with other ILs or solvents or the use of porous liquids are proposed. PMID:27189669

  11. Dispelling some myths about the CO2 solubility in ionic liquids.

    PubMed

    Carvalho, P J; Kurnia, K A; Coutinho, J A P

    2016-06-01

    Ionic liquids have been objects of extensive research for physical sorption of CO2 and a number of myths have been perpetuated in the literature, for lack of a critical analysis, concerning their potential for CO2 capture. This study carries a critical analysis of a number of widely accepted ideas and others not so well accepted that have been repeatedly expressed in the literature concerning the CO2 physical sorption in ionic liquids. Using the CO2 solubility in eicosane as benchmark, it will be shown that there is no evidence that ILs display a physical sorption of CO2 larger than n-alkanes when analyzed in adequate concentration units; the fluorination of the ions has no impact on the CO2 solubility and the oxygenation will marginally contribute to a decrease of the solubility. Ionic liquid-based deep eutectic systems are also shown to have a poor CO2 solubility. Although these widely used approaches to physically enhance the CO2 solubility in ILs do not seem to have any positive influence, this does not mean that other types of interaction cannot provide enhanced CO2 solubility as in the case of the anion [B(CN)4] confirmed here by a critical analysis of the published data. The mechanism of CO2 physical sorption in ionic liquids is discussed based on the results analyzed, supported by spectroscopic measurements and molecular simulations previously reported and further suggestions of possibilities for enhanced physical sorption based on fluorinated aromatic rings, other cyano based anions, mixtures with other ILs or solvents or the use of porous liquids are proposed.

  12. Soluble phosphate fertilizer production using acid effluent from metallurgical industry.

    PubMed

    Mattiello, Edson M; Resende Filho, Itamar D P; Barreto, Matheus S; Soares, Aline R; Silva, Ivo R da; Vergütz, Leonardus; Melo, Leônidas C A; Soares, Emanuelle M B

    2016-01-15

    Preventive and effective waste management requires cleaner production strategies and technologies for recycling and reuse. Metallurgical industries produce a great amount of acid effluent that must be discarded in a responsible manner, protecting the environment. The focus of this study was to examine the use of this effluent to increase reactivity of some phosphate rocks, thus enabling soluble phosphate fertilizer production. The effluent was diluted in deionized water with the following concentrations 0; 12.5; 25; 50; 75% (v v(-1)), which were added to four natural phosphate rocks: Araxá, Patos, Bayovar and Catalão and then left to react for 1 h and 24 h. There was an increase in water (PW), neutral ammonium citrate (PNAC) and citric acid (PCA) soluble phosphorus fractions. Such increases were dependent of rock type while the reaction time had no significant effect (p < 0.05) on the chemical and mineralogical phosphate characteristics. Phosphate fertilizers with low toxic metal concentrations and a high level of micronutrients were produced compared to the original natural rocks. The minimum amount of total P2O5, PNAC and PW, required for national legislation for phosphate partially acidulated fertilizer, were met when using Catalão and the effluent at the concentration of 55% (v v(-1)). Fertilizer similar to partially acidulated phosphate was obtained when Bayovar with effluent at 37.5% (v v(-1)) was used. Even though fertilizers obtained from Araxá and Patos did not contain the minimum levels of total P2O5 required by legislation, they can be used as a nutrient source and for acid effluent recycling and reuse. PMID:26496844

  13. Soluble phosphate fertilizer production using acid effluent from metallurgical industry.

    PubMed

    Mattiello, Edson M; Resende Filho, Itamar D P; Barreto, Matheus S; Soares, Aline R; Silva, Ivo R da; Vergütz, Leonardus; Melo, Leônidas C A; Soares, Emanuelle M B

    2016-01-15

    Preventive and effective waste management requires cleaner production strategies and technologies for recycling and reuse. Metallurgical industries produce a great amount of acid effluent that must be discarded in a responsible manner, protecting the environment. The focus of this study was to examine the use of this effluent to increase reactivity of some phosphate rocks, thus enabling soluble phosphate fertilizer production. The effluent was diluted in deionized water with the following concentrations 0; 12.5; 25; 50; 75% (v v(-1)), which were added to four natural phosphate rocks: Araxá, Patos, Bayovar and Catalão and then left to react for 1 h and 24 h. There was an increase in water (PW), neutral ammonium citrate (PNAC) and citric acid (PCA) soluble phosphorus fractions. Such increases were dependent of rock type while the reaction time had no significant effect (p < 0.05) on the chemical and mineralogical phosphate characteristics. Phosphate fertilizers with low toxic metal concentrations and a high level of micronutrients were produced compared to the original natural rocks. The minimum amount of total P2O5, PNAC and PW, required for national legislation for phosphate partially acidulated fertilizer, were met when using Catalão and the effluent at the concentration of 55% (v v(-1)). Fertilizer similar to partially acidulated phosphate was obtained when Bayovar with effluent at 37.5% (v v(-1)) was used. Even though fertilizers obtained from Araxá and Patos did not contain the minimum levels of total P2O5 required by legislation, they can be used as a nutrient source and for acid effluent recycling and reuse.

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

    PubMed

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

    2008-08-01

    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.

  15. Comparison of a miniaturized shake-flask solubility method with automated potentiometric acid/base titrations and calculated solubilities.

    PubMed

    Glomme, A; März, J; Dressman, J B

    2005-01-01

    Solubility is one of the most important parameters for lead selection and optimization during drug discovery. Its determination should therefore take place as early as possible in the process. Because of the large numbers of compounds involved and the very low amounts of each compound available in the early development stage, it is highly desirable to measure the solubility with as little compound as possible and to be able to improve the throughput of the methods used. In this work, a miniaturized shake-flask method was developed and the solubility results were compared with those measured by semiautomated potentiometric acid/base titrations and computational methods for 21 poorly soluble compounds with solubilities mostly in the range 0.03-30 microg/mL. The potentiometric method is very economical (approximately 100 microg of a poorly soluble compound is needed) and is able to create a pH/solubility profile with one single determination, but is limited to ionizable compounds. The miniaturized shake-flask method can be used for all compounds and a wide variety of media. Its precision and throughput proved superior to the potentiometric method for very poorly soluble compounds. Up to 20 compounds a week can be studied with one set-up. Calculated solubility data seem to be sufficient for a first estimate of the solubility, but they cannot currently be used as a substitute for experimental measurements at key decision points in the development process.

  16. Prediction of the solubility in lipidic solvent mixture: Investigation of the modeling approach and thermodynamic analysis of solubility.

    PubMed

    Patel, Shruti V; Patel, Sarsvatkumar

    2015-09-18

    Self-micro emulsifying drug delivery system (SMEDDS) is one of the methods to improve solubility and bioavailability of poorly soluble drug(s). The knowledge of the solubility of pharmaceuticals in pure lipidic solvents and solvent mixtures is crucial for designing the SMEDDS of poorly soluble drug substances. Since, experiments are very time consuming, a model, which allows for solubility predictions in solvent mixtures based on less experimental data is desirable for efficiency. Solvents employed were Labrafil® M1944CS and Labrasol® as lipidic solvents; Capryol-90®, Capryol-PGMC® and Tween®-80 as surfactants; Transcutol® and PEG-400 as co-solvents. Solubilities of both drugs were determined in single solvent systems at temperature (T) range of 283-333K. In present study, we investigated the applicability of the thermodynamic model to understand the solubility behavior of drugs in the lipiodic solvents. By using the Van't Hoff and general solubility theory, the thermodynamic functions like Gibbs free energy, enthalpy and entropy of solution, mixing and solvation for drug in single and mixed solvents were understood. The thermodynamic parameters were understood in the framework of drug-solvent interaction based on their chemical similarity and dissimilarity. Clotrimazole and Fluconazole were used as active ingredients whose solubility was measured in single solvent as a function of temperature and the data obtained were used to derive mathematical models which can predict solubility in multi-component solvent mixtures. Model dependent parameters for each drug were calculated at each temperature. The experimental solubility data of solute in mixed solvent system were measured experimentally and further correlated with the calculates values obtained from exponent model and log-linear model of Yalkowsky. The good correlation was observed between experimental solubility and predicted solubility.

  17. Solubility increases associated with crystalline drug nanoparticles: methodologies and significance.

    PubMed

    Van Eerdenbrugh, Bernard; Vermant, Jan; Martens, Johan A; Froyen, Ludo; Humbeeck, Jan Van; Van den Mooter, Guy; Augustijns, Patrick

    2010-10-01

    In this manuscript, the determination of solubility of crystalline drug nanosuspensions by a range of methods is critically investigated. As the determinations of solubility were performed in the presence of the solubilizing nanosuspension stabilizer d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), the potential effects of this excipient on the measurements were studied first. Solubility data of nanosuspensions of itraconazole, loviride, phenytoin and naproxen were generated using different methodologies. Data obtained using separation-based methodologies (centrifugation, filtration and ultracentrifugation) proved to be of limited use, due to poor nanoparticle separation efficiencies and/or significant adsorption of TPGS onto the nanoparticle surfaces. Light scattering and turbidity were found to be more suitable for the determination of nanosuspension solubility. The obtained data show that, unlike earlier reports, the solubility increases due to nanosizing are small, with measured increases of only 15%. These solubility increases are in fair agreement with what would be predicted based on the Ostwald-Freundlich equation.

  18. 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

  19. Comparison of solubility databases used for HLW performance assessment

    NASA Astrophysics Data System (ADS)

    McKinley, Ian G.; Savage, David

    1996-02-01

    Elemental solubility limits are employed in many performance assessment studies of the disposal of high-level radioactive waste. A comparison of solubility databases used in a number of recent assessments from Canada, Finland, Japan, Sweden, Switzerland and the U.S.A. is presented. Despite similarities in the chemical conditions under which such solubilities are defined, there are very large ranges in the values selected for most elements (several orders of magnitude). In some cases, differences in solubilities can be attributed to differences in the thermodynamic databases used but, due to generally incomplete documentation, both of such databases and the criteria for data selection, detailed analysis of the reason for such discrepancies is precluded. A key factor, however, is the fairly subjective choice of the solid phase considered to be "solubility-limiting". Procedures are recommended which would increase the transparency of solubility database compilation in future analyses.

  20. Stability and solubility of proteins from extremophiles.

    PubMed

    Greaves, Richard B; Warwicker, Jim

    2009-03-13

    Charges are important for hyperthermophile protein structure and function. However, the number of charges and their predicted contributions to folded state stability are not correlated, implying that more charge does not imply greater stability. The charge properties that distinguish hyperthermophile proteins also differentiate psychrophile proteins from mesophile proteins, but in the opposite direction and to a smaller extent. We conclude that charge number relates to solubility, whereas protein stability is determined by charge location. Most other structural properties are poorly separated over the ambient temperature range, apart from the burial of certain amino acids. Of particular interest are large non-polar sidechains that tend to increased exposure in proteins evolved to function at higher temperatures. Looking at tryptophan in more detail, this increase is often located close to the termini of secondary structure elements, and is discussed in terms of a novel potential role in protein thermostabilisation.

  1. Soluble variants of human recombinant glutaminyl cyclase.

    PubMed

    Castaldo, Cristiana; Ciambellotti, Silvia; de Pablo-Latorre, Raquel; Lalli, Daniela; Porcari, Valentina; Turano, Paola

    2013-01-01

    Recombinant human Glutaminyl Cyclase expressed in E. coli is produced as inclusion bodies. Lack of glycosylation is the main origin of its accumulation in insoluble aggregates. Mutation of single isolated hydrophobic amino acids into negative amino acids was not able to circumvent inclusion bodies formation. On the contrary, substitution with carboxyl-terminal residues of two or three aromatic residues belonging to extended hydrophobic patches on the protein surface provided soluble but still active forms of the protein. These mutants could be expressed in isotopically enriched forms for NMR studies and the maximal attainable concentration was sufficient for the acquisition of (1)H-(15)N HSQC spectra that represent the starting point for future drug development projects targeting Alzheimer's disease. PMID:23977104

  2. DEVELOPMENT OF PETROLUEM RESIDUA SOLUBILITY MEASUREMENT METHODOLOGY

    SciTech Connect

    Per Redelius

    2006-03-01

    In the present study an existing spectrophotometry system was upgraded to provide high-resolution ultraviolet (UV), visible (Vis), and near infrared (NIR) analyses of test solutions to measure the relative solubilities of petroleum residua dissolved in eighteen test solvents. Test solutions were prepared by dissolving ten percent petroleum residue in a given test solvent, agitating the mixture, followed by filtration and/or centrifugation to remove insoluble materials. These solutions were finally diluted with a good solvent resulting in a supernatant solution that was analyzed by spectrophotometry to quantify the degree of dissolution of a particular residue in the suite of test solvents that were selected. Results obtained from this approach were compared with spot-test data (to be discussed) obtained from the cosponsor.

  3. Soluble Adenylyl Cyclase in Health and Disease

    PubMed Central

    Schmid, Andreas; Meili, Dimirela; Salathe, Matthias

    2014-01-01

    The second messenger cAMP is integral for many physiological processes. Soluble adenylyl cyclase (sAC) was recently identified as a widely expressed intracellular source of cAMP in mammalian cells. sAC is evolutionary, structurally, and biochemically distinct from the G-protein-responsive transmembranous adenylyl cyclases (tmAC). The structure of the catalytic unit of sAC is similar to tmAC, but sAC does not contain transmembranous domains, allowing localizations independent of the membranous compartment. sAC activity is stimulated by HCO3-, Ca2+ and is sensitive to physiologically relevant ATP fluctuations. sAC functions as a physiological sensor for carbon dioxide and bicarbonate, and therefore indirectly for pH. Here we review the physiological role of sAC in different human tissues with a major focus on the lung. PMID:25064591

  4. Orally Bioavailable Potent Soluble Epoxide Hydrolase Inhibitors

    PubMed Central

    Hwang, Sung Hee; Tsai, Hsing-Ju; Liu, Jun-Yan; Morisseau, Christophe; Hammock, Bruce D.

    2008-01-01

    A series of N,N′-disubstituted ureas having a conformationally restricted cis- or trans-1,4-cyclohexane α to the urea were prepared and tested as soluble epoxide hydrolase (sEH) inhibitors. This series of compounds showed low nanomolar to picomolar activities against recombinant human sEH. Both isomers showed similar potencies, but the trans isomers were more metabolically stable in human hepatic microsomes. Furthermore, these new potent inhibitors show a greater metabolic stability in vivo than previously described sEH inhibitors. We demonstrated that trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid 13g (t-AUCB, IC50 = 1.3 ± 0.05 nM) had excellent oral bioavailability (98%, n = 2) and blood area under the curve in dogs and was effective in vivo to treat hypotension in lipopolysaccharide challenged murine models. PMID:17616115

  5. Soluble Variants of Human Recombinant Glutaminyl Cyclase

    PubMed Central

    Castaldo, Cristiana; Ciambellotti, Silvia; de Pablo-Latorre, Raquel; Lalli, Daniela; Porcari, Valentina; Turano, Paola

    2013-01-01

    Recombinant human Glutaminyl Cyclase expressed in E. coli is produced as inclusion bodies. Lack of glycosylation is the main origin of its accumulation in insoluble aggregates. Mutation of single isolated hydrophobic amino acids into negative amino acids was not able to circumvent inclusion bodies formation. On the contrary, substitution with carboxyl-terminal residues of two or three aromatic residues belonging to extended hydrophobic patches on the protein surface provided soluble but still active forms of the protein. These mutants could be expressed in isotopically enriched forms for NMR studies and the maximal attainable concentration was sufficient for the acquisition of 1H-15N HSQC spectra that represent the starting point for future drug development projects targeting Alzheimer’s disease. PMID:23977104

  6. Communication: Epistructural thermodynamics of soluble proteins

    NASA Astrophysics Data System (ADS)

    Fernández, Ariel

    2012-03-01

    The epistructural tension of a soluble protein is defined as the reversible work per unit area required to span the interfacial solvent envelope of the protein structure. It includes an entropic penalty term to account for losses in hydrogen-bonding coordination of interfacial water and is determined by a scalar field that indicates the expected coordination of a test water molecule at any given spatial location. An exhaustive analysis of structure-reported monomeric proteins reveals that disulfide bridges required to maintain structural integrity provide the thermodynamic counterbalance to the epistructural tension, yielding a tight linear correlation. Accordingly, deviations from the balance law correlate with the thermal denaturation free energies of proteins under reducing conditions. The picomolar-affinity toxin HsTX1 has the highest epistructural tension, while the metastable cellular form of the human prion protein PrPC represents the least tension-balanced protein.

  7. Polymerized soluble venom--human serum albumin

    SciTech Connect

    Patterson, R.; Suszko, I.M.; Grammer, L.C.

    1985-03-01

    Extensive previous studies have demonstrated that attempts to produce polymers of Hymenoptera venoms for human immunotherapy resulted in insoluble precipitates that could be injected with safety but with very limited immunogenicity in allergic patients. We now report soluble polymers prepared by conjugating bee venom with human serum albumin with glutaraldehyde. The bee venom-albumin polymer (BVAP) preparation was fractionated on Sephacryl S-300 to have a molecular weight range higher than catalase. /sup 125/I-labeled bee venom phospholipase A was almost completely incorporated into BVAP. Rabbit antibody responses to bee venom and bee venom phospholipase A were induced by BVAP. Human antisera against bee venom were absorbed by BVAP. No new antigenic determinants on BVAP were present as evidenced by absorption of antisera against BVAP by bee venom and albumin. BVAP has potential immunotherapeutic value in patients with anaphylactic sensitivity to bee venom.

  8. Solubility of magnesium carbonate in natural waters

    USGS Publications Warehouse

    Wells, R.C.

    1915-01-01

    (1) Under atmospheric conditions it appears possible to attain practically the same state in a solution saturated with MgCO33H2O, whether one starts with a solution containing an excess of magnesium bicarbonate or with the pure trihydrate and water, but the adjustment occurs very slowly. The solution finally contains 0.36 g. magnesium and 1.01 g. carbon dioxide per liter at 20??. (2) The solubility found for magnesite, however, is much smaller, viz., 0.02 g. magnesium and 0.07 g. carbon dioxide per liter. (3) Certain natural waters, freely exposed to the atmosphere, appear to be supersaturated with respect to magnesite but none approaches very closely to the point of saturation of the trihydrate MgCO3.3H2O.

  9. A Path to Soluble Molecularly Imprinted Polymers

    PubMed Central

    Verma, Abhilasha; Murray, George M.

    2011-01-01

    Molecular imprinting is a technique for making a selective binding site for a specific chemical. The technique involves building a polymeric scaffold of molecular complements containing the target molecule. Subsequent removal of the target leaves a cavity with a structural “memory” of the target. Molecularly imprinted polymers (MIPs) can be employed as selective adsorbents of specific molecules or molecular functional groups. In addition, sensors for specific molecules can be made using optical transduction through lumiphores residing in the imprinted site. We have found that the use of metal ions as chromophores can improve selectivity due to selective complex formation. The combination of molecular imprinting and spectroscopic selectivity can result in sensors that are highly sensitive and nearly immune to interferences. A weakness of conventional MIPs with regard to processing is the insolubility of crosslinked polymers. Traditional MIPs are prepared either as monoliths and ground into powders or are prepared in situ on a support. This limits the applicability of MIPs by imposing tedious or difficult processes for their inclusion in devices. The size of the particles hinders diffusion and slows response. These weaknesses could be avoided if a means were found to prepare individual macromolecules with crosslinked binding sites with soluble linear polymeric arms. This process has been made possible by controlled free radical polymerization techniques that can form pseudo-living polymers. Modern techniques of controlled free radical polymerization allow the preparation of block copolymers with potentially crosslinkable substituents in specific locations. The inclusion of crosslinkable mers proximate to the binding complex in the core of a star polymer allows the formation of molecularly imprinted macromolecules that are soluble and processable. Due to the much shorter distance for diffusion, the polymers exhibit rapid responses. This paper reviews the methods

  10. 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.

  11. Are soluble and membrane-bound rat brain acetylcholinesterase different

    SciTech Connect

    Andres, C.; el Mourabit, M.; Stutz, C.; Mark, J.; Waksman, A. )

    1990-11-01

    Salt-soluble and detergent-soluble acetylcholinesterases (AChE) from adult rat brain were purified to homogeneity and studied with the aim to establish the differences existing between these two forms. It was found that the enzymatic activities of the purified salt-soluble AChE as well as the detergent-soluble AChE were dependent on the Triton X-100 concentration. Moreover, the interaction of salt-soluble AChE with liposomes suggests amphiphilic behaviour of this enzyme. Serum cholinesterase (ChE) did not bind to liposomes but its activity was also detergent-dependent. Detergent-soluble AChE remained in solution below critical micellar concentrations of Triton X-100. SDS polyacrylamide gel electrophoresis of purified, Biobeads-treated and iodinated detergent-soluble 11 S AChE showed, under non reducing conditions, bands of 69 kD, 130 kD and greater than 250 kD corresponding, respectively, to monomers, dimers and probably tetramers of the same polypeptide chain. Under reducing conditions, only a 69 kD band was detected. It is proposed that an amphiphilic environment stabilizes the salt-soluble forms of AChE in the brain in vivo and that detergent-soluble Biobeads-treated 11 S AChE possess hydrophobic domain(s) different from the 20 kD peptide already described.

  12. Determination of Solubility Parameters of Ibuprofen and Ibuprofen Lysinate.

    PubMed

    Kitak, Teja; Dumičić, Aleksandra; Planinšek, Odon; Šibanc, Rok; Srčič, Stanko

    2015-01-01

    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.

  13. On Barium Oxide Solubility in Barium-Containing Chloride Melts

    NASA Astrophysics Data System (ADS)

    Nikolaeva, Elena V.; Zakiryanova, Irina D.; Bovet, Andrey L.; Korzun, Iraida V.

    2016-08-01

    Oxide solubility in chloride melts depends on temperature and composition of molten solvent. The solubility of barium oxide in the solvents with barium chloride content is essentially higher than that in molten alkali chlorides. Spectral data demonstrate the existence of oxychloride ionic groupings in such melts. This work presents the results of the BaO solubility in two molten BaCl2-NaCl systems with different barium chloride content. The received data together with earlier published results revealed the main regularities of BaO solubility in molten BaO-BaCl2-MCl systems.

  14. 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.

  15. 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.

  16. [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

  17. [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

  18. 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.

  19. pH-metric solubility. 3. Dissolution titration template method for