RESUMO
Chlorpyrifos (CPF) is a highly toxic commonly used pesticide and can seriously harm human health. This study assessed the potential of galangin (GAL), an antioxidant flavonoid, to attenuate oxidative stress, inflammation and kidney injury caused by CPF, emphasizing the role of farnesoid-x-receptor (FXR) and Nrf2. Rats were supplemented with CPF and GAL for 28 days. CPF increased serum creatinine, urea and Kim-1, provoked several tissue alterations, and increased kidney ROS, malondialdehyde (MDA), NF-κB p65, TNF-α, iNOS, and caspase-3. GAL effectively ameliorated serum kidney injury markers, ROS, MDA, and TNF-α, suppressed NF-κB p65, iNOS, and caspase-3, and enhanced antioxidants. GAL suppressed Keap1 and upregulated FXR, Nrf2, HO-1 and NQO-1 in CPF-administered rats. GAL exhibited binding affinity with Keap1, FXR, caspase-3, iNOS, HO-1, and NF-κB. In conclusion, GAL is effective in preventing CPF nephrotoxicity by attenuating oxidative stress and inflammation. This protection is linked to upregulation of antioxidants, Nrf2/HO-1 signaling and FXR.
RESUMO
Coenzyme Q10 (CoQ10) occurs naturally in the body and possesses antioxidant and cardioprotective effects. Cardiotoxicity has emerged as a serious effect of the exposure to cadmium (Cd). This study investigated the curative potential of CoQ10 on Cd cardiotoxicity in mice, emphasizing the involvement of oxidative stress (OS) and NF-κB/NLRP3 inflammasome axis. Mice received a single intraperitoneal dose of CdCl2 (6.5 mg/kg) and a week after, CoQ10 (100 mg/kg) was supplemented daily for 14 days. Mice that received Cd exhibited cardiac injury manifested by the elevated circulating cardiac troponin T (cTnT), CK-MB, LDH and AST. The histopathological and ultrastructural investigations supported the biochemical findings of cardiotoxicity in Cd-exposed mice. Cd administration increased cardiac MDA, NO and 8-oxodG while suppressed GSH and antioxidant enzymes. CoQ10 decreased serum CK-MB, LDH, AST and cTnT, ameliorated histopathological and ultrastructural changes in the heart of mice, decreased cardiac MDA, NO, and 8-OHdG and improved antioxidants. CoQ10 downregulated NF-κB p65, NLRP3 inflammasome, IL-1ß, MCP-1, JNK1, and TGF-ß in the heart of Cd-administered mice. Moreover, in silico molecular docking revealed the binding potential between CoQ10 and NF-κB, ASC1 PYD domain, NLRP3 PYD domain, MCP-1, and JNK. In conclusion, CoQ10 ameliorated Cd cardiotoxicity by preventing OS and inflammation and modulating NF-κB/NLRP3 inflammasome axis in mice. Therefore, CoQ10 exhibits potent therapeutic benefits in safeguarding cardiac tissue from the harmful consequences of exposure to Cd.
Assuntos
Cádmio , Cardiotoxicidade , Inflamassomos , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Estresse Oxidativo , Ubiquinona , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Camundongos , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Cardiotoxicidade/prevenção & controle , NF-kappa B/metabolismo , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Masculino , Cádmio/toxicidade , Regulação para Baixo/efeitos dos fármacos , Antioxidantes/farmacologiaRESUMO
Hyperuricemia represents a risk factor for the progression of chronic kidney disease. Oxidative stress and inflammation are implicated in the mechanisms underlying hyperuricemia-mediated kidney injury. Monolluma quadrangula possesses several beneficial effects; however, its effect on hyperuricemia has not been investigated. This study evaluated the renoprotective and xanthine oxidase (XO) inhibitory activity of M. quadrangula in hyperuricemic rats. Phytochemical investigation revealed the presence of six known flavonoid isolated for the first time from this species. The rats received M. quadrangula extract (MQE) and potassium oxonate (PO) for 7 days. In vitro assays showed the radical scavenging and XO inhibitory activities of MQE, and in silico molecular docking revealed the inhibitory activity of the isolated flavonoids towards XO. Hyperuricemic rats showed elevated serum uric acid, creatinine, urea, and XO activity, and renal pro-inflammatory cytokines, MDA and NO, and decreased GSH, SOD, and catalase. MQE ameliorated serum uric acid, urea, creatinine, and XO activity, and renal pro-inflammatory cytokines. In addition, MQE attenuated renal oxidative stress, enhanced antioxidants, downregulated URAT-1, and GLUT-9 and upregulated OAT-1 in PO-induced rats. In conclusion, M. quadrangula attenuated hyperuricemia and kidney impairment by suppressing XO activity, oxidative stress and inflammation, and modulating urate transporters.
Assuntos
Hiperuricemia , Animais , Catalase , Creatinina , Citocinas , Flavonoides/toxicidade , Hiperuricemia/induzido quimicamente , Inflamação , Rim , Simulação de Acoplamento Molecular , Ácido Oxônico , Extratos Vegetais/farmacologia , Ratos , Superóxido Dismutase , Ureia/farmacologia , Ácido Úrico , Xantina OxidaseRESUMO
Dyslipidemia is a risk factor for cardiovascular disease, steatohepatitis, and progression of liver disorders. This study investigated the protective effect of farnesol (FAR), a sesquiterpene alcohol, against liver injury in high cholesterol diet (HCD)-fed rats, and its modulatory effect on fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC). HCD was supplemented for 10 weeks, and the rats were concurrently treated with FAR. Rats that received HCD exhibited significant elevation of serum cholesterol, triacylglycerols, LDL and vLDL cholesterol, CRP, and pro-inflammatory cytokines and increased values of the cardiovascular risk indices. Serum transaminases, ALP, LDH and CK-MB, and hepatic lipid peroxidation (LPO), cholesterol, and triacylglycerols were increased in HCD-fed rats. Treatment with FAR greatly ameliorated dyslipidemia and liver function, reduced inflammatory mediators, LPO, and hepatic lipid infiltration and enhanced anti-oxidant defenses. FAR suppressed hepatic FAS, ACC, and SREPB-1c mRNA abundance and FAS activity in HDC-fed rats. In addition, molecular docking simulations pinpointed the binding modes of FAR to the active pocket residues of FAS and ACC. In conclusion, FAR possesses a strong anti-hyperlipidemic/anti-hypercholesterolemic activity mediated through its ability to modulate hepatic FAS, ACC, and SREPB-1c. FAR prevented oxidative stress, inflammation, and liver injury induced by HCD. Thus, FAR may represent a promising lipid-lowering agent that can protect against dyslipidemia and its linked metabolic deregulations.
Assuntos
Acetil-CoA Carboxilase , Farneseno Álcool , Animais , Colesterol , Ácido Graxo Sintases , Fígado , Simulação de Acoplamento Molecular , Estresse Oxidativo , Ratos , TriglicerídeosRESUMO
Olive leaf extract (OLE) has potential health benefits and protects against cytotoxicity in different organs. However, nothing has yet been reported on its potential to prevent cyclophosphamide (CP)-induced nephrotoxicity. This study investigated the possible protective effect of OLE on CP-induced kidney injury in rats, focusing on oxidative stress, inflammation, apoptosis and Nrf2/ARE/HO-1 signaling. Rats received 100 or 200 mg/kg body weight OLE for 15 days and a single injection of 150 mg/kg CP at day 16. CP induced kidney injury evidenced by the significantly increased serum creatinine and urea, and histopathological alterations, including glomerular atrophy, interstitial hemorrhage, dilated urinary space and necrosis. CP-induced rats exhibited increased kidney lipid peroxidation, protein carbonyl, nitric oxide (NO) and pro-inflammatory cytokines, and up-regulated NF-κB, Bax, cytochrome c and caspase-3. OLE ameliorated kidney function markers and prevented CP-induced tissue damage. In addition, OLE significantly prevented oxidative stress, inflammation and apoptosis by enhancing the antioxidant defenses and Bcl-2 expression, and suppressing the pro-inflammatory and pro-apoptotic markers NF-κB, Bax, cytochrome c and caspase-3. OLE up-regulated Nrf2, HO-1 and NQO-1 expression in the kidney of CP-induced rats. In conclusion, OLE has a substantial protective role against CP-induced nephrotoxicity in rats by up-regulating the Nrf2/ARE/HO-1 signaling, enhancing the antioxidant activity and attenuating inflammation and apoptosis.
Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Ciclofosfamida/toxicidade , Heme Oxigenase (Desciclizante)/biossíntese , Rim/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/biossíntese , Olea , Estresse Oxidativo/efeitos dos fármacos , Animais , Elementos de Resposta Antioxidante/fisiologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Relação Dose-Resposta a Droga , Sequestradores de Radicais Livres/isolamento & purificação , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/uso terapêutico , Imunossupressores/toxicidade , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/prevenção & controle , Rim/metabolismo , Rim/patologia , Masculino , Estresse Oxidativo/fisiologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Folhas de Planta , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
Seaweeds are rich in structurally diverse bioactive compounds with promising therapeutic effects. This study aimed to isolate and identify terpenes from the brown alga Padina pavonia and to investigate its antidiabetic activity, pointing to the possible involvement of peroxisome proliferator-activated receptor (PPAR)γ. Type 2 diabetes was induced by feeding rats a high fat diet (HFD) for 4 weeks followed by injection of 35 mg/kg streptozotocin (STZ). The diabetic rats received P. pavonia extract (PPE; 50, 100 and 200 mg/kg) for 4 weeks and samples were collected for analyses. HFD/STZ-induced rats showed hyperglycemia, dyslipidemia, impaired glucose tolerance, decreased insulin, and increased HbA1c and HOMA-IR. PPE ameliorated hyperglycemia and dyslipidemia, and improved glucose tolerance and insulin sensitivity in diabetic rats. Treatment with PPE increased hepatic hexokinase activity and glycogen, suppressed glucose-6-phosphatase, fructose-1,6-biphosphatase, and glycogen phosphorylase, and attenuated oxidative stress, inflammation, and liver injury and lipid infiltration in HFD/STZ-induced rats. In addition, PPE boosted antioxidants and upregulated PPARγ gene and protein expression in the liver of diabetic rats. Phytochemical investigation resulted in the isolation of six terpenes from PPE and in silico analysis revealed their binding affinity toward PPARγ. In conclusion, P. pavonia-derived terpenes attenuated hyperglycemia, dyslipidemia, oxidative stress, and inflammation, and improved insulin sensitivity and carbohydrate metabolism in type 2 diabetic rats. These beneficial effects are mediated via PPARγ activation. However, further studies to explore the exact mechanisms underlying the antidiabetic effect of PPE are recommended.
RESUMO
Hepatic encephalopathy (HE) is a serious neuropsychiatric complication that occurs as a result of liver failure. Umbelliferone (UMB; 7-hydroxycoumarin) is a natural product with proven hepatoprotective activity; however, nothing has yet been reported on its protective effect against hyperammonemia, the main culprit behind the symptoms of HE. Here, we evaluated the effect of UMB against ammonium chloride (NH4Cl)-induced hyperammonemia, oxidative stress, inflammation and hematological alterations in rats. We demonstrated the modulatory role of UMB on the glutamate-nitric oxide (NO)-cGMP pathways in the cerebrum of rats. Rats received intraperitoneal injections of NH4Cl (3 times/week) for 8 weeks and concomitantly received 50â¯mg/kg UMB. NH4Cl-induced rats showed significantly elevated blood ammonia and liver function markers. Lipid peroxidation and NO were increased in the liver and cerebrum of rats while the antioxidant defenses were declined. UMB significantly reduced blood ammonia, liver function markers, lipid peroxidation and NO, and enhanced the antioxidant defenses in NH4Cl-induced rats. UMB significantly prevented anemia, leukocytosis, thrombocytopenia and prolongation of PT and aPTT. Hyperammonemic rats showed elevated levels of cerebral TNF-α, IL-1ß and glutamine as well as increased activity and expression of Na+/K+-ATPase, effects that were significantly reversed by UMB. In addition, UMB down-regulated nitric oxide synthase and soluble guanylate cyclase in the cerebrum of hyperammonemic rats. In conclusion, this study provides evidence that UMB protects against hyperammonemia via attenuation of oxidative stress and inflammation. UMB prevents hyperammonemia associated hematological alterations and therefore represents a promising protective agent against the deleterious effects of excess ammonia.
Assuntos
GMP Cíclico/metabolismo , Ácido Glutâmico/metabolismo , Hiperamonemia/tratamento farmacológico , Inflamação/tratamento farmacológico , Óxido Nítrico/metabolismo , Estresse Oxidativo , Transdução de Sinais , Umbeliferonas/uso terapêutico , Amônia/sangue , Cloreto de Amônio , Anemia/sangue , Anemia/complicações , Anemia/tratamento farmacológico , Anemia/prevenção & controle , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Coagulação Sanguínea/efeitos dos fármacos , Cérebro/efeitos dos fármacos , Cérebro/enzimologia , Cérebro/patologia , Regulação para Baixo/efeitos dos fármacos , Glutamina/biossíntese , Hiperamonemia/sangue , Hiperamonemia/complicações , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Leucocitose/sangue , Leucocitose/complicações , Leucocitose/tratamento farmacológico , Leucocitose/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/patologia , Fígado/fisiopatologia , Testes de Função Hepática , Masculino , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Umbeliferonas/farmacologiaRESUMO
Olive oil and leaf extract have several health benefits; however, their beneficial effect against fluoxetine-induced liver injury has not been investigated. The present study aimed to scrutinize the impact of fluoxetine on the liver of rats and to evaluate the protective effects of olive oil and leaf extract. Rats received fluoxetine orally at dose of 10â¯mg/kg body weight for 7 consecutive days. The fluoxetine-induced rats were concurrently treated with olive oil or leaf extract. At the end of the experiment, blood and liver samples were collected for analysis. Fluoxetine administration significantly increased circulating ALT, AST, ALP and the pro-inflammatory cytokines TNF-α and IL-1ß levels in rats. Histological analysis showed several alterations, such as inflammatory cells infiltration, hepatocyte vacuolation and dilated sinusoids in the liver of fluoxetine-induced rats. Concurrent supplementation of olive oil and olive leaf extract significantly reduced circulating liver function marker enzymes and pro-inflammatory cytokines, and prevented fluoxetine-induced histological alterations. Both olive oil and leaf extract significantly decreased liver lipid peroxidation and nitric oxide, and ameliorated liver glutathione, superoxide dismutase, catalase and glutathione peroxidase. In addition, olive oil and leaf extract prevented fluoxetine-induced apoptosis in the liver of rats as evidenced by decreased expression of Bax and caspase-3, and up-regulated expression of Bcl-2. In conclusion, olive oil and leaf extract protect against ï¬uoxetine-induced liver injury in rats through attenuation of oxidative stress, inflammation and apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Inflamação/tratamento farmacológico , Azeite de Oliva/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Alanina Transaminase/metabolismo , Animais , Antioxidantes/metabolismo , Aspartato Aminotransferases/metabolismo , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Citocinas/metabolismo , Fluoxetina/efeitos adversos , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Hepatócitos/metabolismo , Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Ratos , Superóxido Dismutase/metabolismoRESUMO
A fingerprint of steroid saponins, the major constituent in 80% methanolic fraction from the male flowers of Phoenix dactylifera has been established. Under ESI-MS/MS conditions, the fragmentation patterns of [M - H]- ions exclusively displayed signals corresponding to the cleavage of the glycosidic bonds, thus allowing a rapid identification of 21 steroidal saponins. Moreover, two unique among them conjugated with histidine were detected by LC-ESI (-)-MS and DFT and were given tentative names of 3-o-histidine-26-o-hexosyl-dioscin and 3-o-histidine-26-o-dihexosyl-hydroxydioscin. Their steroidal saponins exhibited a significant improvement of the sperm cells count, motility and viability in male rats. These effects could be attributed to enhancing the levels of sex hormones.
Assuntos
Phoeniceae/química , Saponinas/química , Saponinas/farmacologia , Espermatogênese/efeitos dos fármacos , Animais , Cromatografia Líquida , Avaliação Pré-Clínica de Medicamentos/métodos , Flores/química , Masculino , Ratos Wistar , Saponinas/análise , Espectrometria de Massas por Ionização por Electrospray , Contagem de Espermatozoides , Espermatozoides/efeitos dos fármacos , Esteroides/química , Esteroides/farmacologia , Espectrometria de Massas em TandemRESUMO
Context Cyclophosphamide (CTX) is used to treat different cancer types, although it causes severe hepatotoxicity due to its oxidative stress effect. Rosmarinus officinalis, L. (Lamiaceae) has a therapeutic potential against hepatotoxicity due to its antioxidant activity. Objective The objective of this study is to investigate the phytochemical analysis of the methanol extract of Rosmarinus officianalis leaves (MEROL) and its efficacy against CTX-induced hepatotoxicity. Materials and methods The phytochemical analyses were assessed spectrophotometericaly. To assess the MEROL efficacy, 72 Swiss albino mice were divided into six groups. Group 1 was control, groups 2 and 3 included mice which were injected intraperitoneally (i.p.) with 100 or 200 mg/kg of MEROL at days 1, 4, 7, 10, 13 and 16; group 4 was injected (i.p.) with CTX (200 mg/kg) at day 17, groups 5 and 6 were injected (i.p.) with MEROL as groups 3 and 4 followed by 200 mg/kg CTX at day 17, respectively. At day 22, six mice from each group were sacrificed and the others were sacrificed at day 37. Results MEROL has a high content of total phenolics, saponins, total antioxidant capacity and DPPH radical scavenging activity. The median lethal dose (LD50) value of MEROL was 4.125 g/kg b.w. The inhibitory concentration 50 (IC50) value for DPPH radical scavenging was 55 µg/mL. Pretreatment with 100 mg/kg MEROL for 16 d ameliorated CTX-induced hepatotoxicity represented in lowering the levels of the aspartate aminotransferase (AST) and lipid profile and minimizing the histological damage. Conclusions Pretreatment with 100 mg/kg b.w. MEROL mitigated CTX-induced hepatotoxicity due to its antioxidant activity.
Assuntos
Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Ciclofosfamida , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rosmarinus , Animais , Antioxidantes/isolamento & purificação , Antioxidantes/toxicidade , Biomarcadores/sangue , Compostos de Bifenilo/química , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Dose Letal Mediana , Fígado/metabolismo , Fígado/patologia , Masculino , Metanol/química , Camundongos , Fenóis/isolamento & purificação , Fenóis/farmacologia , Fitoterapia , Picratos/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Folhas de Planta , Plantas Medicinais , Rosmarinus/química , Saponinas/isolamento & purificação , Saponinas/farmacologia , Solventes/química , Análise Espectral , Fatores de TempoRESUMO
CONTEXT: Cyclophosphamide (CTX) is a common anticancer agent used for the treatment of several malignancies. However, upon treatment, it induces severe toxicity due to its oxidative stress capability. Propolis, a natural product collected by honey bees, has shown several biological activities, such as free radical scavenging and antioxidant agent. OBJECTIVE: This study elucidates the protective effects of propolis against CTX-induced changes in mice. MATERIALS AND METHODS: Forty-eight male Swiss albino mice were divided into four groups; group 1 was intraperitoneally (i.p.) injected with 200 µL of phosphate buffer saline (PBS), group 2 was injected with 100 mg/kg/d propolis, group 3 was injected with a single dose of CTX (200 mg/kg), and group 4 was injected with a single dose of CTX (200 mg/kg) followed by propolis (100 mg/kg) for 7 consecutive days. After 12 d, mice were bled and then sacrificed to analyze the hematological, biochemical, and histological parameters. RESULTS: The results indicated that CTX-injected mice showed an increase in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, and creatinine and a decrease in the total number of white blood cells (WBCs) and platelets. Moreover, dramatically changes in the histological architectures of the liver and kidney were observed. The mice that were injected with CTX/propolis showed an improvement in the levels of ALT, AST, urea, creatinine, WBCs, and platelets. Moreover, the histological picture of the liver and kidney was significantly improved. CONCLUSIONS: In conclusion, propolis might be considered an effective agent in ameliorating the toxicity resulted from CTX treatment.