RESUMO
OBJECTIVE: Testicular ischemia-reperfusion induced by testicular torsion-detorsion increases the level of reactive oxygen species, leading to testicular damage. Allicin, one of the most active ingredients in garlic, is a significant exogenous antioxidant. In the research, the efficacy of allicin in treating testicular ischemia-reperfusion injury was assessed. MATERIALS AND METHODS: The study included sixty Sprague-Dawley male rats. Three groups with 20 rats per group were created as follows: control group, testicular ischemia/reperfusion-induced group, and testicular ischemia-reperfusion plus treatment with allicin group. The control group underwent a sham operation of the left testis without other interventions. In the testicular ischemia/reperfusion-induced group, rat left testis was subjected to 720° torsion for two hours and then detorsion. In the allicin-treated group, in addition to testicular ischemia-reperfusion, 50 mg/kg of allicin was injected intraperitoneally, starting immediately following detorsion. Testicular tissue samples were obtained to measure the protein expression of xanthine oxidase, which is a major source of reactive oxygen species formation, malondialdehyde level (a reliable marker of reactive oxygen species), and testicular spermatogenic function. RESULTS: Testicular ischemia-reperfusion significantly increased the expression of xanthine oxidase and malondialdehyde levels in ipsilateral testes while reducing testicular spermatogenic function. The expression of xanthine oxidase and malondialdehyde levels were significantly lower in ipsilateral testes, whereas testicular spermatogenic function in the allicin-treated group was significantly higher compared with those in the testicular ischemia-reperfusion group. CONCLUSIONS: Our findings indicate that allicin administration improves ischemia/reperfusion-induced testicular damage by limiting reactive oxygen species generation via inhibition of xanthine oxidase expression.
Assuntos
Dissulfetos , Traumatismo por Reperfusão , Torção do Cordão Espermático , Ácidos Sulfínicos , Ratos , Masculino , Animais , Humanos , Torção do Cordão Espermático/tratamento farmacológico , Torção do Cordão Espermático/complicações , Torção do Cordão Espermático/metabolismo , Ratos Sprague-Dawley , Xantina Oxidase/metabolismo , Xantina Oxidase/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Testículo , Traumatismo por Reperfusão/metabolismo , Antioxidantes/farmacologia , Isquemia/metabolismo , Malondialdeído/metabolismoRESUMO
In this study, an attempt was made to evaluate the relative efficacy of two important anti-gout agents, viz. allopurinol and febuxostat, in the control of hyperuricaemia/gout using a poultry model. A 21-day study was conducted on 48 Vencobb-400 broiler chicks randomly divided into four groups. In one group hyperuricaemia/gout was induced by the oral administration of diclofenac (group D); in two other groups the ameliorative effect of the two drugs under study was investigated by providing both simultaneously, i.e. diclofenac and allopurinol (group DA), diclofenac and febuxostat (group DF); and the fourth group was kept un-induced and untreated as a control (group C). Both allopurinol and febuxostat inhibit xanthine oxidase enzymes, thereby reducing the production of uric acid. The birds kept on diclofenac alone exhibited the highest level of hyperuricaemia, clinical signs of gout, and overt adverse changes in the visceral organs, whereas these changes were lesser in allopurinol- and febuxostat-treated groups. Furthermore, haematological, biochemical, patho-morphological, and ultra-structural studies using transmission electron microscopy were carried out to evaluate the pathology and, thus, the ameliorative effect of allopurinol and febuxostat. The findings proved that allopurinol and febuxostat carry definite ameliorative potential as anti-hyperuricemic and anti-gout agents in poultry, which was better expressed by febuxostat compared to allopurinol.
Assuntos
Gota , Hiperuricemia , Animais , Alopurinol/farmacologia , Galinhas , Diclofenaco/efeitos adversos , Febuxostat/farmacologia , Gota/induzido quimicamente , Gota/tratamento farmacológico , Gota/veterinária , Supressores da Gota/farmacologia , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Hiperuricemia/veterinária , Aves Domésticas , Resultado do Tratamento , Xantina Oxidase/farmacologia , Modelos Animais de DoençasRESUMO
Purpose: Dispelling dampness, relieving turbidity and dredging collaterals decoction (DED), is a traditional Chinese medicine used in the treatment of hyperuricemia. We aimed to explore the effect and mechanism of DED in the treatment of hyperuricemia. Methods: The effects of DED (9.48, 4.74, and 2.37 g/kg/d) on potassium oxonate (750 mg/kg/d)-induced hyperuricemia in rats were evaluated by serum uric acid (UA), creatinine (CRE), blood urea nitrogen (BUN), and renal pathological changes. Network pharmacology was used to identify the effective components and targets of DED, and the key targets and signaling pathways for its effects on hyperuricemia were screened. Molecular docking was used to predict the action of DED. H&E, immunohistochemistry, WB, and PCR were used to validate the network pharmacology results. Results: DED can effectively alleviate hyperuricemia, inhibit UA, CRE, BUN, and xanthine oxidase (XOD) activity, and reduce renal inflammatory cell infiltration and glomerular atrophy. The experiment identified 27 potential targets of DED for hyperuricemia, involving 9 components: wogonin, stigmasterol 3-O-beta-D-glucopyranoside, 3ß-acetoxyatractylone, beta-sitosterol, stigmasterol, diosgenin, naringenin, astilbin, and quercetin. DED can relieve hyperuricemia mainly by inhibiting RAGE, HMGB1, IL17R, and phospho-TAK1, and by regulating the AGE-RAGE and IL-17 signaling pathways. Conclusion: DED can alleviate hyperuricemia by inhibiting XOD activity and suppressing renal cell apoptosis and inflammation via the AGE-RAGE signaling pathway and IL-17 signaling pathway. This study provides a theoretical basis for the clinical application of DED.
Assuntos
Hiperuricemia , Ratos , Animais , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Interleucina-17/metabolismo , Ácido Úrico , Simulação de Acoplamento Molecular , Rim , Xantina Oxidase/metabolismo , Xantina Oxidase/farmacologiaRESUMO
AIM: This study evaluated the effect of lead, with or without zinc co-administration, on steroidogenic and xanthine oxidase (XO)/uric acid (UA)/caspase 3-mediated apoptotic signaling in the testis. MATERIALS AND METHODS: Forty male Wistar rats were divided into four groups at random; vehicle-treated control, zinc-treated, lead-treated, and lead + zinc-treated groups. RESULTS: Lead exposure significantly lowered overall weight gain, testicular, epididymal, seminal vesicle, and prostate weights. Also, lead decreased sperm count, viability and motility but increased the fraction of sperm with aberrant morphology. In addition, lead caused a marked rise in the level of UA and XO activity but a decrease in nuclear factor erythroid 2-related factor 2 (Nrf2), reduced glutathione (GSH) as well as total antioxidant capacity (TAC) levels, and superoxide dismutase (SOD) and catalase activities. Furthermore, lead increased the testicular levels of nuclear factor kappa B (NFkB), interleukin-1beta (IL-1ß), and tumour necrotic factor-alpha (TNF-α), which were associated with an increase in testicular caspase 3 activity and DNA fragmentation as well as a decline in circulating gonadotropin releasing hormone (GnRH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and testicular 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and 17ß-hydroxysteroid dehydrogenase (17ß-HSD). These were associated with lead-induced degenerative changes in testicular tissues evidenced by shrunken seminiferous tubules, degeneration and sloughing of germ cells. Co-administration of zinc prevented lead-induced testicular injury by ameliorating oxidative stress, apoptosis, and inflammation through downregulation of XO/UA/caspase 3 pathway and upregulation of testicular 3ß-HSD/17ß-HSD. CONCLUSION: This study demonstrated that zinc protected against lead-induced testicular toxicity via the downregulation of XO/UA/caspase 3 signaling.
Assuntos
Testículo , Ácido Úrico , Ratos , Animais , Masculino , Testículo/patologia , Ratos Wistar , Xantina Oxidase/metabolismo , Xantina Oxidase/farmacologia , Zinco/metabolismo , Zinco/farmacologia , Caspase 3/metabolismo , Caspase 3/farmacologia , Sêmen/metabolismo , Testosterona/metabolismo , Antioxidantes/metabolismo , Estresse Oxidativo , ApoptoseRESUMO
AIM: To investigate the effects of cerebrolysin on inflammation, oxidative stress, apoptosis, and neurologic recovery in the setting of an experimental rabbit model of spinal cord ischemia/reperfusion injury (SCIRI). MATERIAL AND METHODS: Rabbits were randomly divided into five groups: control, ischemia, vehicle, methylprednisolone (30 mg/kg), and cerebrolysin (5 ml/kg) group. The rabbits in the control group underwent only laparotomy; the other groups underwent spinal cord ischemia and reperfusion injury for 20 minutes. Neurologic examination after 24 hours was based on the Modified Tarlov scale. Myeloperoxidase activities, catalase and malondialdehyde levels, and caspase-3 concentrations were determined in serum and tissue samples. Serum xanthine oxidase levels were studied and histopathological and ultrastructural changes were examined. RESULTS: After SCIRI, serum and tissue myeloperoxidase activities, malondialdehyde levels, caspase-3 concentrations, and serum xanthine oxidase activities were increased (p < 0.01?0.001). Catalase levels were significantly diminished (p < 0.001). Cerebrolysin treatment correlated with reduced myeloperoxidase and xanthine oxidase activities, malondialdehyde levels and caspase-3 concentrations; and with increased catalase levels (p < 0.001, for all). The cerebrolysin group showed improved histopathological, ultrastructural, and neurological outcomes. CONCLUSION: For the first time in the literature, the current study reports anti-inflammatory, antioxidant, antiapoptotic, and neuroprotective effects of cerebrolysin in a SCIRI rabbit model.
Assuntos
Fármacos Neuroprotetores , Traumatismo por Reperfusão , Isquemia do Cordão Espinal , Animais , Coelhos , Catalase , Peroxidase/farmacologia , Caspase 3 , Xantina Oxidase/farmacologia , Medula Espinal , Isquemia do Cordão Espinal/patologia , Antioxidantes/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , MalondialdeídoRESUMO
Background/Purpose: This research was performed to determine the effect of naringenin (NAR) in experimental hyperuricemia (HU) induced by potassium oxonate (PO) on uric acid levels and xanthine oxidase (XO), inflammation, apoptotic pathway, DNA damage, and antioxidant system in kidney tissue. Study Design: Wistar Albino rats were categorized into four groups: (1) Control group, (2) PO group, (3) [PO+NAR] (2 weeks) group, and (4) PO (2 weeks)+NAR (2 weeks) group. Methods: The first group was not administered any drug. In group 2, PO was administered intraperitoneally 250 mg/kg/day for 2 weeks. In the third group, 100 mg/kg/day NAR was given intraperitoneally 1 hr after PO injection for 2 weeks. In the fourth group, PO was injected for the first 2 weeks, followed by NAR injection for the second 2 weeks. Serum uric acid levels, XO, nuclear factor-kappa B, tumor necrosis factor-alpha, interleukin-17, cytochrome c, 8-Hydroxydeoxyguanosine (8-OHdG), glutathione peroxidase (GPx), and caspase-3 levels in kidney were determined. Results: HU increased the levels of inflammatory and apoptotic parameters, XO, and 8-OHdG levels in kidney. Administration of NAR caused a decrease in these values and an increase in GPx levels. Conclusions: The results of the study show that NAR treatment reduces serum uric acid levels, and apoptosis, inflammation, and DNA damage; increases antioxidant activity in kidney in experimental HU.
Assuntos
Hiperuricemia , Ratos , Animais , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Antioxidantes/metabolismo , Ácido Úrico , Xantina Oxidase/metabolismo , Xantina Oxidase/farmacologia , Xantina Oxidase/uso terapêutico , Rim/metabolismo , Ratos Wistar , Inflamação/metabolismo , Dano ao DNARESUMO
Objectives: Methotrexate (MTX) is commonly used in the management of several malignancies and autoimmune disorders; however, testicular damage is one of the most detrimental effects of MTX administration. The current the protective effect of xanthine oxidase inhibitors either purine analogue; allopurinol (ALL) or non-purine analogue; febuxostat (FEB) in testicular injury induced by MTX in rats.Materials and methods: Thirty-two rats were randomly allocated to four groups; control (received vehicles), MTX (received single dose, 20 mg/kg, i.p.), MTX + ALL (received MTX plus ALL) and MTX + FEB (received MTX plus ALL). ALL and FEB were administered orally at 100- and 10 mg/kg, respectively for 15 days. Total and free testosterone were measured in serum. In addition, total antioxidant capacity (TAC), epidermal growth factor (EGF), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), extracellular signal-regulating kinase1/2 (ERK1/2), and total nitrite/nitrate (NOx) end products were measured in testicular tissues. At the same time, immunoexpression of HO-1in testicular tissue was measured. Histopathological examination was done.Results: ALL and FEB increased total and free serum testosterone. Both drugs showed a significant reduction in testicular MDA, NOx, TNF-α levels with an increase in TAC, EGF, and ERK1/2 levels in testicular tissue. Furthermore, both drugs enhanced HO-1 immunoexpression in testicular tissue. All these findings were parallel to the preservation of normal testicular architecture in rats treated with ALL and FEB.Conclusion: All and FEB were equally protective against testicular damage induced by MTX through anti-inflammatory, anti-apoptotic, and antioxidant actions. Their effects might be through activation of the EGF/ERK1/2/HO-1 pathway.
Assuntos
Antioxidantes , Metotrexato , Ratos , Animais , Metotrexato/toxicidade , Antioxidantes/farmacologia , Fator de Crescimento Epidérmico , Xantina Oxidase/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Sistema de Sinalização das MAP Quinases , Ratos Wistar , Testosterona/farmacologia , Febuxostat/farmacologia , Estresse OxidativoRESUMO
Oxidative stress during cryopreservation causes mechanical, biochemical, and structural damage to the sperm, leading to lower viability and fertility potential. In recent years, a novel method based on the use of mild stress for preconditioning of sperm before cryopreservation has been applied to improve the quality of thawed sperm, although its molecular mechanism remains unknown. In this study, we investigated the protective effects of sublethal oxidative stress by xanthine oxidase (XO) on thawed bull sperm performance through modulations of mitochondrial uncoupling protein 2 (UCP2) expression. Semen samples were collected from six bulls, then mixed and divided into four aliquots: frozen control (XO-0) and frozen groups treated with different concentrations of XO, 0.01 µM (XO-0.01), 0.1 µM (XO-0.1), and 1 µM (XO-1). Thawed sperm were evaluated for motion parameters, viability, acrosome integrity, mitochondria activity, membrane integrity, and UCP2 expression. A significant increase of total motility and viability rate was observed in XO-0.1 compared with other frozen groups (p < 0.05). The highest percentage of progressive motility was in XO-0.01 and XO-0.1 compared with other groups (p < 0.05). Moreover, a significantly higher level of sperm mitochondrial membrane potential and membrane integrity was observed in XO-0.1 (p < 0.05). We also found the lowest percentage of sperm mitochondria activity in XO-1 (p < 0.05). In addition, the highest expression of UCP2 was observed in XO-1 (p < 0.05). Our findings suggest that stress preconditioning of bull sperm before cryopreservation can improve thawed sperm functions, which might be mediated through an increase of UCP2 expression.
Assuntos
Preservação do Sêmen , Sêmen , Masculino , Animais , Bovinos , Xantina Oxidase/farmacologia , Motilidade dos Espermatozoides , Preservação do Sêmen/métodos , Espermatozoides , Criopreservação/métodos , FertilidadeRESUMO
The effectiveness of curcumin in preventing and treating collagen-induced inflammatory arthritis (CIA) in rats and oxidative stress in rats was investigated. We investigated curcumin's curative and preventive effects on paw edema, arthritic size, body weight, and radiologic and histological joint abnormalities. It has been shown that curcumin may dramatically lower the risk of developing arthritis. In addition, the number of white blood cells (WBCs) in the body has dropped, which is a strong indication that curcumin has anti-inflammatory characteristics. A follow-up theoretical investigation of curcumin molecular docking on xanthine oxidase (XO) was carried out after the properties of curcumin were determined using the conductor-like screening model for real solvents (COSMO-RS) theory. Because of the interaction between curcumin and the residues on XO named Ile264, Val259, Asn351, and Leu404, XO may be suppressed by this molecule. Curcumin's anti-inflammatory and antioxidant properties may be responsible for the anti-arthritic effects that have been seen on oxidative stress markers and XO. On the other hand, more research is being conducted to understand its function better in the early stages of rheumatoid arthritis (RA). To determine whether or not curcumin interacts with AR targets, a molecular docking study was conducted using MVD software against TNFRSF11A and cathepsin L.
Assuntos
Artrite Experimental , Curcumina , Ratos , Animais , Curcumina/farmacologia , Curcumina/uso terapêutico , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Xantina Oxidase/metabolismo , Xantina Oxidase/farmacologia , Xantina Oxidase/uso terapêutico , Simulação de Acoplamento Molecular , Catepsina L/efeitos adversos , Anti-Inflamatórios/farmacologia , Estresse OxidativoRESUMO
OBJECTIVES: Although uric acid lowering therapies, including xanthine oxidase (XO) inhibition, may reduce the absolute level of blood pressure (BP), the effect of XO inhibition on BP variability is largely unknown. The aim of the present analysis was to evaluate the impact of febuxostat, an XO inhibitor, on BP variability in a randomised trial setting. METHODS: This was a subanalysis of the PRIZE Study, a randomised trial to evaluate the potential effect of febuxostat on carotid intima-media thickness progression. Patients with hyperuricemia and carotid plaques were randomly assigned to the febuxostat or control group. During a 24-month period, office BP and pulse rate (PR) were measured ≥3 times. BP and PR variabilities were assessed with SD and coefficient of variation (CV). The effect of febuxostat on BP and PR variabilities was adjusted with age, sex and baseline BP or PR, expressed with 95% CIs. RESULTS: A total of 472 patients were included into the present subanalysis. During the 24-month follow-up period, the febuxostat group had a significantly lower adjusted mean systolic BP (128.4 (126.8-130.0) vs 130.7 (129.1-132.2) mm Hg, p=0.04) and CV of systolic BP (7.4 (6.7-8.0) vs 8.2 (7.6-8.8), p=0.04) than the control group. Adjusted SD of PR was also lower in the febuxostat group than their counterpart (5.95 (4.93-6.97) vs 7.33 (6.32-8.33), p=0.04). CONCLUSION: XO inhibition with febuxostat was associated with reduced visit-to-visit BP variability as well as reduced PR variability in patients with hyperuricemia and carotid plaques. TRIAL REGISTRATION NUMBERS: University Hospital Medical Information Network Clinical Trial Registry (UMIN000012911 and UMIN000041322).
Assuntos
Distinções e Prêmios , Hiperuricemia , Pressão Sanguínea/fisiologia , Espessura Intima-Media Carotídea , Febuxostat/farmacologia , Febuxostat/uso terapêutico , Humanos , Hiperuricemia/complicações , Hiperuricemia/tratamento farmacológico , Ácido Úrico , Xantina Oxidase/farmacologia , Xantina Oxidase/uso terapêuticoRESUMO
OBJECTIVE: Dexpanthenol (DXP) reportedly protects tissues against oxidative damage in various inflammation models. This study aimed to evaluate its effects on oxidative stress, inflammation, apoptosis, and neurological recovery in an experimental rabbit spinal cord ischemia/reperfusion injury (SCIRI) model. METHODS: Rabbits were randomized into 5 groups of 8 animals each: group 1 (control), group 2 (ischemia), group 3 (vehicle), group 4 (methylprednisolone, 30 mg/kg), and group 5 (DXP, 500 mg/kg). The control group underwent laparotomy only, whereas other groups were subjected to spinal cord ischemia by aortic occlusion (just caudal to the 2 renal arteries) for 20 min. After 24 h, a modified Tarlov scale was employed to record neurological examination results. Malondialdehyde and caspase-3 levels and catalase and myeloperoxidase activities were analyzed in tissue and serum samples. Xanthine oxidase activity was measured in the serum. Histopathological and ultrastructural evaluations were also performed in the spinal cord. RESULTS: After SCIRI, serum and tissue malondialdehyde and caspase-3 levels and myeloperoxidase and serum xanthine oxidase activities were increased (P < 0.05-0.001). However, serum and tissue catalase activity decreased significantly (P < 0.001). DXP treatment was associated with lower malondialdehyde and caspase-3 levels and reduced myeloperoxidase and xanthine oxidase activities but increased catalase activity (P < 0.05-0.001). Furthermore, DXP was associated with better histopathological, ultrastructural, and neurological outcome scores. CONCLUSIONS: This study was the first to evaluate antioxidant, anti-inflammatory, antiapoptotic, and neuroprotective effects of DXP on SCIRI. Further experimental and clinical investigations are warranted to confirm that DXP can be administered to treat SCIRI.
Assuntos
Fármacos Neuroprotetores , Traumatismo por Reperfusão , Isquemia do Cordão Espinal , Animais , Coelhos , Catalase/farmacologia , Catalase/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Peroxidase , Caspase 3 , Xantina Oxidase/farmacologia , Xantina Oxidase/uso terapêutico , Medula Espinal/patologia , Isquemia do Cordão Espinal/patologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/patologia , Inflamação/patologia , Malondialdeído , Modelos Animais de DoençasRESUMO
Febuxostat is a xanthine oxidase inhibitor used to reduce the formation of uric acid and prevent gout attacks. Previous studies have suggested that febuxostat was associated with a higher risk of cardiovascular events, including atrial fibrillation, compared with allopurinol, another anti-hyperuricemia drug. Whereas in our clinical practice, we identified 2 cases of febuxostat-associated ventricular tachycardia (VT) events. The proarrhythmogenic effects of febuxostat on human cardiomyocytes and underlined mechanisms remain poorly understood. In this study, we employed real-time cell analysis and calcium transient to investigate the effects of febuxostat on the cytotoxicity and electrophysiology properties of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Up to 10 µM febuxostat treatment did not show toxicity to cell viability. However, 48-h febuxostat exposure generated dose-dependent increased irregular calcium transients and decreased calcium transient amplitude. Furthermore, RNA-seq analysis indicated that the MAPK signaling pathway was enriched in the febuxostat-treated group, especially the protein kinases c-Jun N-terminal kinase (JNK). Western blotting of 3 main protein kinases demonstrated that JNK activation is related to febuxostat-induced arrhythmia rather than extracellular signal regulated kinases (ERK) or p38. The dysfunctional calcium dynamics of febuxostat-treated hiPSC-CMs could be ameliorated by SP600125, the inhibitor of JNK. In conclusion, our study demonstrated that febuxostat increases the predisposition to ventricular arrhythmia by dysregulating calcium dynamics.
Assuntos
Febuxostat , Células-Tronco Pluripotentes Induzidas , Alopurinol/metabolismo , Alopurinol/toxicidade , Arritmias Cardíacas/metabolismo , Cálcio/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Febuxostat/metabolismo , Febuxostat/toxicidade , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Miócitos Cardíacos , Ácido Úrico/metabolismo , Ácido Úrico/farmacologia , Xantina Oxidase/metabolismo , Xantina Oxidase/farmacologiaRESUMO
Background: Hyperuricemia (HU) is a metabolic disease characterized by high uric acid levels in the blood. HU is a risk factor for diabetes, cardiovascular complications, metabolic syndrome, and chronic kidney disease. Purpose: The present study was performed to determine the effect of experimental HU on xanthine oxidase (XO), tumor necrosis factor-alpha (TNF-α), nuclear factor-kappa B (NF-κB), interleukin-17 (IL-17), cytochrome C, glutathione peroxidase (GPx), caspase-3, and 8-hydroxydeoxyguanosine (8-OHdG) levels in liver tissues of rats. Study Design: Thirty-five, male, Wistar albino-type rats were used for this study. Experimental groups were formed as follows: Group 1: control group; Group 2: potassium oxonate (PO) group; group 3: PO+NAR (naringenin; 2 weeks) group; and Group 4: PO (2 weeks)+NAR (2 weeks) group (total of 4 weeks). Methods: The first group was not given anything other than normal rat food and drinking water. In the second group, a 250 mg/kg intraperitoneal dose of PO was administered for 2 weeks. In the third group, 250 mg/kg intraperitoneal PO (application for 2 weeks) and 100 mg/kg NAR intraperitoneally 1 hr after each application were administered. In the fourth group, intraperitoneal PO administration was applied for 2 weeks, followed by intraperitoneal administration of NAR for 2 weeks (4 weeks in total). At the end of the experimental period, XO, TNF-α, NF-κB, IL-17, cytochrome C, GPx, caspase-3, and 8-OHdG levels were determined in liver tissues. Results: HU increased XO, TNF-α, NF-κB, IL-17, cytochrome C, caspase-3, and 8-OHdG levels in liver tissues. However, both 2 and 4 weeks of NAR supplementation decreased these values, and also NAR supplementation led to an increase in GPx levels in tissues. Conclusions: The results of the study show that increased inflammation, apoptosis, and DNA damage in experimental HU can be prevented by administration of NAR due to inhibition of cytochrome C, NF-κB, caspase-3, and 8-OHdG.
Assuntos
Água Potável , Hiperuricemia , Masculino , Ratos , Animais , NF-kappa B/genética , NF-kappa B/metabolismo , NF-kappa B/farmacologia , Caspase 3/genética , Caspase 3/metabolismo , Caspase 3/farmacologia , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-17/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Citocromos c/genética , Citocromos c/metabolismo , Citocromos c/farmacologia , 8-Hidroxi-2'-Desoxiguanosina , Xantina Oxidase/genética , Xantina Oxidase/metabolismo , Xantina Oxidase/farmacologia , Ácido Úrico , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Glutationa Peroxidase/farmacologia , Água Potável/efeitos adversos , Água Potável/metabolismo , Ratos Wistar , Apoptose , Inflamação/metabolismo , Fígado/metabolismo , Dano ao DNARESUMO
Background: Given the importance of microvascular injury in infarct formation and expansion, development of therapeutic strategies for microvascular protection against myocardial ischemia/reperfusion injury (IRI) is of great interest. Here, we explored the molecular mechanisms underlying the protective effects of the SGLT2 inhibitor dapagliflozin (DAPA) against cardiac microvascular dysfunction mediated by IRI. Methods: DAPA effects were evaluated both in vivo, in mice subjected to IRI, and in vitro, in human coronary artery endothelial cells (HCAECs) exposed to hypoxia/reoxygenation (H/R). DAPA pretreatment attenuated luminal stenosis, endothelial swelling, and inflammation in cardiac microvessels of IRI-treated mice. Results: In H/R-challenged HCAECs, DAPA treatment improved endothelial barrier function, endothelial nitric oxide synthase (eNOS) activity, and angiogenic capacity, and inhibited H/R-induced apoptosis by preventing cofilin-dependent F-actin depolymerization and cytoskeletal degradation. Inhibition of H/R-induced xanthine oxidase (XO) activation and upregulation, sarco(endo)plasmic reticulum calcium-ATPase 2 (SERCA2) oxidation and inactivation, and cytoplasmic calcium overload was further observed in DAPA-treated HCAECs. DAPA also suppressed calcium/Calmodulin (CaM)-dependent kinase II (CaMKII) activation and cofilin phosphorylation, and preserved cytoskeleton integrity and endothelial cell viability following H/R. Importantly, the beneficial effects of DAPA on cardiac microvascular integrity and endothelial cell survival were largely prevented in IRI-treated SERCA2-knockout mice. Conclusions: These results indicate that DAPA effectively reduces cardiac microvascular damage and endothelial dysfunction during IRI through inhibition of the XO-SERCA2-CaMKII-cofilin pathway.
Assuntos
Traumatismo por Reperfusão Miocárdica , Inibidores do Transportador 2 de Sódio-Glicose , Fatores de Despolimerização de Actina/metabolismo , Fatores de Despolimerização de Actina/farmacologia , Animais , Compostos Benzidrílicos , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Células Endoteliais/metabolismo , Glucosídeos , Humanos , Isquemia/metabolismo , Camundongos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Xantina Oxidase/metabolismo , Xantina Oxidase/farmacologiaRESUMO
AIMS: The study aims to synthesize hybrid molecules containing pyrazole and aryldiazenyl/arylhydrazono fragments with promising anticancer activity. BACKGROUND: The clinical effectiveness of anticancer drugs is limited by their adverse side effects and patient resistance. Therefore, the development of safer classes of drugs through rational drug design is imperative. OBJECTIVE: Considering the anticancer potential of the pyrazole moiety, the study was carried out with the objective of synthesizing some hybrid pyrazole derivatives with anticancer potential. METHODS: The anticancer potential of these pyrazolyl analogues were evaluated by sulforhodamine B assay using three cancer cell lines MCF-7, HepG2, and HCT-116. RESULTS: HCT-116 was the most sensitive cell line against these pyrazolyl analogues. Among these newly synthesised derivatives, 1-(4-((4-bromophenyl)diazenyl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-(naphthalen-2-yloxy)ethan-1-one (5e) emerged as a promising anticancer agent (IC50 3.6-24.6 µM), having a xanthine oxidase inhibitory effect (IC50 10.87 µM). To obtain further insights into the binding interactions of these molecules, molecular docking studies were also carried out. CONCLUSION: In summary, our findings suggest that these hybrid pyrazolyl derivatives can be considered as potential lead molecules for anticancer agents.
Assuntos
Antineoplásicos , Xantina Oxidase , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Relação Estrutura-Atividade , Xantina Oxidase/farmacologiaRESUMO
Febuxostat (FBX), a selective inhibitor of xanthine oxidase, has several biological properties such as antioxidant, anti-inflammatory and anti-apoptosis activities. The purpose of this study was to evaluate the protective effect of FBX against ionizing radiation (IR)-induced lung injury through mitigation of oxidative stress, inflammation and apoptosis. Sixty-four mice were randomized into eight groups as control, FBX (5, 10, and 15 mg/kg), IR (6 Gy), and IR + FBX (IR + FBX in three doses). Mice were received FBX for 8 consecutive days and then were exposed to IR at a single dose (6 Gy) of X-ray. At 1 and 7 days after irradiation, the biochemical parameters were analyzed in lung tissue, while histological and immunohistochemical examinations were evaluated 1 week after irradiation. Irradiation led to elevate of oxidative stress parameters (an increase of MDA, PC, NO, and decrease of GSH), inflammation and apoptosis in lung of mice. Furthermore, IR resulted in histopathological changes in the lung tissues. These changes were significantly mitigated by FBX treatment. FBX also inhibited immunoreactivity of caspase-3, NF-κB, and reduced oxidative stress. This study showed that FBX is able to protect lung injury induced by IR through inhibiting apoptosis (caspase-3), oxidative stress and inflammation (NF-κB).
Assuntos
Febuxostat , Lesão Pulmonar , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Caspase 3 , Febuxostat/farmacologia , Febuxostat/uso terapêutico , Inflamação/tratamento farmacológico , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/etiologia , Lesão Pulmonar/prevenção & controle , NF-kappa B , Estresse Oxidativo , Radiação Ionizante , Xantina Oxidase/metabolismo , Xantina Oxidase/farmacologiaRESUMO
The purpose of this study was to examine the effects of sub-lethal concentration of Xanthine oxidase (XO) on the post-thawed bull sperm quality. Semen samples were collected from four Holstein bulls, twice a week and during three consecutive weeks (nâ¯=â¯24 total ejaculates). After collection in each replicate, semen samples were pooled and then frozen by semen extender containing different concentrations [0 (XO-0), 0.05 (XO-0.05), 0.5 (XO-0.5), 5 (XO-5), 50 (XO-50) and 500 (XO-500) µM] of XO. After thawing, motion parameters (SCA), plasma membrane functionality (HOST), apoptosis status (Phosphatidylserine translocation assay), mitochondrial activity (Rhodamine 123), and acrosome integrity (PSA), were evaluated. The results showed that total motility, VAP, VSL, VCL, STR, and LIN were lower in XO-50 and XO-500 compared to other groups (Pâ¯<â¯0.05). Progressive motility were higher in XO-0.05 and XO-0.5 compared to XO-0, XO-50, and XO-500 (Pâ¯<â¯0.05). Mitochondrial activity was highest in XO-0.05 and XO-0.5 groups. Sperm plasma membrane functionality was significantly greater in XO-0, XO-0.05, XO-0.5, and XO-5 than that of XO-50 and XO-500. Xanthine oxidase had not significant effects on acrosome integrity and dead spermatozoa. Higher percentage of live spermatozoa was recorded for XO-0, XO-0.05, XO-0.5, and XO-5; however, the lower amount of apoptotic spermatozoa was detected in the aforementioned groups (Pâ¯<â¯0.05). In conclusion, it seems that XO at lower doses may have beneficial effects on post-thawed bull sperm quality.
Assuntos
Criopreservação/métodos , Crioprotetores/farmacologia , Preservação do Sêmen/métodos , Motilidade dos Espermatozoides/efeitos dos fármacos , Xantina Oxidase/farmacologia , Acrossomo/metabolismo , Animais , Apoptose , Bovinos , Membrana Celular/efeitos dos fármacos , Congelamento , Masculino , Mitocôndrias/metabolismo , Sêmen/efeitos dos fármacos , Análise do Sêmen , Espermatozoides/efeitos dos fármacosRESUMO
BACKGROUND: A large number of disorders and their symptoms emerge from deficiency or overproduction of specific metabolites has drawn the attention for the discovery of new therapeutic agents for the treatment of disorders. Various approaches such as computational drug design have provided the new methodology for the selection and evaluation of target protein and the lead compound mechanistically. For instance, the overproduction of xanthine oxidase causes the accumulation of uric acid which can prompt gout. OBJECTIVE: In the present study we critically discussed the various techniques such as 3-D QSAR and molecular docking for the study of the natural based xanthine oxidase inhibitors with their mechanistic insight into the interaction of xanthine oxidase and various natural leads. CONCLUSION: The computational studies of deferent natural compounds were discussed as a result the flavonoids, anthraquinones, xanthones shown the remarkable inhibitory potential for xanthine oxidase inhibition moreover the flavonoids such as hesperidin and rutin were found as promising candidates for further exploration.
Assuntos
Produtos Biológicos/antagonistas & inibidores , Produtos Biológicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/farmacologia , Antraquinonas/química , Produtos Biológicos/química , Coenzimas/química , Simulação por Computador , Desenho Assistido por Computador , Desenho de Fármacos , Flavina-Adenina Dinucleotídeo/química , Flavonoides/química , Proteínas Ferro-Enxofre/química , Metaloproteínas/química , Simulação de Acoplamento Molecular , Cofatores de Molibdênio , Conformação Proteica , Pteridinas/química , Relação Quantitativa Estrutura-Atividade , Xantina Oxidase/biossíntese , Xantina Oxidase/química , Xantonas/químicaRESUMO
Red cells from patients with sickle cell anemia (SCA) are under greater oxidative challenge than those from normal individuals. We postulated that oxidants generated by xanthine oxidase (XO) and hypoxanthine (HO) contribute to the pathogenesis of SCA through altering solute permeability. Sickling, activities of the main red cell dehydration pathways (Psickle , Gardos channel, and KCl cotransporter [KCC]), and cell volume were measured at 100, 30, and 0 mmHg O2 , together with deoxygenation-induced nonelectrolyte hemolysis. Unexpectedly, XO/HO mixtures had mainly inhibitory effects on sickling, Psickle , and Gardos channel activities, while KCC activity and nonelectrolyte hemolysis were increased. Gardos channel activity was significantly elevated in red cells pharmacologically loaded with Ca2+ using the ionophore A23187, consistent with an effect on the transport system per se as well as via Ca2+ entry likely via the Psickle pathway. KCC activity is controlled by several pairs of conjugate protein kinases and phosphatases. Its activity, however, was also stimulated by XO/HO mixtures in red cells pretreated with N-ethylmaleimide (NEM), which is thought to prevent regulation via changes in protein phosphorylation, suggesting that the oxidants formed could also have direct effects on this transporter. In the presence of XO/HO, red cell volume was better maintained in deoxygenated red cells. Overall, the most notable effect of XO/HO mixtures was an increase in red cell fragility. These findings increase our understanding of the effects of oxidative challenge in SCA patients and are relevant to the behavior of red cells in vivo.
Assuntos
Anemia Falciforme/metabolismo , Membrana Celular/metabolismo , Eritrócitos/metabolismo , Hipoxantina/farmacologia , Xantina Oxidase/farmacologia , Cálcio/metabolismo , Membrana Celular/efeitos dos fármacos , Tamanho Celular , Eritrócitos/efeitos dos fármacos , Etilmaleimida/farmacologia , Humanos , Oxigênio/metabolismo , Permeabilidade , Espécies Reativas de Oxigênio/metabolismo , Simportadores/metabolismo , Cotransportadores de K e Cl-RESUMO
This study aimed to investigate the anti-oxidant and anti-hypertrophic effects of puerarin-7-O-glucuronide, a water-soluble puerarin metabolite. The anti-oxidant effects of puerarin-7-O-glucuronide were assessed by measurement of intracellular superoxide levels, total superoxide dismutase (SOD) activity, total anti-oxidant capacity, and glutathione (GSH)/glutathione disulfide (GSSG) ratio in cultured neonatal rat cardiomyocytes (NRCMs) stimulated with the xanthine oxidase (XO)/xanthine (X) system or angiotensin II. The activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and expression of NADPH oxidase subunits p22phox and p47phox were determined. The anti-hypertrophic effects of puerarin-7-O-glucuronide in angiotensin II-challenged NRCMs were characterized by changes in cell morphology and expression of hypertrophic genes. In the pharmacokinetic study, the plasma concentration of puerarin-7-O-glucuronide was determined by rapid resolution-liquid chromatography-tandem mass spectrometry (RR-LC-MS/MS). Puerarin-7-O-glucuronide prevented XO/X-induced increase in intracellular superoxide production and decreases in total SOD activity, GSH/GSSG ratio, and total anti-oxidant capacity. Puerarin-7-O-glucuronide also reversed angiotensin II-induced increases in intracellular superoxide production and NADPH oxidase activity and decreases in total SOD activity. These anti-oxidant effects of puerarin-7-O-glucuronide were accompanied by downregulation of p22phox and p47phox. Furthermore, puerarin-7-O-glucuronide prevented angiotensin II-induced increases in cell surface area and perimeter, as well as changes in Nppa, Myh7, and Myh6. In the pharmacokinetic study, puerarin-7-O-glucuronide was cleared with a half-life of 0.94 h after intravenous administration. Puerarin could be detected in rat plasma, albeit in low concentration, as early as 5 min after intravenous administration of puerarin-7-O-glucuronide. These anti-oxidant and anti-hypertrophic properties of puerarin-7-O-glucuronide were similar to those of its parent compound puerarin. These results support the development of puerarin-7-O-glucuronide as a novel pharmaceutical agent for therapeutic application.