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1.
Eur J Pharmacol ; 962: 176187, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37984729

RESUMO

BACKGROUND: Renal ischemia-reperfusion (I/R) is one of the main causes of acute kidney injury (AKI), for which there is currently no effective treatment. Recently, the interaction between endoplasmic reticulum (ER) stress and pyroptosis during AKI has been investigated. AIM: The purpose of this study was to investigate the protective effects of Gypenoside XVII (GP-17) against I/R-induced renal injury. METHODS: In this study, mice were divided into 6 groups, sham group, I/R group, GP-17 low-, medium-, high-dose group, and positive control 4-PBA group. The renal I/R was performed in mice by clamping the bilateral renal pedicles for 40 min, and then reperfusing for 24 h. Blood and kidney samples were collected for analysis. RESULTS: The results showed that GP-17 improved renal function and alleviated renal histopathological abnormalities caused by I/R. In addition, GP-17 pretreatment significantly decreased the expression or phosphorylation of ER stress response proteins including BIP, p-PERK, and CHOP. Besides, GP-17 inhibited the expression of pyroptosis proteins including caspase-1, GSDMD, and apoptotic protein BAX. The inflammatory factor IL-1ß in these GP-17 pretreatment groups was also significantly reduced. CONCLUSION: GP-17 blocked NLRP3 inflammasome activation by inhibiting ERS, thereby inhibiting renal tubular cell pyroptosis and apoptosis, and prevented renal I/R injury.


Assuntos
Injúria Renal Aguda , Traumatismo por Reperfusão , Camundongos , Animais , Piroptose , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Rim/patologia , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/complicações , Injúria Renal Aguda/patologia , Estresse do Retículo Endoplasmático
2.
Toxicon ; 216: 28-36, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35780971

RESUMO

Isobavachalcone (IBC) is one of the flavonoid components in Fructus Psoraleae, and has been found multiple pharmacological effects. However, the hepatotoxicity of IBC has been overlooked and not been carefully studied. We aim to find out the cytotoxicity of IBC on HepG2 cells, and explore the underlying mechanisms. HepG2 cells were treated with IBC for 24 h, then MTT assay and LDH assay were used to detect the cell viability. The apoptosis and reactive oxygen species (ROS) production were reflected by the flow cytometry. Using Seahorse Analyzer, we measured the mitochondrial respiratory capacity. The expression of oxidative stress and mitochondrial apoptosis-related proteins were determined by Western blot. The results showed that IBC induced the cell death and apoptosis of HepG2 cells. IBC initiated the accumulation of ROS in cells and impaired the mitochondrial function, triggered apoptosis and suppressed the phosphorylation of Akt. Additionally, scavenging ROS by the antioxidant N-acetyl-l-cysteine (NAC) reduced IBC-induced mitochondria damage and increased Akt phosphorylation. Taken together, IBC caused mitochondrial damage and induced hepatotoxicity by ROS accumulation and Akt suppression. Targeting oxidative stress and depressing mitochondrial damage may provide a theoretical basis for the treatment and prevention of IBC-induced hepatotoxicity in clinic.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Proteínas Proto-Oncogênicas c-akt , Apoptose , Chalconas , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Humanos , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Respiração
3.
Phytother Res ; 36(7): 2982-2998, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35624528

RESUMO

Gypenoside XVII (GP-17), a tetracyclic triterpene saponin isolated from the functional food Gynostemma pentaphyllum, has been demonstrated protective effects against cerebrovascular and cardiovascular diseases on multiple disease models. In this study, we established a myocardial infarction (MI) model by ligating the left anterior descending coronary artery, and explored whether GP-17 prevent myocardial ischemia/reperfusion (I/R) injuries in mice. Compared with the I/R group, GP-17 significantly improved the cardiac function, reduced the MI, decreased myocardial pathology, activated superoxide dismutase and catalase, and reduced the content of lactate dehydrogenase, creatine kinase, malondialdehyde, and inflammatory factor. The proteomic analysis showed multiple differential proteins between the GP-17 and I/R groups enriched in endoplasmic reticulum and mitochondria. Western-Blot showed that GP-17 significantly decreased the expression of GRP78, ATF6, CHOP, and phosphorylation of PERK, indicating the inhibition of ERS. GP-17 inhibited the expression of ATG5, LC3A/B, and BAX, illustrating the suppression of autophagy and apoptosis. Moreover, both GP-17 and 4-PBA could improve the downregulated Mfn2, meaning that inhibition of ERS regulated the mitochondrial fusion fission balance, thus protected the function of mitochondria. In conclusion, we found that GP-17 prevented against myocardial I/R injury by inhibit ERS-induced cell apoptosis, autophagy, oxidative stress, and mitochondrial division.


Assuntos
Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Saponinas , Animais , Autofagia , Estresse do Retículo Endoplasmático , Camundongos , Dinâmica Mitocondrial , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Proteômica , Saponinas/farmacologia
4.
Drug Chem Toxicol ; 45(4): 1818-1824, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33557643

RESUMO

Psoralen is the main coumarin component of Fructus psoraleae. Previously, we have found that psoralen induced hepatocytes apoptosis via PERK and ATF6 related ER stress pathways in vitro. In this study, we investigated the toxicity and ER stress induced by psoralen in female C57 mice. Mice were fed with 80 mg/kg of psoralen intra-gastrically for either 3, 7, or 21 days. Liver and kidney were weighed and their coefficients were calculated. The serum was isolated to examine the biochemical parameters including alanine aminotransferase (ALT) activity, aspartate aminotransferase (AST) activity, alkaline phosphatase (ALP) activity, blood urea nitrogen (BUN), total bile acid (TBA), total bilirubin (TBIL), and creatinine (CRE). The transcription and expression of ER stress-related markers were determined by Wes-automated Protein Simple system, Western blot and RT-PCR. Psoralen administration for 3 days significantly increased liver coefficients but decreased kidney coefficients of mice. Histopathological examination showed minimal inflammatory cell foci and vacuolar degeneration in the liver. Besides, serum levels of ALT, TBA, BUN, and CRE were markedly altered by psoralen. Moreover, psoralen significantly increased expression and transcription levels of ER stress related markers, including Grp78, PERK, eIF2α, ATF4, IRE1α, ATF6, and XBP1. These results illustrated that psoralen induced liver injuries through ER stress signaling in female mice.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Estresse do Retículo Endoplasmático , Ficusina , Animais , Apoptose , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Feminino , Ficusina/toxicidade , Fígado/patologia , Camundongos
5.
Arch Biochem Biophys ; 701: 108791, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33592181

RESUMO

Human cytochrome P450 enzymes (CYPs or P450s) are known to be reduced by their electron transfer partners in the absence of substrate and in turn to reduce other acceptor molecules such as molecular oxygen, thereby creating superoxide anions (O2-•). This process is known as futile cycling. Using our previously established fission yeast expression system we have monitored cells expressing each one of the 50 human microsomal CYPs in the absence of substrate for oxidation of dihydroethidium in living cells by flow cytometry. It was found that 38 of these display a statistically significant increase in O2-• production. More specifically, cells expressing some CYPs were found to be intermediate strength O2-• producers, which means that their effect was comparable to that of treatment with 3 mM H2O2. Cells expressing other CYPs had an even stronger effect, with those expressing CYP2B6, CYP5A1, CYP2A13, CYP51A1, or CYP1A2, respectively, being the strongest producers of O2-•.


Assuntos
Sistema Enzimático do Citocromo P-450 , Peróxido de Hidrogênio/metabolismo , Microssomos/enzimologia , Schizosaccharomyces , Superóxidos/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Schizosaccharomyces/enzimologia , Schizosaccharomyces/genética
6.
Regul Toxicol Pharmacol ; 73(1): 232-40, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26209270

RESUMO

Diaveridine, a developed dihydrofolate reductase inhibitor, has been widely used as anticoccidial drug and antibacterial synergist. However, few studies have been performed to investigate its toxicity. To provide detailed toxicity with a wide spectrum of doses for diaveridine, acute and sub-chronic toxicity studies were conducted. Calculated LD50 was 2330 mg/kg b.w. in females and 3100 mg/kg b.w. in males, and chromodacryorrhea was noted in some females before their death. In the sub-chronic study, diaveridine was fed to Wistar rats during 90 days at dietary levels of 0, 23, 230, 1150 and 2000 mg/kg, which were about 0, 2.0-2.3, 21.0-23.5, 115.2-126.9 and 212.4-217.9 mg/kg b.w., respectively. Significant decrease in body weights in both genders at 1150 and 2000 mg/kg groups and significant increases in relative weights of brain in both genders, liver in females, kidneys and testis in males, alkaline phosphatase and potassium in both genders at 2000 mg/kg diet were noted. Significant decrease in absolute weights of several organs, hemoglobin and red blood cell count in both genders, albumin and total protein in females were observed at 2000 mg/kg diet. Fibroblasts in the kidneys, cell swelling of the glomerular zone in the adrenals and inflammation in the liver were found at 2000 mg/kg group. The no-observed-adverse-effect level of diaveridine was 230 mg/kg diet (21.0-23.5 mg/kg b.w./day).


Assuntos
Pirimidinas/efeitos adversos , Animais , Peso Corporal/efeitos dos fármacos , Testes de Carcinogenicidade/métodos , Dieta , Feminino , Rim/efeitos dos fármacos , Nefropatias/induzido quimicamente , Fígado/efeitos dos fármacos , Masculino , Testes de Mutagenicidade/métodos , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar
7.
Regul Toxicol Pharmacol ; 59(2): 324-33, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21129430

RESUMO

To investigate the chronic toxicity of cyadox, a growth promoting agent, five groups of Wistar rats (30 rats/group/sex) were fed with the diets containing cyadox (0, 100, 400 and 2000 mg/kg) or olaquindox (400 mg/kg) for 78weeks. There were significant decreases in body weights in both genders during most of the study period in 2000 mg/kg cyadox and 400 mg/kg olaquindox rats. Significant decreases in serum alkaline aminotransferase in the 2000 mg/kg cyadox rats at weeks 26, 52 and 78 were observed. Relative weights of liver and kidney were significantly increased in 2000 mg/kg cyadox and 400 mg/kg olaquindox rats at weeks 26, 52 and 78. A significant increase in relative brain and heart weights in 2000 mg/kg cyadox males was observed. The histopathological examinations revealed that 2000 mg/kg cyadox diet or 400 mg/kg olaquindox diet could induce proliferation of bile canaliculi in the portal area of liver and swelling and fatty degeneration of the proximal renal tubular epithelial cells in kidneys. In conclusion, the target organs of cyadox for rats were liver and kidney. The no-observed-adverse-effect level of cyadox in this study was estimated to be 400 mg/kg diet.


Assuntos
Quinoxalinas/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Quinoxalinas/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Wistar , Testes de Toxicidade Crônica/métodos , Transaminases/sangue
8.
Toxicol Lett ; 198(2): 112-8, 2010 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-20553828

RESUMO

High doses of mequindox (MEQ) are associated with oxidative stress and pathological toxicity in the kidney. In this study, we demonstrated long term effects of MEQ on intra- or extra-adrenal renin-angiotensin-aldosterone system (RAAS) in vivo. RAAS plays a major role in aldosterone secretion. High doses of MEQ in the diet for 180 days in male rats led to inhibition of intra- and extra-adrenal RAAS, concident with down-regulation of Na(+)/K(+)-ATPase (NAKA) and mineralocorticoid receptor (MR), the downstream of aldosterone action. Significant changes of malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) in kidney were also observed in the high doses (110, 275mg/kg) groups. The mRNA levels of most subunits of NADPH oxidase were significantly upregulated at low doses (25-110mg/kg) but the upregulation was diminished at higher doses in both kidney and adrenal gland, indicating a complicated and contradictory effect of MEQ on NADPH. These results highlight the complex interactions of drug metabolism, RAAS, NADPH oxidase and oxidative stress in response to MEQ-induced tissue toxicity and aldosterone secretion.


Assuntos
Aldosterona/metabolismo , Rim/efeitos dos fármacos , NADPH Oxidases/metabolismo , Quinoxalinas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/enzimologia , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Animais , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Rim/enzimologia , Rim/metabolismo , Rim/patologia , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , Ratos , Ratos Wistar , Receptores de Mineralocorticoides/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , ATPase Trocadora de Sódio-Potássio/metabolismo , Superóxido Dismutase/metabolismo
9.
Toxicol Lett ; 191(2-3): 167-73, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19733641

RESUMO

Mequindox (MEQ) is a synthetic quinoxaline 1,4-dioxides (QdNOs) derivative which can effectively improve growth and feed efficiency in animals. This study was to investigate the dose-dependent long-term toxicity in the adrenal of male rats exposed to 180 days of MEQ feed. Our data demonstrated that high doses of MEQ in the diet for 180 days led to adrenal damage and steroid hormone decrease, combined with sodium decrease and potassium increase in rat plasma. Significant changes of GSH and SOD in plasma were observed in the high doses (110, 275 mg/kg) groups. At the same doses, MEQ treatment down-regulated the mRNA levels of CYP11A1, CYP11B1 and CYP11B2 which located in mitochondria, but up-regulated mRNA levels of CYP21 and 3beta-HSD which located in endoplasmic reticulum. In conclusion, we reported the dose-dependent long-term toxicity of MEQ on adrenal gland in male rats, which raise awareness of its toxic effects to animals and consumers, and its mechanism may involve in oxidative stress and steroid hormone biosynthesis pathway.


Assuntos
Glândulas Suprarrenais/enzimologia , Aldosterona/metabolismo , Corticosterona/metabolismo , Quinoxalinas/farmacologia , RNA Mensageiro/biossíntese , Esteroides/biossíntese , Doenças das Glândulas Suprarrenais/induzido quimicamente , Doenças das Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/patologia , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Masculino , Malondialdeído/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxido Dismutase/metabolismo , Equilíbrio Hidroeletrolítico/efeitos dos fármacos
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