Xanthine Oxidase Inhibitor, Febuxostat Is Effective against 5-Fluorouracil-Induced Parotid Salivary Gland Injury in Rats Via Inhibition of Oxidative Stress, Inflammation and Targeting TRPC1/CHOP Signalling Pathway.

The current research aimed to examine the ameliorative role of febuxostat (FEB), a highly potent xanthine oxidase inhibitor, against 5-fluorouracil (5-FU)-induced parotid salivary gland damage in rats, as FEB is a pleiotropic drug that has multiple pharmacological effects. A total of 32 Wistar adult male rats were randomly arranged into four groups. Group 1: the control group; given only the vehicle for 14 days, then given a saline i.p. injection from the 10th to the 14th day. Group 2: the FEB group; rats received FEB (10 mg/kg) once daily po for 14 days before receiving a saline i.p. injection from the 10th to the 14th day. Group 3: the 5-FU group; from the 10th to the 14th day, rats received an intraperitoneal injection of 5-FU (35 mg/kg/day). Group 4: the FEB/5-FU group; rats were pre-treated with FEB po for 14 days before receiving 5-FU i.p injections for five consecutive days from the 10th to the 14th day. Parotid gland damage was detected histologically and biochemically by the evaluation of oxidative stress markers (malondialdehyde (MDA) and nitric oxide levels (NOx)), oxidant defences (reduced glutathione (GSH) and superoxide dismutase (SOD)), inflammatory markers (tumour necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß)), and transient receptor potential canonical1 (TRCP1) and C/EBP homologous protein (CHOP). FEB pre-treatment reduced MDA, TNF-, and IL-1 while increasing SOD, GSH, and NOx. FEB also significantly increased TRPC1 and decreased CHOP in parotid gland tissue. In conclusion, FEB pre-treatment reduced 5-FU-induced parotid salivary gland damage not only through its powerful anti-inflammatory and antioxidant effects, but also through its effect on the TRPC1/CHOP signalling pathway.

Role of Platelet-activating factor and HO-1 in mediating the protective effect of rupatadine against 5-fluorouracil-induced hepatotoxicity in rats.

5-fluorouracil (5-FU) is a widely used chemotherapeutic drug, but its hepatotoxicity challenges its clinical use. Thus, searching for a hepatoprotective agent is highly required to prevent the accompanied hepatic hazards. The current study aimed to investigate the potential benefit and mechanisms of action of rupatadine (RU), a Platelet-activating factor (PAF) antagonist, in the prevention of 5-FU-related hepatotoxicity in rats. Hepatotoxicity was developed in male albino rats by a single 5-FU (150 mg/kg) intra-peritoneal injection on the 7th day of the experiment. RU (3 mg/kg/day) was orally administrated to the rodents for 10 days. Hepatic toxicity was assessed by measuring both liver and body weights, serum alanine aminotransferase and aspartate aminotransferase (ALT and AST), hepatic oxidative stress parameters (malondialdehyde (MDA), nitric oxide levels (NOx), reduced glutathione (GSH), superoxide dismutase (SOD)), and heme oxygenase-1 (HO-1). Inflammatory markers expressions (inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNFα), interleukins; IL-1B, IL-6), the apoptotic marker (caspase-3), and PAF were measured in the hepatic tissue. 5-FU-induced hepatotoxicity was proved by the biochemical along with histopathological assessments. RU ameliorated 5-FU-induced liver damage as proved by the improved serum ALT, AST, and hepatic oxidative stress parameters, the attenuated expression of hepatic pro-inflammatory cytokines and PAF, and the up-regulation of HO-1. Therefore, it can be concluded that RU pretreatment exerted a hepatoprotective effect against 5-FU-induced liver damage through both its powerful anti-inflammatory, antioxidant, and anti-apoptotic effect.

Cardioprotective effects of bosentan in 5-fluorouracil-induced cardiotoxicity.

5-fluorouracil (5-FU) is a widely used chemotherapeutic agent but cardiotoxicity challenges its clinical usefulness. Thus, searching for more cardioprotective drugs is highly required to prevent the accompanied cardiac hazards. Up to date, the different mechanisms involved in 5-FU cardiotoxicity are still unclear and there is no evaluation of bosentan's role in controlling these cardiac complications. This forced us to deeply study and evaluate the possible cardiopreserving properties of bosentan and different mechanisms involved in mediating it. 32 Wistar albino rats were included in our experiment and induction of cardiotoxicity was performed via administration of 5-FU (150 mg/kg) on 5th day of the experiment by intraperitoneal (i.p.) injection with or without co-administration of bosentan (50 mg/kg/day) orally for 7days. Our data revealed that 5-FU could induce cardiotoxicity which was detected as significant increases of troponin I, lactate dehydrogenase (LDH), creatine kinase- MB (CK-MB), endothelin receptors, malondialdehyde (MDA), toll like receptor4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor kappa B (NFκB), and caspase 3 levels. However, there is marked decrease in endothelial nitric oxide synthase (eNOS), reduced glutathione (GSH) and total antioxidant capacity (TAC). In addition, the histopathological examination showed severe toxic features of cardiac injury. Interestingly, co-administration of bosentan could ameliorate 5-FU-induced cardiotoxicity via improving the detected biochemical and histopathological changes besides modulation of TLR4/MyD88/NFκB signaling pathway, eNOS, and endothelin receptors. Bosentan had a significant cardioprotective effect against 5-FU induced cardiac damage. This effect may be attributed to its ability to inhibit endothelin receptors, stimulates eNOS, anti-oxidant, anti-inflammatory, anti-apoptotic properties with modulation of TLR4/MyD88/NFκB signaling pathway.

Protective effects of selenium in tacrolimus-induced lung toxicity: potential role of heme oxygenase 1.

The present study aimed to evaluate the protective effects of selenium (Sel) administration against tacrolimus (Tac) - induced lung toxicity and to assess the relation between heme oxygenase 1 (HO-1) and these effects. The study was conducted on 36 Wistar male albino rats equally divided into four groups: (i) normal control; (ii) Sel (0.1 mg/kg per day p.o. for four weeks); (iii) TAC 3 mg/mL as single oral dose on 27th day; and (iv) Tac + Sel. Lung tissues, lung homogenate, and bronchoalveolar lavage of the sacrificed animals were investigated biochemically and histopathologically, by immunohistochemistry or by PCR. The Tac group showed significantly lower expression of HO-1. Administration of Sel was associated with increased HO-1 expression. Oxidative (malondialdehyde, reduced glutathione, superoxide dismutase, myeloperoxidase, and glutathione peroxidase activity) and nitrosative stress (nitric oxide) markers and markers of inflammation (interleukin 1ß (IL-1ß), IL-6, and IL-10) showed changes corresponding to HO-1 levels in rat groups. Tac group showed the highest expression of caspase-3. Sel exerted a protective role against Tac-induced lung toxicity.

Fenofibrate ameliorates testicular damage in rats with streptozotocin-induced type 1 diabetes: role of HO-1 and p38 MAPK.

BACKGROUND: Since diabetes mellitus type-1 (DM-1) induces testicular oxidative and inflammatory damage with finally an ultimate male infertility, and as fenofibrate (FEN) plays an important antioxidant and anti-inflammatory role, the aim of the present study was to investigate the effects of FEN on diabetes-induced reproductive damage and clarifying the underlying related mechanisms. METHODS: DM-1 was induced in male Wistar rats by a single intraperitoneal injection of streptozotocin (50 mg/kg). FEN (100 mg/kg/day, orally) was administrated to diabetic rats for 4 weeks. Testicular damage was detected by estimation of both testicular and body weights, assessment of serum testosterone, testicular oxidative stress parameters (malondialdehyde and nitric oxide levels) and testicular oxidant defenses (reduced glutathione, superoxide dismutase and hemeoxygenase-1). Expressions of the inflammatory markers (inducible nitric oxide synthase, p38 mitogen-activated protein kinase (MAPK), tumor necrosis factor alpha, interleukin-6 and apoptotic marker (caspase-3) were evaluated in testicular tissue. Our results were confirmed by histopathological examination of testicular tissues. RESULTS: Diabetic testicular damage was proved by both biochemical and histopathological examinations. FEN treatment reversed diabetic testicular damage; normalized the serum testosterone level, improved anti-oxidative capacity, ameliorated the pro-inflammatory cytokine expression in testicular tissue with the down regulation of p38 MAPK mediated-testicular apoptosis. CONCLUSION: FEN treatment exerted a protective effect against streptozotocin-induced diabetic reproductive dysfunction not only through its powerful antioxidant and hypoglycemic effects, but also through its anti-inflammatory and anti-apoptotic effect via down-regulation of testicular p38 MAPK expression in diabetic rats.

Allopurinol potentiates the hepatoprotective effect of metformin and vitamin E in fructose-induced fatty liver in rats.

AIM OF THE STUDY: Non-alcoholic fatty liver disease (NAFLD) is a challenging health problem. Hyperuricemia is a key player in the pathogenesis of NAFLD. This study investigated the effect of allopurinol (uric acid synthesis inhibitor) in combination with metformin and vitamin E in prevention of fructose induced-fatty liver in rats. MATERIAL AND METHODS: Rats were divided into 7 groups: control group, fructose group (model group of NAFLD), allopurinol-treated group, metformin-treated group, vitamin E-treated group, metformin plus vitamin E-treated group and a combination group (received allopurinol plus metformin plus vitamin E). Development of NAFLD was assessed biochemically by serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as well as by histopathological examination. Oxidative stress parameters [reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA)], and the inflammatory mediators tumor necrosis factor α (TNF-α) and inducible nitric oxide synthase (iNOS) were assessed, along with serum levels of uric acid and triglyceride (TG). RESULTS: Combination of allopurinol plus metformin plus vitamin E significantly attenuated fatty changes compared to their respective monotherapy. Interestingly, though all treated groups showed significant attenuation in the oxidative stress markers, TNF-α level and iNOS immunostaining in hepatic tissue, along with a significant decrease in the levels of uric acid and TG, the combination group showed a further significant decrease in the serum level of uric acid and iNOS immunostaining compared to other treated regimens. CONCLUSIONS: Allopurinol synergistically increases the protective effect of metformin and vitamin E in treatment of NAFLD, namely via reduction of uric acid synthesis and iNOS expression.