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1.
J Appl Biomed ; 19(2): 105-112, 2021 05.
Article in English | MEDLINE | ID: mdl-34907710

ABSTRACT

This study evaluates the protective effect of Echinacoside on acute liver toxicity induced by acetaminophen in mice and the mechanism behind it. Echinacoside and N-Acetyl Cysteine were intragastrically administrated for 7 days, and acetaminophen was intraperitoneally injected into mice 1 h after the last treatment on day 7. At the end of the experimental period, histological examination, parameters for the level of oxidative damage, hepatic malondialdehyde, serum pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-1ß), UDP-glucuronosyltransferases, and sulfotransferases changes were examined using enzyme-linked immunosorbent assay and standard biochemical procedures. The expression of cytochrome P450 2E1 protein was assessed by western blot, followed by in silico molecular docking. Acetaminophen treatment obviously increased the levels of ALT and AST, changed hepatic histopathology, promoted oxidative stress, decreased antioxidant enzyme activities, and elevated the pro-inflammatory cytokines. Echinacoside significantly attenuated Acetaminophen-induced liver damage in a dose-dependent manner, with the most effective dose at 100 mg/kg. The pretreatments of Echinacoside in different concentrations altered the Acetaminophen-induced hepatotoxicity levels by decreasing the level of liver enzymes, reducing the liver necrosis with vacuolization, decreasing the hepatic malondialdehyde formation, increasing hepatic antioxidants activities, suppressing the pro-inflammatory cytokines (Tumor Necrosis Factor, Interleukin-6 and Interleukin-1beta), inhibiting Nitric Oxide production, enhancing sulfotransferases and UDP-glucuronosyltransferases activities. Notably, the expression of cytochrome P450 2E1 was inhibited by Echinacoside in a dose-dependent manner and the binding energy was -214.3 MeV. Echinacoside showed a significant protective effect against Acetaminophen-induced hepatotoxicity through the inhibition of oxidative stress, the expression of pro-inflammatory cytokines and cytochrome P450 2E1 protein expression.


Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Chemical and Drug Induced Liver Injury , Cytokines , Glycosides , Oxidative Stress , Acetaminophen/adverse effects , Animals , Antioxidants/pharmacology , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Cytochrome P-450 CYP2E1/metabolism , Cytokines/drug effects , Cytokines/metabolism , Glycosides/pharmacology , Glycosides/therapeutic use , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Malondialdehyde/metabolism , Mice , Molecular Docking Simulation , Oxidative Stress/drug effects , Sulfotransferases/metabolism , Tumor Necrosis Factor-alpha/metabolism , Uridine Diphosphate/metabolism
2.
Bioorg Med Chem Lett ; 26(3): 1097-1101, 2016 Feb 01.
Article in English | MEDLINE | ID: mdl-26631318

ABSTRACT

Gambogic acid (GA), a natural product with a xanthone structure, has a broad range of anti-proliferative effects on cancer cell lines. We evaluated GA for its cytotoxic effects on T98G glioblastoma cells. GA exhibited potent anti-proliferative activity and induced apoptosis in T98G glioblastoma cells in a dose-dependent manner. Incubation of cells with GA revealed apoptotic features including increased Bax and AIF expression, cytochrome c release, and cleavage of caspase-3, -8, -9, and PARP, while Bcl-2 expression was downregulated. Furthermore, GA induced reactive oxygen species (ROS) generation in T98G cells. Our results indicate that GA increases Bax- and AIF-associated apoptotic signaling in glioblastoma cells.


Subject(s)
Antineoplastic Agents/chemistry , Xanthones/chemistry , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Caspase 3/metabolism , Caspase 8/metabolism , Caspase 9/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cytochromes c/metabolism , Down-Regulation/drug effects , Glioma/metabolism , Glioma/pathology , Humans , Proto-Oncogene Proteins c-bcl-2/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Xanthones/isolation & purification , Xanthones/pharmacology
3.
Bioorg Med Chem Lett ; 25(22): 5083-6, 2015 Nov 15.
Article in English | MEDLINE | ID: mdl-26483134

ABSTRACT

New phenazine derivatives with a methylamine linker, Pontemazines A (1) and B (2), were isolated from the culture broth of Streptomyces sp. UT1123. The structures of compounds 1 and 2 were determined by NMR spectroscopy and high-resolution mass spectrometry. These compounds consist of a 9-mehoxyphenazine connected to a benzamide functional group by a unique methylamine linker instead of the more common methyl ether. Pontemazines A and B possess a neuronal cell protective effect on glutamate-induced mouse hippocampal HT-22 cell damage.


Subject(s)
Neuroprotective Agents/pharmacology , Phenazines/pharmacology , Streptomyces/chemistry , Animals , Cell Line , Glutamic Acid/toxicity , Magnetic Resonance Spectroscopy , Mice , Neuroprotective Agents/isolation & purification , Phenazines/isolation & purification
4.
Am J Hypertens ; 23(5): 569-74, 2010 May.
Article in English | MEDLINE | ID: mdl-20186125

ABSTRACT

BACKGROUND: Glucocorticoid-induced hypertension is associated with imbalance between nitric oxide (NO) and superoxide. One of the pathways that causes this imbalance is endothelial NO synthase (eNOS) uncoupling. In the present study, adrenocorticotrophic hormone (ACTH)- and dexamethasone-treated rats were further treated with sepiapterin, a precursor of tetrahydrobiopterin, or N-nitro-L-arginine (NOLA), an inhibitor of NOS, to investigate the role of eNOS uncoupling in glucocorticoid-induced hypertension. METHODS: Male Sprague-Dawley (SD) rats (n = 7-13/group) were treated with either sepiapterin (5 mg/kg/day, IP) or saline (sham) 4 days before and during ACTH (0.2 mg/kg/day, SC), dexamethasone (0.03 mg/kg/day, SC), or saline treatment. NOLA (0.4 mg/ml in drinking water) was given to rats 4 days before and during dexamethasone treatment. Systolic blood pressure (SBP) was measured by the tail-cuff method. RESULTS: Both ACTH (116 +/- 2 to 135 +/- 3 mm Hg (mean +/- s.e.m.), P < 0.001) and dexamethasone (114 +/- 4 to 133 +/- 3 mm Hg, P < 0.0005) increased SBP. Sepiapterin alone did not alter SBP. Sepiapterin did not prevent ACTH- (129 +/- 4 mm Hg, NS) or dexamethasone-induced hypertension (135 +/- 3 mm Hg, NS), although plasma total biopterin concentrations were increased. NOLA increased SBP in rats prior to dexamethasone or saline treatment. NOLA further increased SBP in both saline- (133 +/- 4 to 157 +/- 3 mm Hg, P < 0.05) and dexamethasone-treated rats (135 +/- 5 to 170 +/- 6 mm Hg, P < 0.05). ACTH and dexamethasone increased plasma F(2)-isoprostane concentrations. Neither sepiapterin nor NOLA significantly affected this marker of oxidative stress. CONCLUSION: Sepiapterin did not prevent ACTH- or dexamethasone-induced hypertension. NOLA exacerbated dexamethasone-induced hypertension. These data suggest that eNOS uncoupling does not play a major role in the genesis of glucocorticoid-induced hypertension in the rat.


Subject(s)
Adrenocorticotropic Hormone/adverse effects , Dexamethasone/adverse effects , Hypertension/chemically induced , Hypertension/prevention & control , Nitric Oxide Synthase/antagonists & inhibitors , Pterins/therapeutic use , Adrenocorticotropic Hormone/pharmacology , Animals , Biomarkers/blood , Biopterins/blood , Blood Pressure/drug effects , Dexamethasone/pharmacology , Dietary Supplements , Disease Models, Animal , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , F2-Isoprostanes/blood , Hypertension/metabolism , Male , Nitric Oxide Synthase Type III/metabolism , Nitroarginine/administration & dosage , Nitroarginine/pharmacology , Nitroarginine/therapeutic use , Oxidative Stress , Pterins/administration & dosage , Pterins/pharmacology , Rats , Rats, Sprague-Dawley
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