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Sample records for acid derivative induces

  1. Modulation by glycyrrhetinic acid derivatives of TPA-induced mouse ear oedema.

    PubMed Central

    Inoue, H.; Mori, T.; Shibata, S.; Koshihara, Y.

    1989-01-01

    1. The anti-inflammatory effects of glycyrrhetinic acid and its derivatives on TPA (12-O-tetradecanoylphorbol-13-acetate)-induced mouse ear oedema were studied. The mechanisms of TPA-induced ear oedema were first investigated with respect to the chemical mediators. 2. The formation of ear oedema reached a maximum 5 h after TPA application (2 micrograms per ear) and the prostaglandin E2 (PGE2) production of mouse ear increased with the oedema formation. 3. TPA-induced ear oedema was prevented by actinomycin D and cycloheximide (0.1 mg per ear, respectively) when applied during 60 min after TPA treatment. 4. Of glycyrrhetinic acid derivatives examined, dihemiphthalate derivatives (IIe, IIe', IIIa, IIIa', IVa, IVa') most strongly inhibited ear oedema on both topical (ID50, 1.6 mg per ear for IIe, 2.0 mg per ear for IIIa and 1.6 mg per ear for IVa) and oral (ID50, 88 mg kg-1 for IIe', 130 mg kg-1 for IIIa' and 92 mg kg-1 for IVa') administration. 5. Glycyrrhetinic acid (Ia) and its derivatives applied 30 min before TPA treatment were much more effective in inhibiting oedema than when applied 30 min after TPA. A dihemiphthalate of triterpenoid compound IVa completely inhibited oedema, even when applied 3 h before TPA treatment. 6. Glycyrrhetinic acid (Ia) and deoxoglycyrrhetol (IIa), the parent compounds, produced little inhibition by oral administration at less than 200 mg kg-1. 7. These results suggest that the dihemiphthalate derivatives of triterpenes derived from glycyrrhetinic acid by chemical modification are useful for the treatment of skin inflammation by both topical and oral application. PMID:2924072

  2. Protective effect of bile acid derivatives in phalloidin-induced rat liver toxicity.

    PubMed

    Herraez, Elisa; Macias, Rocio I R; Vazquez-Tato, Jose; Hierro, Carlos; Monte, Maria J; Marin, Jose J G

    2009-08-15

    Phalloidin causes severe liver damage characterized by marked cholestasis, which is due in part to irreversible polymerization of actin filaments. Liver uptake of this toxin through the transporter OATP1B1 is inhibited by the bile acid derivative BALU-1, which does not inhibit the sodium-dependent bile acid transporter NTCP. The aim of the present study was to investigate whether BALU-1 prevents liver uptake of phalloidin without impairing endogenous bile acid handling and hence may have protective effects against the hepatotoxicity induced by this toxin. In anaesthetized rats, i.v. administration of BALU-1 increased bile flow more than taurocholic acid (TCA). Phalloidin administration decreased basal (-60%) and TCA-stimulated bile flow (-55%) without impairing bile acid output. Phalloidin-induced cholestasis was accompanied by liver necrosis, nephrotoxicity and haematuria. In BALU-1-treated animals, phalloidin-induced cholestasis was partially prevented. Moreover haematuria was not observed, which was consistent with histological evidences of BALU-1-prevented injury of liver and kidney tissue. HPLC-MS/MS analysis revealed that BALU-1 was secreted in bile mainly in non-conjugated form, although a small proportion (<5%) of tauro-BALU-1 was detected. BALU-1 did not inhibit the biliary secretion of endogenous bile acids. When highly choleretic bile acids, - ursodeoxycholic (UDCA) and dehydrocholic acid (DHCA) - were administered, they were found less efficient than BALU-1 in preventing phalloidin-induced cholestasis. Biliary phalloidin elimination was low but it was increased by BALU-1>TCA>DHCA>UDCA. In conclusion, BALU-1 is able to protect against phalloidin-induced hepatotoxicity, probably due to an inhibition of the liver uptake and an enhanced biliary secretion of this toxin. PMID:19409403

  3. Protective effect of bile acid derivatives in phalloidin-induced rat liver toxicity

    SciTech Connect

    Herraez, Elisa; Macias, Rocio I.R.; Vazquez-Tato, Jose; Hierro, Carlos; Monte, Maria J.; Marin, Jose J.G.

    2009-08-15

    Phalloidin causes severe liver damage characterized by marked cholestasis, which is due in part to irreversible polymerization of actin filaments. Liver uptake of this toxin through the transporter OATP1B1 is inhibited by the bile acid derivative BALU-1, which does not inhibit the sodium-dependent bile acid transporter NTCP. The aim of the present study was to investigate whether BALU-1 prevents liver uptake of phalloidin without impairing endogenous bile acid handling and hence may have protective effects against the hepatotoxicity induced by this toxin. In anaesthetized rats, i.v. administration of BALU-1 increased bile flow more than taurocholic acid (TCA). Phalloidin administration decreased basal (- 60%) and TCA-stimulated bile flow (- 55%) without impairing bile acid output. Phalloidin-induced cholestasis was accompanied by liver necrosis, nephrotoxicity and haematuria. In BALU-1-treated animals, phalloidin-induced cholestasis was partially prevented. Moreover haematuria was not observed, which was consistent with histological evidences of BALU-1-prevented injury of liver and kidney tissue. HPLC-MS/MS analysis revealed that BALU-1 was secreted in bile mainly in non-conjugated form, although a small proportion (< 5%) of tauro-BALU-1 was detected. BALU-1 did not inhibit the biliary secretion of endogenous bile acids. When highly choleretic bile acids, - ursodeoxycholic (UDCA) and dehydrocholic acid (DHCA) - were administered, they were found less efficient than BALU-1 in preventing phalloidin-induced cholestasis. Biliary phalloidin elimination was low but it was increased by BALU-1 > TCA > DHCA > UDCA. In conclusion, BALU-1 is able to protect against phalloidin-induced hepatotoxicity, probably due to an inhibition of the liver uptake and an enhanced biliary secretion of this toxin.

  4. The influence of the crystal structure on aggregation-induced luminescence of derivatives of aminobenzoic acid

    NASA Astrophysics Data System (ADS)

    Nosova, D. A.; Zarochentseva, E. P.; Vysotskaya, S. O.; Klemesheva, N. A.; Korotkov, V. I.

    2014-12-01

    The luminescence of three derivatives of 2-(phenylamino)-benzoic acid (N-phenylanthranilic, mefenamic, and niflumic acids) in benzene solution, in the polycrystalline state, and in the hexamethylbenzene matrix is studied. In the crystalline state, these compounds exhibit intense aggregation-induced luminescence. An increase in luminescence is also observed in the impurity crystal. The hexamethylbenzene crystal lattice restricts the mobility of molecules, thus ensuring the rigidity of the molecular structure of acids, which decreases the efficiency of nonradiative electron energy degradation. The main reason for the increase in the luminescence intensity in the case of fixation in a crystalline matrix is the formation of intramolecular hydrogen bonds and dimers of acid molecules.

  5. Epoxides Derived from Dietary Dihomo-Gamma-Linolenic Acid Induce Germ Cell Death in C. elegans

    PubMed Central

    Deline, Marshall; Keller, Julia; Rothe, Michael; Schunck, Wolf-Hagen; Menzel, Ralph; Watts, Jennifer L.

    2015-01-01

    Dietary fats are not created equally, slight differences in structure lead to crucial differences in function. Muticellular organisms use polyunsaturated fatty acid as substrates to produce potent signaling molecules crucial for many physiological processes, including reproduction. Here we explored the mechanism responsible for germ cell loss induced by dietary supplementation of dihomo-gamma-linolenic acid (DGLA, 20:3n-6) in the roundworm Caenorhabditis elegans. In this study we found that C. elegans CYP-33E2 activity produces a range of epoxy and hydroxy metabolites from dietary DGLA. Knockdown of cyp-33E2 suppressed the DGLA-induced sterility phenotype. Additionally, direct exposure of two specific DGLA-derived epoxy products, 8,9- and 14,15-epoxyeicosadienoic acids, produced germ cell abnormalities in the C. elegans gonad. We propose that sterility is mediated by the production of toxic DGLA-derived epoxides that trigger germ cell destruction. These studies are the first to establish a biological activity for a CYP-produced metabolite of DGLA. PMID:26486965

  6. Visible-Light-Induced Decarboxylative Functionalization of Carboxylic Acids and Their Derivatives.

    PubMed

    Xuan, Jun; Zhang, Zhao-Guo; Xiao, Wen-Jing

    2015-12-21

    Visible-light-induced radical decarboxylative functionalization of carboxylic acids and their derivatives has recently received considerable attention as a novel and efficient method to create CC and CX bonds. Generally, this visible-light-promoted decarboxylation process can smoothly occur under mild reaction conditions with a broad range of substrates and an excellent functional-group tolerance. The radical species formed from the decarboxylation step can participate in not only single photocatalytic transformations, but also dual-catalytic cross-coupling reactions by combining photoredox catalysis with other catalytic processes. Recent advances in this research area are discussed herein. PMID:26509837

  7. Dehydroabietic Acid Derivative QC4 Induces Gastric Cancer Cell Death via Oncosis and Apoptosis

    PubMed Central

    Luo, Dongjun; Ni, Qing; Ji, Anlai; Gu, Wen; Wu, Junhua

    2016-01-01

    Aim. QC4 is the derivative of rosin's main components dehydroabietic acid (DHA). We investigated the cytotoxic effect of QC4 on gastric cancer cells and revealed the mechanisms beneath the induction of cell death. Methods. The cytotoxic effect of QC4 on gastric cancer cells was evaluated by CCK-8 assay and flow cytometry. The underlying mechanisms were tested by administration of cell death related inhibitors and detection of apoptotic and oncosis related proteins. Cytomembrane integrity and organelles damage were confirmed by lactate dehydrogenase (LDH) leakage assay, mitochondrial function test, and cytosolic free Ca2+ concentration detection. Results. QC4 inhibited cell proliferation dose- and time-dependently and destroyed cell membrane integrity, activated calpain-1 autolysis, and induced apoptotic protein cleavage in gastric cancer cells. The detection of decreased ATP and mitochondrial membrane potential, ROS accumulation, and cytosolic free Ca2+ elevation confirmed organelles damage in QC4-treated gastric cancer cells. Conclusions. DHA derivative QC4 induced the damage of cytomembrane and organelles which finally lead to oncosis and apoptosis in gastric cancer cells. Therefore, as a derivative of plant derived small molecule DHA, QC4 might become a promising agent in gastric cancer therapy. PMID:27057539

  8. A Prosaposin-Derived Peptide Alleviates Kainic Acid-Induced Brain Injury

    PubMed Central

    Nabeka, Hiroaki; Shimokawa, Tetsuya; Doihara, Takuya; Saito, Shouichiro; Wakisaka, Hiroyuki; Hamada, Fumihiko; Kobayashi, Naoto; Matsuda, Seiji

    2015-01-01

    Four sphingolipid activator proteins (i.e., saposins A–D) are synthesized from a single precursor protein, prosaposin (PS), which exerts exogenous neurotrophic effects in vivo and in vitro. Kainic acid (KA) injection in rodents is a good model in which to study neurotrophic factor elevation; PS and its mRNA are increased in neurons and the choroid plexus in this animal model. An 18-mer peptide (LSELIINNATEELLIKGL; PS18) derived from the PS neurotrophic region prevents neuronal damage after ischemia, and PS18 is a potent candidate molecule for use in alleviating ischemia-induced learning disabilities and neuronal loss. KA is a glutamate analog that stimulates excitatory neurotransmitter release and induces ischemia-like neuronal degeneration; it has been used to define mechanisms involved in neurodegeneration and neuroprotection. In the present study, we demonstrate that a subcutaneous injection of 0.2 and 2.0 mg/kg PS18 significantly improved behavioral deficits of Wistar rats (n = 6 per group), and enhanced the survival of hippocampal and cortical neurons against neurotoxicity induced by 12 mg/kg KA compared with control animals. PS18 significantly protected hippocampal synapses against KA-induced destruction. To evaluate the extent of PS18- and KA-induced effects in these hippocampal regions, we performed histological evaluations using semithin sections stained with toluidine blue, as well as ordinal sections stained with hematoxylin and eosin. We revealed a distinctive feature of KA-induced brain injury, which reportedly mimics ischemia, but affects a much wider area than ischemia-induced injury: KA induced neuronal degeneration not only in the CA1 region, where neurons degenerate following ischemia, but also in the CA2, CA3, and CA4 hippocampal regions. PMID:25993033

  9. Hypolipidemic effect of pantothenic acid derivatives in mice with hypothalamic obesity induced by aurothioglucose.

    PubMed

    Naruta, E; Buko, V

    2001-10-01

    The hypolipidemic effects of pantothenic acid derivatives (phosphopantothenate, panthenol and pantethine) were studied in mice with hypothalamic obesity. Hypothalamic obesity in mice was induced by single injection of aurothioglucose (300 mg/kg body wt, i.p.). All the tested substances were administered during the last 10 days before decapitation (i.m., of dosage equivalent to 150 mg/kg body wt of phosphopantothenate). The studied substances inhibited the weight gain of the animals with hypothalamic obesity over the last 10 days of the experiment. The treatment with aurothioglucose increased food intake and mean body weight, blood glucose level; insulin, serum total cholesterol, triglyceride, the sum of LDL + VLDL and LDL-cholesterol concentration; triglyceride and cholesterol fractions in the liver; triglyceride and FFA content as well as lipoprotein lipase activity in adipose tissue of experimental mice. The administration of the assay compounds lowered food intake and mean body weight, insulin and glucose levels and decreased the content of triglycerides, total cholesterol and cholesterol esters in serum and adipose tissue as well as raised the activity of lipoprotein lipase in adipose tissue and serum lipolytic activity in obese mice. Among the compounds studied the reverse effect of panthenol was especially pronounced. The mechanism of hypolipidemic effects of pantothenic acid derivatives can be related to the reduced resistance to insulin and activation of lipolysis in serum and adipose tissue. PMID:11817109

  10. Alpha-eleostearic acid and its dihydroxy derivative are major apoptosis-inducing components of bitter gourd.

    PubMed

    Kobori, Masuko; Ohnishi-Kameyama, Mayumi; Akimoto, Yukari; Yukizaki, Chizuko; Yoshida, Mitsuru

    2008-11-26

    Bitter gourd ( Momordica charantia L.) pericarp, placenta, and seed extracts were previously shown to induce apoptosis in HL60 human leukemia cells. To determine the active component that induces apoptosis in cancer cells, bitter gourd ethanol extract was fractionated by liquid-liquid partition and silica gel column chromatography. Several fractions obtained by silica gel column chromatography inhibited growth and induced apoptosis in HL60 cells. Among them, fraction 7 had the strongest activity in inhibiting growth and inducing apoptosis in HL60 cells. A component that induced apoptosis in HL60 cells was then isolated from fraction 7 by another silica gel column chromatography and high-performance liquid chromatography (HPLC) using a C18 column and was identified as (9Z,11E,13E)-15,16-dihydroxy-9,11,13-octadecatrienoic acid (15,16-dihydroxy alpha-eleostearic acid). 15,16-Dihydroxy alpha-eleostearic acid induced apoptosis in HL60 cells within 5 h at a concentration of 160 microM (50 microg/mL). (9Z,11E,13E)-9,11,13-Octadecatrienoic acid (alpha-eleostearic acid) is known to be the major conjugated linolenic acid in bitter gourd seeds. Therefore, the effect of alpha-eleostearic acid on the growth of some cancer and normal cell lines was examined. alpha-Eleostearic acid strongly inhibited the growth of some cancer and fibroblast cell lines, including those of HL60 leukemia and HT29 colon carcinoma. alpha-Eleostearic acid induced apoptosis in HL60 cells after a 24 h incubation at a concentration of 5 microM. Thus, alpha-eleostearic acid and the dihydroxy derivative from bitter gourd were suggested to be the major inducers of apoptosis in HL60 cells. PMID:18959405

  11. Sinapic Acid and Its Derivatives as Medicine in Oxidative Stress-Induced Diseases and Aging.

    PubMed

    Chen, Chunye

    2016-01-01

    Sinapic acid (3,5-dimethoxy-4-hydroxycinnamic acid) is an orally bioavailable phytochemical, extensively found in spices, citrus and berry fruits, vegetables, cereals, and oilseed crops and is known to exhibit antioxidant, anti-inflammatory, anticancer, antimutagenic, antiglycemic, neuroprotective, and antibacterial activities. The literature reveals that sinapic acid is a bioactive phenolic acid and has the potential to attenuate various chemically induced toxicities. This minireview is an effort to summarize the available literature about pharmacokinetic, therapeutic, and protective potential of this versatile molecule in health related areas. PMID:27069529

  12. Sinapic Acid and Its Derivatives as Medicine in Oxidative Stress-Induced Diseases and Aging

    PubMed Central

    Chen, Chunye

    2016-01-01

    Sinapic acid (3,5-dimethoxy-4-hydroxycinnamic acid) is an orally bioavailable phytochemical, extensively found in spices, citrus and berry fruits, vegetables, cereals, and oilseed crops and is known to exhibit antioxidant, anti-inflammatory, anticancer, antimutagenic, antiglycemic, neuroprotective, and antibacterial activities. The literature reveals that sinapic acid is a bioactive phenolic acid and has the potential to attenuate various chemically induced toxicities. This minireview is an effort to summarize the available literature about pharmacokinetic, therapeutic, and protective potential of this versatile molecule in health related areas. PMID:27069529

  13. Host-derived extracellular nucleic acids enhance innate immune responses, induce coagulation, and prolong survival upon infection in insects.

    PubMed

    Altincicek, Boran; Stötzel, Sabine; Wygrecka, Malgorzata; Preissner, Klaus T; Vilcinskas, Andreas

    2008-08-15

    Extracellular nucleic acids play important roles in human immunity and hemostasis by inducing IFN production, entrapping pathogens in neutrophil extracellular traps, and providing procoagulant cofactor templates for induced contact activation during mammalian blood clotting. In this study, we investigated the functions of extracellular RNA and DNA in innate immunity and hemolymph coagulation in insects using the greater wax moth Galleria mellonella a reliable model host for many insect and human pathogens. We determined that coinjection of purified Galleria-derived nucleic acids with heat-killed bacteria synergistically increases systemic expression of antimicrobial peptides and leads to the depletion of immune-competent hemocytes indicating cellular immune stimulation. These activities were abolished when nucleic acids had been degraded by nucleic acid hydrolyzing enzymes prior to injection. Furthermore, we found that nucleic acids induce insect hemolymph coagulation in a similar way as LPS. Proteomic analyses revealed specific RNA-binding proteins in the hemolymph, including apolipoproteins, as potential mediators of the immune response and hemolymph clotting. Microscopic ex vivo analyses of Galleria hemolymph clotting reactions revealed that oenocytoids (5-10% of total hemocytes) represent a source of endogenously derived extracellular nucleic acids. Finally, using the entomopathogenic bacterium Photorhabdus luminescens as an infective agent and Galleria caterpillars as hosts, we demonstrated that injection of purified nucleic acids along with P. luminescens significantly prolongs survival of infected larvae. Our results lend some credit to our hypothesis that host-derived nucleic acids have independently been co-opted in innate immunity of both mammals and insects, but exert comparable roles in entrapping pathogens and enhancing innate immune responses. PMID:18684961

  14. Synthesis and in vitro antitumor evaluation of betulin acid ester derivatives as novel apoptosis inducers.

    PubMed

    Yang, Sheng-Jie; Liu, Ming-Chuan; Xiang, Hong-Mei; Zhao, Qi; Xue, Wei; Yang, Song

    2015-09-18

    Nineteen betulin derivatives modified at the C-3 and C-28 positions were synthesized and assessed for antitumor activities against the MGC-803, PC3, Bcap-37, A375, and MCF-7 human cancer cell lines in vitro by MTT assay. Some derivatives (compounds 3a-3d and 5) displayed strong antitumor properties, with IC50 values between 4 and 18 μM. Compound 3c, containing piperidine group at C-28 position, had IC50 values of 4.3, 4.5, 5.2, 7.5, and 5.2 μM on the five cancer cell lines, respectively. Subsequent fluorescence staining and flow cytometric analysis indicated that compound 3c induced apoptosis in MGC-803 cell line, with an apoptosis ratio of 31.11% after 36 h of treatment at 10 μM 3c. PMID:26280921

  15. [Cerebroprotective effect of 3-oxypyridine and succinic acid derivatives in acute phase of alloxan-induced diabetes mellitus in rats].

    PubMed

    Volchegorskiĭ, I A; Rassokhina, L M; Miroshnichenko, I Iu

    2011-01-01

    The effects of original domestic derivatives of 3-oxypyridine and succinic acid (emoxipine, reamberin, and mexidol) on cellular composition of cortical and diencephalic structures in rat brain were studied in parallel with monitoring of behavioral, conditional learning, and metabolic disorders in acute phase of alloxan-induced diabetes in rats. The efficiency of 3-oxypyridine derivatives was compared to the results of alpha-lipoic acid administration. Single administration of emoxipine, reamberin, and mexidol in optimal doses prevented lipofuscin deposition in CA1 field neurocytes in hippocampus and/or increased the amount of terminally differentiated cells ofneuroectodermal lineage (oligodendrocytes, pyramid and basket cells) in this zone ofpaleocortex. Concurrently conditional learning capacity in morbid animals was restored. The cerebroprotective and nootropic effects of emoxipine and reamberin were associated with increased exploration motivation in the open field and were independent of their effects on carbohydrate and lipid metabolism dysfunction. On the contrary, the neuroprotective and nootropic effects of mexidol were associated with additional inhibition of morbid rat activity in the open field and a decrease in the level of circulating products of lipid peroxidation. It is established that 3-oxypyridine and succinic acid derivatives significantly exceed alpha-lipoic acid in terms of neuroprotective effects but exhibit significantly lower hypolipdemic activity in acute phase of alloxan diabetes. PMID:21809693

  16. The amphiphilic alkyl ester derivatives of l-ascorbic acid induce reorganization of phospholipid vesicles.

    PubMed

    Giudice, Francesca; Ambroggio, Ernesto E; Mottola, Milagro; Fanani, Maria Laura

    2016-09-01

    l-ascorbic acid alkyl esters (ASCn) are lipophilic forms of vitamin C, which maintain some of its antioxidant power. Those properties make this drug family attractive to be used in pharmacological preparations protecting other redox-sensible drugs or designed to reduce possible toxic oxidative processes. In this work, we tested the ability of l-ascorbic acid alkyl esters (ASCn) to modulate the structure, permeability, and rheological properties of phospholipid bilayers. The ASCn studied here (ASC16, ASC14, and ASC12) alter the structural integrity as well as the rheological properties of phospholipid membranes without showing any evident detergent activity. ASC14 appeared as the most efficient drug in destabilize the membrane structure of nano- and micro-size phospholipid liposomes inducing vesicle content leakage and shape elongation on giant unilamellar vesicles. It also was the most potent enhancer of membrane microviscosity and surface water structuring. Only ASC16 induced the formation of drug-enriched condensed domains after its incorporation into the lipid bilayer, while ASC12 appeared as the less membrane-disturbing compound, likely because of its poor, and more superficial, partition into the membrane. We also found that incorporation of ASCn into the lipid bilayers enhanced the reduction of membrane components, compared with soluble vitamin C. Our study shows that ASCn compounds, which vary in the length of the acyl chain, show different effects on phospholipid vesicles used as biomembrane models. Those variances may account for subtly differences in the effectiveness on their pharmacological applications. PMID:27342371

  17. 12-oxo-phytodienoic acid, a plant-derived oxylipin, attenuates lipopolysaccharide-induced inflammation in microglia.

    PubMed

    Taki-Nakano, Nozomi; Kotera, Jun; Ohta, Hiroyuki

    2016-05-13

    Jasmonates are plant lipid-derived oxylipins that act as key signaling compounds in plant immunity, germination, and development. Although some physiological activities of natural jasmonates in mammalian cells have been investigated, their anti-inflammatory actions in mammalian cells remain unclear. Here, we investigated whether jasmonates protect mouse microglial MG5 cells against lipopolysaccharide (LPS)-induced inflammation. Among the jasmonates tested, only 12-oxo-phytodienoic acid (OPDA) suppressed LPS-induced expression of the typical inflammatory cytokines interleukin-6 and tumor necrosis factor α. In addition, only OPDA reduced LPS-induced nitric oxide production through a decrease in the level of inducible nitric oxide synthase. Further mechanistic studies showed that OPDA suppressed neuroinflammation by inhibiting nuclear factor κB and p38 mitogen-activated protein kinase signaling in LPS-activated MG5 cells. In addition, OPDA induced expression of suppressor of cytokine signaling-1 (SOCS-1), a negative regulator of inflammation, in MG5 cells. Finally, we found that the nuclear factor erythroid 2-related factor 2 signaling cascade induced by OPDA is not involved in the anti-inflammatory effects of OPDA. These results demonstrate that OPDA inhibited LPS-induced cell inflammation in mouse microglial cells via multiple pathways, including suppression of nuclear factor κB, inhibition of p38, and activation of SOCS-1 signaling. PMID:27086850

  18. Eicosapentaenoic acid attenuates dexamethasome-induced apoptosis by inducing adaptive autophagy via GPR120 in murine bone marrow-derived mesenchymal stem cells

    PubMed Central

    Gao, B; Han, Y-H; Wang, L; Lin, Y-J; Sun, Z; Lu, W-G; Hu, Y-Q; Li, J-Q; Lin, X-S; Liu, B-H; Jie, Q; Yang, L; Luo, Z-J

    2016-01-01

    Long-term use of glucocorticoids is a widespread clinical problem, which currently has no effective solution other than discontinuing the use. Eicosapentaenoic acid (EPA), an omega-3 long chain polyunsaturated fatty acid (n-3 PUFA), which is largely contained in fish or fish oil, has been reported to promote cell viability and improve bone metabolism. However, little is known about the effects of EPA on dexamethasome (Dex)-induced cell apoptosis. In this study, we showed that EPA-induced autophagy of murine bone marrow-derived mesenchymal stem cells (mBMMSCs). Meanwhile, EPA, but not arachidonic acid (AA), markedly inhibited Dex-induced apoptosis and promoted the viability of mBMMSCs. We also observed that EPA-induced autophagy was modulated by GPR120, but not GPR40. Further experiments showed that the mechanism of EPA-induced autophagy associated with GPR120 modulation involved an increase in the active form of AMP-activated protein kinase and a decrease in the activity of mammalian target of RAPA. The protective effect of EPA on Dex-induced apoptosis via GPR120-meditated induction of adaptive autophagy was supported by in vivo experiments. In summary, our findings may have important implications in developing future strategies to use EPA in the prevention and therapy of the side effects induced by long-term Dex-abuse. PMID:27228350

  19. Eicosapentaenoic acid attenuates dexamethasome-induced apoptosis by inducing adaptive autophagy via GPR120 in murine bone marrow-derived mesenchymal stem cells.

    PubMed

    Gao, B; Han, Y-H; Wang, L; Lin, Y-J; Sun, Z; Lu, W-G; Hu, Y-Q; Li, J-Q; Lin, X-S; Liu, B-H; Jie, Q; Yang, L; Luo, Z-J

    2016-01-01

    Long-term use of glucocorticoids is a widespread clinical problem, which currently has no effective solution other than discontinuing the use. Eicosapentaenoic acid (EPA), an omega-3 long chain polyunsaturated fatty acid (n-3 PUFA), which is largely contained in fish or fish oil, has been reported to promote cell viability and improve bone metabolism. However, little is known about the effects of EPA on dexamethasome (Dex)-induced cell apoptosis. In this study, we showed that EPA-induced autophagy of murine bone marrow-derived mesenchymal stem cells (mBMMSCs). Meanwhile, EPA, but not arachidonic acid (AA), markedly inhibited Dex-induced apoptosis and promoted the viability of mBMMSCs. We also observed that EPA-induced autophagy was modulated by GPR120, but not GPR40. Further experiments showed that the mechanism of EPA-induced autophagy associated with GPR120 modulation involved an increase in the active form of AMP-activated protein kinase and a decrease in the activity of mammalian target of RAPA. The protective effect of EPA on Dex-induced apoptosis via GPR120-meditated induction of adaptive autophagy was supported by in vivo experiments. In summary, our findings may have important implications in developing future strategies to use EPA in the prevention and therapy of the side effects induced by long-term Dex-abuse. PMID:27228350

  20. An epoxysuccinic acid derivative(loxistatin)-induced hepatic injury in rats and hamsters

    SciTech Connect

    Fukushima, K.; Arai, M.; Kohno, Y.; Suwa, T.; Satoh, T. )

    1990-08-01

    Loxistatin is a possible therapeutic agent of muscular dystrophy. A single oral administration of loxistatin to male rats caused focal necrosis of the liver with inflammatory cell infiltration. The severity of the lesions was dose-dependent up to 200 mg/kg and also manifest by an increase in serum alanine aminotransferase and aspartate aminotransferase activities. Hepatic glutathione (GSH) levels decreased with a maximum 20% depletion within 5 hr after the oral administration of loxistatin. Pretreatment with diethyl maleate did not potentiate the loxistatin-induced hepatic injury. On the other hand, the hepatoprotective effect of cysteamine was observed when cysteamine was administered 24 hr before loxistatin dosing, but the effect was not observed when the antidote was administered concomitantly with loxistatin. Pretreatment of rats with phenobarbital or trans-stilbene oxide provided partial protection against the hepatotoxic effect of loxistatin. Pretreatment with SKF-525A resulted in increased hepatic injury, while pretreatment with piperonyl butoxide, cimetidine, or 3-methylcholanthrene had no effect on hepatic damage by loxistatin. Five hours after (14C)loxistatin administration to rats, the covalent binding of the radioactivity to proteins was greatest in the liver, followed by the kidney, then muscle and blood to a lesser extent. (14C)Loxistatin acid, the pharmacologically active form of loxistatin, irreversibly bound to rat liver microsomal proteins; more binding occurred when the NADPH-generating system was omitted and when the microsomes were boiled first. GSH did not alter the extent of irreversible binding, whereas N-ethylmaleimide decreased the binding of (14C)loxistatin acid to rat liver microsomal proteins by 75%. Unlike the rat, administration of loxistatin to hamsters caused neither hepatic injury nor hepatic GSH depletion.

  1. Protective Effects and Mechanisms of Salvianolic Acid B Against H₂O₂-Induced Injury in Induced Pluripotent Stem Cell-Derived Neural Stem Cells.

    PubMed

    Shu, Tao; Pang, Mao; Rong, Limin; Liu, Chang; Wang, Juan; Zhou, Wei; Wang, Xuan; Liu, Bin

    2015-06-01

    Induced pluripotent stem cells (iPSCs) have the potential to differentiate into neural lineages. Salvianolic acid B (Sal B) is a commonly used, traditional Chinese medicine for enhancing neuroprotective effects, and has antioxidant, anti-inflammatory, and antiapoptotic properties. Here, we explore the potential mechanism of Sal B in protecting iPSC-derived neural stem cells (NSCs) against H2O2-induced injury. iPSCs were induced into NSCs, iPSC-derived NSCs were treated with 50 μM Sal B for 24.5 h and 500 μM H2O2 for 24 h. The resulting effects were examined by flow cytometry analysis, quantitative reverse-transcription polymerase chain reaction, and western blotting. Upon H2O2 exposure, Sal B significantly promoted cell viability and stabilization of the mitochondrial membrane potential. Sal B also visibly decreased the cell apoptotic ratio. In addition, Sal B markedly reduced expression of matrix metalloproteinase (MMP)-2 and -9, and phosphospecific signal transducer and activator of transcription 3 (p-STAT3), and increased the level of tissue inhibitor of metalloproteinase (TIMP)-2 in iPSC-derived NSCs induced by H2O2. These results suggest that Sal B protects iPSC-derived NSCs against H2O2-induced oxidative stress. The mechanisms of this stress tolerance may be attributed to modulation of the MMP/TIMP system and inhibition of the STAT3 signaling pathway. PMID:25855584

  2. AA-PMe, a novel asiatic acid derivative, induces apoptosis and suppresses proliferation, migration, and invasion of gastric cancer cells.

    PubMed

    Jing, Yue; Wang, Gang; Ge, Ying; Xu, Minjie; Tang, Shuainan; Gong, Zhunan

    2016-01-01

    Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid) is widely used for medicinal purposes in many Asian countries due to its various bioactivities. A series of AA derivatives has been synthesized in attempts to improve its therapeutic potencies. Herein we investigated the anti-tumor activities of N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), a novel AA derivative. AA-PMe exhibited a stronger anti-cancer activity than its parent compound AA. AA-PMe inhibited the proliferation of SGC7901 and HGC27 human gastric cancer cells in a dose-dependent manner but had no significant toxicity in human gastric mucosa epithelial cells (GES-1). AA-PMe induced cell cycle arrest in G0/G1 phase and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D1, cyclin-dependent kinase CKD4, and phosphorylated retinoblastoma protein, and increase in cyclin-dependent kinase inhibitor P15. Further, AA-PMe induced apoptosis of human gastric cancer cells by affecting Bcl-2, Bax, c-Myc, and caspase-3. Moreover, AA-PMe suppressed the migration and invasion of human gastric cancer cells (SGC7901 and HGC27) cells by downregulating the expression of MMP-2 and MMP-9. Overall, this study investigated the potential anti-cancer activities of AA-PMe including inducing apoptosis and suppressing proliferation, migration and invasion of gastric cancer cells, as well as the underlying mechanisms, suggesting that AA-PMe is a promising anti-cancer drug candidate in gastric cancer therapy. PMID:27073325

  3. AA-PMe, a novel asiatic acid derivative, induces apoptosis and suppresses proliferation, migration, and invasion of gastric cancer cells

    PubMed Central

    Jing, Yue; Wang, Gang; Ge, Ying; Xu, Minjie; Tang, Shuainan; Gong, Zhunan

    2016-01-01

    Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid) is widely used for medicinal purposes in many Asian countries due to its various bioactivities. A series of AA derivatives has been synthesized in attempts to improve its therapeutic potencies. Herein we investigated the anti-tumor activities of N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), a novel AA derivative. AA-PMe exhibited a stronger anti-cancer activity than its parent compound AA. AA-PMe inhibited the proliferation of SGC7901 and HGC27 human gastric cancer cells in a dose-dependent manner but had no significant toxicity in human gastric mucosa epithelial cells (GES-1). AA-PMe induced cell cycle arrest in G0/G1 phase and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D1, cyclin-dependent kinase CKD4, and phosphorylated retinoblastoma protein, and increase in cyclin-dependent kinase inhibitor P15. Further, AA-PMe induced apoptosis of human gastric cancer cells by affecting Bcl-2, Bax, c-Myc, and caspase-3. Moreover, AA-PMe suppressed the migration and invasion of human gastric cancer cells (SGC7901 and HGC27) cells by downregulating the expression of MMP-2 and MMP-9. Overall, this study investigated the potential anti-cancer activities of AA-PMe including inducing apoptosis and suppressing proliferation, migration and invasion of gastric cancer cells, as well as the underlying mechanisms, suggesting that AA-PMe is a promising anti-cancer drug candidate in gastric cancer therapy. PMID:27073325

  4. Derivatives of Dictyostelium differentiation-inducing factors inhibit lysophosphatidic acid-stimulated migration of murine osteosarcoma LM8 cells.

    PubMed

    Kubohara, Yuzuru; Komachi, Mayumi; Homma, Yoshimi; Kikuchi, Haruhisa; Oshima, Yoshiteru

    2015-08-01

    Osteosarcoma is a common metastatic bone cancer that predominantly develops in children and adolescents. Metastatic osteosarcoma remains associated with a poor prognosis; therefore, more effective anti-metastatic drugs are needed. Differentiation-inducing factor-1 (DIF-1), -2, and -3 are novel lead anti-tumor agents that were originally isolated from the cellular slime mold Dictyostelium discoideum. Here we investigated the effects of a panel of DIF derivatives on lysophosphatidic acid (LPA)-induced migration of mouse osteosarcoma LM8 cells by using a Boyden chamber assay. Some DIF derivatives such as Br-DIF-1, DIF-3(+2), and Bu-DIF-3 (5-20 μM) dose-dependently suppressed LPA-induced cell migration with associated IC50 values of 5.5, 4.6, and 4.2 μM, respectively. On the other hand, the IC50 values of Br-DIF-1, DIF-3(+2), and Bu-DIF-3 versus cell proliferation were 18.5, 7.2, and 2.0 μM, respectively, in LM8 cells, and >20, 14.8, and 4.3 μM, respectively, in mouse 3T3-L1 fibroblasts (non-transformed). Together, our results demonstrate that Br-DIF-1 in particular may be a valuable tool for the analysis of cancer cell migration, and that DIF derivatives such as DIF-3(+2) and Bu-DIF-3 are promising lead anti-tumor agents for the development of therapies that suppress osteosarcoma cell proliferation, migration, and metastasis. PMID:26056940

  5. Novel long chain fatty acid derivatives of quercetin-3-O-glucoside reduce cytotoxicity induced by cigarette smoke toxicants in human fetal lung fibroblasts.

    PubMed

    Warnakulasuriya, Sumudu N; Ziaullah; Rupasinghe, H P Vasantha

    2016-06-15

    Smoking has become a global health concern due to its association with many disease conditions, such as chronic obstructive pulmonary disease (COPD), cardiovascular diseases (CVD) and cancer. Flavonoids are plant polyphenolic compounds, studied extensively for their antioxidant, anti-inflammatory, and anti-carcinogenic properties. Quercetin-3-O-glucoside (Q3G) is a flavonoid which is widely found in plants. Six novel long chain fatty acid [stearic acid, oleic acid, linoleic acid, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] derivatives of Q3G were evaluated for their potential in protecting human lung fibroblasts against cytotoxicity induced by selected cigarette smoke toxicants: 4-(methylnitrosoamino)-1-(3-pyridinyl)-1-butanone (NNK), benzo-α-pyrene (BaP), nicotine and chromium (Cr[VI]). Nicotine and Cr[VI] induced toxicity in fibroblasts and reduced the percentage of viable cells, while BaP and NNK did not affect cell viability. The fatty acid derivatives of Q3G provided protection against nicotine- and Cr[VI]-induced cell death and membrane lipid peroxidation. Based on the evaluation of inflammatory markers of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2), the fatty acid derivatives of Q3G were found to be effective in lowering the inflammatory response. Overall, these novel fatty acid esters of Q3G warrant further investigation as potential cytoprotective agents. PMID:27071958

  6. Partitioning of liquid-ordered/liquid-disordered membrane microdomains induced by the fluidifying effect of 2-hydroxylated fatty acid derivatives.

    PubMed

    Ibarguren, Maitane; López, David J; Encinar, José A; González-Ros, José M; Busquets, Xavier; Escribá, Pablo V

    2013-11-01

    Cellular functions are usually associated with the activity of proteins and nucleic acids. Recent studies have shown that lipids modulate the localization and activity of key membrane-associated signal transduction proteins, thus regulating the cell's physiology. Membrane Lipid Therapy aims to reverse cell dysfunctions (i.e., diseases) by modulating the activity of membrane signaling proteins through regulation of the lipid bilayer structure. The present work shows the ability of a series of 2-hydroxyfatty acid (2OHFA) derivatives, varying in the acyl chain length and degree of unsaturation, to regulate the membrane lipid structure. These molecules have shown greater therapeutic potential than their natural non-hydroxylated counterparts. We demonstrated that both 2OHFA and natural FAs induced reorganization of lipid domains in model membranes of POPC:SM:PE:Cho, modulating the liquid-ordered/liquid-disordered structures ratio and the microdomain lipid composition. Fluorescence spectroscopy, confocal microscopy, Fourier transform infrared spectroscopy and differential detergent solubilization experiments showed a destabilization of the membranes upon addition of the 2OHFAs and FAs which correlated with the observed disordering effect. The changes produced by these synthetic fatty acids on the lipid structure may constitute part of their mechanism of action, leading to changes in the localization/activity of membrane proteins involved in signaling cascades, and therefore modulating cell responses. PMID:23792066

  7. Low oleic acid-derived repression of jasmonic acid-inducible defense responses requires the WRKY50 and WRKY51 proteins

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Signaling induced upon a reduction in oleic acid (18:1) levels simultaneously up-regulates salicylic acid (SA)-mediated responses and inhibits jasmonic acid (JA)-inducible defenses, resulting in enhanced resistance to biotrophs but increased susceptibility to necrotrophs. SA and the signaling compon...

  8. Sonic hedgehog and retinoic Acid induce bone marrow-derived stem cells to differentiate into glutamatergic neural cells.

    PubMed

    Yu, Zhenhai; Wu, Shixing; Liu, Zhen; Lin, Haiyan; Chen, Lei; Yuan, Xinli; Zhang, Zhiying; Liu, Fang; Zhang, Chuansen

    2015-01-01

    Studies have showed that transplanted stem cells in the inner ear won't regenerate to replace the damaged sensory hair cells. They can spontaneously differentiate into mesenchymal cells and fibrocytes in the damaged inner ear. Only mature sensory cells of MSCs-derived possess the great potency for cell transplantation in the treatment of sensorineural hearing loss. So, we try to establish an efficient generation of the glutamatergic sensory neural phenotype for the cell transplantation of the hearing loss. We isolated MSCs from femoral and tibial bones according to their adherence to culture dishes. After purification, proliferation, and passaged, cells became homogeneous in appearance, showing more uniformity and grew in a monolayer with a typical spindle-shape morphology. The cell surface markers were assessed using FACS to characterize the isolated cells. For neural induction to harvest the glutamatergic sensory neurons, passage 3 MSCs were incubated with preinduced medium for 24 hr, and neural-induced medium for an additional 14 days. The cells exhibit a typical neural shape. RT-PCR analysis indicated that the mRNA levels of the neural cell marker nestin, Tau, MAP-2, β-tubulin III, GluR-3, and GluR-4 were higher compared with primary MSCs. Immunohistochemistry and western-blotting proofed that nestin, MAP-2, β-tubulin III, and GluR-4 proteins indeed exhibit their expression difference in the induced cells compared to the MSCs. We show an efficient protocol by the combined applications of Sonic Hedgehog (Shh) and Retinoic Acid (RA) to induce MSCs to differentiate into the glutamatergic sensory neuron which were identified from the morphological, biochemical, and molecular characteristics. PMID:24547891

  9. A new coumarin derivative, IMM-H004, attenuates okadaic acid-induced spatial memory impairment in rats

    PubMed Central

    Song, Xiu-yun; Wang, Ying-ying; Chu, Shi-feng; Hu, Jin-feng; Yang, Peng-fei; Zuo, Wei; Song, Lian-kun; Zhang, Shuai; Chen, Nai-hong

    2016-01-01

    Aim: A novel coumarin derivative 7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-coumarin (IMM-H004) has shown anti-apoptotic, anti-inflammatory and neuroprotective activities. In this study we investigated the effects of IMM-H004 on spatial memory in rats treated with okadaic acid (OKA), which was used to imitate Alzheimer's disease (AD)-like symptoms. Methods: SD rats were administered IMM-H004 (8 mg·kg−1·d−1, ig) or donepezil (positive control, 1 mg·kg−1·d−1, ig) for 25 d. On d 8 and 9, OKA (200 ng) was microinjected into the right ventricle. Morris water maze test was used to evaluate the spatial memory impairments. Tau and β-amyloid (Aβ) pathology in the hippocampus was detected using Western blot and immunohistochemistry. TUNEL staining was used to detect cell apoptosis. Results: OKA-treated rats showed significant impairments of spatial memory in Morris water maze test, which were largely reversed by administration of IMM-H004 or donepezil. Furthermore, OKA-treated rats exhibited significantly increased phosphorylation of tau, deposits of Aβ protein and cell apoptosis in the hippocampus, which were also reversed by administration of IMM-H004 or donepezil. Conclusion: Administration of IMM-H004 or donepezil protects rats against OKA-induced spatial memory impairments via attenuating tau or Aβ pathology. Thus, IMM-H004 may be developed as a therapeutic agent for the treatment of AD. PMID:26838073

  10. 11-Keto-boswellic acid derived amides and monodesmosidic saponins induce apoptosis in breast and cervical cancers cells.

    PubMed

    Csuk, René; Barthel-Niesen, Anja; Barthel, Alexander; Schäfer, Renate; Al-Harrasi, Ahmed

    2015-07-15

    Beta-boswellic acids are considered the main bioactive components of frankincense. Their potential to act as cytotoxic agents, as well as that of their derivatives remained unexploited so far. In this study we were able to prepare derivatives of 11-keto-β-boswellic acid (KBA) that showed lower IC50 values as determined by a sulphorhodamine B (SRB) assay using several different human tumour cell lines. Monodesmosidic saponins of KBA are as cytotoxic as 3-acetyl-KBA. The presence of a free hydroxyl group at position C-3 seems to lower cytotoxicity while the presence of an amide function at C-24 improves cytotoxicity. The most active compound of this series gave IC50 values as low as 4.5 μM. Cell death proceeded mainly via apoptosis. PMID:26073487

  11. Anti-cancer fatty-acid derivative induces autophagic cell death through modulation of PKM isoform expression profile mediated by bcr-abl in chronic myeloid leukemia.

    PubMed

    Shinohara, Haruka; Taniguchi, Kohei; Kumazaki, Minami; Yamada, Nami; Ito, Yuko; Otsuki, Yoshinori; Uno, Bunji; Hayakawa, Fumihiko; Minami, Yosuke; Naoe, Tomoki; Akao, Yukihiro

    2015-04-28

    The fusion gene bcr-abl develops chronic myeloid leukemia (CML), and stimulates PI3K/Akt/mTOR signaling, leading to impaired autophagy. PI3K/Akt/mTOR signaling also plays an important role in cell metabolism. The Warburg effect is a well-recognized hallmark of cancer energy metabolism, and is regulated by the mTOR/c-Myc/hnRNP/PKM signaling cascade. To develop a new strategy for the treatment of CML, we investigated the associations among bcr-abl, the cascade related to cancer energy metabolism, and autophagy induced by a fatty-acid derivative that we had previously reported as being an autophagy inducer. Here we report that a fatty-acid derivative, AIC-47, induced transcriptional repression of the bcr-abl gene and modulated the expression profile of PKM isoforms, resulting in autophagic cell death. We show that c-Myc functioned as a transcriptional activator of bcr-abl, and regulated the hnRNP/PKM cascade. AIC-47, acting through the PPARγ/β-catenin pathway, induced down-regulation of c-Myc, leading to the disruption of the bcr-abl/mTOR/hnRNP signaling pathway, and switching of the expression of PKM2 to PKM1. This switching caused autophagic cell death through an increase in the ROS level. Our findings suggest that AIC-47 induced autophagic cell death through the PPARγ/β-catenin/bcr-abl/mTOR/hnRNP/PKM cascade. PMID:25644089

  12. Urea derivates of ursolic, oleanolic and maslinic acid induce apoptosis and are selective cytotoxic for several human tumor cell lines.

    PubMed

    Sommerwerk, Sven; Heller, Lucie; Kuhfs, Julia; Csuk, René

    2016-08-25

    2,3-Di-O-acetyl-maslinic acid benzylamide (5) has previously been shown to possess high cytotoxicity for a variety of human tumor cell lines while being of low cytotoxicity to non-malignant cells. Structural modifications performed on 5 revealed that the presence of these acetyl groups in 5 and the presence of (2β,3β)-configurated centers seems necessary for obtaining high cytotoxicity combined with best selectivity between malignant cells and non-malignant mouse fibroblasts. Compounds carrying an ursane skeleton showed weaker cytotoxicity than their oleanane derived analogs. In addition, the benzylamide function in compound 5 should be replaced by a phenylurea moiety to gain better cytotoxicity while retaining and improving the selectivity. Thus, maslinic acid derived N-[2β,3β-di-O-acetyl-17β-amino-28-norolean-12-en-17-yl]phenylurea (45) gave best results showing EC50 = 0.9 μM (for A2780 ovarian cancer cells) with EC50 > 120 μM for fibroblasts (NIH 3T3) and triggered apoptosis while caspase-3 was not activated by this compound. PMID:27149037

  13. Glycyrrhizic acid-mediated subdual of myeloid-derived suppressor cells induces antileishmanial immune responses in a susceptible host.

    PubMed

    Bandyopadhyay, Syamdas; Bhattacharjee, Amrita; Banerjee, Sayantan; Halder, Kuntal; Das, Shibali; Paul Chowdhury, Bidisha; Majumdar, Subrata

    2015-12-01

    CD11b(+) Gr1(+) myeloid-derived suppressor cells (MDSCs), a heterogeneous population of precursor cells, modulate protective immunity against visceral leishmaniasis by suppressing T cell functions. We observed that CD11b(+) Gr1(+) MDSCs, which initially expanded in soluble leishmanial antigen (SLA)-immunized mice and later diminished, suppressed proliferation of T cells isolated from SLA-immunized mice, but to a lesser extent than the case in naive mice. This lesser suppression of MDSCs accompanied the expression of F4/80 and the production of Cox-2, arginase I, nitric oxide, and PGE2. However, with SLA immunization, there was no difference in the expression of interleukin-2 (IL-2) or gamma interferon (IFN-γ) by T cells, in contrast to the case in nonimmunized mice, in which there is an influence. Glycyrrhizic acid (a triterpenoid compound)-mediated inhibition of Cox-2 in myeloid-derived suppressor cells influenced the capacity of T cells to proliferate and the expression of IL-2 and IFN-γ in Leishmania donovani-infected BALB/c mice. Further characterization confirmed that administration of glycyrrhizic acid to L. donovani-infected BALB/c mice results in an impairment of the generation of MDSCs and a reciprocal organ-specific proliferation of IFN-γ- and IL-10-expressing CD4(+) and CD8(+) T cells. Comprehensive knowledge on the Cox-2-mediated regulation of myeloid-derived suppressor cells might be involved in unlocking a new avenue for therapeutic interventions during visceral leishmaniasis. PMID:26351281

  14. Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermally derived tissues and heart.

    PubMed Central

    Arceci, R J; King, A A; Simon, M C; Orkin, S H; Wilson, D B

    1993-01-01

    We report the cDNA cloning and characterization of mouse GATA-4, a new member of the family of zinc finger transcription factors that bind a core GATA motif. GATA-4 cDNA was identified by screening a 6.5-day mouse embryo library with oligonucleotide probes corresponding to a highly conserved region of the finger domains. Like other proteins of the family, GATA-4 is approximately 50 kDa in size and contains two zinc finger domains of the form C-X-N-C-(X17)-C-N-X-C. Cotransfection assays in heterologous cells demonstrate that GATA-4 trans activates reporter constructs containing GATA promoter elements. Northern (RNA) analysis and in situ hybridization show that GATA-4 mRNA is expressed in the heart, intestinal epithelium, primitive endoderm, and gonads. Retinoic acid-induced differentiation of mouse F9 cells into visceral or parietal endoderm is accompanied by increased expression of GATA-4 mRNA and protein. In vitro differentiation of embryonic stem cells into embryoid bodies is also associated with increased GATA-4 expression. We conclude that GATA-4 is a tissue-specific, retinoic acid-inducible, and developmentally regulated transcription factor. On the basis of its tissue distribution, we speculate that GATA-4 plays a role in gene expression in the heart, intestinal epithelium, primitive endoderm, and gonads. Images PMID:8455608

  15. Cytotoxic and apoptosis-inducing effect of ent-15-oxo-kaur-16-en-19-oic acid, a derivative of grandiflorolic acid from Espeletia schultzii.

    PubMed

    Ruiz, Yarimar; Rodrígues, Juan; Arvelo, Francisco; Usubillaga, Alfredo; Monsalve, Mariugenia; Diez, Nardy; Galindo-Castro, Iván

    2008-01-01

    ent-Kaurenic acid and many natural derivatives of this diterpene are known to have interesting biological properties. ent-15-Oxo-kaur-16-en-19-oic acid can be easily obtained from grandiflorolic acid which was first isolated from Espeletia grandiflora. The present work describes the proapoptotic effect of ent-15-oxo-kaur-16-en-19-oic acid on the human prostate carcinoma epithelial cell line PC-3 as evidenced by the changes in the expression level of proteins associated with the execution and regulation of apoptosis. Cell viability was affected upon exposure to the compound, the IC(50) were determined as 3.7 microg/ml, which is 4 times lower than that corresponding to a primary cell culture of fibroblasts (14.8 microg/mL). Through Western blot analysis, active forms of caspace-3 associated with the specific proteolysis of Poly(ADP-ribose) polymerase (PARP) were detected. Reduced levels of the antiapoptotic protein Bcl-2, as well as the appearance of internucleosomal DNA fragmentation, were also demonstrated. Thus, ent-15-oxo-kaur-16-en-19-oic acid may be a promising lead compound for new chemopreventive strategies, alone or in combination with traditional chemotherapy agents to overcome drug resistance in tumoral cells. PMID:17869315

  16. DNA damage and repair induced by diazoacetyl derivatives of amino acids with different mechanism of cytotoxicity. Correlations with mutagenicity and carcinogenicity.

    PubMed

    Brambilla, G; Cavanna, M; Carlo, P; Finollo, R; Sciaba, L; Parodi, S; Bolognesi, C

    1979-05-14

    Eight synthetic N-diazoacetyl amino acids, prepared by inserting a diazoacetyl group onto the alpha-nitrogen of a natural amino acid, and two natural diazoazetyl amino acids, azaserine (9-diazoacetyl-L-serine) and DON (6-diazo-5-oxo-L-norleucine), have been studied by autoradiography for their capacity to induce DNA repair synthesis in mouse cells cultivated "in vitro". Dose-dependent unscheduled DNA synthesis was present in cells treated with the eight N-diazoacetyl derivatives, and was absent in cells exposed to approximately equitoxic concentrations of azaserine and DON. Azaserine and DON, unlike N-diazoacetyl derivatives, did not alkylate gamma-(4-nitrobenzyl) pyridine at an appreciable extent. When DNA damage (single stranded breaks or weak points in alkali) was measured by the sensitive technique of alkaline elution, DGA was found about 4 times as potent as azaserine and about 12 times as DON on a molar basis, but about 800 and 17,000 times as potent as azaserine and DON respectively by extrapolating to equitoxic concentrations. Carcinogenicity and mutagenicity seem to follow mainly the capability of inducing DNA damage. PMID:468901

  17. Polyglycolic acid induced inflammation

    PubMed Central

    Ceonzo, Kathleen; Gaynor, Anne; Shaffer, Lisa; Kojima, Koji; Vacanti, Charles A.; Stahl, Gregory L.

    2005-01-01

    Tissue and organ replacement have quickly outpaced available supply. Tissue bioengineering holds the promise for additional tissue availability. Various scaffolds are currently used, whereas polyglycolic acid (PGA), which is currently used in absorbable sutures and orthopedic pins, provides an excellent support for tissue development. Unfortunately, PGA can induce a local inflammatory response following implantation, so we investigated the molecular mechanism of inflammation in vitro and in vivo. Degraded PGA induced an acute peritonitis, characterized by neutrophil (PMN) infiltration following intraperitoneal injection in mice. Similar observations were observed using the metabolite of PGA, glycolide. Dissolved PGA or glycolide, but not native PGA, activated the classical complement pathway in human sera, as determined by classical complement pathway hemolytic assays, C3a and C5a production, C3 and immunoglobulin deposition. To investigate whether these in vitro observations translated to in vivo findings, we used genetically engineered mice. Intraperitoneal administration of glycolide or dissolved PGA in mice deficient in C1q, factor D, C1q and factor D or C2 and factor B demonstrated significantly reduced PMN infiltration compared to congenic controls (WT). Mice deficient in C6 also demonstrated acute peritonitis. However, treatment of WT or C6 deficient mice with a monoclonal antibody against C5 prevented the inflammatory response. These data suggest that the hydrolysis of PGA to glycolide activates the classical complement pathway. Further, complement is amplified via the alternative pathway and inflammation is induced by C5a generation. Inhibition of C5a may provide a potential therapeutic approach to limit the inflammation associated with PGA derived materials following implantation. PMID:16548688

  18. Linoleic acid derivative DCP-LA protects neurons from oxidative stress-induced apoptosis by inhibiting caspase-3/-9 activation.

    PubMed

    Yaguchi, Takahiro; Fujikawa, Hirokazu; Nishizaki, Tomoyuki

    2010-05-01

    The present study aimed at understanding the effect of the linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) on oxidative stress-induced neuronal death. Sodium nitroprusside (SNP; 1 mM) reduced viability of cultured rat cerebral cortical neurons to 50% of basal levels, but DCP-LA significantly prevented the SNP effect in a concentration (1-100 nM)-dependent manner. In addition, DCP-LA (100 nM) rescued neurons from SNP-induced degradation. SNP (1 mM) activated caspase-3 and -9 in cultured rat cerebral cortical neurons, but DCP-LA (100 nM) abolished the caspase activation. For a mouse model of middle cerebral artery occlusion, oral administration with DCP-LA (1 mg/kg) significantly diminished degraded area due to cerebral infarction. The results of the present study, thus, demonstrate that DCP-LA protects neurons at least in part from oxidative stress-induced apoptosis by inhibiting activation of caspase-3/-9. PMID:20099079

  19. Myeloperoxidase-derived hypochlorous acid promotes ox-LDL-induced senescence of endothelial cells through a mechanism involving β-catenin signaling in hyperlipidemia.

    PubMed

    Liu, Wei-Qi; Zhang, Yin-Zhuang; Wu, Yan; Zhang, Jie-Jie; Li, Tin-Bo; Jiang, Tian; Xiong, Xiao-Ming; Luo, Xiu-Ju; Ma, Qi-Lin; Peng, Jun

    2015-11-27

    Myeloperoxidase (MPO)-derived product hypochlorous acid (HOCl) is able to induce cellular senescence and MPO is also expressed in endothelial cells besides the well-recognized immune cells. This study aims to clarify the association of endothelium-derived MPO with endothelial senescence in hyperlipidemia. The rats were fed with high-fat diet for 8 weeks to establish a hyperlipidemic model, which showed an increase in plasma lipids, endothelium-derived MPO expression, endothelial senescence and endothelial dysfunction concomitant with a reduction in glycogen synthase kinase 3 beta (GSK-3β) activity and phosphorylated β-catenin (p-β-catenin) level as well as an increase in β-catenin and p53 levels within the endothelium. Next, human umbilical vein endothelial cells (HUVECs) were incubated with oxidized low density lipoprotein (ox-LDL, 100 μg/ml) for 24 h to establish a senescent cell model in vitro. Consistent with the finding in vivo, ox-LDL-induced MPO expression and HUVECs senescence, accompanied by a decrease in GSK-3β activity and p-β-catenin level as well as an increase in HOCl content, β-catenin and p53 levels; these phenomena were attenuated by MPO inhibitor. Replacement of ox-LDL with HOCl could also induce HUVECs senescence and activate the β-catenin/p53 pathway. Based on these observations, we conclude that endothelium-derived MPO is upregulated in hyperlipidemic rats, which may contribute to the accelerated vascular endothelial senescence through a mechanism involving the β-catenin/p53 pathway. PMID:26474698

  20. Synthesis of new polysialic acid derivatives.

    PubMed

    Su, Yi; Kasper, Cornelia; Kirschning, Andreas; Dräger, Gerald; Berski, Silke

    2010-09-01

    In this paper we report the first synthesis of novel polysialic acid derivatives which is initiated by treatment of polysialic acid with EDC-HCl to yield the inter-residual delta-lactone. Subsequent reaction with amines or hydrazine gives the corresponding polysialic acid amides and hydrazide. Alkylation of the tetrabutylammonium salt of polysialic acid yields polysialic acid esters. In contrast a variety of N-derivatives of polysialic acid can be prepared starting from deacetylated polysialic acid. The N-derivatives prepared in this communication can be used for the Cu-catalyzed as well as Cu-free "click" chemistry. PMID:20602419

  1. Effects of ursolic acid derivatives on Caco-2 cells and their alleviating role in streptozocin-induced type 2 diabetic rats.

    PubMed

    Wu, Panpan; He, Ping; Zhao, Suqing; Huang, Tianming; Lu, Yujing; Zhang, Kun

    2014-01-01

    In this study, the effect and mechanism of a series of ursolic acid (UA) derivatives on glucose uptake were investigated in a Caco-2 cells model. Their effect on hyperglycemia, hyperlipidemia and oxidative stress were also demonstrated in streptozocin (STZ)-induced diabetic rats. 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-glucose (2-NBDG) was used as a fluorescein in Caco-2 cells model to screen UA derivatives by glucose uptake and expression of glucose transporter protein (SGLT-1, GLUT-2). Moreover, STZ-induced diabetic rats were administered with these derivatives for 4 weeks of treatment. The fasting blood glucose (FBG), insulin levels, biochemical parameters, lipid levels, and oxidative stress markers were finally evaluated. The results of this study indicated that compounds 10 and 11 significantly inhibited 2-NBDG uptake under both Na+-dependent and Na+-independent conditions by decreasing SGLT-1 and GLUT-2 expression in the Caco-2 cells model. Further in vivo studies revealed that compound 10 significantly reduced hyperglycemia by increasing levels of serum insulin, total protein, and albumin, while the fasting blood glucose, body weight and food intake were restored much closer to those of normal rats. Compounds 10 and 11 showed hypolipidemic activity by decreasing the total amounts of cholesterol (TC) and triglycerides (TG). Furthermore, compound 10 showed antioxidant potential which was confirmed by elevation of glutathione (GSH) and superoxide dismutase (SOD) and reduction of malondialdehyde (MDA) levels in the liver and kidney of diabetic rats. It was concluded that compound 10 caused an apparent inhibition of intestinal glucose uptake in Caco-2 cells and hypoglycemia, hypolipidemia and augmented oxidative stress in STZ-induced diabetic rats. Thus, compound 10 could be developed as a potentially complementary therapeutic or prophylactic agent for diabetics mellitus and its complications. PMID:25153871

  2. Nucleotide excision repair deficiency increases levels of acrolein-derived cyclic DNA adduct and sensitizes cells to apoptosis induced by docosahexaenoic acid and acrolein.

    PubMed

    Pan, Jishen; Sinclair, Elizabeth; Xuan, Zhuoli; Dyba, Marcin; Fu, Ying; Sen, Supti; Berry, Deborah; Creswell, Karen; Hu, Jiaxi; Roy, Rabindra; Chung, Fung-Lung

    2016-07-01

    The acrolein derived cyclic 1,N(2)-propanodeoxyguanosine adduct (Acr-dG), formed primarily from ω-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) under oxidative conditions, while proven to be mutagenic, is potentially involved in DHA-induced apoptosis. The latter may contribute to the chemopreventive effects of DHA. Previous studies have shown that the levels of Acr-dG are correlated with apoptosis induction in HT29 cells treated with DHA. Because Acr-dG is shown to be repaired by the nucleotide excision repair (NER) pathway, to further investigate the role of Acr-dG in apoptosis, in this study, NER-deficient XPA and its isogenic NER-proficient XAN1 cells were treated with DHA. The Acr-dG levels and apoptosis were sharply increased in XPA cells, but not in XAN1 cells when treated with 125μM of DHA. Because DHA can induce formation of various DNA damage, to specifically investigate the role of Acr-dG in apoptosis induction, we treated XPA knockdown HCT116+ch3 cells with acrolein. The levels of both Acr-dG and apoptosis induction increased significantly in the XPA knockdown cells. These results clearly demonstrate that NER deficiency induces higher levels of Acr-dG in cells treated with DHA or acrolein and sensitizes cells to undergo apoptosis in a correlative manner. Collectively, these results support that Acr-dG, a ubiquitously formed mutagenic oxidative DNA adduct, plays a role in DHA-induced apoptosis and suggest that it could serve as a biomarker for the cancer preventive effects of DHA. PMID:27036235

  3. Uncaria rhynchophylla and rhynchophylline improved kainic acid-induced epileptic seizures via IL-1β and brain-derived neurotrophic factor.

    PubMed

    Ho, Tin-Yun; Tang, Nou-Ying; Hsiang, Chien-Yun; Hsieh, Ching-Liang

    2014-05-15

    Uncaria rhynchophylla (UR) has been used for the treatment of convulsions and epilepsy in traditional Chinese medicine. This study reported the major anti-convulsive signaling pathways and effective targets of UR and rhynchophylline (RP) using genomic and immunohistochemical studies. Epileptic seizure model was established by intraperitoneal injection of kainic acid (KA) in rats. Electroencephalogram and electromyogram recordings indicated that UR and RP improved KA-induced epileptic seizures. Toll-like receptor (TLR) and neurotrophin signaling pathways were regulated by UR in both cortex and hippocampus of KA-treated rats. KA upregulated the expression levels of interleukin-1β (IL-1β) and brain-derived neurotrophin factor (BDNF), which were involved in TLR and neurotrophin signaling pathways, respectively. However, UR and RP downregulated the KA-induced IL-1β and BDNF gene expressions. Our findings suggested that UR and RP exhibited anti-convulsive effects in KA-induced rats via the regulation of TLR and neurotrophin signaling pathways, and the subsequent inhibition of IL-1β and BDNF gene expressions. PMID:24636743

  4. Drug Nanoparticle Formulation Using Ascorbic Acid Derivatives

    PubMed Central

    Moribe, Kunikazu; Limwikrant, Waree; Higashi, Kenjirou; Yamamoto, Keiji

    2011-01-01

    Drug nanoparticle formulation using ascorbic acid derivatives and its therapeutic uses have recently been introduced. Hydrophilic ascorbic acid derivatives such as ascorbyl glycoside have been used not only as antioxidants but also as food and pharmaceutical excipients. In addition to drug solubilization, drug nanoparticle formation was observed using ascorbyl glycoside. Hydrophobic ascorbic acid derivatives such as ascorbyl mono- and di-n-alkyl fatty acid derivatives are used either as drugs or carrier components. Ascorbyl n-alkyl fatty acid derivatives have been formulated as antioxidants or anticancer drugs for nanoparticle formulations such as micelles, microemulsions, and liposomes. ASC-P vesicles called aspasomes are submicron-sized particles that can encapsulate hydrophilic drugs. Several transdermal and injectable formulations of ascorbyl n-alkyl fatty acid derivatives were used, including ascorbyl palmitate. PMID:21603195

  5. MicroRNA-31 negatively regulates peripherally derived regulatory T-cell generation by repressing retinoic acid-inducible protein 3.

    PubMed

    Zhang, Lingyun; Ke, Fang; Liu, Zhaoyuan; Bai, Jing; Liu, Jinlin; Yan, Sha; Xu, Zhenyao; Lou, Fangzhou; Wang, Hong; Zhu, Huiyuan; Sun, Yang; Cai, Wei; Gao, Yuanyuan; Li, Qun; Yu, Xue-Zhong; Qian, Youcun; Hua, Zichun; Deng, Jiong; Li, Qi-Jing; Wang, Honglin

    2015-01-01

    Peripherally derived regulatory T (pT(reg)) cell generation requires T-cell receptor (TCR) signalling and the cytokines TGF-β1 and IL-2. Here we show that TCR signalling induces the microRNA miR-31, which negatively regulates pT(reg)-cell generation. miR-31 conditional deletion results in enhanced induction of pT(reg) cells, and decreased severity of experimental autoimmune encephalomyelitis (EAE). Unexpectedly, we identify Gprc5a as a direct target of miR-31. Gprc5a is known as retinoic acid-inducible protein 3, and its deficiency leads to impaired pT(reg-)cell induction and increased EAE severity. By generating miR-31 and Gprc5a double knockout mice, we show that miR-31 promotes the development of EAE through inhibiting Gprc5a. Thus, our data identify miR-31 and its target Gprc5a as critical regulators for pT(reg)-cell generation, suggesting a previously unrecognized epigenetic mechanism for dysfunctional T(reg) cells in autoimmune diseases. PMID:26165721

  6. Shp2 regulates chlorogenic acid-induced proliferation and adipogenic differentiation of bone marrow-derived mesenchymal stem cells in adipogenesis.

    PubMed

    Zhou, Rong-Ping; Deng, Ming-Tao; Chen, Lan-Ying; Fang, Ning; Du, Chuan; Chen, Lin-Pan; Zou, Ye-Qing; Dai, Jiang-Hua; Zhu, Mei-Lan; Wang, Wei; Lin, Si-Jian; Liu, Rong-Hua; Luo, Jun

    2015-06-01

    Chlorogenic acid (CGA) exhibits various biological properties, including the inhibition of oxidation, obesity, apoptosis and tumorigenesis. CGA is also able to promote cell survival and proliferation. The aim of the present study was to determine the effects and underlying molecular mechanisms of CGA on the adipogenesis of bone marrow‑derived mesenchymal stem cells (BMSCs). Treatment with CGA had a marginal effect on cell proliferation, by promoting the expression levels of phosphorylated Akt and cyclin D1. Furthermore, treatment with CGA also upregulated the phosphorylation of extracellular signal‑regulated kinase (Erk) and inhibited the adipocyte differentiation of BMSCs by inhibiting the expression of peroxisome proliferator‑activated receptor (PPAR)γ and CCAAT/enhancer binding protein (C/EBP)α. However, knockdown of the expression of Shp2 attenuated CGA‑induced proliferation and inhibited the phosphorylation of Akt and expression of cyclin D1. Furthermore, CGA treatment upregulated Erk phosphorylation and decreased the expression levels of PPARγ and CEBPα, which was inhibited by treatment with the Shp2 PTPase activity inhibitor, NSC‑87877. The results of the present study suggested that CGA‑induced Akt and Erk pathways regulate proliferation and differentiation and that Shp2 is important in the proliferation and differentiation of BMSCs. PMID:25634525

  7. 3,4-Dihydroxyphenylacetic acid, a microbiota-derived metabolite of quercetin, attenuates acetaminophen (APAP)-induced liver injury through activation of Nrf-2.

    PubMed

    Xue, Huiting; Xie, Wenyan; Jiang, Zhihui; Wang, Meng; Wang, Jian; Zhao, Hongqiong; Zhang, Xiaoying

    2016-10-01

    1. Acetaminophen (APAP) overdose leads to severe hepatotoxicity. 3,4-dihydroxyphenylacetic acid (DOPAC) is a scarcely studied microbiota-derived metabolite of quercetin. The aim of this study was to determine the protective effect of DOPAC against APAP-induced liver injury. 2. Mice were treated intragastrically with DOPAC (10, 20 or 50 mg/kg) for 3 days before APAP (300 mg/kg) injection. APAP alone caused increase in serum aminotransferase levels and changes in hepatic histopathology. APAP also promoted oxidative stress by increasing lipid peroxidation and decreasing anti-oxidant enzyme activities. These events led to hepatocellular necrosis and reduced liver function. DOPAC increased nuclear factor erythroid 2-related factor 2 (Nrf-2) translocation to the nucleus and enhanced the expression of phase II enzymes and anti-oxidant enzymes, and thereby reduced APAP hepatotoxicity and enhanced anti-oxidant ability. 3. Our data provide evidence that DOPAC protected the liver against APAP-induced injury, which is involved in Nrf-2 activation, implying that DOPAC can be considered as a potential natural hepatoprotective agent. PMID:26931552

  8. Comparison of the response using ICR mice derived from three different sources to ethanol/hydrochloric acid-induced gastric injury.

    PubMed

    Song, Sung Hwa; Kim, Ji Eun; Go, Jun; Koh, Eun Kyoung; Sung, Ji Eun; Lee, Hyun Ah; Choi, Kyung Min; Kim, Hae Deun; Jung, Young Suk; Kim, Kil Soo; Hwang, Dae Youn

    2016-03-01

    Animal models for gastric ulcers produced by physical, pharmacological and surgical methods have been widely employed to evaluate therapeutic drugs and investigate the mechanism of action of this disease. ICR mice were selected to produce this model, even though several mice and rats have been widely used in studies of gastric ulcers. To compare the responses of ICR mice obtained from three different sources to gastric ulcer inducers, alterations in gastric injury, histopathological structure, and inflammation were measured in Korl:ICR (Korea NIFDS source), A:ICR (USA source) and B:ICR (Japan source) treated with three concentrations of ethanol (EtOH) (50, 70, and 90%) in 150 mM hydrochloric acid (HCl) solution. Firstly, the stomach lesion index gradually increased as the EtOH concentration increased in three ICR groups. Moreover, a significant increase in the level of mucosal injury, edema and the number of inflammatory cells was similarly detected in the EtOH/HCl treated group compared with the vehicle treated group in three ICR groups. Furthermore, the number of infiltrated mast cells and IL-1β expression were very similar in the ICR group derived from three different sources, although some differences in IL-1β expression were detected. Especially, the level of IL-1β mRNA in 50 and 90EtOH/HCl treated group was higher in Korl:ICR and A:ICR than B:ICR. Overall, the results of this study suggest that Korl:ICR, A:ICR and B:ICR derived from different sources have an overall similar response to gastric ulcer induced by EtOH/HCl administration, although there were some differences in the magnitude of their responses. PMID:27051443

  9. Comparison of the response using ICR mice derived from three different sources to ethanol/hydrochloric acid-induced gastric injury

    PubMed Central

    Song, Sung Hwa; Kim, Ji Eun; Go, Jun; Koh, Eun Kyoung; Sung, Ji Eun; Lee, Hyun Ah; Choi, Kyung Min; Kim, Hae Deun; Jung, Young Suk; Kim, Kil Soo

    2016-01-01

    Animal models for gastric ulcers produced by physical, pharmacological and surgical methods have been widely employed to evaluate therapeutic drugs and investigate the mechanism of action of this disease. ICR mice were selected to produce this model, even though several mice and rats have been widely used in studies of gastric ulcers. To compare the responses of ICR mice obtained from three different sources to gastric ulcer inducers, alterations in gastric injury, histopathological structure, and inflammation were measured in Korl:ICR (Korea NIFDS source), A:ICR (USA source) and B:ICR (Japan source) treated with three concentrations of ethanol (EtOH) (50, 70, and 90%) in 150 mM hydrochloric acid (HCl) solution. Firstly, the stomach lesion index gradually increased as the EtOH concentration increased in three ICR groups. Moreover, a significant increase in the level of mucosal injury, edema and the number of inflammatory cells was similarly detected in the EtOH/HCl treated group compared with the vehicle treated group in three ICR groups. Furthermore, the number of infiltrated mast cells and IL-1β expression were very similar in the ICR group derived from three different sources, although some differences in IL-1β expression were detected. Especially, the level of IL-1β mRNA in 50 and 90EtOH/HCl treated group was higher in Korl:ICR and A:ICR than B:ICR. Overall, the results of this study suggest that Korl:ICR, A:ICR and B:ICR derived from different sources have an overall similar response to gastric ulcer induced by EtOH/HCl administration, although there were some differences in the magnitude of their responses. PMID:27051443

  10. Valproic Acid Enhances iPSC Induction From Human Bone Marrow-Derived Cells Through the Suppression of Reprogramming-Induced Senescence.

    PubMed

    Chen, Xi; Zhai, Yingying; Yu, Dehai; Cui, Jiuwei; Hu, Ji-Fan; Li, Wei

    2016-08-01

    Reprogramming of human somatic cells into pluripotent cells (iPSCs) by defined transcription factors is an extremely inefficient process. Treatment with the histone deacetylase inhibitor valproic acid (VPA) during reprogramming can improve the induction of iPSCs. To examine the specific mechanism underlying the role of VPA in reprogramming, we transfected human bone marrow-derived cells (HSC-J2 and HSC-L1) with lentiviruses carrying defined factors (OCT4, SOX2, KLF4, and c-MYC, OSKM) in the presence of VPA. We found that, OSKM lentiviruses caused significant senescence in transfected cells. Administration of VPA, however, significantly suppressed this reprogramming-induced stress. Notably, VPA treatment improved cell proliferation in the early stages of reprogramming, and this was related to the down-regulation of the activated p16/p21 pathway. In addition, VPA also released the G2/M phase blockade in lentivirus-transfected cells. This study demonstrates a new mechanistic role of the histone deacetylase inhibitor in enhancing the induction of pluripotency. J. Cell. Physiol. 231: 1719-1727, 2016. © 2015 Wiley Periodicals, Inc. PMID:26620855

  11. Synergism of ursolic acid derivative US597 with 2-deoxy-D-glucose to preferentially induce tumor cell death by dual-targeting of apoptosis and glycolysis.

    PubMed

    Wang, Jichuang; Jiang, Zhou; Xiang, Liping; Li, Yuanfang; Ou, Minrui; Yang, Xiang; Shao, Jingwei; Lu, Yusheng; Lin, Lifeng; Chen, Jianzhong; Dai, Yun; Jia, Lee

    2014-01-01

    Ursolic acid (UA) is a naturally bioactive product that exhibits potential anticancer effects. The relatively safe and effective molecule intrigued us to explore a way to further improve its anti-cancer activity and tumor-targeting specificity. In the present study, a series of structural modifications of UA was achieved, which resulted in significant increase in growth inhibition on various cancer cell lines with minimal effects on normal cells. The leading molecule US597 (UA-4) caused depolarization of mitochondrial membrane potential, cell arrest in G0/G1 phase and apoptosis/necrosis in a dose-dependent manner. Structural docking suggested that the carbon chains of the modified UA derivatives compete strongly with glucose for binding to glucokinase, the key glycolysis enzyme presumably active in cancer cells. The combination of 2-deoxy-D-glucose (2-DG) and UA-4 induced cell cycle arrest in G2/M phase, promoted caspase-dependent cell death, reduced hexokinase activity, aggravated depletion of intracellular ATP, decreased lactate production and synergistically inhibited cancer cell growth in vitro (HepG2) and in vivo (H22). Collectively, our findings suggest that the structural modification enhances efficacy and selectivity of UA, and the combination of UA-4 with 2-DG produces synergistic inhibition on hepatoma cell proliferation by dual targeting of apoptosis and glycolysis. PMID:25833312

  12. 18β-Glycyrrhetinic Acid, a Novel Naturally Derived Agent, Suppresses Prolactin Hyperactivity and Reduces Antipsychotic-Induced Hyperprolactinemia in In Vitro and In Vivo Models.

    PubMed

    Wang, Di; Zhang, Yongfeng; Wang, Chunyue; Jia, Dongxu; Cai, Guangsheng; Lu, Jiahui; Wang, Di; Zhang, Zhang-Jin

    2016-09-01

    The purpose of this study was to examine the effects of 18β-glycyrrhetinic acid (GA), a novel naturally derived agent, in suppressing prolactin (PRL) hyperactivity and reducing antipsychotic-induced hyperprolactinemia (hyperPRL) and the underlying mechanisms in in vitro and in vivo models. GA treatment for 24 h inhibited PRL synthesis and secretion in MMQ cells and cultured pituitary cells in a dose-dependent fashion; but this effect was not reproduced in GH3 cells that lack the expression of functional dopamine D2 receptors. GA suppressed elevated PRL level and growth hormone, and normalized several sex hormones in a rat model of hyperPRL, produced by repeated injection of the dopamine blocker metoclopramide. GA also modulated the expression 5-HT1A and 5-HT2A receptors in both in vivo and in vitro models. These results indicate that GA is effective in suppressing PRL hyperactivity caused by the blockade of dopamine D2 receptors. This suppressive effect of GA may be related to its modulation of the serotonergic system. This study provides additional evidence in support of GA as an adjunct for the treatment of hyperPRL. PMID:27161375

  13. Cholic acid derivatives: novel antimicrobials.

    PubMed

    Savage, P B; Li, C

    2000-02-01

    Mimics of squalamine and polymyxin B (PMB) have been prepared from cholic acid in hope of finding new antimicrobial agents. The squalamine mimics include the polyamine and sulphate functionalities found in the parent antibiotic, however, the positions relative to the steroid nucleus have been exchanged. The PMB mimics include the conservation of functionality among the polymyxin family of antibiotics, the primary amine groups and a hydrophobic chain. Although the squalamine and PMB mimics are morphologically dissimilar, they display similar activities. Both are simple to prepare and demonstrate broad spectrum antimicrobial activity against Gram-negative and Gram-positive organisms. Specific examples may be inactive alone, yet effectively permeabilise the outer membranes of Gram-negative bacteria rendering them sensitive to hydrophobic antibiotics. Problems associated with some of the squalamine and PMB mimics stem from their haemolytic activity and interactions with serum proteins, however, examples exist without these side effects which can sensitise Gram-negative bacteria to hydrophobic antibiotics. PMID:11060676

  14. Inhibition of phosphotidylinositol-3 kinase pathway by a novel naphthol derivative of betulinic acid induces cell cycle arrest and apoptosis in cancer cells of different origin

    PubMed Central

    Majeed, R; Hamid, A; Sangwan, P L; Chinthakindi, P K; Koul, S; Rayees, S; Singh, G; Mondhe, D M; Mintoo, M J; Singh, S K; Rath, S K; Saxena, A K

    2014-01-01

    Betulinic acid (BA) is a pentacyclic triterpenoid natural product reported to inhibit cell growth in a variety of cancers. However, the further clinical development of BA got hampered because of poor solubility and pharmacological properties. Interestingly, this molecule offer several hotspots for structural modifications in order to address its associated issues. In our endeavor, we selected C-3 position for the desirable chemical modification in order to improve its cytotoxic and pharmacological potential and prepared a library of different triazoline derivatives of BA. Among them, we previously reported the identification of a potential molecule, that is, 3{1N(5-hydroxy-naphth-1yl)-1H-1,2,3-triazol-4yl}methyloxy betulinic acid (HBA) with significant inhibition of cancer cell growth and their properties. In the present study, we have shown for the first time that HBA decreased the expression of phosphotidylinositol-3 kinase (PI3K) p110α and p85α and caused significant downregulation of pAKT and of NFκB using human leukemia and breast cancer cells as in vitro models. Further it was revealed that PI3K inhibition by HBA induced cell cycle arrest via effects on different cell cycle regulatory proteins that include CDKis cyclins and pGSK3β. Also, this target-specific inhibition was associated with mitochondrial apoptosis as was reflected by the increased expression of mitochondrial bax, downregulated bcl2 and decreased mitochondrial levels of cytochrome c, together with reactive oxygen species generation and decline in mitochondrial membrane potential. The apoptotic effectors such as caspase 8, caspase 9 and caspase 3 were found to be upregulated besides DNA repair-associated enzyme, that is, PARP cleavage caused cancer cell death. Pharmacodynamic evaluation revealed that both HBA and BA were safe upto the dose of 2000 mg/kg body weight and with acceptable pharmacodynamic parameters. The in vitro data corroborated with in vivo anticancer activity wherein Ehrlich

  15. Synthesis and antihyperlipidemic activity of piperic acid derivatives.

    PubMed

    A, Rong; Bao, Narisu; Sun, Zhaorigetu; Borjihan, Gereltu; Qiao, Yanjiang; Jin, Zhuang

    2015-02-01

    A series of piperic acid derivatives were designed and synthesized from piperine/piperlonguminine, and their antihyperlipidemic activities evaluated in diet-induced hyperlipidemic rats with respect to simvastatin. Two promising analogues 3 and 10 were discovered and their antihyperlipidemic activities were comparable to or better than those of simvastatin. PMID:25920263

  16. Naphthalenedisulfonic acid derivatives inhibit HIV-1-induced cytopathogenesis, syncytia formation and virus-cell binding by interaction with the viral envelope glycoprotein

    SciTech Connect

    Mohan, P.; Schols, D.; De Clercq, E.; Shigeta, S.; Baba, M.

    1993-12-31

    Bis naphthalenedisulfonic acid analogs with biphenyl spacers have exhibited potent and selective inhibition of HIV-1 replication and giant cell formation. FACS analysis has revealed that these agents also inhibit viral binding to the target cell. Further mechanism of action studies by the FACA method demonstrate that the sulfonic acid analogs inhibit binding of anti-gp120 monoclonal antibody to the viral envelope of glycoprotein, gp120. Binding of OKT4A/Leu3a monoclonal antibody to the target cell CD4 receptor is not affected by these compounds. This investigation suggests that these naphthalenedisulfonic acid derivatives exert their anti-HIV-1 activity by inhibiting the gp120-CD4 interaction through binding of these agents to the viral gp120 antigen.

  17. Design, synthesis and biological evaluation of novel betulinic acid derivatives

    PubMed Central

    2012-01-01

    Background Tumor, is one of the major reason for human death, due to its widespread occurrence. Betulinic acid derivatives have attracted considerable attention as cancer chemopreventive agents and also as cancer therapeutics. Many of its derivatives inhibit the growth of human cancer cell lines by triggering apoptosis. With this background, we planned to synthesize a series of betulinic acid derivatives to assess their antiproliferation efficacy on human cancer cell lines. Results A series of novel betulinic acid derivatives were designed and synthesized as highlighted by the preliminary antitumor evaluation against MGC-803, PC3, A375, Bcap-37 and A431 human cancer cell lines in vitro. The pharmacological results showed that some of the compounds displayed moderate to high levels of antitumor activities with most of new exhibiting higher inhibitory activities compared to BA. The IC50 values of compound 3c on the five cancer cell lines were 2.3, 4.6, 3.3, 3.6, and 4.3 μM, respectively. Subsequent fluorescence staining and flow cytometry analysis (FCM) indicated that compound 3c could induce apoptosis in MGC-803 and PC3 cell lines, and the apoptosis ratios reached the peak (37.38% and 33.74%) after 36 h of treatment at 10 μM. Conclusions This study suggests that most of betulinic acid derivatives could inhibit the growth of human cancer cell lines. Furthermore, compound 3c could induce apoptosis of cancer cells. PMID:23174002

  18. Isolation of Lignan and Fatty Acid Derivatives from the Grains of Echinochloa utilis and Their Inhibition of Lipopolysaccharide-Induced Nitric Oxide Production in RAW 264.7 Cells.

    PubMed

    Nguyen, Duc Hung; Zhao, Bing Tian; Le, Duc Dat; Yoon, Young Ho; Ko, Jee Youn; Woo, Koan Sik; Jun, Do Youn; Kim, Young Ho; Woo, Mi Hee

    2016-01-20

    Two new fatty acid derivatives, echinochlorins A (8) and B (9) and a racemic lignan, (±)-anti-1-(4-hydroxy-3-methoxyphenyl)-2-{4-[(E)-3-acetoxypropen-1-yl]-2-methoxyphenoxy}propan-1,3-diol 3-acetate (1), were isolated from Echinochloa utilis grains, along with six known lignans (2-7) and two fatty acid derivatives (10, 11). Their structures were established by spectroscopic data analyses (IR, UV, HR-FABMS, GC-MS, and 1D and 2D NMR). The configuration of 1 was determined by Mosher's method. Compound 5 displayed potential inhibitory activity on lipopolysaccharide-induced NO production in macrophage RAW 264.7 cells with an IC50 value of 4.8 ± 0.5 μM. These isolated compounds in crude EtOH extract were also quantitated by HPLC. PMID:26725284

  19. Evaluation of ascorbic acid in protecting labile folic acid derivatives.

    PubMed Central

    Wilson, S D; Horne, D W

    1983-01-01

    The use of ascorbic acid as a reducing agent to protect labile, reduced derivatives of folic acid has been evaluated by high-performance liquid chromatographic separations and Lactobacillus casei microbiological assay of eluate fractions. Upon heating for 10 min at 100 degrees C, solutions of tetrahydropteroylglutamic acid (H4PteGlu) in 2% sodium ascorbate gave rise to 5,10-methylene-H4PteGlu and 5-methyl-H4PteGlu. H2PteGlu acid gave rise to 5-methyl-H4PteGlu and PteGlu. 10-Formyl-H4PteGlu gave rise to 5-formyl-H4PteGlu and 10-formyl-PteGlu. 5-Formyl-H4-PteGlu gave rise to a small amount of 10-formyl-PteGlu. 5-Methyl-H4PteGlu and PteGlu appeared stable to these conditions. These interconversions were not seen when solutions of these folate derivatives were kept at 0 degrees C in 1% ascorbate. These observations indicate that elevated temperatures are necessary for the interconversions of folates in ascorbate solutions. Assays of ascorbic acid solutions indicated the presence of formaldehyde (approximately equal to 6 mM). This was confirmed by the identification of 3,5-diacetyl-1,4-dihydrolutidine by UV, visible, and fluorescence spectroscopy and by thin-layer chromatography of chloroform extracts of the reaction mixture of ascorbic acid solutions, acetylacetone, and ammonium acetate. These results indicate that solutions of sodium ascorbate used at elevated temperatures are not suitable for extracting tissue for the subsequent assay of the individual folic acid derivatives. PMID:6415653

  20. Antidepressant activity of aspartic acid derivatives.

    PubMed

    Petrov, V I; Sergeev, V S; Onishchenko, N V; Piotrovskii, L B

    2001-04-01

    Antidepressant activity of N-phenyl(benzyl)amino derivatives of aspartic acid was studied on various experimental models of depression. IEM-1770 (30 mg/kg) and IEM-1944 (20 mg/kg) exhibited antidepressant activity after single injection in the forced swimming and tail suspension tests. Antidepressant effect of 14-day administration of these compounds and reference drugs maprotiline (10 mg/kg) and citalopram (10 mg/kg) was confirmed on the model of learned helplessness. PMID:11550022

  1. Synthesis, characterization of α-amino acid Schiff base derived Ru/Pt complexes: Induces cytotoxicity in HepG2 cell via protein binding and ROS generation

    NASA Astrophysics Data System (ADS)

    Alsalme, Ali; Laeeq, Sameen; Dwivedi, Sourabh; Khan, Mohd. Shahnawaz; Al Farhan, Khalid; Musarrat, Javed; Khan, Rais Ahmad

    2016-06-01

    We have synthesized two new complexes of platinum (1) and ruthenium (2) with α-amino acid, L-alanine, and 2,3-dihydroxybenzaldehyde derived Schiff base (L). The ligand and both complexes were characterized by using elemental analysis and several other spectroscopic techniques viz; IR, 1H, 13C NMR, EPR, and ESI-MS. Furthermore, the protein-binding ability of synthesized complexes was monitored by UV-visible, fluorescence and circular dichroism techniques with a model protein, human serum albumin (HSA). Both the PtL2 and RuL2 complexes displayed significant binding towards HSA. Also, in vitro cytotoxicity assay for both complexes was carried out on human hepatocellular carcinoma cancer (HepG2) cell line. The results showed concentration-dependent inhibition of cell viability. Moreover, the generation of reactive oxygen species was also evaluated, and results exhibited substantial role in cytotoxicity.

  2. Synthesis, characterization of α-amino acid Schiff base derived Ru/Pt complexes: Induces cytotoxicity in HepG2 cell via protein binding and ROS generation.

    PubMed

    Alsalme, Ali; Laeeq, Sameen; Dwivedi, Sourabh; Khan, Mohd Shahnawaz; Al Farhan, Khalid; Musarrat, Javed; Khan, Rais Ahmad

    2016-06-15

    We have synthesized two new complexes of platinum (1) and ruthenium (2) with α-amino acid, l-alanine, and 2,3-dihydroxybenzaldehyde derived Schiff base (L). The ligand and both complexes were characterized by using elemental analysis and several other spectroscopic techniques viz; IR, (1)H, (13)C NMR, EPR, and ESI-MS. Furthermore, the protein-binding ability of synthesized complexes was monitored by UV-visible, fluorescence and circular dichroism techniques with a model protein, human serum albumin (HSA). Both the PtL2 and RuL2 complexes displayed significant binding towards HSA. Also, in vitro cytotoxicity assay for both complexes was carried out on human hepatocellular carcinoma cancer (HepG2) cell line. The results showed concentration-dependent inhibition of cell viability. Moreover, the generation of reactive oxygen species was also evaluated, and results exhibited substantial role in cytotoxicity. PMID:27002605

  3. Four New Dicaffeoylquinic Acid Derivatives from Glasswort (Salicornia herbacea L.) and Their Antioxidative Activity.

    PubMed

    Cho, Jeong-Yong; Kim, Jin Young; Lee, Yu Geon; Lee, Hyoung Jae; Shim, Hyun Jeong; Lee, Ji Hye; Kim, Seon-Jae; Ham, Kyung-Sik; Moon, Jae-Hak

    2016-01-01

    Four new dicaffeoylquinic acid derivatives and two known 3-caffeoylquinic acid derivatives were isolated from methanol extracts using the aerial parts of Salicornia herbacea. The four new dicaffeoylquinic acid derivatives were established as 3-caffeoyl-5-dihydrocaffeoylquinic acid, 3-caffeoyl-5-dihydrocaffeoylquinic acid methyl ester, 3-caffeoyl-4-dihydrocaffeoylquinic acid methyl ester, and 3,5-di-dihydrocaffeoylquinic acid methyl ester. Their chemical structures were determined by nuclear magnetic resonance and electrospray ionization-mass spectroscopy (LC-ESI-MS). In addition, the presence of dicaffeoylquinic acid derivatives in this plant was reconfirmed by LC-ESI-MS/MS analysis. The isolated compounds strongly scavenged 1,1-diphenyl-2-picrylhydrazyl radicals and inhibited cholesteryl ester hydroperoxide formation during rat blood plasma oxidation induced by copper ions. These results indicate that the caffeoylquinic acid derivatives may partially contribute to the antioxidative effect of S. herbacea. PMID:27556430

  4. 21 CFR 172.862 - Oleic acid derived from tall oil fatty acids.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Oleic acid derived from tall oil fatty acids. 172... FOOD FOR HUMAN CONSUMPTION Multipurpose Additives § 172.862 Oleic acid derived from tall oil fatty acids. The food additive oleic acid derived from tall oil fatty acids may be safely used in food and...

  5. 21 CFR 172.862 - Oleic acid derived from tall oil fatty acids.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Oleic acid derived from tall oil fatty acids. 172... FOOD FOR HUMAN CONSUMPTION Multipurpose Additives § 172.862 Oleic acid derived from tall oil fatty acids. The food additive oleic acid derived from tall oil fatty acids may be safely used in food and...

  6. 21 CFR 172.862 - Oleic acid derived from tall oil fatty acids.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Oleic acid derived from tall oil fatty acids. 172... FOOD FOR HUMAN CONSUMPTION Multipurpose Additives § 172.862 Oleic acid derived from tall oil fatty acids. The food additive oleic acid derived from tall oil fatty acids may be safely used in food and...

  7. 21 CFR 172.862 - Oleic acid derived from tall oil fatty acids.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Oleic acid derived from tall oil fatty acids. 172... FOOD FOR HUMAN CONSUMPTION Multipurpose Additives § 172.862 Oleic acid derived from tall oil fatty acids. The food additive oleic acid derived from tall oil fatty acids may be safely used in food and...

  8. Gastroprotective effect and cytotoxicity of carnosic acid derivatives.

    PubMed

    Theoduloz, Cristina; Pertino, Mariano Walter; Rodríguez, Jaime A; Schmeda-Hirschmann, Guillermo

    2011-06-01

    Carnosic acid (CA) is the main phenolic diterpene of rosemary (Rosmarinus officinalis L., Lamiaceae) and presents gastroprotective effect in vitro and in vivo. To determine structure-activity relationships, seventeen esters and ethers of CA were prepared, comprising aliphatic, aromatic, and heterocyclic compounds. The naturally occurring 12-O-methylcarnosic acid (14) was also included in the study. The compounds were evaluated for their gastroprotective activity in the HCl/EtOH-induced gastric lesions model in mice, and for cytotoxicity in human adenocarcinoma AGS cells, Hep G2 hepatocellular carcinoma cells, and human lung fibroblasts. At 10 mg/kg, some of the CA derivatives (5, 8, 9, 12, 14, and 18) were more effective preventing gastric lesions than the reference compound lansoprazole at the same dose. The dibenzoate 9, diindoleacetate 12, and the derivative 18 showed the best gastroprotective effect combined with the lowest cytotoxicity. PMID:21246485

  9. 40 CFR 721.6097 - Phosphoric acid derivative (generic name).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Phosphoric acid derivative (generic... Specific Chemical Substances § 721.6097 Phosphoric acid derivative (generic name). (a) Chemical substance... phosphoric acid derivative (PMN P-95-284) is subject to reporting under this section for the significant...

  10. 40 CFR 721.6097 - Phosphoric acid derivative (generic name).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Phosphoric acid derivative (generic... Specific Chemical Substances § 721.6097 Phosphoric acid derivative (generic name). (a) Chemical substance... phosphoric acid derivative (PMN P-95-284) is subject to reporting under this section for the significant...

  11. 40 CFR 721.6097 - Phosphoric acid derivative (generic name).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Phosphoric acid derivative (generic... Specific Chemical Substances § 721.6097 Phosphoric acid derivative (generic name). (a) Chemical substance... phosphoric acid derivative (PMN P-95-284) is subject to reporting under this section for the significant...

  12. 40 CFR 721.6097 - Phosphoric acid derivative (generic name).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Phosphoric acid derivative (generic... Specific Chemical Substances § 721.6097 Phosphoric acid derivative (generic name). (a) Chemical substance... phosphoric acid derivative (PMN P-95-284) is subject to reporting under this section for the significant...

  13. 40 CFR 721.6097 - Phosphoric acid derivative (generic name).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Phosphoric acid derivative (generic... Specific Chemical Substances § 721.6097 Phosphoric acid derivative (generic name). (a) Chemical substance... phosphoric acid derivative (PMN P-95-284) is subject to reporting under this section for the significant...

  14. Metallo-beta-lactamase inhibitory activity of phthalic acid derivatives.

    PubMed

    Hiraiwa, Yukiko; Morinaka, Akihiro; Fukushima, Takayoshi; Kudo, Toshiaki

    2009-09-01

    4-Butyl-3-methylphthalic acid was recognized as a metallo-beta-lactamase inhibitor. The structure-activity relationship study of substituted phthalic acids afforded 3-phenylphthalic acid derivatives as potent IMP-1 inhibitors. On the other hand, 3-substituted with 4-hydroxyphenyl phthalic acid derivative displayed a potent combination effect with biapenem (BIPM) against Pseudomonas aeruginosa that produce IMP-1. PMID:19632114

  15. Biological Activities of Oleanolic Acid Derivatives from Calendula officinalis Seeds.

    PubMed

    Zaki, Ahmed; Ashour, Ahmed; Mira, Amira; Kishikawa, Asuka; Nakagawa, Toshinori; Zhu, Qinchang; Shimizu, Kuniyoshi

    2016-05-01

    Phytochemical examination of butanol fraction of Calendula officinalis seeds led to the isolation of two compounds identified as 28-O-β-D-glucopyranosyl-oleanolic acid 3-O-β-D-glucopyranosyl (1→3)-β-D-glucopyranosiduronic acid (CS1) and oleanolic acid 3-O-β-D-glucopyranosyl (1→3)-β-D-glucopyranosiduronic acid (CS2). Biological evaluation was carried out for these two compounds such as melanin biosynthesis inhibitory, hyaluronic acid production activities, anti obesity using lipase inhibition and adipocyte differentiation as well as evaluation of the protective effect against hydrogen peroxide induced neurotoxicity in neuro-2A cells. The results showed that, compound CS2 has a melanin biosynthesis stimulatory activity; however, compound CS1 has a potent stimulatory effect for the production of hyaluronic acid on normal human dermal fibroblast from adult (NHDF-Ad). Both compounds did not show any inhibitory effect on both lipase and adipocyte differentiation. Compound CS2 could protect neuro-2A cells and increased cell viability against H2 O2 . These activities (melanin biosynthesis stimulatory and protective effect against H2 O2 of CS2 and hyaluronic acid productive activities of these triterpene derivatives) have been reported for the first time. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26887328

  16. Effect of mitotic inducers and retinoic acid blocker on expression of pluripotent genes in ES cells derived from early stage in vitro-produced embryos in buffalo.

    PubMed

    Kumar, Ashok; Kumar, Kuldeep; Singh, Renu; Puri, Gopal; Ranjan, R; Yasotha, T; Singh, R K; Sarkar, M; Bag, Sadhan

    2012-12-01

    So far, it has been difficult to generate embryonic stem (ES) cell from early stage preimplantation embryos of buffalo. These ES cells will be more helpful for efficient embryo cloning and generation of body cells as they are more primitive than inner cell mass (ICM)-derived ES cells. The present study was conducted to find the effect of lipopolysaccharide (LPS), melatonin (N-acetyl-5-methoxytryptamine, a pineal gland product), and citral (3,7-dimethyl-2,6-octadienal and a retinoic acid synthesis blocker) on establishment of primary ES cell colonies, the comparative size of the ES cell colonies, and expression of pluripotent genes during extended period of culture in buffalo. Zona-free eight-cell stage in vitro fertilization (IVF) embryos were cultured in ES cell medium supplemented with none (media I as control), LPS (media II), citral melatonin (media III), or melatonin (media IV). The multiplication of blastomere leading to ES cell colony formation and expression of pluripotent genes were assessed up to day 20 of culture. The primary colony formation, the comparative size of the ES cell colonies, and expression of pluripotent genes in these colonies were better in the medium supplemented with melatonin in all days of culture. Within melatonin supplementation, the colony size was comparatively larger on day 8 and day 12 of culture. Further, with this supplementation, the Oct-4 and Nanog expression was comparatively higher on all days of culture. The results indicated that supplementation of melatonin helped in the formation of better primary ES cell colony as well as in the maintenance of pluripotency. The results also indicated that primary colonies developed on day 8 to day 12 of culture may be better for passaging them for establishment of ES cell line from early stage preimplantation IVF embryos of in buffalo. PMID:23093464

  17. NCX-1015, a nitric-oxide derivative of prednisolone, enhances regulatory T cells in the lamina propria and protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice

    PubMed Central

    Fiorucci, Stefano; Antonelli, Elisabetta; Distrutti, Eleonora; Del Soldato, Piero; Flower, Roderick J.; Clark, Mark J. Paul; Morelli, Antonio; Perretti, Mauro; Ignarro, Louis J.

    2002-01-01

    NCX-1015 is a nitric oxide (NO)-releasing derivative of prednisolone. In this study we show NCX-1015 protects mice against the S. A. development and induces healing of T helper cell type 1-mediated experimental colitis induced by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). The beneficial effect of NCX-1015 was reflected in increased survival rates, improvement of macroscopic and histologic scores, a decrease in the mucosal content of T helper cell type 1 cytokines (protein and mRNA), and diminished myeloperoxidase activity in the colon. In contrast to its NO derivative, only very high doses of prednisolone were effective in reproducing these beneficial effects. NCX-1015 was 10- to 20-fold more potent than the parent compound in inhibiting IFN-γ secretion by lamina propria mononuclear cells. Protection against developing colitis correlated with inhibition of nuclear translocation of p65/Rel A in these cells. In vivo treatment with NCX-1015 potently stimulated IL-10 production, suggesting that the NO steroid induces a regulatory subset of T cells that negatively modulates intestinal inflammation. PMID:12427966

  18. 4-Hydroxybenzyl-substituted amino acid derivatives from Gastrodia elata

    PubMed Central

    Guo, Qinglan; Wang, Yanan; Lin, Sheng; Zhu, Chenggen; Chen, Minghua; Jiang, Zhibo; Xu, Chengbo; Zhang, Dan; Wei, Huailing; Shi, Jiangong

    2015-01-01

    Seven new 4-hydroxybenzyl-substituted amino acid derivatives (1−7), together with 11 known compounds, were isolated from an aqueous extract of the rhizomes of Gastrodia elata Blume. Their structures were determined by spectroscopic and chemical methods. Compounds 1−3 are pyroglutamate derivatives containing 4-hydroxybenzyl units at the N atom and 4−7 are the first examples of natural products with the 4-hydroxybenzyl unit linked via a thioether bond to 2-hydroxy-3-mercaptopropanoic acid (4−6) and 2-hydroxy-4-mercaptobutanoic acid (7), which would be biogenetically derived from cysteine and homocysteine, respectively. The structures of 1 and 2 were verified by synthesis, while the absolute configurations of 4, 5 and 7 were assigned using Mosher’s method based on the MPA determination rule of ΔδRS values. The known compound 4-(hydroxymethyl)-5-nitrobenzene-1,2-diol (8) exhibited activity against Fe2+-cysteine induced rat liver microsomal lipid peroxidation with IC50 values of 9.99×10−6 mol/L. PMID:26579466

  19. Anti-Inflammatory Activity of Tanzawaic Acid Derivatives from a Marine-Derived Fungus Penicillium steckii 108YD142.

    PubMed

    Shin, Hee Jae; Pil, Gam Bang; Heo, Soo-Jin; Lee, Hyi-Seung; Lee, Jong Seok; Lee, Yeon-Ju; Lee, Jihoon; Won, Ho Shik

    2016-01-01

    Chemical investigation of a marine-derived fungus, Penicillium steckii 108YD142, resulted in the discovery of a new tanzawaic acid derivative, tanzawaic acid Q (1), together with four known analogues, tanzawaic acids A (2), C (3), D (4), and K (5). The structures of tanzawaic acid derivatives 1-5 were determined by the detailed analysis of 1D, 2D NMR and LC-MS data, along with chemical methods and literature data analysis. These compounds significantly inhibited nitric oxide (NO) production and the new tanzawaic acid Q (1) inhibited the lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins and mRNA expressions in RAW 264.7 macrophages. Additionally, compound 1 reduced the mRNA levels of inflammatory cytokines. Taken together, the results of this study demonstrated that the new tanzawaic acid derivative inhibits LPS-induced inflammation. This is the first report on the anti-inflammatory activity of tanzawaic acid Q (1). PMID:26761016

  20. Anti-Inflammatory Activity of Tanzawaic Acid Derivatives from a Marine-Derived Fungus Penicillium steckii 108YD142

    PubMed Central

    Shin, Hee Jae; Pil, Gam Bang; Heo, Soo-Jin; Lee, Hyi-Seung; Lee, Jong Seok; Lee, Yeon-Ju; Lee, Jihoon; Won, Ho Shik

    2016-01-01

    Chemical investigation of a marine-derived fungus, Penicillium steckii 108YD142, resulted in the discovery of a new tanzawaic acid derivative, tanzawaic acid Q (1), together with four known analogues, tanzawaic acids A (2), C (3), D (4), and K (5). The structures of tanzawaic acid derivatives 1–5 were determined by the detailed analysis of 1D, 2D NMR and LC-MS data, along with chemical methods and literature data analysis. These compounds significantly inhibited nitric oxide (NO) production and the new tanzawaic acid Q (1) inhibited the lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins and mRNA expressions in RAW 264.7 macrophages. Additionally, compound 1 reduced the mRNA levels of inflammatory cytokines. Taken together, the results of this study demonstrated that the new tanzawaic acid derivative inhibits LPS-induced inflammation. This is the first report on the anti-inflammatory activity of tanzawaic acid Q (1). PMID:26761016

  1. Polyunsaturated Branched-Chain Fatty Acid Geranylgeranoic Acid Induces Unfolded Protein Response in Human Hepatoma Cells

    PubMed Central

    Iwao, Chieko; Shidoji, Yoshihiro

    2015-01-01

    The acyclic diterpenoid acid geranylgeranoic acid (GGA) has been reported to induce autophagic cell death in several human hepatoma-derived cell lines; however, the molecular mechanism for this remains unknown. In the present study, several diterpenoids were examined for ability to induce XBP1 splicing and/or lipotoxicity for human hepatoma cell lines. Here we show that three groups of diterpenoids emerged: 1) GGA, 2,3-dihydro GGA and 9-cis retinoic acid induce cell death and XBP1 splicing; 2) all-trans retinoic acid induces XBP1 splicing but little cell death; and 3) phytanic acid, phytenic acid and geranylgeraniol induce neither cell death nor XBP1 splicing. GGA-induced ER stress/ unfolded protein response (UPR) and its lipotoxicity were both blocked by co-treatment with oleic acid. The blocking activity of oleic acid for GGA-induced XBP1 splicing was not attenuated by methylation of oleic acid. These findings strongly suggest that GGA at micromolar concentrations induces the so-called lipid-induced ER stress response/UPR, which is oleate-suppressive, and shows its lipotoxicity in human hepatoma cells. PMID:26186544

  2. Linoleic acid derivative DCP-LA ameliorates stress-induced depression-related behavior by promoting cell surface 5-HT1A receptor translocation, stimulating serotonin release, and inactivating GSK-3β.

    PubMed

    Kanno, Takeshi; Tanaka, Akito; Nishizaki, Tomoyuki

    2015-04-01

    Impairment of serotonergic neurotransmission is the major factor responsible for depression and glycogen synthase kinase 3β (GSK-3β) participates in serotonergic transmission-mediated signaling networks relevant to mental illnesses. In the forced-swim test to assess depression-like behavior, the immobility time for mice with restraint stress was significantly longer than that for nonstressed control mice. Postsynaptic cell surface localization of 5-HT1A receptor, but not 5-HT2A receptor, in the hypothalamus for mice with restraint stress was significantly reduced as compared with that for control mice, which highly correlated to prolonged immobility time, i.e., depression-like behavior. The linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) restored restraint stress-induced reduction of cell surface 5-HT1A receptor and improved depression-like behavior in mice with restraint stress. Moreover, DCP-LA stimulated serotonin release from hypothalamic slices and cancelled restraint stress-induced reduction of GSK-3β phosphorylation at Ser9. Taken together, the results of the present study indicate that DCP-LA could ameliorate depression-like behavior by promoting translocation of 5-HT1A receptor to the plasma membrane on postsynaptic cells, stimulating serotonin release, and inactivating GSK-3β. PMID:24788685

  3. [Mechanism of Platinum Derivatives Induced Kidney Injury].

    PubMed

    Yan, Feifei; Duan, Jianchun; Wang, Jie

    2015-09-20

    Platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors, lung cancer, and colorectal cancer. Two major problems exist, however, in the clinic use of platinum derivatives. One is the development of tumor resistance to the drug during therapy, leading to treatment failure. The other is the drug's toxicity such as the cisplatin's nephrotoxicity, which limits the dose that can be administered. This paper describes the mechanism of platinum derivatives induced kidney injury. PMID:26383983

  4. Synthesis and anticancer activity of novel fluorinated asiatic acid derivatives.

    PubMed

    Gonçalves, Bruno M F; Salvador, Jorge A R; Marín, Silvia; Cascante, Marta

    2016-05-23

    A series of novel fluorinated Asiatic Acid (AA) derivatives were successfully synthesized, tested for their antiproliferative activity against HeLa and HT-29 cell lines, and their structure activity relationships were evaluated. The great majority of fluorinated derivatives showed stronger antiproliferative activity than AA in a concentration dependent manner. The most active compounds have a pentameric A-ring containing an α,β-unsaturated carbonyl group. The compounds with better cytotoxic activity were then evaluated against MCF-7, Jurkat, PC-3, A375, MIA PaCa-2 and BJ cell lines. Derivative 14 proved to be the most active compound among all tested derivatives and its mechanism of action was further investigated in HeLa cell line. The results showed that compound 14 induced cell cycle arrest in G0/G1 stage as a consequence of up-regulation of p21(cip1/waf1) and p27(kip1) and down-regulation of cyclin D3 and Cyclin E. Furthermore, compound 14 was found to induce caspase driven-apoptosis with activation of caspases-8 and caspase-3 and the cleavage of PARP. The cleavage of Bid into t-Bid, the up-regulation of Bax and the down-regulation of Bcl-2 were also observed after treatment of HeLa cells with compound 14. Taken together, these mechanistic studies revealed the involvement of extrinsic and intrinsic pathways in the apoptotic process induced by compound 14. Importantly, the antiproliferative activity of this compound on the non-tumor BJ human fibroblast cell line is weaker than in the tested cancer cell lines. The enhanced potency (between 45 and 90-fold more active than AA in a panel of cancer cell lines) and selectivity of this new AA derivative warrant further preclinical evaluation. PMID:26974379

  5. Caffeic acid derivatives in the roots of yacon (Smallanthus sonchifolius).

    PubMed

    Takenaka, Makiko; Yan, Xiaojun; Ono, Hiroshi; Yoshida, Mitsuru; Nagata, Tadahiro; Nakanishi, Tateo

    2003-01-29

    Five caffeic acid derivatives were found in the roots of yacon, Smallanthus sonchifolius (Poepp. and Endl.) H. Robinson, Asteraceae, as the major water-soluble phenolic compounds. The structures of these compounds were determined by analysis of spectroscopic data. Two of these were chlorogenic acid (3-caffeoylquinic acid) and 3,5-dicaffeoylquinic acid, common phenolic compounds in plants of the family Asteraceae. Three were esters of caffeic acid with the hydroxy groups of aldaric acid, derived from hexose. The structure of the aldaric moiety was determined by hydrolysis and comparison of NMR spectra with those of standard aldaric acids. The compounds were novel caffeic acid esters of altraric acid: 2,4- or 3,5-dicaffeoylaltraric acid, 2,5-dicaffeoylaltraric acid, and 2,3,5- or 2,4,5-tricaffeoylaltraric acid. PMID:12537459

  6. Anti-inflammatory effects of hydroxycinnamic acid derivatives

    SciTech Connect

    Nagasaka, Reiko; Chotimarkorn, Chatchawan; Shafiqul, Islam Md.; Hori, Masatoshi; Ozaki, Hiroshi; Ushio, Hideki . E-mail: hushio@kaiyodai.ac.jp

    2007-06-29

    NF-{kappa}B family of transcription factors are involved in numerous cellular processes, including differentiation, proliferation, and inflammation. It was reported that hydroxycinnamic acid derivatives (HADs) are inhibitors of NF-{kappa}B activation. Rice bran oil contains a lot of phytosteryl ferulates, one of HADs. We have investigated effects of phytosteryl ferulates on NF-{kappa}B activation in macrophage. Cycloartenyl ferulate (CAF), one of phytosteryl ferulates, significantly reduced lipopolysaccharide (LPS)-induced NO production and mRNA expression of inducible NO synthase and cyclooxygenese-2 but upregulated SOD activity. Electrophoresis mobility shift assay revealed that CAF inhibited DNA-binding of NF-{kappa}B. CAF and phytosteryl ferulates probably have potentially anti-inflammatory properties.

  7. Antioxidant and antimicrobial activities of cinnamic acid derivatives.

    PubMed

    Sova, M

    2012-07-01

    Cinnamic acid is an organic acid occurring naturally in plants that has low toxicity and a broad spectrum of biological activities. In the search for novel pharmacologically active compounds, cinnamic acid derivatives are important and promising compounds with high potential for development into drugs. Many cinnamic acid derivatives, especially those with the phenolic hydroxyl group, are well-known antioxidants and are supposed to have several health benefits due to their strong free radical scavenging properties. It is also well known that cinnamic acid has antimicrobial activity. Cinnamic acid derivatives, both isolated from plant material and synthesized, have been reported to have antibacterial, antiviral and antifungal properties. Acids, esters, amides, hydrazides and related derivatives of cinnamic acid with such activities are here reviewed. PMID:22512578

  8. Synthesis of Hydroxymethylenebisphosphonic Acid Derivatives in Different Solvents.

    PubMed

    Nagy, Dávid Illés; Grün, Alajos; Garadnay, Sándor; Greiner, István; Keglevich, György

    2016-01-01

    The syntheses of hydroxymethylenebisphosphonic acid derivatives (dronic acid derivatives) starting from the corresponding substituted acetic acids and P-reagents, mainly phosphorus trichloride and phosphorous acid are surveyed according to the solvents applied. The nature of the solvent is a critical point due to the heterogeneity of the reaction mixtures. This review sheds light on the optimum choice and ratio of the P-reactants, and on the optimum conditions. PMID:27529200

  9. Polyhydroxy Fatty Acids Derived from Sophorolipids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Starting from 17-hydroxyoleic acid, which is readily available from acid alcoholysis of sophorolipids, several new polyhydroxy fatty acids have been synthesized. These compounds contain from 2 to 5 hydroxy groups, in some instances combined with other functional groups. The added hydroxy groups ca...

  10. Saturated Free Fatty Acids Induce Cholangiocyte Lipoapoptosis

    PubMed Central

    Natarajan, Sathish Kumar; Ingham, Sally A.; Mohr, Ashley M.; Wehrkamp, Cody J.; Ray, Anuttoma; Roy, Sohini; Cazanave, Sophie C.; Phillippi, Mary Anne; Mott, Justin L.

    2015-01-01

    Recent studies have identified a cholestatic variant of nonalcoholic fatty liver disease (NAFLD) with portal inflammation and ductular reaction. Based on reports of biliary damage, as well as increased circulating free fatty acids (FFAs) in NAFLD, we hypothesized the involvement of cholangiocyte lipoapoptosis as a mechanism of cellular injury. Here, we demonstrate that the saturated FFAs palmitate and stearate induced robust and rapid cell death in cholangiocytes. Palmitate and stearate induced cholangiocyte lipoapoptosis in a concentration-dependent manner in multiple cholangiocyte-derived cell lines. The mechanism of lipoapoptosis relied on the activation of caspase 3/7 activity. There was also a significant up-regulation of the proapoptotic BH3-containing protein, PUMA. In addition, palmitate-induced cholangiocyte lipoapoptosis involved a time-dependent increase in the nuclear localization of forkhead family of transcription factor 3 (FoxO3). We show evidence for posttranslational modification of FoxO3, including early (6 hours) deacetylation and dephosphorylation that coincide with localization of FoxO3 in the nuclear compartment. By 16 hours, nuclear FoxO3 is both phosphorylated and acetylated. Knockdown studies confirmed that FoxO3 and its downstream target, PUMA, were critical for palmitate- and stearate-induced cholangiocyte lipoapoptosis. Interestingly, cultured cholangiocyte-derived cells did not accumulate appreciable amounts of neutral lipid upon FFA treatment. Conclusion Our data show that the saturated FFAs palmitate and stearate induced cholangiocyte lipoapoptosis by way of caspase activation, nuclear translocation of FoxO3, and increased proapoptotic PUMA expression. These results suggest that cholangiocyte injury may occur through lipoapoptosis in NAFLD and nonalcoholic steatohepatitis patients. PMID:24753158

  11. Acetylcholinesterase inhibitory properties of some benzoic acid derivatives

    NASA Astrophysics Data System (ADS)

    Yildiz, Melike; Kiliç, Deryanur; Ünver, Yaǧmur; Şentürk, Murat; Askin, Hakan; Küfrevioǧlu, Ömer Irfan

    2016-04-01

    Acetylcholinesterase (AChE) hydrolyses the neurotransmitter acetylcholine to acetic acid and choline. AChE inhibitors are used in treatment of several neurodegeneartive disorder and Alzheimer's disease. In the present study, inhibition of AChE with some benzoic acid derivatives were investigated. 3-Chloro-benzoic acid (1), 2-hydroxy-5-sulfobenzoic acid (2), 2-(sulfooxy) benzoic acid (3), 2-hydroxybenzoic acid (4), 2,3-dimethoxybenzoic (5), and 3,4,5-trimethoxybenzoic (6) were calculated IC50 values AChE enzyme. Kinetic investigations showed that similarly to AChE inhibitors. Benzoic acid derivatives (1-6) investigated are encouraging agents which may be used as lead molecules in order to derivative novel AChE inhibitors that might be useful in medical applications.

  12. Biomarkers of myeloperoxidase-derived hypochlorous acid.

    PubMed

    Winterbourn, C C; Kettle, A J

    2000-09-01

    Hypochlorous acid is the major strong oxidant generated by neutrophils. The heme enzyme myeloperoxidase catalyzes the production of hypochlorous acid from hydrogen peroxide and chloride. Although myeloperoxidase has been implicated in the tissue damage that occurs in numerous diseases that involve inflammatory cells, it has proven difficult to categorically demonstrate that it plays a crucial role in any pathology. This situation should soon be rectified with the advent of sensitive biomarkers for hypochlorous acid. In this review, we outline the advantages and limitations of chlorinated tyrosines, chlorohydrins, 5-chlorocytosine, protein carbonyls, antibodies that recognize HOCl-treated proteins, and glutathione sulfonamide as potential biomarkers of hypochlorous acid. Levels of 3-chlorotyrosine and 3,5-dichlorotyrosine are increased in proteins after exposure to low concentrations of hypochlorous acid and we conclude that their analysis by gas chromatography and mass spectrometry is currently the best method available for probing the involvement of oxidation by myeloperoxidase in the pathology of particular diseases. The appropriate use of other biomarkers should provide complementary information.Keywords-Free radicals, Myeloperoxidase, Neutrophil oxidant, Hypochlorous acid, Chlorotyrosine, Chlorohydrin, Oxidant biomarker PMID:11020661

  13. Natural cinnamic acids, synthetic derivatives and hybrids with antimicrobial activity.

    PubMed

    Guzman, Juan David

    2014-01-01

    Antimicrobial natural preparations involving cinnamon, storax and propolis have been long used topically for treating infections. Cinnamic acids and related molecules are partly responsible for the therapeutic effects observed in these preparations. Most of the cinnamic acids, their esters, amides, aldehydes and alcohols, show significant growth inhibition against one or several bacterial and fungal species. Of particular interest is the potent antitubercular activity observed for some of these cinnamic derivatives, which may be amenable as future drugs for treating tuberculosis. This review intends to summarize the literature data on the antimicrobial activity of the natural cinnamic acids and related derivatives. In addition, selected hybrids between cinnamic acids and biologically active scaffolds with antimicrobial activity were also included. A comprehensive literature search was performed collating the minimum inhibitory concentration (MIC) of each cinnamic acid or derivative against the reported microorganisms. The MIC data allows the relative comparison between series of molecules and the derivation of structure-activity relationships. PMID:25429559

  14. Loss-of-Function of HtrA1 Abrogates All-Trans Retinoic Acid-Induced Osteogenic Differentiation of Mouse Adipose-Derived Stromal Cells Through Deficiencies in p70S6K Activation.

    PubMed

    Glanz, Stephan; Mirsaidi, Ali; López-Fagundo, Cristina; Filliat, Gladys; Tiaden, André N; Richards, Peter J

    2016-05-01

    All-trans retinoic acid (ATRA) is a potent inducer of osteogenic differentiation in mouse adipose-derived stromal cells (mASCs), although the underlying mechanisms responsible for its mode of action have yet to be completely elucidated. High temperature requirement protease A1 (HtrA1) is a newly recognized modulator of human multipotent stromal cell (MSC) osteogenesis and as such, may play a role in regulating ATRA-dependent osteogenic differentiation of mASCs. In this study, we assessed the influence of small interfering RNA (siRNA)-induced repression of HtrA1 production on mASC osteogenesis and examined its effects on ATRA-mediated mammalian target of rapamycin (mTOR) signaling. Inhibition of HtrA1 production in osteogenic mASCs resulted in a significant reduction of alkaline phosphatase activity and mineralized matrix formation. Western blot analyses revealed the rapid activation of Akt (Ser473) and p70S6K (Thr389) in ATRA-treated mASCs, and that levels of phosphorylated p70S6K were noticeably reduced in HtrA1-deficient mASCs. Further studies using mTOR inhibitor rapamycin and siRNA specific for the p70S6K gene Rps6kb1 confirmed ATRA-mediated mASC osteogenesis as being dependent on p70S6K activation. Finally, transfection of cells with a constitutively active rapamycin-resistant p70S6K mutant could restore the mineralizing capacity of HtrA1-deficient mASCs. These findings therefore lend further support for HtrA1 as a positive mediator of MSC osteogenesis and provide new insights into the molecular mode of action of ATRA in regulating mASC lineage commitment. PMID:26950191

  15. Piperazic acid derivatives inhibit Gli1 in Hedgehog signaling pathway.

    PubMed

    Khatra, Harleen; Kundu, Jayanta; Khan, Pragya Paramita; Duttagupta, Indranil; Pattanayak, Sankha; Sinha, Surajit

    2016-09-15

    Piperazic acid, a non-proteinogenic amino acid, found in complex secondary metabolites and peptide natural substances, has shown down regulation of Gli1 expression in Hedgehog signaling pathway in cell based assays. Further structure activity relationship study indicated that amide derivatives of piperazic acid are more potent than piperazic acid itself, with little to no toxicity. However, other cellular components involved in the pathway were not affected. To the best of our knowledge, this is the first report on the inhibitory property of piperazic acid in this pathway. Hence, this molecule could serve as a useful tool for studying Hedgehog signaling. PMID:27528433

  16. Caffeic Acid Derivatives in Dried Lamiaceae and Echinacea purpurea Products

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The concentrations of caffeic acid derivatives within Lamiaceae and Echinacea (herb, spice, tea, and dietary supplement forms) readily available in the U.S. marketplace (n=72) were determined. After the first identification of chicoric acid in Ocimum basilicum (basil), the extent to which chicoric a...

  17. Cannabimimetic fatty acid derivatives in cancer and inflammation.

    PubMed

    Di Marzo, V; Melck, D; De Petrocellis, L; Bisogno, T

    2000-04-01

    Evidence for the role of the cannabimimetic fatty acid derivatives (CFADs), i.e. anandamide (arachidonoylethanolamide, AEA), 2-arachidonoylglycerol (2-AG) and palmitoylethanolamide (PEA), in the control of inflammation and of the proliferation of tumor cells is reviewed here. The biosynthesis of AEA, PEA, or 2-AG can be induced by stimulation with either Ca(2+) ionophores, lipopolysaccharide, or platelet activating factor in macrophages, and by ionomycin or antigen challenge in rat basophilic leukemia (RBL-2H3) cells (a widely used model for mast cells). These cells also inactivate CFADs through re-uptake and/or hydrolysis and/or esterification processes. AEA and PEA modulate cytokine and/or arachidonate release from macrophages in vitro, regulate serotonin secretion from RBL-2H3 cells, and are analgesic in some animal models of inflammatory pain. However, the involvement of endogenous CFADs and cannabinoid CB(1) and CB(2) receptors in these effects is still controversial. In human breast and prostate cancer cells, AEA and 2-AG, but not PEA, potently inhibit prolactin and/or nerve growth factor (NGF)-induced cell proliferation. Vanillyl-derivatives of anandamide, such as olvanil and arvanil, exhibit even higher anti-proliferative activity. These effects are due to suppression of the levels of the 100 kDa prolactin receptor or of the high affinity NGF receptors (trk), are mediated by CB(1)-like cannabinoid receptors, and are enhanced by other CFADs. Inhibition of adenylyl cyclase and activation of mitogen-activated protein kinase underlie the anti-mitogenic actions of AEA. The possibility that CFADs act as local inhibitors of the proliferation of human breast cancer is discussed here. PMID:10785541

  18. Bile acids in radiation-induced diarrhea

    SciTech Connect

    Arlow, F.L.; Dekovich, A.A.; Priest, R.J.; Beher, W.T.

    1987-10-01

    Radiation-induced bowel disease manifested by debilitating diarrhea is an unfortunate consequence of therapeutic irradiation for pelvic malignancies. Although the mechanism for this diarrhea is not well understood, many believe it is the result of damage to small bowel mucosa and subsequent bile acid malabsorption. Excess amounts of bile acids, especially the dihydroxy components, are known to induce water and electrolyte secretion and increase bowel motility. We have directly measured individual and total bile acids in the stool samples of 11 patients with radiation-induced diarrhea and have found bile acids elevated two to six times normal in eight of them. Our patients with diarrhea and increased bile acids in their stools had prompt improvement when given cholestyramine. They had fewer stools and returned to a more normal life-style.

  19. Synthesis and biological evaluation of novel lipoamino acid derivatives.

    PubMed

    Kaki, Shiva Shanker; Arukali, Sammaiah; Korlipara, Padmaja V; Prasad, R B N; Yedla, Poornachandra; Ganesh Kumar, C

    2016-01-01

    Seven novel lipoamino acid conjugates were synthesized from methyl oleate and amino acids. Methyl oleate was grafted to different amino acids using thioglycolic acid as a spacer group. Seven derivatives (3a-g) were prepared and characterized by spectral data (NMR, IR and MS spectral studies). All the derivatives were studied for their antimicrobial, anti-biofilm and anticancer activities. Among all the derivatives, it was found that compound 3b was the most potent antibacterial compound which showed good activity against four Gram positive bacterial strains and also exhibited excellent antifungal activity against a fungal strain. In the anti-biofilm assay, compound 3b showed promising activity with IC50 value of 2.8μM against Bacillus subtilis MTCC 121. All the compounds showed anticancer activities with 3c showing promising anticancer activity (IC50=15.3-22.4μM) against the four cell lines tested. PMID:26586599

  20. Catalytic conversion of lactic acid and its derivatives

    SciTech Connect

    Kokitkar, P.B.; Langford, R.; Miller, D.J.; Jackson, J.E.

    1993-12-31

    The catalytic upgrading of lactic acid and methyl lactate is being investigated. With the commercialization of inexpensive starch fermentation technologies, US production of lactic acid is undergoing a surge. Dropping cost and increased availability offer a major opportunity to develop lactic acid as a renewable feedstock for chemicals production. IT can be catalytically converted into several important chemical intermediates currently derived from petroleum including acrylic acid, propanoic acid, and 2,3-pentanedione. The process can expand the potential of biomass as a substitute feedstock for petroleum and can benefit both the US chemical process industry and US agriculture via increased production of high-value, non-food products from crops and crop byproducts. Reaction studies of lactic acid and its ester are conducted in fixed bed reactors at 250-380{degrees}C and 0.1-0.5 MPa (1-5 atm) using salt catalysts on low surface area supports. Highest selectivities achieved are 42% to acrylic acid and 55% to 2,3-pentanedione from lactic acid over NaNO{sub 3} catalyst on low surface area silica support. High surface area (microporous) or highly acidic supports promote fragmentation to acetaldehyde and thus reduce yields of desirable products. The support acidity gives rice to lactic acid from neat methyl lactate feed but the lactic acid yield goes down after the nitrate salt is impregnated on the support. Both lactic acid and methyl lactate form 2,3-pentanedione. Methyl lactate reactions are more complex since it forms all the products obtained from lactic acid as well as many corresponding esters of the acids obtained from lactic acid (mainly methyl acrylate, methyl propionate, methyl acetate). At high temperatures, methyl acetate and acetic acid yields become significant from methyl lactate whereas lactic acid gives significant amount of acetol at high temperatures.

  1. Oleanolic acid and related derivatives as medicinally important compounds.

    PubMed

    Sultana, Nighat; Ata, Athar

    2008-12-01

    Oleanolic acid has been isolated from chloroform extract of Olea ferruginea Royle after removal of organic bases and free acids. The literature survey revealed it to be biologically very important. In this review the biological significance of oleanolic acid and its derivatives has been discussed. The aim of this review is to update current knowledge on oleanolic acid and its natural and semisynthetic analogs, focussing on its cytotoxic, antitumer, antioxidant, anti-inflamatory, anti-HIV, acetyl cholinesterase, alpha-glucosidase, antimicrobial, hepatoprotective, anti-inflammatory, antipruritic, spasmolytic activity, anti-angiogenic, antiallergic, antiviral and immunomodulatory activities. We present in this review, for the first time, a compilation of the most relevant scientific papers and technical reports of the chemical, pre-clinical and clinical research on the properties of oleanolic acid and its derivatives. PMID:18618318

  2. Conformational Interconversions of Amino Acid Derivatives.

    PubMed

    Kaminský, Jakub; Jensen, Frank

    2016-02-01

    Exhaustive conformational interconversions including transition structure analyses of N-acetyl-l-glycine-N-methylamide as well as its alanine, serine, and cysteine analogues have been investigated at the MP2/6-31G** level, yielding a total of 142 transition states. Improved estimates of relative energies were obtained by separately extrapolating the Hartree-Fock and MP2 energies to the basis set limit and adding the difference between CCSD(T) and MP2 results with the cc-pVDZ basis set to the extrapolated MP2 results. The performance of eight empirical force fields (AMBER94, AMBER14SB, MM2, MM3, MMFFs, CHARMM22_CMAP, OPLS_2005, and AMOEBAPRO13) in reproducing ab initio energies of transition states was tested. Our results indicate that commonly used class I force fields employing a fixed partial charge model for the electrostatic interaction provide mean errors in the ∼10 kJ/mol range for energies of conformational transition states for amino acid conformers. Modern reparametrized versions, such as CHARMM22_CMAP, and polarizable force fields, such as AMOEBAPRO13, have slightly lower mean errors, but maximal errors are still in the 35 kJ/mol range. There are differences between the force fields in their ability for reproducing conformational transitions classified according to backbone/side-chain or regions in the Ramachandran angles, but the data set is likely too small to draw any general conclusions. Errors in conformational interconversion barriers by ∼10 kJ/mol suggest that the commonly used force field may bias certain types of transitions by several orders of magnitude in rate and thus lead to incorrect dynamics in simulations. It is therefore suggested that information for conformational transition states should be included in parametrizations of new force fields. PMID:26691979

  3. Nutritional value of D-amino acids, D-peptides, and amino acid derivatives in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This paper describes a method for determining the nutritional value of D-amino acids, D-peptides, and amino acid derivatives using a growth assay in mice fed a synthetic all-amino acid diet. A large number of experiments were carried out in which a molar equivalent of the test compound replaced a n...

  4. A new ellagic acid derivative from Polygonum runcinatum.

    PubMed

    Zhou, Zhi-Hong; Liu, Min-Zhuo; Wang, Meng-Hua; Qu, Wei; Sun, Jian-Bo; Liang, Jing-Yu; Wu, Fei-Hua

    2015-01-01

    A new ellagic acid derivative, 3,3'-dimethylellagic acid-4'-O-(6″-galloyl)-β-D-glucoside, named runcinatside (5), together with four known compounds 3,3'-dimethylellagic acid (1), 3,3',4'-trimethylellagic acid (2), 3,3'-dimethylellagic acid-4'-O-β-D-glucoside (3) and 3-methylellagic acid-4'-O-α-L-rhamno-pyranoside (4), was isolated from the roots of Polygonum runcinatum Buch.-Ham. ex D.Don Var. sinense Hemsl and the structures of these compounds were established by spectroscopic methods and comparison with previously reported data. All compounds showed antioxidant activities in vitro and compound 5 possessed the highest activity. PMID:25560313

  5. Production of Diethyl Terephthalate from Biomass-Derived Muconic Acid.

    PubMed

    Lu, Rui; Lu, Fang; Chen, Jiazhi; Yu, Weiqiang; Huang, Qianqian; Zhang, Junjie; Xu, Jie

    2016-01-01

    We report a cascade synthetic route to directly obtain diethyl terephthalate, a replacement for terephthalic acid, from biomass-derived muconic acid, ethanol, and ethylene. The process involves two steps: First, a substituted cyclohexene system is built through esterification and Diels-Alder reaction; then, a dehydrogenation reaction provides diethyl terephthalate. The key esterification reaction leads to improved solubility and modulates the electronic properties of muconic acid, thus promoting the Diels-Alder reaction with ethylene. With silicotungstic acid as the catalyst, nearly 100% conversion of muconic acid was achieved, and the cycloadducts were formed with more than 99.0% selectivity. The palladium-catalyzed dehydrogenation reaction preferentially occurs under neutral or mildly basic conditions. The total yield of diethyl terephthalate reached 80.6% based on the amount of muconic acid used in the two-step synthetic process. PMID:26592149

  6. OH-radical induced degradation of hydroxybenzoic- and hydroxycinnamic acids and formation of aromatic products—A gamma radiolysis study

    NASA Astrophysics Data System (ADS)

    Krimmel, Birgit; Swoboda, Friederike; Solar, Sonja; Reznicek, Gottfried

    2010-12-01

    The OH-radical induced degradation of hydroxybenzoic acids (HBA), hydroxycinnamic acids (HCiA) and methoxylated derivatives, as well as of chlorogenic acid and rosmarinic acid was studied by gamma radiolysis in aerated aqueous solutions. Primary aromatic products resulting from an OH-radical attachment to the ring (hydroxylation), to the position occupied by the methoxyl group (replacement -OCH 3 by -OH) as well as to the propenoic acid side chain of the cinnamic acids (benzaldehyde formations) were analysed by HPLC-UV and LC-ESI-MS. A comparison of the extent of these processes is given for 3,4-dihydroxybenzoic acid, vanillic acid, isovanillic acid, syringic acid, cinnamic acid, 4-hydroxycinnamic acid, caffeic acid, ferulic acid, isoferulic acid, chlorogenic acid, and rosmarinic acid. For all cinnamic acids and derivatives benzaldehydes were significant oxidation products. With the release of caffeic acid from chlorogenic acid the cleavage of a phenolic glycoside could be demonstrated. Reaction mechanisms are discussed.

  7. Lipoproteini lipase-derived fatty acids: physiology and dysfunction.

    PubMed

    Lee, Jee; Goldberg, Ira J

    2007-12-01

    Under normal circumstances, most energy substrate used for heart contraction derives from fatty acids in the form of nonesterified fatty acids bound to albumin or fatty acids derived from lipolysis of lipoprotein-bound triglyceride by lipoprotein lipase (LpL). By creating LpL knockout mice (hLpL0), we learned that loss of cardiac LpL leads to myocardial dysfunction; therefore, neither nonesterified fatty acids nor increased glucose metabolism can replace LpL actions. hLpL0 mice do not survive abdominal aortic constriction and they develop more heart failure with hypertension. Conversely, we created a mouse overexpressing cardiomyocyte-anchored LpL. This transgene produced cardiac lipotoxicity and dilated cardiomyopathy. Methods to alter this phenotype and the causes of other models of lipotoxicity are currently being studied and will provide further insight into the physiology of lipid metabolism in the heart. PMID:18367009

  8. Contact allergy to dehydroabietic acid derivatives isolated from Portuguese colophony.

    PubMed

    Karlberg, A T; Boman, A; Hacksell, U; Jacobsson, S; Nilsson, J L

    1988-09-01

    7-oxodehydroabietic acid and 15-hydroxydehydroabietic acid were isolated as their methyl esters from Portuguese colophony of the gum rosin type and identified as contact allergens. Another oxidation product of dehydroabietic acid, 15-hydroxy-7-oxodehydroabietic acid, was synthesized and identified as a component of Portuguese gum rosin. 7-oxodehydroabietic acid was found to a be a grade III allergen according to the GPMT method. Guinea pigs induced with gum rosin showed only a low response to the isolated compounds, while patients with a known allergy to gum rosin reacted to a greater extent. The results imply that the content of oxidized dehydroabietic acids in gum rosin is too low to give a marked sensitization in the animals. However, the patients might have come in contact with the allergens in technically modified rosins. The compounds showed a pattern of cross-reactivity in the animal experiments as well as among the patch tested patients. PMID:3191677

  9. Design, Synthesis, and Antimycobacterial Activity of Novel Theophylline-7-Acetic Acid Derivatives With Amino Acid Moieties.

    PubMed

    Stavrakov, Georgi; Valcheva, Violeta; Voynikov, Yulian; Philipova, Irena; Atanasova, Mariyana; Konstantinov, Spiro; Peikov, Plamen; Doytchinova, Irini

    2016-03-01

    The theophylline-7-acetic acid (7-TAA) scaffold is a promising novel lead compound for antimycobacterial activity. Here, we derive a model for antitubercular activity prediction based on 14 7-TAA derivatives with amino acid moieties and their methyl esters. The model is applied to a combinatorial library, consisting of 40 amino acid and methyl ester derivatives of 7-TAA. The best three predicted compounds are synthesized and tested against Mycobacterium tuberculosis H37Rv. All of them are stable, non-toxic against human cells and show antimycobacterial activity in the nanomolar range being 60 times more active than ethambutol. PMID:26502828

  10. Antitumor effects of tyropeptin-boronic acid derivatives: New proteasome inhibitors

    PubMed Central

    Momose, Isao; Abe, Hikaru; Watanabe, Takumi; Ohba, Shun-ichi; Yamazaki, Kanami; Dan, Shingo; Yamori, Takao; Masuda, Tohru; Nomoto, Akio

    2014-01-01

    The proteasome degrades numerous regulatory proteins that are critical for tumor growth. Thus, proteasome inhibitors are promising antitumor agents. New proteasome inhibitors, such as tyropeptins and tyropeptin-boronic acid derivatives, have a potent inhibitory activity. Here we report the antitumor effects of two new tyropeptin-boronic acid derivatives, AS-06 and AS-29. AS-06 and AS-29 significantly suppress the degradation of the proteasome-sensitive fluorescent proteins in HEK293PS cells, and induce the accumulation of ubiquitinated proteins in human multiple myeloma cells. We show that these derivatives also suppress the degradation of the NF-κB inhibitor IκB-α and the nuclear translocation of NF-κB p65 in multiple myeloma cells, resulting in the inhibition of NF-κB activation. Furthermore, we demonstrate that AS-06 and AS-29 induce apoptosis through the caspase-8 and caspase-9 cascades. In a xenograft mouse model, i.v. administration of tyropeptin-boronic acid derivatives inhibits proteasome in tumors and clearly suppresses tumor growth in mice bearing human multiple myeloma. Our results indicate that tyropeptin-boronic acid derivatives could be lead therapeutic agents against human multiple myeloma. PMID:25251038

  11. Extracting metal ions with diphosphonic acid, or derivative thereof

    DOEpatents

    Horwitz, Earl P.; Gatrone, Ralph C.; Nash, Kenneth L.

    1994-01-01

    Thermodynamically-unstable complexing agents which are diphosphonic acids and diphosphonic acid derivatives (or sulphur containing analogs), like carboxyhydroxymethanediphosphonic acid and vinylidene-1,1-diphosphonic acid, are capable of complexing with metal ions, and especially metal ions in the II, III, IV, V and VI oxidation states, to form stable, water-soluble metal ion complexes in moderately alkaline to highly-acidic media. However, the complexing agents can be decomposed, under mild conditions, into non-organic compounds which, for many purposes are environmentally-nondamaging compounds thereby degrading the complex and releasing the metal ion for disposal or recovery. Uses for such complexing agents as well as methods for their manufacture are also described.

  12. Extracting metal ions with diphosphonic acid, or derivative thereof

    DOEpatents

    Horwitz, E.P.; Gatrone, R.C.; Nash, K.L.

    1994-07-26

    Thermodynamically-unstable complexing agents which are diphosphonic acids and diphosphonic acid derivatives (or sulfur containing analogs), like carboxyhydroxymethanediphosphonic acid and vinylidene-1,1-diphosphonic acid, are capable of complexing with metal ions, and especially metal ions in the II, III, IV, V and VI oxidation states, to form stable, water-soluble metal ion complexes in moderately alkaline to highly-acidic media. However, the complexing agents can be decomposed, under mild conditions, into non-organic compounds which, for many purposes are environmentally-nondamaging compounds thereby degrading the complex and releasing the metal ion for disposal or recovery. Uses for such complexing agents as well as methods for their manufacture are also described. 1 fig.

  13. Membrane extraction with thermodynamically unstable diphosphonic acid derivatives

    DOEpatents

    Horwitz, E.P.; Gatrone, R.C.; Nash, K.L.

    1997-10-14

    Thermodynamically-unstable complexing agents which are diphosphonic acids and diphosphonic acid derivatives (or sulphur containing analogs), like carboxyhydroxymethanediphosphonic acid and vinylidene-1,1-diphosphonic acid, are capable of complexing with metal ions, and especially metal ions in the II, III, IV, V and VI oxidation states, to form stable, water-soluble metal ion complexes in moderately alkaline to highly-acidic media. However, the complexing agents can be decomposed, under mild conditions, into non-organic compounds which, for many purposes are environmentally-nondamaging compounds thereby degrading the complex and releasing the metal ion for disposal or recovery. Uses for such complexing agents as well as methods for their manufacture are also described. 1 fig.

  14. Membrane extraction with thermodynamically unstable diphosphonic acid derivatives

    DOEpatents

    Horwitz, Earl Philip; Gatrone, Ralph Carl; Nash, Kenneth LaVerne

    1997-01-01

    Thermodynamically-unstable complexing agents which are diphosphonic acids and diphosphonic acid derivatives (or sulphur containing analogs), like carboxyhydroxymethanediphosphonic acid and vinylidene-1,1-diphosphonic acid, are capable of complexing with metal ions, and especially metal ions in the II, III, IV, V and VI oxidation states, to form stable, water-soluble metal ion complexes in moderately alkaline to highly-acidic media. However, the complexing agents can be decomposed, under mild conditions, into non-organic compounds which, for many purposes are environmentally-nondamaging compounds thereby degrading the complex and releasing the metal ion for disposal or recovery. Uses for such complexing agents as well as methods for their manufacture are also described.

  15. Bile acids are toxic for isolated cardiac mitochondria: a possible cause for hepatic-derived cardiomyopathies?

    PubMed

    Ferreira, Manuela; Coxito, Pedro M; Sardão, Vilma A; Palmeira, Carlos M; Oliveira, Paulo J

    2005-01-01

    Cholestasis and other liver diseases may affect the heart through the toxic effects of the retained bile acids on cardiac mitochondria, which could explain the origin of hepatic-derived cardiomyopathies. The objective of this work was to test the hypothesis that bile acids are toxic to heart mitochondria for concentrations that are relevant for cholestasis. Heart mitochondria were isolated from rat and subjected to incubation with selected bile acids (litocholic acid [LCA], deoxycholic acid [DCA], chenodeoxycholic acid [CDCA], glycochenodeoxycholic acid [GCDC], taurodeoxycholic acid [TDCA], and glycoursodeoxycholic acid [GUDC]). We observed that the most toxic bile acids were also the most lipophilic ones (LCA, DCA, and CDCA), inducing a decrease on state 3 respiration, respiratory control ratio, and membrane potential and causing the induction of the mitochondrial permeability transition. GUDC was the bile acid with lower indexes of toxicity on isolated heart mitochondria. The results of this research indicate that at toxicologically relevant concentrations, most bile acids (mainly the most lipophilic) alter mitochondrial bioenergetics. The impairment of cardiac mitochondrial function may be an important cause for the observed cardiac alterations during cholestasis. PMID:15738586

  16. Pseudoephedrine-Directed Asymmetric α-Arylation of α-Amino Acid Derivatives.

    PubMed

    Atkinson, Rachel C; Fernández-Nieto, Fernando; Mas Roselló, Josep; Clayden, Jonathan

    2015-07-27

    Available α-amino acids undergo arylation at their α position in an enantioselective manner on treatment with base of N'-aryl urea derivatives ligated to pseudoephedrine as a chiral auxiliary. In situ silylation and enolization induces diastereoselective migration of the N'-aryl group to the α position of the amino acid, followed by ring closure to a hydantoin with concomitant explulsion of the recyclable auxiliary. The hydrolysis of the hydantoin products provides derivatives of quaternary amino acids. The arylation avoids the use of heavy-metal additives, and is successful with a range of amino acids and with aryl rings of varying electronic character. PMID:26083236

  17. Anticancer activity of branched-chain derivatives of oleic acid

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A number of novel branched-chain derivatives (methyl, n-butyl, phenyl) of methyl oleate were produced by bromination in the allylic position and subsequent treatment with organocuprate reagents. These compounds and their free acid counterparts were tested in vitro for their antiproliferative activi...

  18. Palladium(III)-catalyzed fluorination of arylboronic acid derivatives.

    PubMed

    Mazzotti, Anthony R; Campbell, Michael G; Tang, Pingping; Murphy, Jennifer M; Ritter, Tobias

    2013-09-25

    A practical, palladium-catalyzed synthesis of aryl fluorides from arylboronic acid derivatives is presented. The reaction is operationally simple and amenable to multigram-scale synthesis. Evaluation of the reaction mechanism suggests a single-electron-transfer pathway, involving a Pd(III) intermediate that has been isolated and characterized. PMID:24040932

  19. Photochromic switching of the DNA helicity induced by azobenzene derivatives

    PubMed Central

    Deiana, Marco; Pokladek, Ziemowit; Olesiak-Banska, Joanna; Młynarz, Piotr; Samoc, Marek; Matczyszyn, Katarzyna

    2016-01-01

    The photochromic properties of azobenzene, involving conformational changes occurring upon interaction with light, provide an excellent tool to establish new ways of selective regulation applied to biosystems. We report here on the binding of two water-soluble 4-(phenylazo)benzoic acid derivatives (Azo-2N and Azo-3N) with double stranded DNA and demonstrate that the photoisomerization of Azo-3N leads to changes in DNA structure. In particular, we show that stabilization and destabilization of the B-DNA secondary structure can be photochemically induced in situ by light. This photo-triggered process is fully reversible and could be an alternative pathway to control a broad range of biological processes. Moreover, we found that the bicationic Azo-3N exhibited a higher DNA-binding constant than the monocationic Azo-2N pointing out that the number of positive charges along the photosensitive polyamines chain plays a pivotal role in stabilizing the photochrome-DNA complex. PMID:27339811

  20. Photochromic switching of the DNA helicity induced by azobenzene derivatives.

    PubMed

    Deiana, Marco; Pokladek, Ziemowit; Olesiak-Banska, Joanna; Młynarz, Piotr; Samoc, Marek; Matczyszyn, Katarzyna

    2016-01-01

    The photochromic properties of azobenzene, involving conformational changes occurring upon interaction with light, provide an excellent tool to establish new ways of selective regulation applied to biosystems. We report here on the binding of two water-soluble 4-(phenylazo)benzoic acid derivatives (Azo-2N and Azo-3N) with double stranded DNA and demonstrate that the photoisomerization of Azo-3N leads to changes in DNA structure. In particular, we show that stabilization and destabilization of the B-DNA secondary structure can be photochemically induced in situ by light. This photo-triggered process is fully reversible and could be an alternative pathway to control a broad range of biological processes. Moreover, we found that the bicationic Azo-3N exhibited a higher DNA-binding constant than the monocationic Azo-2N pointing out that the number of positive charges along the photosensitive polyamines chain plays a pivotal role in stabilizing the photochrome-DNA complex. PMID:27339811

  1. Photochromic switching of the DNA helicity induced by azobenzene derivatives

    NASA Astrophysics Data System (ADS)

    Deiana, Marco; Pokladek, Ziemowit; Olesiak-Banska, Joanna; Młynarz, Piotr; Samoc, Marek; Matczyszyn, Katarzyna

    2016-06-01

    The photochromic properties of azobenzene, involving conformational changes occurring upon interaction with light, provide an excellent tool to establish new ways of selective regulation applied to biosystems. We report here on the binding of two water-soluble 4-(phenylazo)benzoic acid derivatives (Azo-2N and Azo-3N) with double stranded DNA and demonstrate that the photoisomerization of Azo-3N leads to changes in DNA structure. In particular, we show that stabilization and destabilization of the B-DNA secondary structure can be photochemically induced in situ by light. This photo-triggered process is fully reversible and could be an alternative pathway to control a broad range of biological processes. Moreover, we found that the bicationic Azo-3N exhibited a higher DNA-binding constant than the monocationic Azo-2N pointing out that the number of positive charges along the photosensitive polyamines chain plays a pivotal role in stabilizing the photochrome-DNA complex.

  2. Gastroprotective mechanisms of action of semisynthetic carnosic acid derivatives in human cells.

    PubMed

    Theoduloz, Cristina; Pertino, Mariano Walter; Schmeda-Hirschmann, Guillermo

    2013-01-01

    Carnosic acid (CA) and its semisynthetic derivatives display relevant gastroprotective effects on HCl/ethanol induced gastric lesions in mice. However, little is known on the mechanisms of action of the new compounds. The aim of the present work was to assess the gastroprotective action mechanisms of CA and its derivatives using human cell culture models. A human gastric adenocarcinoma cell line (AGS) and lung fibroblasts (MRC-5) were used to reveal the possible mechanisms involved. The ability of the compounds to protect cells against sodium taurocholate (NaT)-induced damage, and to increase the cellular reduced glutathione (GSH) and prostaglandin E2 (PGE2) content was determined using AGS cells. Stimulation of cell proliferation was studied employing MRC-5 fibroblasts. Carnosic acid and its derivatives 10-18 raised GSH levels in AGS cells. While CA did not increase the PGE2 content in AGS cells, all derivatives significantly stimulated PGE2 synthesis, the best effect being found for the 12-O-indolebutyrylmethylcarnosate 13. A significant increase in MRC-5 fibroblast proliferation was observed for the derivatives 7 and 16-18. The antioxidant effect of the compounds was assessed by the inhibition of lipid peroxidation in human erythrocyte membranes, scavenging of superoxide anion and DPPH discoloration assay. The new CA derivatives showed gastroprotective effects by different mechanisms, including protection against cell damage induced by NaT, increase in GSH content, stimulation of PGE2 synthesis and cell proliferation. PMID:24399049

  3. Amoxicillin/Clavulanic Acid-Induced Thrombocytopenia

    PubMed Central

    Saad, Aline; Azar, Marina; Khoueiry, Paul

    2014-01-01

    Introduction and Objective: Drug-induced thrombocytopenia is a common adverse effect reported in the literature. Typically patients present with a low platelet count with signs and symptoms ranging from bruising to bleeding, and major organ damage. Penicillin-induced thrombocytopenia previously reported in the literature is explained primarily through the hapten-dependent antibody process. The goal of this report is to present a case of an amoxicillin/clavulanic acid-induced thrombocytopenia. Case Presentation: A 23-year-old male presented to the emergency department with bruises on his arms and legs after completing a full course of amoxicillin/clavulanic acid of 625 mg twice a day for 5 days for tonsillitis. After several tests, the patient was diagnosed with thrombocytopenia induced by amoxicillin/clavulanic acid. The patient was treated with a corticosteroids taper regimen for 3 weeks. He was discharged after 3 days of inpatient treatment with instructions to avoid physical activity for 2 weeks. Two weeks post discharge, the follow-up showed that the platelet count had increased. Discussion: Penicillin-induced thrombocytopenia has been previously reported in the inpatient setting where bleeding was observed. However, the patient in this case report presented with bruises on his arms and legs. The diagnosis was made by the process of elimination; not all possible tests were conducted. The patient was prescribed corticosteroids that are not indicated for drug-induced thrombocytopenia. The Naranjo scale showed that this is a probable adverse event of amoxicillin/clavulanic acid. Conclusion: This is a unique case where amoxicillin/clavulanic acid was reported to be a probable cause of thrombocytopenia in an outpatient setting without signs of bleeding and without concomitant medications. PMID:25477568

  4. Synthesis and properties of coumaric acid derivative homo-polymers.

    PubMed

    Thi, Tran Hang; Matsusaki, Michiya; Shi, Dongjian; Kaneko, Tatsuo; Akashi, Mitsuru

    2008-01-01

    Poly(4-hydroxycinnamic acid) (P4HCA), poly(3-hydroxycinnamic acid) (P3HCA), poly(3-methoxy-4-hydroxycinnamic acid) (PMHCA) and poly(3,4-dihydroxycinnamic acid) (PDHCA) were synthesized by the thermal poly-condensation of the corresponding monomers, which are lignin precursors, coumaric acid derivatives consisting of cinnamoyl groups and different position and number of OH groups. The solubility of the homo-polymers in organic solvents decreased in the order of P3HCA > PDHCA > P4HCA > PMHCA. The wide angle X-ray diffraction (WAXD) results indicated that P4HCA or PMHCA with p-OH group had higher crystallinity, in contrast to P3HCA or PDHCA with m-OH group which had lower crystallinity. Crossed-polarizing microscopy suggested that P4HCA had the nematic liquid crystal properties at 220 degrees C and PDHCA showed birefringence properties at 200 degrees C. In cell-adhesion tests, PDHCA showed the highest cell adhesion (ca. 70%), whereas P3HCA, P4HCA and PMHCA had 50, 18 and 10% cell adhesion, respectively. The coumaric acid derivative homo-polymers can be useful as cell adhesion controllable thermotropic polymers for biomedical and environmental fields. PMID:18177555

  5. Mevalonates restore zoledronic acid-induced osteoclastogenesis inhibition.

    PubMed

    Nagaoka, Y; Kajiya, H; Ozeki, S; Ikebe, T; Okabe, K

    2015-04-01

    Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is likely to be caused by continuous imperfection of bone healing after surgical treatments in patients with long-term administration of nitrogen-containing bisphosphonates (NBPs). NBPs inhibit osteoclastic bone resorption by impairing the mevalonic acid sterol pathway in osteoclasts. Thus, we hypothesized that exogenous mevalonic acid metabolites restore the inhibitory effects of NBPs on osteoclastogenesis and bone remodeling. To clarify the effects of mevalonic acid metabolites, especially geranylgeranyl pyrophosphate (GGPP) and geranylgeranyl transferase substrate geranylgeranyl acid (GGOH), we examined the effects of zoledronic acid with or without GGOH or GGPP on osteoclast differentiation, multinucleation, and bone mineral deposition in tooth-extracted sockets. Zoledronic acid decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells derived from mouse osteoclast precursors treated with receptor activator of nuclear factor-κB ligand and macrophage colony-stimulating factor. Zoledronic acid simultaneously suppressed not only the expressions of osteoclastic differentiation-related molecules such as TRAP, cathepsin K, calcitonin receptor, and vacuolar H-ATPase but also those of multinucleation-related molecules such as dendrocyte-expressed 7 transmembrane proteins and osteoclast stimulatory transmembrane protein. Treatment with GGOH or GGPP, but not farnesyl acid, restored the zoledronic acid-inhibited number of TRAP-positive multinuclear cells together with the expressions of these molecules. Although intraperitoneal administration of zoledronic acid and lipopolysaccharide into mice appeared to induce BRONJ-like lesions with empty bone lacunae and decreased mineral deposition in tooth-extracted socket, both GGOH and GGPP partially restored the inhibitory effects on zoledronic acid-related mineral deposition. These results suggest the potential of mevalonic acid

  6. Cyclic phosphatidic acid and lysophosphatidic acid induce hyaluronic acid synthesis via CREB transcription factor regulation in human skin fibroblasts.

    PubMed

    Maeda-Sano, Katsura; Gotoh, Mari; Morohoshi, Toshiro; Someya, Takao; Murofushi, Hiromu; Murakami-Murofushi, Kimiko

    2014-09-01

    Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator and an analog of the growth factor-like phospholipid lysophosphatidic acid (LPA). cPA has a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. We showed before that a metabolically stabilized cPA derivative, 2-carba-cPA, relieved osteoarthritis pathogenesis in vivo and induced hyaluronic acid synthesis in human osteoarthritis synoviocytes in vitro. This study focused on hyaluronic acid synthesis in human fibroblasts, which retain moisture and maintain health in the dermis. We investigated the effects of cPA and LPA on hyaluronic acid synthesis in human fibroblasts (NB1RGB cells). Using particle exclusion and enzyme-linked immunosorbent assays, we found that both cPA and LPA dose-dependently induced hyaluronic acid synthesis. We revealed that the expression of hyaluronan synthase 2 messenger RNA and protein is up-regulated by cPA and LPA treatment time dependently. We then characterized the signaling pathways up-regulating hyaluronic acid synthesis mediated by cPA and LPA in NB1RGB cells. Pharmacological inhibition and reporter gene assays revealed that the activation of the LPA receptor LPAR1, Gi/o protein, phosphatidylinositol-3 kinase (PI3K), extracellular-signal-regulated kinase (ERK), and cyclic adenosine monophosphate response element-binding protein (CREB) but not nuclear factor κB induced hyaluronic acid synthesis by the treatment with cPA and LPA in NB1RGB cells. These results demonstrate for the first time that cPA and LPA induce hyaluronic acid synthesis in human skin fibroblasts mainly through the activation of LPAR1-Gi/o followed by the PI3K, ERK, and CREB signaling pathway. PMID:24845645

  7. Amino acid decarboxylations produced by lipid-derived reactive carbonyls in amino acid mixtures.

    PubMed

    Hidalgo, Francisco J; León, M Mercedes; Zamora, Rosario

    2016-10-15

    The formation of 2-phenylethylamine and phenylacetaldehyde in mixtures of phenylalanine, a lipid oxidation product, and a second amino acid was studied to determine the role of the second amino acid in the degradation of phenylalanine produced by lipid-derived reactive carbonyls. The presence of the second amino acid usually increased the formation of the amine and reduced the formation of the Strecker aldehyde. The reasons for this behaviour seem to be related to the α-amino group and the other functional groups (mainly amino or similar groups) present in the side-chain of the amino acid. These groups are suggested to modify the lipid-derived reactive carbonyl but not the reaction mechanism because the Ea of formation of both 2-phenylethylamine and phenylacetaldehyde remained unchanged in all studied systems. All these results suggest that the amine/aldehyde ratio obtained by amino acid degradation can be modified by adding free amino acids during food formulation. PMID:27173560

  8. Pantothenic acid and its derivatives protect Ehrlich ascites tumor cells against lipid peroxidation.

    PubMed

    Slyshenkov, V S; Rakowska, M; Moiseenok, A G; Wojtczak, L

    1995-12-01

    Preincubation of Ehrlich ascites tumor cells at 22 or 32 degrees C, but not at 0 degree C, with pantothenic acid, 4'-phosphopantothenic acid, pantothenol, or pantethine reduced lipid peroxidation (measured by production of thiobarbituric acid-reactive compounds) induced by the Fenton reaction (Fe2+ + H2O2) and partly protected the plasma membrane against the leakiness to cytoplasmic proteins produced by the same reagent. Pantothenic acid and its derivatives did not inhibit (Fe2+ + H2O2)-induced peroxidation of phospholipid multilamellar vesicles, thus indicating that their effect on the cells was not due to the scavenging mechanism. Homopantothenic acid and its 4'-phosphate ester (which are not precursors of CoA) neither protected Ehrlich ascites tumor cells against lipid peroxidation nor prevented plasma membrane leakiness under the same conditions. Incubation of the cells with pantothenic acid, 4'-phosphopantothenic acid, pantothenol, or pantethine significantly increased the amount of cellular CoA and potentiated incorporation of added palmitate into phospholipids and cholesterol esters. It is concluded that pantothenic acid and its related compounds protect the plasma membrane of Ehrlich ascites tumor cells against the damage by oxygen free radicals due to increasing cellular level of CoA. The latter compound may act by diminishing propagation of lipid peroxidation and promoting repair mechanisms, mainly the synthesis of phospholipids. PMID:8582649

  9. [Cardioprotective properties of new glutamic acid derivative under stress conditions].

    PubMed

    Perfilova, V N; Sadikova, N V; Berestovitskaia, V M; Vasil'eva, O S

    2014-01-01

    The effect of new glutamic acid derivative on the cardiac ino- and chronotropic functions has been studied in experiments on rats exposed to 24-hour immobilization-and-pain stress. It is established that glutamic acid derivative RGPU-238 (glufimet) at a dose of 28.7 mg/kg increases the increment of myocardial contractility and relaxation rates and left ventricular pressure in stress-tested animals by 13 1,1, 72.4, and 118.6%, respectively, as compared to the control group during the test for adrenoreactivity. Compound RGPU-238 increases the increment of the maximum intensity of myocardium functioning by 196.5 % at 30 sec of isometric workload as compared to the control group. The cardioprotective effect of compound RGPU-238 is 1.5 - 2 times higher than that of the reference drug phenibut. PMID:25365864

  10. Synthesis and antifungal activity of bile acid-derived oxazoles.

    PubMed

    Fernández, Lucía R; Svetaz, Laura; Butassi, Estefanía; Zacchino, Susana A; Palermo, Jorge A; Sánchez, Marianela

    2016-04-01

    Peracetylated bile acids (1a-g) were used as starting materials for the preparation of fourteen new derivatives bearing an oxazole moiety in their side chain (6a-g, 8a-g). The key step for the synthetic path was a Dakin-West reaction followed by a Robinson-Gabriel cyclodehydration. A simpler model oxazole (12) was also synthesized. The antifungal activity of the new compounds (6a-g) as well as their starting bile acids (1a-g) was tested against Candida albicans. Compounds 6e and 6g showed the highest percentages of inhibition (63.84% and 61.40% at 250 μg/mL respectively). Deacetylation of compounds 6a-g, led to compounds 8a-g which showed lower activities than the acetylated derivatives. PMID:26827629

  11. Microbial production of fatty acid-derived fuels and chemicals

    PubMed Central

    Lennen, Rebecca M; Pfleger, Brian F

    2013-01-01

    Fatty acid metabolism is an attractive route to produce liquid transportation fuels and commodity oleochemicals from renewable feedstocks. Recently, genes and enzymes, which comprise metabolic pathways for producing fatty acid-derived compounds (e.g. esters, alkanes, olefins, ketones, alcohols, polyesters) have been elucidated and used in engineered microbial hosts. The resulting strains often generate products at low percentages of maximum theoretical yields, leaving significant room for metabolic engineering. Economically viable processes will require strains to approach theoretical yields, particularly for replacement of petroleum-derived fuels. This review will describe recent progress toward this goal, highlighting the scientific discoveries of each pathway, ongoing biochemical studies to understand each enzyme, and metabolic engineering strategies that are being used to improve strain performance. PMID:23541503

  12. Branched-chain 2-keto acid decarboxylases derived from Psychrobacter.

    PubMed

    Wei, Jiashi; Timler, Jacobe G; Knutson, Carolann M; Barney, Brett M

    2013-09-01

    The conversion of branched-chain amino acids to branched-chain acids or alcohols is an important aspect of flavor in the food industry and is dependent on the Ehrlich pathway found in certain lactic acid bacteria. A key enzyme in the pathway, the 2-keto acid decarboxylase (KDC), is also of interest in biotechnology applications to produce small branched-chain alcohols that might serve as improved biofuels or other commodity feedstocks. This enzyme has been extensively studied in the model bacterium Lactococcus lactis, but is also found in other bacteria and higher organisms. In this report, distinct homologs of the L. lactis KDC originally annotated as pyruvate decarboxylases from Psychrobacter cryohalolentis K5 and P. arcticus 273-4 were cloned and characterized, confirming a related activity toward specific branched-chain 2-keto acids derived from branched-chain amino acids. Further, KDC activity was confirmed in intact cells and cell-free extracts of P. cryohalolentis K5 grown on both rich and defined media, indicating that the Ehrlich pathway may also be utilized in some psychrotrophs and psychrophiles. A comparison of the similarities and differences in the P. cryohalolentis K5 and P. arcticus 273-4 KDC activities to other bacterial KDCs is presented. PMID:23826991

  13. Interactions of salicylic acid derivatives with calcite crystals.

    PubMed

    Ukrainczyk, Marko; Gredičak, Matija; Jerić, Ivanka; Kralj, Damir

    2012-01-01

    Investigation of basic interactions between the active pharmaceutical compounds and calcium carbonates is of great importance because of the possibility to use the carbonates as a mineral carrier in drug delivery systems. In this study the mode and extent of interactions of salicylic acid and its amino acid derivates, chosen as pharmaceutically relevant model compounds, with calcite crystals are described. Therefore, the crystal growth kinetics of well defined rhombohedral calcite seed crystals in the systems containing salicylic acid (SA), 5-amino salicylic acid (5-ASA), N-salicyloil-l-aspartic acid (N-Sal-Asp) or N-salicyloil-l-glutamic acid (N-Sal-Glu), were investigated. The precipitation systems were of relatively low initial supersaturation and of apparently neutral pH. The data on the crystal growth rate reductions in the presence of the applied salicylate molecules were analyzed by means of Cabrera & Vermileya's, and Kubota & Mullin's models of interactions of the dissolved additives and crystal surfaces. The crystal growth kinetic experiments were additionally supported with the appropriate electrokinetic, spectroscopic and adsorption measurements. The Langmuir adsorption constants were determined and they were found to be in a good correlation with values obtained from crystal growth kinetic analyses. The results indicated that salicylate molecules preferentially adsorb along the steps on the growing calcite surfaces. The values of average spacing between the adjacent salicylate adsorption active sites and the average distance between the neighboring adsorbed salicylate molecules were also estimated. PMID:21963207

  14. Bile acids induce hepatic differentiation of mesenchymal stem cells

    PubMed Central

    Sawitza, Iris; Kordes, Claus; Götze, Silke; Herebian, Diran; Häussinger, Dieter

    2015-01-01

    Mesenchymal stem cells (MSC) have the potential to differentiate into multiple cell lineages and their therapeutic potential has become obvious. In the liver, MSC are represented by stellate cells which have the potential to differentiate into hepatocytes after stimulation with growth factors. Since bile acids can promote liver regeneration, their influence on liver-resident and bone marrow-derived MSC was investigated. Physiological concentrations of bile acids such as tauroursodeoxycholic acid were able to initiate hepatic differentiation of MSC via the farnesoid X receptor and transmembrane G-protein-coupled bile acid receptor 5 as investigated with knockout mice. Notch, hedgehog, transforming growth factor-β/bone morphogenic protein family and non-canonical Wnt signalling were also essential for bile acid-mediated differentiation, whereas β-catenin-dependent Wnt signalling was able to attenuate this process. Our findings reveal bile acid-mediated signalling as an alternative way to induce hepatic differentiaion of stem cells and highlight bile acids as important signalling molecules during liver regeneration. PMID:26304833

  15. Benzoic Acid-Inducible Gene Expression in Mycobacteria

    PubMed Central

    Dragset, Marte S.; Barczak, Amy K.; Kannan, Nisha; Mærk, Mali; Flo, Trude H.; Valla, Svein; Rubin, Eric J.; Steigedal, Magnus

    2015-01-01

    Conditional expression is a powerful tool to investigate the role of bacterial genes. Here, we adapt the Pseudomonas putida-derived positively regulated XylS/Pm expression system to control inducible gene expression in Mycobacterium smegmatis and Mycobacterium tuberculosis, the causative agent of human tuberculosis. By making simple changes to a Gram-negative broad-host-range XylS/Pm-regulated gene expression vector, we prove that it is possible to adapt this well-studied expression system to non-Gram-negative species. With the benzoic acid-derived inducer m-toluate, we achieve a robust, time- and dose-dependent reversible induction of Pm-mediated expression in mycobacteria, with low background expression levels. XylS/Pm is thus an important addition to existing mycobacterial expression tools, especially when low basal expression is of particular importance. PMID:26348349

  16. Synthesis and properties of synthetic fulvic acid derived from hematoxylin

    NASA Astrophysics Data System (ADS)

    Litvin, Valentina A.; Minaev, Boris F.; Baryshnikov, Gleb V.

    2015-04-01

    A model fulvic acid (FA) was synthesized from a natural dye, hematoxylin, in a slow oxidative polymerization/condensation reaction catalysed by OH- at pH ca. 12. The resulting dark-brown product, acidified to pH ca. 2, did not precipitate from the reaction solution. It was isolated and purified by cation-exchange resin. Its physicochemical and spectroscopic properties, as determined by means of elemental analysis, molecular weight analyses, Fourier transform infra red (FTIR) and ultraviolet-visible (UV-VIS) spectroscopy, X-ray diffraction and electron paramagnetic resonance (EPR) spectroscopy, showed a close resemblance to natural FA. The similarity and differences between synthetic fulvic acids derived from hematoxylin and the natural fulvic acids substances are discussed. Quantum-chemical calculations of the supposed primary oxidation products of hematoxylin are performed and compared with observations.

  17. Template directed reactions of 2-aminoadenylic acid derivatives

    NASA Technical Reports Server (NTRS)

    Webb, T. R.; Orgel, L. E.

    1982-01-01

    The template-directed oligomerization of activated derivatives of 2-aminoadenylic acid (paA) on polyuridylic acid (poly(U)) in aqueous buffers was studied. The reaction differs from that of adenylic acid (pA) under identical conditions, in that only di- and tri-nucleotides are observed as substantial products rather than a longer sequence of oligomers. The reaction of paA also differs from that of pA in that it does not require Mg (2+), and is less susceptible to increased temperature. The relevance of these observations to the chemical evolution of polynucleotide replication is discussed. Improved syntheses of paA and its diphosphate are reported.

  18. Tranexamic Acid Diminishes Laser-Induced Melanogenesis

    PubMed Central

    Kim, Myoung Shin; Bang, Seung Hyun; Kim, Jeong-Hwan; Shin, Hong-Ju; Choi, Jee-Ho

    2015-01-01

    Background The treatment of post-inflammatory hyperpigmentation (PIH) remains challenging. Tranexamic acid, a well-known anti-fibrinolytic drug, has recently demonstrated a curative effect towards melasma and ultraviolet-induced PIH in Asian countries. However, the precise mechanism of its inhibitory effect on melanogenesis is not fully understood. Objective In order to clarify the inhibitory effect of tranexamic acid on PIH, we investigated its effects on mouse melanocytes (i.e., melan-a cells) and human melanocytes. Methods Melan-a cells and human melanocytes were cultured with fractional CO2 laser-treated keratinocyte-conditioned media. Melanin content and tyrosinase activity were evaluated in cells treated with or without tranexamic acid. Protein levels of tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2 were evaluated in melan-a cells. Signaling pathway molecules involved in melanogenesis in melanoma cells were also investigated. Results Tranexamic acid-treated melanocytes exhibited reduced melanin content and tyrosinase activity. Tranexamic acid also decreased tyrosinase, TRP-1, and TRP-2 protein levels. This inhibitory effect on melanogenesis was considered to be involved in extracellular signal-regulated kinase signaling pathways and subsequently microphthalmia-associated transcription factor degradation. Conclusion Tranexamic acid may be an attractive candidate for the treatment of PIH. PMID:26082580

  19. Accumulation of phenylpropanoid derivatives in chitosan-induced cell suspension culture of Cocos nucifera.

    PubMed

    Chakraborty, Moumita; Karun, Anitha; Mitra, Adinpunya

    2009-01-01

    Chitosan-induced elicitation responses of dark-incubated Cocos nucifera (coconut) endosperm cell suspension cultures led to the rapid formation of phenylpropanoid derivatives, which essentially mimics the defense-induced biochemical changes in coconut palm as observed under in vivo conditions. An enhanced accumulation of p-hydroxybenzoic acid as the major wall-bound phenolics was evident. This was followed by p-coumaric acid and ferulic acid. Along with enhanced peroxidases activities in elicited lines, the increase in activities of the early phenylpropanoid pathway enzymes such as, phenylalanine ammonia lyase (PAL), p-coumaroyl-CoA ligase (4CL) and p-hydroxybenzaldehyde dehydrogenase (HBD) in elicited cell cultures were also observed. Furthermore, supplementation of specific inhibitors of PAL, C4H and 4CL in elicited cell cultures led to suppressed accumulation of p-hydroxybenzoic acid, which opens up interesting questions regarding the probable route of the biosynthesis of this phenolic acid in C. nucifera. PMID:18448193

  20. Shoot-derived abscisic acid promotes root growth.

    PubMed

    McAdam, Scott A M; Brodribb, Timothy J; Ross, John J

    2016-03-01

    The phytohormone abscisic acid (ABA) plays a major role in regulating root growth. Most work to date has investigated the influence of root-sourced ABA on root growth during water stress. Here, we tested whether foliage-derived ABA could be transported to the roots, and whether this foliage-derived ABA had an influence on root growth under well-watered conditions. Using both application studies of deuterium-labelled ABA and reciprocal grafting between wild-type and ABA-biosynthetic mutant plants, we show that both ABA levels in the roots and root growth in representative angiosperms are controlled by ABA synthesized in the leaves rather than sourced from the roots. Foliage-derived ABA was found to promote root growth relative to shoot growth but to inhibit the development of lateral roots. Increased root auxin (IAA) levels in plants with ABA-deficient scions suggest that foliage-derived ABA inhibits root growth through the root growth-inhibitor IAA. These results highlight the physiological and morphological importance, beyond the control of stomata, of foliage-derived ABA. The use of foliar ABA as a signal for root growth has important implications for regulating root to shoot growth under normal conditions and suggests that leaf rather than root hydration is the main signal for regulating plant responses to moisture. PMID:26514625

  1. Biarylalkyl Carboxylic Acid Derivatives as Novel Antischistosomal Agents.

    PubMed

    Mäder, Patrick; Blohm, Ariane S; Quack, Thomas; Lange-Grünweller, Kerstin; Grünweller, Arnold; Hartmann, Roland K; Grevelding, Christoph G; Schlitzer, Martin

    2016-07-01

    Parasitic platyhelminths are responsible for serious infectious diseases, such as schistosomiasis, which affect humans as well as animals across vast regions of the world. The drug arsenal available for the treatment of these diseases is limited; for example, praziquantel is the only drug currently used to treat ≥240 million people each year infected with Schistosoma spp., and there is justified concern about the emergence of drug resistance. In this study, we screened biarylalkyl carboxylic acid derivatives for their antischistosomal activity against S. mansoni. These compounds showed significant influence on egg production, pairing stability, and vitality. Tegumental lesions or gut dilatation was also observed. Substitution of the terminal phenyl residue in the biaryl scaffold with a 3-hydroxy moiety and derivatization of the terminal carboxylic acid scaffold with carboxamides yielded compounds that displayed significant antischistosomal activity at concentrations as low as 10 μm with satisfying cytotoxicity values. The present study provides detailed insight into the structure-activity relationships of biarylalkyl carboxylic acid derivatives and thereby paves the way for a new drug-hit moiety for fighting schistosomiasis. PMID:27159334

  2. Synthesis and evaluation of colletoic acid core derivatives.

    PubMed

    Ling, Taotao; Gautam, Lekh Nath; Griffith, Elizabeth; Das, Sourav; Lang, Walter; Shadrick, William R; Shelat, Anang; Lee, Richard; Rivas, Fatima

    2016-03-01

    Cortisol homeostasis has been linked to the pathogenesis of metabolic syndrome (MetS), since it stimulates hepatic gluconeogenesis and adipogenesis. MetS is classified as a constellation of health conditions that increase the risk of type 2 diabetes and cardiovascular disease. Intracellular cortisol levels are regulated by 11β-hydroxysteroid dehydrogenase (type 1 and type 2) in a tissue dependent manner. The type 1 enzyme (11β-HSD1) is widely expressed in glucocorticoid targeted tissues and is responsible for the conversion of cortisone to the active cortisol. Local reduction of cortisol regeneration presents a potential strategy for MetS treatment. Recently we disclosed the total synthesis of (+)-colletoic acid as a potent 11β-HSD1 inhibitor. Herein, we describe our improved processing chemistry for the synthesis of the colletoic acid core to access a diverse number of derivatives for evaluation against 11β-HSD1. The Evan's chiral auxiliary was utilized to construct the acyclic precursor 12 to afford the acorane core 9 using a modified Heck reaction in excellent chemical yields. The colletoic acid core derivatives showed modest activity against 11β-HSD1 and will serve for further biological evaluation. PMID:26820555

  3. Targeting leukemic side population cells by isatin derivatives of nicotinic acid amide.

    PubMed

    Naglah, A M; Shinwari, Z; Bhat, M A; Al-Tahhan, M; Al-Omar, M A; Al-Dhfyan, A

    2016-01-01

    Side population (SP) cells mediate chemoresistance in leukemia. However, chemical inhibition approach to target SP cells has been poorly studied. Herein, we report the discovery of isatin derivatives of nicotinic acid amide as potent side population cell inhibitors. The selected derivatives showed superior potency over the reference drug verapamil. Furthermore, the treatment increased chemosensitivity and inhibited the cell proliferation on three different leukemic cell lines, K562, THP-1 and U937, suggesting that both SP and the bulk of leukemic cells are affected. Moreover, treatment with the most potent compound Nic9 reduced the expression of ABCG2, demonstrating that side population inhibition effect of the target derivatives is at least via ABCG2 inhibition. Importantly, the target derivatives induced erythrocyte/dendritic differentiation to leukemic cells mainly through Musashi/Numb pathway modulation. PMID:27358121

  4. Abscisic-acid-induced cellular apoptosis and differentiation in glioma via the retinoid acid signaling pathway.

    PubMed

    Zhou, Nan; Yao, Yu; Ye, Hongxing; Zhu, Wei; Chen, Liang; Mao, Ying

    2016-04-15

    Retinoid acid (RA) plays critical roles in regulating differentiation and apoptosis in a variety of cancer cells. Abscisic acid (ABA) and RA are direct derivatives of carotenoids and share structural similarities. Here we proposed that ABA may also play a role in cellular differentiation and apoptosis by sharing a similar signaling pathway with RA that may be involved in glioma pathogenesis. We reported for the first time that the ABA levels were twofold higher in low-grade gliomas compared with high-grade gliomas. In glioma tissues, there was a positive correlation between the ABA levels and the transcription of cellular retinoic acid-binding protein 2 (CRABP2) and a negative correlation between the ABA levels and transcription of fatty acid-binding protein 5 (FABP5). ABA treatment induced a significant increase in the expression of CRABP2 and a decrease in the expression of peroxisome proliferator-activated receptor (PPAR) in glioblastoma cells. Remarkably, both cellular apoptosis and differentiation were increased in the glioblastoma cells after ABA treatment. ABA-induced cellular apoptosis and differentiation were significantly reduced by selectively silencing RAR-α, while RAR-α overexpression exaggerated the ABA-induced effects. These results suggest that ABA may play a role in the pathogenesis of glioma by promoting cellular apoptosis and differentiation through the RA signaling pathway. PMID:26594836

  5. Novel sustainable polymers derived from renewable rosin and fatty acids

    NASA Astrophysics Data System (ADS)

    Wilbon, Perry

    In the work of this dissertation, polymers derived from renewable bio-based resources prepared by various polymerization techniques were investigated. The properties of these polymeric materials were characterized and discussed. Rosin was first converted into acrylate or methacrylate monomers for atom transfer radical polymerization (ATRP). Second, rosin was combined with vegetable oil to produce completely renewable novel polyesters by acyclic diene metathesis (ADMET) polymerization. Third, degradable block copolymers were synthesized composed of polycaprolactone and rosin grafted polycaprolactone with the aid of ring-opening polymerization (ROP). Finally, degradable polyesters were produced using vegetable oil derivatives as starting materials. These new rosin and fatty acid based renewable polymer materials will have potential applications as sustainable thermoplastics, thermoplastic elastomers, etc.

  6. Esterification of fermentation-derived acids via pervaporation

    DOEpatents

    Datta, R.; Tsai, S.P.

    1998-03-03

    A low temperature method for esterifying ammonium- and amine-containing salts is provided whereby the salt is reacted with an alcohol in the presence of heat and a catalyst and then subjected to a dehydration and deamination process using pervaporation. The invention also provides for a method for producing esters of fermentation derived, organic acid salt comprising first cleaving the salt into its cationic part and anionic part, mixing the anionic part with an alcohol to create a mixture; heating the mixture in the presence of a catalyst to create an ester; dehydrating the now heated mixture; and separating the ester from the now-dehydrated mixture. 2 figs.

  7. Esterification of fermentation-derived acids via pervaporation

    DOEpatents

    Datta, Rathin; Tsai, Shih-Perng

    1998-01-01

    A low temperature method for esterifying ammonium- and amine-containing salts is provided whereby the salt is reacted with an alcohol in the presence of heat and a catalyst and then subjected to a dehydration and deamination process using pervaporation. The invention also provides for a method for producing esters of fermentation derived, organic acid salt comprising first cleaving the salt into its cationic part and anionic part, mixing the anionic part with an alcohol to create a mixture; heating the mixture in the presence of a catalyst to create an ester; dehydrating the now heated mixture; and separating the ester from the now-dehydrated mixture.

  8. Synthesis and biological activity of novel deoxycholic acid derivatives.

    PubMed

    Popadyuk, Irina I; Markov, Andrey V; Salomatina, Oksana V; Logashenko, Evgeniya B; Shernyukov, Andrey V; Zenkova, Marina A; Salakhutdinov, Nariman F

    2015-08-01

    We report the synthesis and biological activity of new semi-synthetic derivatives of naturally occurring deoxycholic acid (DCA) bearing 2-cyano-3-oxo-1-ene, 3-oxo-1(2)-ene or 3-oxo-4(5)-ene moieties in ring A and 12-oxo or 12-oxo-9(11)-ene moieties in ring C. Bioassays using murine macrophage-like cells and tumour cells show that the presence of the 9(11)-double bond associated with the increased polarity of ring A or with isoxazole ring joined to ring A, improves the ability of the compounds to inhibit cancer cell growth. PMID:26037611

  9. Dietary linoleic acid-induced alterations in pro- and anti-nociceptive lipid autacoids

    PubMed Central

    Ringel, Amit; Majchrzak-Hong, Sharon F; Yang, Jun; Blanchard, Helene; Zamora, Daisy; Loewke, James D; Rapoport, Stanley I; Hibbeln, Joseph R; Davis, John M; Hammock, Bruce D; Taha, Ameer Y

    2016-01-01

    Background Chronic idiopathic pain syndromes are major causes of personal suffering, disability, and societal expense. Dietary n-6 linoleic acid has increased markedly in modern industrialized populations over the past century. These high amounts of linoleic acid could hypothetically predispose to physical pain by increasing the production of pro-nociceptive linoleic acid-derived lipid autacoids and by interfering with the production of anti-nociceptive lipid autacoids derived from n-3 fatty acids. Here, we used a rat model to determine the effect of increasing dietary linoleic acid as a controlled variable for 15 weeks on nociceptive lipid autacoids and their precursor n-6 and n-3 fatty acids in tissues associated with idiopathic pain syndromes. Results Increasing dietary linoleic acid markedly increased the abundance of linoleic acid and its pro-nociceptive derivatives and reduced the abundance of n-3 eicosapentaenoic acid and docosahexaenoic acid and their anti-nociceptive monoepoxide derivatives. Diet-induced changes occurred in a tissue-specific manner, with marked alterations of nociceptive lipid autacoids in both peripheral and central tissues, and the most pronounced changes in their fatty acid precursors in peripheral tissues. Conclusions The present findings provide biochemical support for the hypothesis that the high linoleic acid content of modern industrialized diets may create a biochemical susceptibility to develop chronic pain. Dietary linoleic acid lowering should be further investigated as part of an integrative strategy for the prevention and management of idiopathic pain syndromes. PMID:27030719

  10. Interactions of amino acids, carboxylic acids, and mineral acids with different quinoline derivatives

    NASA Astrophysics Data System (ADS)

    Kalita, Dipjyoti; Deka, Himangshu; Samanta, Shyam Sundar; Guchait, Subrata; Baruah, Jubaraj B.

    2011-03-01

    A series of quinoline containing receptors having amide and ester bonds are synthesized and characterised. The relative binding abilities of these receptors with various amino acids, carboxylic acids and mineral acids are determined by monitoring the changes in fluorescence intensity. Among the receptors bis(2-(quinolin-8-yloxy)ethyl) isophthalate shows fluorescence enhancement on addition of amino acids whereas the other receptors shows fluorescence quenching on addition of amino acids. The receptor N-(quinolin-8-yl)-2-(quinolin-8-yloxy) propanamide has higher binding affinity for amino acids. However, the receptor N-(quinolin-8-yl)-2-(quinolin-8-yloxy)acetamide having similar structure do not bind to amino acids. This is attributed to the concave structure of the former which is favoured due to the presence of methyl substituent. The receptor bis(2-(quinolin-8-yloxy)ethyl) isophthalate do not bind to hydroxy carboxylic acids, but is a good receptor for dicarboxylic acids. The crystal structure of bromide and perchlorate salts of receptor 2-bromo-N-(quinolin-8-yl)-propanamide are determined. In both the cases the amide groups are not in the plane of quinoline ring. The structure of N-(quinolin-8-yl)-2-(quinolin-8-yloxy)acetamide, N-(2-methoxyphenethyl)-2-(quinolin-8-yloxy)acetamide and their salts with maleic acid as well as fumaric acid are determined. It is observed that the solid state structures are governed by the double bond geometry of these two acid. Maleic acid forms salt in both the cases, whereas fumaric acid forms either salt or co-crystals.

  11. Human Neutrophils Convert the Sebum-derived Polyunsaturated Fatty Acid Sebaleic Acid to a Potent Granulocyte Chemoattractant*

    PubMed Central

    Cossette, Chantal; Patel, Pranav; Anumolu, Jaganmohan R.; Sivendran, Sashikala; Lee, Gue Jae; Gravel, Sylvie; Graham, François D.; Lesimple, Alain; Mamer, Orval A.; Rokach, Joshua; Powell, William S.

    2008-01-01

    Sebaleic acid (5,8-octadecadienoic acid) is the major polyunsaturated fatty acid in human sebum and skin surface lipids. The objective of the present study was to investigate the metabolism of this fatty acid by human neutrophils and to determine whether its metabolites are biologically active. Neutrophils converted sebaleic acid to four major products, which were identified by their chromatographic properties, UV absorbance, and mass spectra as 5-hydroxy-(6E,8Z)-octadecadienoic acid (5-HODE), 5-oxo-(6E,8Z)-octadecadienoic acid (5-oxo-ODE), 5S,18-dihydroxy-(6E,8Z)-octadecadienoic acid, and 5-oxo-18-hydroxy-(6E,8Z)-octadecadienoic acid. The identities of these metabolites were confirmed by comparison of their properties with those of authentic chemically synthesized standards. Both neutrophils and human keratinocytes converted 5-HODE to 5-oxo-ODE. This reaction was stimulated in neutrophils by phorbol myristate acetate and in keratinocytes by oxidative stress (t-butyl-hydroperoxide). Both treatments dramatically elevated intracellular levels of NADP+, the cofactor required by 5-hydroxyeicosanoid dehydrogenase. In keratinocytes, this was accompanied by a rapid increase in intracellular GSSG levels, consistent with the involvement of glutathione peroxidase. 5-Oxo-ODE stimulated calcium mobilization in human neutrophils and induced desensitization to 5-oxo-6,8,11,14-eicosatetraenoic acid but not leukotriene B4, indicating that this effect was mediated by the OXE receptor. 5-Oxo-ODE and its 8-trans isomer were equipotent with 5-oxo-6,8,11,14-eicosatetraenoic acid in stimulating actin polymerization and chemotaxis in human neutrophils, whereas 5-HODE, 5-oxo-18-hydroxy-(6E,8Z)-octadecadienoic acid, and 5S,18-dihydroxy-(6E,8Z)-octadecadienoic acid were much less active. We conclude that neutrophil 5-lipoxygenase converts sebaleic acid to 5-HODE, which can be further metabolized to 5-oxo-ODE by 5-hydroxyeicosanoid dehydrogenase in neutrophils and keratinocytes. Because of

  12. Valproic Acid-Induced Hyperammonemia in the Elderly: A Review of the Literature

    PubMed Central

    Mittal, Vikrant; Muralee, Sunanda; Tampi, Rajesh R.

    2009-01-01

    Valproic acid and its derivatives are commonly used to treat many psychiatric conditions in the elderly. Hyperammonemia is a less common but important side effect of these drugs. The elderly patient appears highly vulnerable to this side effect of this group of medications. In this paper, we systematically review the published literature for hyperammonemia induced by valproic acid and its derivatives. We describe the three reported cases and review possible treatment strategies for this condition. PMID:19724652

  13. Synthesis and screening of ursolic acid-benzylidine derivatives as potential anti-cancer agents.

    PubMed

    Dar, Bilal Ahmad; Lone, Ali Mohd; Shah, Wajaht Amin; Qurishi, Mushtaq Ahmad

    2016-03-23

    Ursolic acid present abundantly in plant kingdom is a well-known compound with various promising biological activities including, anti-cancer, anti-inflammatory, hepatoprotective, antiallergic and anti-HIV properties. Herein, a library of ursolic acid-benzylidine derivatives have been designed and synthesized using Claisen Schmidt condensation of ursolic acid with various aromatic aldehydes in an attempt to develop potent antitumor agents. The compounds were evaluated against a panel of four human carcinoma cell lines including, A-549 (lung), MCF-7 (breast), HCT-116 (colon), THP-1 (leukemia) and a normal human epithelial cell line (FR-2). The results from MTT assay revealed that all the compounds displayed high level of antitumor activities compared with the triazole analogs (previously reported) and the parent ursolic acid. However, compound 3b, the most active derivative was subjected to mechanistic studies to understand the underlying mechanism. The results revealed that compound 3b induced apoptosis in HCT-116 cell lines, arrest cell cycle in the G1 phase, caused accumulation of cytochrome c in the cytosol and increased the expression levels of caspase-9 and caspase-3 proteins. Therefore, compound 3b induces apoptosis in HCT-116 cells through mitochondrial pathway. PMID:26854375

  14. Synthesis and biological evaluation of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists.

    PubMed

    Wang, Xuekun; Zhao, Tianxiao; Yang, Baowei; Li, Zheng; Cui, Jian; Dai, Yuxuan; Qiu, Qianqian; Qiang, Hao; Huang, Wenlong; Qian, Hai

    2015-01-01

    Free fatty acid receptor 1 (FFA1) is a new potential drug target for the treatment of type 2 diabetes because of its role in amplifying glucose-stimulated insulin secretion in pancreatic β-cell. In the present studies, we identified phenoxyacetic acid derivative (18b) as a potent FFA1 agonist (EC50=62.3 nM) based on the structure of phenylpropanoic acid derivative 4p. Moreover, compound 18b could significantly improve oral glucose tolerance in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice without observation of hypoglycemic side effect. Additionally, compound 18b exhibited acceptable PK profiles. In summary, compound 18b with ideal PK profiles exhibited good activity in vitro and in vivo, and might be a promising drug candidate for the treatment of diabetes mellitus. PMID:25481394

  15. Synthesis and antimicrobial activities of new higher amino acid Schiff base derivatives of 6-aminopenicillanic acid and 7-aminocephalosporanic acid

    NASA Astrophysics Data System (ADS)

    Özdemir (nee Güngör), Özlem; Gürkan, Perihan; Özçelik, Berrin; Oyardı, Özlem

    2016-02-01

    Novel β-lactam derivatives (1c-3c) (1d-3d) were produced by using 6-aminopenicillanic acid (6-APA), 7-aminocephalosporanic acid (7-ACA) and the higher amino acid Schiff bases. The synthesized compounds were characterized by elemental analysis, IR, 1H/13C NMR and UV-vis spectra. Antibacterial activities of all the higher amino acid Schiff bases (1a-3a) (1b-3b) and β-lactam derivatives were screened against three gram negative bacteria (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Acinetobacter baumannii RSKK 02026), three gram positive bacteria (Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 07005, Bacillus subtilis ATCC 6633) and their drug-resistant isolates by using broth microdilution method. Two fungi (Candida albicans and Candida krusei) were used for antifungal activity.

  16. Synthesis and Pro-Apoptotic Activity of Novel Glycyrrhetinic Acid Derivatives

    PubMed Central

    Logashenko, Evgeniya B; Salomatina, Oksana V; Markov, A V; Korchagina, Dina V; Salakhutdinov, Nariman F; Tolstikov, Genrikh A; Vlassov, Valentin V; Zenkova, Marina A

    2011-01-01

    Triterpenoids are used for medicinal purposes in many countries. Some, such as oleanolic and glycyrrhetinic acids, are known to be anti-inflammatory and anticarcinogenic. However, the biological activities of these naturally occurring molecules against their particular targets are weak, so the synthesis of new synthetic analogues with enhanced potency is needed. By combining modifications to both the A and C rings of 18βH-glycyrrhetinic acid, the novel synthetic derivative methyl 2-cyano-3,12-dioxo-18βH-olean-9(11),1(2)-dien-30-oate was obtained. This derivative displays high antiproliferative activity in cancer cells, including a cell line with a multidrug-resistance phenotype. It causes cell death by inducing the intrinsic caspase-dependent apoptotic pathway. PMID:21328513

  17. 40 CFR 721.6110 - Alkyldi(alkyloxyhydroxypropyl) derivative, phosphoric acid esters, potassium salts.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...) derivative, phosphoric acid esters, potassium salts. 721.6110 Section 721.6110 Protection of Environment...) derivative, phosphoric acid esters, potassium salts. (a) Chemical substance and significant new uses subject...) derivative, phosphoric acid esters, potassium salts (PMN P-91-818) is subject to reporting under this...

  18. 40 CFR 721.6110 - Alkyldi(alkyloxyhydroxypropyl) derivative, phosphoric acid esters, potassium salts.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...) derivative, phosphoric acid esters, potassium salts. 721.6110 Section 721.6110 Protection of Environment...) derivative, phosphoric acid esters, potassium salts. (a) Chemical substance and significant new uses subject...) derivative, phosphoric acid esters, potassium salts (PMN P-91-818) is subject to reporting under this...

  19. 40 CFR 721.6110 - Alkyldi(alkyloxyhydroxypropyl) derivative, phosphoric acid esters, potassium salts.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...) derivative, phosphoric acid esters, potassium salts. 721.6110 Section 721.6110 Protection of Environment...) derivative, phosphoric acid esters, potassium salts. (a) Chemical substance and significant new uses subject...) derivative, phosphoric acid esters, potassium salts (PMN P-91-818) is subject to reporting under this...

  20. 40 CFR 721.6110 - Alkyldi(alkyloxyhydroxypropyl) derivative, phosphoric acid esters, potassium salts.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) derivative, phosphoric acid esters, potassium salts. 721.6110 Section 721.6110 Protection of Environment...) derivative, phosphoric acid esters, potassium salts. (a) Chemical substance and significant new uses subject...) derivative, phosphoric acid esters, potassium salts (PMN P-91-818) is subject to reporting under this...

  1. 40 CFR 721.6110 - Alkyldi(alkyloxyhydroxypropyl) derivative, phosphoric acid esters, potassium salts.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...) derivative, phosphoric acid esters, potassium salts. 721.6110 Section 721.6110 Protection of Environment...) derivative, phosphoric acid esters, potassium salts. (a) Chemical substance and significant new uses subject...) derivative, phosphoric acid esters, potassium salts (PMN P-91-818) is subject to reporting under this...

  2. Carboxylic Acid Fullerene (C60) Derivatives Attenuated Neuroinflammatory Responses by Modulating Mitochondrial Dynamics

    NASA Astrophysics Data System (ADS)

    Ye, Shefang; Zhou, Tong; Cheng, Keman; Chen, Mingliang; Wang, Yange; Jiang, Yuanqin; Yang, Peiyan

    2015-05-01

    Fullerene (C60) derivatives, a unique class of compounds with potent antioxidant properties, have been reported to exert a wide variety of biological activities including neuroprotective properties. Mitochondrial dynamics are an important constituent of cellular quality control and function, and an imbalance of the dynamics eventually leads to mitochondria disruption and cell dysfunctions. This study aimed to assess the effects of carboxylic acid C60 derivatives (C60-COOH) on mitochondrial dynamics and elucidate its associated mechanisms in lipopolysaccharide (LPS)-stimulated BV-2 microglial cell model. Using a cell-based functional screening system labeled with DsRed2-mito in BV-2 cells, we showed that LPS stimulation led to excessive mitochondrial fission, increased mitochondrial localization of dynamin-related protein 1 (Drp1), both of which were markedly suppressed by C60-COOH pretreatment. LPS-induced mitochondria reactive oxygen species (ROS) generation and collapse of mitochondrial membrane potential (Δ Ψm) were also significantly inhibited by C60-COOH. Moreover, we also found that C60-COOH pretreatment resulted in the attenuation of LPS-mediated activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling, as well as the production of pro-inflammatory mediators. Taken together, these findings demonstrated that carboxylic acid C60 derivatives may exert neuroprotective effects through regulating mitochondrial dynamics and functions in microglial cells, thus providing novel insights into the mechanisms of the neuroprotective properties of carboxylic acid C60 derivatives.

  3. Neuroprotective effect of caffeic acid phenethyl ester in 3-nitropropionic acid-induced striatal neurotoxicity.

    PubMed

    Bak, Jia; Kim, Hee Jung; Kim, Seong Yun; Choi, Yun-Sik

    2016-05-01

    Caffeic acid phenethyl ester (CAPE), derived from honeybee hives, is a bioactive compound with strong antioxidant activity. This study was designed to test the neuroprotective effect of CAPE in 3-nitropropionic acid (3NP)-induced striatal neurotoxicity, a chemical model of Huntington's disease (HD). Initially, to test CAPE's antioxidant activity, a 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) antioxidant assay was employed, and CAPE showed a strong direct radical-scavenging eff ect. In addition, CAPE provided protection from 3NP-induced neuronal cell death in cultured striatal neurons. Based on these observations, the in vivo therapeutic potential of CAPE in 3NP-induced HD was tested. For this purpose, male C57BL/6 mice were repeatedly given 3NP to induce HD-like pathogenesis, and 30 mg/kg of CAPE or vehicle (5% dimethyl sulfoxide and 95% peanut oil) was administered daily. CAPE did not cause changes in body weight, but it reduced mortality by 29%. In addition, compared to the vehicle-treated group, robustly reduced striatal damage was observed in the CAPE-treated animals, and the 3NP-induced behavioral defi cits on the rotarod test were signifi cantly rescued after the CAPE treatment. Furthermore, immunohistochemical data showed that immunoreactivity to glial fibrillary acidic protein (GFAP) and CD45, markers for astrocyte and microglia activation, respectively, were strikingly reduced. Combined, these data unequivocally indicate that CAPE has a strong antioxidant eff ect and can be used as a potential therapeutic agent against HD. PMID:27162482

  4. Neuroprotective effect of caffeic acid phenethyl ester in 3-nitropropionic acid-induced striatal neurotoxicity

    PubMed Central

    Bak, Jia; Kim, Hee Jung; Kim, Seong Yun

    2016-01-01

    Caffeic acid phenethyl ester (CAPE), derived from honeybee hives, is a bioactive compound with strong antioxidant activity. This study was designed to test the neuroprotective effect of CAPE in 3-nitropropionic acid (3NP)-induced striatal neurotoxicity, a chemical model of Huntington's disease (HD). Initially, to test CAPE's antioxidant activity, a 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) antioxidant assay was employed, and CAPE showed a strong direct radical-scavenging eff ect. In addition, CAPE provided protection from 3NP-induced neuronal cell death in cultured striatal neurons. Based on these observations, the in vivo therapeutic potential of CAPE in 3NP-induced HD was tested. For this purpose, male C57BL/6 mice were repeatedly given 3NP to induce HD-like pathogenesis, and 30 mg/kg of CAPE or vehicle (5% dimethyl sulfoxide and 95% peanut oil) was administered daily. CAPE did not cause changes in body weight, but it reduced mortality by 29%. In addition, compared to the vehicle-treated group, robustly reduced striatal damage was observed in the CAPE-treated animals, and the 3NP-induced behavioral defi cits on the rotarod test were signifi cantly rescued after the CAPE treatment. Furthermore, immunohistochemical data showed that immunoreactivity to glial fibrillary acidic protein (GFAP) and CD45, markers for astrocyte and microglia activation, respectively, were strikingly reduced. Combined, these data unequivocally indicate that CAPE has a strong antioxidant eff ect and can be used as a potential therapeutic agent against HD. PMID:27162482

  5. Angiotensin II modification by decomposition products of linoleic acid-derived lipid hydroperoxide.

    PubMed

    Takahashi, Ryo; Goto, Takaaki; Oe, Tomoyuki; Lee, Seon Hwa

    2015-09-01

    Polyunsaturated fatty acids are highly susceptible to oxidation induced by reactive oxygen species and enzymes, leading to the formation of lipid hydroperoxides. The linoleic acid (LA)-derived hydroperoxide, 13-hydroperoxyoctadecadienoic acid (HPODE) undergoes homolytic decomposition to reactive aldehydes, 4-oxo-2(E)-nonenal (ONE), 4-hydroxy-2(E)-nonenal, trans-4,5-epoxy-2(E)-decenal (EDE), and 4-hydroperoxy-2(E)-nonenal (HPNE), which can covalently modify peptides and proteins. ONE and HNE have been shown to react with angiotensin (Ang) II (DRVYIHPF) and modify the N-terminus, Arg(2), and His(6). ONE-derived pyruvamide-Ang II (Ang P) alters the biological activities of Ang II considerably. The present study revealed that EDE and HPNE preferentially modified the N-terminus and His(6) of Ang II. In addition to the N-substituted pyrrole of [N-C4H2]-Ang II and Michael addition products of [His(6)(EDE)]-Ang II, hydrated forms were detected as major products, suggesting considerable involvement of the vicinal dihydrodiol (formed by epoxide hydration) in EDE-derived protein modification in vivo. Substantial amounts of [N-(EDE-H2O)]-Ang II isomers were also formed and their synthetic pathway might involve the tautomerization of a carbinolamine intermediate, followed by intramolecular cyclization and dehydration. The main HPNE-derived products were [His(6)(HPNE)]-Ang II and [N-(HPNE-H2O)]-Ang II. However, ONE, HNE, and malondialdehyde-derived modifications were dominant, because HPNE is a precursor of these aldehydes. A mixture of 13-HPODE and [(13)C18]-13-HPODE (1:1) was then used to determine the major modifications derived from LA peroxidation. The characteristic doublet (1:1) observed in the mass spectrum and the mass difference of the [M+H](+) doublet aided the identification of Ang P (N-terminal α-ketoamide), [N-ONE]-Ang II (4-ketoamide), [Arg(2)(ONE-H2O)]-Ang II, [His(6)(HNE)]-Ang II (Michael addition product), [N-C4H2]-Ang II (EDE-derived N-substituted pyrrole

  6. Hypolipidaemic and antiplatelet activity of phenoxyacetic acid derivatives related to alpha-asarone.

    PubMed

    Pérez-Pastén, Ricardo; García, Rosa Virginia; Garduño, Leticia; Reyes, Elba; Labarrios, Fernando; Tamariz, Joaquín; Chamorro, Germán

    2006-10-01

    The phenoxyacetic acid derivatives 1-6 [2-methoxy-4-(2-propenyl)phenoxyacetic acid (1); 2-methoxy-5-nitro-4-(2-propenyl)phenoxyacetic acid (2); methyl 2-methoxy-4-(2-propenyl)phenoxyacetate (3); ethyl 2-methoxy-4-(2-propenyl)phenoxyacetate (4); methyl 2-methoxy-5-nitro-4-(2-propenyl)phenoxyacetate (5); ethyl 2-methoxy-5-nitro-4-(2-propenyl)phenoxyacetate (6)] related to alpha-asarone have been reported previously as hypolipidaemic agents in diet-induced hyperlipidaemic mice. We have aimed to expand the pharmacological profile of these derivatives by investigating their hypolipidaemic activity in rats and mice under different experimental conditions. The antiplatelet activity was tested also in-vitro from blood derived from consenting healthy volunteers. In normolipidaemic rats, compounds 2, 3 and 5 at oral doses of 40 and 80 mg kg(-1) significantly decreased total cholesterol and LDL-cholesterol levels. Moreover, analogues 3 and 5 administered to hypercholesterolaemic rats at the same doses for seven days also produced a reduction in the content of these same lipoproteins. In neither case were the high-density lipoprotein cholesterol and triglyceride concentrations affected. However, practically all tested compounds were found to be hypocholesterolaemic agents, and were shown to effectively lower low-density lipoprotein cholesterol and triglyceride levels in Triton-induced hyperlipidaemic mice at oral doses of 50 and 100 mg kg(-1). In all tests, all animals appeared to be healthy throughout the experimental period in their therapeutic ranges. Triton-induced hypercholesterolaemic mice appeared to be a desirable model for this class of hypolipidaemic drugs. On the other hand, compounds 1, 2, 4 and 5 significantly inhibited ADP-induced aggregation in-vitro. These findings indicated that all of these compounds appeared to be promising for the treatment of human hyperlipidaemia and thrombotic diseases. PMID:17034657

  7. Chronic Arachidonic Acid Administration Decreases Docosahexaenoic Acid- and Eicosapentaenoic Acid-Derived Metabolites in Kidneys of Aged Rats

    PubMed Central

    Katakura, Masanori; Hashimoto, Michio; Inoue, Takayuki; Mamun, Abdullah Al; Tanabe, Yoko; Arita, Makoto; Shido, Osamu

    2015-01-01

    Arachidonic acid (ARA) metabolites produced by cyclo-oxygenase and lipoxygenase are important mediators maintaining physiological renal function. However, the effects of exogenous ARA on kidney function in vivo remain unknown. This study examined the effects of long-term oral ARA administration on normal renal function as well as inflammation and oxidative stress in aged rats. In addition, we measured levels of renal eicosanoids and docosanoids using liquid chromatography–tandem mass spectrometry. Control or ARA oil (240 mg/kg body weight/day) was orally administered to 21-month-old Wistar rats for 13 weeks. Levels of plasma creatinine, blood urea nitrogen, inflammatory and anti-inflammatory cytokines, reactive oxygen species, and lipid peroxidation were not significantly different between the two groups. The ARA concentration in the plasma, kidney, and liver increased in the ARA-administered group. In addition, levels of free-form ARA, prostaglandin E2, and 12- and 15-hydroxyeicosatetraenoic acid increased in the ARA-administered group, whereas renal concentration of docosahexaenoic acid and eicosapentaenoic acid decreased in the ARA-administered group. Levels of docosahexaenoic acid-derived protectin D1, eicosapentaenoic acid-derived 5-, and 18-hydroxyeicosapentaenoic acids, and resolvin E2 and E3 decreased in the ARA-administered group. Our results indicate that long-term ARA administration led to no serious adverse reactions under normal conditions and to a decrease in anti-inflammatory docosahexaenoic acid- and eicosapentaenoic acid-derived metabolites in the kidneys of aged rats. These results indicate that there is a possibility of ARA administration having a reducing anti-inflammatory effect on the kidney. PMID:26485038

  8. Chronic Arachidonic Acid Administration Decreases Docosahexaenoic Acid- and Eicosapentaenoic Acid-Derived Metabolites in Kidneys of Aged Rats.

    PubMed

    Katakura, Masanori; Hashimoto, Michio; Inoue, Takayuki; Mamun, Abdullah Al; Tanabe, Yoko; Arita, Makoto; Shido, Osamu

    2015-01-01

    Arachidonic acid (ARA) metabolites produced by cyclo-oxygenase and lipoxygenase are important mediators maintaining physiological renal function. However, the effects of exogenous ARA on kidney function in vivo remain unknown. This study examined the effects of long-term oral ARA administration on normal renal function as well as inflammation and oxidative stress in aged rats. In addition, we measured levels of renal eicosanoids and docosanoids using liquid chromatography-tandem mass spectrometry. Control or ARA oil (240 mg/kg body weight/day) was orally administered to 21-month-old Wistar rats for 13 weeks. Levels of plasma creatinine, blood urea nitrogen, inflammatory and anti-inflammatory cytokines, reactive oxygen species, and lipid peroxidation were not significantly different between the two groups. The ARA concentration in the plasma, kidney, and liver increased in the ARA-administered group. In addition, levels of free-form ARA, prostaglandin E2, and 12- and 15-hydroxyeicosatetraenoic acid increased in the ARA-administered group, whereas renal concentration of docosahexaenoic acid and eicosapentaenoic acid decreased in the ARA-administered group. Levels of docosahexaenoic acid-derived protectin D1, eicosapentaenoic acid-derived 5-, and 18-hydroxyeicosapentaenoic acids, and resolvin E2 and E3 decreased in the ARA-administered group. Our results indicate that long-term ARA administration led to no serious adverse reactions under normal conditions and to a decrease in anti-inflammatory docosahexaenoic acid- and eicosapentaenoic acid-derived metabolites in the kidneys of aged rats. These results indicate that there is a possibility of ARA administration having a reducing anti-inflammatory effect on the kidney. PMID:26485038

  9. 15-oxoeicosatetraenoic acid is a 15-hydroxyprostaglandin dehydrogenase-derived electrophilic mediator of inflammatory signaling pathways

    PubMed Central

    Snyder, Nathaniel W.; Golin-Bisello, Franca; Gao, Yang; Blair, Ian A.; Freeman, Bruce A.; Wendell, Stacy Gelhaus

    2014-01-01

    Bioactive lipids govern cellular homeostasis and pathogenic inflammatory processes. Current dogma holds that bioactive lipids, such as prostaglandins and lipoxins, are inactivated by 15-hydroxyprostaglandin dehydrogenase (15PGDH). In contrast, the present results reveal that catabolic “inactivation” of hydroxylated polyunsaturated fatty acids (PUFAs) yields electrophilic α,β-unsaturated ketone derivatives. These endogenously produced species are chemically reactive signaling mediators that induce tissue protective events. Electrophilic fatty acids diversify the proteome through post-translational alkylation of nucleophilic cysteines in key transcriptional regulatory proteins and enzymes that govern cellular metabolic and inflammatory homeostasis. 15PGDH regulates these processes as it is responsible for the formation of numerous electrophilic fatty acids including the arachidonic acid metabolite, 15-oxoeicosatetraenoic acid (15-oxoETE). Herein, the role of 15-oxoETE in regulating signaling responses is reported. In cell cultures, 15-oxoETE activates Nrf2-regulated antioxidant responses (AR) and inhibits NF-κB-mediated pro-inflammatory responses via IKKβ inhibition. Inhibition of glutathione S-transferases using ethacrynic acid incrementally increased the signaling capacity of 15-oxoETE by decreasing 15-oxoETE-GSH adduct formation. This work demonstrates that 15PGDH plays a role in the regulation of cell and tissue homeostasis via the production of electrophilic fatty acid signaling mediators. PMID:25450232

  10. The Omega-3 Polyunsaturated Fatty Acid Docosahexaenoic Acid (DHA) Reverses Corticosterone-Induced Changes in Cortical Neurons

    PubMed Central

    Pusceddu, Matteo M.; Nolan, Yvonne M.; Green, Holly F.; Robertson, Ruairi C.; Stanton, Catherine; Kelly, Philip; Dinan, Timothy G.

    2016-01-01

    Background: Chronic exposure to the glucocorticoid hormone corticosterone exerts cellular stress-induced toxic effects that have been associated with neurodegenerative and psychiatric disorders. Docosahexaenoic acid is a polyunsaturated fatty acid that has been shown to be of benefit in stress-related disorders, putatively through protective action in neurons. Methods: We investigated the protective effect of docosahexaenoic acid against glucocorticoid hormone corticosterone-induced cellular changes in cortical cell cultures containing both astrocytes and neurons. Results: We found that glucocorticoid hormone corticosterone (100, 150, 200 μM) at different time points (48 and 72 hours) induced a dose- and time-dependent reduction in cellular viability as assessed by methyl thiazolyl tetrazolium. Moreover, glucocorticoid hormone corticosterone (200 μM, 72 hours) decreased the percentage composition of neurons while increasing the percentage of astrocytes as assessed by βIII-tubulin and glial fibrillary acidic protein immunostaining, respectively. In contrast, docosahexaenoic acid treatment (6 μM) increased docosahexaenoic acid content and attenuated glucocorticoid hormone corticosterone (200 μM)-induced cell death (72 hours) in cortical cultures. This translates into a capacity for docosahexaenoic acid to prevent neuronal death as well as astrocyte overgrowth following chronic exposure to glucocorticoid hormone corticosterone. Furthermore, docosahexaenoic acid (6 μM) reversed glucocorticoid hormone corticosterone-induced neuronal apoptosis as assessed by terminal deoxynucleotidyl transferase–mediated nick-end labeling and attenuated glucocorticoid hormone corticosterone-induced reductions in brain derived neurotrophic factor mRNA expression in these cultures. Finally, docosahexaenoic acid inhibited glucocorticoid hormone corticosterone-induced downregulation of glucocorticoid receptor expression on βIII- tubulin-positive neurons. Conclusions: This work

  11. Docosahexaenoic Acid-Derived Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) With Anti-inflammatory Properties.

    PubMed

    Kuda, Ondrej; Brezinova, Marie; Rombaldova, Martina; Slavikova, Barbora; Posta, Martin; Beier, Petr; Janovska, Petra; Veleba, Jiri; Kopecky, Jan; Kudova, Eva; Pelikanova, Terezie; Kopecky, Jan

    2016-09-01

    White adipose tissue (WAT) is a complex organ with both metabolic and endocrine functions. Dysregulation of all of these functions of WAT, together with low-grade inflammation of the tissue in obese individuals, contributes to the development of insulin resistance and type 2 diabetes. n-3 polyunsaturated fatty acids (PUFAs) of marine origin play an important role in the resolution of inflammation and exert beneficial metabolic effects. Using experiments in mice and overweight/obese patients with type 2 diabetes, we elucidated the structures of novel members of fatty acid esters of hydroxy fatty acids-lipokines derived from docosahexaenoic acid (DHA) and linoleic acid, which were present in serum and WAT after n-3 PUFA supplementation. These compounds contained DHA esterified to 9- and 13-hydroxyoctadecadienoic acid (HLA) or 14-hydroxydocosahexaenoic acid (HDHA), termed 9-DHAHLA, 13-DHAHLA, and 14-DHAHDHA, and were synthesized by adipocytes at concentrations comparable to those of protectins and resolvins derived from DHA in WAT. 13-DHAHLA exerted anti-inflammatory and proresolving properties while reducing macrophage activation by lipopolysaccharides and enhancing the phagocytosis of zymosan particles. Our results document the existence of novel lipid mediators, which are involved in the beneficial anti-inflammatory effects attributed to n-3 PUFAs, in both mice and humans. PMID:27313314

  12. Hydroxamic acid derivatives of mycophenolic acid inhibit histone deacetylase at the cellular level.

    PubMed

    Batovska, Daniela I; Kim, Dong Hoon; Mitsuhashi, Shinya; Cho, Yoon Sun; Kwon, Ho Jeong; Ubukata, Makoto

    2008-10-01

    Mycophenolic acid (MPA, 1), an inhibitor of IMP-dehydrogenase (IMPDH) and a latent PPARgamma agonist, is used as an effective immunosuppressant for clinical transplantation and recently entered clinical trials in advanced multiple myeloma patients. On the other hand, suberoylanilide hydroxamic acid (SAHA), a non-specific histone deacetylase (HDAC) inhibitor, has been approved for treating cutaneous T-cell lymphoma. MPA seemed to bear a cap, a linker, and a weak metal-binding site as a latent inhibitor of HDAC. Therefore, the hydroxamic acid derivatives of mycophenolic acid having an effective metal-binding site, mycophenolic hydroxamic acid (MPHA, 2), 7-O-acetyl mycophenolic acid (7-O-Ac MPHA, 3), and 7-O-lauroyl mycophenolic hydroxamic acid (7-O-L MPHA, 4) were designed and synthesized. All these compounds inhibited histone deacetylase with IC50 values of 1, 0.9 and 0.5 microM, and cell proliferation at concentrations of 2, 1.5 and 1 microM, respectively. PMID:18838793

  13. A potential plant-derived antifungal acetylenic acid mediates its activity by interfering with fatty acid homeostasis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogens Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses...

  14. Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases.

    PubMed

    Schwarz, Stefan; Lucas, Susana Dias; Sommerwerk, Sven; Csuk, René

    2014-07-01

    The development of remedies against the Alzheimer's disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. PMID:24853320

  15. Uptake of Acidic and Basic Sugar Derivatives in Lemna gibba G1 1

    PubMed Central

    Sanz, Amparo; Ullrich, Cornelia I.

    1989-01-01

    The uptake of acidic and basic sugar derivatives in Lemna gibba L. was studied. Uronic acids applied to the experimental solution (50 millimolar) induced a small decrease of the membrane potential (10 ± 1 millivolt galacturonic acid, and 20 ± 4 millivolt glucuronic acid). After incubation of the plants in a 0.1 millimolar solution of these substrates, no decrease in the concentration of reducing groups in the external solution was detected. Respiration increased by 31% with 50 millimolar galacturonic acid, whereas no effect was found with the same concentration of glucuronic acid. Glucosamine caused a considerable concentration-dependent membrane depolarization. (14C)glucosamine uptake followed Michaelis-Menten kinetics together with a linear component. Influx of this substrate was inhibited by glucose but the type of competition could not be clearly distinguished. Glucosamine, 50 millimolar, inhibited the respiration rate by 30%. The glucosamine uptake was pH-dependent, with maximum uptake at around pH 7. Lack of enhancement of uptake by low pH as well as the permanent membrane depolarization suggest a uniport mechanism for the charged species of the substrate and an electroneutral diffusion of the uncharged species. PMID:16666961

  16. Stability of Hydroxycinnamic Acid Derivatives, Flavonol Glycosides, and Anthocyanins in Black Currant Juice.

    PubMed

    Mäkilä, Leenamaija; Laaksonen, Oskar; Alanne, Aino-Liisa; Kortesniemi, Maaria; Kallio, Heikki; Yang, Baoru

    2016-06-01

    The stability of phenolic compounds was followed in black currant juice at ambient temperatures (in light and in dark conditions) and at +4 °C for a year. Analyses were based on high-performance liquid chromatography-diode-array detection-electrospray ionization-mass spectrometry (or tandem mass spectrometry) and high-performance liquid chromatography-diode-array detection-electrospray ionization-quadrupole time-of-flight mass spectrometry methods supported by nuclear magnetic resonance after selective high-performance liquid chromatography isolation. Altogether, 43 metabolites were identified, of which 2-(Z)-p-coumaroyloxymethylene-4-β-d-glucopyranosyloxy-2-(Z)-butenenitrile, 2-(E)-caffeoyloxymethylene-4-β-d-glucopyranosyloxy-2-(Z)-butenenitrile, 1-O-(Z)-p-coumaroyl-β-d-glucopyranose, (Z)-p-coumaric acid 4-O-β-d-glucopyranoside, and (Z)-p-coumaric acid were novel findings in black currant juice. Hydroxycinnamic acid derivatives degraded 20-40% at room temperature during one year of storage, releasing free hydroxycinnamic acids. O-Glucosides of hydroxycinnamic acid compounds were the most stable, followed by O-acylquinic acids, acyloxymethyleneglucosyloxybutenenitriles, and O-acylglucoses. Light induced the isomerization of (E)-coumaric acid compounds into corresponding Z-isomers. Flavonol glycosides stayed fairly stable. Flavonol aglycones were derived mainly from malonylglucosides. Over 90% of anthocyanins were lost at room temperature in a year, practically independent of light. Storage at low temperatures, preferably excluding light, is necessary to retain the original composition of phenolic compounds. PMID:27147482

  17. Semisynthesis of Derivatives of Oleanolic Acid from Syzygium aromaticum and Their Antinociceptive and Anti-Inflammatory Properties.

    PubMed

    Rali, Sibusiso; Oyedeji, Opeoluwa O; Aremu, Olukayode O; Oyedeji, Adebola O; Nkeh-Chungag, Benedicta N

    2016-01-01

    Oleanolic acid is a pentacyclic triterpenoid compound widely found in plants and well known for its medicinal properties. Oleanolic acid (OA) was isolated from the ethyl acetate extract of Syzygium aromaticum flower buds. Semisynthesis afforded both acetate and ester derivatives. The derived compounds were monitored with thin layer chromatography and confirmed with nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), Fourier infrared (FT-IR) spectroscopy, and melting point (Mp). All these compounds were evaluated for their analgesic and anti-inflammatory properties at a dose of 40 mg/kg. Significant analgesic and anti-inflammatory effects were noted for all OA-derived compounds. In the formalin-induced pain test, the derivatives showed better analgesic effects compared to their precursor, whereas, in the tale flick test, oleanolic acid proved to be superior in analgesic effects compared to all its derivatives with the exception of the acetyl derivative. Acute inflammatory tests showed that acetyl derivatives possessed better anti-inflammatory activity compared to the other compounds. In conclusion, semisynthesis of oleanolic acid yielded several derivatives with improved solubility and enhanced analgesic and anti-inflammatory properties. PMID:27382191

  18. Semisynthesis of Derivatives of Oleanolic Acid from Syzygium aromaticum and Their Antinociceptive and Anti-Inflammatory Properties

    PubMed Central

    Rali, Sibusiso; Aremu, Olukayode O.; Oyedeji, Adebola O.; Nkeh-Chungag, Benedicta N.

    2016-01-01

    Oleanolic acid is a pentacyclic triterpenoid compound widely found in plants and well known for its medicinal properties. Oleanolic acid (OA) was isolated from the ethyl acetate extract of Syzygium aromaticum flower buds. Semisynthesis afforded both acetate and ester derivatives. The derived compounds were monitored with thin layer chromatography and confirmed with nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), Fourier infrared (FT-IR) spectroscopy, and melting point (Mp). All these compounds were evaluated for their analgesic and anti-inflammatory properties at a dose of 40 mg/kg. Significant analgesic and anti-inflammatory effects were noted for all OA-derived compounds. In the formalin-induced pain test, the derivatives showed better analgesic effects compared to their precursor, whereas, in the tale flick test, oleanolic acid proved to be superior in analgesic effects compared to all its derivatives with the exception of the acetyl derivative. Acute inflammatory tests showed that acetyl derivatives possessed better anti-inflammatory activity compared to the other compounds. In conclusion, semisynthesis of oleanolic acid yielded several derivatives with improved solubility and enhanced analgesic and anti-inflammatory properties. PMID:27382191

  19. A new ferulic acid ester, a new ellagic acid derivative, and other constituents from pachycentria formosana: effects on neutrophil pro-inflammatory responses.

    PubMed

    Cho, Jui-Ying; Lee, Tzong-Huei; Hwang, Tsong-Long; Yang, Sheng-Zehn; Chen, Ih-Sheng; Chou, Tsung-Hsien; Sung, Ping-Jyun; Chen, Jih-Jung

    2011-09-01

    A new ferulic acid ester derivative, tetracosane-1,24-diyl di[(Z)-ferulate] (1), and a new ellagic acid derivative, 3,4 : 3',4'-bis(O,O-methylene)ellagic acid (2), have been isolated from leaves and twigs of Pachycentria formosana, together with eight known compounds. Their structures were determined by in-depth spectroscopic and mass-spectrometric analyses. Among the isolated compounds, oleanolic acid (6), ursolic acid acetate (7), and 3-epibetulinic acid (9) exhibited potent inhibition (IC(50) values ≤ 21.8 μM) of O₂(-) generation by human neutrophils in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB). In addition, oleanolic acid (6), 3-O-[(E)-feruloyl]ursolic acid (8), 3-epibetulinic acid (9), and lawsonic acid (10) also inhibited fMLP/CB-induced elastase release with IC(50) values ≤ 18.6 μM. PMID:21922659

  20. Synthesis, acute toxicity and anti-inflammatory effect of bornyl salicylate, a salicylic acid derivative.

    PubMed

    Vasconcelos, Renata Marcia Costa; Leite, Fagner Carvalho; Leite, Jacqueline Alves; Rodrigues Mascarenhas, Sandra; Rodrigues, Luis Cezar; Piuvezam, Marcia Regina

    2012-12-01

    Bornyl salicylate (BS) is a salicylic derivative, obtained by sterification of salicylic acid and monoterpene (-)-borneol, and its topical use in inflammatory diseases was described in the early 20th century. It is also known that borneol presents neuroprotective, genoprotective and analgesic properties. The purpose of this study was to evaluate BS in experimental models of acute inflammation. The toxicity of BS was analyzed by measuring water and food intake, weight, mortality and weight of main organs. To assess its anti-inflammatory effect, BS-treated mice were challenged with carrageenan, prostaglandin E2 (PGE2), bradikynin (BK) or histamine (HIS)-induced paw edema, zymosan-induced peritonitis and vascular permeability induced by acetic acid. Nitric oxide (NO) production was analyzed in peritoneal macrophage cultures. There was no sign of acute toxicity of BS in male and female mice. Furthermore, treatment with BS was significantly (p < 0.05) effective in reducing paw edema induced by carrageenan in early and late phases; this effect was related to PGE2 and BK, but HIS independent. Neutrophil migration and cytokine release (TNF-α, IL-1β and IL-6) induced by zymosan and fluid leakage induced by acetic acid were also reduced in BS-treated animals. In vitro, BS (10 µg/mL) reduced NO production in LPS-stimulated macrophages. These data suggest that BS has an anti-inflammatory effect, which is related, at least in part, with decrease of mediators as PGE2, NO and pro-inflammatory cytokines. However, further studies should be done to explore its potential as an anti-inflammatory drug. PMID:22712758

  1. Amino Acid-Derived Bifunctional Phosphines for Enantioselective Transformations.

    PubMed

    Wang, Tianli; Han, Xiaoyu; Zhong, Fangrui; Yao, Weijun; Lu, Yixin

    2016-07-19

    Even though seminal reports on phosphine catalysis appeared in the 1960s, in the last few decades of the past century trivalent phosphines were viewed primarily as useful ligands for transition-metal-mediated processes. The 1990s saw revived interest in using phosphines in organic catalysis, but the key advances in asymmetric phosphine catalysis have all come within the past decade. The uniqueness of phosphine catalysis can be attributed to the high nucleophilicity of the phosphorus atom. In typical phosphine-catalyzed reactions, nucleophilic attacks of the phosphorus atom on electron-deficient multiple bonds create different reactive ylide-type intermediates. When such structurally diverse zwitterionic species react with a variety of suitable substrates, new reaction patterns are often discovered and a diverse array of reactions can be developed. In recent years, substantial progress has been made in the field of asymmetric phosphine catalysis; many new reactions have been discovered, and numerous enantioselective processes have been reported. However, we felt that powerful and versatile phosphine catalysts that can work for a wide range of asymmetric reactions are still lacking. We therefore set our goal to develop a family of easily derived phosphine catalysts that are efficient in asymmetric induction for a broad range of phosphine-mediated transformations. This Account describes our efforts in the past few years on the development of amino acid-based bifunctional phosphines and their applications to enantioselective processes. Building upon our previous success in primary-amine-mediated enamine catalysis, we first established that bifunctional phosphines could be readily prepared from amino acids. In most of our studies, we chose threonine as the key backbone for catalyst development, and threonine-based monoamino acid or dipeptide bifunctional phosphines have displayed remarkable stereochemical control. We began our investigations by demonstrating the

  2. Gallic acid and gallic acid derivatives: effects on drug metabolizing enzymes.

    PubMed

    Ow, Yin-Yin; Stupans, Ieva

    2003-06-01

    Gallic acid and its structurally related compounds are found widely distributed in fruits and plants. Gallic acid, and its catechin derivatives are also present as one of the main phenolic components of both black and green tea. Esters of gallic acid have a diverse range of industrial uses, as antioxidants in food, in cosmetics and in the pharmaceutical industry. In addition, gallic acid is employed as a source material for inks, paints and colour developers. Studies utilising these compounds have found them to possess many potential therapeutic properties including anti-cancer and antimicrobial properties. In this review, studies of the effects of gallic acid, its esters, and gallic acid catechin derivatives on Phase I and Phase II enzymes are examined. Many published reports of the effects of the in vitro effects of gallic acid and its derivatives on drug metabolising enzymes concern effects directly on substrate (generally drug or mutagen) metabolism or indirectly through observed effects in Ames tests. In the case of the Ames test an antimutagenic effect may be observed through inhibition of CYP activation of indirectly acting mutagens and/or by scavenging of metabolically generated mutagenic electrophiles. There has been considerable interest in the in vivo effects of the gallate esters because of their incorporation into foodstuffs as antioxidants and in the catechin gallates with their potential role as chemoprotective agents. Principally an induction of Phase II enzymes has been observed however more recent studies using HepG2 cells and primary cultures of human hepatocytes provide evidence for the overall complexity of actions of individual components versus complex mixtures, such as those in food. Further systematic studies of mechanisms of induction and inhibition of drug metabolising enzymes by this group of compounds are warranted in the light of their distribution and consequent ingestion, current uses and suggested therapeutic potential. However, it

  3. 40 CFR 721.10045 - Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (generic). 721.10045... Substances § 721.10045 Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid... heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (PMN P-02-737)...

  4. 40 CFR 721.10045 - Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (generic). 721.10045... Substances § 721.10045 Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid... heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (PMN P-02-737)...

  5. 40 CFR 721.10045 - Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (generic). 721.10045... Substances § 721.10045 Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid... heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (PMN P-02-737)...

  6. 40 CFR 721.10045 - Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (generic). 721.10045... Substances § 721.10045 Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid... heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (PMN P-02-737)...

  7. 40 CFR 721.430 - Oxo-substituted amino-al-kanoic acid derivative.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Oxo-substituted amino-al-kanoic acid... Specific Chemical Substances § 721.430 Oxo-substituted amino-al-kanoic acid derivative. (a) Chemical... as oxo-substituted amino al-kan-oic acid derivative (PMN No. P-92-692) is subject to reporting...

  8. 40 CFR 721.430 - Oxo-substituted amino-al-kanoic acid derivative.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Oxo-substituted amino-al-kanoic acid... Specific Chemical Substances § 721.430 Oxo-substituted amino-al-kanoic acid derivative. (a) Chemical... as oxo-substituted amino al-kan-oic acid derivative (PMN No. P-92-692) is subject to reporting...

  9. 40 CFR 721.430 - Oxo-substituted amino-al-kanoic acid derivative.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Oxo-substituted amino-al-kanoic acid... Specific Chemical Substances § 721.430 Oxo-substituted amino-al-kanoic acid derivative. (a) Chemical... as oxo-substituted amino al-kan-oic acid derivative (PMN No. P-92-692) is subject to reporting...

  10. Potential gastroprotective effect of novel cyperenoic acid/quinone derivatives in human cell cultures.

    PubMed

    Theoduloz, Cristina; Carrión, Ivanna Bravo; Pertino, Mariano Walter; Valenzuela, Daniela; Schmeda-Hirschmann, Guillermo

    2012-11-01

    The stem bark of Tabebuia species and the rhizomes of Jatropha isabelii are used in Paraguayan traditional medicine to treat gastric lesions and as anti-inflammatory agents. The sesquiterpene cyperenoic acid obtained from J. isabelii has been shown to display a gastroprotective effect in animal models of induced gastric ulcers while the quinone lapachol shows several biological effects associated with the use of the crude drug. The aim of this work was to prepare hybrid molecules presenting a terpene and a quinone moiety and to obtain an assessment of the gastroprotective activity of the new compounds using human cell cultures (MRC-5 fibroblasts and AGS epithelial gastric cells). Eight compounds, including the natural products and semisynthetic derivatives were assessed for proliferation of MRC-5 fibroblasts, protection against sodium taurocholate-induced damage, prostaglandin E2 content, and stimulation of cellular-reduced glutathione synthesis in AGS cells. The following antioxidant assays were performed: DPPH discoloration, scavenging of the superoxide anion, and inhibition of induced lipoperoxidation in erythrocyte membranes. 3-Hydroxy-β-lapachone (3) and cyperenoic acid (4) stimulated fibroblast proliferation. Lapachol (1), dihydroprenyl lapachol (2), 3-hydroxy-β-lapachone (3), and lapachoyl cyperenate (6) protected against sodium taurocholate-induced damage in AGS cells. Lapachol (1) and dihydroprenyl lapachoyl cyperenate (7) significantly stimulated prostaglandin E2 synthesis in AGS cells. Compounds 3, 4, and 7 raised reduced glutathione levels in AGS cells. The hybrid compounds presented activities different than those of the starting sesquiterpene or quinones. PMID:23047252

  11. 40 CFR 721.10045 - Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (generic). 721.10045... derivative, nickel complex, alkaline salt (generic). (a) Chemical substance and significant new uses subject... heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (PMN P-02-737)...

  12. Antileishmanial Activity of Semisynthetic Lupane Triterpenoids Betulin and Betulinic Acid Derivatives: Synergistic Effects with Miltefosine

    PubMed Central

    Sousa, Maria C.; Varandas, Raquel; Santos, Rita C.; Santos-Rosa, Manuel; Alves, Vera; Salvador, Jorge A. R.

    2014-01-01

    Leishmaniasis is a neglected tropical disease (NTDs), endemic in 88 countries, affecting more than 12 million people. The treatment consists in pentavalent antimony compounds, amphotericin B, pentamidine and miltefosine, among others. However, these current drugs are limited due to their toxicity, development of biological resistance, length of treatment and high cost. Thus, it is important to continue the search for new effective and less toxic treatments. The anti-Leishmania activity of sixteen semisynthetic lupane triterpenoids derivatives of betulin (BT01 to BT09) and betulinic acid (AB10 to AB16) were evaluated. Drug interactions between the active compounds and one current antileishmanial drug, miltefosine, were assessed using the fixed ratio isobologram method. In addition, effects on the cell cycle, apoptosis/necrosis events, morphology and DNA integrity were studied. The derivatives BT06 (3β-Hydroxy-(20R)-lupan-29-oxo-28-yl-1H-imidazole-1-carboxylate) and AB13 (28-(1H-imidazole-1-yl)-3,28-dioxo-lup-1,20(29)-dien-2-yl-1H-imidazole-1-carboxylate) were found to be the most active, with IC50 values of 50.8 µM and 25.8 µM, respectively. Interactions between these two compounds and miltefosine were classified as synergistic, with the most effective association being between AB13 and miltefosine, where decreases of IC50 values to 6 µM were observed, similar to the miltefosine activity alone. AB13 induced significant morphological changes, while both derivatives produced anti-proliferative activity through cell cycle arrest at the G0/G1 phase. Neither of these derivatives induced significant apoptosis/necrosis, as indicated by phosphatidylserine externalization and DNA fragmentation assays. In addition, neither of the derivatives induced death in macrophage cell lines. Thus, they do not present any potential risk of toxicity for the host cells. This study has identified the betulin derivative BT06 and the betulinic acid derivative AB13 as promising molecules

  13. Production of chlorogenic acid and its derivatives in hairy root cultures of Stevia rebaudiana.

    PubMed

    Fu, Xiao; Yin, Zhong-Ping; Chen, Ji-Guang; Shangguan, Xin-Chen; Wang, Xiaoqiang; Zhang, Qing-Feng; Peng, Da-Yong

    2015-01-14

    Chlorogenic acid and its derivatives (CADs) are valuable bioactive plant secondary metabolites with many health benefits. In the present study, Stevia rebaudiana hairy root cultures were established, and the culture conditions for the production of CADs were optimized. The hairy roots were induced by coculture of S. rebaudiana leaves and Agrobacterium rhizogenes (C58C1) after infection, which were further verified by PCR detection of rolB and rolC genes. HPLC-MS and HPLC analysis showed that chlorogenic acid (3-caffeoylquinic acid, 3-CQA), 3,5-dicaffeoylquinic acid (3,5-CQA), and 4,5-dicaffeoylquinic acid (4,5-CQA) were the major CADs in the hairy roots. Eight single roots with rapid growth rate were selected. Among them, T3 had the highest yield of CADs. B5 medium supplemented with 40 g/L sucrose was more suitable for the production of CADs than others. Under optimal culture conditions, the total content of these three compounds reached 105.58 mg/g and total yield was 234.40 mg/100 mL. PMID:25548875

  14. Drug Resistance Reversal Potential of Ursolic Acid Derivatives against Nalidixic Acid- and Multidrug-resistant Escherichia coli.

    PubMed

    Dwivedi, Gaurav Raj; Maurya, Anupam; Yadav, Dharmendra Kumar; Khan, Feroz; Darokar, Mahendra P; Srivastava, Santosh Kumar

    2015-09-01

    As a part of our drug discovery program, ursolic acid was chemically transformed into six semi-synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in combination with conventional antibiotic nalidixic acid against the nalidixic acid-sensitive and nalidixic acid-resistant strains of Escherichia coli. Although ursolic acid and its all semi-synthetic derivatives did not show antibacterial activity of their own, but in combination, they significantly reduced the minimum inhibitory concentration of nalidixic acid up to eightfold. The 3-O-acetyl-urs-12-en-28-isopropyl ester (UA-4) and 3-O-acetyl-urs-12-en-28-n-butyl ester (UA-5) derivatives of ursolic acid reduced the minimum inhibitory concentration of nalidixic acid by eightfold against nalidixic acid-resistant and four and eightfold against nalidixic acid-sensitive, respectively. The UA-4 and UA-5 were further evaluated for their synergy potential with another antibiotic tetracycline against the multidrug-resistant clinical isolate of Escherichia coli-KG4. The results showed that both these derivatives in combination with tetracycline reduced the cell viability in concentration-dependent manner by significantly inhibiting efflux pump. This was further supported by the in silico binding affinity of UA-4 and UA-5 with efflux pump proteins. These ursolic acid derivatives may find their potential use as synergistic agents in the treatment of multidrug-resistant Gram-negative infections. PMID:25476148

  15. Effect of arachidonic and eicosapentaenoic acids on acute lung injury induced by hypochlorous acid

    PubMed Central

    Wahn, H; Ruenauver, N; Hammerschmidt, S

    2002-01-01

    Background: Hypochlorous acid (HOCl) is the main oxidant of activated polymorphonuclear neutrophil granulocytes (PMN) and generated by myeloperoxidase during respiratory burst. This study investigates the effects of HOCl on pulmonary artery pressure (PAP) and vascular permeability and characterises the influence of arachidonic acid (AA) and eicosapentaenoic acid (EPA) on the observed effects. Methods: HOCl (500, 1000, 2000 nmol/min) was continuously infused into the perfusate (Krebs-Henseleit buffer solution, KHB). AA or EPA in subthreshold doses (both 2 nmol/min) or buffer were simultaneously infused using a separate port. PAP, pulmonary venous pressure (PVP), ventilation pressure, and lung weight gain were continuously recorded. The capillary filtration coefficient (Kf,c) was calculated before and 30, 60, and 90 minutes after starting the HOCl infusion. Results: HOCl application resulted in a dose dependent increase in PAP and Kf,c. The onset of these changes was inversely related to the HOCl dose used. The combined infusion of AA with HOCl resulted in a significant additional rise in pressure and oedema formation which forced premature termination of all experiments. The combination of EPA with HOCl did not result in an enhancement of the HOCl induced rise in pressure and oedema formation. Conclusions: Changes in the pulmonary microvasculature caused by HOCl are differently influenced by ω-6 and ω-3 polyunsaturated free fatty acids, suggesting a link between neutrophil derived oxidative stress and pulmonary eicosanoid metabolism. PMID:12454302

  16. Bioactive 1,4-dihydroisonicotinic acid derivatives prevent oxidative damage of liver cells.

    PubMed

    Borovic, Suzana; Tirzitis, Gunars; Tirzite, Dace; Cipak, Ana; Khoschsorur, Gholam A; Waeg, Georg; Tatzber, Franz; Scukanec-Spoljar, Mira; Zarkovic, Neven

    2006-05-10

    1,4-Dihydroisonicotinic acid derivatives (1,4-DHINA) are compounds closely related to derivatives of 1,4-dihydropyridine, a well-known calcium channel antagonists. 1,4-DHINA we used were derived from a well-known antioxidant Diludin. Although some compounds have neuromodulatory or antimutagenic properties, their activity mechanisms are not well known. This study was performed to obtain data on antioxidant and bioprotective activities of: 2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydroisonicotinic acid (Ia); sodium 2-(2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine-4-carboxamido)glutamate (Ib) and sodium 2-(2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine-4-carboxamido)ethane-sulphate (Ic). 1,4-DHINA's activities were studied in comparison to Trolox by: N,N-Diphenyl-N'-picrylhydrazyl (DPPH*), deoxyribose degradation, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS) radical scavenging and antioxidative capacity assays; copper-induced lipid peroxidation of cultured rat liver cells (malondialdehyde determination by high performance liquid chromatography and 4-hydroxynonenal-protein conjugates by dot-blot); (3)H-thymidine incorporation and trypan blue assay for liver cells growth and viability. In all assays used Ia was the most potent antioxidant. Ia was also a potent antioxidant at non-toxic concentrations for liver cell cultures. It completely abolished, while Ic only slightly decreased copper-induced lipid peroxidation of liver cells. Thus, antioxidant capacities are important activity principle of Ia, which was even superior to Trolox in the cell cultures used, while activity principles of Ic and Ib remain yet to be determined. PMID:16600211

  17. A mushroom-derived amino acid, ergothioneine, is a potential inhibitor of inflammation-related DNA halogenation.

    PubMed

    Asahi, Takashi; Wu, Xiaohong; Shimoda, Hiroshi; Hisaka, Shinsuke; Harada, Etsuko; Kanno, Tomomi; Nakamura, Yoshimasa; Kato, Yoji; Osawa, Toshihiko

    2016-01-01

    Myeloperoxidase (MPO)-generated halogenating molecules, such as hypochlorous acid and hypobromous acid (HOBr), in inflammatory regions are postulated to contribute to disease progression. In this study, we showed that ergothioneine (EGT), derived from an edible mushroom, inhibited MPO activity as well as the formation of 8-bromo-2'-deoxyguanosine in vitro. The HOBr scavenging effect of EGT is higher than those of ascorbic acid and glutathione. We initially observed that the administration of Coprinus comatus, an edible mushroom containing a high amount of EGT, inhibited the UV-B-induced inflammatory responses and DNA halogenation, suggesting that EGT is a promising anti-inflammatory agent from mushrooms. PMID:26338495

  18. Acid aspiration-induced airways hyperresponsiveness in mice.

    PubMed

    Allen, Gilman B; Leclair, Timothy R; von Reyn, Jessica; Larrabee, Yuna C; Cloutier, Mary E; Irvin, Charles G; Bates, Jason H T

    2009-12-01

    The role of gastroesophageal reflux and micro-aspiration as a trigger of airways hyperresponsiveness (AHR) in patients with asthma is controversial. The role of acid reflux and aspiration as a direct cause of AHR in normal subjects is also unclear. We speculated that aspiration of a weak acid with a pH (1.8) equivalent to the upper range of typical gastric contents would lead to AHR in naive mice. We further speculated that modest reductions in aspirate acidity to a level expected during gastric acid suppression therapy (pH 4.0) would impede aspiration-induced AHR. BALB/c female mice were briefly anesthetized with isoflurane and allowed to aspirate 75 microl of saline with HCl (pH 1.8, 4.0, or 7.4) or underwent sham aspiration. Mice were re-anesthetized 2 or 24 h later, underwent tracheostomy, and were coupled to a mechanical ventilator. Forced oscillations were used to periodically measure respiratory impedance (Zrs) following aerosol delivery of saline and increasing doses of methacholine to measure for AHR. Values for elastance (H), airways resistance (R(N)), and tissue damping (G) were derived from Zrs. Aspirate pH of 1.8 led to a significant overall increase in peak R(N), G, and H compared with pH 4.0 and 7.4 at 2 and 24 h. Differences between pH 7.4 and 4.0 were not significant. In mice aspirating pH 1.8 compared with controls, airway lavage fluid contained more neutrophils, higher protein, and demonstrated higher permeability. We conclude that acid aspiration triggers an acute AHR, driven principally by breakdown of epithelial barrier integrity within the airways. PMID:19797689

  19. Acid aspiration-induced airways hyperresponsiveness in mice

    PubMed Central

    Leclair, Timothy R.; von Reyn, Jessica; Larrabee, Yuna C.; Cloutier, Mary E.; Irvin, Charles G.; Bates, Jason H. T.

    2009-01-01

    The role of gastroesophageal reflux and micro-aspiration as a trigger of airways hyperresponsiveness (AHR) in patients with asthma is controversial. The role of acid reflux and aspiration as a direct cause of AHR in normal subjects is also unclear. We speculated that aspiration of a weak acid with a pH (1.8) equivalent to the upper range of typical gastric contents would lead to AHR in naive mice. We further speculated that modest reductions in aspirate acidity to a level expected during gastric acid suppression therapy (pH 4.0) would impede aspiration-induced AHR. BALB/c female mice were briefly anesthetized with isoflurane and allowed to aspirate 75 μl of saline with HCl (pH 1.8, 4.0, or 7.4) or underwent sham aspiration. Mice were re-anesthetized 2 or 24 h later, underwent tracheostomy, and were coupled to a mechanical ventilator. Forced oscillations were used to periodically measure respiratory impedance (Zrs) following aerosol delivery of saline and increasing doses of methacholine to measure for AHR. Values for elastance (H), airways resistance (RN), and tissue damping (G) were derived from Zrs. Aspirate pH of 1.8 led to a significant overall increase in peak RN, G, and H compared with pH 4.0 and 7.4 at 2 and 24 h. Differences between pH 7.4 and 4.0 were not significant. In mice aspirating pH 1.8 compared with controls, airway lavage fluid contained more neutrophils, higher protein, and demonstrated higher permeability. We conclude that acid aspiration triggers an acute AHR, driven principally by breakdown of epithelial barrier integrity within the airways. PMID:19797689

  20. Energy densification of biomass-derived organic acids

    DOEpatents

    Wheeler, M. Clayton; van Walsum, G. Peter; Schwartz, Thomas J.; van Heiningen, Adriaan

    2013-01-29

    A process for upgrading an organic acid includes neutralizing the organic acid to form a salt and thermally decomposing the resulting salt to form an energy densified product. In certain embodiments, the organic acid is levulinic acid. The process may further include upgrading the energy densified product by conversion to alcohol and subsequent dehydration.

  1. Synthesis and in vitro antitumor evaluation of dihydroartemisinin-cinnamic acid ester derivatives.

    PubMed

    Xu, Cang-Cang; Deng, Ting; Fan, Meng-Lin; Lv, Wen-Bo; Liu, Ji-Hua; Yu, Bo-Yang

    2016-01-01

    To explore novel high efficiency and low toxicity antitumor agents, a series of dihydroartemisinin-cinnamic acid ester derivatives modified on C-12 and/or C-9 position (s) were synthesized and the in vitro antitumor activities against PC-3, SGC-7901, A549 and MDA-MB-435s cancer cell lines were assessed. The hybrids (3-36) were prepared by esterification of 9α-hydroxyl-dihydroartemisinin (9α-OH DHA), the biotransformation product of dihydroartemisinin (DHA), and cinnamic acid derivatives. Compound 17 (IC50 = 0.20 μM) was the most potent anti-proliferative agent against the human lung carcinoma A549 cells, although it displayed low cytotoxicity on normal hepatic L-02 cells. The mechanism of action of compound 17 was further investigated by analysis of cell apoptosis and intracellular ROS generation. The results indicated that both ROS and ferrous ion contributed to the compound 17-induced cell death. Meanwhile, high intracellular ferrous ion and endogenous oxidative stress in A549 cells made them easier to suffer to compound 17-induced apoptosis. Our promising findings indicated the compound 17 could stand as drug candidate against lung cancer for further investigation. PMID:26595184

  2. Synthesis and Biological Evaluation of Novel Ursolic acid Derivatives as Potential Anticancer Prodrugs.

    PubMed

    Yang, Xiang; Li, Yuanfang; Jiang, Wei; Ou, Minrui; Chen, Yali; Xu, Yu; Wu, Qiong; Zheng, Qing; Wu, Fuqiang; Wang, Lue; Zou, Wentao; Zhang, Yitong J; Shao, Jingwei

    2015-12-01

    Ursolic acid (UA) is a natural product which has been shown to possess a wide range of pharmacological activities, in particular those with anticancer activity. In this study, 13 novel ursolic acid derivatives were designed and synthesized in an attempt to further improve compound potency. The structures of the newly synthesized compounds were confirmed using mass spectrometry, infrared spectroscopy, and (1) H NMR. The ability of the UA derivatives to inhibit cell growth was assayed against both various tumor cell lines and a non-pathogenic cell line, HELF. Analysis of theoretical toxicity risks for all derivatives was performed using OSIRIS and indicated that the majority of compounds would present moderate to low risks. Pharmacological results indicated that the majority of the derivatives were more potent growth inhibitors than UA. In particular, 5b demonstrated IC50 values ranging from 4.09 ± 0.27 to 7.78 ± 0.43 μm against 12 different tumor cell lines. Flow cytometry analysis indicated that 5b induced G0/G1 arrest in three of these cell lines. These results were validated by structural docking studies, which confirmed that UA could bind to cyclins D1 (Cyc D1) and cyclin-dependent kinases (CDK6), the key regulators of G0/G1 transition in cell cycle, while the piperazine moiety of 5b could bind with glucokinase (GK), glucose transporter 1 (GLUT1), and ATPase, which are the main proteins involved in cancer cell metabolism. Acridine orange/ethidium bromide staining confirmed that 5b was capable of inducing apoptosis and decreasing cell viability in a dose-dependent manner. PMID:26077799

  3. Benzoic acid derivatives from Piper species and their antiparasitic activity.

    PubMed

    Flores, Ninoska; Jiménez, Ignacio A; Giménez, Alberto; Ruiz, Grace; Gutiérrez, David; Bourdy, Genevieve; Bazzocchi, Isabel L

    2008-09-01

    Piper glabratum and P. acutifolium were analyzed for their content of main secondary constituents, affording nine new benzoic acid derivatives (1, 2, 4, 5, 7, and 10-13), in addition to four known compounds (3, 6, 8, and 9). Their structures were elucidated on the basis of spectroscopic data. Riguera ester reactions and optical rotation measurements established the new compounds as racemates. In the search for antiparasitic agents, the compounds were evaluated in vitro against the promastigote forms of Leishmania spp., Trypanosoma cruzi, and Plasmodium falciparum. Among the evaluated compounds, methyl 3,4-dihydroxy-5-(3'-methyl-2'-butenyl)benzoate (7) exhibited leishmanicidal effect (IC50 13.8-18.5 microg/mL) against the three Leishmania strains used, and methyl 3,4-dihydroxy-5-(2-hydroxy-3-methylbutenyl)benzoate (1), methyl 4-hydroxy-3-(2-hydroxy-3-methyl-3-butenyl)benzoate (3), and methyl 3,4-dihydroxy-5-(3-methyl-2-butenyl) benzoate (7) showed significant trypanocidal activity, with IC50 values of 16.4, 15.6, and 18.5 microg/mL, respectively. PMID:18712933

  4. Discotic liquid crystal derived from zinc tetraaminophthalocyanine and perfluorooctanoic acid

    NASA Astrophysics Data System (ADS)

    Meng, Fanbao; Zhou, Naiyu; Diao, Na; Du, Chang

    2013-12-01

    A novel kind of metallo-phthalocyanine derivative, zinc 2,9,16,23-tetraaminophthalocyanine perfluorooctanoate (Zn-APc-pFOA), was synthesized from zinc tetraaminophthalocyanine and perfluorooctanoic acid. The chemical structure, liquid crystalline behavior, and electrorheological properties were characterized by the use of various experimental techniques, methods, and instruments, including FT-IR and UV-vis spectroscopy, 1H-NMR, x-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, polarized optical microscopy, the four-point method, a relative permittivity test instrument, and a rotating viscometer. Zn-APc-pFOA shows a discotic hexagonal columnar mesophase over a wide temperature range. The dielectric constant and conductivity of Zn-APc-pFOA are 11.4 and 6.34 × 10-3 S cm-1, respectively. The 20 V% silicone oil-Zn-APc-pFOA fluid shows an electrorheological (ER) effect. Zn-APc-pFOA is a semiconductor with a high dielectric constant, causing a mismatch of conductivity and dielectric constant between the Zn-APc-pFOA and silicone oil. Furthermore, some synergistic effect could occur between the semiconducting property and the molecular orientation of the discotic liquid crystals in Zn-APc-pFOA suspensions, resulting in a high ER effect.

  5. Glycyrrhetinic acid-induced permeability transition in rat liver mitochondria.

    PubMed

    Salvi, Mauro; Fiore, Cristina; Armanini, Decio; Toninello, Antonio

    2003-12-15

    Glycyrrhetinic acid, a hydrolysis product of one of the main constituents of licorice, the triterpene glycoside of glycyrrhizic acid, when added to rat liver mitochondria at micromolar concentrations induces swelling, loss of membrane potential, pyridine nucleotide oxidation, and release of cytochrome c and apoptosis inducing factor. These changes are Ca(2+) dependent and are prevented by cyclosporin A, bongkrekic acid, and N-ethylmaleimide. All these observations indicate that glycyrrhetinic acid is a potent inducer of mitochondrial permeability transition and can trigger the pro-apoptotic pathway. PMID:14637195

  6. Zoledronic Acid-Induced Interface Dermatitis.

    PubMed

    Succaria, Farah; Collier, Mary; Mahalingam, Meera

    2015-12-01

    Zoledronic acid (ZA) is a bisphosphonate given intravenously, most commonly for the treatment of postmenopausal osteoporosis. Increase in usage of ZA because it was FDA-approved has resulted in increasing reports of side effects. For the most part, these are systemic. Cutaneous side effects associated with ZA are infrequent and limited to 2 reports of dermatomyositis to date. In both, patients presented with clinical and laboratory stigmata of dermatomyositis soon after initiation of therapy. In this report, we describe a 62-year-old woman who presented with diffuse, erythematous scaly plaques over the right thigh after 12 hours of infusion of ZA. Histopathologic examination of a skin biopsy from the right thigh revealed patchy scale crust containing neutrophils and inspissated serum, interface change with scattered individually necrotic keratinocytes, and a mild, superficial perivascular lymphocytic infiltrate with scattered eosinophils and pigment incontinence-findings consistent with an interface dermatitis. Given that the patient had no other systemic manifestations or laboratory abnormalities, to the best of our knowledge, ours is the first report of interface dermatitis secondary to ZA with the caveat that longer follow-up is required to definitively exclude the development of drug-induced connective tissue disease. PMID:26588338

  7. In vitro inhibition of OATP-mediated uptake of phalloidin using bile acid derivatives

    SciTech Connect

    Herraez, Elisa; Macias, Rocio I.R.; Vazquez-Tato, Jose; Vicens, Marta; Monte, Maria J.; Marin, Jose J.G.

    2009-08-15

    Hepatocyte uptake of phalloidin is carried out mainly by OATP1B1. We have used this compound as a prototypic substrate and assayed the ability to inhibit OATP-mediated phalloidin transport of four bile acid derivatives (BALU-1, BALU-2, BALU-3 and BALU-4) that showed positive results in preliminary screening. Using Xenopus laevis oocytes for heterologous expression of transporters, BALUs were found to inhibit taurocholic acid (TCA) transport by OATP1B1 (but not OATP1B3) as well as by rat Oatp1a1, Oatp1a4 and Oatp1b2. The study of their ability to inhibit sodium-dependent bile acid transporters revealed that the four BALUs induced an inhibition of rat Asbt-mediated TCA transport, which was similar to TCA-induced self-inhibition. Regarding human NTCP and rat Ntcp, BALU-1 differs from the other three BALUS in its lack of effect on TCA transport by these proteins. Using HPLC-MS/MS and CHO cells stably expressing OATP1B1 the ability of BALU-1 to inhibit the uptake of phalloidin itself by this transporter was confirmed. Kinetic analysis using X. laevis oocytes revealed that BALU-1-induced inhibition of OATP1B1 was mainly due to a competitive mechanism (Ki = 8 {mu}M). In conclusion, BALU-1 may be useful as a pharmacological tool to inhibit the uptake of compounds mainly taken up by OATP1B1 presumably without impairing bile acid uptake by the major carrier accounting for this process, i.e., NTCP.

  8. Pharmaceuticals and Surfactants from Alga-Derived Feedstock: Amidation of Fatty Acids and Their Derivatives with Amino Alcohols.

    PubMed

    Tkacheva, Anastasia; Dosmagambetova, Inkar; Chapellier, Yann; Mäki-Arvela, Päivi; Hachemi, Imane; Savela, Risto; Leino, Reko; Viegas, Carolina; Kumar, Narendra; Eränen, Kari; Hemming, Jarl; Smeds, Annika; Murzin, Dmitry Yu

    2015-08-24

    Amidation of renewable feedstocks, such as fatty acids, esters, and Chlorella alga based biodiesel, was demonstrated with zeolites and mesoporous materials as catalysts and ethanolamine, alaninol, and leucinol. The last two can be derived from amino acids present in alga. The main products were fatty alkanol amides and the corresponding ester amines, as confirmed by NMR and IR spectroscopy. Thermal amidation of technical-grade oleic acid and stearic acid at 180 °C with ethanolamine were non-negligible; both gave 61% conversion. In the amidation of stearic acid with ethanolamine, the conversion over H-Beta-150 was 80% after 3 h, whereas only 63% conversion was achieved for oleic acid; this shows that a microporous catalyst is not suitable for this acid and exhibits a wrinkled conformation. The highest selectivity to stearoyl ethanolamide of 92% was achieved with mildly acidic H-MCM-41 at 70% conversion in 3 h at 180 °C. Highly acidic catalysts favored the formation of the ester amine, whereas the amide was obtained with a catalyst that exhibited an optimum acidity. The conversion levels achieved with different fatty acids in the range C12-C18 were similar; this shows that the fatty acid length does not affect the amidation rate. The amidation of methyl palmitate and biodiesel gave low conversions over an acidic catalyst, which suggested that the reaction mechanism in the amidation of esters was different. PMID:26197759

  9. Massive production of farnesol-derived dicarboxylic acids in mice treated with the squalene synthase inhibitor zaragozic acid A.

    PubMed

    Vaidya, S; Bostedor, R; Kurtz, M M; Bergstrom, J D; Bansal, V S

    1998-07-01

    The zaragozic acids are potent inhibitors of squalene synthase. In vivo studies in mice confirmed our earlier observations that inhibition of squalene synthase by zaragozic acid A was accompanied by an increase in the incorporation of label from [3H]mevalonate into farnesyl-diphosphate (FPP)-derived isoprenoic acids (J. D. Bergstrom et al., 1993, Proc. Natl. Acad. Sci. USA 90, 80-84). Farnesyl-diphosphate-derived metabolites appear transiently in the liver. We were unable to detect any farnesol formation in the zaragozic acid-treated animals which indicates that FPP is readily converted to farnesoic acid and dicarboxylic acids in the liver. These metabolites were found to be produced only in the liver and not in the kidney. trans-3,7-Dimethyl-2-octaen-1,8-dioic acid and 3, 7-dimethyloctan-1,8-dioic acid were identified as the major end products of farnesyl-diphosphate metabolism in the urine of mice treated with zaragozic acid A. Quantitative analysis of these FPP-derived dicarboxylic acids by gas-liquid chromatography revealed that approximately 11 mg of total dicarboxylic acids is excreted per day into the urine of a mouse after 3 days of treatment with zaragozic acid A. PMID:9647670

  10. Vacuolar deposition of ascorbate-derived oxalic acid in barley

    SciTech Connect

    Wagner, G.J.

    1981-03-01

    L-(1-/sup 14/C)Ascorbic acid was supplied to detached barley seedlings to determine the subcellular location of oxalic acid, one of its metabolic products. Intact vacuoles isolated from protoplasts of labeled leaves contained (/sup 14/C)oxalic acid which accounted for about 70% of the intraprotoplast soluble oxalic acid. Tracer-labeled oxalate accounted for 36 and 72% of the /sup 14/C associated with leaf vacuoles of seedlings labeled for 22 and 96 hours, respectively.

  11. Metabolic engineering of yeast to produce fatty acid-derived biofuels: bottlenecks and solutions.

    PubMed

    Sheng, Jiayuan; Feng, Xueyang

    2015-01-01

    Fatty acid-derived biofuels can be a better solution than bioethanol to replace petroleum fuel, since they have similar energy content and combustion properties as current transportation fuels. The environmentally friendly microbial fermentation process has been used to synthesize advanced biofuels from renewable feedstock. Due to their robustness as well as the high tolerance to fermentation inhibitors and phage contamination, yeast strains such as Saccharomyces cerevisiae and Yarrowia lipolytica have attracted tremendous attention in recent studies regarding the production of fatty acid-derived biofuels, including fatty acids, fatty acid ethyl esters, fatty alcohols, and fatty alkanes. However, the native yeast strains cannot produce fatty acids and fatty acid-derived biofuels in large quantities. To this end, we have summarized recent publications in this review on metabolic engineering of yeast strains to improve the production of fatty acid-derived biofuels, identified the bottlenecks that limit the productivity of biofuels, and categorized the appropriate approaches to overcome these obstacles. PMID:26106371

  12. Metabolic engineering of yeast to produce fatty acid-derived biofuels: bottlenecks and solutions

    PubMed Central

    Sheng, Jiayuan; Feng, Xueyang

    2015-01-01

    Fatty acid-derived biofuels can be a better solution than bioethanol to replace petroleum fuel, since they have similar energy content and combustion properties as current transportation fuels. The environmentally friendly microbial fermentation process has been used to synthesize advanced biofuels from renewable feedstock. Due to their robustness as well as the high tolerance to fermentation inhibitors and phage contamination, yeast strains such as Saccharomyces cerevisiae and Yarrowia lipolytica have attracted tremendous attention in recent studies regarding the production of fatty acid-derived biofuels, including fatty acids, fatty acid ethyl esters, fatty alcohols, and fatty alkanes. However, the native yeast strains cannot produce fatty acids and fatty acid-derived biofuels in large quantities. To this end, we have summarized recent publications in this review on metabolic engineering of yeast strains to improve the production of fatty acid-derived biofuels, identified the bottlenecks that limit the productivity of biofuels, and categorized the appropriate approaches to overcome these obstacles. PMID:26106371

  13. Acanthoic acid ameliorates lipopolysaccharide-induced acute lung injury.

    PubMed

    Qiushi, Wang; Guanghua, Li; Guangquan, Xu

    2015-03-01

    Acanthoic acid, a pimaradiene diterpene isolated from Acanthopanax koreanum, has been reported to have anti-inflammatory activities. However, the effects of acanthoic acid on LPS-induced acute lung injury have not been reported. The purpose of this study was to investigate the protective effect of acanthoic acid on LPS-induced ALI and to clarify the possible anti-inflammatory mechanisms. In vivo, an LPS-induced ALI model in mice was used to assess the protective effects of acanthoic acid on ALI. Meanwhile, mouse alveolar macrophages MH-S were stimulated with LPS in the presence or absence of acanthoic acid. The expressions of TNF-α, IL-6 and IL-1β were measured by ELISA. LXRα and NF-κB expression were detected by Western blot analysis. The results showed that acanthoic acid downregulated LPS-induced TNF-α, IL-6 and IL-1β production in BALF. MPO activity and lung wet-to-dry ratio were also inhibited by acanthoic acid. In addition, acanthoic acid attenuated lung histopathologic changes. In vitro, acanthoic acid inhibited inflammatory cytokines TNF-α, IL-6 and IL-1β production and NF-κB activation in LPS-stimulated alveolar macrophages. Acanthoic acid was found to up-regulated the expression of LXRα. The inhibition of acanthoic acid on LPS-induced cytokines and NF-κB activation can be abolished by LXRα siRNA. In conclusion, our results suggested that the protective effect of acanthoic acid on LPS-induced ALI was due to its ability to activate LXRα, thereby inhibiting LPS-induced inflammatory response. PMID:25620130

  14. Blockade of swelling-induced chloride channels by phenol derivatives.

    PubMed Central

    Gschwentner, M.; Jungwirth, A.; Hofer, S.; Wöll, E.; Ritter, M.; Susanna, A.; Schmarda, A.; Reibnegger, G.; Pinggera, G. M.; Leitinger, M.; Frick, J.; Deetjen, P.; Paulmichl, M.

    1996-01-01

    1. In NIH3T3 fibroblasts, the chloride channel involved in regulatory volume decrease (RVD) was identified as ICln, a protein isolated from a cDNA library derived from Madin Darby canine Kidney (MDCK) cells. ICln expressed in Xenopus laevis oocytes gives rise to an outwardly rectifying chloride current, sensitive to the extracellular addition of nucleotides and the known chloride channel blockers, DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid) and NPPB (5-nitro-2-(3-phenylpropylamino)-benzoic acid). We set out to study whether substances structurally similar to NPPB are able to interfere with RVD. 2. RVD in NIH3T3 fibroblasts and MDCK cells is temperature-dependent. 3. RVD, the swelling-dependent chloride current and the depolarization seen after reducing extracellular osmolarity can be blocked by gossypol and NDGA (nordihydroguaiaretic acid), both structurally related to NPPB. 4. The cyclic AMP-dependent chloride current elicited in CaCo cells is less sensitive to the two substances tested while the calcium-activated chloride current in fibroblasts is insensitive. 5. The binding site for the two phenol derivatives onto ICln seems to be distinct but closely related to the nucleotide binding site identified as G x G x G, a glycine repeat located at the predicted outer mouth of the ICln channel protein. PMID:8733574

  15. Lysophosphatidic acid-induced chemotaxis of bone cells.

    SciTech Connect

    Karagiosis, Sue A.; Masiello, Lisa M.; Bollinger, Nikki; Karin, Norm J.

    2006-07-01

    Lysophosphatidic acid (LPA) is a platelet-derived bioactive lipid that is postulated to regulate wound healing. LPA activates G protein-coupled receptors to induce Ca2+ signaling in MC3T3-E1 pre-osteoblasts, and is a potent chemotactic stimulus for these cells. Since bone fracture healing requires the migration of osteoblast progenitors, we postulate that LPA is among the factors that stimulate bone repair. UMR 106-01 cells, which express a more mature osteoblastic phenotype than MC3T3-E1 cells, did not migrate in response to LPA, although they express LPA receptors and exhibit LPA-induced Ca2+ signals. This suggests that LPA differentially induces pre-osteoblast chemotaxis, consistent with our hypothesis that LPA stimulates the motility of osteoblast progenitors during bone healing. LPA-stimulated MC3T3-E1 cells exhibit striking changes in morphology and F-actin architecture, and phosphatidylinositol-3 kinase (PI3K) is required for motility-associated cytoskeletal rearrangements in many cell types. We found a dose-dependent reduction in LPA-induced osteoblast migration when cells also were treated with the PI3K inhibitor, LY294002. Treatment of many cell types with LPA is associated with an autocrine/paracrine transactivation of the EGF receptor (EGFR) via shedding of surface-tethered EGFR ligands, a phenomenon often required for LPA-induced chemotaxis. MC3T3-E1 cells express multiple EGFR ligands (epigen, epiregulin, HB-EGF and amphiregulin) and migrated in response to EGF. However, while EGF-stimulated motility in MC3T3-E1 cells was blocked by an EGFR inhibitor, there was no significant effect on LPA-induced chemotaxis. Activation of MAP kinases is a hallmark of EGFR-mediated signaling, and EGF treatment of MC3T3-E1 cells led to a strong stimulation of ERK1/2 kinase. In contrast, LPA induced only a minor elevation in ERK activity. Thus, it is likely that the increase in ERK activity by LPA is related to cell proliferation associated with lipid treatment. We

  16. Derivation of Induced Pluripotent Stem Cells for Human Disease Modeling

    PubMed Central

    Narsinh, Kamileh; Narsinh, Kazim H.; Wu, Joseph C.

    2011-01-01

    The successful derivation of human induced pluripotent stem cells (hiPSCs) by de-differentiation of somatic cells offers significant potential to overcome obstacles in the field of cardiovascular disease. hiPSC derivatives offer incredible potential for new disease models and regenerative medicine therapies. However, many questions remain regarding the optimal starting materials and methods to enable safe, efficient derivation of hiPSCs suitable for clinical applications. Initial reprogramming experiments were carried out using lentiviral or retroviral gene delivery methods. More recently, various non-viral methods that avoid permanent and random transgene insertion have emerged as alternatives. These include transient DNA transfection approaches using transposons or minicircle plasmids, protein transduction approaches, and RNA transfection approaches. In addition, several small molecules have been found to significantly augment iPSC derivation efficiency, allowing the use of a fewer number of genes during pluripotency induction. Here, we review these various methods for the derivation of hiPSCs, focusing on their ultimate clinical applicability, with an emphasis on their potential for use as cardiovascular therapies and disease modeling platforms. PMID:21527744

  17. Effects of amino acid derivatives on physical, mental, and physiological activities.

    PubMed

    Luckose, Feby; Pandey, Mohan Chandra; Radhakrishna, Kolpe

    2015-01-01

    Nutritional ergogenic aids have been in use for a long time to enhance exercise and sports performance. Dietary components that exhibit ergogenic activity are numerous and their consumption is common and popular among athletes. They often come under scrutiny by legal authorities for their claimed benefits and safety concerns. Amino acid derivatives are propagated as being effective aids to enhance physical and mental performance in many ways, even though studies have pointed out that individuals who are deficient are more likely to benefit from dietary supplementation of amino acid derivatives than normal humans. In this review, some of the most common and widely used amino acids derivatives in sports and athletics namely creatine, tyrosine, carnitine, HMB, and taurine have been discussed for their effects on exercise performance, mental activity as well as body strength and composition. Creatine, carnitine, HMB, and taurine are reported to delay the onset of fatigue, improve exercise performance, and body strength. HMB helps in increasing fat-free mass and reduce exercise induced muscle injury. Taurine has been found to reduce oxidative stress during exercise and also act as an antihypertensive agent. Although, studies have not been able to find any favorable effect of tyrosine administration on exercise performance, it has been proved to be very effective in fighting stress, improving mood and cognitive performance particularly in sleep-deprived subjects. While available data from published studies and findings are equivocal about the efficacy of creatine, tyrosine, and HMB, more comprehensive researches on carnitine and taurine are necessary to provide evidence for the theoretical basis of their ergogenic role in nutritional modification and supplementation. PMID:24279396

  18. Detection of boronic acid derivatives in cells using a fluorescent sensor.

    PubMed

    Hattori, Yoshihide; Ishimura, Miki; Ohta, Youichirou; Takenaka, Hiroshi; Watanabe, Tsubasa; Tanaka, Hiroki; Ono, Koji; Kirihata, Mitsunori

    2015-07-01

    The detection of boron-containing compounds requires very expensive facilities and/or tedious sample pretreatments. In an effort to develop a convenient detection method for boronic acid derivatives, boron chelating-ligands were synthesized for use as fluorescent sensors. In this paper, the synthesis and properties of fluorescent sensors for boronic acid derivatives are reported. PMID:26022725

  19. Hydroxyoctadecadienoic acids: Oxidised derivatives of linoleic acid and their role in inflammation associated with metabolic syndrome and cancer.

    PubMed

    Vangaveti, Venkat N; Jansen, Holger; Kennedy, Richard Lee; Malabu, Usman H

    2016-08-15

    Linoleic acid (LA) is a major constituent of low-density lipoproteins. An essential fatty acid, LA is a polyunsaturated fatty acid, which is oxidised by endogenous enzymes and reactive oxygen species in the circulation. Increased levels of low-density lipoproteins coupled with oxidative stress and lack of antioxidants drive the oxidative processes. This results in synthesis of a range of oxidised derivatives, which play a vital role in regulation of inflammatory processes. The derivatives of LA include, hydroxyoctadecadienoic acids, oxo-​octadecadienoic acids, epoxy octadecadecenoic acid and epoxy-keto-octadecenoic acids. In this review, we examine the role of LA derivatives and their actions on regulation of inflammation relevant to metabolic processes associated with atherogenesis and cancer. The processes affected by LA derivatives include, alteration of airway smooth muscles and vascular wall, affecting sensitivity to pain, and regulating endogenous steroid hormones associated with metabolic syndrome. LA derivatives alter cell adhesion molecules, this initial step, is pivotal in regulating inflammatory processes involving transcription factor peroxisome proliferator-activated receptor pathways, thus, leading to alteration of metabolic processes. The derivatives are known to elicit pleiotropic effects that are either beneficial or detrimental in nature hence making it difficult to determine the exact role of these derivatives in the progress of an assumed target disorder. The key may lie in understanding the role of these derivatives at various stages of development of a disorder. Novel pharmacological approaches in altering the synthesis or introduction of synthesised LA derivatives could possibly help drive processes that could regulate inflammation in a beneficial manner. Chemical Compounds: Linoleic acid (PubChem CID: 5280450), 9- hydroxyoctadecadienoic acid (PubChem CID: 5312830), 13- hydroxyoctadecadienoic acid (PubChem CID: 6443013), 9-oxo

  20. Multipotent hematopoietic cell lines derived from C/EBPalpha(-/-) knockout mice display granulocyte macrophage-colony-stimulating factor, granulocyte- colony-stimulating factor, and retinoic acid-induced granulocytic differentiation.

    PubMed

    Collins, S J; Ulmer, J; Purton, L E; Darlington, G

    2001-10-15

    The transcription factor C/EBPalpha is an important mediator of granulocyte differentiation and regulates the expression of multiple granulocyte-specific genes including the granulocyte-colony-stimulating factor (G-CSF) receptor, neutrophil elastase, and myeloperoxidase. Indeed C/EBPalpha knockout mice display a profound block in granulocyte differentiation. To study this block in granulocytic differentiation in more detail, retroviral vector-mediated transduction of a dominant-negative retinoic acid receptor was used to establish hematopoietic growth factor-dependent, lympho-myeloid progenitor cell lines from the fetal livers of both the C/EBPalpha knockout animals (C/EBPalpha(-/-)) and their heterozygous littermates (C/EBPalpha(+/-)). Surprisingly, the C/EBPalpha(-/-) cell lines displayed significant spontaneous granulocytic differentiation, and this differentiation was markedly enhanced when the cells were stimulated with granulocyte macrophage (GM)-CSF. This GM-CSF-mediated differentiation was associated with the up-regulation of G-CSF receptor mRNA, and the combination of GM-CSF and G-CSF generated more than 95% mature neutrophils in the C/EBPalpha(-/-) cultures. The addition of all-trans retinoic acid also enhanced this granulocytic differentiation of the cultured C/EBPalpha(-/-) cells, indicating that the activated retinoic acid receptors can enhance granulocytic differentiation through a molecular pathway that is independent of C/EBPalpha. These studies clearly indicate that terminal granulocytic differentiation associated with the up-regulation of C/EBPalpha-responsive genes can occur in the absence of C/EBPalpha, and they indicate the existence of multiple independent molecular pathways potentially used by primitive hematopoietic precursors that can lead to the development of mature granulocytes. PMID:11588034

  1. Impact of lipid oxidation-derived aldehydes and ascorbic acid on the antioxidant activity of model melanoidins.

    PubMed

    Kitrytė, Vaida; Adams, An; Venskutonis, Petras Rimantas; De Kimpe, Norbert

    2012-12-01

    As the heat-induced formation of antioxidants throughout the Maillard reaction is known, this study was undertaken to evaluate the impact of lipid oxidation-derived aldehydes and ascorbic acid in Maillard model systems on the resulting antioxidant activity. For this purpose, various fractions of melanoidin-like polycondensation products were obtained from mixtures of amino acids (glycine, lysine, arginine) and lipid oxidation-derived aldehydes (hexanal, (E)-2-hexenal), in the presence or absence of glucose or ascorbic acid. All fractions showed a significant radical scavenging capacity (DPPH assay) and ferric reducing power (FRAP assay). The activity varied according to the composition of the model system tested, although some similar trends were discovered in both assays applied. The presence of lipid oxidation products in the browning products augmented the antioxidant activity in specific cases. For instance, the combined presence of arginine, hexanal and glucose in heated model systems resulted in a significantly higher antioxidant capacity. With an exception of ascorbic acid-containing model systems, melanoidin-like polycondensation products possessed significantly stronger antioxidant activities than the corresponding unheated initial reactant mixtures. Water-soluble high molecular weight (>12kDa) and nonsoluble fractions comprised the major part of the antioxidants derived from amino acid/lipid oxidation product model systems, with or without glucose or ascorbic acid. PMID:22953854

  2. Salicylic acid and some of its derivatives as antibacterial agents for viscose fabric.

    PubMed

    Kantouch, A; El-Sayed, A Atef; Salama, M; El-Kheir, A Abou; Mowafi, S

    2013-11-01

    Salicylic acid and three of its derivatives were used to provide antibacterial properties to viscose fabrics. The four bactericides used were bonded to the viscose fabrics using epichlorohydrin or polymer binders. Optimization of the salicylic acid and its derivatives as well as the concentration of polymers was reported. The ability of the polymer binders to attract and bind the four bactericides was observed. The overall results show that the antibacterial reactivity of salicylic acid and its derivatives are in the following order 5-bromosalicylic acid>salicylic acid>5-chlorosalicylic acid>4-chlorosalicylic acid. Using epichlorohydrin as a binding agent, unfortunately, inhibits the bactericidal activity of the four bactericides. The FTIR study concludes that the reaction between salicylic acid as well as its derivatives with epichlorohydrin takes place through the phenolic group of the acids. The unexpected deterioration in the bactericidal properties of salicylic acid and its derivatives as a result of the treatment with epichlorohydrin could be due to the nature of interaction between the epichlorohydrin molecule and the acids molecules. PVP and PU show superior ability to sustain the four bactericides used even after 10 washing cycles. PMID:24076193

  3. Distillation of natural fatty acids and their chemical derivatives

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Well over 1,000 different fatty acids are known which are natural components of fats, oils (triacylglycerols), and other related compounds. These fatty acids can have different alkyl chain lengths, 0-6 carbon-carbon double bonds possessing cis- or trans-geometry, and can contain a variety of functio...

  4. Production and applications of carbohydrate-derived sugar acids as generic biobased chemicals.

    PubMed

    Mehtiö, Tuomas; Toivari, Mervi; Wiebe, Marilyn G; Harlin, Ali; Penttilä, Merja; Koivula, Anu

    2016-10-01

    This review considers the chemical and biotechnological synthesis of acids that are obtained by direct oxidation of mono- or oligosaccharide, referred to as sugar acids. It focuses on sugar acids which can be readily derived from plant biomass sources and their current and future applications. The three main classes of sugar acids are aldonic, aldaric and uronic acids. Interest in organic acids derived from sugars has recently increased, as part of the interest to develop biorefineries which produce not only biofuels, but also chemicals to replace those currently derived from petroleum. More than half of the most desirable biologically produced platform chemicals are organic acids. Currently, the only sugar acid with high commercial production is d-gluconic acid. However, other sugar acids such as d-glucaric and meso-galactaric acids are being produced at a lower scale. The sugar acids have application as sequestering agents and binders, corrosion inhibitors, biodegradable chelators for pharmaceuticals and pH regulators. There is also considerable interest in the use of these molecules in the production of synthetic polymers, including polyamides, polyesters and hydrogels. Further development of these sugar acids will lead to higher volume production of the appropriate sugar acids and will help support the next generation of biorefineries. PMID:26177333

  5. The nomenclature of 1-aminoalkylphosphonic acids and derivatives: evolution of the code system.

    PubMed

    Drabowicz, Józef; Jakubowski, Hieronim; Kudzin, Marcin H; Kudzin, Zbigniew H

    2015-01-01

    The approach for the unification of published proposals for the nomenclature and abbreviations of aminoalkylphosphonic acids and their derivatives is presented. Their modification was made on the basis of the IUPAC-IUB rules concerning the nomenclature and code system of proteinogenic amino acids. Our present proposal formulates the supplementary code and nomenclature system allowing unambiguous description of phosphonic analogs of proteinogenic amino acids, their analogs, homologs, metabolites, and derivatives including phosphonopeptides. PMID:25730210

  6. Penta- and hexadienoic acid derivatives: a novel series of 5-lipoxygenase inhibitors.

    PubMed

    Malleron, J L; Roussel, G; Gueremy, G; Ponsinet, G; Robin, J L; Terlain, B; Tissieres, J M

    1990-10-01

    The synthesis of a series of pentadienoic and hexadienoic acid derivatives is reported. These compounds were tested as inhibitors of 5-lipoxygenase (5 LO) and cyclooxygenase (CO) in vitro and as inhibitors of arachidonic acid (AA) induced ear edema in mice in vivo. Their potency is compared with that of the standard inhibitors nafazatrom, BW 755C, NDGA, KME4, quercetine, and L 652,243. The most potent compound in vivo, diethyl 2-hydroxy-5-(ethylthio)-2(Z),4(Z)-hexadienedioate (20) inhibited AA-induced ear edema when administered topically or orally, with an ED50 value of 0.01 mg/ear and 20 mg/kg, respectively. Among the standard compounds tested, L 652,243 was the most active compound in this test with an ED50 value of 0.01 mg/ear and 1 mg/kg po, but unlike this compound, 20 is a selective inhibitor of 5-LO (IC50 = 2 microM) without any significant activity against CO (IC50 greater than 50 microM). Most of the other compounds in this series are also selective 5-LO inhibitors. PMID:2213827

  7. Sophorolipid-derived unsaturated and epoxy fatty acid estolides as plasticizers for poly(3-hydroxybutyrate)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Unsaturated and epoxy fatty acid estolides were synthesized from the omega and omega-1 hydroxy fatty acids derived from sophorolipids (SLs) prepared by fermentation from glucose:soybean oil and glucose:oleic acid, respectively. These estolides were utilized as additives in solution-cast poly(3-hydro...

  8. Cinnamic Acid and Its Derivatives Inhibit Fructose-Mediated Protein Glycation

    PubMed Central

    Adisakwattana, Sirichai; Sompong, Weerachat; Meeprom, Aramsri; Ngamukote, Sathaporn; Yibchok-anun, Sirintorn

    2012-01-01

    Cinnamic acid and its derivatives have shown a variety of pharmacologic properties. However, little is known about the antiglycation properties of cinnamic acid and its derivatives. The present study sought to characterize the protein glycation inhibitory activity of cinnamic acid and its derivatives in a bovine serum albumin (BSA)/fructose system. The results demonstrated that cinnamic acid and its derivatives significantly inhibited the formation of advanced glycation end products (AGEs) by approximately 11.96–63.36% at a concentration of 1 mM. The strongest inhibitory activity against the formation of AGEs was shown by cinnamic acid. Furthermore, cinnamic acid and its derivatives reduced the level of fructosamine, the formation of Nɛ-(carboxymethyl) lysine (CML), and the level of amyloid cross β-structure. Cinnamic acid and its derivatives also prevented oxidative protein damages, including effects on protein carbonyl formation and thiol oxidation of BSA. Our findings may lead to the possibility of using cinnamic acid and its derivatives for preventing AGE-mediated diabetic complications. PMID:22408423

  9. Arginine- and Polyamine-Induced Lactic Acid Resistance in Neisseria gonorrhoeae.

    PubMed

    Gong, Zheng; Tang, M Matt; Wu, Xueliang; Phillips, Nancy; Galkowski, Dariusz; Jarvis, Gary A; Fan, Huizhou

    2016-01-01

    Microbe-derived lactic acid protects women from pathogens in their genital tract. The purpose of this study was to determine lactic acid susceptibility of Neisseria gonorrhoeae, and identify potential acid resistance mechanisms present in this pathogen. Tested in vitro, lactic acid killed all 10 gonococcal strains analyzed in a low pH-dependent manner. Full inactivation occurred at pH 4.5. At low pH, lactic acid treatment resulted in the entry of the DNA-binding fluorochrome propidium iodide into the microbial cells, suggesting that hydrogen ions from lactic acid compromise the integrity of the bacterial cell wall/membrane. Most likely, hydrogen ions also inactivate intracellular proteins since arginine rendered significant protection against lactic acid presumably through action of the gonococcal arginine decarboxylase, an enzyme located in the bacterial cytoplasm. Surprisingly, arginine also lessened lactic acid-mediated cell wall/membrane disruption. This effect is probably mediated by agmatine, a triamine product of arginine decarboxylase, since agmatine demonstrated a stronger protective effect on GC than arginine at equal molar concentration. In addition to agmatine, diamines cadaverine and putrescine, which are generated by bacterial vaginosis-associated microbes, also induced significant resistance to lactic acid-mediated GC killing and cell wall/membrane disruption. These findings suggest that the arginine-rich semen protects gonococci through both neutralization-dependent and independent mechanisms, whereas polyamine-induced acid resistance contributes to the increased risk of gonorrhea in women with bacterial vaginosis. PMID:26808268

  10. Arginine- and Polyamine-Induced Lactic Acid Resistance in Neisseria gonorrhoeae

    PubMed Central

    Gong, Zheng; Tang, M. Matt; Wu, Xueliang; Phillips, Nancy; Galkowski, Dariusz; Jarvis, Gary A.; Fan, Huizhou

    2016-01-01

    Microbe-derived lactic acid protects women from pathogens in their genital tract. The purpose of this study was to determine lactic acid susceptibility of Neisseria gonorrhoeae, and identify potential acid resistance mechanisms present in this pathogen. Tested in vitro, lactic acid killed all 10 gonococcal strains analyzed in a low pH-dependent manner. Full inactivation occurred at pH 4.5. At low pH, lactic acid treatment resulted in the entry of the DNA-binding fluorochrome propidium iodide into the microbial cells, suggesting that hydrogen ions from lactic acid compromise the integrity of the bacterial cell wall/membrane. Most likely, hydrogen ions also inactivate intracellular proteins since arginine rendered significant protection against lactic acid presumably through action of the gonococcal arginine decarboxylase, an enzyme located in the bacterial cytoplasm. Surprisingly, arginine also lessened lactic acid-mediated cell wall/membrane disruption. This effect is probably mediated by agmatine, a triamine product of arginine decarboxylase, since agmatine demonstrated a stronger protective effect on GC than arginine at equal molar concentration. In addition to agmatine, diamines cadaverine and putrescine, which are generated by bacterial vaginosis-associated microbes, also induced significant resistance to lactic acid-mediated GC killing and cell wall/membrane disruption. These findings suggest that the arginine-rich semen protects gonococci through both neutralization-dependent and independent mechanisms, whereas polyamine-induced acid resistance contributes to the increased risk of gonorrhea in women with bacterial vaginosis. PMID:26808268

  11. Antiparasitic activity of prenylated benzoic acid derivatives from Piper species.

    PubMed

    Flores, Ninoska; Jiménez, Ignacio A; Giménez, Alberto; Ruiz, Grace; Gutiérrez, David; Bourdy, Genevieve; Bazzocchi, Isabel L

    2009-03-01

    Fractionation of dichloromethane extracts from the leaves of Piper heterophyllum and P. aduncum afforded three prenylated hydroxybenzoic acids, 3-[(2E,6E,10E)-11-carboxy-3,7,15-trimethyl-2,6,10,14-hexadecatetraenyl)-4,5-dihydroxybenzoic acid, 3-[(2E,6E,10E)-11-carboxy-13-hydroxy-3,7,15-trimethyl-2,6,10,14-hexadecatetraenyl]-4,5-dihydroxybenzoic acid and 3-[(2E,6E,10E)-11-carboxy-14-hydroxy-3,7,15-trimethyl-2,6,10,15-hexadecatetraenyl]-4,5-dihydroxybenzoic acid, along with the known compounds, 4,5-dihydroxy-3-(E,E,E-11-formyl-3,7,15-trimethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid (arieianal), 3,4-dihydroxy-5-(E,E,E-3,7,11,15-tetramethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid, 4-hydroxy-3-(E,E,E-3,7,11,15-tetramethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid, 3-(3,7-dimethyl-2,6-octadienyl)-4-methoxy-benzoic acid, 4-hydroxy-3-(3,7-dimethyl-2,6-octadienyl)benzoic acid and 4-hydroxy-3-(3-methyl-1-oxo-2-butenyl)-5-(3-methyl-2-butenyl)benzoic acid. Their structures were elucidated on the basis of spectroscopic data, including homo- and heteronuclear correlation NMR experiments (COSY, HSQC and HMBC) and comparison with data reported in the literature. Riguera ester reactions and optical rotation measurements established the compounds as racemates. The antiparasitic activity of the compounds were tested against three strains of Leishmania spp., Trypanosoma cruzi and Plasmodium falciparum. The results showed that 3-(3,7-dimethyl-2,6-octadienyl)-4-methoxy-benzoic acid exhibited potent and selective activity against L. braziliensis (IC(50) 6.5 microg/ml), higher that pentamidine used as control. Moreover, 3-[(2E,6E,10E)-11-carboxy-3,7,15-trimethyl- 2,6,10,14-hexadecatetraenyl)-4,5-dihydroxybenzoic acid and 4-hydroxy-3-(3-methyl-1-oxo-2-butenyl)-5-(3-methyl-2-butenyl)benzoic acid showed moderate antiplasmodial (IC(50) 3.2 microg/ml) and trypanocidal (16.5 microg/ml) activities, respectively. PMID:19361822

  12. Human placenta-derived adherent cells induce tolerogenic immune responses.

    PubMed

    Liu, Wei; Morschauser, Andrew; Zhang, Xin; Lu, Xiaohua; Gleason, Joseph; He, Shuyang; Chen, Hong-Jung; Jankovic, Vladimir; Ye, Qian; Labazzo, Kristen; Herzberg, Uri; Albert, Vivian R; Abbot, Stewart E; Liang, Bitao; Hariri, Robert

    2014-05-01

    Human placenta-derived adherent cells (PDAC cells) are a culture expanded, undifferentiated mesenchymal-like population derived from full-term placental tissue, with immunomodulatory and anti-inflammatory properties. PDA-001 (cenplacel-L), an intravenous formulation of PDAC cells, is in clinical development for the treatment of autoimmune and inflammatory diseases. To elucidate the mechanisms underlying the immunoregulatory properties of PDAC cells, we investigated their effects on immune cell populations, including T cells and dendritic cells (DC) in vitro and in vivo. PDAC cells suppressed T-cell proliferation in an OT-II T-cell adoptive transfer model, reduced the severity of myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis and ameliorated inflammation in a delayed type hypersensitivity response model. In vitro, PDAC cells suppressed T-cell proliferation and inhibited Th1 and Th17 differentiation. Analysis of tissues derived from PDAC cell-treated animals revealed diminished CD86 expression on splenic DC, suggesting that they can also modulate DC populations. Furthermore, PDAC cells modulate the differentiation and maturation of mouse bone marrow-derived DC. Similarly, human DC differentiated from CD14(+) monocytes in the presence of PDAC cells acquired a tolerogenic phenotype. These tolerogenic DC failed to induce allogeneic T-cell proliferation and differentiation toward Th1, but skewed T-cell differentiation toward Th2. Inhibition of cyclo-oxygenase-2 activity resulted in a significant, but not complete, abrogation of PDAC cells' effects on DC phenotype and function, implying a role for prostaglandin E2 in PDAC-mediated immunomodulation. This study identifies modulation of DC differentiation toward immune tolerance as a key mechanism underlying the immunomodulatory activities of PDAC cells. PMID:25505962

  13. Synthesis, Activity, and Docking Study of Novel Phenylthiazole-Carboxamido Acid Derivatives as FFA2 Agonists.

    PubMed

    Ma, Liang; Wang, Taijin; Shi, Min; Fu, Ping; Pei, Heying; Ye, Haoyu

    2016-07-01

    Free fatty acid receptor 2 (FFA2), also known as GPR43, is activated by short-chain fatty acids (SCFAs) that are mainly produced by the gut microbiota through the fermentation of undigested carbohydrates and dietary fibers. FFA2 currently appears to be a potential target in the management of obesity, diabetes, inflammatory diseases, and cancer. In the study, a series of novel phenylthiazole-carboxamido acid derivatives has been synthesized and evaluated as potential orthosteric FFA2 ligands for the study of structure-activity relationships. Compound 6e was found to exhibit the twofold potent agonistic activity in the stable hFFA2-transfected CHO-K1 cells (EC50 = 23.1 μm) as that of positive control propionate (EC50 = 43.3 μm). We also reported the results of mutagenesis studies based on the crystal structure of hFFA1 bound to TAK-875 at 2.3 Å resolution to identify important residues for orthosteric agonist 6e inducing FFA2 activation. PMID:26808470

  14. Reactions and reactivity of myeloperoxidase-derived oxidants: differential biological effects of hypochlorous and hypothiocyanous acids.

    PubMed

    Pattison, David I; Davies, Michael J; Hawkins, Clare L

    2012-08-01

    Myeloperoxidase (MPO) is recognised to play important roles both in the immune system and during the development of numerous human pathologies. MPO is released by activated neutrophils, monocytes and some tissue macrophages, where it catalyses the conversion of hydrogen peroxide to hypohalous acids (HOX; X = Cl, Br, SCN) in the presence of halide and pseudo-halide ions. The major reactive species produced by MPO under physiological conditions are hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN), with the ratio of these oxidants critically dependent on the concentration of thiocyanate ions (SCN⁻). The reactivity and selectivity of HOCl and HOSCN for biological targets are markedly different, indicating that SCN⁻ ions have the potential to modulate both the extent and nature of oxidative damage in vivo. This article reviews recent developments in our understanding of the role of SCN⁻ in modulating the formation of MPO-derived oxidants, particularly in respect to the differences in reaction kinetics and targets of HOCl compared to HOSCN and the ability of these two oxidants to induce damage in biological systems. PMID:22348603

  15. Protective effects of a dimeric derivative of ferulic acid in animal models of Alzheimer's disease.

    PubMed

    Jung, Jun-Sub; Yan, Ji-Jing; Li, Hong-Mei; Sultan, Md Tipu; Yu, Jaehoon; Lee, Hee-Sul; Shin, Kye-Jung; Song, Dong-Keun

    2016-07-01

    Ferulic acid is a compound with potent anti-oxidant and anti-inflammatory activities. We previously reported the protective effects of ferulic acid administration against two animal models of Alzheimer's disease (AD): intracerebroventricular (i.c.v.) injection of Aß1-42 in mice and APP/PS1 mutant transgenic mice. In this study using the same AD animal models, we examined the effect of KMS4001, one of dimeric derivatives of ferulic acid. Intragastric pretreatment of mice with KMS4001 (30mg/kg/day) for 5 days significantly attenuated the Aß1-42 (i.c.v.)-induced memory impairment both in passive avoidance test and in Y-maze test. APP/PS1 mutant transgenic mice at KMS4001 doses of 3 and 30mg/kg/day via drinking water showed the significantly enhanced novel-object recognition memory at both 1.5 and 3 months after the start of KMS4001 treatment. Treatment of APP/PS1 mutant transgenic mice with KMS4001 for 3 months at the doses of 3 and 30mg/kg/day markedly decreased Aβ1-40 and Aβ1-42 levels in the frontal cortex. The KMS4001 dose-response relationships for Aβ decrease and for improvement in novel-object recognition test corresponded to each other. Taken together, these results suggest that KMS4001 could be an effective drug candidate against AD. PMID:27118174

  16. Betulinic acid derived hydroxamates and betulin derived carbamates are interesting scaffolds for the synthesis of novel cytotoxic compounds.

    PubMed

    Wiemann, Jana; Heller, Lucie; Perl, Vincent; Kluge, Ralph; Ströhl, Dieter; Csuk, René

    2015-12-01

    The betulinic acid-derived hydroxamates 5-18, the amides 19-24, and betulin-derived bis-carbamates 25-28 as well as the carbamates 31-40 and 44-48 were prepared and evaluated for their antiproliferative activity in a photometric sulforhodamine B (SRB) assay against several human cancer cell lines and nonmalignant mouse fibroblasts (NIH 3T3). While for 3-O-acetyl hydroxamic acid 5 EC50 values as low as EC50 = 1.3 μM were found, N,O-bis-alkyl substituted hydroxamates showed lowered cytotoxicity (EC50 = 16-20 μM). In general, hydroxamic acid derivatives showed only reduced selectivity for tumor cells, except for allyl substituted compound 13 (EC50 = 5.9 μM for A2780 human ovarian carcinoma cells and EC50 > 30 μM for nonmalignant mouse fibroblasts). The cytotoxicity of betulinic acid derived amides 19-24 and of betulin derived bis-carbamates 25-28 was low, except for N-ethyl substituted 25. Hexyl substituted 39 showed EC50 = 5.6 μM (518A2 cells) while for mouse fibroblasts EC50 > 30 was determined. PMID:26547057

  17. Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis

    SciTech Connect

    Woolbright, Benjamin L.; Dorko, Kenneth; Antoine, Daniel J.; Clarke, Joanna I.; Gholami, Parviz; Li, Feng; Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson; Fan, Fang; Jenkins, Rosalind E.; Park, B. Kevin; Hagenbuch, Bruno; Olyaee, Mojtaba; Jaeschke, Hartmut

    2015-03-15

    Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box 1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models. - Highlights: • Cholestatic liver injury is due to cytoplasmic bile acid accumulation in hepatocytes. • Primary human hepatocytes are resistant to BA-induced injury

  18. Synthesis and evaluation of asiatic acid derivatives as anti-fibrotic agents: structure/activity studies.

    PubMed

    Li, Yong; Yang, Fang; Yuan, Mingxing; Jiang, Lijuan; Yuan, Li; Zhang, Xiaowei; Li, Ying; Dong, Lin; Bao, Xu; Yin, Shufan

    2015-04-01

    Fibrotic diseases are characterized by the over-accumulation of fibrous components in the extracellular matrix and the liver, which can lead to liver cirrhosis. Current treatment options cannot reverse or halt liver fibrosis, motivating a search for newer treatment options. Previously, we showed that asiaticoside, a bioactive triterpene glycoside from Centella asiatica, has anti-fibrotic properties. Here, the aglycone asiatic acid was chemically modified, and these derivatives were evaluated for their potential as anti-fibrotic agents. The data obtained from in vivo testing of these compounds in a rodent CCl4-induced liver injury model are discussed. The information obtained from these studies may be useful in the design of novel anti-fibrotic agents. PMID:25461275

  19. Eicosanoids Derived From Arachidonic Acid and Their Family Prostaglandins and Cyclooxygenase in Psychiatric Disorders

    PubMed Central

    Yui, Kunio; Imataka, George; Nakamura, Hiroyuki; Ohara, Naoki; Naito, Yukiko

    2015-01-01

    Arachidonic acid (AA)-derived lipid mediators are called eicosanoids. Eicosanoids have emerged as key regulators of a wide variety of physiological responses and pathological processes, and control important cellular processes. AA can be converted into biologically active compounds by metabolism by cyclooxygenases (COX). Beneficial effect of COX-2 inhibitor celecoxib add-on therapy has been reported in early stage of schizophrenia. Moreover, add-on treatment of celecoxib attenuated refractory depression and bipolar depression. Further, the COX/prostaglandin E pathway play an important role in synaptic plasticity and may be included in pathophysiology in autism spectrum disorders (ASD). In this regard, plasma transferrin, which is an iron mediator related to eicosanoid signaling, may be related to social impairment of ASD. COX-2 is typically induced by inflammatory stimuli in the majority of tissues, and the only isoform responsible for propagating the inflammatory response. Thus, COX-2 inhibitors considered as the best target for Alzheimer’s disease. PMID:26521945

  20. The effect of short-chain fatty acids on human monocyte-derived dendritic cells.

    PubMed

    Nastasi, Claudia; Candela, Marco; Bonefeld, Charlotte Menné; Geisler, Carsten; Hansen, Morten; Krejsgaard, Thorbjørn; Biagi, Elena; Andersen, Mads Hald; Brigidi, Patrizia; Ødum, Niels; Litman, Thomas; Woetmann, Anders

    2015-01-01

    The gut microbiota is essential for human health and plays an important role in the pathogenesis of several diseases. Short-chain fatty acids (SCFA), such as acetate, butyrate and propionate, are end-products of microbial fermentation of macronutrients that distribute systemically via the blood. The aim of this study was to investigate the transcriptional response of immature and LPS-matured human monocyte-derived DC to SCFA. Our data revealed distinct effects exerted by each individual SCFA on gene expression in human monocyte-derived DC, especially in the mature ones. Acetate only exerted negligible effects, while both butyrate and propionate strongly modulated gene expression in both immature and mature human monocyte-derived DC. An Ingenuity pathway analysis based on the differentially expressed genes suggested that propionate and butyrate modulate leukocyte trafficking, as SCFA strongly reduced the release of several pro-inflammatory chemokines including CCL3, CCL4, CCL5, CXCL9, CXCL10, and CXCL11. Additionally, butyrate and propionate inhibited the expression of lipopolysaccharide (LPS)-induced cytokines such as IL-6 and IL-12p40 showing a strong anti-inflammatory effect. This work illustrates that bacterial metabolites far from the site of their production can differentially modulate the inflammatory response and generally provides new insights into host-microbiome interactions. PMID:26541096

  1. Chemical Synthesis of Uncommon Natural Bile Acids: The 9α-Hydroxy Derivatives of Chenodeoxycholic and Lithocholic Acids.

    PubMed

    Iida, Takashi; Namegawa, Kazunari; Nakane, Naoya; Iida, Kyoko; Hofmann, Alan Frederick; Omura, Kaoru

    2016-09-01

    The chemical synthesis of the 9α-hydroxy derivatives of chenodeoxycholic and lithocholic acids is reported. For initiating the synthesis of the 9α-hydroxy derivative of chenodeoxycholic acid, cholic acid was used; for the synthesis of the 9α-hydroxy derivative of lithocholic acid, deoxycholic acid was used. The principal reactions involved were (1) decarbonylation of conjugated 12-oxo-Δ(9(11))-derivatives using in situ generated monochloroalane (AlH2Cl) prepared from LiAlH4 and AlCl3, (2) epoxidation of the deoxygenated Δ(9(11))-enes using m-chloroperbenzoic acid catalyzed by 4,4'-thiobis-(6-tert-butyl-3-methylphenol), (3) subsequent Markovnikov 9α-hydroxylation of the Δ(9(11))-enes with AlH2Cl, and (4) selective oxidation of the primary hydroxyl group at C-24 in the resulting 3α,9α,24-triol and 3α,7α,9α,24-tetrol to the corresponding C-24 carboxylic acids using sodium chlorite (NaClO2) in the presence of a catalytic amount of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO) and sodium hypochlorite (NaOCl). The (1)H- and (13)C-NMR spectra are reported. The 3α,7α,9α-trihydroxy-5β-cholan-24-oic acid has been reported to be present in the bile of the Asian bear, and its 7-deoxy derivative is likely to be a bacterial metabolite. These bile acids are now available as authentic reference standards, permitting their identification in vertebrate bile acids. PMID:27319285

  2. Lysophosphatidic acid induces osteocyte dendrite outgrowth

    SciTech Connect

    Karagiosis, Sue A.; Karin, Norm J.

    2007-05-25

    A method was developed to measure dendrite formation in bone cells. Lysophosphatidic acid (LPA) was found to stimulate dendrite outgrowth. It is postulated that LPA plays a role in regulating the osteocyte network in vivo.

  3. Trophoblast lineage cells derived from human induced pluripotent stem cells

    SciTech Connect

    Chen, Ying; Wang, Kai; Chandramouli, Gadisetti V.R.; Knott, Jason G.; Leach, Richard

    2013-07-12

    Highlights: •Epithelial-like phenotype of trophoblast lineage cells derived from human iPS cells. •Trophoblast lineage cells derived from human iPS cells exhibit trophoblast function. •Trophoblasts from iPS cells provides a proof-of-concept in regenerative medicine. -- Abstract: Background: During implantation, the blastocyst trophectoderm attaches to the endometrial epithelium and continues to differentiate into all trophoblast subtypes, which are the major components of a placenta. Aberrant trophoblast proliferation and differentiation are associated with placental diseases. However, due to ethical and practical issues, there is almost no available cell or tissue source to study the molecular mechanism of human trophoblast differentiation, which further becomes a barrier to the study of the pathogenesis of trophoblast-associated diseases of pregnancy. In this study, our goal was to generate a proof-of-concept model for deriving trophoblast lineage cells from induced pluripotency stem (iPS) cells from human fibroblasts. In future studies the generation of trophoblast lineage cells from iPS cells established from patient’s placenta will be extremely useful for studying the pathogenesis of individual trophoblast-associated diseases and for drug testing. Methods and results: Combining iPS cell technology with BMP4 induction, we derived trophoblast lineage cells from human iPS cells. The gene expression profile of these trophoblast lineage cells was distinct from fibroblasts and iPS cells. These cells expressed markers of human trophoblasts. Furthermore, when these cells were differentiated they exhibited invasive capacity and placental hormone secretive capacity, suggesting extravillous trophoblasts and syncytiotrophoblasts. Conclusion: Trophoblast lineage cells can be successfully derived from human iPS cells, which provide a proof-of-concept tool to recapitulate pathogenesis of patient placental trophoblasts in vitro.

  4. Acid fog-induced bronchoconstriction. The role of hydroxymethanesulfonic acid

    SciTech Connect

    Aris, R.; Christian, D.; Sheppard, D.; Balmes, J.R. )

    1990-03-01

    Hydroxymethanesulfonate (HMSA), the bisulfite (HSO3-) adduct of formaldehyde (CH2O), is a common constituent of California acid fogs. HMSA, most stable in a fog pH range of 3 to 5, dissociates at 6.6, the pH of the fluid lining human airways. The dissociation of inhaled HMSA should theoretically generate sulfur dioxide and CH2O, both of which have bronchoconstrictor potential. Thus, we hypothesized that HMSA may have a specific bronchoconstrictor effect independent of its strength as an acid. To determine whether HMSA has such an effect, 19 subjects with mild to moderate asthma were studied using two different protocols. Initially, a mouthpiece study was performed in which 9 subjects, on 2 separate days, inhaled five aerosols containing either sequentially increasing concentrations (0, 30, 100, 300, and 1000 microM) of HMSA in 50 microM sulfuric acid (H2SO4) or 50 microM H2SO4 alone. The subjects inhaled each aerosol for 3 min during tidal breathing at rest. Specific airway resistance (SRaw) was measured before and after each 3-min exposure. There were no significant differences in the mean changes in SRaw among the various aerosol exposures. To confirm this lack of bronchoconstrictor effect of HMSA, we then performed a chamber study in which 10 freely breathing, intermittently exercising subjects were exposed to fog containing either 1 mM HMSA in 5 mM H2SO4 or 5 mM H2SO4 alone for 1 h. SRaw was measured before, during, and at the end of the 1-h exposure.

  5. Synthesis of α-santonin derived acetyl santonous acid triazole derivatives and their bioevaluation for T and B-cell proliferation.

    PubMed

    Dangroo, Nisar A; Singh, Jasvinder; Dar, Alamgir A; Gupta, Nidhi; Chinthakindi, Praveen K; Kaul, Anpurna; Khuroo, Mohmmed A; Sangwan, Payare L

    2016-09-14

    A new series of α-santonin derived acetyl santonous acid 1,2,3-triazole derivatives were synthesised using Huisgen 1,3-dipolar cyclo-addition reaction (click chemistry approach) and evaluated for their in vitro inhibition activity on concanavalin A (ConA) induced T cell proliferation and lipopolysaccharide (LPS) induced B cell proliferation. Among the synthesised series, compounds 2-10 and 19 exhibited significant inhibition against ConA and LPS stimulated T-cell and B-cell proliferation in a dose dependent manner. More significantly compounds 4, 9-10 and 19 exhibited potent inhibition activity with remarkably lower cytotoxicity on the mitogen-induced T cell and B cell proliferation at 1 μM concentration. The compound 6 displayed potent immunosuppressive effects with ∼89% against LPS induced B-cell and ∼83% against ConA stimulated T-cell proliferation at 100 μM concentration without cytotoxicity. Compound 10 was more selective against B cell proliferation and exhibited 81% and 69% suppression at 100 and 1 μM concentration respectively. The present study led to the identification of several santonin analogs with reduced cytotoxicity and strong inhibition activity against the cell proliferation induced by the mitogens. PMID:27191613

  6. Establishment of Hairy Root Cultures of Rhaponticum carthamoides (Willd.) Iljin for the Production of Biomass and Caffeic Acid Derivatives

    PubMed Central

    Skała, Ewa; Kicel, Agnieszka; Olszewska, Monika A.; Kiss, Anna K.

    2015-01-01

    The aim of the study was to obtain transformed roots of Rhaponticum carthamoides and evaluate their phytochemical profile. Hairy roots were induced from leaf explants by the transformation of Agrobacterium rhizogenes strains A4 and ATCC 15834. The best response (43%) was achieved by infection with A4 strain. The effects of different liquid media (WPM, B5, SH) with full and half-strength concentrations of macro- and micronutrients on biomass accumulation of the best grown hairy root line (RC3) at two different lighting conditions (light or dark) were investigated. The highest biomass (93 g L−1 of the fresh weight after 35 days) was obtained in WPM medium under periodic light. UPLC-PDA-ESI-MS3 and HPLC-PDA analyses of 80% aqueous methanol extracts from the obtained hairy roots revealed the presence of eleven caffeoylquinic acids and their derivatives and five flavonoid glycosides. The production of caffeoylquinic acids and their derivatives was elevated in hairy roots grown in the light. Only light-grown hairy roots demonstrated the capability for the biosynthesis of such flavonoid glycosides as quercetagetin, quercetin, luteolin, and patuletin hexosides. Chlorogenic acid, 3,5-di-O-caffeoylquinic acid and a tentatively identified tricaffeoylquinic acid derivative were detected as the major compounds present in the transformed roots. PMID:25811023

  7. Farnesol-derived dicarboxylic acids in the urine of animals treated with zaragozic acid A or with farnesol.

    PubMed

    Bostedor, R G; Karkas, J D; Arison, B H; Bansal, V S; Vaidya, S; Germershausen, J I; Kurtz, M M; Bergstrom, J D

    1997-04-01

    Farnesyl diphosphate, the substrate for squalene synthase, accumulates in the presence of zaragozic acid A, a squalene synthase inhibitor. A possible metabolic fate for farnesyl diphosphate is its conversion to farnesol, then to farnesoic acid, and finally to farnesol-derived dicarboxylic acids (FDDCAs) which would then be excreted in the urine. Seven dicarboxylic acids were isolated by high performance liquid chromatography (HPLC) from urine of either rats or dogs treated with zaragozic acid A or rats fed farnesol. Their structures were determined by nuclear magnetic resonance analysis. Two 12-carbon, four 10-carbon, and one 7-carbon FDDCA were identified. The profile of urinary dicarboxylic acids from rats fed farnesol was virtually identical to that produced by treating with zaragozic acid A, establishing that these dicarboxylic acids are farnesol-derived. By feeding [1-14C]farnesol and comparing the mass of the dicarboxylic acids produced with the ultraviolet absorption of the HPLC peaks, a method to quantitate the ultraviolet-absorbing FDDCAs was devised. When rats were treated with zaragozic acid A, large amounts of FDDCAs were excreted in the urine. The high level of FDDCAs that were found suggests that their synthesis is the major metabolic fate for carbon diverted from cholesterol synthesis by a squalene synthase inhibitor. A metabolic pathway is proposed to explain the production of each of these FDDCAs. PMID:9083051

  8. Unsaturated amino acids derived from isoleucine trigger early membrane effects on plant cells.

    PubMed

    Roblin, Gabriel; Laduranty, Joëlle; Bonmort, Janine; Aidene, Mohand; Chollet, Jean-François

    2016-10-01

    Unsaturated amino acids (UnsAA) have been shown to affect the activity of various biological processes. However, their mode of action has been investigated poorly thus far. We show in this work that 2-amino-3-methyl-4-pentenoic acid (C2) and 2-amino-3-methyl-4-pentynoic acid (C3) structurally derived from isoleucine (Ile) exhibited a multisite action on plant cells. For one, C2 and C3 induced early modifications at the plasma membrane level, as shown by the hyperpolarization monitored by microelectrode implantation in the pulvinar cells of Mimosa pudica, indicating that these compounds are able to modify ionic fluxes. In particular, proton (H(+)) fluxes were modified, as shown by the pH rise monitored in the bathing medium of pulvinar tissues. A component of this effect may be linked to the inhibitory effect observed on the proton pumping and the vanadate-sensitive activity of the plasma membrane H(+)-ATPase monitored in plasma membrane vesicles (PMVs) purified from pulvinar tissues of M. pudica and leaf tissues of Beta vulgaris. This effect may explain, in part, the inhibitory effect of the compounds on the uptake capacity of sucrose and valine by B. vulgaris leaf tissues. In contrast, an unexpected action was observed in cell reactions, implicating ion fluxes and water movement. Indeed, the osmocontractile reactions of pulvini induced either by a mechanical shock in M. pudica or by dark and light signals in Cassia fasciculata were increased, indicating that, compared to Ile, these compounds may modify in a specific way the plasma membrane permeability to water and ions. PMID:27254795

  9. Novel biomarkers of the metabolism of caffeic acid derivatives in vivo.

    PubMed

    Rechner, A R; Spencer, J P; Kuhnle, G; Hahn, U; Rice-Evans, C A

    2001-06-01

    The purpose of this study was to investigate biomarkers of the bioavailability and metabolism of hydroxycinnamate derivatives through the determination of the pharmacokinetics of their urinary elimination and identification of the metabolites excreted. Coffee was used as a rich source of caffeic acid derivatives and human supplementation was undertaken. The results show a highly significant increase in the excretion of ferulic, isoferulic, dihydroferulic acid (3-(4-hydroxy-3-methoxyphenyl)-propionic acid), and vanillic acid postsupplementation relative to the levels presupplementation. Thus, ferulic, isoferulic, and dihydroferulic acids are specific biomarkers for the bioavailability and metabolism of dietary caffeic acid esters. Isoferulic acid is a unique biomarker as it is not a dietary component, however, dihydroferulic acid may well derive from other flavonoids with a structurally related B-ring. 3-Hydroxyhippuric acid has also been identified as an indicator for bioavailability and metabolism of phenolic compounds, and shows a highly significant excretion increase postsupplementation. The results reveal isoferulic acid (and possibly dihydroferulic acid) as novel markers of caffeoyl quinic acid metabolism. PMID:11368919

  10. [Phenolic acid derivatives from Bauhinia glauca subsp. pernervosa].

    PubMed

    Zhao, Qiao-Li; Wu, Zeng-Bao; Zheng, Zhi-Hui; Lu, Xin-Hua; Liang, Hong; Cheng, Wei; Zhang, Qing-Ying; Zhao, Yu-Ying

    2011-08-01

    To study the chemical constituents of Bauhinia glauca subsp. pernervosa, eleven phenolic acids were isolated from a 95% ethanol extract by using a combination of various chromatographic techniques including column chromatography over silica gel, ODS, MCI, Sephadex LH-20, and semi-preparative HPLC. By spectroscopic techniques including 1H NMR, 13C NMR, 2D NMR, and HR-ESI-MS, these compounds were identified as isopropyl O-beta-(6'-O-galloyl)-glucopyranoside (1), ethyl O-beta-(6'-O-galloyl)-glucopyranoside (2), 3, 4, 5-trimethoxyphenyl-(6'-O-galloyl)-O-beta-D-glucopyranoside (3), 3, 4, 5-trimethoxyphenyl-beta-D-glucopyranoside (4), gallic acid (5), methyl gallate (6), ethyl gallate (7), protocatechuic acid (8), 3, 5-dimethoxy-4-hydroxybenzoic acid (9), erigeside C (10) and glucosyringic acid (11). Among them, compound 1 is a new polyhydroxyl compound; compounds 2, 10, and 11 were isolated from the genus Bauhinia for the first time, and the other compounds were isolated from the plant for the first time. Compounds 6 and 8 showed significant protein tyrosine phosphatase1B (PTP1B) inhibitory activity in vitro with the IC50 values of 72.3 and 54.1 micromol x L(-1), respectively. PMID:22007520

  11. Perflurooctanoic Acid Induces Developmental Cardiotoxicity in Chicken Embryos and Hatchlings

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA) is a widespread environmental contaminant that is detectable in serum of the general U.S. population. PFOA is a known developmental toxicant that induces mortality in mammalian embryos and is thought to induce toxicity via interaction with the peroxi...

  12. Folic acid and pantothenic acid protection against valproic acid-induced neural tube defects in CD-1 mice

    SciTech Connect

    Dawson, Jennifer E.; Raymond, Angela M.; Winn, Louise M. . E-mail: winnl@biology.queensu.ca

    2006-03-01

    In utero exposure to valproic acid (VPA) during pregnancy is associated with an increased risk of neural tube defects (NTDs). Although the mechanism by which VPA mediates these effects is unknown, VPA-initiated changes in embryonic protein levels have been implicated. The objectives of this study were to investigate the effect of in utero VPA exposure on embryonic protein levels of p53, NF-{kappa}B, Pim-1, c-Myb, Bax, and Bcl-2 in the CD-1 mouse. We also evaluated the protective effects of folic acid and pantothenic acid on VPA-induced NTDs and VPA-induced embryonic protein changes in this model. Pregnant CD-1 mice were administered a teratogenic dose of VPA prior to neural tube closure and embryonic protein levels were analyzed. In our study, VPA (400 mg/kg)-induced NTDs (24%) and VPA-exposed embryos with an NTD showed a 2-fold increase in p53, and 4-fold decreases in NF-{kappa}B, Pim-1, and c-Myb protein levels compared to their phenotypically normal littermates (P < 0.05). Additionally, VPA increased the ratio of embryonic Bax/Bcl-2 protein levels (P < 0.05). Pretreatment of pregnant dams with either folic acid or pantothenic acid prior to VPA significantly protected against VPA-induced NTDs (P < 0.05). Folic acid also reduced VPA-induced alterations in p53, NF-{kappa}B, Pim-1, c-Myb, and Bax/Bcl-2 protein levels, while pantothenic acid prevented VPA-induced alterations in NF-{kappa}B, Pim-1, and c-Myb. We hypothesize that folic acid and pantothenic acid protect CD-1 embryos from VPA-induced NTDs by independent, but not mutually exclusive mechanisms, both of which may be mediated by the prevention of VPA-induced alterations in proteins involved in neurulation.

  13. Development of nitrilase promoter-derived inducible vectors for Streptomyces.

    PubMed

    Matsumoto, Masako; Hashimoto, Yoshiteru; Saitoh, Yuki; Kumano, Takuto; Kobayashi, Michihiko

    2016-06-01

    An inducible expression vector, pSH19, which harbors regulatory expression system PnitA-NitR, for streptomycetes was constructed previously. Here, we have modified pSH19 to obtain shuttle vectors for Streptomyces-E. coli by introducing the replication origin of a plasmid for E. coli (ColE1) and an antibiotic-resistant gene. Six inducible shuttle vectors, pESH19cF, pESH19cR, pESH19kF, pESH19kR, pESH19aF, and pESH19aR, for Streptomyces-E. coli, were successfully developed. The stability of these vectors was examined in five different E. coli strains and Streptomyces lividans TK24. The stability test showed that the pSH19-derived shuttle vectors were stable in E. coli Stbl2 and S. lividans TK24. Heterologous expression experiments involving each of the catechol 2,3-dioxygenase, nitrilase, and N-substituted formamide deformylase genes as a reporter gene showed that pESH19cF, pESH19kF, and pESH19aF possess inducible expression ability in S. lividans TK24. Thus, these vectors were found to be useful expression tools for experiments on both Gram-negative and Gram-positive bacterial genes. PMID:26923287

  14. Synthesis and antimycobacterial evaluation of new trans-cinnamic acid hydrazide derivatives.

    PubMed

    Carvalho, Samir A; da Silva, Edson F; de Souza, Marcus V N; Lourenço, Maria C S; Vicente, Felipe R

    2008-01-15

    In this work, we report the synthesis and the antimycobacterial evaluation of new trans-cinnamic acid derivatives of isonicotinic acid series (5) and benzoic acid series (6), designed by exploring the molecular hybridization approach between isoniazid (1) and trans-cinnamic acid derivative (3). The minimum inhibitory concentration (MIC) of the compounds 5a-d and 6c exhibited activity between 3.12 and 12.5 microg/mL and could be a good start point to find new lead compounds against multi-drug resistant tuberculosis. PMID:18068364

  15. Lactic acid as an invaluable green solvent for ultrasound-assisted scalable synthesis of pyrrole derivatives.

    PubMed

    Wang, Shi-Fan; Guo, Chao-Lun; Cui, Ke-ke; Zhu, Yan-Ting; Ding, Jun-Xiong; Zou, Xin-Yue; Li, Yi-Hang

    2015-09-01

    Lactic acid has been used as a bio-based green solvent to study the ultrasound-assisted scale-up synthesis. We report here, for the first time, on the novel and scalable process for synthesis of pyrrole derivatives in lactic acid solvent under ultrasonic radiation. Eighteen pyrrole derivatives have been synthesized in lactic acid solvent under ultrasonic radiation and characterized by (1)H NMR, IR, ESI MS. The results show, under ultrasonic radiation, lactic acid solvent can overcome the scale-up challenges and exhibited many advantages, such as bio-based origin, shorter reaction time, lower volatility, higher yields, and ease of isolating the products. PMID:25605585

  16. Collision induced dissociation of alpha hydroxy acids

    NASA Astrophysics Data System (ADS)

    Bandu, Mary L.; Grubbs, Thomas; Kater, Marcus; Desaire, Heather

    2006-03-01

    Alpha hydroxy acids typically dissociate in tandem mass spectrometric experiments to produce product ions representing a neutral loss of 46 Da (CH2O2) in negative ion mode. Although it is widely accepted that the carboxylate group is lost in the dissociation process, the origin of the remaining two hydrogens is unclear. The current study utilizes an alpha hydroxy acid chemical library and deuterium labeling experiments to identify the origin of the two hydrogens lost during dissociation. Secondly, this study investigates the lower m/z region of the CID spectrum, a region previously unexplored, to aid in characterizing the dissociation mechanism. Further experiments testing the energy requirements and time parameters of the dissociation also are consistent with criteria previously defined for ion-neutral complex formation. In addition to describing the mechanism for the loss of CH2O2, we have conducted experiments that demonstrate the important chemical features of molecules that can prevent alpha hydroxy acids from undergoing the loss of 46 Da. By understanding the chemical composition of the 46 Da loss, the dissociation mechanism responsible for the loss, and the factors that hinder this mechanistic pathway, chemical information about alpha hydroxy acids can be obtained from their CID data.

  17. Superoxide dismutase derivative prevents oxidative damage in liver and kidney of rats induced by exhausting exercise.

    PubMed

    Radák, Z; Asano, K; Inoue, M; Kizaki, T; Oh-Ishi, S; Suzuki, K; Taniguchi, N; Ohno, H

    1996-01-01

    To prevent oxidative tissue damage induced by strenuous exercise in the liver and kidney superoxide dismutase derivative (SM-SOD), which circulated bound to albumin with a half-life of 6 h, was injected intraperitoneally into rats. Exhausting treadmill running caused a significant increase in the activities of xanthine oxidase (XO), and glutathione peroxidase (GPX) in addition to concentrations of thiobarbituric acid-reactive substances (TBARS) in hepatic tissue immediately after running. There was a definite increase in the immunoreactive content of mitochondrial superoxide dismutase (Mn-SOD) 1 day after the running. Meanwhile, the TBARS concentration in the kidney was markedly elevated 3 days after running. The activities of GPX, and catalase in the kidney increased significantly immediately and on days 1 and 3 following the test. The immunoreactive content of Mn-SOD also increased 1 day after running. The exercise induced no significant changes in immunoreactive Cu, Zn-SOD content in either tissue. The administration of SM-SOD provided effective protection against lipid peroxidation, and significantly attenuated the alterations in XO and all the anti-oxidant enzymes, measured. In summary, the present data would suggest that exhausting exercise may induce XO-derived oxidative damage in the liver, while the increase in lipid peroxidation in the kidney might be the result of washout-dependent accumulation of peroxidised metabolites. We found that the administration of SM-SOD provided excellent protection against exercise-induced oxidative stress in both liver and kidney. PMID:8820884

  18. Technetium radiodiagnostic fatty acids derived from bisamide bisthiol ligands

    DOEpatents

    Jones, Alun G.; Lister-James, John; Davison, Alan

    1988-05-24

    A bisamide-bisthiol ligand containing fatty acid substituted thiol useful for producing Tc-labelled radiodiagnostic imaging agents is described. The ligand forms a complex with the radionuclide .sup.99m Tc suitable for administration as a radiopharmaceutical to obtain images of the heart for diagnosis of myocardial disfunction.

  19. Nitrogen Derivatives of Soybean Oil and Fatty Acid Methyl Esters

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vegetable oil based products are eco-friendly and non-toxic in nature, which is increasing their utilization in lot of applications. The presence of double bonds in some of the fatty acids, are attractive sites for functionalization. In this study we have used these sites for functionalization usi...

  20. Spectroscopic studies on the interaction of cinnamic acid and its hydroxyl derivatives with human serum albumin

    NASA Astrophysics Data System (ADS)

    Min, Jiang; Meng-Xia, Xie; Dong, Zheng; Yuan, Liu; Xiao-Yu, Li; Xing, Chen

    2004-04-01

    Cinnamic acid and its derivatives possess various biological effects in remedy of many diseases. Interaction of cinnamic acid and its hydroxyl derivatives, p-coumaric acid and caffeic acid, with human serum albumin (HSA), and concomitant changes in its conformation were studied using fluorescence and Fourier transform infrared spectroscopic methods. Fluorescence data revealed the presence of one binding site on HSA for cinnamic acid and its hydroxyl derivatives, and their binding constants ( KA) are caffeic acid> p-coumaric acid> cinnamic acid when Cdrug/ CHSA ranging from 1 to 10. The changes of the secondary structure of HSA after interacting with the three drugs are estimated, respectively by combining the curve-fitting results of amid I and amid III bands. The α-helix structure has a decrease of ≈9, 5 and 3% after HSA interacted with caffeic acid, p-coumaric acid and cinnamic acid, respectively. It was found that the hydroxyls substituted on aromatic ring of the drugs play an important role in the changes of protein's secondary structure. Combining the result of fluorescence quenching and the changes of secondary structure of HSA after interaction with the three drugs, the drug-HSA interaction mode was discussed.

  1. An Alkyne Diboration/6π-Electrocyclization Strategy for the Synthesis of Pyridine Boronic Acid Derivatives.

    PubMed

    Mora-Radó, Helena; Bialy, Laurent; Czechtizky, Werngard; Méndez, María; Harrity, Joseph P A

    2016-05-01

    A new and efficient synthesis of pyridine-based heteroaromatic boronic acid derivatives is reported through a novel diboration/6π-electrocyclization strategy. This method delivers a range of functionalized heterocycles from readily available starting materials. PMID:27059895

  2. Fragmentation patterns of {alpha}-phenylcinnamic acid derivatives upon electron impact ionization; a computational approach

    SciTech Connect

    Palinko, I.; Tasi, G.; Toeroek, B.

    1995-04-01

    Secondary transformations such as fragmentation and rearrangement reacting are computed for {proportional_to}-phenylcinnamic acid derivations upon electron impact ionization. (AIP) {copyright}{ital 1995 American Institute of Physics}

  3. Cadmium induces retinoic acid signaling by regulating retinoic acid metabolic gene expression.

    PubMed

    Cui, Yuxia; Freedman, Jonathan H

    2009-09-11

    The transition metal cadmium is an environmental teratogen. In addition, cadmium and retinoic acid can act synergistically to induce forelimb malformations. The molecular mechanism underlying the teratogenicity of cadmium and the synergistic effect with retinoic acid has not been addressed. An evolutionarily conserved gene, beta,beta-carotene 15,15'-monooxygenase (BCMO), which is involved in retinoic acid biosynthesis, was studied in both Caenorhabditis elegans and murine Hepa 1-6 cells. In C. elegans, bcmo-1 was expressed in the intestine and was cadmium inducible. Similarly, in Hepa 1-6 cells, Bcmo1 was induced by cadmium. Retinoic acid-mediated signaling increased after 24-h exposures to 5 and 10 microm cadmium in Hepa 1-6 cells. Examination of gene expression demonstrated that the induction of retinoic acid signaling by cadmium may be mediated by overexpression of Bcmo1. Furthermore, cadmium inhibited the expression of Cyp26a1 and Cyp26b1, which are involved in retinoic acid degradation. These results indicate that cadmium-induced teratogenicity may be due to the ability of the metal to increase the levels of retinoic acid by disrupting the expression of retinoic acid-metabolizing genes. PMID:19556237

  4. Cadmium Induces Retinoic Acid Signaling by Regulating Retinoic Acid Metabolic Gene Expression*

    PubMed Central

    Cui, Yuxia; Freedman, Jonathan H.

    2009-01-01

    The transition metal cadmium is an environmental teratogen. In addition, cadmium and retinoic acid can act synergistically to induce forelimb malformations. The molecular mechanism underlying the teratogenicity of cadmium and the synergistic effect with retinoic acid has not been addressed. An evolutionarily conserved gene, β,β-carotene 15,15′-monooxygenase (BCMO), which is involved in retinoic acid biosynthesis, was studied in both Caenorhabditis elegans and murine Hepa 1–6 cells. In C. elegans, bcmo-1 was expressed in the intestine and was cadmium inducible. Similarly, in Hepa 1–6 cells, Bcmo1 was induced by cadmium. Retinoic acid-mediated signaling increased after 24-h exposures to 5 and 10 μm cadmium in Hepa 1–6 cells. Examination of gene expression demonstrated that the induction of retinoic acid signaling by cadmium may be mediated by overexpression of Bcmo1. Furthermore, cadmium inhibited the expression of Cyp26a1 and Cyp26b1, which are involved in retinoic acid degradation. These results indicate that cadmium-induced teratogenicity may be due to the ability of the metal to increase the levels of retinoic acid by disrupting the expression of retinoic acid-metabolizing genes. PMID:19556237

  5. Ursodeoxycholic acid induced generalized fixed drug eruption.

    PubMed

    Ozkol, Hatice Uce; Calka, Omer; Dulger, Ahmet Cumhur; Bulut, Gulay

    2014-09-01

    Fixed drug eruption (FDE) is a rare form of drug allergies that recur at the same cutaneous or mucosal site in every usage of drug. Single or multiple round, sharply demarcated and dusky red plaques appear soon after drug exposure. Ursodeoxycholic acid (UDCA: 3α,7β-dihydroxy-5β-cholanic acid) is used for the treatment of cholestatic liver diseases. Some side effects may be observed, such as diarrhea, dyspepsia, pruritus and headaches. We encountered only three cases of lichenoid reaction regarding the use of UDCA among previous studies. In this article, we reported a generalized FDE case related to UDCA intake in a 59-year-old male patient with cholestasis for the first time in the literature. PMID:24147950

  6. Anticonvulsant and behavioral effects observed in mice following treatment with an ester derivative of ferulic acid: Isopentyl ferulate.

    PubMed

    Machado, Keylla C; Oliveira, George Laylson S; Machado, Kátia C; Islam, Md Torequl; Junior, Antonio Luiz G; De Sousa, Damião P; Freitas, Rivelilson M

    2015-12-01

    The objective of this study was to evaluate the potential anticonvulsant effect of isopentyl ferulate, a new ester derived from ferulic acid in mice (Mus musculus) subjected to two models of induced seizures. According to the results obtained, the IF at doses of 25, 50 and 75 mg/kg (i.p.) showed protective effect against induced seizures by pilocarpine (400 mg/kg, i.p.) and pentylenetetrazole (70 mg/kg, i.p.). In the two animal models of seizures, the pretreatment of the IF (25, 50 and 75 mg/kg) with flumazenil blocked the anticonvulsant effect, suggesting that the mechanism of action of this ester derived of ferulic acid may be related to activity in the benzodiazepine-binding site of the GABAA receptor (γ-aminobutyric acid, type A). In addition to the anticonvulsant effect, behavioral changes as neurotoxicity indication were assessed by using the rota rod and open field tests. The results obtained showed that the IF (25, 50 and 75 mg/kg) does not induce significant changes in locomotor activity and motor coordination when compared with the control group, unlike the results presented by diazepam. Thus, these results demonstrate a new pharmacological knowledge of IF with potential application against epileptic seizures. However, further studies are needed to elucidate other neurobiological mechanisms underlying epilepsy. PMID:26456888

  7. Silica with immobilized phosphinic acid-derivative for uranium extraction.

    PubMed

    Budnyak, Tetyana M; Strizhak, Alexander V; Gładysz-Płaska, Agnieszka; Sternik, Dariusz; Komarov, Igor V; Kołodyńska, Dorota; Majdan, Marek; Tertykh, Valentin А

    2016-08-15

    A novel adsorbent benzoimidazol-2-yl-phenylphosphinic acid/aminosilica adsorbent (BImPhP(O)(OH)/SiO2NH2) was prepared by carbonyldiimidazole-mediated coupling of aminosilica with 1-carboxymethylbenzoimidazol-2-yl-phenylphosphinic acid. It was obtained through direct phosphorylation of 1-cyanomethylbenzoimidazole by phenylphosphonic dichloride followed by basic hydrolysis of the nitrile. The obtained sorbent was well characterized by physicochemical methods, such as differential scanning calorimetry-mass spectrometry (DSC-MS), surface area and pore distribution analysis (ASAP), scanning electron microscopy (SEM), X-ray photoelectron (XPS) and Fourier transform infrared (FTIR) spectroscopies. The adsorption behavior of the sorbent and initial silica gel as well as aminosilica gel with respect to uranium(VI) from the aqueous media has been studied under varying operating conditions of pH, concentration of uranium(VI), contact time, and desorption in different media. The synthesized material was found to show an increase in adsorption activity with respect to uranyl ions in comparison with the initial compounds. In particular, the highest adsorption capacity for the obtained modified silica was found at the neutral pH, where one gram of the adsorbent can extract 176mg of uranium. Under the same conditions the aminosilica extracts 166mg/g, and the silica - 144mg/g of uranium. In the acidic medium, which is common for uranium nuclear wastes, the synthesized adsorbent extracts 27mg/g, the aminosilica - 16mg/g, and the silica - 14mg/g of uranium. It was found that 15% of uranium ions leached from the prepared material in acidic solutions, while 4% of uranium can be removed in a phosphate solution. PMID:27177215

  8. Threshold collision induced dissociation experiment for azobenzene and its derivatives

    NASA Astrophysics Data System (ADS)

    Rezaee, Mohammadreza; Compton, Robert

    In this study we investigated protonated azobenzene cation and properties of trans 2,2',6,6'-tetrafluoroazobenzene anion using the collision induced dissociation method and the results are compared with the results from ab initio electronic structure calculations. We measured the bond dissociation energies experimentally and found which theoretical quantum chemistry methods yield best results. Several high accuracy multi-level calculations such as CBS-QB3, G3 and G4 had been carried out to obtain reliable thermochemical information for azobenzene and several of its derivatives and their anion or cation. We also performed other experiments such as Raman spectroscopy to study these light sensitive molecules with promising applications such as photo-switching.

  9. Usnic Acid Derivatives with Cytotoxic and Antifungal Activities from the Lichen Usnea longissima.

    PubMed

    Yu, Xuelong; Guo, Qiang; Su, Guozhu; Yang, Ailin; Hu, Zhongdong; Qu, Changhai; Wan, Zhe; Li, Ruoyu; Tu, Pengfei; Chai, Xingyun

    2016-05-27

    Eight usnic acid derivatives, that is, usenamines A-F (1-6), usone (7), and isousone (8), together with the known (+)-usnic acid (9), were isolated from the lichen Usnea longissima. Their structures were elucidated using 1D and 2D NMR and MS data, and the absolute configurations of compounds 1 and 2 were defined by single-crystal X-ray diffraction analyses. Compounds 1, 2, and 8 showed inhibitory effects on the growth of human hepatoma HepG2 cells with IC50 values of 6.0-53.3 μM compared with methotrexate as the positive control, which had an IC50 value of 15.8 μM. Furthermore, 1 induced apoptosis of HepG2 cells in a dose-dependent manner at concentrations of 0-15.0 μM. The isolated compounds were also evaluated for their antifungal and antibacterial activities, with 7 and 8 exhibiting weak inhibitory effects on fungal Trichophyton rubrum spp. with an MIC value of 41.0 μM. PMID:27186821

  10. Conversion of covalently mercurated nucleic acids to tritiated and halogenated derivatives.

    PubMed Central

    Dale, R M; Ward, D C; Livingston, D C; Martin, E

    1975-01-01

    Mercurated nucleic acids are converted to the corresponding tritiated, brominated, and iodinated derivatives by treatment with sodium borotritiide, N-bromosuccinimide, and elemental iodine, respectively. All three reactions occur under mild conditions in neutral aqueous solutions. Mercury-halogen conversions are essentially quantitative at both the mono- and polynucleotide levels. Tritiation reactions also proceed efficiently with mononucleotides, although polymers undergo incomplete demercuration. In spite of the latter limitation , these reactions provide novel and efficient synthetic routes to radiolabeled nucleic acid derivatives. PMID:1144066

  11. Solid-State Characterization and Biological Activity of Betulonic Acid Derivatives.

    PubMed

    Ledeţi, Ionuţ; Avram, Ştefana; Bercean, Vasile; Vlase, Gabriela; Vlase, Titus; Ledeţi, Adriana; Zupko, Istvan; Mioc, Marius; Şuta, Lenuţa-Maria; Şoica, Codruţa; Dehelean, Cristina

    2015-01-01

    Betulonic acid belongs to the pentacyclic triterpenic derivative class and can be obtained through the selective oxidation of betulin. In this study we set obtaining several functionalized derivatives of this compound by its condensation with several amino compounds such as aminoguanidine, hydroxylamine, n-butylamine and thiosemicarbazide as our goal. The functionalization of the parent compound led to several molecules with antiproliferative potential, the most promising being 3-2-carbamothioylhydrazonolup-20(29)-en-28-oic acid. PMID:26694347

  12. An Inducible Fusaric Acid Tripartite Efflux Pump Contributes to the Fusaric Acid Resistance in Stenotrophomonas maltophilia

    PubMed Central

    Hu, Rouh-Mei; Liao, Sih-Ting; Huang, Chiang-Ching; Huang, Yi-Wei; Yang, Tsuey-Ching

    2012-01-01

    Background Fusaric acid (5-butylpicolinic acid), a mycotoxin, is noxious to some microorganisms. Stenotrophomonas maltophilia displays an intrinsic resistance to fusaric acid. This study aims to elucidate the mechanism responsible for the intrinsic fusaric acid resistance in S. maltophilia. Methodology A putative fusaric acid resistance-involved regulon fuaR-fuaABC was identified by the survey of the whole genome sequence of S. maltophilia K279a. The fuaABC operon was verified by reverse transcriptase-PCR. The contribution of the fuaABC operon to the antimicrobial resistance was evaluated by comparing the antimicrobials susceptibility between the wild-type strain and fuaABC knock-out mutant. The regulatory role of fuaR in the expression of the fuaABC operon was assessed by promoter transcription fusion assay. Results The fuaABC operon was inducibly expressed by fusaric acid and the inducibility was fuaR dependent. FuaR functioned as a repressor of the fuaABC operon in absence of a fusaric acid inducer and as an activator in its presence. Overexpression of the fuaABC operon contributed to the fusaric acid resistance. Significance A novel tripartite fusaric acid efflux pump, FuaABC, was identified in this study. Distinct from the formally classification, the FuaABC may constitute a new type of subfamily of the tripartite efflux pump. PMID:23236431

  13. Fibroblastic reticular cell-derived lysophosphatidic acid regulates confined intranodal T-cell motility

    PubMed Central

    Takeda, Akira; Kobayashi, Daichi; Aoi, Keita; Sasaki, Naoko; Sugiura, Yuki; Igarashi, Hidemitsu; Tohya, Kazuo; Inoue, Asuka; Hata, Erina; Akahoshi, Noriyuki; Hayasaka, Haruko; Kikuta, Junichi; Scandella, Elke; Ludewig, Burkhard; Ishii, Satoshi; Aoki, Junken; Suematsu, Makoto; Ishii, Masaru; Takeda, Kiyoshi; Jalkanen, Sirpa; Miyasaka, Masayuki; Umemoto, Eiji

    2016-01-01

    Lymph nodes (LNs) are highly confined environments with a cell-dense three-dimensional meshwork, in which lymphocyte migration is regulated by intracellular contractile proteins. However, the molecular cues directing intranodal cell migration remain poorly characterized. Here we demonstrate that lysophosphatidic acid (LPA) produced by LN fibroblastic reticular cells (FRCs) acts locally to LPA2 to induce T-cell motility. In vivo, either specific ablation of LPA-producing ectoenzyme autotaxin in FRCs or LPA2 deficiency in T cells markedly decreased intranodal T cell motility, and FRC-derived LPA critically affected the LPA2-dependent T-cell motility. In vitro, LPA activated the small GTPase RhoA in T cells and limited T-cell adhesion to the underlying substrate via LPA2. The LPA-LPA2 axis also enhanced T-cell migration through narrow pores in a three-dimensional environment, in a ROCK-myosin II-dependent manner. These results strongly suggest that FRC-derived LPA serves as a cell-extrinsic factor that optimizes T-cell movement through the densely packed LN reticular network. DOI: http://dx.doi.org/10.7554/eLife.10561.001 PMID:26830463

  14. Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity

    PubMed Central

    Zha, Weibin; Edin, Matthew L.; Vendrov, Kimberly C.; Schuck, Robert N.; Lih, Fred B.; Jat, Jawahar Lal; Bradbury, J. Alyce; DeGraff, Laura M.; Hua, Kunjie; Tomer, Kenneth B.; Falck, John R.; Zeldin, Darryl C.; Lee, Craig R.

    2014-01-01

    Adipogenesis plays a critical role in the initiation and progression of obesity. Although cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have emerged as a potential therapeutic target for cardiometabolic disease, the functional contribution of EETs to adipogenesis and the pathogenesis of obesity remain poorly understood. Our studies demonstrated that induction of adipogenesis in differentiated 3T3-L1 cells (in vitro) and obesity-associated adipose expansion in high-fat diet (HFD)-fed mice (in vivo) significantly dysregulate the CYP epoxygenase pathway and evoke a marked suppression of adipose-derived EET levels. Subsequent in vitro experiments demonstrated that exogenous EET analog administration elicits potent anti-adipogenic effects via inhibition of the early phase of adipogenesis. Furthermore, EET analog administration to mice significantly mitigated HFD-induced weight gain, adipose tissue expansion, pro-adipogenic gene expression, and glucose intolerance. Collectively, these findings suggest that suppression of EET bioavailability in adipose tissue is a key pathological consequence of obesity, and strategies that promote the protective effects of EETs in adipose tissue offer enormous therapeutic potential for obesity and its downstream pathological consequences. PMID:25114171

  15. Stress-induced biosynthesis of dicaffeoylquinic acids in globe artichoke.

    PubMed

    Moglia, Andrea; Lanteri, Sergio; Comino, Cinzia; Acquadro, Alberto; de Vos, Ric; Beekwilder, Jules

    2008-09-24

    Leaf extracts from globe artichoke ( Cynara cardunculus L. var. scolymus) have been widely used in medicine as hepatoprotectant and choleretic agents. Globe artichoke leaves represent a natural source of phenolic acids with dicaffeoylquinic acids, such as cynarin (1,3-dicaffeoylquinic acid), along with its biosynthetic precursor chlorogenic acid (5-caffeoylquinic acid) as the most abundant molecules. This paper reports the development of an experimental system to induce caffeoylquinic acids. This system may serve to study the regulation of the biosynthesis of (poly)phenolic compounds in globe artichoke and the genetic basis of this metabolic regulation. By means of HPLC-PDA and accurate mass LC-QTOF MS and MS/MS analyses, the major phenolic compounds in globe artichoke leaves were identified: four isomers of dicaffeoylquinic acid, three isomers of caffeoylquinic acid, and the flavone luteolin 7-glucoside. Next, plant material was identified in which the concentration of phenolic compounds was comparable in the absence of particular treatments, with the aim to use this material to test the effect of stress application on the regulation of biosynthesis of caffeoylquinic acids. Using this material, the effect of UV-C, methyl jasmonate, and salicylic acid treatments on (poly)phenolic compounds was tested in different globe artichoke genotypes. UV-C exposure consistently increased the levels of dicaffeoylquinic acids in all genotypes, whereas the effect on compounds from the same biosynthetic pathway, for example, chlorogenic acid and luteolin-7-glucoside, was much less pronounced and was not statistically significant. No effect of methyl jasmonate or salicylic acid was found. Time-response experiments indicated that the level of dicaffeoylquinic acids reached a maximum at 24 h after UV radiation. On the basis of these results a role of dicaffeoylquinic acids in UV protection in globe artichoke is hypothesized. PMID:18710252

  16. Effects of Lipoic Acid on Acrylamide Induced Testicular Damage

    PubMed Central

    Lebda, Mohamed; Gad, Shereen; Gaafar, Hossam

    2014-01-01

    Introduction: Acrylamide is very toxic to various organs and associated with significant increase of oxidative stress and depletion of antioxidants. Alpha-lipoic acid enhances cellular antioxidant defense capacity, thereby protecting cells from oxidative stress. Aim of the study: This study aimed to evaluate the protective role of alpha-lipoic acid on the oxidative damage induced by acrylamide in testicular and epididymal tissues. Material and methods: Forty adult male rats were divided into four groups (10 rats each). Control group; acrylamide treated group administered acrylamide 0.05% (w/v) in drinking water for 21 days; alpha-lipoic acid group received basal diet supplemented with 1% alpha-lipoic acid and forth group was exposed to acrylamide and treated with alpha-lipoic acid at the same doses and treatment regimen mentioned before. Results: The administration of acrylamide resulted in significant elevation in testicular and epididymal malondialdehyde level (MDA) and significant reduction in the level of reduced glutathione (GSH) and the activities of glutathione-S-transferase (GST), glutathione peroxidase (GPX) and glutathione reductase (GR). Also, acrylamide significantly reduced serum total testosterone and progesterone but increased estradiol (E2) levels. Treatment with alpha-lipoic acid prior to acrylamide induced protective effects and attenuated these biochemical changes. Conclusion: Alpha-lipoic acid has been shown to possess antioxidant properties offering promising efficacy against oxidative stress induced by acrylamide administration. PMID:25126019

  17. The potential of induced pluripotent stem cell derived hepatocytes.

    PubMed

    Hannoun, Zara; Steichen, Clara; Dianat, Noushin; Weber, Anne; Dubart-Kupperschmitt, Anne

    2016-07-01

    Orthotopic liver transplantation remains the only curative treatment for liver disease. However, the number of patients who die while on the waiting list (15%) has increased in recent years as a result of severe organ shortages; furthermore the incidence of liver disease is increasing worldwide. Clinical trials involving hepatocyte transplantation have provided encouraging results. However, transplanted cell function appears to often decline after several months, necessitating liver transplantation. The precise aetiology of the loss of cell function is not clear, but poor engraftment and immune-mediated loss appear to be important factors. Also, primary human hepatocytes (PHH) are not readily available, de-differentiate, and die rapidly in culture. Hepatocytes are available from other sources, such as tumour-derived human hepatocyte cell lines and immortalised human hepatocyte cell lines or porcine hepatocytes. However, all these cells suffer from various limitations such as reduced or differences in functions or risk of zoonotic infections. Due to their significant potential, one possible inexhaustible source of hepatocytes is through the directed differentiation of human induced pluripotent stem cells (hiPSCs). This review will discuss the potential applications and existing limitations of hiPSC-derived hepatocytes in regenerative medicine, drug screening, in vitro disease modelling and bioartificial livers. PMID:26916529

  18. Derivation of Ethnically Diverse Human Induced Pluripotent Stem Cell Lines.

    PubMed

    Chang, Eun Ah; Tomov, Martin L; Suhr, Steven T; Luo, Jiesi; Olmsted, Zachary T; Paluh, Janet L; Cibelli, Jose

    2015-01-01

    The human genome with all its ethnic variations contributes to differences in human development, aging, disease, repair, and response to medical treatments and is an exciting area of research and clinical study. The availability of well-characterized ethnically diverse stem cell lines is limited and has not kept pace with other advances in stem cell research. Here we derived xenofree ethnically diverse-human induced pluripotent stem cell (ED-iPSC) lines from fibroblasts obtained from individuals of African American, Hispanic-Latino, Asian, and Caucasian ethnic origin and have characterized the lines under a uniform platform for comparative analysis. Derived ED-iPSC lines are low passage number and evaluated in vivo by teratoma formation and in vitro by high throughput microarray analysis of EB formation and early differentiation for tri-lineage commitment to endoderm, ectoderm and mesoderm. These new xenofree ED-iPSC lines represent a well-characterized valuable resource with potential for use in future research in drug discovery or clinical investigations. PMID:26482195

  19. Pd(II)-catalysed meta-C–H functionalizations of benzoic acid derivatives

    PubMed Central

    Li, Shangda; Cai, Lei; Ji, Huafang; Yang, Long; Li, Gang

    2016-01-01

    Benzoic acids are highly important structural motifs in drug molecules and natural products. Selective C–H bond functionalization of benzoic acids will provide synthetically useful tools for step-economical organic synthesis. Although direct ortho-C–H functionalizations of benzoic acids or their derivatives have been intensely studied, the ability to activate meta-C–H bond of benzoic acids or their derivatives in a general manner via transition-metal catalysis has been largely unsuccessful. Although chelation-assisted meta-C–H functionalization of electron-rich arenes was reported, chelation-assisted meta-C–H activation of electron-poor arenes such as benzoic acid derivatives remains a formidable challenge. Herein, we report a general protocol for meta-C–H olefination of benzoic acid derivatives using a nitrile-based sulfonamide template. A broad range of benzoic acid derivatives are meta-selectively olefinated using molecular oxygen as the terminal oxidant. The meta-C–H acetoxylation, product of which is further transformed at the meta-position, is also reported. PMID:26813919

  20. Myeloperoxidase-Derived Oxidants Induce Blood-Brain Barrier Dysfunction In Vitro and In Vivo

    PubMed Central

    Üllen, Andreas; Singewald, Evelin; Konya, Viktoria; Fauler, Günter; Reicher, Helga; Nusshold, Christoph; Hammer, Astrid; Kratky, Dagmar; Heinemann, Akos; Holzer, Peter; Malle, Ernst; Sattler, Wolfgang

    2013-01-01

    Peripheral leukocytes can exacerbate brain damage by release of cytotoxic mediators that disrupt blood-brain barrier (BBB) function. One of the oxidants released by activated leukocytes is hypochlorous acid (HOCl) formed via the myeloperoxidase (MPO)-H2O2-Cl− system. In the present study we examined the role of leukocyte activation, leukocyte-derived MPO and MPO-generated oxidants on BBB function in vitro and in vivo. In a mouse model of lipopolysaccharide (LPS)-induced systemic inflammation, neutrophils that had become adherent released MPO into the cerebrovasculature. In vivo, LPS-induced BBB dysfunction was significantly lower in MPO-deficient mice as compared to wild-type littermates. Both, fMLP-activated leukocytes and the MPO-H2O2-Cl− system inflicted barrier dysfunction of primary brain microvascular endothelial cells (BMVEC) that was partially rescued with the MPO inhibitor 4-aminobenzoic acid hydrazide. BMVEC treatment with the MPO-H2O2-Cl− system or activated neutrophils resulted in the formation of plasmalogen-derived chlorinated fatty aldehydes. 2-chlorohexadecanal (2-ClHDA) severely compromised BMVEC barrier function and induced morphological alterations in tight and adherens junctions. In situ perfusion of rat brain with 2-ClHDA increased BBB permeability in vivo. 2-ClHDA potently activated the MAPK cascade at physiological concentrations. An ERK1/2 and JNK antagonist (PD098059 and SP600125, respectively) protected against 2-ClHDA-induced barrier dysfunction in vitro. The current data provide evidence that interference with the MPO pathway could protect against BBB dysfunction under (neuro)inflammatory conditions. PMID:23691142

  1. Neutrophil-derived resistin release induced by Aggregatibacter actinomycetemcomitans.

    PubMed

    Furugen, Reiko; Hayashida, Hideaki; Yoshii, Yumiko; Saito, Toshiyuki

    2011-08-01

    Resistin is an adipokine that induces insulin resistance in mice. In humans, resistin is not produced in adipocytes, but in various leukocytes instead, and it acts as a proinflammatory molecule. The present investigation demonstrated high levels of resistin in culture supernatants of neutrophils that are stimulated by a highly leukotoxic strain of Aggregatibacter actinomycetemcomitans. In contrast, the level of resistin was remarkably low when neutrophils were exposed to two other strains that produce minimal levels of leukotoxin and a further isogenic mutant strain incapable of producing leukotoxin. Pretreatment of neutrophils with a monoclonal antibody to CD18, β chain of lymphocyte function-associated molecule 1 (LFA-1), or an Src family tyrosine kinase inhibitor before incubation with the highly leukotoxic strain inhibited the release of resistin. These results show that A. actinomycetemcomitans-expressed leukotoxin induces extracellular release of human neutrophil-derived resistin by interacting with LFA-1 on the surface of neutrophils and, consequently, activating Src family tyrosine kinases. PMID:21658109

  2. The retinoic acid derivative, ABPN, inhibits pancreatic cancer through induction of Nrdp1.

    PubMed

    Byun, Sanguine; Shin, Seung Ho; Lee, Eunjung; Lee, Jihoon; Lee, Sung-Young; Farrand, Lee; Jung, Sung Keun; Cho, Yong-Yeon; Um, Soo-Jong; Sin, Hong-Sig; Kwon, Youn-Ja; Zhang, Chengjuan; Tsang, Benjamin K; Bode, Ann M; Lee, Hyong Joo; Lee, Ki Won; Dong, Zigang

    2015-12-01

    Combination chemotherapy for the treatment of pancreatic cancer commonly employs gemcitabine with an EGFR inhibitor such as erlotinib. Here, we show that the retinoic acid derivative, ABPN, exhibits more potent anticancer effects than erlotinib, while exhibiting less toxicity toward noncancerous human control cells. Low micromolar concentrations of ABPN induced apoptosis in BxPC3 and HPAC pancreatic cancer cell lines, concomitant with a reduction in phosphorylated EGFR as well as decreased ErbB3, Met and BRUCE protein levels. The degradation of ErbB3 is a result of proteasomal degradation, possibly due to the ABPN-dependent upregulation of Nrdp1. Administration of ABPN showed significant reductions in tumor size when tested using a mouse xenograft model, with higher potency than erlotinib at the same concentration. Analysis of the tumors demonstrated that ABPN treatment suppressed ErbB3 and Met and induced Nrdp1 in vivo. The data suggest that ABPN may be more suitable in combination chemotherapy with gemcitabine than the more widely used EGFR inhibitor, erlotinib. PMID:26464195

  3. Hypoxia enhances the antiglioma cytotoxicity of B10, a glycosylated derivative of betulinic acid.

    PubMed

    Fischer, Sebastian; Ronellenfitsch, Michael W; Thiepold, Anna-Luisa; Harter, Patrick N; Reichert, Sebastian; Kögel, Donat; Paschke, Reinhard; Mittelbronn, Michel; Weller, Michael; Steinbach, Joachim P; Fulda, Simone; Bähr, Oliver

    2014-01-01

    B10 is a glycosylated derivative of betulinic acid with promising activity against glioma cells. Lysosomal cell death pathways appear to be essential for its cytotoxicity. We investigated the influence of hypoxia, nutrient deprivation and current standard therapies on B10 cytotoxicity. The human glioma cell lines LN-308 and LNT-229 were exposed to B10 alone or together with irradiation, temozolomide, nutrient deprivation or hypoxia. Cell growth and viability were evaluated by crystal violet staining, clonogenicity assays, propidium iodide uptake and LDH release assays. Cell death was examined using an inhibitor of lysosomal acidification (bafilomycin A1), a cathepsin inhibitor (CA074-Me) and a short-hairpin RNA targeting cathepsin B. Hypoxia substantially enhanced B10-induced cell death. This effect was sensitive to bafilomycin A1 and thus dependent on hypoxia-induced lysosomal acidification. Cathepsin B appeared to mediate cell death because either the inhibitor CA074-Me or cathepsin B gene silencing rescued glioma cells from B10 toxicity under hypoxia. B10 is a novel antitumor agent with substantially enhanced cytotoxicity under hypoxia conferred by increased lysosomal cell death pathway activation. Given the importance of hypoxia for therapy resistance, malignant progression, and as a result of antiangiogenic therapies, B10 might be a promising strategy for hypoxic tumors like malignant glioma. PMID:24743710

  4. Hypoxia Enhances the Antiglioma Cytotoxicity of B10, a Glycosylated Derivative of Betulinic Acid

    PubMed Central

    Thiepold, Anna-Luisa; Harter, Patrick N.; Reichert, Sebastian; Kögel, Donat; Paschke, Reinhard; Mittelbronn, Michel; Weller, Michael; Steinbach, Joachim P.; Fulda, Simone; Bähr, Oliver

    2014-01-01

    B10 is a glycosylated derivative of betulinic acid with promising activity against glioma cells. Lysosomal cell death pathways appear to be essential for its cytotoxicity. We investigated the influence of hypoxia, nutrient deprivation and current standard therapies on B10 cytotoxicity. The human glioma cell lines LN-308 and LNT-229 were exposed to B10 alone or together with irradiation, temozolomide, nutrient deprivation or hypoxia. Cell growth and viability were evaluated by crystal violet staining, clonogenicity assays, propidium iodide uptake and LDH release assays. Cell death was examined using an inhibitor of lysosomal acidification (bafilomycin A1), a cathepsin inhibitor (CA074-Me) and a short-hairpin RNA targeting cathepsin B. Hypoxia substantially enhanced B10-induced cell death. This effect was sensitive to bafilomycin A1 and thus dependent on hypoxia-induced lysosomal acidification. Cathepsin B appeared to mediate cell death because either the inhibitor CA074-Me or cathepsin B gene silencing rescued glioma cells from B10 toxicity under hypoxia. B10 is a novel antitumor agent with substantially enhanced cytotoxicity under hypoxia conferred by increased lysosomal cell death pathway activation. Given the importance of hypoxia for therapy resistance, malignant progression, and as a result of antiangiogenic therapies, B10 might be a promising strategy for hypoxic tumors like malignant glioma. PMID:24743710

  5. Induced differentiation of adipose-derived stromal cells into myoblasts.

    PubMed

    Wu, Guizhu; Zheng, Xiu; Jiang, Zhongqing; Wang, Jinhua; Song, Yanfeng

    2010-06-01

    This study aimed to induce the differentiation of isolated and purified adipose-derived stromal cells (ADSCs) into myoblasts, which may provide a new strategy for tissue engineering in patients with stress urinary incontinence (SUI). ADSCs, isolated and cultured ex vivo, were identified by flow cytometry and induced to differentiate into myoblasts in the presence of an induction solution consisting of DMEM supplemented with 5-azacytidine (5-aza), 5% FBS, and 5% horse serum. Cellular morphology was observed under an inverted microscope. Ultrastructural changes occurring during the differentiation were observed by transmission electron microscopy and confocal laser scanning microscopy. Cellular immunohistochemical staining was applied to determine the expression of desmin protein in cells with and without induced differentiation. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to detect mRNA and protein expression, respectively, of sarcomeric and desmin smooth muscle proteins. The results showed that ADSCs were mainly of a spindle or polygon shape. Flow cytometry analysis revealed that ADSCs did not express CD34, CD45, and CD106 but high levels of CD44 and CD90, which confirmed that the cultured cells were indeed ADSCs. After induction with a 5-aza-containing solution, morphological changes in ADSCs, including irregular cell size, were observed. Cells gradually changed from long spindles to polygons and star-shaped cells with microvilli on the cell surface. Many organelles were observed and the cytoplasm was found to contain many mitochondria, rough endoplasmic reticulum (rER), and myofilament-like structures. Cell immunohistochemical staining revealed different levels of desmin expression in each phase of the induction process, with the highest expression level found on day 28 of induction. RT-PCR and Western blot results confirmed significantly higher desmin gene expression in induced cells compared with control cells, but no

  6. Conversion of methyl oleate to branched-chain hydroxy fatty acid derivatives

    Technology Transfer Automated Retrieval System (TEKTRAN)

    As part of a project to develop new and expanded uses of oilseed products and by-products (such as biodiesel, fuel additives, and lubricants), studies were conducted on the synthetic conversion of oleic acid (in ester form) to branched-chain fatty acid ester derivatives. In these studies, methyl ol...

  7. 40 CFR 721.430 - Oxo-substituted amino-al-kanoic acid derivative.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Oxo-substituted amino-al-kanoic acid... Specific Chemical Substances § 721.430 Oxo-substituted amino-al-kanoic acid derivative. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified...

  8. 40 CFR 721.430 - Oxo-substituted amino-al-kanoic acid derivative.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Oxo-substituted amino-al-kanoic acid... Specific Chemical Substances § 721.430 Oxo-substituted amino-al-kanoic acid derivative. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified...

  9. Mass spectral analysis of C3 and C4 aliphatic amino acid derivatives.

    NASA Technical Reports Server (NTRS)

    Lawless, J. G.; Chadha, M. S.

    1971-01-01

    Diagnostic criteria are obtained for the distinction of alpha, beta, gamma, and N-methyl isomers of the C3 and C4 aliphatic amino acids, using mass spectral analysis of the derivatives of these acids. The use of deuterium labeling has helped in the understanding of certain fragmentation pathways.

  10. Biodiesel Derived from a Source Enriched in Palmitoleic Acid, Macadamia Nut Oil

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Biodiesel is an alternative diesel fuel commonly produced from commodity vegetable oils such as palm, rapeseeed (canola) and soybean. These oils generally have fatty acid profiles that vary within the range of C16 and C18 fatty acids. Thus, the biodiesel fuels derived from these oils possess the c...

  11. Fatty acid profile and Unigene-derived simple sequence repeat markers in tung tree (Vernicia fordii)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tung tree (Vernicia fordii) provides the sole source of tung oil widely used in industry. Lack of fatty acid composition and molecular markers hinders biochemical, genetic and breeding research. The objectives of this study were to determine fatty acid profiles and develop unigene-derived simple se...

  12. Amino Acid-Derived Metabolites from the Ascidian Aplidium sp.

    PubMed

    Won, Tae Hyung; Kim, Chang-Kwon; Lee, So-Hyoung; Rho, Boon Jo; Lee, Sang Kook; Oh, Dong-Chan; Oh, Ki-Bong; Shin, Jongheon

    2015-06-01

    Four new iodobenzene-containing dipeptides (1-4), a related bromotryptophan-containing dipeptide (5), and an iodophenethylamine (6) were isolated from the ascidian Aplidium sp. collected off the coast of Chuja-do, Korea. The structures of these novel compounds, designated as apliamides A-E (1-5) and apliamine A (6) were determined via combined spectroscopic analyses. The absolute configuration of the amino acid residue in 1 was determined by advanced Marfey's analysis. Several of these compounds exhibited moderate cytotoxicity and significant inhibition against Na+/K+-ATPase (4). PMID:26087023

  13. CYP2J2-Derived Epoxyeicosatrienoic Acids Suppress Endoplasmic Reticulum Stress in Heart Failure

    PubMed Central

    Wang, Xingxu; Ni, Li; Yang, Lei; Duan, Quanlu; Chen, Chen; Edin, Matthew L.; Zeldin, Darryl C.

    2014-01-01

    Prolonged endoplasmic reticulum (ER) stress causes apoptosis and is associated with heart failure. Whether CYP2J2 and its arachidonic acid metabolites [epoxyeicosatrienoic acids (EETs)] have a protective influence on ER stress and heart failure has not been studied. Assays of myocardial samples from patients with end-stage heart failure showed evidence of ER stress. Chronic infusion of isoproterenol (ISO) or angiotensin II (AngII) by osmotic mini-pump induced cardiac hypertrophy and heart failure in mice as evaluated by hemodynamic measurements and echocardiography. Interestingly, transgenic (Tr) mice with cardiomyocyte-specific CYP2J2 expression were protected against heart failure compared with wild-type mice. ISO or AngII administration induced ER stress and apoptosis, and increased levels of intracellular Ca2+. These phenotypes were abolished by CYP2J2 overexpression in vivo or exogenous EETs treatment of cardiomyocytes in vitro. ISO or AngII reduced sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) expression in hearts or isolated cardiomyocytes; however, loss of SERCA2a expression was prevented in CYP2J2 Tr hearts in vivo or in cardiomyocytes treated with EETs in vitro. The reduction of SERCA2a activity was concomitant with increased oxidation of SERCA2a. EETs reversed SERCA2a oxidation through increased expression of antioxidant enzymes and reduced reactive oxygen species levels. Tempol, a membrane-permeable radical scavenger, similarly decreased oxidized SERCA2a levels, restored SERCA2a activity, and markedly reduced ER stress response in the mice treated with ISO. In conclusion, CYP2J2-derived EETs suppress ER stress response in the heart and protect against cardiac failure by maintaining intracellular Ca2+ homeostasis and SERCA2a expression and activity. PMID:24145329

  14. CYP2J2-derived epoxyeicosatrienoic acids suppress endoplasmic reticulum stress in heart failure.

    PubMed

    Wang, Xingxu; Ni, Li; Yang, Lei; Duan, Quanlu; Chen, Chen; Edin, Matthew L; Zeldin, Darryl C; Wang, Dao Wen

    2014-01-01

    Prolonged endoplasmic reticulum (ER) stress causes apoptosis and is associated with heart failure. Whether CYP2J2 and its arachidonic acid metabolites [epoxyeicosatrienoic acids (EETs)] have a protective influence on ER stress and heart failure has not been studied. Assays of myocardial samples from patients with end-stage heart failure showed evidence of ER stress. Chronic infusion of isoproterenol (ISO) or angiotensin II (AngII) by osmotic mini-pump induced cardiac hypertrophy and heart failure in mice as evaluated by hemodynamic measurements and echocardiography. Interestingly, transgenic (Tr) mice with cardiomyocyte-specific CYP2J2 expression were protected against heart failure compared with wild-type mice. ISO or AngII administration induced ER stress and apoptosis, and increased levels of intracellular Ca(2+). These phenotypes were abolished by CYP2J2 overexpression in vivo or exogenous EETs treatment of cardiomyocytes in vitro. ISO or AngII reduced sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) expression in hearts or isolated cardiomyocytes; however, loss of SERCA2a expression was prevented in CYP2J2 Tr hearts in vivo or in cardiomyocytes treated with EETs in vitro. The reduction of SERCA2a activity was concomitant with increased oxidation of SERCA2a. EETs reversed SERCA2a oxidation through increased expression of antioxidant enzymes and reduced reactive oxygen species levels. Tempol, a membrane-permeable radical scavenger, similarly decreased oxidized SERCA2a levels, restored SERCA2a activity, and markedly reduced ER stress response in the mice treated with ISO. In conclusion, CYP2J2-derived EETs suppress ER stress response in the heart and protect against cardiac failure by maintaining intracellular Ca(2+) homeostasis and SERCA2a expression and activity. PMID:24145329

  15. Structure-Dependent cis/trans Isomerization of Tetraphenylethene Derivatives: Consequences for Aggregation-Induced Emission.

    PubMed

    Zhang, Chong-Jing; Feng, Guangxue; Xu, Shidang; Zhu, Zhenshu; Lu, Xianmao; Wu, Jien; Liu, Bin

    2016-05-17

    The isomerization and optical properties of the cis and trans isomers of tetraphenylethene (TPE) derivatives with aggregation-induced emission (AIEgens) have been sparsely explored. We have now observed the tautomerization-induced isomerization of a hydroxy-substituted derivative, TPETH-OH, under acidic but not under basic conditions. Replacing the proton of the hydroxy group in TPETH-OH with an alkyl group leads to the formation of TPETH-MAL, for which the pure cis and trans isomers were obtained and characterized by HPLC analysis and NMR spectroscopy. Importantly, cis-TPETH-MAL emits yellow fluorescence in DMSO at -20 °C whereas trans-TPETH-MAL shows red fluorescence under the same conditions. Moreover, the geometry of cis- and trans-TPETH-MAL remains unchanged when they undergo thiol-ene reactions to form cis- and trans-TPETH-cRGD, respectively. Collectively, our findings improve our fundamental understanding of the cis/trans isomerization and photophysical properties of TPE derivatives, which will guide further AIEgen design for various applications. PMID:27071955

  16. Sulfonic acid catalysts prepared by radiation-induced graft polymerization

    SciTech Connect

    Mizota, Tomotoshi; Tsuneda, Satoshi; Saito, Kyoichi, Saito

    1994-09-01

    In this study, the authors prepared two variations of graft-type acid catalysts with different adjacent groups by radiation-induced graft polymerization (RIGP), and compared the hydrolytic activity of the resultant acid catalysts for methyl acetate with that of commercially available SO{sub 3}H-type ion-exchange beads with different degrees of cross-linking. 8 refs., 3 figs.

  17. Effects of epigallocatechin gallate, L-ascorbic acid, alpha-tocopherol, and dihydrolipoic acid on the formation of deoxyguanosine adducts derived from lipid peroxidation.

    PubMed

    Nath, Raghu G; Wu, Mona Y; Emami, Armaghan; Chung, Fung-Lung

    2010-01-01

    Oxidation of polyunsaturated fatty acids (PUFAs) releases alpha,beta-unsaturated aldehydes that modify deoxyguanosine (dG) to form cyclic 1,N(2)-propanodeoxyguanosine adducts. One of the major adducts detected in vivo is acrolein (Acr)-derived 1,N(2)-propanodeoxyguanosine (Acr-dG). We used a chemical model system to examine the effects of 4 antioxidants known to inhibit fatty acid oxidation on the formation of Acr-dG and 8-oxodeoxyguaonsine (8-oxodG) from the PUFA docosahexaenoic acid (DHA) under oxidative conditions. We found that epigallocatechin gallate (EGCG) and dihydrolipoic acid (DHLA) inhibit both Acr-dG and 8-oxodG formation. In contrast, ascorbic acid and alpha-tocopherol actually increase Acr-dG at high concentrations and do not show a concentration-dependant inhibition of 8-oxodG. We also studied their effects on blocking Acr-dG formation directly from Acr. EGCG and DHLA can both effectively block Acr-dG formation, but ascorbic acid and alpha-tocopherol show weak or little effect. These results highlight the complexity of antioxidant mechanisms and also reveal that EGCG and DHLA are effective at suppressing lipid peroxidation-induced Acr-dG and 8-oxodG formation as well as blocking the reaction of dG with Acr. PMID:20574923

  18. Mycophenolic Acid and Its Derivatives as Potential Chemotherapeutic Agents Targeting Inosine Monophosphate Dehydrogenase in Trypanosoma congolense.

    PubMed

    Suganuma, Keisuke; Sarwono, Albertus Eka Yudistira; Mitsuhashi, Shinya; Jąkalski, Marcin; Okada, Tadashi; Nthatisi, Molefe; Yamagishi, Junya; Ubukata, Makoto; Inoue, Noboru

    2016-07-01

    This study aimed to evaluate the trypanocidal activity of mycophenolic acid (MPA) and its derivatives for Trypanosoma congolense The proliferation of T. congolense was completely inhibited by adding <1 μM MPA and its derivatives. In addition, the IMP dehydrogenase in T. congolense was molecularly characterized as the target of these compounds. The results suggest that MPA and its derivatives have the potential to be new candidates as novel trypanocidal drugs. PMID:27139487

  19. Lipoic acid attenuates Aroclor 1260-induced hepatotoxicity in adult rats.

    PubMed

    Aly, Hamdy A A; Mansour, Ahmed M; Hassan, Memy H; Abd-Ellah, Mohamed F

    2016-08-01

    The present study was aimed to investigate the mechanistic aspect of Aroclor 1260-induced hepatotoxicity and its protection by lipoic acid. The adult male Albino rats were divided into six groups. Group I served as control. Group II received lipoic acid (35 mg/kg/day). Aroclor 1260 was given to rats by oral gavage at doses 20, 40, or 60 mg/kg/day (Groups III, IV, and V, respectively). Group VI was pretreated with lipoic acid (35 mg/kg/day) 24 h before Aroclor 1260 (40 mg/kg/day). Treatment in all groups was continued for further 15 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities and total bilirubin, total cholesterol, and triglycerides were significantly increased while total protein, total albumin, and high-density lipoprotein were significantly decreased. Hydrogen peroxide production and lipid peroxidation were significantly increased while superoxide dismutase and catalase activities and reduced glutathione (GSH) content was significantly decreased in liver. Caspase-3 & -9 activities were significantly increased in liver. Lipoic acid pretreatment significantly reverted all these abnormalities toward their normal levels. In conclusion, Aroclor 1260 induced liver dysfunction, at least in part, by induction of oxidative stress. Apoptotic effect of hepatic cells is involved in Aroclor 1260-induced liver injury. Lipoic acid could protect rats against Aroclor 1260-induced hepatotoxicity. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 913-922, 2016. PMID:25533183

  20. Percutaneous absorption of nicotinic acid derivatives in vitro.

    PubMed

    Dal Pozzo, A; Donzelli, G; Liggeri, E; Rodriguez, L

    1991-01-01

    The permeation rates through isolated epidermis of a homologous series of glycol, polyglycol, and alkyl esters of nicotinic acid were measured in vitro in a two-compartment diffusion cell assembly, using an isotonic buffered solution as the receiving phase. The esters were applied from aqueous solutions and also as the pure liquids. The results were consistent with those reported by other using compounds of equal or different structures either in vitro or in vivo. The experiments are compared in terms of partition equilibrium between vehicle and tissue and distribution from tissue to the receiving phase. It was demonstrated that the plateau observed in skin permeabilities of the compounds beyond a certain degree of lipophilicity is the result of the effect of water when used as the vehicle in the laboratory models. PMID:2013851

  1. Benfotiamine attenuates nicotine and uric acid-induced vascular endothelial dysfunction in the rat.

    PubMed

    Balakumar, Pitchai; Sharma, Ramica; Singh, Manjeet

    2008-01-01

    The study has been designed to investigate the effect of benfotiamine, a thiamine derivative, in nicotine and uric acid-induced vascular endothelial dysfunction (VED) in rats. Nicotine (2 mg kg(-1)day(-1), i.p., 4 weeks) and uric acid (150 mg kg(-1)day(-1), i.p., 3 weeks) were administered to produce VED in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating serum and aortic concentration of nitrite/nitrate. Further, the integrity of vascular endothelium was assessed using the scanning electron microscopy (SEM) of thoracic aorta. Moreover, the oxidative stress was assessed by estimating serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide anion generation. The administration of nicotine and uric acid produced VED by impairing the integrity of vascular endothelium and subsequently decreasing serum and aortic concentration of nitrite/nitrate and attenuating acetylcholine-induced endothelium dependent relaxation. Further, nicotine and uric acid produced oxidative stress, which was assessed in terms of increase in serum TBARS and aortic superoxide generation. However, treatment with benfotiamine (70 mg kg(-1)day(-1), p.o.) or atorvastatin (30 mg kg(-1)day(-1) p.o., a standard agent) markedly prevented nicotine and uric acid-induced VED and oxidative stress by improving the integrity of vascular endothelium, increasing the concentration of serum and aortic nitrite/nitrate, enhancing the acetylcholine-induced endothelium dependent relaxation and decreasing serum TBARS and aortic superoxide anion generation. Thus, it may be concluded that benfotiamine reduces the oxidative stress and consequently improves the integrity of vascular endothelium and enhances the generation of nitric oxide to prevent nicotine and uric acid-induced experimental VED. PMID:18951979

  2. New ambuic acid derivatives from the solid culture of Pestalotiopsis neglecta and their nitric oxide inhibitory activity

    PubMed Central

    Qi, Qiu-Yue; Li, Er-Wei; Han, Jun-Jie; Pei, Yun-Fei; Ma, Ke; Bao, Li; Huang, Ying; Zhao, Feng; Liu, Hong-Wei

    2015-01-01

    Four new ambuic acid derivatives (1–4), and four known derivatives (5–8), were isolated from the solid culture of a plant pathogenic fungus Pestalotiopsis neglecta. Their structures were elucidated by extensive NMR experiments. The absolute configuration of the C-16 secondary alcohol in 1 was deduced via the CD data of the in situ formed [Rh2(OCOCF3)4] complex with the acetonide derivative of 1. The absolute configuration in 3 was assigned by comparison of the experimental and simulated electronic circular dichroism (ECD) spectrum. The NMR data of compound 5 was reported for the first time. In the nitric oxide (NO) inhibition assay, compounds 4, 6 and 7 showed inhibitory activity against the NO production in the lipopolysaccharide (LPS)-induced macrophage with IC50 values of 88.66, 11.20, and 20.80 µM, respectively. PMID:25989228

  3. Photosensitization and mechanism of cytotoxicity induced by the use of ALA derivatives in photodynamic therapy

    PubMed Central

    Casas, A; Fukuda, H; Di Venosa, G; Batlle, A

    2001-01-01

    The use of more lipophilic derivatives of 5-aminolevulinic acid (ALA) is expected to have better diffusing properties, and after conversion into the parent ALA, to reach a higher protoporphyrin IX (PPIX) formation rate, thus improving the efficacy of topical photodynamic therapy (PDT). Here we have analysed the behaviour of 3 ALA derivatives (ALA methyl-ester, hexyl ester and a 2-sided derivative) regarding PPIX formation, efficiency in photosensitizing cells and mechanism of cellular death. The maximum amount of porphyrins synthesized from 0.6 mM ALA was 47 ± 8 ng/105 cells. The same amount was formed by a concentration 60-fold lower of hexyl-ALA and 2-fold higher of methyl-ALA. The 2-sided derivative failed to produce PPIX accumulation. Applying a 0.6 J cm−2 light dose, cell viability decreased to 50%. With the 1.5 J cm−2 light dose, less than 20% of the cells survive, and higher light doses produced nearly total cell killing. Comparing the PPIX production and the induced phototoxicity, the more the amount of porphyrins, the greater the cellular killing, and PPIX formed from either ALA or ALA-esters equally sensitize the cells to photoinactivation. ALA-PDT treated cells exhibited features of apoptosis, independently on the pro-photosensitizer employed. ALA-PDT can be improved with the use of ALA derivatives, reducing the amount of ALA necessary to induce efficient photosensitization. ©2001 Cancer Research Campaign http://www.bjcancer.com PMID:11461090

  4. Synthesis and preliminary biological evaluations of (+)-isocampholenic acid-derived amides.

    PubMed

    Grošelj, Uroš; Golobič, Amalija; Knez, Damijan; Hrast, Martina; Gobec, Stanislav; Ričko, Sebastijan; Svete, Jurij

    2016-08-01

    The synthesis of two novel (+)-isocampholenic acid-derived amines has been realized starting from commercially available (1S)-(+)-10-camphorsulfonic acid. The novel amines as well as (+)-isocampholenic acid have been used as building blocks in the construction of a library of amides using various aliphatic, aromatic, and amino acid-derived coupling partners using BPC and CDI as activating agents. Amide derivatives have been assayed against several enzymes that hold potential for the development of new drugs to battle bacterial infections and Alzheimer's disease. Compounds 20c and 20e showed promising selective sub-micromolar inhibition of human butyrylcholinesterase [Formula: see text] ([Formula: see text] values [Formula: see text] and [Formula: see text], respectively). PMID:27017352

  5. Valerenic acid derivatives as novel subunit-selective GABAA receptor ligands –in vitro and in vivo characterization

    PubMed Central

    Khom, S; Strommer, B; Ramharter, J; Schwarz, T; Schwarzer, C; Erker, T; Ecker, GF; Mulzer, J; Hering, S

    2010-01-01

    BACKGROUND AND PURPOSE Subunit-specific modulators of γ-aminobutyric acid (GABA) type A (GABAA) receptors can help to assess the physiological function of receptors with different subunit composition and also provide the basis for the development of new drugs. Valerenic acid (VA) was recently identified as a β2/3 subunit-specific modulator of GABAA receptors with anxiolytic potential. The aim of the present study was to generate VA derivatives as novel GABAA receptor modulators and to gain insight into the structure–activity relation of this molecule. EXPERIMENTAL APPROACH The carboxyl group of VA was substituted by an uncharged amide or amides with different chain length. Modulation of GABAA receptors composed of different subunit compositions by the VA derivatives was studied in Xenopus oocytes by means of the two-microelectrode voltage-clamp technique. Half-maximal stimulation of GABA-induced chloride currents (IGABA) through GABAA receptors (EC50) and efficacies (maximal stimulation of IGABA) were estimated. Anxiolytic activity of the VA derivatives was studied in mice, applying the elevated plus maze test. KEY RESULTS Valerenic acid amide (VA-A) displayed the highest efficacy (more than twofold greater IGABA enhancement than VA) and highest potency (EC50= 13.7 ± 2.3 µM) on α1β3 receptors. Higher efficacy and potency of VA-A were also observed on α1β2γ2s and α3β3γ2s receptors. Anxiolytic effects were most pronounced for VA-A. CONCLUSIONS AND IMPLICATIONS Valerenic acid derivatives with higher efficacy and affinity can be generated. Greater in vitro action of the amide derivative correlated with a more pronounced anxiolytic effect in vivo. The data give further confidence in targeting β3 subunit containing GABAA receptors for development of anxiolytics. PMID:20718740

  6. Hydroxycinnamic Acid Derivatives Obtained from a Commercial Crataegus Extract and from Authentic Crataegus spp.

    PubMed

    Kuczkowiak, Ulrich; Petereit, Frank; Nahrstedt, Adolf

    2014-12-01

    Eleven hydroxycinnamic acid derivatives were isolated from a 70% methanolic Crataegus extract (Crataegi folium cum flore) and partly verified and quantified for individual Crataegus species (C. laevigata, C. monogyna, C. nigra, C. pentagyna) by HPLC: 3-O-(E)-p-coumaroylquinic acid (1), 5-O-(E)-p-coumaroyl-quinic acid (2), 4-O-(E)-p-coumaroylquinic acid (3), 3-O-(E)-caffeoylquinic acid (4), 4-O-(E)-caffeoylquinic acid (5), 5-O-(E)-caffeoylquinic acid (6), 3,5-di-O-(E)-caffeoylquinic acid (7), 4,5-di-O-(E)-caffeoylquinic acid (8), (-)-2-O-(E)-caffeoyl-L-threonic acid (9), (-)-4-O-(E)-caffeoyl-L-threonic acid (10), and (-)-4-O-(E)-p-coumaroyl-L-threonic acid (11). Further, (-)-2-O-(E)-caffeoyl-D-malic acid (12) was isolated from C. submollis and also identified for C. pentagyna and C. nigra by co-chromatography. The isolates 10 and 11 were not found in the authentic fresh specimen, indicating that they may be formed during extraction by acyl migration from the 2-O-acylderivatives. Also, 9 and 11 are described here for the first time. All structures were assigned on the basis of their spectroscopic data ((1)H-, (13)C-NMR, MS, optical rotation). PMID:26171328

  7. Hydroxycinnamic Acid Derivatives Obtained from a Commercial Crataegus Extract and from Authentic Crataegus spp.§

    PubMed Central

    Kuczkowiak, Ulrich; Petereit, Frank; Nahrstedt, Adolf

    2014-01-01

    Abstract Eleven hydroxycinnamic acid derivatives were isolated from a 70% methanolic Crataegus extract (Crataegi folium cum flore) and partly verified and quantified for individual Crataegus species (C. laevigata, C. monogyna, C. nigra, C. pentagyna) by HPLC: 3-O-(E)-p-coumaroylquinic acid (1), 5-O-(E)-p-coumaroyl-quinic acid (2), 4-O-(E)-p-coumaroylquinic acid (3), 3-O-(E)-caffeoylquinic acid (4), 4-O-(E)-caffeoylquinic acid (5), 5-O-(E)-caffeoylquinic acid (6), 3,5-di-O-(E)-caffeoylquinic acid (7), 4,5-di-O-(E)-caffeoylquinic acid (8), (-)-2-O-(E)-caffeoyl-L-threonic acid (9), (-)-4-O-(E)-caffeoyl-L-threonic acid (10), and (-)-4-O-(E)-p-coumaroyl-L-threonic acid (11). Further, (-)-2-O-(E)-caffeoyl-D-malic acid (12) was isolated from C. submollis and also identified for C. pentagyna and C. nigra by co-chromatography. The isolates 10 and 11 were not found in the authentic fresh specimen, indicating that they may be formed during extraction by acyl migration from the 2-O-acylderivatives. Also, 9 and 11 are described here for the first time. All structures were assigned on the basis of their spectroscopic data (1H-, 13C-NMR, MS, optical rotation). PMID:26171328

  8. Parahydrogen-induced polarization of carboxylic acids: a pilot study of valproic acid and related structures.

    PubMed

    Lego, Denise; Plaumann, Markus; Trantzschel, Thomas; Bargon, Joachim; Scheich, Henning; Buntkowsky, Gerd; Gutmann, Torsten; Sauer, Grit; Bernarding, Johannes; Bommerich, Ute

    2014-07-01

    Parahydrogen-induced polarization (PHIP) is a promising new tool for medical applications of MR, including MRI. The PHIP technique can be used to transfer high non-Boltzmann polarization, derived from parahydrogen, to isotopes with a low natural abundance or low gyromagnetic ratio (e.g. (13)C), thus improving the signal-to-noise ratio by several orders of magnitude. A few molecules acting as metabolic sensors have already been hyperpolarized with PHIP, but the direct hyperpolarization of drugs used to treat neurological disorders has not been accomplished until now. Here, we report on the first successful hyperpolarization of valproate (valproic acid, VPA), an important and commonly used antiepileptic drug. Hyperpolarization was confirmed by detecting the corresponding signal patterns in the (1)H NMR spectrum. To identify the optimal experimental conditions for the conversion of an appropriate VPA precursor, structurally related molecules with different side chains were analyzed in different solvents using various catalytic systems. The presented results include hyperpolarized (13)C NMR spectra and proton images of related systems, confirming their applicability for MR studies. PHIP-based polarization enhancement may provide a new MR technique to monitor the spatial distribution of valproate in brain tissue and to analyze metabolic pathways after valproate administration. PMID:24812006

  9. Efficient Modulation of γ-Aminobutyric Acid Type A Receptors by Piperine Derivatives

    PubMed Central

    2014-01-01

    Piperine activates TRPV1 (transient receptor potential vanilloid type 1 receptor) receptors and modulates γ-aminobutyric acid type A receptors (GABAAR). We have synthesized a library of 76 piperine analogues and analyzed their effects on GABAAR by means of a two-microelectrode voltage-clamp technique. GABAAR were expressed in Xenopus laevis oocytes. Structure–activity relationships (SARs) were established to identify structural elements essential for efficiency and potency. Efficiency of piperine derivatives was significantly increased by exchanging the piperidine moiety with either N,N-dipropyl, N,N-diisopropyl, N,N-dibutyl, p-methylpiperidine, or N,N-bis(trifluoroethyl) groups. Potency was enhanced by replacing the piperidine moiety by N,N-dibutyl, N,N-diisobutyl, or N,N-bistrifluoroethyl groups. Linker modifications did not substantially enhance the effect on GABAAR. Compound 23 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dipropyl-2,4-pentadienamide] induced the strongest modulation of GABAA (maximal GABA-induced chloride current modulation (IGABA-max = 1673% ± 146%, EC50 = 51.7 ± 9.5 μM), while 25 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dibutyl-2,4-pentadienamide] displayed the highest potency (EC50 = 13.8 ± 1.8 μM, IGABA-max = 760% ± 47%). Compound 23 induced significantly stronger anxiolysis in mice than piperine and thus may serve as a starting point for developing novel GABAAR modulators. PMID:24905252

  10. A newly synthesized sinapic acid derivative inhibits endothelial activation in vitro and in vivo.

    PubMed

    Zeng, Xiaoyun; Zheng, Jinhong; Fu, Chenglai; Su, Hang; Sun, Xiaoli; Zhang, Xuesi; Hou, Yingjian; Zhu, Yi

    2013-05-01

    Inhibition of oxidative stress and inflammation in vascular endothelial cells (ECs) may represent a new therapeutic strategy against endothelial activation. Sinapic acid (SA), a phenylpropanoid compound, is found in natural herbs and high-bran cereals and has moderate antioxidant activity. We aimed to develop new SA agents with the properties of antioxidation and blocking EC activation for possible therapy of cardiovascular disease. We designed and synthesized 10 SA derivatives according to their chemical structures. Preliminary screening of the compounds involved scavenging hydroxyl radicals and 2,2-diphenyl-1-picrylhydrazyl (DPPH(⋅)), croton oil-induced ear edema in mice, and analysis of the mRNA expression of adhesion molecules in ECs. 1-Acetyl-sinapic acyl-4-(3'-chlorine-)benzylpiperazine (SA9) had the strongest antioxidant and anti-inflammatory activities both in vitro and in vivo. Thus, the effect of SA9 was further studied. SA9 inhibited tumor necrosis factor α-induced upregulation of adhesion molecules in ECs at both mRNA and protein levels, as well as the consequent monocyte adhesion to ECs. In vivo, result of face-to-face immunostaining showed that SA9 reduced lipopolysaccharide-induced expression of intercellular adhesion molecule-1 in mouse aortic intima. To study the molecular mechanism, results from luciferase assay, nuclear translocation of NF-κB, and Western blot indicated that the mechanism of the anti-inflammatory effects of SA9 might be suppression of intracellular generation of ROS and inhibition of NF-κB activation in ECs. SA9 is a prototype of a novel class of antioxidant with anti-inflammatory effects in ECs. It may represent a new therapeutic approach for preventing endothelial activation in cardiovascular disorders. PMID:23470287

  11. Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents.

    PubMed

    Grover, Gaurav; Kini, Suvarna G

    2006-02-01

    In continuation of our work on synthesis of biheterocycles carrying the biodynamic heterocyclic systems at position 3, a series of new nalidixic acid derivatives having quinazolones moiety were synthesised to achieve enhanced biological activity and wide spectrum of activity. Nalidixic acid was first converted into its acid chloride using thionyl chloride as an acylating agent at laboratory temperature. Later it was converted to methyl ester. Nalidixoyl chloride formed vigorously reacts with methanol to give a methyl ester of nalidixic acid. The ester on addition of hydrazine hydrate furnished nalidixic acid hydrazide. Appropriate anthranilic acid was refluxed with acetic anhydride to form Benzoxazine/Acetanthranil. 5-iodo-derivative of anthranilic acid was prepared and also utilised to obtain 6-iodo-Benzoxazine/Acetanthranil. Also, 6-nitro-Benzoxazine/Acetanthranil was obtained by nitration of acetanthranil using conc. H(2)SO(4) and fuming HNO(3). Equimolar proportions of the appropriate synthesised acetanthranils and nalidixic acid hydrazide in the presence of ethanol were refluxed to synthesise quinazolones. Elemental analysis and IR spectra confirmed nalidixic acid hydrazide formation. The structures of the compounds obtained have been established on the basis of Spectral (IR, (1)H NMR and mass) data. The current study also involves in vitro antimicrobial screening (using Agar dilution and Punch well diffusion method) of synthesised quinazolone derivatives bearing nalidixic acid moiety on randomly collected microbial strains. The derivatives Ga (NAH), Gb (QN) and Gd (NiQNA) showed marked inhibitory activity against enteric pathogen like Aeromonas hydrophila, a causative agent of diarrhoea in both children as well as adults. Among the respiratory pathogens included in study, derivative Gd (NiQNA) was found to be active against Streptococcus pyogenes. No significant inhibitory activity was seen by any of synthesised derivatives against Coagulase negative

  12. Irbic acid, a dicaffeoylquinic acid derivative from Centella asiatica cell cultures.

    PubMed

    Antognoni, Fabiana; Perellino, Nicoletta Crespi; Crippa, Sergio; Dal Toso, Roberto; Danieli, Bruno; Minghetti, Anacleto; Poli, Ferruccio; Pressi, Giovanna

    2011-10-01

    3,5-O-dicaffeoyl-4-O-malonilquinic acid (1) (irbic acid) has been isolated for the first time from cell cultures of Centella asiatica and till now it has never been reported to be present in the intact plant. Evidence of its structure was obtained by spectroscopic analyses (MS/NMR). Besides 1, cell cultures produce also the known 3,5-O-dicaffeoylquinic acid, chlorogenic acid, and the triferulic acid 2 (4-O-8'/4'-O-8″-didehydrotriferulic acid). Biological activities were evaluated for compound 1, which showed to have a strong radical scavenging capacity, together with a high inhibitory activity on collagenase. This suggests a possible utilization of this substance as a topical agent to reduce the skin ageing process. PMID:21635941

  13. Identification and quantitation of new glutamic acid derivatives in soy sauce by UPLC/MS/MS.

    PubMed

    Frerot, Eric; Chen, Ting

    2013-10-01

    Glutamic acid is an abundant amino acid that lends a characteristic umami taste to foods. In fermented foods, glutamic acid can be found as a free amino acid formed by proteolysis or as a non-proteolytic derivative formed by microorganisms. The aim of the present study was to identify different structures of glutamic acid derivatives in a typical fermented protein-based food product, soy sauce. An acidic fraction was prepared with anion-exchange solid-phase extraction (SPE) and analyzed by UPLC/MS/MS and UPLC/TOF-MS. α-Glutamyl, γ-glutamyl, and pyroglutamyl dipeptides, as well as lactoyl amino acids, were identified in the acidic fraction of soy sauce. They were chemically synthesized for confirmation of their occurrence and quantified in the selected reaction monitoring (SRM) mode. Pyroglutamyl dipeptides accounted for 770 mg/kg of soy sauce, followed by lactoyl amino acids (135 mg/kg) and γ-glutamyl dipeptides (70 mg/kg). In addition, N-succinoylglutamic acid was identified for the first time in food as a minor compound in soy sauce (5 mg/kg). PMID:24130027

  14. A biosynthetic pathway for a prominent class of microbiota-derived bile acids

    PubMed Central

    Devlin, A. Sloan; Fischbach, Michael A.

    2015-01-01

    The gut bile acid pool is millimolar in concentration, varies widely in composition among individuals, and is linked to metabolic disease and cancer. Although these molecules derive almost exclusively from the microbiota, remarkably little is known about which bacterial species and genes are responsible for their biosynthesis. Here, we report a biosynthetic pathway for the second most abundant class in the gut, iso (3β-hydroxy) bile acids, whose levels exceed 300 µM in some humans and are absent in others. We show, for the first time, that iso bile acids are produced by Ruminococcus gnavus, a far more abundant commensal than previously known producers; and that the iso bile acid pathway detoxifies deoxycholic acid, favoring the growth of the keystone genus Bacteroides. By revealing the biosynthetic genes for an abundant class of bile acids, our work sets the stage for predicting and rationally altering the composition of the bile acid pool. PMID:26192599

  15. Microbial production of amino acids and derived chemicals: synthetic biology approaches to strain development.

    PubMed

    Wendisch, Volker F

    2014-12-01

    Amino acids are produced at the multi-million-ton-scale with fermentative production of l-glutamate and l-lysine alone being estimated to amount to more than five million tons in the year 2013. Metabolic engineering constantly improves productivities of amino acid producing strains, mainly Corynebacterium glutamicum and Escherichia coli strains. Classical mutagenesis and screening have been accelerated by combination with intracellular metabolite sensing. Synthetic biology approaches have allowed access to new carbon sources to realize a flexible feedstock concept. Moreover, new pathways for amino acid production as well as fermentative production of non-native compounds derived from amino acids or their metabolic precursors were developed. These include dipeptides, α,ω-diamines, α,ω-diacids, keto acids, acetylated amino acids and ω-amino acids. PMID:24922334

  16. Astrocyte-derived phosphatidic acid promotes dendritic branching

    PubMed Central

    Zhu, Yan-Bing; Gao, Weizhen; Zhang, Yongbo; Jia, Feng; Zhang, Hai-Long; Liu, Ying-Zi; Sun, Xue-Fang; Yin, Yuhua; Yin, Dong-Min

    2016-01-01

    Astrocytes play critical roles in neural circuit formation and function. Recent studies have revealed several secreted and contact-mediated signals from astrocytes which are essential for neurite outgrowth and synapse formation. However, the mechanisms underlying the regulation of dendritic branching by astrocytes remain elusive. Phospholipase D1 (PLD1), which catalyzes the hydrolysis of phosphatidylcholine (PC) to generate phosphatidic acid (PA) and choline, has been implicated in the regulation of neurite outgrowth. Here we showed that knockdown of PLD1 selectively in astrocytes reduced dendritic branching of neurons in neuron-glia mixed culture. Further studies from sandwich-like cocultures and astrocyte conditioned medium suggested that astrocyte PLD1 regulated dendritic branching through secreted signals. We later demonstrated that PA was the key mediator for astrocyte PLD1 to regulate dendritic branching. Moreover, PA itself was sufficient to promote dendritic branching of neurons. Lastly, we showed that PA could activate protein kinase A (PKA) in neurons and promote dendritic branching through PKA signaling. Taken together, our results demonstrate that astrocyte PLD1 and its lipid product PA are essential regulators of dendritic branching in neurons. These results may provide new insight into mechanisms underlying how astrocytes regulate dendrite growth of neurons. PMID:26883475

  17. Effect of the structure of gallic acid and its derivatives on their interaction with plant ferritin.

    PubMed

    Wang, Qunqun; Zhou, Kai; Ning, Yong; Zhao, Guanghua

    2016-12-15

    Gallic acid and its derivatives co-exist with protein components in foodstuffs, but there is few report on their interaction with proteins. On the other hand, plant ferritin represents not only a novel class of iron supplement, but also a new nanocarrier for encapsulation of bioactive nutrients. However, plant ferritin is easy to be degraded by pepsin in the stomach, thereby limiting its application. Herein, we investigated the interaction of gallic acid and its derivatives with recombinant soybean seed H-2 ferritin (rH-2). We found that these phenolic acids interacted with rH-2 in a structure-dependent manner; namely, gallic acid (GA), methyl gallate (MEGA) and propyl gallate (PG) having three HO groups can bind to rH-2, while their analogues with two HO groups cannot. Consequently, such binding largely inhibited ferritin degradation by pepsin. These findings advance our understanding of the relationship between the structure and function of phenolic acids. PMID:27451180

  18. Bioconversion of volatile fatty acids derived from waste activated sludge into lipids by Cryptococcus curvatus.

    PubMed

    Liu, Jia; Liu, Jia-Nan; Yuan, Ming; Shen, Zi-Heng; Peng, Kai-Ming; Lu, Li-Jun; Huang, Xiang-Feng

    2016-07-01

    Pure volatile fatty acid (VFA) solution derived from waste activated sludge (WAS) was used to produce microbial lipids as culture medium in this study, which aimed to realize the resource recovery of WAS and provide low-cost feedstock for biodiesel production simultaneously. Cryptococcus curvatus was selected among three oleaginous yeast to produce lipids with VFAs derived from WAS. In batch cultivation, lipid contents increased from 10.2% to 16.8% when carbon to nitrogen ratio increased from about 3.5 to 165 after removal of ammonia nitrogen by struvite precipitation. The lipid content further increased to 39.6% and the biomass increased from 1.56g/L to 4.53g/L after cultivation for five cycles using sequencing batch culture (SBC) strategy. The lipids produced from WAS-derived VFA solution contained nearly 50% of monounsaturated fatty acids, including palmitic acid, heptadecanoic acid, ginkgolic acid, stearic acid, oleic acid, and linoleic acid, which showed the adequacy of biodiesel production. PMID:27038264

  19. Photochemical synthesis and anticancer activity of barbituric acid, thiobarbituric acid, thiosemicarbazide, and isoniazid linked to 2-phenyl indole derivatives.

    PubMed

    Laxmi, S Vijaya; Rajitha, G; Rajitha, B; Rao, Asha Jyothi

    2016-04-01

    2-Phenyl-1H-indole-3-carbaldehyde-based barbituric acid, thiobarbituric acid, thiosemicarbazide, isoniazid, and malononitrile derivatives were synthesized under photochemical conditions. The antitumor activities of the synthesized compounds were evaluated on three different human cancer cell lines representing prostate cancer cell line DU145, Dwivedi (DWD) cancer cell lines, and breast cancer cell line MCF7. All the screened compounds possessed moderate anticancer activity, and out of all the screened compounds, 5-{1[2-(4-chloro-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2b) and 5-{1[2-(4-methoxy-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2d) exhibited marked antitumor activity against used cell lines. Additionally, barbituric acid derivatives were selective to inhibit cell line DWD and breast cancer cell lines. PMID:27118996

  20. Bile Acid-Induced Necrosis in Primary Human Hepatocytes and in Patients with Obstructive Cholestasis

    PubMed Central

    Woolbright, Benjamin L.; Dorko, Kenneth; Antoine, Daniel J.; Clarke, Joanna I.; Gholami, Parviz; Li, Feng; Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson; Fan, Fang; Jenkins, Rosalind E.; Park, B. Kevin; Hagenbuch, Bruno; Olyaee, Mojtaba; Jaeschke, Hartmut

    2015-01-01

    Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models. PMID:25636263

  1. Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid

    PubMed Central

    Uchiyama, Ayako; Mukai, Mutsuko; Fujiwara, Yuko; Kobayashi, Susumu; Kawai, Nobuyuki; Murofushi, Hiromu; Inoue, Masahiro; Enoki, Shigenori; Tanaka, Yuichiro; Niki, Tamotsu; Kobayashi, Tetsuyuki; Tigyi, Gabor; Murakami-Murofushi, Kimiko

    2010-01-01

    Cyclic phosphatidic acid (1-acyl-sn-glycerol-2,3-cyclic phosphate; cPA) is a naturally occurring analog of lysophosphatidic acid (LPA) with a variety of distinctly different biological activities from those of LPA. In contrast to LPA, a potent inducer of tumor cell invasion, palmitoyl-cPA inhibits FBS- and LPA-induced transcellular migration and metastasis. To prevent the conversion of cPA to LPA we synthesized cPA derivatives by stabilizing the cyclic phosphate ring; to prevent the cleavage of the fatty acid we generated alkyl ether analogs of cPA. Both sets of compounds were tested for inhibitory activity on transcellular tumor cell migration. Carba derivatives, in which the phosphate oxygen was replaced with a methylene group at either the sn-2 or the sn-3 position, showed much more potent inhibitory effects on MM1 tumor cell transcellular migration and the pulmonary metastasis of B16-F0 melanoma than the natural pal-cPA. The antimetastatic effect of carba-cPA was accompanied by the inhibition of RhoA activation and was not due to inhibition of the activation of LPA receptors. PMID:17123862

  2. Thiourea derivatives incorporating a hippuric acid moiety: synthesis and evaluation of antibacterial and antifungal activities.

    PubMed

    Abbas, Samir Y; El-Sharief, Marwa A M Sh; Basyouni, Wahid M; Fakhr, Issa M I; El-Gammal, Eman W

    2013-06-01

    New series of thiourea derivatives incorporating a hippuric acid moiety have been synthesized through the reaction of 4-hippuric acid isothiocyanate with various nitrogen nucleophiles such as aliphatic amines, aromatic amines, sulfa drugs, aminopyrazoles, phenylhydrazine and hydrazides. The synthesized compounds were tested against bacterial and fungal strains. Most of compounds, such as 2-(4-(3-(3-bromophenyl)thioureido)benzamido)acetic acid and 2-(4-(3-(4-(N-pyrimidin-2-ylsulfamoyl)phenyl)thioureido)benzamido)acetic acid, showed significant antibacterial and antifungal activities. These compounds comprise a new class of promising broad-spectrum antibacterial and antifungal agents. PMID:23644194

  3. Polyunsaturated fatty acid relatively decreases cholesterol content in THP-1 macrophage-derived foam cell: partly correlates with expression profile of CIDE and PAT members

    PubMed Central

    2013-01-01

    Background Polyunsaturated fatty acids (PUFAs) have positive effect on the regulation of plasma lipids. But the mechanism for them to modulate lipid homeostasis in macrophage is still unclear. In this study, we employed PUFA to pretreat macrophages and evaluated the variations of lipid droplet (LD) content, lipid composition, and expressions of LD-associated genes in macrophage-derived foam cells. Method THP-1-derived macrophages or human peripheral blood monocyte-derived macrophages were pre-treated with four non-esterified fatty acids (NEFAs) separately: saturated fatty acid (SFA)-palmitic acid (PA), monounsaturated fatty acids (MUFAs)-oleic acid (OA), PUFAs-linoleic acid (LA) and eicosapentaenoic acid (EPA). Intracellular lipid content and cholesterol efflux were analyzed in THP-1 macrophage-derived foam cells. Related gene expressions were detected by quantitative real-time PCR. Results PUFA pre-treatment reduced cholesterol content in foam cells and increased cholesterol efflux to lipid-free apoAI in conditioned medium compared with PA or OA group. Cell death-inducing DFF45 like effector (CIDE) and Perilipin-Adipophilin-TIP47 (PAT) family members, as LD-associated proteins, showed specific gene expression profiles after PUFA pre-treatment. These results may help to explain the process of lipid metabolism within foam cells. Conclusion PUFA (LA or EPA) had a potential protective effect against cholesterol accumulation. The specific expressions of CIDE and PAT genes may provide clues to explore the protective mechanism of PUFA in foam cells. PMID:23879935

  4. Derivation, characterization and retinal differentiation of induced pluripotent stem cells.

    PubMed

    Mekala, Subba Rao; Vauhini, Vasundhara; Nagarajan, Usha; Maddileti, Savitri; Gaddipati, Subhash; Mariappan, Indumathi

    2013-03-01

    Millions of people world over suffer visual disability due to retinal dystrophies which can be age-related or a genetic disorder resulting in gradual degeneration of the retinal pigmented epithelial (RPE) cells and photoreceptors. Therefore, cell replacement therapy offers a great promise in treating such diseases. Since the adult retina does not harbour any stem cells, alternative stem cell sources like the embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) offer a great promise for generating different cell types of the retina. Here, we report the derivation of four iPSC lines from mouse embryonic fibroblasts (MEFs) using a cocktail of recombinant retroviruses carrying the genes for Oct4, Sox2, Klf4 and cMyc. The iPS clone MEF-4F3 was further characterized for stemness marker expression and stable reprogramming by immunocytochemistry, FACS and RT-PCR analysis. Methylation analysis of the nanog promoter confirmed the reprogrammed epigenetic state. Pluripotency was confirmed by embryoid body (EB) formation and lineage-specific marker expression. Also, upon retinal differentiation, patches of pigmented cells with typical cobble-stone phenotype similar to RPE cells are generated within 6 weeks and they expressed ZO-1 (tight junction protein), RPE65 and bestrophin (mature RPE markers) and showed phagocytic activity by the uptake of fluorescent latex beads. PMID:23385820

  5. Naphthalene Derivatives Induce Acyl Chain Interdigitation in Dipalmitoylphosphatidylcholine Bilayers.

    PubMed

    Kamal, Md Arif; Raghunathan, V A

    2016-01-14

    The interdigitated phase of the lipid bilayer results when acyl chains from opposing monolayers fully interpenetrate such that the terminal methyl groups of the respective lipid chains are located at the interfacial region on the opposite sides of the bilayer. Usually, chain interdigitation is not encountered in a symmetric chain phosphatidylcholine (PC) membrane but can be induced under certain special conditions. In this article, we elucidate the contribution of small amphiphatic molecules in altering the physical properties of a symmetric chain PC bilayer membrane, which results in acyl chain interdigitation. Using small-angle X-ray scattering (SAXS), we have carried out a systematic investigation of the physical interactions of three naphthalene derivatives containing hydroxyl groups: β-naphthol, 2,3-dihydroxynaphthalene, and 2,7-dihydroxynaphthalene, with dipalmitoylphosphatidylcholine (DPPC) bilayers. On the basis of the diffraction patterns, we have determined the temperature-composition phase diagrams of these binary mixtures. The present study not only enables us to gain insight into the role played by small molecules in altering the packing arrangement of the acyl chains of the constituting PC lipids of the bilayer but also brings to light some important features that have not yet been reported hitherto. One such feature is the stabilization of the enigmatic asymmetric ripple phase over a wide temperature and concentration range. The results presented here strongly point toward a clear correlation between chain interdigitation and the stability of the ripple phase. PMID:26687052

  6. Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia.

    PubMed

    Fukawa, Tomoya; Yan-Jiang, Benjamin Chua; Min-Wen, Jason Chua; Jun-Hao, Elwin Tan; Huang, Dan; Qian, Chao-Nan; Ong, Pauline; Li, Zhimei; Chen, Shuwen; Mak, Shi Ya; Lim, Wan Jun; Kanayama, Hiro-Omi; Mohan, Rosmin Elsa; Wang, Ruiqi Rachel; Lai, Jiunn Herng; Chua, Clarinda; Ong, Hock Soo; Tan, Ker-Kan; Ho, Ying Swan; Tan, Iain Beehuat; Teh, Bin Tean; Shyh-Chang, Ng

    2016-06-01

    Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer, presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer. Additionally, although many people with cachexia show hypermetabolism, the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell-based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo. Therefore, fatty acid-induced oxidative stress could be targeted to prevent cancer-induced cachexia. PMID:27135739

  7. ASCORBIC ACID IS DECREASED IN INDUCED SPUTUM OF MILD ASTHMATICS

    EPA Science Inventory

    Asthma is primarily an airways inflammatory disease, and the bronchial airways have been shown to be particularly susceptible to oxidant-induced tissue damage. The antioxidant ascorbic acid (AA) plays an essential role in defending against oxidant attack in the airways. Decreased...

  8. Glycation inhibits trichloroacetic acid (TCA)-induced whey protein precipitation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Four different WPI saccharide conjugates were successfully prepared to test whether glycation could inhibit WPI precipitation induced by trichloroacetic acid (TCA). Conjugates molecular weights after glycation were analyzed with SDS-PAGE. No significant secondary structure change due to glycation wa...

  9. Docosapentaenoic acid derived metabolites and mediators - The new world of lipid mediator medicine in a nutshell.

    PubMed

    Weylandt, Karsten-H

    2016-08-15

    Recent years have seen the description and elucidation of a new class of anti-inflammatory and pro-resolving lipid mediators. The arachidonic acid (AA)-derived compounds in this class are called lipoxins and have been described in great detail since their discovery thirty years ago. The new players are mediators derived from fish oil omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), called resolvins, protectins and maresins. Taken together, these mediators are also called specialized pro-resolution mediators (SPMs). As compared to the AA/EPA/DHA-derived compounds, research regarding mediators formed from the n-3 and n-6 docosapentaenoic acids (DPAn-3 and DPAn-6) is sparse. However, mono- di- and trihydroxy derivates of the DPAs have anti-inflammatory properties as well, even though mechanisms of their anti-inflammatory action have not been fully elucidated. This review aims to summarize current knowledge regarding the DPA-derived SPMs and their actions. PMID:26546723

  10. Increased isoprostane levels in oleic acid-induced lung injury

    SciTech Connect

    Ono, Koichi; Koizumi, Tomonobu; Tsushima, Kenji; Yoshikawa, Sumiko; Yokoyama, Toshiki; Nakagawa, Rikimaru; Obata, Toru

    2009-10-16

    The present study was performed to examine a role of oxidative stress in oleic acid-induced lung injury model. Fifteen anesthetized sheep were ventilated and instrumented with a lung lymph fistula and vascular catheters for blood gas analysis and measurement of isoprostanes (8-epi prostaglandin F2{alpha}). Following stable baseline measurements, oleic acid (0.08 ml/kg) was administered and observed 4 h. Isoprostane was measured by gas chromatography mass spectrometry with the isotope dilution method. Isoprostane levels in plasma and lung lymph were significantly increased 2 h after oleic acid administration and then decreased at 4 h. The percent increases in isoprostane levels in plasma and lung lymph at 2 h were significantly correlated with deteriorated oxygenation at the same time point, respectively. These findings suggest that oxidative stress is involved in the pathogenesis of the pulmonary fat embolism-induced acute lung injury model in sheep and that the increase relates with the deteriorated oxygenation.

  11. Can valproic acid be an inducer of clozapine metabolism?

    PubMed Central

    Diaz, Francisco J.; Eap, Chin B.; Ansermot, Nicolas; Crettol, Severine; Spina, Edoardo; de Leon, Jose

    2014-01-01

    Introduction Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that 1) VPA is a net inducer of clozapine metabolism, and 2) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study. Methods After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model. Results VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14% to 39%) after controlling for confounding variables including smoking (35% lower, 28% to 56%). Discussion Prospective studies are needed to definitively establish that VPA may 1) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and 2) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism. PMID:24764199

  12. Salicylic Acid Inhibits Synthesis of Proteinase Inhibitors in Tomato Leaves Induced by Systemin and Jasmonic Acid.

    PubMed Central

    Doares, S. H.; Narvaez-Vasquez, J.; Conconi, A.; Ryan, C. A.

    1995-01-01

    Salicylic acid (SA) and acetylsalicylic acid (ASA), previously shown to inhibit proteinase inhibitor synthesis induced by wounding, oligouronides (H.M. Doherty, R.R. Selvendran, D.J. Bowles [1988] Physiol Mol Plant Pathol 33: 377-384), and linolenic acid (H. Pena-Cortes, T. Albrecht, S. Prat, E.W. Weiler, L. Willmitzer [1993] Planta 191: 123-128), are shown here to be potent inhibitors of systemin-induced and jasmonic acid (JA)-induced synthesis of proteinase inhibitor mRNAs and proteins. The inhibition by SA and ASA of proteinase inhibitor synthesis induced by systemin and JA, as well as by wounding and oligosaccharide elicitors, provides further evidence that both oligosaccharide and polypeptide inducer molecules utilize the octadecanoid pathway to signal the activation of proteinase inhibitor genes. Tomato (Lycopersicon esculentum) leaves were pulse labeled with [35S]methionine, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the inhibitory effects of SA are shown to be specific for the synthesis of a small number of JA-inducible proteins that includes the proteinase inhibitors. Previous results have shown that SA inhibits the conversion of 13S-hydroperoxy linolenic acid to 12-oxo-phytodienoic acid, thereby inhibiting the signaling pathway by blocking synthesis of JA. Here we report that the inhibition of synthesis of proteinase inhibitor proteins and mRNAs by SA in both light and darkness also occurs at a step in the signal transduction pathway, after JA synthesis but preceding transcription of the inhibitor genes. PMID:12228577

  13. Neuraminidase inhibition of Dietary chlorogenic acids and derivatives - potential antivirals from dietary sources.

    PubMed

    Gamaleldin Elsadig Karar, Mohamed; Matei, Marius-Febi; Jaiswal, Rakesh; Illenberger, Susanne; Kuhnert, Nikolai

    2016-04-01

    Plants rich in chlorogenic acids (CGAs), caffeic acids and their derivatives have been found to exert antiviral effects against influenza virus neuroaminidase. In this study several dietary naturally occurring chlorogenic acids, phenolic acids and derivatives were screened for their inhibitory activity against neuroaminidases (NAs) from C. perfringens, H5N1 and recombinant H5N1 (N-His)-Tag using a fluorometric assay. There was no significant difference in inhibition between the different NA enzymes. The enzyme inhibition results indicated that chlorogenic acids and selected derivatives, exhibited high activities against NAs. It seems that the catechol group from caffeic acid was important for the activity. Dietary CGA therefore show promise as potential antiviral agents. However, caffeoyl quinic acids show low bioavailibility and are intensly metabolized by the gut micro flora, only low nM concentrations are observed in plasma and urine, therefore a systemic antiviral effect of these compounds is unlikely. Nevertheless, gut floral metabolites with a catechol moiety or structurally related dietary phenolics with a catechol moiety might serve as interesting compounds for future investigations. PMID:27010419

  14. Analysis of β-Subunit-dependent GABAA Receptor Modulation and Behavioral Effects of Valerenic Acid Derivatives.

    PubMed

    Khom, S; Hintersteiner, J; Luger, D; Haider, M; Pototschnig, G; Mihovilovic, M D; Schwarzer, C; Hering, S

    2016-06-01

    Valerenic acid (VA)-a β2/3-selective GABA type A (GABAA) receptor modulator-displays anxiolytic and anticonvulsive effects in mice devoid of sedation, making VA an interesting drug candidate. Here we analyzed β-subunit-dependent enhancement of GABA-induced chloride currents (IGABA) by a library of VA derivatives and studied their effects on pentylenetetrazole (PTZ)-induced seizure threshold and locomotion. Compound-induced IGABA enhancement was determined in oocytes expressing α1β1γ2S, α1β2γ2S, or α1β3γ2S receptors. Effects on seizure threshold and locomotion were studied using C57BL/6N mice and compared with saline-treated controls. β2/3-selective VA derivatives such as VA-amide (VA-A) modulating α1β3γ2S (VA-A: Emax = 972 ± 69%, n = 6, P < 0.05) and α1β2γ2S receptors (Emax = 1119 ± 72%, n = 6, P < 0.05) more efficaciously than VA (α1β3γ2S: VA: Emax = 632 ± 88%, n = 9 versus α1β2γ2S: VA: Emax = 721 ± 68%, n = 6) displayed significantly more pronounced seizure threshold elevation than VA (saline control: 40.4 ± 1.4 mg/kg PTZ versus VA 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ versus VA-A 3 mg/kg: 57.9 ± 1.9 mg/kg PTZ, P < 0.05). Similarly, VA's methylamide (VA-MA) enhancing IGABA through β3-containing receptors more efficaciously than VA (Emax = 1043 ± 57%, P < 0.01, n = 6) displayed stronger anticonvulsive effects. Increased potency of IGABA enhancement and anticonvulsive effects at lower doses compared with VA were observed for VA-tetrazole (α1β3γ2S: VA-TET: EC50 = 6.0 ± 1.0 μM, P < 0.05; VA-TET: 0.3 mg/kg: 47.3 ± 0.5 mg/kg PTZ versus VA: 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ, P < 0.05). At higher doses (≥10 mg/kg), VA-A, VA-MA, and VA-TET reduced locomotion. In contrast, unselective VA derivatives induced anticonvulsive effects only at high doses (30 mg/kg) or did not display any behavioral effects. Our data indicate that the β2/3-selective compounds VA-A, VA-MA, and VA-TET induce anticonvulsive effects at low doses (≤10 mg/kg), whereas

  15. Analysis of β-Subunit-dependent GABAA Receptor Modulation and Behavioral Effects of Valerenic Acid Derivatives

    PubMed Central

    Hintersteiner, J.; Luger, D.; Haider, M.; Pototschnig, G.; Mihovilovic, M. D.; Schwarzer, C.; Hering, S.

    2016-01-01

    Valerenic acid (VA)—a β2/3-selective GABA type A (GABAA) receptor modulator—displays anxiolytic and anticonvulsive effects in mice devoid of sedation, making VA an interesting drug candidate. Here we analyzed β-subunit-dependent enhancement of GABA-induced chloride currents (IGABA) by a library of VA derivatives and studied their effects on pentylenetetrazole (PTZ)-induced seizure threshold and locomotion. Compound-induced IGABA enhancement was determined in oocytes expressing α1β1γ2S, α1β2γ2S, or α1β3γ2S receptors. Effects on seizure threshold and locomotion were studied using C57BL/6N mice and compared with saline-treated controls. β2/3-selective VA derivatives such as VA-amide (VA-A) modulating α1β3γ2S (VA-A: Emax = 972 ± 69%, n = 6, P < 0.05) and α1β2γ2S receptors (Emax = 1119 ± 72%, n = 6, P < 0.05) more efficaciously than VA (α1β3γ2S: VA: Emax = 632 ± 88%, n = 9 versus α1β2γ2S: VA: Emax = 721 ± 68%, n = 6) displayed significantly more pronounced seizure threshold elevation than VA (saline control: 40.4 ± 1.4 mg/kg PTZ versus VA 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ versus VA-A 3 mg/kg: 57.9 ± 1.9 mg/kg PTZ, P < 0.05). Similarly, VA’s methylamide (VA-MA) enhancing IGABA through β3-containing receptors more efficaciously than VA (Emax = 1043 ± 57%, P < 0.01, n = 6) displayed stronger anticonvulsive effects. Increased potency of IGABA enhancement and anticonvulsive effects at lower doses compared with VA were observed for VA-tetrazole (α1β3γ2S: VA-TET: EC50 = 6.0 ± 1.0 μM, P < 0.05; VA-TET: 0.3 mg/kg: 47.3 ± 0.5 mg/kg PTZ versus VA: 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ, P < 0.05). At higher doses (≥10 mg/kg), VA-A, VA-MA, and VA-TET reduced locomotion. In contrast, unselective VA derivatives induced anticonvulsive effects only at high doses (30 mg/kg) or did not display any behavioral effects. Our data indicate that the β2/3-selective compounds VA-A, VA-MA, and VA-TET induce anticonvulsive effects at low doses (≤10 mg

  16. Oleanolic Acid Induces the Type III Secretion System of Ralstonia solanacearum

    PubMed Central

    Wu, Dousheng; Ding, Wei; Zhang, Yong; Liu, Xuejiao; Yang, Liang

    2015-01-01

    Ralstonia solanacearum, the causal agent of bacterial wilt, can naturally infect a wide range of host plants. The type III secretion system (T3SS) is a major virulence determinant in this bacterium. Studies have shown that plant-derived compounds are able to inhibit or induce the T3SS in some plant pathogenic bacteria, though no specific T3SS inhibitor or inducer has yet been identified in R. solanacearum. In this study, a total of 50 different compounds were screened and almost half of them (22 of 50) significantly inhibited or induced the T3SS expression of R. solanacearum. Based on the strong induction activity on T3SS, the T3SS inducer oleanolic acid (OA) was chosen for further study. We found that OA induced the expression of T3SS through the HrpG-HrpB pathway. Some type III effector genes were induced in T3SS inducing medium supplemented with OA. In addition, OA targeted only the T3SS and did not affect other virulence determinants. Finally, we observed that induction of T3SS by OA accelerated disease progress on tobacco. Overall our results suggest that plant-derived compounds are an abundant source of R. solanacearum T3SS regulators, which could prove useful as tools to interrogate the regulation of this key virulence pathway. PMID:26732647

  17. Possible involvement of abscisic acid in the induction of secondary somatic embryogenesis on seed-coat-derived carrot somatic embryos.

    PubMed

    Ogata, Yumiko; Iizuka, Misato; Nakayama, Daisuke; Ikeda, Miho; Kamada, Hiroshi; Koshiba, Tomokazu

    2005-06-01

    When seed coats (pericarps) were picked from 14-day-old carrot (Daucus carota) seedlings and cultured on agar plates, embryogenic cell clusters were produced very rapidly at a high frequency on the open side edge. Embryo induction progressed without auxin treatment; indeed treatment caused the formation of non-embryogenic callus. The embryogenic tissues (primary embryos) developed normally until the torpedo stage; however, after this a number of secondary somatic embryos were produced in the hypocotyl and root regions. "Tertiary" embryos were formed on some of the secondary embryos, but many developed into normal plantlets. The primary embryos contained significantly higher levels of abscisic acid (ABA) than the hypocotyl-derived normal and seed-coat-derived secondary embryos. Fluridone inhibited the induction of secondary embryogenesis, while exogenously supplied ABA induced not only "tertiary" embryogenesis on the seed-coat-derived secondary embryos, but also secondary embryos on the hypocotyl-derived normal somatic embryos. These results indicate that ABA is one of the important endogenous factors for the induction of secondary embryogenesis on carrot somatic embryos. Higher levels of indole-3-acetic acid (IAA) in primary embryos also suggest the presence of some concerted effect of ABA and IAA on the induction of secondary embryogenesis in primary embryos. PMID:15770487

  18. Encapsulation-Induced Stress Helps Saccharomyces cerevisiae Resist Convertible Lignocellulose Derived Inhibitors

    PubMed Central

    Westman, Johan O.; Manikondu, Ramesh Babu; Franzén, Carl Johan; Taherzadeh, Mohammad J.

    2012-01-01

    The ability of macroencapsulated Saccharomyces cerevisiae CBS8066 to withstand readily and not readily in situ convertible lignocellulose-derived inhibitors was investigated in anaerobic batch cultivations. It was shown that encapsulation increased the tolerance against readily convertible furan aldehyde inhibitors and to dilute acid spruce hydrolysate, but not to organic acid inhibitors that cannot be metabolized anaerobically. Gene expression analysis showed that the protective effect arising from the encapsulation is evident also on the transcriptome level, as the expression of the stress-related genes YAP1, ATR1 and FLR1 was induced upon encapsulation. The transcript levels were increased due to encapsulation already in the medium without added inhibitors, indicating that the cells sensed low stress level arising from the encapsulation itself. We present a model, where the stress response is induced by nutrient limitation, that this helps the cells to cope with the increased stress added by a toxic medium, and that superficial cells in the capsules degrade convertible inhibitors, alleviating the inhibition for the cells deeper in the capsule. PMID:23109889

  19. Evaluation of the pharmacological properties of salicylic acid-derivative organoselenium: 2-hydroxy-5-selenocyanatobenzoic acid as an anti-inflammatory and antinociceptive compound.

    PubMed

    Chagas, Pietro Maria; Rosa, Suzan Gonçalves; Sari, Marcel Henrique Marcondes; Oliveira, Carla Elena Sartori; Canto, Rômulo Faria Santos; da Luz, Sônia Cristina Almeida; Braga, Antonio Luiz; Nogueira, Cristina Wayne

    2014-03-01

    The present study evaluated the antinociceptive and anti-inflammatory effects of per oral (p.o.) administration of salicylic acid-derivative organoselenium compounds in chemical models of nociception in mice. The compounds (50 mg/kg; p.o.) were administered 30 and 60 min before the nociceptive behavior and compared to the positive-control, acetylsalicylic acid (ASA; 200 mg/kg; p.o.). In addition, a dose-response curve (25-100 mg/kg) for compounds was carried out in the formalin test. When assessed in the chemical models, acetic acid-induced writhing behavior, formalin and glutamate tests, the compounds showed the following antinociceptive profile 1B>2B>1A>2A, suggesting a chemical structure-dependent relationship. Then, the anti-inflammatory properties and toxicological potential of compound 1B were investigated. Compound 1B, similar to the positive-control, ASA, diminished the edema formation and decreased the myeloperoxidase activity induced by croton oil (2.5%) in the ear tissue. The results also indicate that a single oral administration of 1B caused neither signs of acute toxicity nor those of gastrointestinal injury. The administration of 1B did not alter the water and food intakes, plasma alanine and aspartate aminotransferase activities or urea levels and cerebral or hepatic δ-aminolevulinate dehydratase activity. Salicylic acid-derivative organoseleniums, mainly compound 1B, have been found to be novel compounds with antinociceptive/anti-inflammatory properties; nevertheless, more studies are required to examine their therapeutic potential for pain treatment. PMID:24398148

  20. Glial cell derived neurotrophic factor induces spermatogonial stem cell marker genes in chicken mesenchymal stem cells.

    PubMed

    Boozarpour, Sohrab; Matin, Maryam M; Momeni-Moghaddam, Madjid; Dehghani, Hesam; Mahdavi-Shahri, Naser; Sisakhtnezhad, Sajjad; Heirani-Tabasi, Asieh; Irfan-Maqsood, Muhammad; Bahrami, Ahmad Reza

    2016-06-01

    Mesenchymal stem cells (MSCs) are known with the potential of multi-lineage differentiation. Advances in differentiation technology have also resulted in the conversion of MSCs to other kinds of stem cells. MSCs are considered as a suitable source of cells for biotechnology purposes because they are abundant, easily accessible and well characterized cells. Nowadays small molecules are introduced as novel and efficient factors to differentiate stem cells. In this work, we examined the potential of glial cell derived neurotrophic factor (GDNF) for differentiating chicken MSCs toward spermatogonial stem cells. MSCs were isolated and characterized from chicken and cultured under treatment with all-trans retinoic acid (RA) or glial cell derived neurotrophic factor. Expression analysis of specific genes after 7days of RA treatment, as examined by RT-PCR, proved positive for some germ cell markers such as CVH, STRA8, PLZF and some genes involved in spermatogonial stem cell maintenance like BCL6b and c-KIT. On the other hand, GDNF could additionally induce expression of POU5F1, and NANOG as well as other genes which were induced after RA treatment. These data illustrated that GDNF is relatively more effective in diverting chicken MSCs towards Spermatogonial stem cell -like cells in chickens and suggests GDNF as a new agent to obtain transgenic poultry, nevertheless, exploitability of these cells should be verified by more experiments. PMID:27026484

  1. Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis.

    PubMed

    Navab, Mohamad; Chattopadhyay, Arnab; Hough, Greg; Meriwether, David; Fogelman, Spencer I; Wagner, Alan C; Grijalva, Victor; Su, Feng; Anantharamaiah, G M; Hwang, Lin H; Faull, Kym F; Reddy, Srinivasa T; Fogelman, Alan M

    2015-04-01

    We previously reported that i) a Western diet increased levels of unsaturated lysophosphatidic acid (LPA) in small intestine and plasma of LDL receptor null (LDLR(-/-)) mice, and ii) supplementing standard mouse chow with unsaturated (but not saturated) LPA produced dyslipidemia and inflammation. Here we report that supplementing chow with unsaturated (but not saturated) LPA resulted in aortic atherosclerosis, which was ameliorated by adding transgenic 6F tomatoes. Supplementing chow with lysophosphatidylcholine (LysoPC) 18:1 (but not LysoPC 18:0) resulted in dyslipidemia similar to that seen on adding LPA 18:1 to chow. PF8380 (a specific inhibitor of autotaxin) significantly ameliorated the LysoPC 18:1-induced dyslipidemia. Supplementing chow with LysoPC 18:1 dramatically increased the levels of unsaturated LPA species in small intestine, liver, and plasma, and the increase was significantly ameliorated by PF8380 indicating that the conversion of LysoPC 18:1 to LPA 18:1 was autotaxin dependent. Adding LysoPC 18:0 to chow increased levels of LPA 18:0 in small intestine, liver, and plasma but was not altered by PF8380 indicating that conversion of LysoPC 18:0 to LPA 18:0 was autotaxin independent. We conclude that i) intestinally derived unsaturated (but not saturated) LPA can cause atherosclerosis in LDLR(-/-) mice, and ii) autotaxin mediates the conversion of unsaturated (but not saturated) LysoPC to LPA. PMID:25646365

  2. Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis

    PubMed Central

    Navab, Mohamad; Chattopadhyay, Arnab; Hough, Greg; Meriwether, David; Fogelman, Spencer I.; Wagner, Alan C.; Grijalva, Victor; Su, Feng; Anantharamaiah, G. M.; Hwang, Lin H.; Faull, Kym F.; Reddy, Srinivasa T.; Fogelman, Alan M.

    2015-01-01

    We previously reported that i) a Western diet increased levels of unsaturated lysophosphatidic acid (LPA) in small intestine and plasma of LDL receptor null (LDLR−/−) mice, and ii) supplementing standard mouse chow with unsaturated (but not saturated) LPA produced dyslipidemia and inflammation. Here we report that supplementing chow with unsaturated (but not saturated) LPA resulted in aortic atherosclerosis, which was ameliorated by adding transgenic 6F tomatoes. Supplementing chow with lysophosphatidylcholine (LysoPC) 18:1 (but not LysoPC 18:0) resulted in dyslipidemia similar to that seen on adding LPA 18:1 to chow. PF8380 (a specific inhibitor of autotaxin) significantly ameliorated the LysoPC 18:1-induced dyslipidemia. Supplementing chow with LysoPC 18:1 dramatically increased the levels of unsaturated LPA species in small intestine, liver, and plasma, and the increase was significantly ameliorated by PF8380 indicating that the conversion of LysoPC 18:1 to LPA 18:1 was autotaxin dependent. Adding LysoPC 18:0 to chow increased levels of LPA 18:0 in small intestine, liver, and plasma but was not altered by PF8380 indicating that conversion of LysoPC 18:0 to LPA 18:0 was autotaxin independent. We conclude that i) intestinally derived unsaturated (but not saturated) LPA can cause atherosclerosis in LDLR−/− mice, and ii) autotaxin mediates the conversion of unsaturated (but not saturated) LysoPC to LPA. PMID:25646365

  3. A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy

    PubMed Central

    Hsu, Tsung-I; Chen, Ying-Jung; Hung, Chia-Yang; Wang, Yi-Chang; Lin, Sin-Jin; Su, Wu-Chou; Lai, Ming-Derg; Kim, Sang-Yong; Wang, Qiang; Qian, Keduo; Goto, Masuo; Zhao, Yu; Kashiwada, Yoshiki; Lee, Kuo-Hsiung; Chang, Wen-Chang; Hung, Jan-Jong

    2015-01-01

    Herein, we evaluated the anti-cancer effect and molecular mechanisms of a novel betulinic acid (BA) derivative, SYK023, by using two mouse models of lung cancer driven by KrasG12D or EGFRL858R. We found that SYK023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro. SYK023 triggered endoplasmic reticulum (ER) stress. Blockage of ER stress in SYK023-treated cells inhibited SYK023-induced apoptosis. In addition, we found that the expression of cell cycle-related genes, including cyclin A2, B1, D3, CDC25a, and CDC25b decreased but, while those of p15INK4b, p16INK4a, and p21CIP1 increased following SYK023 treatment. Finally, low doses of SYK023 significantly decreased lung cancer metastasis in vitro and in vivo. Expression of several genes related to cell migration, including synaptopodin, were downregulated by SYK023, thereby impairing F-actin polymerization and metastasis. Therefore, SYK023 may be a potentially therapeutic treatment for metastatic lung cancer. PMID:25909174

  4. A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy.

    PubMed

    Hsu, Tsung-I; Chen, Ying-Jung; Hung, Chia-Yang; Wang, Yi-Chang; Lin, Sin-Jin; Su, Wu-Chou; Lai, Ming-Derg; Kim, Sang-Yong; Wang, Qiang; Qian, Keduo; Goto, Masuo; Zhao, Yu; Kashiwada, Yoshiki; Lee, Kuo-Hsiung; Chang, Wen-Chang; Hung, Jan-Jong

    2015-05-30

    Herein, we evaluated the anti-cancer effect and molecular mechanisms of a novel betulinic acid (BA) derivative, SYK023, by using two mouse models of lung cancer driven by KrasG12D or EGFRL858R. We found that SYK023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro. SYK023 triggered endoplasmic reticulum (ER) stress. Blockage of ER stress in SYK023-treated cells inhibited SYK023-induced apoptosis. In addition, we found that the expression of cell cycle-related genes, including cyclin A2, B1, D3, CDC25a, and CDC25b decreased but, while those of p15INK4b, p16INK4a, and p21CIP1 increased following SYK023 treatment. Finally, low doses of SYK023 significantly decreased lung cancer metastasis in vitro and in vivo. Expression of several genes related to cell migration, including synaptopodin, were downregulated by SYK023, thereby impairing F-actin polymerization and metastasis. Therefore, SYK023 may be a potentially therapeutic treatment for metastatic lung cancer. PMID:25909174

  5. Lanthanum(III) and praseodymium(III) derivatives with dithiocarbamates derived from α-amino acids

    NASA Astrophysics Data System (ADS)

    Rai, Anita; Sengupta, Soumitra K.; Pandey, Om P.

    2006-06-01

    Lanthanum(III) and praseodymium(III) complexes with dithiocarbamates have been synthesized by the reactions of lanthanum(III) and praseodymium(III) chloride with barium dithiocarbamate and complexes of type [LnCl(L)H 2O] n have been obtained (where Ln = La(III) or Pr(III); L = barium salt of dithiocarbamate derived from glycine, L-leucine, L-valine, DL-alanine). The complexes have been characterized by elemental analysis, molar conductance, electronic absorption and fluorescence, infrared, far infrared, 1H NMR spectral studies. The presence of coordinated water molecule is inferred from thermogravimetric analysis which indicates the loss of one water molecule at 150-170 °C. The oscillator strength, Judd-Ofelt intensity parameter, stimulated emission cross-section, etc. have been obtained for different transitions of Pr 3+.

  6. Pigment Epithelium Derived Factor Peptide Protects Murine Hepatocytes from Carbon Tetrachloride-Induced Injury

    PubMed Central

    Shih, Shou-Chuan; Ho, Tsung-Chuan; Chen, Show-Li; Tsao, Yeou-Ping

    2016-01-01

    Fibrogenesis is induced by repeated injury to the liver and reactive regeneration and leads eventually to liver cirrhosis. Pigment epithelium derived factor (PEDF) has been shown to prevent liver fibrosis induced by carbon tetrachloride (CCl4). A 44 amino acid domain of PEDF (44-mer) was found to have a protective effect against various insults to several cell types. In this study, we investigated the capability of synthetic 44-mer to protect against liver injury in mice and in primary cultured hepatocytes. Acute liver injury, induced by CCl4, was evident from histological changes, such as cell necrosis, inflammation and apoptosis, and a concomitant reduction of glutathione (GSH) and GSH redox enzyme activities in the liver. Intraperitoneal injection of the 44-mer into CCl4-treated mice abolished the induction of AST and ALT and markedly reduced histological signs of liver injury. The 44-mer treatment can reduce hepatic oxidative stress as evident from lower levels of lipid hydroperoxide, and higher levels of GSH. CCl4 caused a reduction of Bcl-xL, PEDF and PPARγ, which was markedly restored by the 44-mer treatment. Consequently, the 44-mer suppressed liver fibrosis induced by repeated CCl4 injury. Furthermore, our observations in primary culture of rat hepatocytes showed that PEDF and the 44-mer protected primary rat hepatocytes against apoptosis induced by serum deprivation and TGF-β1. PEDF/44-mer induced cell protective STAT3 phosphorylation. Pharmacological STAT3 inhibition prevented the antiapoptotic action of PEDF/44-mer. Among several PEDF receptor candidates that may be responsible for hepatocyte protection, we demonstrated that PNPLA2 was essential for PEDF/44-mer-mediated STAT3 phosphorylation and antiapoptotic activity by using siRNA to selectively knockdown PNPLA2. In conclusion, the PEDF 44-mer protects hepatocytes from single and repeated CCl4 injury. This protective effect may stem from strengthening the counter oxidative stress capacity and

  7. Human GAPDH Is a Target of Aspirin's Primary Metabolite Salicylic Acid and Its Derivatives.

    PubMed

    Choi, Hyong Woo; Tian, Miaoying; Manohar, Murli; Harraz, Maged M; Park, Sang-Wook; Schroeder, Frank C; Snyder, Solomon H; Klessig, Daniel F

    2015-01-01

    The plant hormone salicylic acid (SA) controls several physiological processes and is a key regulator of multiple levels of plant immunity. To decipher the mechanisms through which SA's multiple physiological effects are mediated, particularly in immunity, two high-throughput screens were developed to identify SA-binding proteins (SABPs). Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH) from plants (Arabidopsis thaliana) was identified in these screens. Similar screens and subsequent analyses using SA analogs, in conjunction with either a photoaffinity labeling technique or surface plasmon resonance-based technology, established that human GAPDH (HsGAPDH) also binds SA. In addition to its central role in glycolysis, HsGAPDH participates in several pathological processes, including viral replication and neuronal cell death. The anti-Parkinson's drug deprenyl has been shown to suppress nuclear translocation of HsGAPDH, an early step in cell death and the resulting cell death induced by the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine. Here, we demonstrate that SA, which is the primary metabolite of aspirin (acetyl SA) and is likely responsible for many of its pharmacological effects, also suppresses nuclear translocation of HsGAPDH and cell death. Analysis of two synthetic SA derivatives and two classes of compounds from the Chinese medicinal herb Glycyrrhiza foetida (licorice), glycyrrhizin and the SA-derivatives amorfrutins, revealed that they not only appear to bind HsGAPDH more tightly than SA, but also exhibit a greater ability to suppress translocation of HsGAPDH to the nucleus and cell death. PMID:26606248

  8. Human GAPDH Is a Target of Aspirin’s Primary Metabolite Salicylic Acid and Its Derivatives

    PubMed Central

    Manohar, Murli; Harraz, Maged M.; Park, Sang-Wook; Schroeder, Frank C.; Snyder, Solomon H.; Klessig, Daniel F.

    2015-01-01

    The plant hormone salicylic acid (SA) controls several physiological processes and is a key regulator of multiple levels of plant immunity. To decipher the mechanisms through which SA’s multiple physiological effects are mediated, particularly in immunity, two high-throughput screens were developed to identify SA-binding proteins (SABPs). Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH) from plants (Arabidopsis thaliana) was identified in these screens. Similar screens and subsequent analyses using SA analogs, in conjunction with either a photoaffinity labeling technique or surface plasmon resonance-based technology, established that human GAPDH (HsGAPDH) also binds SA. In addition to its central role in glycolysis, HsGAPDH participates in several pathological processes, including viral replication and neuronal cell death. The anti-Parkinson’s drug deprenyl has been shown to suppress nuclear translocation of HsGAPDH, an early step in cell death and the resulting cell death induced by the DNA alkylating agent N-methyl-N’-nitro-N-nitrosoguanidine. Here, we demonstrate that SA, which is the primary metabolite of aspirin (acetyl SA) and is likely responsible for many of its pharmacological effects, also suppresses nuclear translocation of HsGAPDH and cell death. Analysis of two synthetic SA derivatives and two classes of compounds from the Chinese medicinal herb Glycyrrhiza foetida (licorice), glycyrrhizin and the SA-derivatives amorfrutins, revealed that they not only appear to bind HsGAPDH more tightly than SA, but also exhibit a greater ability to suppress translocation of HsGAPDH to the nucleus and cell death. PMID:26606248

  9. Bio-derived poly(gamma-glutamic acid) nanogels as controlled anticancer drug delivery carriers.

    PubMed

    Bae, Hee Ho; Cho, Mi Young; Hong, Ji Hyeon; Poo, Haryoung; Sung, Moon-Hee; Lim, Yong Taik

    2012-12-01

    We have developed a novel type of polymer nanogel loaded with anticancer drug based on bio-derived poly(gamma- glutamic acid) (gamma-PGA). gamma-PGA is a highly anionic polymer that is synthesized naturally by microbial species, most prominently in various bacilli, and has been shown to have excellent biocompatibility. Thiolated gamma-PGA was synthesized by covalent coupling between the carboxyl groups of gamma-PGA and the primary amine group of cysteamine. Doxorubicin (Dox)-loaded gamma-PGA nanogels were fabricated using the following steps: (1) an ionic nanocomplex was formed between thiolated gamma-PGA as the negative charge component, and Dox as the positive charge component; (2) addition of poly(ethylene glycol) (PEG) induced hydrogen-bond interactions between thiol groups of thiolated gamma-PGA and hydroxyl groups of PEG, resulting in the nanocomplex; and (3) disulfide crosslinked gamma-PGA nanogels were fabricated by ultrasonication. The average size and surface charge of Dox-loaded disulfide cross-linked gamma-PGA nanogels in aqueous solution were 136.3 +/- 37.6 nm and -32.5 +/- 5.3 mV, respectively. The loading amount of Dox was approximately 38.7 microgram per mg of gamma-PGA nanogel. The Dox-loaded disulfide cross-linked gamma-PGA nanogels showed controlled drug release behavior in the presence of reducing agents, glutathione (GSH) (1- 10 mM). Through fluorescence microscopy and FACS, the cellular uptake of gamma-PGA nanogels into breast cancer cells (MCF-7) was analyzed. The cytotoxic effect was evaluated using the MTT assay and was determined to be dependent on both the concentration and treatment time of gamma-PGA nanogels. The bio-derived gamma-PGA nanogels are expected to be a well-designed delivery carrier for controlled drug delivery applications. PMID:23221543

  10. A Direct, Biomass-Based Synthesis of Benzoic Acid: Formic Acid-Mediated Deoxygenation of the Glucose-Derived Materials Quinic Acid and Shikimic Acid

    SciTech Connect

    Arceo, Elena; Ellman, Jonathan; Bergman, Robert

    2010-05-03

    An alternative biomass-based route to benzoic acid from the renewable starting materials quinic acid and shikimic acid is described. Benzoic acid is obtained selectively using a highly efficient, one-step formic acid-mediated deoxygenation method.

  11. Technological and economic potential of poly(lactic acid) and lactic acid derivatives

    SciTech Connect

    Datta, R.; Tsai, S.P.; Bonsignore, P.; Moon, S.H.; Frank, J.R.

    1993-10-01

    Lactic acid has been an intermediate-volume specialty chemical (world production {approximately}40,000 tons/yr) used in a wide range of food processing and industrial applications. lactic acid h,as the potential of becoming a very large volume, commodity-chemical intermediate produced from renewable carbohydrates for use as feedstocks for biodegradable polymers, oxygenated chemicals, plant growth regulators, environmentally friendly ``green`` solvents, and specially chemical intermediates. In the past, efficient and economical technologies for the recovery and purification of lactic acid from crude fermentation broths and the conversion of tactic acid to the chemical or polymer intermediates had been the key technology impediments and main process cost centers. The development and deployment of novel separations technologies, such as electrodialysis (ED) with bipolar membranes, extractive distillations integrated with fermentation, and chemical conversion, can enable low-cost production with continuous processes in large-scale operations. The use of bipolar ED can virtually eliminate the salt or gypsum waste produced in the current lactic acid processes. In this paper, the recent technical advances in tactic and polylactic acid processes are discussed. The economic potential and manufacturing cost estimates of several products and process options are presented. The technical accomplishments at Argonne National Laboratory (ANL) and the future directions of this program at ANL are discussed.

  12. The saturated fatty acid, palmitic acid, induces anxiety-like behavior in mice

    PubMed Central

    Moon, Morgan L.; Joesting, Jennifer J.; Lawson, Marcus A.; Chiu, Gabriel S.; Blevins, Neil A.; Kwakwa, Kristin A.; Freund, Gregory G.

    2014-01-01

    Objectives Excess fat in the diet can impact neuropsychiatric functions by negatively affecting cognition, mood and anxiety. We sought to show that the free fatty acid (FFA), palmitic acid, can cause adverse biobehaviors in mice that lasts beyond an acute elevation in plasma FFAs. Methods Mice were administered palmitic acid or vehicle as a single intraperitoneal (IP) injection. Biobehaviors were profiled 2 and 24 hrs after palmitic acid treatment. Quantification of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and their major metabolites was performed in cortex, hippocampus and amygdala. FFA concentration was determined in plasma. Relative fold change in mRNA expression of unfolded protein response (UPR)-associated genes was determined in brain regions. Results In a dose-dependent fashion, palmitic acid rapidly reduced mouse locomotor activity by a mechanism that did not rely on TLR4, MyD88, IL-1, IL-6 or TNFα but was dependent on fatty acid chain length. Twenty-four hrs after palmitic acid administration mice exhibited anxiety-like behavior without impairment in locomotion, food intake, depressive-like behavior or spatial memory. Additionally, the serotonin metabolite 5-HIAA was increased by 33% in the amygdala 24 hrs after palmitic acid treatment. Conclusions Palmitic acid induces anxiety-like behavior in mice while increasing amygdala-based serotonin metabolism. These effects occur at a time point when plasma FFA levels are no longer elevated. PMID:25016520

  13. Regioselective Enzymatic β-Carboxylation of para-Hydroxy- styrene Derivatives Catalyzed by Phenolic Acid Decarboxylases

    PubMed Central

    Wuensch, Christiane; Pavkov-Keller, Tea; Steinkellner, Georg; Gross, Johannes; Fuchs, Michael; Hromic, Altijana; Lyskowski, Andrzej; Fauland, Kerstin; Gruber, Karl; Glueck, Silvia M; Faber, Kurt

    2015-01-01

    We report on a ‘green’ method for the utilization of carbon dioxide as C1 unit for the regioselective synthesis of (E)-cinnamic acids via regioselective enzymatic carboxylation of para-hydroxystyrenes. Phenolic acid decarboxylases from bacterial sources catalyzed the β-carboxylation of para-hydroxystyrene derivatives with excellent regio- and (E/Z)-stereoselectivity by exclusively acting at the β-carbon atom of the C=C side chain to furnish the corresponding (E)-cinnamic acid derivatives in up to 40% conversion at the expense of bicarbonate as carbon dioxide source. Studies on the substrate scope of this strategy are presented and a catalytic mechanism is proposed based on molecular modelling studies supported by mutagenesis of amino acid residues in the active site. PMID:26190963

  14. Camphorquinone-10-sulfonic acid and derivatives: convenient reagents for reversible modification of arginine residues

    SciTech Connect

    Pande, C.S.; Pelzig, M.; Glass, J.D.

    1980-02-01

    Camphorquinone-10-sulfonic acid hydrate was prepared by the action of selenous acid on camphor-10-sulfonic acid. Camphorquinone-10-sulfonylnorleucine was prepared either from the sulfonic acid via the sulfonyl chloride or by selenous acid oxidation of camphor-10-sulfonylnorleucine. These reagents are useful for specific, reversible modification of the guanidino groups of arginine residues. Camphorquinonsulfonic acid is a crystalline water-soluble reagent that is especially suitable for use with small arginine-containing molecules, because the sulfonic acid group of the reagent is a convenient handle for analytical and preparative separation of products. Camphorquinonesulfonylnorleucine is more useful for work with large polypeptides and proteins, because hydrolysates of modified proteins may be analyzed for norleucine to determine the extent of arginine modification. The adducts of the camphorquinone derivatives with the guanidino group are stable to 0.5 M hydroxylamine solutions at pH 7, the recommended conditions for cleavage of the corresponding cyclohexanedione adducts. At pH 8-9 the adducts of the camphorquinone derivatives with the guanidino group are cleaved by o-phenylenediamine. The modification and regeneration of arginine, of the dipeptide arginylaspartic acid, of ribonuclease S-peptide, and of soybean trypsin inhibitor are presented as demonstrations of the use of the reagents.The use of camphorquinonesulfonyl chloride to prepare polymers containing arginine-specific ligands is discussed.

  15. Computerized image analysis for acetic acid induced intraepithelial lesions

    NASA Astrophysics Data System (ADS)

    Li, Wenjing; Ferris, Daron G.; Lieberman, Rich W.

    2008-03-01

    Cervical Intraepithelial Neoplasia (CIN) exhibits certain morphologic features that can be identified during a visual inspection exam. Immature and dysphasic cervical squamous epithelium turns white after application of acetic acid during the exam. The whitening process occurs visually over several minutes and subjectively discriminates between dysphasic and normal tissue. Digital imaging technologies allow us to assist the physician analyzing the acetic acid induced lesions (acetowhite region) in a fully automatic way. This paper reports a study designed to measure multiple parameters of the acetowhitening process from two images captured with a digital colposcope. One image is captured before the acetic acid application, and the other is captured after the acetic acid application. The spatial change of the acetowhitening is extracted using color and texture information in the post acetic acid image; the temporal change is extracted from the intensity and color changes between the post acetic acid and pre acetic acid images with an automatic alignment. The imaging and data analysis system has been evaluated with a total of 99 human subjects and demonstrate its potential to screening underserved women where access to skilled colposcopists is limited.

  16. Acid-induced secretory cell metaplasia in hamster bronchi

    SciTech Connect

    Christensen, T.G.; Lucey, E.C.; Breuer, R.; Snider, G.L.

    1988-02-01

    Hamsters were exposed to an intratracheal instillation of 0.5 ml of 0.08 N nitric, hydrochloric, or sulfuric acid to determine their airway epithelial response. Three weeks after exposure, the left intrapulmonary bronchi in Alcian blue/PAS-strained paraffin sections were evaluated for the amount of secretory product in the airway epithelium as a measure of secretory cell metaplasia (SCM). Compared to saline-treated control animals, all three acids caused statistically significant SCM. In addition to the bronchial lesion, all three acids caused similar interstitial fibrosis, bronchiolectasis, and bronchiolization of alveoli that varied in individual animals from mild to severe. In a separate experiment to study the persistence of the SCM, hamsters treated with a single instillation of 0.1 N nitric acid showed significant SCM 3, 7, and 17 weeks after exposure. There was a high correlation (r = 0.96) between a subjective assessment of SCM and objective assessment using a digital image-analysis system. We conclude that protons induce SCM independently of the associated anion; the SCM persists at least 17 weeks. Sulfuric acid is an atmospheric pollutant and nitric acid may form locally on the mucosa of lungs exposed to nitrogen dioxide. These acids may contribute to the development of maintenance of the SCM seen in the conducting airways of humans with chronic obstructive pulmonary disease.

  17. Paecilonic acids A and B, bicyclic fatty acids from the jellyfish-derived fungus Paecilomyces variotii J08NF-1.

    PubMed

    Wang, Haibo; Hong, Jongki; Yin, Jun; Liu, Juan; Liu, Yonghong; Choi, Jae Sue; Jung, Jee H

    2016-05-01

    Two new bicyclic fatty acids, paecilonic acids A and B (1 and 2), were isolated from the culture broth of the marine fungus Paecilomyces variotii derived from the jellyfish Nemopilema nomurai. Compounds 1 and 2 share the same molecular formula and possess a 6,8-dioxabicyclo[3.2.1]octane core skeleton. The planar structures of compounds 1 and 2 were established by spectroscopic analysis, which included NMR and ESI-MS/MS. Relative and absolute configurations were determined by analyzing coupling constants, NOESY correlations, and optical rotations. PMID:27009897

  18. Antagonistic activity of lactic acid bacteria as probiotics against selected bacteria of the Enterobaceriacae family in the presence of polyols and their galactosyl derivatives.

    PubMed

    Klewicki, Robert; Klewicka, Elzbieta

    2004-02-01

    Probiotic lactic acid bacteria were grown on erythritol, xylitol, sorbitol or lactitol and produced various derivatives: gal-erythritol, gal-xylitol, and gal-sorbitol as prebiotics. Galactosyl derivatives of erythritol, xylitol and sorbitol were metabolised by Lactobacillus spp. This resulted in their antagonistic activity against the test microflora. No activity was observed in the presence of xylitol and erythritol. Gal-sorbitol obtained by enzymatic transglycosylation from lactose had the same abilities of inducing the antagonistic activity of lactic acid bacteria that lactitol had. PMID:15055768

  19. Phenolic acid composition, antiatherogenic and anticancer potential of honeys derived from various regions in Greece.

    PubMed

    Spilioti, Eliana; Jaakkola, Mari; Tolonen, Tiina; Lipponen, Maija; Virtanen, Vesa; Chinou, Ioanna; Kassi, Eva; Karabournioti, Sofia; Moutsatsou, Paraskevi

    2014-01-01

    The phenolic acid profile of honey depends greatly on its botanical and geographical origin. In this study, we carried out a quantitative analysis of phenolic acids in the ethyl acetate extract of 12 honeys collected from various regions in Greece. Our findings indicate that protocatechuic acid, p-hydroxybenzoic acid, vanillic acid, caffeic acid and p-coumaric acid are the major phenolic acids of the honeys examined. Conifer tree honey (from pine and fir) contained significantly higher concentrations of protocatechuic and caffeic acid (mean: 6640 and 397 µg/kg honey respectively) than thyme and citrus honey (mean of protocatechuic and caffeic acid: 437.6 and 116 µg/kg honey respectively). p-Hydroxybenzoic acid was the dominant compound in thyme honeys (mean: 1252.5 µg/kg honey). We further examined the antioxidant potential (ORAC assay) of the extracts, their ability to influence viability of prostate cancer (PC-3) and breast cancer (MCF-7) cells as well as their lowering effect on TNF- α-induced adhesion molecule expression in endothelial cells (HAEC). ORAC values of Greek honeys ranged from 415 to 2129 µmol Trolox equivalent/kg honey and correlated significantly with their content in protocatechuic acid (p<0.001), p-hydroxybenzoic acid (p<0.01), vanillic acid (p<0.05), caffeic acid (p<0.01), p-coumaric acid (p<0.001) and their total phenolic content (p<0.001). Honey extracts reduced significantly the viability of PC-3 and MCF-7 cells as well as the expression of adhesion molecules in HAEC. Importantly, vanillic acid content correlated significantly with anticancer activity in PC-3 and MCF-7 cells (p<0.01, p<0.05 respectively). Protocatechuic acid, vanillic acid and total phenolic content correlated significantly with the inhibition of VCAM-1 expression (p<0.05, p<0.05 and p<0.01 respectively). In conclusion, Greek honeys are rich in phenolic acids, in particular protocatechuic and p-hydroxybenzoic acid and exhibit significant antioxidant, anticancer and

  20. Phenolic Acid Composition, Antiatherogenic and Anticancer Potential of Honeys Derived from Various Regions in Greece

    PubMed Central

    Spilioti, Eliana; Jaakkola, Mari; Tolonen, Tiina; Lipponen, Maija; Virtanen, Vesa; Chinou, Ioanna; Kassi, Eva; Karabournioti, Sofia; Moutsatsou, Paraskevi

    2014-01-01

    The phenolic acid profile of honey depends greatly on its botanical and geographical origin. In this study, we carried out a quantitative analysis of phenolic acids in the ethyl acetate extract of 12 honeys collected from various regions in Greece. Our findings indicate that protocatechuic acid, p-hydroxybenzoic acid, vanillic acid, caffeic acid and p-coumaric acid are the major phenolic acids of the honeys examined. Conifer tree honey (from pine and fir) contained significantly higher concentrations of protocatechuic and caffeic acid (mean: 6640 and 397 µg/kg honey respectively) than thyme and citrus honey (mean of protocatechuic and caffeic acid: 437.6 and 116 µg/kg honey respectively). p-Hydroxybenzoic acid was the dominant compound in thyme honeys (mean: 1252.5 µg/kg honey). We further examined the antioxidant potential (ORAC assay) of the extracts, their ability to influence viability of prostate cancer (PC-3) and breast cancer (MCF-7) cells as well as their lowering effect on TNF- α-induced adhesion molecule expression in endothelial cells (HAEC). ORAC values of Greek honeys ranged from 415 to 2129 µmol Trolox equivalent/kg honey and correlated significantly with their content in protocatechuic acid (p<0.001), p-hydroxybenzoic acid (p<0.01), vanillic acid (p<0.05), caffeic acid (p<0.01), p-coumaric acid (p<0.001) and their total phenolic content (p<0.001). Honey extracts reduced significantly the viability of PC-3 and MCF-7 cells as well as the expression of adhesion molecules in HAEC. Importantly, vanillic acid content correlated significantly with anticancer activity in PC-3 and MCF-7 cells (p<0.01, p<0.05 respectively). Protocatechuic acid, vanillic acid and total phenolic content correlated significantly with the inhibition of VCAM-1 expression (p<0.05, p<0.05 and p<0.01 respectively). In conclusion, Greek honeys are rich in phenolic acids, in particular protocatechuic and p-hydroxybenzoic acid and exhibit significant antioxidant, anticancer and

  1. Morphology-controlled growth of perylene derivative induced by double-hydrophilic block copolymers

    NASA Astrophysics Data System (ADS)

    Huang, Minghua; Antonietti, Markus; Cölfen, Helmut

    2016-01-01

    Controlled growth of technically relevant perylene derivative 3, 4, 9, 10-perylenetetracarboxylic acid potassium salt (PTCAPS), with tuneable morpologies, has been successfully realized by a recrystallization method using a double-hydrophilic block copolymer poly (ethylene glycol)-block poly (ethyleneimine) (PEG-b-PEI) as the structure directing agent. The {001} faces of PTCAPS are most polar and adsorb the oppositively charged polymer additive PEG-b-PEI well by electrostatic attraction. By simply adjusting the PEG-b-PEI concentration, systematic morphogenesis of PTCAPS from plates to microparticles composed of various plates splaying outwards could be realized. Furthermore, the variation of pH value of the recrystallization solution could induce the change of the interaction strength between PEG-b-PEI additive and PTCAPS and thus modify the morphology of PTCAPS from microparticles composed of various plates to ultralong microbelts.

  2. Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia

    PubMed Central

    Narushima, Seiko; Sugiura, Yuki; Oshima, Kenshiro; Atarashi, Koji; Hattori, Masahira; Suematsu, Makoto; Honda, Kenya

    2014-01-01

    The gut microbiota plays important roles in the development of the host immune system. We have previously shown that a combination of 46 strains of commensal Clostridia isolated from conventionally reared mice can induce the accumulation of CD4+Foxp3+ regulatory T (Treg) cells in the mouse colonic lamina propria. Subsequently, we succeeded in isolating and selecting 17 strains of Clostridia from a healthy human fecal sample that can significantly increase the number and function of colonic Treg cells in colonized rodents, thereby attenuating symptoms of experimental allergic diarrhea and colitis. Here we characterize each of the 17 strains of human-derived Clostridia in terms of sensitivity to antibiotics and ability to produce short chain fatty acids and other metabolites, and discuss their potential as biotherapeutics to correct dysbiosis and treat immune-inflammatory diseases. PMID:24642476

  3. Antiradiation compounds. 20. 1-Methylquinolinium(and pyridinium)-2-dithioacetic acid derivatives

    SciTech Connect

    Foye, W.O.; Jones, R.W.; Ghoshal, P.K.; Almassian, B.

    1987-01-01

    A new class of radiation-protective compounds has been found in the bis(methylthio) and methylthio amino derivatives of 1-methylquinolinium- and 1-methylpyridinium-2-dithioacetic acids. The compounds gave good protection to mice vs. 1000-rad gamma-radiation in ip doses of 10 mg/kg or less, much lower than those required for the aminoalkyl thiols (approximately 150-600 mg/kg). The dithioacetic acid zwitterions were prepared from the base-catalyzed reaction of carbon disulfide with quinaldine and picoline methiodides, and the bis(methylthio) derivatives resulted from reaction with methyl iodide at room temperature. Replacement of one methylthio moiety took place readily on reaction of the bis(methylthio) derivatives with 1 molar equiv of an amine. The best protective activity was found with the methylthio piperidino derivative in both the quinolinium and pyridinium series.

  4. Comparative analysis of the anxiolytic effects of 3-hydroxypyridine and succinic acid derivatives.

    PubMed

    Volchegorskii, I A; Miroshnichenko, I Yu; Rassokhina, L M; Faizullin, R M; Malkin, M P; Pryakhina, K E; Kalugina, A V

    2015-04-01

    Threefold administration of 3-hydroxypyridine derivatives emoxipine and mexidol in optimal doses corresponding to the therapeutic dose range for humans produced an anxiolytic effect and stimulated risk behavior in the elevated plus maze test in rats. These effects were most pronounced after injection of 3-hydroxypyridine derivative emoxipine. Combination of 3-hydroxypyridine cation and succinate anion in the mexidol structure led to attenuation of the anxiolytic effect and less pronounced stimulation of the risk behavior. By the anxiolytic effect and induction of risk behavior, emoxipine and mexidol were close to the reference substance amitriptyline. Reamberin, a succinic acid derivative, had no pronounced tranquilizing properties, but risk behavior induction was similar to that produced by mexidol. In contrast to other test agents, the reference substance α-lipoic acid produced anxiogenic effects and suppressed risk behavior. The obtained results suggest that Russian-made 3-hydroxypyridine derivatives emoxipine and mexidol are promising preparations for the treatment of anxiety disorders. PMID:25894772

  5. Combination of chlorogenic acid and salvianolic acid B protects against polychlorinated biphenyls-induced oxidative stress through Nrf2.

    PubMed

    Chen, Lijun; Li, Yuan; Yin, Wenqin; Shan, Wenqi; Dai, Jinfeng; Yang, Ye; Li, Lei

    2016-09-01

    Caffeic acid derivatives (CADs) are well-known phytochemicals with multiple physiological and pharmacological activities. This study aimed to investigate the combined protective effects of CADs on PCB126-induced liver damages and oxidative stress in mice. Here, we used chemiluminescence and chose chlorogenic acid (CGA), salvianolic acid B (Sal B) as the best antioxidants. Then, mice were intragastrically administered with 60mg/kg/d CGA, Sal B, and CGA plus Sal B (1:1) for 3 weeks before exposing to 0.05mg/kg/d PCB126 for 2 weeks. We found that pretreatment with CGA, Sal B, and CGA plus Sal B effectively attenuated liver injury and cytotoxicity caused by PCB126, but improved the expressions of superoxide dismutase (SOD), glutathione reduced (GSH), heme oxygenase-1 (HO-1) and nuclear factor E2-related factor 2 (Nrf2), CGA plus Sal B especially, was found to have the best effects that indicated a synergetic protective effect. Taken together, as the Nrf2 regulates the cyto-protective response by up-regulating the expression of antioxidant genes, we suggested that CGA plus Sal B had a combined protection on PCB126-induced tissue damages and that the Nrf2 signaling might be involved. PMID:27513569

  6. Lactobacillus casei microbiological assay of folic acid derivatives in 96-well microtiter plates.

    PubMed

    Horne, D W; Patterson, D

    1988-11-01

    Microbiological assay is still widely used for estimating folic acid derivatives in serum and other biological samples. We describe here a modification of this procedure involving use of 96-well microtiter plates. This procedure, used with modern, computer-interfaced microtiter-plate readers and data-reduction software, greatly shortens the time and minimizes reagent costs for this assay. Under the conditions of our assay procedures, all folic acid derivatives tested gave equal growth response for Lactobacillus casei. Results for assays of rat liver extracts showed excellent agreement between the standard bioassay and the 96-well procedure. PMID:3141087

  7. Synthesis of α,ω-polyfluorinated α-amino acid derivatives and δ,δ-difluoronorvaline.

    PubMed

    Ulbrich, Dirk; Daniliuc, Constantin G; Haufe, Günter

    2016-03-01

    Intending to synthesize ω,ω-difluoroalkyl amino acid derivatives by oxidative desulfurization-fluorination reactions of suitable arylthio-2-phthalimido butanoates and pentanoates, in addition to small amounts of the target products, mainly α,ω-polyfluorinated amino acid derivatives were formed by additional sulfur-assisted α-fluorination. This novel structural motif was verified spectroscopically as well as by X-ray analysis. A plausible mechanism of formation is suggested. Using a different approach, δ,δ-difluoronorvaline hydrochloride was synthesized with at least 36% enantiomeric excess via deoxofluorination of the corresponding aldehyde. PMID:26857261

  8. [Biological activity and mechanisms of therapeutic action of rosmarinic acid, luteolin and its sulphated derivatives].

    PubMed

    Popov, A M; Krivoshapko, O N; Klimovich, A A; Artyukov, A A

    2016-01-01

    The review considers recent experimental studies of biological activity and mechanisms of therapeutic action of rosmarinic acid, luteolin and its sulfated derivatives in diseases associated with disorders of carbohydrate and lipid metabolism. Particular attention is focused on the results of studies showing a high therapeutic potential of these phenolic compounds in their prophylactic and therapeutic use at experimental modeling of type 2 diabetes and hyperlipidemia. Based on the analysis of our results and the literature data putative mechanisms of therapeutic action of rosmarinic acid, luteolin and its sulfated derivatives have been proposed. PMID:26973183

  9. Nucleosides of 4-methylthio-1,2,3-triazol-5-yl-carboxylic acid derivatives

    SciTech Connect

    Shingarova, I.D.; Yartseva, I.V.; Preobrazhenskaya, M.N.

    1987-08-01

    2-..beta..-D-Ribofuranosyl-4-methylthio-5-methoxycarbonyl-1,2,3-triazole was obtained by fusing 4-methylthio-5-methoxycarbonyl-1,2,3-triazole together with tetraacyl-D-ribofuranose, followed by deacylation, and its amide and hydrazide were prepared. The structures of the new nucleosides were established by converting them into known 2-nucleosides of 1,2,3-triazol-4-yl-carboxylic acid derivatives. By comparing PMR spectra with previously reported PMR spectra for the isomeric 1- and 2-nucleosides of 1,2,3-triazol-4-yl-carboxylic acid derivatives, the synthesized nucleosides could be assigned to 2-substituted triazoles.

  10. Enzymatic synthesis of bile acid derivatives and biological evaluation against Trypanosoma cruzi.

    PubMed

    García Liñares, Guadalupe; Antonela Zígolo, M; Simonetti, Leandro; Longhi, Silvia A; Baldessari, Alicia

    2015-08-01

    Enzyme catalysis was applied to synthesize derivatives of three bile acids and their biological activity was evaluated as growth inhibitors of the protozoan Trypanosoma cruzi. Twelve mono-, diacetyl and ester derivatives of deoxycholic, chenodeoxycholic and lithocholic acid, seven of them new compounds, were obtained through lipase-catalyzed acetylation, esterification and alcoholysis reactions in very good to excellent yield and a highly regioselective way. Among them, acetylated ester products, in which the lipase catalyzed both reactions in one-pot, were obtained. The influence of various reaction parameters in the enzymatic reactions, such as enzyme source, acylating agent/substrate ratio, enzyme/substrate ratio, solvent and temperature, was studied. Some of the evaluated compounds showed a remarkable activity as Trypanosoma cruzi growth inhibitors, obtaining the best results with ethyl chenodeoxycholate 3-acetate and chenodeoxycholic acid 3,7-diacetate, which showed IC50: 8.6 and 22.8 μM, respectively. In addition, in order to shed light to bile acids behavior in enzymatic reactions, molecular modeling was applied to some derivatives. The advantages showed by the enzymatic methodology, such as mild reaction conditions and low environmental impact, make the biocatalysis a convenient way to synthesize these bile acid derivatives with application as potential antiparasitic agents. PMID:26072173

  11. Bioactivity and chemical synthesis of caffeic acid phenethyl ester and its derivatives.

    PubMed

    Zhang, Pengxuan; Tang, Yuping; Li, Nian-Guang; Zhu, Yue; Duan, Jin-Ao

    2014-01-01

    Caffeic acid phenethyl ester (CAPE), as one of the main active ingredients of the natural product propolis, shows the unique biological activities such as anti-tumor, anti-oxidation, anti-inflammatory, immune regulation, and so on. These have attracted the attention of many researchers to explore the compound with potent biological activities. This review aims to summarize its bioactivities, synthetic methods and derivatives, which will be helpful for further study and development of CAPE and its derivatives. PMID:25314606

  12. Field evaluation of the bacterial volatile derivative 3-pentanol in priming for induced resistance in pepper.

    PubMed

    Choi, Hye Kyung; Song, Geun Cheol; Yi, Hwe-Su; Ryu, Choong-Min

    2014-08-01

    Plants are defended from attack by emission of volatile organic compounds (VOCs) that can act directly against pathogens and herbivores or indirectly by recruiting natural enemies of herbivores. However, microbial VOC have been less investigated as potential triggers of plant systemic defense responses against pathogens in the field. Bacillus amyloliquefaciens strain IN937a, a plant growth-promoting rhizobacterium that colonizes plant tissues, stimulates induced systemic resistance (ISR) via its emission of VOCs. We investigated the ISR capacity of VOCs and derivatives collected from strain IN937a against bacterial spot disease caused by Xanthomonas axonopodis pv. vesicatoria in pepper. Of 15 bacterial VOCs and their derivatives, 3-pentanol, which is a C8 amyl alcohol reported to be a component of sex pheromones in insects, was selected for further investigation. Pathogens were infiltrated into pepper leaves 10, 20, 30, and 40 days after treatment and transplantation to the field. Disease severity was assessed 7 days after transplantation. Treatment with 3-pentanol significantly reduced disease severity caused by X. axonopodis and naturally occurring Cucumber mosaic virus in field trials over 2 years. We used quantitative real-time polymerase chain analysis to examine Pathogenesis-Related genes associated with salicylic acid (SA), jasmonic acid (JA), and ethylene defense signaling. The expression of Capsicum annuum Pathogenesis-Related protein 1 (CaPR1), CaPR2, and Ca protease inhibitor2 (CaPIN2) increased in field-grown pepper plants treated with 3-pentanol. Taken together, our results show that 3-pentanol triggers induced resistance by priming SA and JA signaling in pepper under field conditions. PMID:25149655

  13. Synthesis of 4-substituted nipecotic acid derivatives and their evaluation as potential GABA uptake inhibitors.

    PubMed

    Hellenbrand, Tim; Höfner, Georg; Wein, Thomas; Wanner, Klaus T

    2016-05-01

    In this study, we disclose the design and synthesis of novel 4-susbtituted nipecotic acid derivatives as inhibitors of the GABA transporter mGAT1. Based on molecular modeling studies the compounds are assumed to adopt a binding pose similar to that of the potent mGAT1 inhibitor nipecotic acid. As substitution in 4-position should not cause an energetically unfavorable orientation of nipecotic acid as it is the case for N-substituted derivatives this is expected to lead to highly potent binders. For the synthesis of novel 4-substituted nipecotic acid derivatives a linear synthetic strategy was employed. As a key step, palladium catalyzed cross coupling reactions were used to attach the required biaryl moieties to the ω-position of the alkenyl- or alkynyl spacers of varying length in the 4-position of the nipecotic acid scaffold. The resulting amino acids were characterized with respect to their binding affinities and inhibitory potencies at mGAT1. Though the biological activities found were generally insignificant to poor, two compounds, one of which possesses a reasonable binding affinity for mGAT1, rac-57, the other a notable inhibitory potency at mGAT4, rac-84, both displaying a slight subtype selectivity for the individual transporters, could be identified. PMID:27039250

  14. Microbiological degradation of bile acids. Nitrogenous hexahydroindane derivatives formed from cholic acid by Streptomyces rubescens.

    PubMed Central

    Hayakawa, S; Hashimoto, S; Onaka, T

    1976-01-01

    The metabolism of cholic acid (I) by Streptomyces rubescens was investigated. This organism effected ring A cleavage, side-chain shortening and amide bond formation and gave the following metabolites: (4R)-4-[4alpha-(2-carboxyethyl)-3aalpha-hexahydro-7abeta-methyl-5-oxoindan-1 beta-yl]valeric acid (IIa) and its mono-amide (valeramide) (IIb); and 2,3,4,6, 6abeta,7,8,9,9aalpha,9bbeta-decahydro-6abeta-methyl-1H-cyclopenta[f]quinoline-3,7-dione(IIIe)and its homologues with the beta-oriented side chains, valeric acid, valeramide, butanone and propionic acid, in the place of the oxo group at C-7, i.e.compounds (IIIa), (IIIb), (IIIc) and (IIId) respectively. All the nitrogenous metabolites were new compounds, and their structures were established by partial synthesis except for the metabolite (IIIc). The mechanism of formation of these metabolites is considered. A degradative pathway of cholic acid (I) into the metabolites is also tentatively proposed. PMID:1016253

  15. Implications for eicosapentaenoic acid- and docosahexaenoic acid-derived resolvins as therapeutics for arthritis.

    PubMed

    Souza, Patricia R; Norling, Lucy V

    2016-08-15

    Omega-3 polyunsaturated fatty acids are essential for health and are known to possess anti-inflammatory properties, improving cardiovascular health as well as benefiting inflammatory diseases. Indeed, dietary supplementation with omega-3 polyunsaturated fatty acids has proved efficacious in reducing joint pain, morning stiffness and nonsteroidal anti-inflammatory drugs usage in rheumatoid arthritis patients. However, the mechanisms by which omega-3 polyunsaturated fatty acids exert their beneficial effects have not been fully explored. Seminal discoveries by Serhan and colleagues have unveiled a novel class of bioactive lipid mediators that are enzymatically biosynthesized in vivo from omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), termed resolvins, protectins and maresins. These bioactive pro-resolving lipid mediators provide further rationale for the beneficial effects of fish-oil enriched diets. These endogenous lipid mediators are spatiotemporally biosynthesized to actively regulate resolution by acting on specific G protein-coupled receptors (GPCRs) to initiate anti-inflammatory and pro-resolving signals that terminate inflammation. In this review, we will discuss the mechanism of actions of these molecules, including their analgesic and bone-sparing properties making them ideal therapeutic agonists for the treatment of inflammatory diseases such as rheumatoid arthritis. PMID:26165764

  16. Safety assessment of animal- and plant-derived amino acids as used in cosmetics.

    PubMed

    Burnett, Christina; Heldreth, Bart; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

    2014-01-01

    The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of animal- and plant-derived amino acid mixtures, which function as skin and hair conditioning agents. The safety of α-amino acids as direct food additives has been well established, based on extensive research through acute and chronic dietary exposures and the Panel previously has reviewed the safety of individual α-amino acids in cosmetics. The Panel focused its review on dermal irritation and sensitization data relevant to the use of these ingredients in topical cosmetics. The Panel concluded that these 21 ingredients are safe in the present practices of use and concentration as used in cosmetics. PMID:25323218

  17. Preparation of certain derivatives of ursolic acid and their antimicrobial activity

    SciTech Connect

    Zaletova, N.I.; Shchavlinskii, A.N.; Tolkachev, O.N.; Vichkanova, S.A.; Fateeva, T.V.; Krutikova, N.M.; Yartseva, I.V.; Klyuev, N.A.

    1987-03-01

    The authors studied the industrial wastes from the production of an antitumorigenic preparation rosevin, in which about 18% of ursolic acid was found. They obtained several oxygen-substituted derivatives of ursolic acid by oxidation with chromic acid and KMnO/sub 4/ in different media to study their biological activity. The structure of the compounds obtained was confirmed by the data of IR and PMR spectra and also by the data of molecular mass spectroscopy with ionization of the molecules under an electron impact.

  18. Nahuoic Acids B-E, Polyhydroxy Polyketides from the Marine-Derived Streptomyces sp. SCSGAA 0027.

    PubMed

    Nong, Xu-Hua; Zhang, Xiao-Yong; Xu, Xin-Ya; Wang, Jie; Qi, Shu-Hua

    2016-01-22

    Four new polyol polyketides containing a decalin ring, nahuoic acids B-E (1-4), together with a known analogue, nahuoic acid A (5), possessing an unprecedented carbon skeleton, were isolated from a culture broth of the marine-derived Streptomyces sp. SCSGAA 0027. Their structures were determined by detailed analysis of spectroscopic data and chemical transformations including acetonide formation and Mosher's ester method. Compounds 1-5 showed weak antibiofilm activity against Shewanella onedensis MR-1 biofilm. This is the first series of analogues of the novel selective SETD8 inhibitor nahuoic acid A. PMID:26684286

  19. Bile acid derivatives as ligands of the farnesoid x receptor: molecular determinants for bile acid binding and receptor modulation.

    PubMed

    Gioiello, Antimo; Cerra, Bruno; Mostarda, Serena; Guercini, Chiara; Pellicciari, Roberto; Macchiarulo, Antonio

    2014-01-01

    Bile acids are a peculiar class of steroidal compounds that never cease to amaze. From being simple detergents with a primary role in aiding the absorption of fats and fat-soluble vitamins, bile acids are now widely considered as crucial hormones endowed with genomic and non-genomic functions that are mediated by their interaction with several proteins including the nuclear receptor Farnesoid X Receptor (FXR). Taking advantages of the peculiar properties of bile acids in interacting with the FXR receptor, several biliary derivatives have been synthesized and tested as FXR ligands. The availability of these compounds has contributed to characterize the receptor from a structural, patho-physiological and therapeutic standpoint. Among these, obeticholic acid is a first-in-class FXR agonist that is demonstrating hepatoprotective effects upon FXR activation in patients with liver diseases such as primary biliary cirrhosis and nonalcoholic steatohepatitis. This review provides an historical overview of the rationale behind the discovery of obeticholic acid and chemical tools generated to depict the molecular features and bio-pharmacological relevance of the FXR receptor, as well as to summarize structure-activity relationships of bile acid-based FXR ligands so far reported. PMID:25388535

  20. Obestatin Accelerates the Healing of Acetic Acid-Induced Colitis in Rats

    PubMed Central

    Matuszyk, Aleksandra; Ceranowicz, Piotr; Warzecha, Zygmunt; Cieszkowski, Jakub; Bonior, Joanna; Jaworek, Jolanta; Kuśnierz-Cabala, Beata; Konturek, Peter; Ambroży, Tadeusz; Dembiński, Artur

    2016-01-01

    Obestatin, a 23-amino acid peptide derived from the proghrelin, has been shown to exhibit some protective and therapeutic effects in the gut. The aim of present study was to determine the effect of obestatin administration on the course of acetic acid-induced colitis in rats. Materials and Methods. Studies have been performed on male Wistar rats. Colitis was induced by a rectal enema with 3.5% acetic acid solution. Obestatin was administered intraperitoneally twice a day at a dose of 8 nmol/kg, starting 24 h after the induction of colitis. Seven or 14 days after the induction of colitis, the healing rate of the colon was evaluated. Results. Treatment with obestatin after induction of colitis accelerated the healing of colonic wall damage and this effect was associated with a decrease in the colitis-evoked increase in mucosal activity of myeloperoxidase and content of interleukin-1β. Moreover, obestatin administration significantly reversed the colitis-evoked decrease in mucosal blood flow and DNA synthesis. Conclusion. Administration of exogenous obestatin exhibits therapeutic effects in the course of acetic acid-induced colitis and this effect is related, at least in part, to the obestatin-evoked anti-inflammatory effect, an improvement of local blood flow, and an increase in cell proliferation in colonic mucosa. PMID:26798415

  1. A Surprising Mechanistic “Switch” in Lewis Acid Activation: A Bifunctional, Asymmetric Approach to α-Hydroxy Acid Derivatives

    PubMed Central

    Abraham, Ciby J.; Paull, Daniel H.; Bekele, Tefsit; Scerba, Michael T.; Dudding, Travis; Lectka, Thomas

    2009-01-01

    We report a detailed synthetic and mechanistic study of an unusual bifunctional, sequential hetero-Diels–Alder/ring-opening reaction in which chiral, metal complexed ketene enolates react with o-quinones to afford highly enantioenriched, α-hydroxylated carbonyl derivatives in excellent yield. A number of Lewis acids were screened in tandem with cinchona alkaloid derivatives; surprisingly, trans-(Ph3P)2PdCl2 was found to afford the most dramatic increase in yield and rate of reaction. A series of Lewis acid binding motifs were explored through molecular modeling, as well as IR, UV and NMR spectroscopy. Our observations document a fundamental mechanistic “switch” – namely the formation of a tandem Lewis base/Lewis acid activated metal enolate in preference to a metal-coordinated quinone species (as observed in other reactions of o-quinone derivatives). This new method was applied to the syntheses of several pharmaceutical targets, each of which was obtained in high yield and enantioselectivity. PMID:19053448

  2. Polychlorinated biphenyl (PCB) alters acid-sensitivity of cultured neurons derived from the medulla oblongata.

    PubMed

    Okada, Junichi; Shimokawa, Noriaki; Koibuchi, Noriyuki

    2005-07-01

    Polychlorinated biphenyls (PCBs) are known as environmental pollutants that may cause adverse health problems. However, little is known about the effects of PCBs on acid-sensitive neurons of the medulla oblongata, which regulate respiration. Therefore, the present study was designed to examine whether PCB alters acid-sensitivity of cultured neurons derived from the rat medulla oblongata. When extracellular pH was shifted from 7.4 to 7.0, acid-sensitive neurons showed depolarization, which was measured by voltage-sensitive fluorescent dye. Exposure to PCB (Aroclor 1254) decreased the amplitude of depolarization in low pH and increased the resting membrane potential in a dose-dependent manner. Taken together, our results indicate that PCB potentially influences acid-sensitivity through alteration of the membrane potential of acid-sensitive neurons, which could affect the regulation of respiration. PMID:15833269

  3. Interactions of cyclic and non-cyclic naphthalene diimide derivatives with different nucleic acids.

    PubMed

    Czerwinska, Izabella; Sato, Shinobu; Juskowiak, Bernard; Takenaka, Shigeori

    2014-05-01

    Recently, strategy based on stabilization of G-quadruplex telomeric DNA by small organic molecule has been realized by naphthalene diimide derivatives (NDIs). At the same time NDIs bind to DNA duplex as threading intercalators. Here we present cyclic derivative of naphthalene diimide (ligand 1) as DNA-binding ligand with ability to recognition of different structures of telomeric G-quadruplexes and ability to bis-intercalate to double-stranded helixes. The results have been compared to non-cyclic derivative (ligand 2) and revealed that preferential binding of ligands to nucleic acids strongly depends on their topology and structural features of ligands. PMID:24726302

  4. Simultaneous determination of 2-naphthoxyacetic acid and indole-3-acetic acid by first derivation synchronous fluorescence spectroscopy.

    PubMed

    Liu, Xiangxiang; Wan, Yiqun

    2013-07-01

    A simple, rapid, sensitive and selective method for simultaneously determining 2-naphthoxyacetic acid (BNOA) and Indole-3-Acetic Acid (IAA) in mixtures has been developed using derivation synchronous fluorescence spectroscopy based on their synchronous fluorescence. The synchronous fluorescence spectra were obtained with Δλ=100 nm in a pH 8.5 NaH2PO4-NaOH buffer solution, and the detected wavelengths of quantitative analysis were set at 239 nm for BNOA and 293 nm for IAA respectively. The over lapped fluorescence spectra were well separated by the synchronous derivative method. Under optimized conditions, the limits of detection (LOD) were 0.003 μg/mL for BNOA and 0.012 μg/mL for IAA. This method is simple and expeditious, and it has been successfully applied to the determination of 2-naphthoxyacetic acid and indole-3-acetic acid in fruit juice samples with satisfactory results. The samples were only filtrated through a 0.45 μm membrane filter, which was free from the tedious separation procedures. The obtaining recoveries were in the range of 83.88-87.43% for BNOA and 80.76-86.68% for IAA, and the relative standard deviations were all less than 5.0%. Statistical comparison of the results with high performance liquid chromatography Mass Spectrometry (HPLC-MS) method revealed good agreement and proved that there were no significant difference in the accuracy and precision between these two methods. PMID:23651742

  5. C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors.

    PubMed

    Liu, Zheng; Swidorski, Jacob J; Nowicka-Sans, Beata; Terry, Brian; Protack, Tricia; Lin, Zeyu; Samanta, Himadri; Zhang, Sharon; Li, Zhufang; Parker, Dawn D; Rahematpura, Sandhya; Jenkins, Susan; Beno, Brett R; Krystal, Mark; Meanwell, Nicholas A; Dicker, Ira B; Regueiro-Ren, Alicia

    2016-04-15

    A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50=16nM for 9a compared to 10nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI. PMID:26968652

  6. Simultaneous determination of 2-naphthoxyacetic acid and indole-3-acetic acid by first derivation synchronous fluorescence spectroscopy

    NASA Astrophysics Data System (ADS)

    Liu, Xiangxiang; Wan, Yiqun

    2013-07-01

    A simple, rapid, sensitive and selective method for simultaneously determining 2-naphthoxyacetic acid (BNOA) and Indole-3-Acetic Acid (IAA) in mixtures has been developed using derivation synchronous fluorescence spectroscopy based on their synchronous fluorescence. The synchronous fluorescence spectra were obtained with Δλ = 100 nm in a pH 8.5 NaH2PO4-NaOH buffer solution, and the detected wavelengths of quantitative analysis were set at 239 nm for BNOA and 293 nm for IAA respectively. The over lapped fluorescence spectra were well separated by the synchronous derivative method. Under optimized conditions, the limits of detection (LOD) were 0.003 μg/mL for BNOA and 0.012 μg/mL for IAA. This method is simple and expeditious, and it has been successfully applied to the determination of 2-naphthoxyacetic acid and indole-3-acetic acid in fruit juice samples with satisfactory results. The samples were only filtrated through a 0.45 μm membrane filter, which was free from the tedious separation procedures. The obtaining recoveries were in the range of 83.88-87.43% for BNOA and 80.76-86.68% for IAA, and the relative standard deviations were all less than 5.0%. Statistical comparison of the results with high performance liquid chromatography Mass Spectrometry (HPLC-MS) method revealed good agreement and proved that there were no significant difference in the accuracy and precision between these two methods.

  7. Retinoic acid-primed human dendritic cells inhibit Th9 cells and induce Th1/Th17 cell differentiation.

    PubMed

    Rampal, Ritika; Awasthi, Amit; Ahuja, Vineet

    2016-07-01

    All-trans-retinoic acid plays a central role in mucosal immunity, where it promotes its synthesis by up-regulating CD103 expression on dendritic cells, induces gut tropic (α4β7(+) and CCR9(+)) T cells, and inhibits Th1/Th17 differentiation. Recently, murine studies have highlighted the proinflammatory role of retinoic acid in maintaining inflammation under a variety of pathologic conditions. However, as a result of limited human data, we investigated the effect of retinoic acid on human dendritic cells and CD4(+) T cell responses in the presence of polarizing (Th1/Th9/Th17) and inflammatory (LPS-induced dendritic cells) conditions. We report a novel role of retinoic acid in an inflammatory setup, where retinoic acid-primed dendritic cells (retinoic acid-monocyte-derived dendritic cells) up-regulated CCR9(+)T cells, which were observed to express high levels of IFN-γ in the presence of Th1/Th17 conditions. Retinoic acid-monocyte-derived dendritic cells, under Th17 conditions, also favored the induction of IL-17(+) T cells. Furthermore, in the presence of TGF-β1 and IL-4, retinoic acid-monocyte-derived dendritic cells inhibited IL-9 and induced IFN-γ expression on T cells. Experiments with naïve CD4(+) T cells, activated in the presence of Th1/Th17 conditions and absence of DCs, indicated that retinoic acid inhibited IFN-γ and IL-17 expression on T cells. These data revealed that in the face of inflammatory conditions, retinoic acid, in contrast from its anti-inflammatory role, could maintain or aggravate the intestinal inflammation. PMID:26980802

  8. γ-Hydroxybutyric Acid-Induced Electrographic Seizures

    PubMed Central

    Cheung, Joseph; Lucey, Brendan P.; Duntley, Stephen P.; Darken, Rachel S.

    2014-01-01

    We describe a case of absence-like electrographic seizures during NREM sleep in a patient who was taking sodium oxybate, a sodium salt of γ-hydroxybutyric acid (GHB). An overnight full montage electroencephalography (EEG) study revealed numerous frontally predominant rhythmic 1.5-2 Hz sharp waves and spike-wave activity during stage N2 and N3 sleep at the peak dose time for sodium oxybate, resembling atypical absence-like electrographic seizures. The patient was later weaned off sodium oxybate, and a repeat study did not show any such electrographic seizures. Absence-like seizures induced by GHB had previously been described in experimental animal models. We present the first reported human case of absence-like electrographic seizure associated with sodium oxybate. Citation: Cheung J, Lucey BP, Duntley SP, Darken RS. γ-hydroxybutyric acid-induced electrographic seizures. J Clin Sleep Med 2014;10(7):811-812. PMID:25024661

  9. Spontaneous H2 loss through the interaction of squaric acid derivatives and BeH2.

    PubMed

    Montero-Campillo, M Merced; Yáñez, Manuel; Lamsabhi, Al Mokhtar; Mó, Otilia

    2014-04-25

    The most stable complexes between squaric acid and its sulfur- and selenium-containing analogues (C4X4H2 ; X = O, S, Se) with BeY2 (Y = H, F) were studied by means of the Gaussian 04 (G4) composite ab initio theory. Squaric acid derivatives are predicted to be very strong acids in the gas phase; their acidity increases with the size of the chalcogen, with C4Se4H2 being the strongest acid of the series and stronger than sulfuric acid. The relative stability of the C4X4H2⋅BeY2 (X = O, S, Se; Y = H, F) complexes changes with the nature of the chalcogen atom; but more importantly, the formation of the C4X4H2⋅BeF2 complexes results in a substantial acidity enhancement of the squaric moiety owing to the dramatic electron-density redistribution undergone by the system when the beryllium bond is formed. The most significant consequence of this acidity enhancement is that when BeF2 is replaced by BeH2, a spontaneous exergonic loss of H2 is observed regardless of the nature of the chalcogen atom. This is another clear piece of evidence of the important role that closed-shell interactions play in the modulation of physicochemical properties of the Lewis acid and/or the Lewis base. PMID:24665080

  10. Growth behavior of anodic oxide formed by aluminum anodizing in glutaric and its derivative acid electrolytes

    NASA Astrophysics Data System (ADS)

    Nakajima, Daiki; Kikuchi, Tatsuya; Natsui, Shungo; Suzuki, Ryosuke O.

    2014-12-01

    The growth behavior of anodic oxide films formed via anodizing in glutaric and its derivative acid solutions was investigated based on the acid dissociation constants of electrolytes. High-purity aluminum foils were anodized in glutaric, ketoglutaric, and acetonedicarboxylic acid solutions under various electrochemical conditions. A thin barrier anodic oxide film grew uniformly on the aluminum substrate by glutaric acid anodizing, and further anodizing caused the film to breakdown due to a high electric field. In contrast, an anodic porous alumina film with a submicrometer-scale cell diameter was successfully formed by ketoglutaric acid anodizing at 293 K. However, the increase and decrease in the temperature of the ketoglutaric acid resulted in non-uniform oxide growth and localized pitting corrosion of the aluminum substrate. An anodic porous alumina film could also be fabricated by acetonedicarboxylic acid anodizing due to the relatively low dissociation constants associated with the acid. Acid dissociation constants are an important factor for the fabrication of anodic porous alumina films.

  11. Free and bound cinnamic acid derivatives in corsica sweet blond oranges.

    PubMed

    Carrera, Eric; El Kebir, Mohamed Vall Ould; Jacquemond, Camille; Luro, François; Lozano, Yves; Gaydou, Emile M

    2010-03-01

    Total determination of cinnamic acids (CA), including hydroxycinnamic acid derivatives is generally not accurate since, during hydrolysis, a possible degradation of dihydroxy CA such as caffeic acid could occur. Evaluations of CA (ferulic, p-coumaric, sinapic, cinnamic and caffeic acids) before and after hydrolysis have been undertaken using standards and either with or without addition of ascorbic acid and EDTA. The method was then applied to the determination of free and bound CA in five blond cultivars (Navelina, Washington navel, Pera, Salustiana and Valencia late) of sweet oranges [Citrus sinensis (L.) Osb.]. Four parts of the fruits (peel juice, flavedo, albedo and juice) have been investigated. Results show that CA are mainly bound (86% up to 92%) in the four fruit parts. The mean of total CA contents was found to be higher in peel juice (1.5 g kg(-1)) in comparison with flavedo (0.7 g kg(-1)), albedo (0.1 g kg(-1)) and juice (0.6 g kg(-1)). Free and bound ferulic acid represented 55-70% of CA in juices, followed by p-coumaric acid (20%), sinapic acid (10%) and caffeic acid (9%). Total contents of each CA in the four fruit parts are discussed and show the potential interest in orange peel wastes. PMID:20420324

  12. In vitro inhibition of salicylic acid derivatives on human cytosolic carbonic anhydrase isozymes I and II.

    PubMed

    Bayram, Esra; Senturk, Murat; Kufrevioglu, O Irfan; Supuran, Claudiu T

    2008-10-15

    The inhibition of two human cytosolic carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, hCA I and II, with a series of salicylic acid derivatives was investigated by using the esterase method with 4-nitrophenyl acetate as substrate. IC(50) values for sulfasalazine, diflunisal, 5-chlorosalicylic acid, dinitrosalicylic acid, 4-aminosalicylic acid, 4-sulfosalicylic acid, 5-sulfosalicylic acid, salicylic acid, acetylsalicylic acid (aspirin) and 3-metylsalicylic acid were of 3.04 microM, 3.38 microM, 4.07 microM, 7.64 microM, 0.13 mM, 0.29 mM, 0.42 mM, 0.56 mM, 2.71 mM and 3.07 mM for hCA I and of 4.49 microM, 2.70 microM, 0.72 microM, 2.80 microM, 0.75 mM, 0.72 mM, 0.29 mM, 0.68 mM, 1.16 mM and 4.70 mM for hCA II, respectively. Lineweaver-Burk plots were also used for the determination of the inhibition mechanism of these substituted phenols, most of which were noncompetitive inhibitors with this substrate. Some salicylic acid derivatives investigated here showed effective hCA I and II inhibitory activity, and might be used as leads for generating enzyme inhibitors eventually targeting other isoforms which have not been assayed yet for their interactions with such agents. PMID:18819808

  13. Oleanolic acid prevents glucocorticoid-induced hypertension in rats.

    PubMed

    Bachhav, Sagar S; Patil, Savita D; Bhutada, Mukesh S; Surana, Sanjay J

    2011-10-01

    The present study was designed to evaluate the antihypertensive activity of oleanolic acid isolated from Viscum articulatum, Burm. (Loranthaceae) in glucocorticoid (dexamethasone)-induced hypertension in rats and to propose a probable mechanism of action for this effect. Male Wistar rats (300-350 g) received dexamethasone (20 μg/kg/day s.c.) or saline (vehicle) for 10 days. In a prevention study, the rats received oleanolic acid (60 mg/kg i.p.) for 5 days, followed by dexamethasone or saline for 10 days. During this period the systolic blood pressure and body weight were evaluated on alternate days. At the end of the experiment, the weight of the thymus gland, plasma nitrate/nitrite (nitric oxide metabolites) concentration and cardiac lipid peroxidation value were determined. Oleanolic acid (60 mg/kg i.p.) significantly prevented a rise in the systolic blood pressure and cardiac lipid peroxidation level after administration of dexamethasone (p < 0.01 and p < 0.05, respectively) without showing any significant effect on the dexamethasone-induced change in body and thymus weights. The decrease in concentration of plasma nitrate/nitrite due to dexamethasone was prevented significantly in the group treated with oleanolic acid (p < 0.05). These findings suggest that oleanolic acid (60 mg/kg i.p.) prevents dexamethasone-induced hypertension in rats, which may be attributed to its antioxidant and nitric oxide releasing action. PMID:21953707

  14. Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid.

    PubMed

    Zhang, Dongxian; Lee, Brian; Nutter, Anthony; Song, Paul; Dolatabadi, Nima; Parker, James; Sanz-Blasco, Sara; Newmeyer, Traci; Ambasudhan, Rajesh; McKercher, Scott R; Masliah, Eliezer; Lipton, Stuart A

    2015-06-01

    Cyanide is a life-threatening, bioterrorist agent, preventing cellular respiration by inhibiting cytochrome c oxidase, resulting in cardiopulmonary failure, hypoxic brain injury, and death within minutes. However, even after treatment with various antidotes to protect cytochrome oxidase, cyanide intoxication in humans can induce a delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Additional mechanisms are thought to underlie cyanide-induced neuronal damage, including generation of reactive oxygen species. This may account for the fact that antioxidants prevent some aspects of cyanide-induced neuronal damage. Here, as a potential preemptive countermeasure against a bioterrorist attack with cyanide, we tested the CNS protective effect of carnosic acid (CA), a pro-electrophilic compound found in the herb rosemary. CA crosses the blood-brain barrier to up-regulate endogenous antioxidant enzymes via activation of the Nrf2 transcriptional pathway. We demonstrate that CA exerts neuroprotective effects on cyanide-induced brain damage in cultured rodent and human-induced pluripotent stem cell-derived neurons in vitro, and in vivo in various brain areas of a non-Swiss albino mouse model of cyanide poisoning that simulates damage observed in the human brain. Cyanide, a potential bioterrorist agent, can produce a chronic delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Here, cyanide poisoning treated with the proelectrophillic compound carnosic acid, results in reduced neuronal cell death in both in vitro and in vivo models through activation of the Nrf2/ARE transcriptional pathway. Carnosic acid is therefore a potential treatment for the toxic central nervous system (CNS) effects of cyanide poisoning. ARE, antioxidant responsive element; Nrf2 (NFE2L2, Nuclear factor (erythroid-derived 2)-like 2). PMID:25692407

  15. Acidic environments induce differentiation of Proteus mirabilis into swarmer morphotypes.

    PubMed

    Fujihara, Masatoshi; Obara, Hisato; Watanabe, Yusaku; Ono, Hisaya K; Sasaki, Jun; Goryo, Masanobu; Harasawa, Ryô

    2011-07-01

    Although swarmer morphotypes of Proteus mirabilis have long been considered to result from surfaced-induced differentiation, the present findings show that, in broth medium containing urea, acidic conditions transform some swimmer cells into elongated swarmer cells. This study has also demonstrates that P. mirabilis cells grown in acidic broth medium containing urea enhance virulence factors such as flagella production and cytotoxicity to human bladder carcinoma cell line T24, though no significant difference in urease activity under different pH conditions was found. Since there is little published data on the behavior of P. mirabilis at various hydrogen-ion concentrations, the present study may clarify aspects of cellular differentiation of P. mirabilis in patients at risk of struvite formation due to infection with urease-producing bacteria, as well as in some animals with acidic or alkaline urine. PMID:21707738

  16. Docosahexaenoic Acid Induces Apoptosis in Primary Chronic Lymphocytic Leukemia Cells

    PubMed Central

    Gyan, Emmanuel; Tournilhac, Olivier; Halty, Christelle; Veyrat-Masson, Richard; Akil, Saïda; Berger, Marc; Hérault, Olivier; Callanan, Mary; Bay, Jacques-Olivier

    2015-01-01

    Chronic lymphocytic leukemia is an indolent disorder with an increased infectious risk remaining one of the main causes of death. Development of therapies with higher safety profile is thus a challenging issue. Docosahexaenoic acid (DHA, 22:6) is an omega-3 fatty acid, a natural compound of normal cells, and has been shown to display antitumor potency in cancer. We evaluated the potential in vitro effect of DHA in primary CLL cells. DHA induces high level of in vitro apoptosis compared to oleic acid in a dose-dependent and time-dependent manner. Estimation of IC50 was only of 4.813 µM, which appears lower than those reported in solid cancers. DHA is highly active on CLL cells in vitro. This observation provides a rationale for further studies aiming to understand its mechanisms of action and its potent in vivo activity. PMID:26734128

  17. Correlation between chemical structure and rodent repellency of benzoic acid derivatives

    USGS Publications Warehouse

    Fearn, J.E.; DeWitt, J.B.

    1965-01-01

    Sixty-five benzoic acid derivatives were either prepared or obtained from commercial concerns, tested for rat repellency, and their indices of repellency computed. The data from these tests were considered analytically for any correlation between chemical structure and rat repellency. The results suggest a qualitative relationship which is useful in deciding probability of repellency in other compounds.

  18. Tracking of Drug Release and Material Fate for Naturally Derived Omega-3 Fatty Acid Biomaterials.

    PubMed

    Faucher, Keith M; Artzi, Natalie; Beck, Moshe; Beckerman, Rita; Moodie, Geoff; Albergo, Theresa; Conroy, Suzanne; Dale, Alicia; Corbeil, Scott; Martakos, Paul; Edelman, Elazer R

    2016-03-01

    In vitro and in vivo studies were conducted on omega-3 fatty acid-derived biomaterials to determine their utility as an implantable material for adhesion prevention following soft tissue hernia repair and as a means to allow for the local delivery of antimicrobial or antibiofilm agents. Naturally derived biomaterials offer several advantages over synthetic materials in the field of medical device development. These advantages include enhanced biocompatibility, elimination of risks posed by the presence of toxic catalysts and chemical crosslinking agents, and derivation from renewable resources. Omega-3 fatty acids are readily available from fish and plant sources and can be used to create implantable biomaterials either as a stand-alone device or as a device coating that can be utilized in local drug delivery applications. In-depth characterization of material erosion degradation over time using non-destructive imaging and chemical characterization techniques provided mechanistic insight into material structure: function relationship. This in turn guided rational tailoring of the material based on varying fatty acid composition to control material residence time and hence drug release. These studies demonstrate the utility of omega-3 fatty acid derived biomaterials as an absorbable material for soft tissue hernia repair and drug delivery applications. PMID:26502170

  19. Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport

    PubMed Central

    Michaelis, Martin; Rothweiler, Florian; Wurglics, Mario; Aniceto, Natália; Dittrich, Michaela; Zettl, Heiko; Wiese, Michael; Wass, Mark; Ghafourian, Taravat; Schubert-Zsilavecz, Manfred; Cinatl, Jindrich

    2016-01-01

    Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARα, PPARγ, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARα, and PPARγ represent potential anti-cancer drug targets, we here investigated the effects of 39 pirinixic acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPARα, or PPARγ. Most strikingly, pirinixic acid derivatives interfered with drug transport by the ATP-binding cassette (ABC) transporter ABCB1 in a drug-specific fashion. LP117, the compound that exerted the strongest effect on ABCB1, interfered in the investigated concentrations of up to 2μM with the ABCB1-mediated transport of vincristine, vinorelbine, actinomycin D, paclitaxel, and calcein-AM but not of doxorubicin, rhodamine 123, or JC-1. In silico docking studies identified differences in the interaction profiles of the investigated ABCB1 substrates with the known ABCB1 binding sites that may explain the substrate-specific effects of LP117. Thus, pirinixic acid derivatives may offer potential as drug-specific modulators of ABCB1-mediated drug transport. PMID:26887049

  20. Molecular structure of terrecyclodiol: a derivative of the antifungal metabolite terrecyclic acid A from Aspergillus terreus.

    PubMed

    Almassi, F; Ghisalberti, E L; Skelton, B W; White, A H

    1996-01-01

    A strain of Aspergillus terreus, which was isolated from organic mulch and inhibited the growth of the plant pathogen Phytophthora cinnamomi, produces an antifungal metabolite when grown in liquid culture. This metabolite was isolated by bioassay-guided fractionation and identified as terrecyclic acid A (1). X-ray diffraction studies and spectroscopic details of the derived terrecyclodiol (2) are described. PMID:8984154

  1. Copper-mediated ortho C-H sulfonylation of benzoic acid derivatives with sodium sulfinates.

    PubMed

    Liu, Jidan; Yu, Lin; Zhuang, Shaobo; Gui, Qingwen; Chen, Xiang; Wang, Wenduo; Tan, Ze

    2015-04-14

    Copper-mediated direct ortho C-H bond sulfonylation of benzoic acid derivatives with sodium sulfinates was achieved by employing an 8-aminoquinoline moiety as the bidentate directing group. Various aryl sulfones were synthesized in good yields with excellent regioselectivity. PMID:25766975

  2. Antioxidant glucosylated caffeoylquinic acid derivatives in the invasive tropical soda apple, Solanum viarum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The eggplant (Solanum melongena) and other species within the “spiny solanums” (Solanum subgenus Leptostemonum) contain diverse and abundant antioxidant caffeoylquinic acid (CQA) derivatives. The fruit of an aggressive invasive species in the spiny solanums, Solanum viarum, contain numerous CQA deri...

  3. Heterogeneous catalysts for the transformation of fatty acid triglycerides and their derivatives to fuel hydrocarbons

    NASA Astrophysics Data System (ADS)

    Yakovlev, Vadim A.; Khromova, Sofia A.; Bukhtiyarov, Valerii I.

    2011-10-01

    The results of studies devoted to the catalysts for transformation of fatty acid triglycerides and their derivatives to fuel hydrocarbons are presented and described systematically. Various approaches to the use of heterogeneous catalysts for the production of biofuel from these raw materials are considered. The bibliography includes 134 references.

  4. Nickel(II) and copper(II) complexes with humic acid anions and their derivatives

    SciTech Connect

    Ryabova, I.N.

    2008-01-15

    Complexation of Ni(II) and Cu(II) in aqueous solutions with anions of humic acids, extracted from naturally oxidized coal, and with their hydroxymethyl derivatives is studied spectrophotometrically and potentiometrically. The complexation stoichiometry and the stability constants of the complexes are determined.

  5. Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport.

    PubMed

    Michaelis, Martin; Rothweiler, Florian; Wurglics, Mario; Aniceto, Natália; Dittrich, Michaela; Zettl, Heiko; Wiese, Michael; Wass, Mark; Ghafourian, Taravat; Schubert-Zsilavecz, Manfred; Cinatl, Jindrich

    2016-03-01

    Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARα, PPARγ, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARα, and PPARγ represent potential anti-cancer drug targets, we here investigated the effects of 39 pirinixic acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPARα, or PPARγ. Most strikingly, pirinixic acid derivatives interfered with drug transport by the ATP-binding cassette (ABC) transporter ABCB1 in a drug-specific fashion. LP117, the compound that exerted the strongest effect on ABCB1, interfered in the investigated concentrations of up to 2μM with the ABCB1-mediated transport of vincristine, vinorelbine, actinomycin D, paclitaxel, and calcein-AM but not of doxorubicin, rhodamine 123, or JC-1. In silico docking studies identified differences in the interaction profiles of the investigated ABCB1 substrates with the known ABCB1 binding sites that may explain the substrate-specific effects of LP117. Thus, pirinixic acid derivatives may offer potential as drug-specific modulators of ABCB1-mediated drug transport. PMID:26887049

  6. Organocatalytic enantioselective γ-aminoalkylation of unsaturated ester: access to pipecolic acid derivatives.

    PubMed

    Xu, Jianfeng; Jin, Zhichao; Chi, Yonggui Robin

    2013-10-01

    The direct γ-carbon functionalization of α,β-unsaturated esters via N-Heterocyclic Carbene (NHC) catalysis is disclosed. This catalytically generated nucleophilic γ-carbon undergoes highly enantioselective additions to hydrazones. The resulting δ-lactam products can be readily transformed to optically enriched pipecolic acid derivatives. PMID:24067098

  7. Diet derived phenolic acids regulate osteoblast and adipocyte lineage commitment and differentiation in young mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A blueberry (BB) supplemented diet previously has been shown to significantly stimulate bone formation in rapidly growing male and female rodents. Phenolic acids (PAs) are metabolites derived from polyphenols found in fruits and vegetables as a result of the actions of gut bacteria, and they were fo...

  8. Production of Fatty Acid-Derived Valuable Chemicals in Synthetic Microbes

    PubMed Central

    Yu, Ai-Qun; Pratomo Juwono, Nina Kurniasih; Leong, Susanna Su Jan; Chang, Matthew Wook

    2014-01-01

    Fatty acid derivatives, such as hydroxy fatty acids, fatty alcohols, fatty acid methyl/ethyl esters, and fatty alka(e)nes, have a wide range of industrial applications including plastics, lubricants, and fuels. Currently, these chemicals are obtained mainly through chemical synthesis, which is complex and costly, and their availability from natural biological sources is extremely limited. Metabolic engineering of microorganisms has provided a platform for effective production of these valuable biochemicals. Notably, synthetic biology-based metabolic engineering strategies have been extensively applied to refactor microorganisms for improved biochemical production. Here, we reviewed: (i) the current status of metabolic engineering of microbes that produce fatty acid-derived valuable chemicals, and (ii) the recent progress of synthetic biology approaches that assist metabolic engineering, such as mRNA secondary structure engineering, sensor-regulator system, regulatable expression system, ultrasensitive input/output control system, and computer science-based design of complex gene circuits. Furthermore, key challenges and strategies were discussed. Finally, we concluded that synthetic biology provides useful metabolic engineering strategies for economically viable production of fatty acid-derived valuable chemicals in engineered microbes. PMID:25566540

  9. Polyhydroxyalkanoate-based 3-hydroxyoctanoic acid and its derivatives as a platform of bioactive compounds.

    PubMed

    Radivojevic, Jelena; Skaro, Sanja; Senerovic, Lidija; Vasiljevic, Branka; Guzik, Maciej; Kenny, Shane T; Maslak, Veselin; Nikodinovic-Runic, Jasmina; O'Connor, Kevin E

    2016-01-01

    A library of 18 different compounds was synthesized starting from (R)-3-hydroxyoctanoic acid which is derived from the bacterial polymer polyhydroxyalkanoate (PHA). Ten derivatives, including halo and unsaturated methyl and benzyl esters, were synthesized and characterized for the first time. Given that (R)-3-hydroxyalkanoic acids are known to have biological activity, the new compounds were evaluated for antimicrobial activity and in vitro antiproliferative effect with mammalian cell lines. The presence of the carboxylic group was essential for the antimicrobial activity, with minimal inhibitory concentrations against a panel of bacteria (Gram-positive and Gram-negative) and fungi (Candida albicans and Microsporum gypseum) in the range 2.8-7.0 mM and 0.1-6.3 mM, respectively. 3-Halogenated octanoic acids exhibited the ability to inhibit C. albicans hyphae formation. In addition, (R)-3-hydroxyoctanoic and (E)-oct-2-enoic acids inhibited quorum sensing-regulated pyocyanin production in the opportunistic pathogen Pseudomonas aeruginosa PAO1. Generally, derivatives did not inhibit mammalian cell proliferation even at 3-mM concentrations, while only (E)-oct-2-enoic and 3-oxooctanoic acid had IC50 values of 1.7 and 1.6 mM with the human lung fibroblast cell line. PMID:26399414

  10. IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid.

    PubMed

    Naujoks, Jan; Tabeling, Christoph; Dill, Brian D; Hoffmann, Christine; Brown, Andrew S; Kunze, Mareike; Kempa, Stefan; Peter, Andrea; Mollenkopf, Hans-Joachim; Dorhoi, Anca; Kershaw, Olivia; Gruber, Achim D; Sander, Leif E; Witzenrath, Martin; Herold, Susanne; Nerlich, Andreas; Hocke, Andreas C; van Driel, Ian; Suttorp, Norbert; Bedoui, Sammy; Hilbi, Hubert; Trost, Matthias; Opitz, Bastian

    2016-02-01

    Macrophages can be niches for bacterial pathogens or antibacterial effector cells depending on the pathogen and signals from the immune system. Here we show that type I and II IFNs are master regulators of gene expression during Legionella pneumophila infection, and activators of an alveolar macrophage-intrinsic immune response that restricts bacterial growth during pneumonia. Quantitative mass spectrometry revealed that both IFNs substantially modify Legionella-containing vacuoles, and comparative analyses reveal distinct subsets of transcriptionally and spatially IFN-regulated proteins. Immune-responsive gene (IRG)1 is induced by IFNs in mitochondria that closely associate with Legionella-containing vacuoles, and mediates production of itaconic acid. This metabolite is bactericidal against intravacuolar L. pneumophila as well as extracellular multidrug-resistant Gram-positive and -negative bacteria. Our study explores the overall role IFNs play in inducing substantial remodeling of bacterial vacuoles and in stimulating production of IRG1-derived itaconic acid which targets intravacuolar pathogens. IRG1 or its product itaconic acid might be therapeutically targetable to fight intracellular and drug-resistant bacteria. PMID:26829557

  11. IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid

    PubMed Central

    Naujoks, Jan; Kunze, Mareike; Kempa, Stefan; Peter, Andrea; Mollenkopf, Hans-Joachim; Dorhoi, Anca; Kershaw, Olivia; Gruber, Achim D.; Sander, Leif E.; Witzenrath, Martin; Herold, Susanne; Nerlich, Andreas; Hocke, Andreas C.; van Driel, Ian; Suttorp, Norbert; Bedoui, Sammy; Hilbi, Hubert; Trost, Matthias; Opitz, Bastian

    2016-01-01

    Macrophages can be niches for bacterial pathogens or antibacterial effector cells depending on the pathogen and signals from the immune system. Here we show that type I and II IFNs are master regulators of gene expression during Legionella pneumophila infection, and activators of an alveolar macrophage-intrinsic immune response that restricts bacterial growth during pneumonia. Quantitative mass spectrometry revealed that both IFNs substantially modify Legionella-containing vacuoles, and comparative analyses reveal distinct subsets of transcriptionally and spatially IFN-regulated proteins. Immune-responsive gene (IRG)1 is induced by IFNs in mitochondria that closely associate with Legionella-containing vacuoles, and mediates production of itaconic acid. This metabolite is bactericidal against intravacuolar L. pneumophila as well as extracellular multidrug-resistant Gram-positive and -negative bacteria. Our study explores the overall role IFNs play in inducing substantial remodeling of bacterial vacuoles and in stimulating production of IRG1-derived itaconic acid which targets intravacuolar pathogens. IRG1 or its product itaconic acid might be therapeutically targetable to fight intracellular and drug-resistant bacteria. PMID:26829557

  12. Sm(II)-Mediated Electron Transfer to Carboxylic Acid Derivatives: Development of Complexity-Generating Cascades.

    PubMed

    Just-Baringo, Xavier; Procter, David J

    2015-05-19

    Reductive electron transfer (ET) to organic compounds is a powerful method for the activation of substrates via the formation of radicals, radical anions, anions, and dianions that can be exploited in bond-cleaving and bond-forming processes. Since its introduction to the synthetic community in 1977 by Kagan, SmI2 has become one of the most important reducing agents available in the laboratory. Despite its widespread application in aldehyde and ketone reduction, it was widely accepted that carboxylic acid derivatives could not be reduced by SmI2; only recently has our work led to this dogma being overturned, and the reduction of carboxylic acid derivatives using SmI2 can now take its place alongside aldehyde/ketone reduction as a powerful activation mode for synthesis. In this Account, we set out our studies of the reduction of carboxylic acid derivatives using SmI2, SmI2-H2O, and SmI2-H2O-NR3 and the exploitation of the unusual radical anions that are now accessible in unprecedented carbon-carbon bond-forming processes. The Account begins with our serendipitous discovery that SmI2 mixed with H2O is able to reduce six-membered lactones to diols, a transformation previously thought to be impossible. After the successful development of selective monoreductions of Meldrum's acid and barbituric acid heterocyclic feedstocks, we then identified the SmI2-H2O-NR3 reagent system for the efficient reduction of a range of acyclic carboxylic acid derivatives that typically present a significant challenge for ET reductants. Mechanistic studies have led us to propose a common mechanism for the reduction of carboxylic acid derivatives using Sm(II), with only subtle changes observed as the carboxylic acid derivative and Sm(II) reagent system are varied. At the center of our postulated mechanism is the proposed reversibility of the first ET to the carbonyl of carboxylic acid derivatives, and this led us to devise several strategies that allow the radical anion intermediates to be

  13. [Effect of excitant amino acid antagonists on glutamate receptors in the locust and on convulsions induced by glutamate, aspartate, kynurenine and quinolinic acid in mice].

    PubMed

    Ryzhov, I V; Slepokurov, M V; Lapin, I P; Mandel'shtam, Iu E; Aleksandrov, V G

    1986-03-01

    All excitatory amino acid antagonists studied: diethyl esters of aspartic (DEEA) and glutamic (DEEG) acids, 2-amino-3-phosphono-propionic acid (APPA) and 2-amino-4-phosphono-butanoic acid (APBA), diminished the amplitude of excitatory postsynaptic potentials (EPP) of the locust (Locusta migratoria migratorioides) muscle fibers and arbitrary blocked glutamate (GLU) and aspartate (ASP) responses. Kynurenine (KYN) and quinolinic (QUI) acid had no effect on EPP even at a concentration of 2 X 10(-2) M. The antagonists were not strictly selective against intracerebroventricularly administered endogenous convulsants: GLU, ASP, KYN and QUI and in simulation of experimental seizures in mice. The antagonists structurally similar to ASP prevented ASP- and KYN-induced seizures in lower doses than GLU derivatives. Anti-KYN, but not anti-QUI DEEA, DEEG, APPA and APBA efficacy suggests that KYN and QUI act on different structures or binding sites. PMID:2869799

  14. Search for novel histone deacetylase inhibitors. Part II: design and synthesis of novel isoferulic acid derivatives.

    PubMed

    Lu, Wen; Wang, Fang; Zhang, Tao; Dong, Jinyun; Gao, Hongping; Su, Ping; Shi, Yaling; Zhang, Jie

    2014-05-01

    Previously, we described the discovery of potent ferulic acid-based histone deacetylase inhibitors (HDACIs) with halogeno-acetanilide as novel surface recognition moiety (SRM). In order to improve the affinity and activity of these HDACIs, twenty seven isoferulic acid derivatives were described herein. The majority of title compounds displayed potent HDAC inhibitory activity. In particular, IF5 and IF6 exhibited significant enzymatic inhibitory activities, with IC50 values of 0.73 ± 0.08 and 0.57 ± 0.16 μM, respectively. Furthermore, these compounds showed moderate antiproliferative activity against human cancer cells. Especially, IF6 displayed promising profile as an antitumor candidate with IC50 value of 3.91 ± 0.97 μM against HeLa cells. The results indicated that these isoferulic acid derivatives could serve as promising lead compounds for further optimization. PMID:24702857

  15. [The influence of docosahexaenoic acid moiety on cytotoxic activity of 1,2,4-thiadiazole derivatives].

    PubMed

    Akimov, M G; Gretskaia, N M; Karnoukhova, V A; Serkov, I V; Proshin, A N; Shtratnikova, V Iu; Bezuglov, V V

    2014-01-01

    Among 3-(2-aminopropyl)-1,2,4-thiadiazole derivatives contatining substitution-ready secondary amino group and exhibiting cytotoxic towards rat C 6 glioma cells three compounds with LD 50 values ranged from 6 to 48 мM were chosen. For these compounds amides with docosahexaenoic acid were synthetised and their cytotoxic activity was studied. It was shown that, although docosahexaenoic acid itself was not toxic for C 6 glioma cells, its addition to the amino derivatives of 1,2,4-thiadiazole increased or decreased resultant cytotoxicity. The effect depended on the structure of 1,2,4-thiadiazole substituents. The obtained data show that the acylation of cytotoxic compounds with docosahexaenoic acid does not necessarily lead to the increase of their activity, but sometimes can inactivate a compound. This fact should be taken into account, especially in the case of anti-cancer drug development. PMID:25249531

  16. Medicinal importance of gallic acid and its ester derivatives: a patent review.

    PubMed

    Choubey, Sneha; Varughese, Lesley Rachel; Kumar, Vinod; Beniwal, Vikas

    2015-01-01

    Gallic acid and its derivatives have a large number of applications in various fields of science. In nature, these compounds are widely distributed in plants and fruits, and thus they are being used as food stuffs, preservatives, etc. directly or indirectly by human community. They have also been implicated as anticarcinogenic, antimicrobial, antimutagenic, antiangiogenic and anti-inflammatory agents besides their use in treating critical diseases like depression, cancer, microbial infections, lipid-related diseases, etc. Herein, an attempt has been made to summarize the important uses of gallic acid derivatives which have extensively been disclosed particularly in various patents. This review would certainly create a great interest of the scientific community toward the developments and uses of gallic acid based compounds in the future. PMID:26174568

  17. Synthesis, structure and cytotoxic activity of acetylenic derivatives of betulonic and betulinic acids

    NASA Astrophysics Data System (ADS)

    Bębenek, Ewa; Chrobak, Elwira; Wietrzyk, Joanna; Kadela, Monika; Chrobak, Artur; Kusz, Joachim; Książek, Maria; Jastrzębska, Maria; Boryczka, Stanisław

    2016-02-01

    A series of acetylenic derivatives of betulonic and betulinic acids has been synthesized and characterized by 1H and 13C NMR, IR and MS spectroscopy. The structure of propargyl betulonate 4 and propargyl betulinate-DMF solvate 8A was solved by X-ray diffraction. Thermal properties were examined using a DSC technique. The resulting alkynyl derivatives, as well as betulin 1 and betulinic acid 3, were evaluated in vitro for their cytotoxic activity against human T47D breast cancer, CCRF/CEM leukemia, SW707 colorectal, murine P388 leukemia and BALB3T3 normal fibroblasts cell lines. Several of the obtained compounds have a favorable cytotoxic profile than betulin 1. Propargyl betulinate 8 was the most active derivative, being up to 3-fold more potent than betulin 1 against the human leukemia (CCRF/CEM) cell line, with an IC50 value of 3.9 μg/mL.

  18. Local Solvent Acidities in β-Cyclodextrin Complexes with PRODAN Derivatives

    PubMed Central

    Naughton, Hannah R.; Abelt, Christopher J.

    2013-01-01

    The local solvent acidities (SA scale) of six 6-carbonyl-2-aminonaphthalene derivatives as β-cyclodextrin complexes in water are determined through fluorescence quenching. The local polarities (ETN scale) are determined through the shift of the emission center-of-mass. The apparent SA values reflect the solvent structure surrounding the guest’s carbonyl group, whereas the apparent ETN values reveal the net polarity of the entire guest molecule. Comparison of these values affords greater insight into the structures of the host-guest complexes. Derivatives 1 and 5 show unusually large acidities indicative of highly exposed carbonyl groups. The remaining compounds give emission intensities pointing to shielded carbonyl groups. In this study PRODAN and its derivatives are functioning as dual channel sensors of their local environment. PMID:23473052

  19. Structure-activity relationships of anthraquinone derivatives derived from bromaminic acid as inhibitors of ectonucleoside triphosphate diphosphohydrolases (E-NTPDases)

    PubMed Central

    Baqi, Younis; Weyler, Stefanie; Iqbal, Jamshed; Zimmermann, Herbert

    2008-01-01

    Reactive blue 2 (RB-2) had been characterized as a relatively potent ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) inhibitor with some selectivity for NTPDase3. In search for the pharmacophore and to analyze structure-activity relationships we synthesized a series of truncated derivatives and analogs of RB-2, including 1-amino-2-sulfo-4-ar(alk)ylaminoanthraquinones, 1-amino-2-methyl-4-arylaminoanthraquinones, 1-amino-4-bromoanthraquinone 2-sulfonic acid esters and sulfonamides, and bis-(1-amino-4-bromoanthraquinone) sulfonamides, and investigated them in preparations of rat NTPDase1, 2, and 3 using a capillary electrophoresis assay. Several 1-amino-2-sulfo-4-ar(alk)ylaminoanthraquinone derivatives inhibited E-NTPDases in a concentration-dependent manner. The 2-sulfonate group was found to be required for inhibitory activity, since 2-methyl-substituted derivatives were inactive. 1-Amino-2-sulfo-4-p-chloroanilinoanthraquinone (18) was identified as a nonselective competitive blocker of NTPDases1, 2, and 3 (Ki 16–18 μM), while 1-amino-2-sulfo-4-(2-naphthylamino)anthraquinone (21) was a potent inhibitor with preference for NTPDase1 (Ki 0.328 μM) and NTPDase3 (Ki 2.22 μM). Its isomer, 1-amino-2-sulfo-4-(1-naphthylamino)anthraquinone (20), was a potent and selective inhibitor of rat NTPDase3 (Ki 1.5 μM). PMID:18528783

  20. RNA:DNA Ratio and Other Nucleic Acid Derived Indices in Marine Ecology

    PubMed Central

    Chícharo, Maria Alexandra; Chícharo, Luis

    2008-01-01

    Some of most used indicators in marine ecology are nucleic acid-derived indices. They can be divided by target levels in three groups: 1) at the organism level as ecophysiologic indicators, indicators such as RNA:DNA ratios, DNA:dry weight and RNA:protein, 2) at the population level, indicators such as growth rate, starvation incidence or fisheries impact indicators, and 3) at the community level, indicators such as trophic interactions, exergy indices and prey identification. The nucleic acids derived indices, especially RNA:DNA ratio, have been applied with success as indicators of nutritional condition, well been and growth in marine organisms. They are also useful as indicators of natural or anthropogenic impacts in marine population and communities, such as upwelling or dredge fisheries, respectively. They can help in understanding important issues of marine ecology such as trophic interactions in marine environment, fish and invertebrate recruitment failure and biodiversity changes, without laborious work of counting, measuring and identification of small marine organisms. Besides the objective of integrate nucleic acid derived indices across levels of organization, the paper will also include a general characterization of most used nucleic acid derived indices in marine ecology and also advantages and limitations of them. We can conclude that using indicators, such RNA:DNA ratios and other nucleic acids derived indices concomitantly with organism and ecosystems measures of responses to climate change (distribution, abundance, activity, metabolic rate, survival) will allow for the development of more rigorous and realistic predictions of the effects of anthropogenic climate change on marine systems. PMID:19325815

  1. Phytotoxicity of new furan-derived aminophosphonic acids, N-aryl furaldimines and 5-nitrofuraldimine.

    PubMed

    Matusiak, Agnieszka; Lewkowski, Jarosław; Rychter, Piotr; Biczak, Robert

    2013-08-14

    The aim of this work was to synthesize selected furaldimines and their aminophosphonic derivatives and evaluation the phytotoxicity of new obtained products according to OECD 208 Guideline. Four Schiff bases, N-furfurylidene-p-anisidine (1a), N-furfurylidene-p-toluidine (1b), N-furfurylidene-benzhydrylamine (1c), and N-(2-nitrofurfurylidene)-p-toluidine (1d) were synthesized and three new furan-derived N-substituted aminomethylphosphonic acids, namely: 2-furyl N-(p-methoxyphenyl)-aminomethylphosphonic acid (2a), 2-furyl N-(p-methylphenyl)-aminomethylphosphonic acid (2b) and 2-furyl N-(diphenylmethyl)-aminomethylphosphonic acid (2c) were synthesized by the addition of in situ generated bis-(trimethylsilyl) phosphite to azomethine bond of corresponding Schiff bases 1a-c. Three Schiff bases 1a-b and 1d as well as all three aminophosphonic acids 2a-c were analyzed in regard with their phytotoxicity toward two plants, radish (Raphanus sativus) and oat (Avena sativa). It has been found that tested N-furfurylidene-p-anisidine (1a), N-(2-nitrofurfurylidene)-p-toluidine (1d) and aminophosphonic acids 2a-c are toxic for selected plants. N-furfurylidene-p-toluidine (1b) did not show any ecotoxicological impact in used plant growth test. PMID:23869973

  2. Potential Biological Applications of Bio-Based Anacardic Acids and Their Derivatives

    PubMed Central

    Hamad, Fatma B.; Mubofu, Egid B.

    2015-01-01

    Cashew nut shells (CNS), which are agro wastes from cashew nut processing factories, have proven to be among the most versatile bio-based renewable materials in the search for functional materials and chemicals from renewable resources. CNS are produced in the cashew nut processing process as waste, but they contain cashew nut shell liquid (CNSL) up to about 30–35 wt. % of the nut shell weight depending on the method of extraction. CNSL is a mixture of anacardic acid, cardanol, cardol, and methyl cardol, and the structures of these phenols offer opportunities for the development of diverse products. For anacardic acid, the combination of phenolic, carboxylic, and a 15-carbon alkyl side chain functional group makes it attractive in biological applications or as a synthon for the synthesis of a multitude of bioactive compounds. Anacardic acid, which is about 65% of a CNSL mixture, can be extracted from the agro waste. This shows that CNS waste can be used to extract useful chemicals and thus provide alternative green sources of chemicals, apart from relying only on the otherwise declining petroleum based sources. This paper reviews the potential of anacardic acids and their semi-synthetic derivatives for antibacterial, antitumor, and antioxidant activities. The review focuses on natural anacardic acids from CNS and other plants and their semi-synthetic derivatives as possible lead compounds in medicine. In addition, the use of anacardic acid as a starting material for the synthesis of various biologically active compounds and complexes is reported. PMID:25894225

  3. Potential biological applications of bio-based anacardic acids and their derivatives.

    PubMed

    Hamad, Fatma B; Mubofu, Egid B

    2015-01-01

    Cashew nut shells (CNS), which are agro wastes from cashew nut processing factories, have proven to be among the most versatile bio-based renewable materials in the search for functional materials and chemicals from renewable resources. CNS are produced in the cashew nut processing process as waste, but they contain cashew nut shell liquid (CNSL) up to about 30-35 wt. % of the nut shell weight depending on the method of extraction. CNSL is a mixture of anacardic acid, cardanol, cardol, and methyl cardol, and the structures of these phenols offer opportunities for the development of diverse products. For anacardic acid, the combination of phenolic, carboxylic, and a 15-carbon alkyl side chain functional group makes it attractive in biological applications or as a synthon for the synthesis of a multitude of bioactive compounds. Anacardic acid, which is about 65% of a CNSL mixture, can be extracted from the agro waste. This shows that CNS waste can be used to extract useful chemicals and thus provide alternative green sources of chemicals, apart from relying only on the otherwise declining petroleum based sources. This paper reviews the potential of anacardic acids and their semi-synthetic derivatives for antibacterial, antitumor, and antioxidant activities. The review focuses on natural anacardic acids from CNS and other plants and their semi-synthetic derivatives as possible lead compounds in medicine. In addition, the use of anacardic acid as a starting material for the synthesis of various biologically active compounds and complexes is reported. PMID:25894225

  4. Fermentation of biomass-derived glucuronic acid by pet expressing recombinants of E. coli B

    SciTech Connect

    Lawford, H.G.; Rousseau, J.D.

    1997-12-31

    The economics of large-scale production of fuel ethanol from biomass and wastes requires the efficient utilization of all the sugars derived from the hydrolysis of the heteropolymeric hemicellulose component of lignocellulosic feedstocks. Glucuronic and 4-0-methyl-glucuronic acids are major side chains in xylans of the grasses and hardwoods that have been targeted as potential feedstocks for the production of cellulosic ethanol. The amount of these acids is similar to that of arabinose, which is now being viewed as another potential substrate in the production of biomass-derived ethanol. This study compared the end-product distribution associated with the fermentation of D-glucose (Glc) and D-glucuronic acid (GlcUA) (as sole carbon and energy sources) by Escherichia coli B (ATCC 11303) and two different ethanologenic recombinants--a strain in which pet expression was via a multicopy plasmid (pLOI297) and a chromosomally integrated construct, strain KO11. pH-stat batch fermentations were conducted using a modified LB medium with 2% (w/v) Glc or GlcUA with the set-point for pH control at either 6.3 or 7.0. The nontransformed host culture produced only lactic acid from glucose, but fermentation of GlcUA yielded a mixture of ethanol, acetic, and lactic acids, with acetic acid being the predominant end-product. 73 refs., 6 figs., 2 tabs.

  5. Synthesis of benzamide derivatives of anacardic acid and their cytotoxic activity.

    PubMed

    Chandregowda, Venkateshappa; Kush, Anil; Reddy, Goukanapalli Chandrasekara

    2009-06-01

    Several benzamide derivatives were synthesized from anacardic acid (1a) which was the product of hydrogenation of the naturally occurring anacardic acid mixture (1a-d), a major constituent of cashew nut shell liquid. Anacardic acid (1a) was first alkylated followed by hydrolysis of the ester to obtain synthones namely, 2-ethoxy-6-pentadecylbenzoic acid (5) and 2-isopropoxy-6-pentadecylbenzoic acid (6). These salicylic acid derivatives were then coupled with a variety of anilines to obtain novel benzamide compounds (7-39). Cytotoxic effect of these synthesized compounds was tested on HeLa cell line of wild type with relatively high expression of p300 and on HCT-15, which is p300 negative. Of all the compounds, 2-isopropoxy-6-pentadecyl-N-pyridin-4-ylbenzamide (27), 2-ethoxy-N-(3-nitrophenyl)-6-pentadecylbenzamide (22) and 2-ethoxy-6-pentadecyl-N-pyridin-4-ylbenzamide (10) were found to be more potent with the respective IC(50) values 11.02 microM, 13.55 microM, 15.29 microM on HeLa cell line. Their activities are comparable with garcinol which is a cell permeable histone acetyltransferase (HAT) inhibitor and 10 fold more active than p300 HAT activators so far reported. PMID:19246131

  6. Aromatic and volatile acid intermediates observed during anaerobic metabolism of lignin-derived oligomers

    SciTech Connect

    Colberg, P.J.; Young, L.Y.

    1985-02-01

    Anaerobic enrichment cultures acclimated for 2 years to use a /sup 14/C-labeled, lignin-derived substrate with a molecular weight of 600 as a sole source of carbon were characterized by capillary and packed column gas chromatography. After acclimation, several of the active methanogenic organisms were inhibited with 2-bromoethanesulfonic acid, which suppressed methane formation and enhanced accumulation of a series of metabolic intermediates. Volatile fatty acids levels in 2-bromoethansulfonic acid-amended cultures were 10 times greater than those in the uninhibited, methane-forming organisms with acetate as the predominant component. Furthermore, in the 2-bromoethanesulfonic acid-amended organisms, almost half of the original substrate carbon was metabolized to 10 monaromatic compounds, with the most appreciable quantities accumulated as cinnamic, benzoic, caffeic, vanillic, and ferulic acids. 2-Bromoethanesulfonic acid seemed to effectively block CH/sub 4/ formation in the anaerobic food chain, resulting in the observed buildup of volatile fatty acids and monoaromatic intermediates. Neither fatty acids nor aromatic compounds were detected in the oligolignol substrate before its metabolism, suggesting that these anaerobic organisms have the ability to mediate the cleavage of the ..beta..-aryl-ether bond, the most common intermonomeric linkage in lignin, with the subsequent release of the observed constituent aromatic monomers.

  7. Phenolic Acids (Gallic and Tannic Acids) Modulate Antioxidant Status and Cisplatin Induced Nephrotoxicity in Rats

    PubMed Central

    Akomolafe, Seun F.; Akinyemi, Ayodele J.; Anadozie, Scholarstical O.

    2014-01-01

    Cisplatin (cis-diamminedichloroplatinum (II) or CDDP), used in the treatment of many solid-tissue cancers, has its chief side-effect in nephrotoxicity. Hence, this study sought to investigate and compare the protective effect of gallic acid (GA) and tannic acid (TA) against cisplatin induced nephrotoxicity in rats. The rats were given a prophylactic treatment of GA and TA orally at a dose of 20 and 40 mg/kg body weight for 7 consecutive days before the administration of a single intraperitoneal (i.p.) injection of cisplatin (CP) at 7.5 mg/kg bwt. The protective effects of both GA and TA on CP induced nephrotoxicity were investigated by assaying renal function, oxidative stress biomarkers, and histopathological examination of kidney architecture. A single dose of cisplatin (7.5 mg/kg bwt) injected i.p. caused a significant increase in some biomarkers of renal function (creatinine, uric acid, and urea levels), with a marked elevation in malondialdehyde (MDA) content accompanied by a significant (P < 0.05) decrease in reduced glutathione (GSH) content (103.27%) of kidney tissue as compared to control group. Furthermore, a significant (P < 0.05) reduction in kidney antioxidant enzymes (SOD, catalase, GPx, and GST) activity was observed. However, pretreatment with oral administration of tannic acid and gallic acid at a dose of 20 and 40 mg/kg body weight, respectively, for 7 days prior to cisplatin administration reduced histological renal damage and suppressed the generation of ROS, lipid peroxidation, and oxidative stress in kidney tissues. These results indicate that both gallic and tannic acids could serve as a preventive strategy against cisplatin induced nephrotoxicity. PMID:27382634

  8. Human lactoferricin derived di-peptides deploying loop structures induce apoptosis specifically in cancer cells through targeting membranous phosphatidylserine.

    PubMed

    Riedl, Sabrina; Leber, Regina; Rinner, Beate; Schaider, Helmut; Lohner, Karl; Zweytick, Dagmar

    2015-11-01

    Host defense-derived peptides have emerged as a novel strategy for the development of alternative anticancer therapies. In this study we report on characteristic features of human lactoferricin (hLFcin) derivatives which facilitate specific killing of cancer cells of melanoma, glioblastoma and rhabdomyosarcoma compared with non-specific derivatives and the synthetic peptide RW-AH. Changes in amino acid sequence of hLFcin providing 9-11 amino acids stretched derivatives LF11-316, -318 and -322 only yielded low antitumor activity. However, the addition of the repeat (di-peptide) and the retro-repeat (di-retro-peptide) sequences highly improved cancer cell toxicity up to 100% at 20 μM peptide concentration. Compared to the complete parent sequence hLFcin the derivatives showed toxicity on the melanoma cell line A375 increased by 10-fold and on the glioblastoma cell line U-87mg by 2-3-fold. Reduced killing velocity, apoptotic blebbing, activation of caspase 3/7 and formation of apoptotic DNA fragments proved that the active and cancer selective peptides, e.g. R-DIM-P-LF11-322, trigger apoptosis, whereas highly active, though non-selective peptides, such as DIM-LF11-318 and RW-AH seem to kill rapidly via necrosis inducing membrane lyses. Structural studies revealed specific toxicity on cancer cells by peptide derivatives with loop structures, whereas non-specific peptides comprised α-helical structures without loop. Model studies with the cancer membrane mimic phosphatidylserine (PS) gave strong evidence that PS only exposed by cancer cells is an important target for specific hLFcin derivatives. Other negatively charged membrane exposed molecules as sialic acid, heparan and chondroitin sulfate were shown to have minor impact on peptide activity. PMID:26239537

  9. Vasopressin induces release of arachidonic acid from vascular smooth muscle cells

    SciTech Connect

    Grillone, L.R.; Clark, M.A.; Heckman, G.; Schmidt, D.; Stassen, F.L.; Crooke, S.T.

    1986-05-01

    Cultured smooth muscle cells (A-10), derived from rat thoracic aorta, have vascular (V/sub 1/) vasopressin receptors. They have previously shown that these receptors mediate phosphatidylinositol turnover, Ca/sup 2 +/ efflux, and inhibition of isoproterenol-induced increases in cAMP. Here they studied the effect of vasopressin on arachidonic acid metabolism of A-10 cells. Cells were incubated for 18-20 hr with (/sup 3/H)-arachidonic acid (80 Ci/mmol). Vasopressin stimulated release of arachidonic acid in a time- and dose-dependent manner. Significant release of arachidonic acid was observed after 4 min with 10/sup -9/ M vasopressin. Maximum release was reached 4 min after addition of 10/sup -7/ M vasopressin (1100 dpm/10/sup 6/ cells). About 800 dmp were released after 1 and 4 min with 10/sup -7/ M and 10/sup -8/ M vasopressin, respectively. The vasopressin-stimulated release of arachidonic acid was blocked by the specific V/sub 1//V/sub 2/ vasopressin antagonist d(CH2)5D-Tyr(Et)VAVP. These data indicate that vascular smooth muscle cells increase arachidonic acid release in response to vasopressin. This response is likely mediated by V/sub 1/ receptors.

  10. Scaleable production and separation of fermentation-derived acetic acid. Final CRADA report.

    SciTech Connect

    Snyder, S. W.; Energy Systems

    2010-02-08

    Half of U.S. acetic acid production is used in manufacturing vinyl acetate monomer (VAM) and is economical only in very large production plants. Nearly 80% of the VAM is produced by methanol carbonylation, which requires high temperatures and exotic construction materials and is energy intensive. Fermentation-derived acetic acid production allows for small-scale production at low temperatures, significantly reducing the energy requirement of the process. The goal of the project is to develop a scaleable production and separation process for fermentation-derived acetic acid. Synthesis gas (syngas) will be fermented to acetic acid, and the fermentation broth will be continuously neutralized with ammonia. The acetic acid product will be recovered from the ammonium acid broth using vapor-based membrane separation technology. The process is summarized in Figure 1. The two technical challenges to success are selecting and developing (1) microbial strains that efficiently ferment syngas to acetic acid in high salt environments and (2) membranes that efficiently separate ammonia from the acetic acid/water mixture and are stable at high enough temperature to facilitate high thermal cracking of the ammonium acetate salt. Fermentation - Microbial strains were procured from a variety of public culture collections (Table 1). Strains were incubated and grown in the presence of the ammonium acetate product and the fastest growing cultures were selected and incubated at higher product concentrations. An example of the performance of a selected culture is shown in Figure 2. Separations - Several membranes were considered. Testing was performed on a new product line produced by Sulzer Chemtech (Germany). These are tubular ceramic membranes with weak acid functionality (see Figure 3). The following results were observed: (1) The membranes were relatively fragile in a laboratory setting; (2) Thermally stable {at} 130 C in hot organic acids; (3) Acetic acid rejection > 99%; and (4

  11. Ameliorative effects of amide derivatives of 1,3,4-thiadiazoles on scopolamine induced cognitive dysfunction.

    PubMed

    Kulshreshtha, Akanksha; Piplani, Poonam

    2016-10-21

    The present study reports the effect of amide derivatives of 1,3,4-thiadizoles on scopolamine induced deficit cholinergic neurotransmission and oxidative stress serving as promising leads for the therapeutics of cognitive dysfunction. Fourteen compounds (2c-8d) have been synthesised and evaluated against behavioural alterations using step down passive avoidance protocol and morris water maze and at a dose of 0.5 mg/kg with reference to the standard, Rivastigmine. All the synthesised compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibition at five different concentrations using mice brain homogenate as the source of the enzyme. Biochemical estimation of markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione, plasma nitrite, catalase) has also been carried out to assess the role of synthesised molecules on the oxidative damage induced by scopolamine. The compounds 5c, 6c and 8c displayed appreciable activity with an IC50 value of 3 μM, 3.033 μM and 2.743 μM, respectively towards acetylcholinesterase inhibition. These compounds also decreased scopolamine induced oxidative stress, thus serving as promising leads for the amelioration of oxidative stress induced cognitive decline. The molecular docking study performed to predict the binding mode of the compounds also suggested that these compounds bind appreciably with the amino acids present in the active site of recombinant human acetylcholinesterase (rhAChE). The results indicated that these compounds could be further traversed as inhibitors of AChE and oxidative stress for the treatment of cognitive dysfunction. PMID:27448914

  12. Effects of Erythropoietin in Murine-Induced Pluripotent Cell-Derived Panneural Progenitor Cells

    PubMed Central

    Offen, Nils; Flemming, Johannes; Kamawal, Hares; Ahmad, Ruhel; Wolber, Wanja; Geis, Christian; Zaehres, Holm; Schöler, Hans R; Ehrenreich, Hannelore; Müller, Albrecht M; Sirén, Anna-Leena

    2013-01-01

    Induced cell fate changes by reprogramming of somatic cells offers an efficient strategy to generate autologous pluripotent stem (iPS) cells from any adult cell type. The potential of iPS cells to differentiate into various cell types is well established, however the efficiency to produce functional neurons from iPS cells remains modest. Here, we generated panneural progenitor cells (pNPCs) from mouse iPS cells and investigated the effect of the neurotrophic growth factor erythropoietin (EPO) on their survival, proliferation and neurodifferentiation. Under neural differentiation conditions, iPS-derived pNPCs gave rise to microtubule-associated protein-2 positive neuronlike cells (34% to 43%) and platelet-derived growth factor receptor positive oligodendrocytelike cells (21% to 25%) while less than 1% of the cells expressed the astrocytic marker glial fibrillary acidic protein. Neuronlike cells generated action potentials and developed active presynaptic terminals. The pNPCs expressed EPO receptor (EPOR) mRNA and displayed functional EPOR signaling. In proliferating cultures, EPO (0.1–3 U/mL) slightly improved pNPC survival but reduced cell proliferation and neurosphere formation in a concentration-dependent manner. In differentiating cultures EPO facilitated neurodifferentiation as assessed by the increased number of β-III-tubulin positive neurons. Our results show that EPO inhibits iPS pNPC self-renewal and promotes neurogenesis. PMID:24408113

  13. Motoneurons Derived from Induced Pluripotent Stem Cells Develop Mature Phenotypes Typical of Endogenous Spinal Motoneurons

    PubMed Central

    Toma, Jeremy S.; Shettar, Basavaraj C.; Chipman, Peter H.; Pinto, Devanand M.; Borowska, Joanna P.; Ichida, Justin K.; Fawcett, James P.; Zhang, Ying; Eggan, Kevin

    2015-01-01

    Induced pluripotent cell-derived motoneurons (iPSCMNs) are sought for use in cell replacement therapies and treatment strategies for motoneuron diseases such as amyotrophic lateral sclerosis (ALS). However, much remains unknown about the physiological properties of iPSCMNs and how they compare with endogenous spinal motoneurons or embryonic stem cell-derived motoneurons (ESCMNs). In the present study, we first used a proteomic approach and compared protein expression profiles between iPSCMNs and ESCMNs to show that <4% of the proteins identified were differentially regulated. Like ESCs, we found that mouse iPSCs treated with retinoic acid and a smoothened agonist differentiated into motoneurons expressing the LIM homeodomain protein Lhx3. When transplanted into the neural tube of developing chick embryos, iPSCMNs selectively targeted muscles normally innervated by Lhx3 motoneurons. In vitro studies showed that iPSCMNs form anatomically mature and functional neuromuscular junctions (NMJs) when cocultured with chick myofibers for several weeks. Electrophysiologically, iPSCMNs developed passive membrane and firing characteristic typical of postnatal motoneurons after several weeks in culture. Finally, iPSCMNs grafted into transected mouse tibial nerve projected axons to denervated gastrocnemius muscle fibers, where they formed functional NMJs, restored contractile force. and attenuated denervation atrophy. Together, iPSCMNs possess many of the same cellular and physiological characteristics as ESCMNs and endogenous spinal motoneurons. These results further justify using iPSCMNs as a source of motoneurons for cell replacement therapies and to study motoneuron diseases such as ALS. PMID:25609642

  14. 2,5-PRODAN derivatives as highly sensitive sensors of low solvent acidity.

    PubMed

    Yoon, Alexandra H; Whitworth, Laura C; Wagner, Joel D; Abelt, Christopher J

    2014-01-01

    Two 5-acyl-2-dimethylaminonaphthalene derivatives, one with a propionyl group and the other with a fused cyclohexanone ring, are investigated as sensors of H-bond-donating ability in protic solvents of low solvent acidity. Their fluorescence is highly quenched in protic solvents, and the quenching order of magnitude is linearly related to the H-bond-donating ability of the solvent as quantified by the solvent acidity (SA) scale. As the solvent acidity increases from 0.15 to 0.40, the fluorescence for both is quenched by more than a factor of ten; thus, they are extremely sensitive sensors of the hydrogen-bond-donating ability in this weakly acidic range. Preferential solvation studies suggest that quenching occurs from a doubly H-bonded excited state. PMID:24853615

  15. EIMS Fragmentation Pathways and MRM Quantification of 7α/β-Hydroxy-Dehydroabietic Acid TMS Derivatives.

    PubMed

    Rontani, Jean-François; Aubert, Claude; Belt, Simon T

    2015-09-01

    EI mass fragmentation pathways of TMS derivatives οf 7α/β-hydroxy-dehydroabietic acids resulting from NaBH(4)-reduction of oxidation products of dehydroabietic acid (a component of conifers) were investigated and deduced by a combination of (1) low energy CID-GC-MS/MS, (2) deuterium labeling, (3) different derivatization methods, and (4) GC-QTOF accurate mass measurements. Having identified the main fragmentation pathways, the TMS-derivatized 7α/β-hydroxy-dehydroabietic acids could be quantified in multiple reaction monitoring (MRM) mode in sea ice and sediment samples collected from the Arctic. These newly characterized transformation products of dehydroabietic acid constitute potential tracers of biotic and abiotic degradation of terrestrial higher plants in the environment. PMID:26138887

  16. Five organic salts assembled from carboxylic acids and bis-imidazole derivatives through collective noncovalent interactions

    NASA Astrophysics Data System (ADS)

    Jin, Shouwen; Guo, Jianzhong; Liu, Li; Wang, Daqi

    2011-10-01

    Five multicomponent crystals of bis(imidazole) derivatives have been prepared with 5-nitrosalicylic acid, 5-sulfosalicylic acid, and phthalic acid. The five crystalline forms reported are organic salts of which the crystal structures have all been determined by X-ray diffraction. The results presented herein indicate that the strength and directionality of the N sbnd H⋯O, O sbnd H⋯O, and N sbnd H⋯N hydrogen bonds (ionic or neutral) between carboxylic acids and ditopic imidazoles are sufficient to bring about the formation of binary organic salts. All supramolecular architectures of the organic salts 1- 5 involve extensive O sbnd H⋯O, and N sbnd H⋯O hydrogen bonds as well as other noncovalent interactions. The role of weak and strong noncovalent interactions in the crystal packing is ascertained. These noncovalent interactions combined, all the complexes displayed 3D framework structure.

  17. MOF-Derived Tungstated Zirconia as Strong Solid Acids toward High Catalytic Performance for Acetalization.

    PubMed

    Wang, Peng; Feng, Jian; Zhao, Yupei; Wang, Shaobin; Liu, Jian

    2016-09-14

    A strong solid acid, tungstated zirconia (WZ), has been prepared first using tungstate immobilized UiO-66 as precursors through a "double-solvent" impregnation method under mild calcination temperature. With moderate W contents, the as-synthesized WZ catalysts possess a high density of acid sites, and the proper heat treatment also has facilely led to a bunch of oligomeric tungsten clusters on stabilized tetragonal ZrO2. The resultant solid acids show an improved catalytic performance toward the benzaldehyde's acetalization in comparison with traditional zirconium hydroxide-prepared WZ. Notably, due to large surface area and additionally introduced strong acid sites, the MOF-derived WZ catalysts afforded conversion up to 86.0%. The facile method endows the WZ catalysts with superior catalytic activities and excellent recyclability, thus opening a new avenue for preparation of metal oxide-based solid superacids and superbases. PMID:27557351

  18. EIMS Fragmentation Pathways and MRM Quantification of 7α/β-Hydroxy-Dehydroabietic Acid TMS Derivatives

    NASA Astrophysics Data System (ADS)

    Rontani, Jean-François; Aubert, Claude; Belt, Simon T.

    2015-09-01

    EI mass fragmentation pathways of TMS derivatives οf 7α/β-hydroxy-dehydroabietic acids resulting from NaBH4-reduction of oxidation products of dehydroabietic acid (a component of conifers) were investigated and deduced by a combination of (1) low energy CID-GC-MS/MS, (2) deuterium labeling, (3) different derivatization methods, and (4) GC-QTOF accurate mass measurements. Having identified the main fragmentation pathways, the TMS-derivatized 7α/β-hydroxy-dehydroabietic acids could be quantified in multiple reaction monitoring (MRM) mode in sea ice and sediment samples collected from the Arctic. These newly characterized transformation products of dehydroabietic acid constitute potential tracers of biotic and abiotic degradation of terrestrial higher plants in the environment.

  19. Valproic Acid Induces Antimicrobial Compound Production in Doratomyces microspores

    PubMed Central

    Zutz, Christoph; Bacher, Markus; Parich, Alexandra; Kluger, Bernhard; Gacek-Matthews, Agnieszka; Schuhmacher, Rainer; Wagner, Martin; Rychli, Kathrin; Strauss, Joseph

    2016-01-01

    One of the biggest challenges in public health is the rising number of antibiotic resistant pathogens and the lack of novel antibiotics. In recent years there is a rising focus on fungi as sources of antimicrobial compounds due to their ability to produce a large variety of bioactive compounds and the observation that virtually every fungus may still contain yet unknown so called “cryptic,” often silenced, compounds. These putative metabolites could include novel bioactive compounds. Considerable effort is spent on methods to induce production of these “cryptic” metabolites. One approach is the use of small molecule effectors, potentially influencing chromatin landscape in fungi. We observed that the supernatant of the fungus Doratomyces (D.) microsporus treated with valproic acid (VPA) displayed antimicrobial activity against Staphylococcus (S.) aureus and two methicillin resistant clinical S. aureus isolates. VPA treatment resulted in enhanced production of seven antimicrobial compounds: cyclo-(L-proline-L-methionine) (cPM), p-hydroxybenzaldehyde, cyclo-(phenylalanine-proline) (cFP), indole-3-carboxylic acid, phenylacetic acid (PAA) and indole-3-acetic acid. The production of the antimicrobial compound phenyllactic acid was exclusively detectable after VPA treatment. Furthermore three compounds, cPM, cFP, and PAA, were able to boost the antimicrobial activity of other antimicrobial compounds. cPM, for the first time isolated from fungi, and to a lesser extent PAA, are even able to decrease the minimal inhibitory concentration of ampicillin in MRSA strains. In conclusion we could show in this study that VPA treatment is a potent tool for induction of “cryptic” antimicrobial compound production in fungi, and that the induced compounds are not exclusively linked to the secondary metabolism. Furthermore this is the first discovery of the rare diketopiperazine cPM in fungi. Additionally we could demonstrate that cPM and PAA boost antibiotic activity

  20. Increase of EPA-derived hydroxy, epoxy and dihydroxy fatty acid levels in human plasma after a single dose of long-chain omega-3 PUFA

    PubMed Central

    Schuchardt, Jan Philipp; Schneider, Inga; Willenberg, Ina; Yang, Jun; Hammock, Bruce D.; Hahn, Andreas; Schebb, Nils Helge

    2014-01-01

    Introduction Several supplementation studies with long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) describe an increase of EPA-derived hydroxy, epoxy and dihydroxy fatty acids in blood, while changes in levels of other LC n-3 and n-6 PUFA-derived oxylipins were minor. In order to investigate the kinetics of changes in oxylipin levels in response to LC n-3 PUFA ingestion, we conducted a single dose treatment study with healthy subjects. Subjects and methods In the present kinetic study, we compared patterns of hydroxy, epoxy and dihydroxy fatty acids in plasma of 6 healthy men before and after 6, 8, 24, and 48 h of fish oil (1008 mg EPA and 672 mg DHA) ingestion. Levels of EPA- as well as other LC PUFA-derived hydroxy, epoxy and dihydroxy fatty acids were analyzed in plasma by LC–MS. Additionally, levels of these oxylipins were compared with their parent PUFA levels in plasma phospholipids. Results All EPA-derived oxylipin levels were significantly increased 6 h after LC n-3 PUFA ingestion and gradually drop thereafter reaching the baseline levels about 48 h after treatment. The relative increase in EPA plasma phospholipid levels highly correlated with the increase of plasma EPA-derived oxylipin levels at different time points. In contrast, plasma levels of arachidonic acid- and DHA-derived oxylipins as well as parent PUFA levels in plasma phospholipids were hardly changed. Discussion and conclusions Our findings demonstrate that a single dose of LC n-3 PUFAs can rapidly induce a shift in the EPA oxylipin profile of healthy subjects within a few hours. Taking the high biological activity of the EPA-derived epoxy fatty acids into account, even short-term treatment with LC n-3 PUFAs may cause systemic effects, which warrant further investigation. PMID:24667634

  1. Composition, assimilation and degradation of Phaeocystis globosa-derived fatty acids in the North Sea

    NASA Astrophysics Data System (ADS)

    Hamm, Christian E.; Rousseau, Veronique

    2003-12-01

    The fate of a Phaeocystis globosa bloom in the southern North Sea off Belgium, the Netherlands and Germany in May 1995 was investigated during a cruise with RV 'Belgica'. We used fatty acids as biomarkers to follow the fate of Phaeocystis-derived biomass of a Phaeocystis-dominated spring bloom. The bloom, in which up to >99% of the biomass was contributed by Phaeocystis, showed a fatty acid composition with a characteristically high abundance of polyunsaturated C 18-fatty acids, which increased in concentration with number of double bonds up to 18:5 (n-3), and high concentrations of 20:5 (n-3) and 22:6 (n-3). In contrast to most previous studies, fatty acid analysis of the mesozooplankton community (mainly calanoid copepods) and meroplankton ( Carcinus maenas megalope) indicated that P. globosa was a major component (ca. 70% and 50%, respectively) in the diet of these organisms. Massive accumulations of amorphous grey aggregates, in which Phaeocystis colonies were major components, were dominated by saturated fatty acids and contained only few of the polyunsaturated C 18-fatty acids. A hydrophobic surface slick that covered the water surface during the bloom showed very similar patterns. Foam patches contained few Phaeocystis-typical fatty acids, but increased amounts of diatom-typical compounds such as 16:1 (n-7) and 20:5 (n-3), and 38% fatty alcohols, indicating that wax esters dominated the lipid fraction in the foam with ca. 76% (w/w). The fatty acid compositions of surface sediment showed that no sedimentation of fresh Phaeocystis occurred during the study. The results indicate that Phaeocystis-derived organic matter degraded while floating or in suspension, and had not reached the sediment in substantial amounts.

  2. The myeloperoxidase-derived oxidant hypothiocyanous acid inhibits protein tyrosine phosphatases via oxidation of key cysteine residues.

    PubMed

    Cook, Naomi L; Moeke, Cassidy H; Fantoni, Luca I; Pattison, David I; Davies, Michael J

    2016-01-01

    Phosphorylation of protein tyrosine residues is critical to cellular processes, and is regulated by kinases and phosphatases (PTPs). PTPs contain a redox-sensitive active site Cys residue, which is readily oxidized. Myeloperoxidase, released from activated leukocytes, catalyzes thiocyanate ion (SCN(-)) oxidation by H2O2 to form hypothiocyanous acid (HOSCN), an oxidant that targets Cys residues. Dysregulated phosphorylation and elevated MPO levels have been associated with chronic inflammatory diseases where HOSCN can be generated. Previous studies have shown that HOSCN inhibits isolated PTP1B and induces cellular dysfunction in cultured macrophage-like cells. The present study extends this previous work and shows that physiologically-relevant concentrations of HOSCN alter the activity and structure of other members of the wider PTP family (including leukocyte antigen-related PTP, PTP-LAR; T-cell PTP, TC-PTP; CD45 and Src homology phosphatase-1, Shp-1) by targeting Cys residues. Isolated PTP activity, and activity in lysates of human monocyte-derived macrophages (HMDM) was inhibited by 0-100 µM HOSCN with this being accompanied by reversible oxidation of Cys residues, formation of sulfenic acids or sulfenyl-thiocyanates (detected by Western blotting, and LC-MS as dimedone adducts), and structural changes. LC-MS/MS peptide mass-mapping has provided data on the modified Cys residues in PTP-LAR. This study indicates that inflammation-induced oxidants, and particularly myeloperoxidase-derived species, can modulate the activity of multiple members of the PTP superfamily via oxidation of Cys residues to sulfenic acids. This alteration of the balance of PTP/kinase activity may perturb protein phosphorylation and disrupt cell signaling with subsequent induction of apoptosis at sites of inflammation. PMID:26616646

  3. Antiparasitic evaluation of betulinic acid derivatives reveals effective and selective anti-Trypanosoma cruzi inhibitors.

    PubMed

    Meira, Cássio Santana; Barbosa-Filho, José Maria; Lanfredi-Rangel, Adriana; Guimarães, Elisalva Teixeira; Moreira, Diogo Rodrigo Magalhães; Soares, Milena Botelho Pereira

    2016-07-01

    Betulinic acid is a pentacyclic triterpenoid with several biological properties already described, including antiparasitic activity. Here, the anti-Trypanosoma cruzi activity of betulinic acid and its semi-synthetic amide derivatives (BA1-BA8) was investigated. The anti-Trypanosoma cruzi activity and selectivity were enhanced in semi-synthetic derivatives, specially on derivatives BA5, BA6 and BA8. To understand the mechanism of action underlying betulinic acid anti-T. cruzi activity, we investigated ultrastructural changes by electron microscopy. Ultrastructural studies showed that trypomastigotes incubated with BA5 had membrane blebling, flagella retraction, atypical cytoplasmic vacuoles and Golgi cisternae dilatation. Flow cytometry analysis showed that parasite death is mainly caused by necrosis. Treatment with derivatives BA5, BA6 or BA8 reduced the invasion process, as well as intracellular parasite development in host cells, with a potency and selectivity similar to that observed in benznidazole-treated cells. More importantly, the combination of BA5 and benznidazole revealed synergistic effects on trypomastigote and amastigote forms of T. cruzi. In conclusion, we demonstrated that BA5 compound is an effective and selective anti-T. cruzi agent. PMID:27080160

  4. NAD(P)H:quinone oxidoreductase 1 inducer activity of some novel anilinoquinazoline derivatives

    PubMed Central

    Ghorab, Mostafa M; Alsaid, Mansour S; Higgins, Maureen; Dinkova-Kostova, Albena T; Shahat, Abdelaaty A; Elghazawy, Nehal H; Arafa, Reem K

    2016-01-01

    The Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements pathway enables cells to survive oxidative stress conditions through regulating the expression of cytoprotective enzymes such as NAD(P)H:quinone oxidoreductase 1 (NQO1). This work presents the design and synthesis of novel anilinoquinazoline derivatives (2–16a) and evaluation of their NQO1 inducer activity in murine cells. Molecular docking of the new compounds was performed to assess their ability to inhibit Keap1–Nrf2 protein–protein interaction through occupying the Keap1–Nrf2-binding domain, which leads to Nrf2 accumulation and enhanced gene expression of NQO1. Docking results showed that all compounds can potentially interact with Keap1; however, 1,5-dimethyl-2-phenyl-4-(2-phenylquinazolin-4-ylamino)-1,2-dihydropyrazol-3-one (9), the most potent inducer, showed the largest number of interactions with key amino acids in the binding pocket (Arg483, Tyr525, and Phe478) compared to the native ligand or any other compound in this series. PMID:27540279

  5. High Fat Feeding Induces Hepatic Fatty Acid Elongation in Mice

    PubMed Central

    Oosterveer, Maaike H.; van Dijk, Theo H.; Tietge, Uwe J. F.; Boer, Theo; Havinga, Rick; Stellaard, Frans; Groen, Albert K.; Kuipers, Folkert; Reijngoud, Dirk-Jan

    2009-01-01

    Background High-fat diets promote hepatic lipid accumulation. Paradoxically, these diets also induce lipogenic gene expression in rodent liver. Whether high expression of these genes actually results in an increased flux through the de novo lipogenic pathway in vivo has not been demonstrated. Methodology/Principal Findings To interrogate this apparent paradox, we have quantified de novo lipogenesis in C57Bl/6J mice fed either chow, a high-fat or a n-3 polyunsaturated fatty acid (PUFA)-enriched high-fat diet. A novel approach based on mass isotopomer distribution analysis (MIDA) following 1-13C acetate infusion was applied to simultaneously determine de novo lipogenesis, fatty acid elongation as well as cholesterol synthesis. Furthermore, we measured very low density lipoprotein-triglyceride (VLDL-TG) production rates. High-fat feeding promoted hepatic lipid accumulation and induced the expression of lipogenic and cholesterogenic genes compared to chow-fed mice: induction of gene expression was found to translate into increased oleate synthesis. Interestingly, this higher lipogenic flux (+74 µg/g/h for oleic acid) in mice fed the high-fat diet was mainly due to an increased hepatic elongation of unlabeled palmitate (+66 µg/g/h) rather than to elongation of de novo synthesized palmitate. In addition, fractional cholesterol synthesis was increased, i.e. 5.8±0.4% vs. 8.1±0.6% for control and high fat-fed animals, respectively. Hepatic VLDL-TG production was not affected by high-fat feeding. Partial replacement of saturated fat by fish oil completely reversed the lipogenic effects of high-fat feeding: hepatic lipogenic and cholesterogenic gene expression levels as well as fatty acid and cholesterol synthesis rates were normalized. Conclusions/Significance High-fat feeding induces hepatic fatty acid synthesis in mice, by chain elongation and subsequent desaturation rather than de novo synthesis, while VLDL-TG output remains unaffected. Suppression of lipogenic fluxes

  6. Peroxisome proliferator-activated receptor-γ mediates the anti-inflammatory effect of 3-hydroxy-4-pyridinecarboxylic acid derivatives: synthesis and biological evaluation.

    PubMed

    Brun, Paola; Dean, Annalisa; Di Marco, Valerio; Surajit, Pathak; Castagliuolo, Ignazio; Carta, Davide; Ferlin, Maria Grazia

    2013-04-01

    Seven 3-hydroxy-4-pyridinecarboxylic acid derivatives (HPs), aza-analogues of salicylic acid and structurally close to other potent inflammatory pyridine compounds such as aminopyridinylmethanols and aminopyridinamines, were synthesized, and their anti-inflammatory activity was evaluated. The synthesis was performed by adopting a general procedure involving an intramolecular Diels-Alder cycloaddition of oxazoles with acrylic acid to form various substituted pyridinic acids. The newly synthesized HPs did not exhibit cytotoxic activity on human monocytes-derived macrophages at concentrations up to 10(2) μM. Anti-inflammatory activity of the compounds was screened in vitro by evaluating the capability to inhibit cytokines release from lipopolysaccharide (LPS) stimulated human macrophages. 3-Hydroxy-1-methyl-4-pyridinecarboxylic acid (24) was found to be the most active HP. At 10 μM concentration, HP 24 reduced LPS-induced and nuclear factor-κB activation and cyclooxygenase-2 expression, while increased intracellular reactive oxygen species generation and peroxisome proliferator-activated receptor (PPAR-γ) mRNA transcript level. Indeed, pre-treatment of LPS-exposed human macrophages with PPAR-γ specific antagonist completely prevented HP 24-induced TNF-α and IL8 down regulation, demonstrating that the PPARγ pathway is mandatory for the HP 24 anti-inflammatory effect. Finally, daily treatment with HP 24 ameliorated the outcome of DSS-induced colitis in mice, significantly reducing colonic MPO activity and IL-1β tissue levels. PMID:23416190

  7. Mononuclear phagocyte accumulates a stearic acid derivative during differentiation into macrophages. Effects of stearic acid on macrophage differentiation and Mycobacterium tuberculosis control.

    PubMed

    Mosquera-Restrepo, Sergio Fabián; Caro, Ana Cecilia; Peláez-Jaramillo, Carlos Alberto; Rojas, Mauricio

    2016-05-01

    The fatty acid composition of monocytes changes substantially during differentiation into macrophages, increasing the proportion of saturated fatty acids. These changes prompted us to investigate whether fatty acid accumulation in the extracellular milieu could affect the differentiation of bystander mononuclear phagocytes. An esterified fatty acid derivative, stearate, was the only fatty acid that significantly increased in macrophage supernatants, and there were higher levels when cells differentiated in the presence of Mycobacterium tuberculosis H37Rv or purified protein derivative (PPD). Exogenous stearic acid enhanced the expression of HLA-DR and CD64; there was also accumulation of IL-12, TNF-α, IL-6, MIP-1 α and β and a reduction in MCP-1 and the bacterial load. These results suggested that during differentiation, a derivative of stearic acid, which promotes the process as well as the effector mechanisms of phagocytes against the mycobacterium, accumulates in the cell supernatants. PMID:26932544

  8. Beta-oxidation of very-long-chain fatty acids and their coenzyme A derivatives by human skin fibroblasts.

    PubMed

    Singh, H; Derwas, N; Poulos, A

    1987-05-01

    The beta-oxidation of lignoceric acid (C24:0), hexacosanoic acid (C26:0), and their coenzyme A derivatives was investigated in human skin fibroblast homogenates. The cofactor requirements for oxidation of lignoceric acid and hexacosanoic acid were identical but were different from their coenzyme A derivatives. For example, lignoceric acid and hexacosanoic acid oxidation was strictly ATP dependent whereas the oxidation of the corresponding coenzyme A derivatives was ATP independent. Also the rate of oxidation of coenzyme A derivatives of lignoceric acid or hexacosanoic acid was much higher compared to the free fatty acids. In patients with Zellweger's syndrome, X-linked adrenoleukodystrophy and infantile Refsum's disease, the beta-oxidation of lignoceric and hexacosanoic acids was defective whereas the oxidation of their corresponding coenzyme A derivatives was nearly normal. The results presented in this communication suggest strongly that the beta-oxidation of very-long-chain fatty acids occurs exclusively in peroxisomes. However, the coenzyme A derivatives of very-long-chain fatty acids can be oxidized in mitochondria as well as in peroxisomes. The inability of the mitochondrial system to oxidize free fatty acids may be due to its inability to convert them to their corresponding coenzyme A derivatives. Our results suggest that a specific very-long-chain fatty acyl CoA synthetase may be required for the activation of the free fatty acids and that this synthetase may be deficient in patients with Zellweger's syndrome and possibly X-linked adrenoleukodystrophy, as well. The results presented suggest that substrate specificity and the subcellular localization of the synthetase may regulate the beta-oxidation of very-long-chain fatty acids in the cell. PMID:2437859

  9. Early membrane events induced by salicylic acid in motor cells of the Mimosa pudica pulvinus.

    PubMed

    Saeedi, Saed; Rocher, Françoise; Bonmort, Janine; Fleurat-Lessard, Pierrette; Roblin, Gabriel

    2013-04-01

    Salicylic acid (o-hydroxy benzoic acid) (SA) induced a rapid dose-dependent membrane hyperpolarization (within seconds) and a modification of the proton secretion (within minutes) of Mimosa pudica pulvinar cells at concentrations higher than 0.1mM. Observations on plasma membrane vesicles isolated from pulvinar tissues showed that SA acted directly at the membrane level through a protonophore action as suggested by the inhibition of the proton gradient and the lack of effect on H(+)-ATPase catalytic activity. Comparative data obtained with protonophores (carbonylcyanide-m-chlorophenylhydrazone and 2,4-dinitrophenol) and inhibitors of ATPases (vanadate, N,N'-dicyclohexylcarbodiimide, and diethylstilbestrol) corroborated this conclusion. Consequently, the collapse of the proton motive force led to an impairment in membrane functioning. This impairment is illustrated by the inhibition of the ion-driven turgor-mediated seismonastic reaction of the pulvinus following SA treatment. SA acted in a specific manner as its biosynthetic precursor benzoic acid induced much milder effects and the m- and p-OH benzoic acid derivatives did not trigger similar characteristic effects. Therefore, SA may be considered both a membrane signal molecule and a metabolic effector following its uptake in the cells. PMID:23487303

  10. Subcellular Compartmentation of the Diterpene Carnosic Acid and Its Derivatives in the Leaves of Rosemary1

    PubMed Central

    Munné-Bosch, Sergi; Alegre, Leonor

    2001-01-01

    The potent antioxidant properties of rosemary (Rosmarinus officinalis) extracts have been attributed to its major diterpene, carnosic acid. Carnosic acid has received considerable attention in food science and biomedicine, but little is known about its function in the plant in vivo. We recently found that highly oxidized diterpenes increase in rosemary plants exposed to drought and high light stress as a result of the antioxidant activity of carnosic acid (S. Munné-Bosch, K. Schwarz, L. Alegre [1999] Plant Physiol 121: 1047–1052). To elucidate the significance of the antioxidant function of carnosic acid in vivo we measured the relative amounts of carnosic acid and its metabolites in different compartments of rosemary leaves. Subcellular localization studies show that carnosic acid protects chloroplasts from oxidative stress in vivo by following a highly regulated compartmentation of oxidation products. Carnosic acid scavenges free radicals within the chloroplasts, giving rise to diterpene alcohols, mainly isorosmanol. This oxidation product is O-methylated within the chloroplasts, and the resulting form, 11,12-di-O-methylisorosmanol, is transferred to the plasma membrane. This appears to represent a mechanism of a way out for free radicals from chloroplasts. Carnosic acid also undergoes direct O-methylation within the chloroplasts, and its derived product, 12-O-methylcarnosic acid, accumulates in the plasma membrane. O-methylated diterpenes do not display antioxidant activity, but they may influence the stability of the plasma membrane. This study shows the relevance of the compartmentation of carnosic acid metabolism to the protection of rosemary plants from oxidative stress in vivo. PMID:11161064

  11. Comparison of inhibition effects of some benzoic acid derivatives on sheep heart carbonic anhydrase

    NASA Astrophysics Data System (ADS)

    Kiliç, Deryanur; Yildiz, Melike; Şentürk, Murat; Erdoǧan, Orhan; Küfrevioǧlu, Ömer Irfan

    2016-04-01

    Carbonic anhydrase (CA) is a family of metalloenzymes that requires Zn as a cofactor and catalyze the quick conversion of CO2 to HCO3- and H+. Inhibitors of the carbonic anhydrases (CAs) have medical usage of significant diseases such as glaucoma, epilepsy, gastroduodenal ulcers, acid-base disequilibria and neurological disorders. In the present study, inhibition of CA with some benzoic derivatives (1-6) were investigated. Sheep heart CA (shCA) enzyme was isolated by means of designed affinity chromatography gel (cellulose-benzyl-sulfanylamide) 42.45-fold in a yield of 44 % with 564.65 EU/mg. Purified shCA enzyme was used in vitro studies. In the studies, IC50 values were calculated for 3-aminobenzoic acid (1), 4-aminobenzoic acid (2), 2-hydroxybenzoic acid (3), 2-benzoylbenzoic acid (4), 2,3-dimethoxybenzoic acid (5), and 3,4,5-trimethoxybenzoic acid (6), showing the inhibition effects on the purified enzyme. Such molecules can be used as pioneer for discovery of novel effective CA inhibitors for medicinal chemistry applications.

  12. Transformation of cellulose and its derived carbohydrates into formic and lactic acids catalyzed by vanadyl cations.

    PubMed

    Tang, Zhenchen; Deng, Weiping; Wang, Yanliang; Zhu, Enze; Wan, Xiaoyue; Zhang, Qinghong; Wang, Ye

    2014-06-01

    The transformation of cellulose or cellulose-derived carbohydrates into platform chemicals is the key to establish biomass-based sustainable chemical processes. The systems able to catalyze the conversion of cellulose into key chemicals in water without the consumption of hydrogen are limited. We report that simple vanadyl (VO(2+)) cations catalyze the conversions of cellulose and its monomer, glucose, into lactic acid and formic acid in water. We have discovered an interesting shift of the major product from formic acid to lactic acid on switching the reaction atmosphere from oxygen to nitrogen. Our studies suggest that VO(2+) catalyzes the isomerization of glucose to fructose, the retro-aldol fragmentation of fructose to two trioses, and the isomerization of trioses, which leads to the formation of lactic acid under anaerobic conditions. The oxidative cleavage of C-C bonds in the intermediates caused by the redox conversion of VO2(+)/VO(2+) under aerobic conditions results in formic acid and CO2. We demonstrate that the addition of an alcohol suppresses the formation of CO2 and enhances the formic acid yield significantly to 70-75 %. PMID:24798653

  13. Interaction of cinnamic acid derivatives with β-cyclodextrin in water: experimental and molecular modeling studies.

    PubMed

    Liu, Benguo; Zeng, Jie; Chen, Chen; Liu, Yonglan; Ma, Hanjun; Mo, Haizhen; Liang, Guizhao

    2016-03-01

    Cyclodextrins (CDs) can be used to improve the solubility and stability of cinnamic acid derivatives (CAs). However, there was no detailed report about understanding the effects of the substituent groups in the benzene ring on the inclusion behavior between CAs and CDs in aqueous solution. Here, the interaction of β-CD with CAs, including caffeic acid, ferulic acid, and p-coumaric acid, in water was investigated by phase-solubility method, UV, fluorescence, and (1)H NMR spectroscopy, together with ONIOM (our Own N-layer Integrated Orbital molecular Mechanics)-based QM/MM (Quantum Mechanics/Molecular Mechanics) calculations. Experimental results demonstrated that CAs could form 1:1 stoichiometric inclusion complex with β-CD by non-covalent bonds, and that the maximum apparent stability constants were found in caffeic acid (176M(-1)) followed by p-coumaric acid (160M(-1)) and ferulic acid (133M(-1)). Moreover, our calculations reasonably illustrated the binding orientations of β-CD with CAs determined by experimental observations. PMID:26471667

  14. Lysophosphatidic acid induces necrosis and apoptosis in hippocampal neurons.

    PubMed

    Holtsberg, F W; Steiner, M R; Keller, J N; Mark, R J; Mattson, M P; Steiner, S M

    1998-01-01

    A diverse body of evidence indicates a role for the lipid biomediator lysophosphatidic acid (LPA) in the CNS. This study identifies and characterizes the induction of neuronal death by LPA. Treatment of cultured hippocampal neurons from embryonic rat brains with 50 microM LPA resulted in neuronal necrosis, as determined morphologically and by the release of lactate dehydrogenase. A concentration of LPA as low as 10 microM led to the release of lactate dehydrogenase. In contrast, treatment of neurons with 0.1 or 1.0 microM LPA resulted in apoptosis, as determined by chromatin condensation. In addition, neuronal death induced by 1 microM LPA was characterized as apoptotic on the basis of terminal dUTP nick end-labeling (TUNEL) staining, externalization of phosphatidylserine, and protection against chromatin condensation, TUNEL staining, and phosphatidylserine externalization by treatment with N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad-spectrum inhibitor of caspases, i.e., members of the interleukin-1beta converting enzyme family. Studies with antagonists of ionotropic glutamate receptors did not indicate a significant role for these receptors in apoptosis induced by 1 microM LPA. LPA (1 microM) also induced a decrease in mitochondrial membrane potential. Moreover, pretreatment of neurons with cyclosporin A protected against the LPA-induced decrease in mitochondrial membrane potential and neuronal apoptosis. Thus, LPA, at pathophysiological levels, can induce neuronal apoptosis and could thereby participate in neurodegenerative disorders. PMID:9422348

  15. Fluorinated amphiphilic amino acid derivatives as antioxidant carriers: a new class of protective agents.

    PubMed

    Ortial, Stéphanie; Durand, Grégory; Poeggeler, Burkhard; Polidori, Ange; Pappolla, Miguel A; Böker, Jutta; Hardeland, Rüdiger; Pucci, Bernard

    2006-05-01

    The use of classical antioxidants is limited by their low bioavailabilities, and therefore, high doses are usually required to display significant protective activity. In a recent article (J. Med. Chem. 2003, 46, 5230) we showed that the ability of the alpha-phenyl-N-tert-butylnitrone (PBN) to restore the viability of ATPase-deficient human skin fibroblasts was greatly enhanced by grafting it on a fluorinated amphiphilic carrier. With the aim of extending this concept to other antioxidants, we present here the design, the synthesis, and the physicochemical measurements of a new series of fluorinated amphiphilic antioxidant derivatives. The hydroxyl radical scavenging activity and the radical reducing potency of these newly designed compounds were respectively demonstrated in an ABTS competition and an ABTS(*+) reduction assay. We also showed that the protective effects of amphiphilic antioxidants derived from PBN, Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) or lipoic acid (5-[1,2]-dithiolan-3-ylpentanoic acid) in primary cortical mixed cell cultures exposed to oxidotoxins are greatly improved compared to their parent compounds in the following rank-order: (1) PBN, (2) Trolox, and (3) lipoic acid. In contrast, the protective activity of indole-3-propionic acid was slightly decreased by grafting it on the amphiphilic carrier. Similar observations were made in in vivo experiments using aquatic invertebrate microorganisms, called rotifers, which were exposed to lethal concentrations of nonselective (H(2)O(2)) and mitochondria-selective (doxorubicin) oxidotoxins. The conclusion of these studies is that fluorinated amphiphilic PBN, Trolox, and lipoic acid derivatives exhibit very potent protective activities in in vitro and in vivo experiments. The findings demonstrated herein therefore strongly suggest that the amphiphilic character enhances the bioavailability of the antioxidants and allows for a selective targeting of mitochondria. PMID:16640342

  16. Orexin A attenuates palmitic acid-induced hypothalamic cell death.

    PubMed

    Duffy, Cayla M; Nixon, Joshua P; Butterick, Tammy A

    2016-09-01

    Palmitic acid (PA), an abundant dietary saturated fatty acid, contributes to obesity and hypothalamic dysregulation in part through increase in oxidative stress, insulin resistance, and neuroinflammation. Increased production of reactive oxygen species (ROS) as a result of PA exposure contributes to the onset of neuronal apoptosis. Additionally, high fat diets lead to changes in hypothalamic gene expression profiles including suppression of the anti-apoptotic protein B cell lymphoma 2 (Bcl-2) and upregulation of the pro-apoptotic protein B cell lymphoma 2 associated X protein (Bax). Orexin A (OXA), a hypothalamic peptide important in obesity resistance, also contributes to neuroprotection. Prior studies have demonstrated that OXA attenuates oxidative stress induced cell death. We hypothesized that OXA would be neuroprotective against PA induced cell death. To test this, we treated an immortalized hypothalamic cell line (designated mHypoA-1/2) with OXA and PA. We demonstrate that OXA attenuates PA-induced hypothalamic cell death via reduced caspase-3/7 apoptosis, stabilization of Bcl-2 gene expression, and reduced Bax/Bcl-2 gene expression ratio. We also found that OXA inhibits ROS production after PA exposure. Finally, we show that PA exposure in mHypoA-1/2 cells significantly reduces basal respiration, maximum respiration, ATP production, and reserve capacity. However, OXA treatment reverses PA-induced changes in intracellular metabolism, increasing basal respiration, maximum respiration, ATP production, and reserve capacity. Collectively, these results support that OXA protects against PA-induced hypothalamic dysregulation, and may represent one mechanism through which OXA can ameliorate effects of obesogenic diet on brain health. PMID:27449757

  17. Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization

    PubMed Central

    Yanai, Ryoji; Mulki, Lama; Hasegawa, Eiichi; Takeuchi, Kimio; Sweigard, Harry; Suzuki, Jun; Gaissert, Philipp; Vavvas, Demetrios G.; Sonoda, Koh-Hei; Rothe, Michael; Schunck, Wolf-Hagen; Miller, Joan W.; Connor, Kip M.

    2014-01-01

    Ocular neovascularization, including age-related macular degeneration (AMD), is a primary cause of blindness in individuals of industrialized countries. With a projected increase in the prevalence of these blinding neovascular diseases, there is an urgent need for new pharmacological interventions for their treatment or prevention. Increasing evidence has implicated eicosanoid-like metabolites of long-chain polyunsaturated fatty acids (LCPUFAs) in the regulation of neovascular disease. In particular, metabolites generated by the cytochrome P450 (CYP)–epoxygenase pathway have been shown to be potent modulators of angiogenesis, making this pathway a reasonable previously unidentified target for intervention in neovascular ocular disease. Here we show that dietary supplementation with ω-3 LCPUFAs promotes regression of choroidal neovessels in a well-characterized mouse model of neovascular AMD. Leukocyte recruitment and adhesion molecule expression in choroidal neovascular lesions were down-regulated in mice fed ω-3 LCPUFAs. The serum of these mice showed increased levels of anti-inflammatory eicosanoids derived from eicosapentaenoic acid and docosahexaenoic acid. 17,18-epoxyeicosatetraenoic acid and 19,20-epoxydocosapentaenoic acid, the major CYP-generated metabolites of these primary ω-3 LCPUFAs, were identified as key lipid mediators of disease resolution. We conclude that CYP-derived bioactive lipid metabolites from ω-3 LCPUFAs are potent inhibitors of intraocular neovascular disease and show promising therapeutic potential for resolution of neovascular AMD. PMID:24979774

  18. Induced pluripotent stem cell-derived neuron as a human model for testing environmentally induced developmental neurotoxicity

    EPA Science Inventory

    Induced pluripotent stem cell-derived neurons as a human model for testing environmentally induced developmental neurotoxicity Ingrid L. Druwe1, Timothy J. Shafer2, Kathleen Wallace2, Pablo Valdivia3 ,and William R. Mundy2. 1University of North Carolina, Curriculum in Toxicology...

  19. Retinoic acid-induced neural differentiation of embryonal carcinoma cells.

    PubMed Central

    Jones-Villeneuve, E M; Rudnicki, M A; Harris, J F; McBurney, M W

    1983-01-01

    We have previously shown that the P19 line of embryonal carcinoma cells develops into neurons, astroglia, and fibroblasts after aggregation and exposure to retinoic acid. The neurons were initially identified by their morphology and by the presence of neurofilaments within their cytoplasm. We have more fully documented the neuronal nature of these cells by showing that their cell surfaces display tetanus toxin receptors, a neuronal cell marker, and that choline acetyl-transferase and acetyl cholinesterase activities appear coordinately in neuron-containing cultures. Several days before the appearance of neurons, there is a marked decrease in the amount of an embryonal carcinoma surface antigen, and at the same time there is a substantial decrease in the volumes of individual cells. Various retinoids were able to induce the development of neurons in cultures of aggregated P19 cells, but it did not appear that polyamine metabolism was involved in the effect. We have isolated a mutant clone which does not differentiate in the presence of any of the drugs which are normally effective in inducing differentiation of P19 cells. This mutant and others may help to elucidate the chain of events triggered by retinoic acid and other differentiation-inducing drugs. Images PMID:6656766

  20. Oil palm trunk and sugarcane bagasse derived solid acid catalysts for rapid esterification of fatty acids and moisture-assisted transesterification of oils under pseudo-infinite methanol.

    PubMed

    Ezebor, Francis; Khairuddean, Melati; Abdullah, Ahmad Zuhairi; Boey, Peng Lim

    2014-04-01

    The use of pseudo-infinite methanol in increasing the rate of esterification and transesterification reactions was studied using oil palm trunk (OPT) and sugarcane bagasse (SCB) derived solid acid catalysts. The catalysts were prepared by incomplete carbonisation at 400°C for 8h, followed by sulfonation at 150°C for 15h and characterised using TGA/DTA, XRD, FT-IR, SEM-EDS, EA and titrimetric determinations of acid sites. Under optimal reaction conditions, the process demonstrated rapid esterification of palmitic acid, with FAME yields of 93% and 94% in 45min for OPT and SCB catalysts, respectively. With the process, moisture levels up to 16.7% accelerated the conversion of low FFA oils by sulfonated carbon catalysts, through moisture-induced violent bumping. Moisture assisted transesterification of palm olein containing 1.78% FFA and 8.33% added water gave FAME yield of 90% in 10h, which was two folds over neat oil. PMID:24561631

  1. Nerve cell death induced in vivo by kainic acid and quinolinic acid does not involve apoptosis.

    PubMed

    Ignatowicz, E; Vezzani, A M; Rizzi, M; D'Incalci, M

    1991-11-01

    We investigated whether in vivo excitotoxicity was mediated by a mechanism of programmed cell death called apoptosis. Neurotoxic doses of kainic acid (1.2 nmol) and quinolinic acid (120 nmol) were unilaterally injected in the dorsal hippocampus of anesthetized rats. Eight or 16 h later the animals were killed and DNA was extracted from the injected hippocampi. DNA from mouse thymocytes exposed to methylprednisolone (10(-5) M for 6 h at 37 degrees C) was used as a positive control of apoptotic cells. No typical 'ladder' of DNA fragments (multimers of approximately 200 Kb) which characterizes apoptosis was seen in hippocampal cells after toxic doses of kainic or quinolinic acid, as assessed by agarose gel electrophoresis. This suggests that hippocampal nerve cell death induced in vivo by the excitotoxins is not mediated by apoptosis. PMID:1839770

  2. Diverse Bacterial PKS Sequences Derived From Okadaic Acid-Producing Dinoflagellates

    PubMed Central

    Perez, Roberto; Liu, Li; Lopez, Jose; An, Tianying; Rein, Kathleen S.

    2008-01-01

    Okadaic acid (OA) and the related dinophysistoxins are isolated from dinoflagellates of the genus Prorocentrum and Dinophysis. Bacteria of the Roseobacter group have been associated with okadaic acid producing dinoflagellates and have been previously implicated in OA production. Analysis of 16S rRNA libraries reveals that Roseobacter are the most abundant bacteria associated with OA producing dinoflagellates of the genus Prorocentrum and are not found in association with non-toxic dinoflagellates. While some polyketide synthase (PKS) genes form a highly supported Prorocentrum clade, most appear to be bacterial, but unrelated to Roseobacter or Alpha-Proteobacterial PKSs or those derived from other Alveolates Karenia brevis or Crytosporidium parvum. PMID:18728765

  3. Electrooxidation of pyrrole-terminated self-assembled lipoic acid derivatives

    NASA Astrophysics Data System (ADS)

    Cabrita, Joana F.; Viana, Ana S.; Eberle, Christoph; Montforts, Franz-Peter; Mourato, Ana; Abrantes, Luisa M.

    2009-08-01

    New pyrrole derivatives, pyrrolyl lipoic acid (Py-LA 3) and dipyrrolyl lipoic acid (Py 2-LA 2) have been used for surface attachment and immobilisation on gold surfaces, by self-assembly. The electrooxidation of the surface-confined pyrroles was analysed by cyclic voltammetry and the modified electrodes morphological and thickness changes addressed by scanning probe microscopy and ellipsometry. The data support the formation of oligomers as a result of the pendant-pyrrolyl units ease oxidation but provide no evidence of an effective subsequent polymerisation.

  4. Bioinspired bioadhesive polymers: dopa-modified poly(acrylic acid) derivatives.

    PubMed

    Laulicht, Bryan; Mancini, Alexis; Geman, Nathanael; Cho, Daniel; Estrellas, Kenneth; Furtado, Stacia; Hopson, Russell; Tripathi, Anubhav; Mathiowitz, Edith

    2012-11-01

    The one-step synthesis and characterization of novel bioinspired bioadhesive polymers that contain Dopa, implicated in the extremely adhesive byssal fibers of certain gastropods, is reported. The novel polymers consist of combinations of either of two polyanhydride backbones and one of three amino acids, phenylalanine, tyrosine, or Dopa, grafted as side chains. Dopa-grafted hydrophobic backbone polymers exhibit as much as 2.5 × the fracture strength and 2.8 × the tensile work of bioadhesion of a commercially available poly(acrylic acid) derivative as tested on live, excised, rat intestinal tissue. PMID:23008096

  5. Kinetics of the reaction of adamantane and its derivatives with nitric acid

    SciTech Connect

    Klimochkin, Yu.N.; Moiseev, I.K.

    1988-08-10

    The reaction of adamantane compounds with nitric acid in methylene chloride is of first order with respect to the substrate, and its rate is proportional to the fifth power of the nitric acid concentration. A considerable kinetic isotope effect was found (4.4 /plus minus/ 0.3). The rate constants are linearly related to the solvolysis rate constants of the corresponding bromine derivatives and the Taft induction constants. A possible mechanism for oxynitration, including the removal of a hydride ion as controlling stage is proposed.

  6. Fluorosulfonic acid and chlorosulfonic acid: possible candidates for OH-stretching overtone-induced photodissociation.

    PubMed

    Lane, Joseph R; Kjaergaard, Henrik G

    2007-10-01

    We have calculated the stationary points and internal reaction coordinate pathway for the dissociation of fluorosulfonic acid (FSO3H) and chlorosulfonic acid (ClSO3H). These sulfonic acids dissociate to sulfur trioxide and hydrogen fluoride and chloride, respectively. We have calculated the frequencies and intensities of the OH-stretching transitions of FSO3H and ClSO3H with an anharmonic oscillator local mode model. We find that excitation of the fourth and third OH-stretching overtones provide adequate energy for photodissociation of FSO3H and ClSO3H, respectively. We propose that experimental detection of the products of OH-stretching overtone-induced photodissociation of FSO3H and ClSO3H would be easier than the sulfuric acid (H2SO4) equivalent. The photodissociation of H2SO4 is thought to be important in the stratosphere. The FSO3H and ClSO3H experiment could be used in proxy to support the recently proposed OH-stretching overtone-induced photodissociation mechanism of H2SO4. PMID:17764162

  7. Investigation on the ZBG-functionality of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase inhibitors.

    PubMed

    Musso, Loana; Cincinelli, Raffaella; Zuco, Valentina; Zunino, Franco; Nurisso, Alessandra; Cuendet, Muriel; Giannini, Giuseppe; Vesci, Loredana; Pisano, Claudio; Dallavalle, Sabrina

    2015-10-15

    A series of alternative Zn-binding groups were explored in the design of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Most of the synthesized compounds were less effective than the parent hydroxamic acid. However, the profile of activity shown by the analog bearing a hydroxyurea head group, makes this derivative promising for further investigation. PMID:26376355

  8. Ursolic acid improves domoic acid-induced cognitive deficits in mice

    SciTech Connect

    Wu, Dong-mei; Lu, Jun; Zhang, Yan-qiu; Zheng, Yuan-lin; Hu, Bin; Cheng, Wei; Zhang, Zi-feng; Li, Meng-qiu

    2013-09-01

    Our previous findings suggest that mitochondrial dysfunction is the mechanism underlying cognitive deficits induced by domoic acid (DA). Ursolic acid (UA), a natural triterpenoid compound, possesses many important biological functions. Evidence shows that UA can activate PI3K/Akt signaling and suppress Forkhead box protein O1 (FoxO1) activity. FoxO1 is an important regulator of mitochondrial function. Here we investigate whether FoxO1 is involved in the oxidative stress-induced mitochondrial dysfunction in DA-treated mice and whether UA inhibits DA-induced mitochondrial dysfunction and cognitive deficits through regulating the PI3K/Akt and FoxO1 signaling pathways. Our results showed that FoxO1 knockdown reversed the mitochondrial abnormalities and cognitive deficits induced by DA in mice through decreasing HO-1 expression. Mechanistically, FoxO1 activation was associated with oxidative stress-induced JNK activation and decrease of Akt phosphorylation. Moreover, UA attenuated the mitochondrial dysfunction and cognitive deficits through promoting Akt phosphorylation and FoxO1 nuclear exclusion in the hippocampus of DA-treated mice. LY294002, an inhibitor of PI3K/Akt signaling, significantly decreased Akt phosphorylation in the hippocampus of DA/UA mice, which weakened UA actions. These results suggest that UA could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in excitotoxic brain disorders. - Highlights: • Ursolic acid (UA) is a naturally triterpenoid compound. • UA attenuated the mitochondrial dysfunction and cognitive deficits. • Mechanistically, UA activates PI3K/Akt signaling and suppresses FoxO1 activity. • UA could be recommended as a possible candidate for anti-excitotoxic brain disorders.

  9. Mechanism of hepatic megamitochondria formation by ammonia derivatives. Correlation between structure of chemicals and their ability to induce the formation of megamitochondria.

    PubMed

    Wakabayashi, T; Horiuchi, M; Sakaguchi, M; Misawa, K; Onda, H; Iijima, M; Allmann, D W

    1984-09-01

    Correlation between the chemical structure and the ability to induce hepatic megamitochondria formation was studied by feeding mice and rats diets containing a wide spectrum of ammonia derivatives. Ammonia derivatives with electron-releasing groups, such as hydrazine, phenylhydrazine, hydroxylamine and aniline were effective in inducing megamitochondria. Ammonia derivatives with electron-withdrawing groups, such as formamide, sulfamic acid, acetamide were ineffective in inducing megamitochondria. Inducibility of ammonia derivatives with electron-releasing groups plus electron-withdrawing groups for the megamitochondria formation was dependent upon nucleophilicity of the chemical: 2,4-dinitrophenylhydrazine induced megamitochondria, while acetanilide did not induce megamitochondria. The megamitochondria formation induced by ammonia derivatives was a reversible process. Freeze-fracture studies on megamitochondria indicated that megamitochondria were formed by the fusion of adjacent mitochondria. Phosphorylating capacity of megamitochondria (hydrazine-induced megamitochondria, for example) were normal despite morphological changes. These data might suggest that the nucleophilicity of chemicals plays a key role in the induction of hepatic megamitochondria. These data might also suggest that the phenomenon is an adaptive process to changes of intracellular milieu. PMID:6468403

  10. A benzoic acid derivative and flavokawains from Piper species as schistosomiasis vector controls.

    PubMed

    Rapado, Ludmila N; Freitas, Giovana C; Polpo, Adriano; Rojas-Cardozo, Maritza; Rincón, Javier V; Scotti, Marcus T; Kato, Massuo J; Nakano, Eliana; Yamaguchi, Lydia F

    2014-01-01

    The search of alternative compounds to control tropical diseases such as schistosomiasis has pointed to secondary metabolites derived from natural sources. Piper species are candidates in strategies to control the transmission of schistosomiasis due to their production of molluscicidal compounds. A new benzoic acid derivative and three flavokawains from Piper diospyrifolium, P. cumanense and P. gaudichaudianum displayed significant activities against Biomphalaria glabrata snails. Additionally, "in silico" studies were performed using docking assays and Molecular Interaction Fields to evaluate the physical-chemical differences among the compounds in order to characterize the observed activities of the test compounds against Biomphalaria glabrata snails. PMID:24762961

  11. PFR peptide, one of the antimicrobial peptides identified from the derivatives of lactoferrin, induces necrosis in leukemia cells

    PubMed Central

    Lu, Yan; Zhang, Teng-Fei; Shi, Yue; Zhou, Han-Wei; Chen, Qi; Wei, Bu-Yun; Wang, Xi; Yang, Tian-Xin; Chinn, Y. Eugene; Kang, Jian; Fu, Cai-Yun

    2016-01-01

    LF11-322 (PFWRIRIRR-NH2) (PFR peptide), a nine amino acid-residue peptide fragment derived from human lactoferricin, possesses potent cytotoxicity against bacteria. We report here the discovery and characterization of its antitumor activity in leukemia cells. PFR peptide inhibited the proliferation of MEL and HL-60 leukemia cells by inducing cell death in the absence of the classical features of apoptosis, including chromatin condensation, Annexin V staining, Caspase activation and increase of abundance of pro-apoptotic proteins. Instead, necrotic cell death as evidenced by increasing intracellular PI staining and LDH release, inducing membrane disruption and up-regulating intracellular calcium level, was observed following PFR peptide treatment. In addition to necrotic cell death, PFR peptide also induced G0/G1 cell cycle arrest. Moreover, PFR peptide exhibited favorable antitumor activity and tolerability in vivo. These findings thus provide a new clue of antimicrobial peptides as a potential novel therapy for leukemia. PMID:26860588

  12. Hepatoprotective effect of trimethylgallic acid esters against carbon tetrachloride-induced liver injury in rats.

    PubMed

    Sachdeva, Mamta; Chadha, Renu; Kumar, Anil; Karan, Maninder; Singh, Tejvir; Dhingra, Sameer

    2015-12-01

    Gallic acid and its derivatives are potential therapeutic agents for treating various oxidative stress mediated disorders. In the present study, we investigated the hepatoprotective effects of newly synthesized conjugated trimethylgallic acid (TMGA) esters against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Animals were pre-treated with TMGA esters at their respective doses for 7 days against CCl4-induced hepatotoxicity. The histopathological changes were evaluated to find out degenerative fatty changes including vacuole formation, inflammation and tissue necrosis. Various biomarkers of oxidative stress (lipid peroxidation, glutathione levels, and endogenous antioxidant enzyme activities), liver enzymes (AST and ALT), triacylglycerol and cholesterol were evaluated. Pre-treatment with TMGA esters (MRG, MGG, MSG, and MUG at the dose of 28.71, 30.03, 31.35, 33.62 mg/kg/day), respectively reversed the CCl4-induced liver injury scores (reduced vacuole formation, inflammation and necrosis), biochemical parameters of plasma (increased AST, ALT, TG, and cholesterol), antioxidant enzymes (increased lipid peroxidation and nitrite levels; decreased glutathione levels, superoxide dismutase and catalase activities) in liver tissues and inflammatory surge (serum TNF-α) significantly. The study revealed that TMGA esters exerted hepatoprotective effects in CCl4-induced rats, specifically by modulating oxidative-nitrosative stress and inflammation. PMID:26742325

  13. HPLC quantification of all five ginkgolic acid derivatives in Ginkgo biloba extracts using 13 : 0 ginkgolic acid as a single marker compound.

    PubMed

    Wang, Ruwei; Kobayashi, Yuta; Lin, Yu; Rauwald, Hans Wilhelm; Yao, Jianbiao; Fang, Ling; Qiao, Hongxiang; Kuchta, Kenny

    2015-01-01

    An HPLC quantification method for ginkgolic acid derivatives in Ginkgo biloba leaf extracts was developed. Using 13 : 0 ginkgolic acid as a marker compound, the relative correlation factors of the four other ginkgolic acid derivatives - namely, 15 : 0 ginkgolic acid, 15 : 1 ginkgolic acid, 17 : 1 ginkgolic acid, and 17 : 2 ginkgolic acid - to 13 : 0 ginkgolic acid were determined by HPLC and subsequently used for calculating their contents in ten hydro-ethanolic refined extract samples. In other words, the content of 13 : 0 ginkgolic acid in the extracts was determined using the isolated compound as an external standard. Subsequently the now known concentration of this compound functioned as an internal standard for the quantification of the other four ginkgolic acid derivatives via the described correlation factors. This HPLC method was validated by two independent control measurements, one with an external standard for every individual compound and one based on the present method with the single marker compound alone. The results did not differ significantly in any of the 10 tested extract samples. The protocol presented here thus not only uses the same reference substance for G. biloba extracts as the current Chinese Pharmacopoeia method but also incorporates the advantages of the current European Pharmacopoeia approach. It is simple, reproducible, and can be used to determine the total contents of ginkgolic acid derivatives in G. biloba leaf extracts. PMID:25519835

  14. Matrine derivate MASM suppresses LPS-induced phenotypic and functional maturation of murine bone marrow-derived dendritic cells.

    PubMed

    Xu, Jing; Qi, Yang; Xu, Wei-Heng; Liu, Ying; Qiu, Lie; Wang, Ke-Qi; Hu, Hong-Gang; He, Zhi-Gao; Zhang, Jun-Ping

    2016-07-01

    Dendritic cell (DC) maturation process is a crucial step for the development of T cell immune responses and immune tolerance. In this study, we evaluated MASM, a novel derivative of the natural compound matrine that possesses a significant anti-inflammatory and immune-regulating property, for its efficacy to inhibit lipopolysaccharides (LPS)-induced maturation of murine bone marrow-derived dendritic cells. Here we show that MASM profoundly suppresses LPS-induced phenotypic and functional DC maturation. MASM inhibited LPS-induced expression of costimulatory molecules CD80 and CD86 in a concentration-dependent manner. MASM also attenuated LPS-induced IL-12p70, TNF-α, IL-6 and NO release of DCs. The MASM-treated DCs were highly efficient at antigen capture via mannose receptor-mediated endocytosis but showed weak stimulatory capacity for allogeneic T cell proliferation. Furthermore, MASM inhibited LPS-induced PI3K/Akt, MAPK and NF-κB pathways. These novel findings provide new insight into the immunopharmacological role of MASM in impacting on the DCs. PMID:27107799

  15. Saturated phosphatidic acids mediate saturated fatty acid-induced vascular calcification and lipotoxicity.

    PubMed

    Masuda, Masashi; Miyazaki-Anzai, Shinobu; Keenan, Audrey L; Okamura, Kayo; Kendrick, Jessica; Chonchol, Michel; Offermanns, Stefan; Ntambi, James M; Kuro-O, Makoto; Miyazaki, Makoto

    2015-12-01

    Recent evidence indicates that saturated fatty acid-induced (SFA-induced) lipotoxicity contributes to the pathogenesis of cardiovascular and metabolic diseases; however, the molecular mechanisms that underlie SFA-induced lipotoxicity remain unclear. Here, we have shown that repression of stearoyl-CoA desaturase (SCD) enzymes, which regulate the intracellular balance of SFAs and unsaturated FAs, and the subsequent accumulation of SFAs in vascular smooth muscle cells (VSMCs), are characteristic events in the development of vascular calcification. We evaluated whether SMC-specific inhibition of SCD and the resulting SFA accumulation plays a causative role in the pathogenesis of vascular calcification and generated mice with SMC-specific deletion of both Scd1 and Scd2. Mice lacking both SCD1 and SCD2 in SMCs displayed severe vascular calcification with increased ER stress. Moreover, we employed shRNA library screening and radiolabeling approaches, as well as in vitro and in vivo lipidomic analysis, and determined that fully saturated phosphatidic acids such as 1,2-distearoyl-PA (18:0/18:0-PA) mediate SFA-induced lipotoxicity and vascular calcification. Together, these results identify a key lipogenic pathway in SMCs that mediates vascular calcification. PMID:26517697

  16. Stereoselective Synthesis of α-Amino-C-phosphinic Acids and Derivatives.

    PubMed

    Viveros-Ceballos, José Luis; Ordóñez, Mario; Sayago, Francisco J; Cativiela, Carlos

    2016-01-01

    α-Amino-C-phosphinic acids and derivatives are an important group of compounds of synthetic and medicinal interest and particular attention has been dedicated to their stereoselective synthesis in recent years. Among these, phosphinic pseudopeptides have acquired pharmacological importance in influencing physiologic and pathologic processes, primarily acting as inhibitors for proteolytic enzymes where molecular stereochemistry has proven to be critical. This review summarizes the latest developments in the asymmetric synthesis of acyclic and phosphacyclic α-amino-C-phosphinic acids and derivatives, following in the first case an order according to the strategy used, whereas for cyclic compounds the nitrogen embedding in the heterocyclic core is considered. In addition selected examples of pharmacological implications of title compounds are also disclosed. PMID:27589703

  17. Transition-Metal-Free ipso-Functionalization of Arylboronic Acids and Derivatives

    PubMed Central

    Zhu, Chen; Falck, John R.

    2014-01-01

    Arylboronic acids and their derivatives have been widely exploited as important synthetic precursors in organic synthesis, materials science, and pharmaceutical development. In addition to numerous applications in transition-metal-mediated cross-coupling reactions, transition-metal-free transformations involving arylboronic acids and derivatives have recently received a surge of attention for converting the C-B bond to C-C, C-N, C-O, and many other C-X bonds. Consequently, a wide range of useful compounds, e.g., phenols, anilines, nitroarenes, and haloarenes, have been readily synthesized. Amongst these efforts, many versatile reagents have been developed and a lot of practical approaches demonstrated. The research in this promising field is summarized in the current review and organized on the basis of the type of bonds being formed. PMID:25414624

  18. Syntheses and Cellular Investigations of 173-, 152- and 131-Amino Acid Derivatives of Chlorin e61

    PubMed Central

    Waruna Jinadasa, R. G.; Hu, Xiaoke; Vicente, M. Graça H.; Smith, Kevin M.

    2011-01-01

    A series of amino acid conjugates of chlorin e6, containing lysine or aspartic acid residues in positions 173, 152 or 131 of the macrocycle were synthesized and investigated as photosensitizers for photodynamic therapy of tumors. All three regioisomers were synthesized in good yields and in 5 steps or less from pheophytin a (1). In vitro investigations using human carcinoma HEp2 cells show that the 152-lysyl regioisomers accumulate the most within cells, and the most phototoxic are the 131 regioisomers. The main determinant of biological efficacy appears to be the conjugation site, probably because of molecular conformation. Molecular modeling investigations reveal that the 173-substituted chlorin e6 conjugates are L-shaped, the 152 and 131 regioisomers assume extended conformations, and the 131 derivatives are nearly linear. It is hypothesized that the 131-aspartylchlorin e6 conjugate may be a more efficient photosensitizer for PDT than the commercial currently used 152 derivative. PMID:21936519

  19. Rupestonic acid derivative YZH-106 suppresses influenza virus replication by activation of heme oxygenase-1-mediated interferon response.

    PubMed

    Ma, Lin-Lin; Wang, Hui-Qiang; Wu, Ping; Hu, Jin; Yin, Jin-Qiu; Wu, Shuo; Ge, Miao; Sun, Wen-Fang; Zhao, Jiang-Yu; Aisa, Haji Akber; Li, Yu-Huan; Jiang, Jian-Dong

    2016-07-01

    Given the limitation of available antiviral drugs and vaccines, there remains to be a pressing need for novel anti-influenza drugs. Rupestonic acid derivatives were reported to have an anti-influenza virus activity, but their mechanism remains to be elucidated. Herein, we aim to evaluate the antiviral activity of YZH-106, a rupestonic acid derivative, against a broad-spectrum of influenza viruses and to dissect its antiviral mechanisms. Our results demonstrated that YZH-106 exhibited a broad-spectrum antiviral activity against influenza viruses, including drug-resistant strains in vitro. Furthermore, YZH-106 provided partial protection of the mice to Influenza A virus (IAV) infection, as judged by decreased viral load in lungs, improved lung pathology, reduced body weight loss and partial survival benefits. Mechanistically, YZH-106 induced p38 MAPK and ERK1/2 phosphorylation, which led to the activation of erythroid 2-related factor 2 (Nrf2) that up-regulated heme oxygenase-1 (HO-1) expression in addition to other genes. HO-1 inhibited IAV replication by activation of type I IFN expression and subsequent induction of IFN-stimulated genes (ISGs), possibly in a HO-1 enzymatic activity-independent manner. These results suggest that YZH-106 inhibits IAV by up-regulating HO-1-mediated IFN response. HO-1 is thus a promising host target for antiviral therapeutics against influenza and other viral infectious diseases. PMID:27107768

  20. Potentiation of phenobarbital-induced anticonvulsant activity by pipecolic acid.

    PubMed

    Takahama, K; Miyata, T; Okano, Y; Kataoka, M; Hitoshi, T; Kasé, Y

    1982-07-01

    Pipecolic acid (PA) is an intermediate of lysine metabolism in the mammalian brain. Recent findings suggest a functional connection of PA as neuromodulator in GABAergic transmission. Since many drugs are postulated to produce their effects by interaction with the central GABA system, the influence of PA on the anticonvulsant activity of phenobarbital was examined. Pretreatment of mice with 50 mg . kg-1 of PA potentiated the suppressing effects of the barbiturate on electrically and chemically induced convulsions. However, there was no potentiation of the behavioral effects and hypothermia induced by phenobarbital. PA itself had no or only little effect on the convulsions, motor function and rectal temperature when given in i.p. doses up to 500 mg . kg-1. Intraventricular administration of 500 microgram of PA also did not suppress either type of convulsion, although it produced ptosis, hypotonia, sedation and hypothermia. The results are discussed in relation to GABA system. PMID:6288409

  1. [Sunitinib and zoledronic acid induced osteonecrosis of the jaw].

    PubMed

    Soós, Balázs; Vajta, László; Szalma, József

    2015-11-15

    The tendency for bisphosphonate and non-bisphosphonate (eg.: antiresorptive or anti-angiogenesis drugs) induced osteonecrosis is increasing. Treatment of these patients is a challenge both for dentists and for oral and maxillofacial surgeons. Cooperation with the drug prescribing general medicine colleagues to prevent osteonecrosis is extremely important. Furthermore, prevention should include dental focus elimination, oral hygienic instructions and education, dental follow-up and, in case of manifest necrosis, referral to maxillofacial departments. Authors outline the difficulties of conservative and surgical treatment of a patient with sunitinib and zoledronic acid induced osteonecrosis. The patient became symptomless and the operated area healed entirely six and twelve months postoperatively. A long term success further follow-up is necessary to verify long-term success. PMID:26548471

  2. [Synthesis and properties of nuclear hydroxylated derivatives of flufenamic acid and etofenamate (author's transl)].

    PubMed

    Boltze, K H; Bäcker, U; Kreisfeld, H

    1982-01-01

    Synthesis of six nuclear hydroxylated derivatives of flufenamic acid and etofenamate (5-OH-, 4'-OH and 5,4'-(OH2) on a preparative scale is described. All compounds show low toxicity, but only weak anti-inflammatory activity in the rat paw kaolin edema test as compared to 2-(2-hydroxyethoxy)ethyl-N-(a,a,a-trifluoro-m-tolyl)-anthranilate (etofenamate, active substance of Rheumon Gel). PMID:7200776

  3. Manzamenone O, new trimeric fatty acid derivative from a marine sponge Plakortis sp.

    PubMed

    Tanaka, Naonobu; Asai, Miki; Takahashi-Nakaguchi, Azusa; Gonoi, Tohru; Fromont, Jane; Kobayashi, Jun'ichi

    2013-05-17

    A new structurally unique trimeric fatty acid derivative, manzamenone O (1), was isolated from a marine sponge Plakortis sp. Manzamenone O (1) has a novel skeleton consisting of C-C bonded octahydroindenone and dioxabicyclo[3.3.0]octane moieties and three long aliphatic chains. The structure of 1 was elucidated on the basis of spectroscopic data and conformational analysis. Manzamenone O (1) exhibited antimicrobial activity against Micrococcus luteus, Aspergillis niger, and Trichophyton mentagrophytes. PMID:23651077

  4. Carbonylative Suzuki Couplings of Aryl Bromides with Boronic Acid Derivatives under Base-Free Conditions

    PubMed Central

    2015-01-01

    The carbonylative Suzuki–Miyaura reaction between aryl bromides and arylboronic acid equivalents is herein reported, using base-free conditions and a limited excess of carbon monoxide generated ex situ from stable CO-precursors. Under these conditions, unsymmetrical biaryl ketones were obtained in modest to excellent yields. This method was adapted to the synthesis of the triglyceride and cholesterol regulator drug, fenofibrate, and its 13C-labeled derivative in good yields from the appropriate CO-precursor. PMID:24635142

  5. INDUCED SPUTUM DERIVES FROM THE CENTRAL AIRWAYS: CONFIRMATION USING A RADIOLABELED AEROSOL BOLUS DELIVERY TECHNIQUE

    EPA Science Inventory

    Indirect evidence suggests that induced sputum derives from the surfaces of the bronchial airways. To confirm this experimentally, we employed a radiolabeled aerosol bolus delivery technique that preferentially deposits aerosol in the central airways in humans. We hypothesized th...

  6. Interaction of inflammatory and anti-inflammatory responses in microglia by Staphylococcus aureus-derived lipoteichoic acid

    SciTech Connect

    Huang, Bor-Ren; Tsai, Cheng-Fang; Lin, Hsiao-Yun; Tseng, Wen-Pei; Huang, Shiang-Suo; Wu, Chi-Rei; Lin, Chingju; Yeh, Wei-Lan; Lu, Dah-Yuu

    2013-05-15

    We investigated the interaction between proinflammatory and inflammatory responses caused by Staphylococcus aureus-derived lipoteichoic acid (LTA) in primary cultured microglial cells and BV-2 microglia. LTA induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein levels increase in a concentration- and time-dependent manner. Meanwhile, LTA also increased nitric oxide (NO) and PGE{sub 2} production in microglia. Administration of TLR2 antagonist effectively inhibited LTA-induced NO, iNOS, and COX-2 expression. Moreover, treatment of cells with LTA caused a time-dependent activation of ERK, p38, JNK, as well as AKT. We also found that LTA-induced iNOS and COX-2 up-regulation were attenuated by p38, JNK, and PI3-kinase inhibitors. On the other hand, LTA-enhanced HO-1 expression was attenuated by p38 and PI3-kinase inhibitors. Treatment of cells with NF-κB and AP-1 inhibitors antagonized LTA-induced iNOS and COX-2 expression. However, only NF-κB inhibitors reduced LTA-induced HO-1 expression in microglia. Furthermore, stimulation of cells with LTA also activated IκBα phosphorylation, p65 phosphorylation at Ser{sup 536}, and c-Jun phosphorylation. Moreover, LTA-induced increases of κB-DNA and AP-1-DNA binding activity were inhibited by p38, JNK, and PI3-kinase inhibitors. HO-1 activator CoPP IX dramatically reversed LTA-induced iNOS expression. Our results provided mechanisms linking LTA and inflammation/anti-inflammation, and indicated that LTA plays a regulatory role in microglia activation. - Highlights: • LTA causes an increase in iNOS, COX-2, and HO-1 expression in microglia. • LTA induces iNOS and COX-2 expression through TLR-2/NF-κB and AP-1 pathways. • HO-1 expression is regulated through p38, JNK, PI3K/AKT and AP-1 pathways. • Induced HO-1 reduces LTA-induced iNOS expression. • LTA plays a regulatory role on inflammatory/anti-inflammatory responses.

  7. Electrochemical Biosensors Based on Ferroceneboronic Acid and Its Derivatives: A Review

    PubMed Central

    Wang, Baozhen; Takahashi, Shigehiro; Du, Xiaoyan; Anzai, Jun-ichi

    2014-01-01

    We review recent progress in the development of electrochemical biosensors based on ferroceneboronic acid (FcBA) and ferrocene (Fc)-modified boronic acids. These compounds can be used to construct electrochemical biosensors because they consist of a binding site (i.e., a boronic acid moiety) and an electrochemically active part (i.e., an Fc residue). By taking advantage of the unique properties of FcBA and its derivatives, electrochemical sensors sensitive to sugars, glycated hemoglobin (HbA1c), fluoride (F−) ions, and so forth have been widely studied. FcBA-based sugar sensors rely on the selective binding of FcBA to 1,2- or 1,3-diol residues of sugars through the formation of cyclic boronate ester bonds. The redox properties of FcBA-sugar adduct differ from those of free FcBA, which forms the basis of the electrochemical determination of sugars. Thus, non-enzymatic glucose sensors are now being actively studied using FcBA and Fc-modified boronic acids as redox markers. Using a similar principle, HbA1c can be detected by FcBA-based electrochemical systems because it contains hydrocarbon chains on the polypeptide chain. HbA1c sensors are useful for monitoring blood glucose levels over the preceding 8–12 weeks. In addition, FcBA and Fc-modified boronic acids have been used for the detection of F− ions due to the selective binding of boronic acid to F− ions. F−-ion sensors may be useful alternatives to conventional ion-selective electrodes sensitive to F− ion. Furthermore, FcBA derivatives have been studied to construct lectin; steroids; nucleotides; salicylic acid; and bacteria sensors. One of the limitations of FcBA-based sensors comes from the fact that FcBA derivatives are added in sample solutions as reagents. FcBA derivatives should be immobilized on the surface of electrodes for developing reagentless sensors. PMID:25587421

  8. Electrochemical biosensors based on ferroceneboronic Acid and its derivatives: a review.

    PubMed

    Wang, Baozhen; Takahashi, Shigehiro; Du, Xiaoyan; Anzai, Jun-Ichi

    2014-09-01

    We review recent progress in the development of electrochemical biosensors based on ferroceneboronic acid (FcBA) and ferrocene (Fc)-modified boronic acids. These compounds can be used to construct electrochemical biosensors because they consist of a binding site (i.e., a boronic acid moiety) and an electrochemically active part (i.e., an Fc residue). By taking advantage of the unique properties of FcBA and its derivatives, electrochemical sensors sensitive to sugars, glycated hemoglobin (HbA1c), fluoride (F(-)) ions, and so forth have been widely studied. FcBA-based sugar sensors rely on the selective binding of FcBA to 1,2- or 1,3-diol residues of sugars through the formation of cyclic boronate ester bonds. The redox properties of FcBA-sugar adduct differ from those of free FcBA, which forms the basis of the electrochemical determination of sugars. Thus, non-enzymatic glucose sensors are now being actively studied using FcBA and Fc-modified boronic acids as redox markers. Using a similar principle, HbA1c can be detected by FcBA-based electrochemical systems because it contains hydrocarbon chains on the polypeptide chain. HbA1c sensors are useful for monitoring blood glucose levels over the preceding 8-12 weeks. In addition, FcBA and Fc-modified boronic acids have been used for the detection of F(-) ions due to the selective binding of boronic acid to F(-) ions. F(-)-ion sensors may be useful alternatives to conventional ion-selective electrodes sensitive to F(-) ion. Furthermore, FcBA derivatives have been studied to construct lectin; steroids; nucleotides; salicylic acid; and bacteria sensors. One of the limitations of FcBA-based sensors comes from the fact that FcBA derivatives are added in sample solutions as reagents. FcBA derivatives should be immobilized on the surface of electrodes for developing reagentless sensors. PMID:25587421

  9. Docosahexaenoic acid, an omega-3 polyunsaturated acid protects against indomethacin-induced gastric injury.

    PubMed

    Pineda-Peña, Elizabeth Arlen; Jiménez-Andrade, Juan Miguel; Castañeda-Hernández, Gilberto; Chávez-Piña, Aracely Evangelina

    2012-12-15

    Previous studies have shown gastroprotective effect of fish oil in several experimental models. However, the mechanisms and active compounds underlying this effect are not fully understood. Fish oil has several components; among them, one of the most studied is docosahexaenoic acid (DHA), which is an omega-3 long-chain polyunsaturated fatty acid. The aim of this study was to examine the gastroprotective effect of DHA as a pure compound in a rat model of indomethacin-induced gastric injury as well as elucidate some of the mechanism(s) behind DHA's gastroprotective effect. Indomethacin was orally administered to induce an acute gastric injury (3, 10 and 30mg/kg). Omeprazol (a proton pump inhibitor, 30mg/kg, p.o.) and DHA (3, 10, 30mg/kg, p.o.) were gavaged 30 and 120min, respectively, before indomethacin insult (30mg/kg p.o.). Three hours after indomethacin administration, rats were sacrificed, gastric injury was evaluated by determining the total damaged area. A sample of gastric tissue was harvested and processed to quantify prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) levels by enzyme-linked immunosorbent assay. Indomethacin produced gastric injury in dose-dependent manner. DHA protected against indomethacin-induced gastric damage, and this effect was comparable with omeprazol's gastroprotective effect. DHA did not reverse the indomethacin-induced reduction of PGE(2) gastric levels. In contrast, DHA partially prevented the indomethacin-induced increase in LTB(4) gastric levels. This is the first report demonstrating DHA's gastroprotective effect as a pure compound. Furthermore, the results reveal that the gastroprotective effect is mediated by a decrease in gastric LTB(4) levels in indomethacin-induced gastric damage. PMID:23063544

  10. Metabolic engineering of Saccharomyces cerevisiae for production of fatty acid-derived biofuels and chemicals.

    PubMed

    Runguphan, Weerawat; Keasling, Jay D

    2014-01-01

    As the serious effects of global climate change become apparent and access to fossil fuels becomes more limited, metabolic engineers and synthetic biologists are looking towards greener sources for transportation fuels. In recent years, microbial production of high-energy fuels by economically efficient bioprocesses has emerged as an attractive alternative to the traditional production of transportation fuels. Here, we engineered the budding yeast Saccharomyces cerevisiae to produce fatty acid-derived biofuels and chemicals from simple sugars. Specifically, we overexpressed all three fatty acid biosynthesis genes, namely acetyl-CoA carboxylase (ACC1), fatty acid synthase 1 (FAS1) and fatty acid synthase 2 (FAS2), in S. cerevisiae. When coupled to triacylglycerol (TAG) production, the engineered strain accumulated lipid to more than 17% of its dry cell weight, a four-fold improvement over the control strain. Understanding that TAG cannot be used directly as fuels, we also engineered S. cerevisiae to produce drop-in fuels and chemicals. Altering the terminal "converting enzyme" in the engineered strain led to the production of free fatty acids at a titer of approximately 400 mg/L, fatty alcohols at approximately 100mg/L and fatty acid ethyl esters (biodiesel) at approximately 5 mg/L directly from simple sugars. We envision that our approach will provide a scalable, controllable and economic route to this important class of chemicals. PMID:23899824

  11. Co-culture-inducible bacteriocin production in lactic acid bacteria.

    PubMed

    Chanos, Panagiotis; Mygind, Tina

    2016-05-01

    It is common knowledge that microorganisms have capabilities, like the production of antimicrobial compounds, which do not normally appear in ideal laboratory conditions. Common antimicrobial discovery techniques require the isolation of monocultures and their individual screening against target microorganisms. One strategy to achieve expression of otherwise hidden antimicrobials is induction by co-cultures. In the area of bacteriocin-producing lactic acid bacteria, there has been some research focusing into the characteristics of co-culture-inducible bacteriocin production and particularly the molecular mechanism(s) of such interactions. No clear relationship has been seen between bacteriocin-inducing and bacteriocin-producing microorganisms. The three-component regulatory system seems to be playing a central role in the induction, but inducing compounds have not been identified or characterized. However, the presence of the universal messenger molecule autoinducer-2 has been associated in some cases with the co-culture-inducible bacteriocin phenotype and it may play the role in the additional regulation of the three-component regulatory system. Understanding the mechanisms of induction would facilitate the development of strategies for screening and development of co-culture bacteriocin-producing systems and novel products as well as the perseverance of such systems in food and down to the intestinal tract, possibly conferring a probiotic effect on the host. PMID:27037694

  12. Depressed phosphatidic acid-induced contractile activity of failing cardiomyocytes.

    PubMed

    Tappia, Paramjit S; Maddaford, Thane G; Hurtado, Cecilia; Panagia, Vincenzo; Pierce, Grant N

    2003-01-10

    The effects of phosphatidic acid (PA), a known inotropic agent, on Ca(2+) transients and contractile activity of cardiomyocytes in congestive heart failure (CHF) due to myocardial infarction were examined. In control cells, PA induced a significant increase (25%) in active cell shortening and Ca(2+) transients. The phospholipase C (PLC) inhibitor, 2-nitro-4-carboxyphenyl N,N-diphenylcarbonate, blocked the positive inotropic action induced by PA, indicating that PA induces an increase in contractile activity and Ca(2+) transients through stimulation of PLC. Conversely, in failing cardiomyocytes there was a loss of PA-induced increase in active cell shortening and Ca(2+) transients. PA did not alter resting cell length. Both diastolic and systolic [Ca(2+)] were significantly elevated in the failing cardiomyocytes. In vitro assessment of the cardiac sarcolemmal (SL) PLC activity revealed that the impaired failing cardiomyocyte response to PA was associated with a diminished stimulation of SL PLC activity by PA. Our results identify an important defect in the PA-PLC signaling pathway in failing cardiomyocytes, which may have significant implications for the depressed contractile function during CHF. PMID:12504106

  13. Safety evaluation of pectin-derived acidic oligosaccharides (pAOS): genotoxicity and sub-chronic studies.

    PubMed

    Garthoff, Jossie A; Heemskerk, Suzanne; Hempenius, Rixta A; Lina, Ben A R; Krul, Cyrille A M; Koeman, Jan H; Speijers, Gerrit J A

    2010-06-01

    Pectin-derived acidic oligosaccharides (pAOS) are non-digestible carbohydrates to be used in infant formulae and medical nutrition. To support its safety, the genotoxic potential of pAOS was evaluated. pAOS was not mutagenic in the Ames test. Positive results were obtained in the chromosome aberration test only at highly cytotoxic concentrations. The effects obtained in the mouse lymphoma test were equivocal; pAOS was not mutagenic in vivo. A sub-chronic dietary study, preceded by 4-week parental and in utero exposure phase, investigated general safety. Administration of pAOS did not affect parental health nor pup characteristics. No effects specific for acidic oligosaccharides were observed in the subsequent sub-chronic study. Slight diffuse hyperplasia of epithelial layer of the urinary bladder was noted to result from concurrently elevated urinary sodium, due to high sodium in pAOS, and elevated urinary pH. This phenomenon was confirmed in a mechanistic (sub-chronic) study. In contrast, in rats fed pAOS in combination with NH(4)Cl, an acidifying agent, the induced low urinary pH completely prevented the development of urothelial hyperplasia. Hyperplasia induced by this mechanism in rats is considered not relevant to man. Based on the current knowledge we consider pAOS safe for human consumption under its intended use. PMID:20026148

  14. Combined anticalcification treatment of bovine pericardium with decellularization and hyaluronic acid derivative.

    PubMed

    Zhu, Deyi; Jin, Liqiang; Wang, Xuemei; Xu, Li; Liu, Tianqi

    2014-01-01

    The objective of this work was to evaluate the effect of decellularization and hyaluronic acid derivative on the improvement of anticalcification of glutaraldehyde fixed bovine pericardium (GFBP) using a rat subcutaneous implantation model A cell extraction process was employed to remove the cells and cellular components from bovine pericardium (BP), leaving a framework of largely insoluble collagen. Then acellular BP was cross-linked by glutaraldehyde solution and treated with hyaluronic acid derivative (HA-ADH) which was obtained by coupling adipic dihydrazide (ADH) on-COOH of hyaluronic acid (HA). The results of in vivo calcification tests showed that the calcium content was decreased dramatically by decellularization alone (from 28.07 ± 18.87 to 2.44 ± 0.55 μg Ca/mg dry tissue after 8 weeks' implantation), and even less concentration was shown by the combination of HA derivative treatment and decellularization (GFaBP-HA group) (0.25 ± 0.08 μg Ca/mg dry tissue after 8 weeks' implantation). In addition, GFaBP-HA group not only presented a lower degree of calcification, but also showed lower ratios of Ca/P molar, which corresponded to amorphous calcium phosphates. The obtained results indicated that GFaBP-HA was a potential candidate for the manufacture of anticalcification bioprostheses. PMID:24211959

  15. [Possible ways of regulating detoxifying processes in the alcohol dehydrogenase reaction with pantothenic acid derivatives].

    PubMed

    Chernikevich, I P; Dorofeev, B F; Moĭseenok, A G

    1993-01-01

    Oxidation of derivatives and precursors of pantothenic acid was studied in alcohol dehydrogenase reactions. Despite the presence of free hydroxymethyl groups in a number of pantothenic acid derivatives only panthenol with Km = 8 x 10(-3) M was shown to serve as a substrate for alcohol dehydrogenase from horse liver tissue (EC 1.1.1.1) Pantethine, sodium phosphopantothenate, CoA and acetyl-CoA decreased the rate of ethanol oxidation, where pantethine and sodium phosphopantothenate were competitive inhibitors, while CoA and acetyl-CoA inhibited the enzyme noncompetitively Ki = 1.2 x 10(-2) M, 2.1 x 10(-2) M, 4.4 x 10(-4) M and 5.1 x 10(-4) M, respectively. Metabolic precursors, which were different from pantothenic acid in their structure, were not involved in the alcohol dehydrogenase reaction. Possible regulation of alcohol intoxication using derivatives and precursors of vitamin B3 is discussed. PMID:8511887

  16. Development of novel ferulic acid derivatives as potent histone deacetylase inhibitors.

    PubMed

    Wang, Fang; Lu, Wen; Zhang, Tao; Dong, Jinyun; Gao, Hongping; Li, Pengfei; Wang, Sicen; Zhang, Jie

    2013-11-15

    Histone deacetylase inhibitors (HDACIs) offer a promising strategy for cancer therapy. The discovery of potent ferulic acid-based HDACIs with hydroxamic acid or 2-aminobenzamide group as zinc binding group was reported. The halogeno-acetanilide was introduced as novel surface recognition moiety (SRM). The majority of title compounds displayed potent HDAC inhibitory activity. In particular, FA6 and FA16 exhibited significant enzymatic inhibitory activities, with IC50 values of 3.94 and 2.82 μM, respectively. Furthermore, these compounds showed moderate antiproliferative activity against a panel of human cancer cells. FA17 displayed promising profile as an antitumor candidate. The results indicated that these ferulic acid derivatives could serve as promising lead compounds for further optimization. PMID:24095016

  17. Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity.

    PubMed

    Lamberth, Clemens

    2016-04-01

    Several naturally occurring amino acid derivatives display significant activities against weeds, fungi and insects: some of them have been even commercialized and are applied as crop protection agents. The 53 most important amino acid natural products with such efficacy are presented in this review together with their natural source, mode of action and biological activity. The diversity of the manifold bacterial, fungal and plantal sources of these compounds is impressive as well as their completely different structural scaffolds, ranging from cyclopeptides via unique non-proteinogenic amino acids to peptidyl nucleosides, the broad range of target enzymes from several different biochemical pathways, which they inhibit and also the plethora of different weeds, fungi and insects they are able to control. PMID:26801938

  18. Fatty Acid-Derived Biofuels and Chemicals Production in Saccharomyces cerevisiae.

    PubMed

    Zhou, Yongjin J; Buijs, Nicolaas A; Siewers, Verena; Nielsen, Jens

    2014-01-01

    Volatile energy costs and environmental concerns have spurred interest in the development of alternative, renewable, sustainable, and cost-effective energy resources. Environment-friendly processes involving microbes can be used to synthesize advanced biofuels. These fuels have the potential to replace fossil fuels in supporting high-power demanding machinery such as aircrafts and trucks. From an engineering perspective, the pathway for fatty acid biosynthesis is an attractive route for the production of advanced fuels such as fatty acid ethyl esters, fatty alcohols, and alkanes. The robustness and excellent accessibility to molecular genetics make the yeast Saccharomyces cerevisiae a suitable host for the purpose of bio-manufacturing. Recent advances in metabolic engineering, as well as systems and synthetic biology, have now provided the opportunity to engineer yeast metabolism for the production of fatty acid-derived fuels and chemicals. PMID:25225637

  19. Effect of pH on fecal recovery of energy derived from volatile fatty acids.

    PubMed

    Kien, C L; Liechty, E A

    1987-01-01

    We assessed the effect of pH on volatilization of short-chain fatty acids during lyophilization. Acetic, propionic, valeric, and butyric acids were added to a fecal homogenate in amounts sufficient to raise the energy density by 18-27%. Fecal homogenate samples were either acidified (pH 2.8-3.2), alkalinized (pH 7.9-8.7), or left unchanged (4.0-4.8) prior to lyophilization and subsequent bomb calorimetry. Alkalinizing the fecal samples prevented the 20% loss of energy derived from each of these volatile fatty acids observed in samples either acidified or without pH adjustment. These data suggest that in energy balance studies involving subjects with active colonic fermentation, fecal samples should be alkalinized prior to lyophilization and bomb calorimetry. PMID:3681570

  20. Phenalenone derivatives and the unusual tricyclic sesterterpene acid from the marine fungus Lophiostoma bipolare BCC25910.

    PubMed

    Intaraudom, Chakapong; Nitthithanasilp, Sutichai; Rachtawee, Pranee; Boonruangprapa, Tanapong; Prabpai, Samran; Kongsaeree, Palangpon; Pittayakhajonwut, Pattama

    2015-12-01

    Ten compounds including nine phenalenone derivatives (five bipolarides and four bipolarols) and a sesterterpene acid (bipolarenic acid), were isolated from a marine isolated of the fungus Lophiostoma bipolare (BCC25910), along with the known compounds, (-)-scleroderolide, (-)-sclerodin, and oxasetin. Chemical structures were elucidated based on NMR spectroscopic data and HRESIMS analysis. In addition, the absolute configurations of the phenalenones were resolved using specific rotations and chemical means, while the relative configuration of bipolarenic acid was confirmed by X-ray crystallographic analysis. The compounds were evaluated for biological activity against the Plasmodium falciparum K-1 strain, Candida albicans, and Bacillus cereus, and for cytotoxicity against both cancerous and non-cancerous cells. PMID:26582262