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BACKGROUND AND AIMS: Sepsis induced liver injury is recognized as a serious complication in intensive care units, it is deeply associated with oxidative stress, inflammation and subsequent pyroptosis. Hepatic pyroptosis known to aggravate sepsis-induced liver injury. Previous studies proved that granisetron has anti-inflammatory and antioxidant properties. Accordingly, this study aimed to evaluate the efficacy of granisetron on sepsis-induced liver damage using a cecal ligation and puncture (CLP) model in rats. MAIN METHODS: Male albino rats were randomly divided into four groups: a sham control group, a granisetron control group, a CLP-induced sepsis group and a granisetron-treated CLP group. Markers of oxidative stress, inflammation, pyroptosis-related proteins and liver function were measured in addition to the histopathological study. KEY FINDINGS: Granisetron pretreatment significantly decreased mortality and improved liver function, as indicated by decreased ALT, AST, and total bilirubin and increased albumin content. Moreover, granisetron increased GPx activity and downregulated hepatic MDA. Furthermore, granisetron administration significantly reduced TNF-α, IL-6, HMGB1 and NF-κB. It also decreased the expression of receptor for advanced glycation end and TLR4 in the liver tissue. Interestingly, granisetron inhibited pyroptosis as it reduced NLRP3, IL-1ß and caspase-1. Granisetron was shown to increase Nrf2 and HO-1. In addition, granisetron treatment repaired, to some extent, the abnormal architecture of hepatic tissue. SIGNIFICANCE: Our results suggested that granisetron is a potential therapeutic agent for sepsis-associated liver injury, possibly acting by inhibiting oxidative stress, inflammation and subsequent pyroptosis.

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INTRODUCTION: Cisplatin (CDDP) nephrotoxicity is one of the most significant complications limiting its use in cancer therapy. OBJECTIVES: This study investigated the pivotal role played by thrombin in CDDP-mediated nephrotoxicity. This work also aimed to clarify the possible preventive effect of Dabigatran (Dab), a direct thrombin inhibitor, on CDDP nephrotoxicity. METHODS: Animals were grouped as follow; normal control group, CDDP nephrotoxicity group, CDDP + Dab 15, and CDDP + Dab 25 groups. Four days following CDDP administration, blood and urine samples were collected to evaluate renal function. Moreover, tissue samples were collected from the kidney to determine apoptosis markers, oxidative stress and histopathological evaluation. An immunofluorescence analysis of tissue factor (TF), thrombin, protease-activated receptor-2 (PAR2), fibrin, pERK1/2 and P53 proteins expression was also performed. RESULTS: Thrombin, pERK, cleaved caspase-3, and oxidative stress markers were significantly elevated in CDDP-treated group. However, pretreatment of animals with either low or high doses of Dab significantly improved kidney function and decreased oxidative stress and apoptotic markers. CONCLUSION: We conclude that thrombin is an important factor in the pathogenesis of CDDP kidney toxicity via activation of ERK1/2, P53 and caspase-3 pathway, which can be effectively blocked by Dab.

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PURPOSE: The present study aimed to evaluate the possible hepatoprotective effects of nicorandil and atorvastatin against experimentally induced liver fibrosis. MATERIALS AND METHODS: Wistar male rats wereassigned tofivegroups; control group, fibrosis group, the remaining three groups received in addition to CCl4, N-acetyl cysteine (300 mg/kg), nicorandil(15 mg/kg) and atorvastatin (20 mg/kg), respectively. Liver fibrosis was induced by intraperitoneal injection of rats with CCl4 (2 ml/kg), twice weekly for five consecutive weeks. All treatments were administered daily starting from the first day of fibrosis induction for five consecutive weeks. By the end of the experiment, fibrosis biomarkers [hepatic transforming growth factor ß1 (TGF-ß1) and hydroxyproline (HYP)], liver function [serum alanine transaminase (ALT), aspartate transaminase (AST), albumin and total bilirubin] were assessed. Moreover, lipid profile [total cholesterol, serum triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)], inflammatory biomarkers [hepatic myeloperoxidase (MPO), serum tumor necrosis factor alpha (TNF-α)], relative liver weight] and oxidative stress biomarkers [malondialdehyde (MDA), glutathione (GSH) and catalase (CAT)] were evaluated. In support, histopathological and immunohistochemical examination of liver alpha smooth muscle actin (α-SMA) were performed. RESULTS: Nicorandil and atorvastatin effectively reduced fibrosis and liver function biomarkers. They both restored serum lipid profile, TNF-α, MPO, relative liver weight, and hepatic MDA content. Alternatively, they markedly elevated albumin, HDL-C and hepatic content of GSH and CAT. Additionally, a marked histopathological and immunohistochemical improvement of α-SMA was observed. CONCLUSION: Nicorandil and atorvastatin might be promising protective agents against liver fibrosis through amelioration of liver function, modulation of fibrous formation, anti-inflammatory and antioxidant potentials.

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BACKGROUND: In the current investigation, the effects of the P2Y12 blocker ticagrelor, the sodium/glucose transporter-2-inhibitor empagliflozin, and the selective estrogen receptor modulator tamoxifen were examined against rheumatoid arthritis (RA)/diabetes mellitus (DM)-co-morbidity-induced defects in vascular reactivity. METHODS: After model setting, rats were allocated into a normal control, an RA/DM-co-morbidity, and three treatment groups receiving ticagrelor, empagliflozin and tamoxifen. Aorta tissue was isolated for enzyme-linked immunosorbent assay (ELISA) and western blot estimation of the pro-inflammatory molecules angiotensin-II (Ang-II) and endothelin-1 (ET-1), the adhesion molecules P-selectin and vascular cell adhesion molecule-1 (VCAM-1), the energy preserving molecule adenosine-5'-monophosphate-activated protein kinase (AMPK), and the anti-inflammatory molecule vasoactive intestinal peptide (VIP). Estimations of endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase (MMP)-2 were performed immunohistochemically, together with histopathological examination using hematoxylin and eosin and Masson trichrome staining. An in vitro study on rat aortic strips was conducted to assess aorta vasorelaxation. RESULTS: Ticagrelor, empagliflozin and tamoxifen significantly increased aorta tissue AMPK and eNOS and decreased Ang-II, ET-1, P-selectin, VCAM-1 and VIP levels compared with RA/DM-co-morbidity, coupled with improved acetylcholine vasorelaxation in vitro. CONCLUSION: Ticagrelor, empagliflozin and tamoxifen may correct vascular reactivity defects, where modulation of vascular AMPK, eNOS, Ang-II, ET-1, P-selectin, VCAM-1 and MMP-2 underline their protective effects.

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Endothelial dysfunction and vascular reactivity defects secondary to metabolic and immunological disorders carry risk of serious cardiovascular complications. Here, the effects of the phosphodiesterase (PDE) inhibitors vardenafil and cilostazol were examined against rheumatoid arthritis (RA)/diabetes mellitus (DM)-co-morbidity-induced endothelial dysfunction and vascular reactivity defects. After setting of RA/DM-co-morbidity model, rats were divided into a normal control group, an RA/DM-co-morbidity group, and two treatment groups receiving oral vardenafil (10 mg/kg/day) and cilostazol (30 mg/kg/day) for 21 days after RA/DM-co-morbidity induction. Aorta was isolated for biochemical estimations of the pro-inflammatory vasoconstrictor molecules angiotensin-II (Ang-II) and endothelin-1 (ET-1), the adhesion molecules P-selectin and vascular cell adhesion molecule-1 (VCAM-1), the energy sensor adenosine-5'-monophosphate-activated protein kinase (AMPK), and the vasodilator anti-inflammatory molecule vasoactive intestinal peptide (VIP) using enzyme-linked immunosorbent assay (ELISA) and western blot analysis. Immunohistochemical estimations of endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase (MMP)-2 were performed coupled with histopathological examination using routine hematoxylin and eosin (H&E) and special Masson trichrome staining. The in vitro study was conducted using aortic strips where cumulative concentration response curves were done for the endothelium-dependent relaxing factor acetylcholine and the endothelium-independent relaxing factor sodium nitroprusside after submaximal contraction with phenylephrine. Vardenafil and cilostazol significantly improved endothelial integrity biomarkers in vivo supported with histopathological findings in addition to improved vasorelaxation in vitro. Apart from their known PDE inhibition, up-regulation of vascular AMPK and eNOS coupled with down-regulation of Ang-II, ET-1, P-selectin, VCAM-1 and MMP-2 may explain vardenafil and cilostazol protective effect against RA/DM-co-morbidity-induced endothelial dysfunction and vascular reactivity defects.

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Activated factor X has a central role in the coagulation activation and also contributes to chronic inflammation and tissue fibrosis. In this study, rivaroxaban, a direct factor X inhibitor, attenuates liver fibrosis induced by carbon tetrachloride (CCl4 ). Male rats were randomly allocated into three groups: a control group, CCl 4 fibrotic group, and CCl 4 +rivaroxaban (5 mg/kg) group. Liver fibrosis was induced by subcutaneous injection of CCl 4 twice a week for 6 weeks. Rivaroxaban significantly restored the biochemical parameter including inflammatory and fibrosis markers with histopathological evidence using routine and Masson trichrome staining. It reduced also the expression of tissue factor, fibrin, transforming growth factor and α-smooth muscle actin in the liver tissues. This concludes that rivaroxaban attenuates liver injury caused by CCl 4 , at least in part by inhibiting coagulation and proinflammatory activation. In conclusion, rivaroxaban may be used for the management of liver fibrosis.

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Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by joint infiltration and bone damage. The aim of the present study was to evaluate the beneficial effects of losartan in adjuvant-induced arthritis (AIA). Arthritis was induced in rats by subcutaneous injection of 0.2 mL of Complete Freund's adjuvant (CFA) in the planter surface of the hind paw. Arthritic rats were allocated into three groups (n = 10), the first group (arthritis control), received 1% of tween 80, the second and the third groups received prednisolone (10 mg/kg/day; p.o) and losartan (20 mg/kg/day; p.o) respectively for two weeks. A fourth group (vehicle control) received 1% tween 80. At the end of the experiment, blood samples were collected for biochemical, oxidative stress, and hematological analysis. Histopathological and macroscopical examinations on joints were also performed. Our results revealed that losartan significantly reduced serum levels of tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6) , rheumatoid factor (RF), and erythrocytes sedimentation rate (ESR).It significantly decreased serum malondialdehyde and increased blood glutathione .Losartan exhibited significant decrease in serum level of total cholesterol (TC), triglycerides (TG) and low density lipoprotein (LDL) coupled with marked increase in high density lipoprotein (HDL).Furthermore, losartan decreased white blood cell cells (WBC's) count and increased red blood cells (RBC's) , hemoglobin (Hb) , platelets, and hematocrit (Hct) counts. These findings were further supported by histopathological and macroscopical examinations. It could be concluded that losartan was able to repress biochemical, oxidative and hematological changes associated with AIA. These effects could be attributed to anti-arthritic, hypolipidemic, antioxidant and anti-anemic properties.

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CONTEXT: Saponins from different sources are historically reported in Chinese medicine to possess many beneficial effects. However, insufficient experimental data are available regarding the hepatoprotective potential of Quillaja bark saponin. OBJECTIVE: The protective effect of Quillaja saponaria Molina (Quillajaceae) bark triterpenoid saponin against iron-induced hepatotoxicity is compared to the standard N-acetylcysteine in adult male Wistar rats. MATERIALS AND METHODS: Animals were divided into (six) groups, namely a normal control, an N-acetylcysteine control (300 mg/kg/day, p.o., 10 days), a saponin control (100 mg/kg/day, p.o., for 10 days), a hepatotoxicity control (two doses of ferrous sulphate, 30 mg/kg/day each, i.p., on 9th and 10th day), an N-acetylcysteine plus ferrous sulphate (standard treatment) and a saponin plus ferrous sulphate (test treatment) group. Hepatocyte integrity loss markers (serum ALT, AST, ALP, GGT and LDH), oxidative stress markers (hepatic MDA, GSH and NOx), dyslipidaemic markers (serum TC and TG) and hepatocyte functioning markers (serum bilirubin and albumin) were assessed. RESULTS: Quillaja bark saponin decreased iron-induced elevation of ALT (reaching 57% of hepatotoxicity control), AST (66%), ALP (76%), GGT (60%), LDH (54%), MDA (65%), NOx (77%), TC (70%), TG (54%), and total (54%), direct (54%) and indirect (54%) bilirubin, coupled with increased GSH (219%) and albumin (159%) levels. Histopathological study strongly supported biochemical estimations, while immunohistochemical study showed marked effect on eNOS and iNOS expression. CONCLUSIONS: Quillaja bark saponin has a good hepatoprotective effect. Amelioration of oxidative stress and suppression of NOS expression, with resultant maintenance of hepatocyte integrity and functioning, may explain this beneficial effect.

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CONTEXT: Rheumatoid arthritis (RA), a disabling autoimmune disorder of the joints as well as other organs, affects about 1% of population. Unfortunately, all current treatments of RA cause severe gastrointestinal, renal and other complications. OBJECTIVE: We aimed to evaluate the possible antiarthritic effects of a serotonin 5-HT3 receptor blocker, granisetron, and a nonselective adrenergic receptor blocker, carvedilol, on complete Freund's adjuvant-induced RA in adult female albino rats. MATERIALS AND METHODS: Rats were allocated into a normal control group, an arthritis control group, two reference treatment groups receiving dexamethasone (1.5 mg/kg/day) and methotrexate (1 mg/kg/day), and two treatment groups receiving granisetron (2.5 mg/kg/day) and carvedilol (10 mg/kg/day). Serum-specific rheumatoid, immunological, inflammatory and oxidative stress biomarkers were assessed. A confirmatory histopathological study on joints and spleens was performed. RESULTS: Granisetron administration significantly improved all the measured biomarkers, with the values of rheumatoid factor, matrix metalloproteinase-3, cartilage oligomeric matrix protein, immunoglobulin G, antinuclear antibody and myeloperoxidase being restored back to normal levels. Carvedilol administration significantly improved all biomarkers, with serum MPO value restored back to normal levels. DISCUSSION AND CONCLUSIONS: Serotonin 5-HT3 receptor blockers and adrenergic receptor blockers, represented by granisetron and carvedilol, may represent new promising protective strategies against RA, at least owing to immune-modulator, anti-inflammatory and antioxidant potentials.

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Coenzyme Q10 (Co-Q10) is a vitamin-like supplement which appears to be safe, with minimal side effects and low drug interaction potential. Co-Q10 is used in the treatment of a variety of disorders related primarily to suboptimal cellular energy metabolism and oxidative injury. Studies supporting the efficacy of Co-Q10 appear most promising for a variety of diseases, including ulcerative colitis (UC). The present investigation aims to elucidate the possible protective effects of Co-Q10 against UC, as induced by the administration of iodoacetamide to adult male albino rats. In our study, Co-Q10 showed potent anti-oxidant and anti-inflammatory activities through a significant increase in catalase activity and glutathione content. In addition, it significantly decreased myeloperoxidase activity, malondialdehyde content and nitrate/nitrite production. These results suggest that Co-Q10 protects against UC in rats via anti-oxidant and anti-inflammatory potentials, and therefore seems promising for use in further clinical trials.

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BACKGROUND/AIMS: Rheumatoid arthritis (RA) is a disabling autoimmune disease for which most current treatments cause massive complications, thereby limiting treatment dose and duration. The anti-arthritic effects of the 3-hydroxy-3-metylglutary-CoA reductase inhibitor, simvastatin, and the natural flavonoid, hesperidin, were investigated against complete Freund's adjuvant-induced RA in rats. METHODS: A normal control group, an arthritis control group, 2 reference treatment groups receiving dexamethasone (1.5 mg/kg/day) and methotrexate (1 mg/kg/day), and 2 treatment groups receiving simvastatin (0.5 mg/kg/day) and hesperidin (200 mg/kg/day) were included in the study. Serum rheumatoid factor, matrix metalloprotinease-3 (MMP-3) and cartilage oligomeric matrix protein (COMP) as specific rheumatoid biomarkers, serum immunoglobulin G (IgG) and antinuclear antibody (ANA) as immunological biomarkers, serum tumor necrosis factor-alpha and interleukin-10 as immunomodulatory cytokines, serum myeloperoxidase (MPO) and C-reactive protein as inflammatory biomarkers, and malondialdehyde (MDA) and glutathione (GSH) as oxidative stress biomarkers were assessed, supported by joint and spleen histopathological study. RESULTS: Simvastatin significantly improved all the measured biomarkers, with MMP-3, COMP, and GSH restored to normal levels. Hesperidin significantly improved all the measured biomarkers, with COMP, IgG, ANA, MPO, MDA and GSH restored to normal levels. CONCLUSION: Simvastatin and hesperidin may be promising protective agents against RA through immunomodulatory, anti-inflammatory and antioxidant potentials.

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Rheumatoid arthritis (RA) is a challenging autoimmune disorder, whose treatments usually cause severe gastrointestinal, renal and other complications. We aimed to evaluate the beneficial anti-arthritic effects of an angiotensin converting enzyme (ACE) inhibitor, ramipril and a dopamine receptor blocker, haloperidol, on Complete Freund's Adjuvant-induced RA in adult female albino rats. Rats were allocated into a normal control group, an arthritis control group, two reference treatment groups receiving dexamethasone (1.5 mg/kg/day) and methotrexate (1 mg/kg/day), and two treatment groups receiving ramipril (0.9 mg/kg/day) and haloperidol (1 mg/kg/day). Serum rheumatoid factor, matrix metalloprotinease-3 (MMP-3) and cartilage oligomeric matrix protein as specific rheumatoid biomarkers, serum immunoglobulin G and antinuclear antibody as immunological biomarkers, serum tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) as immunomodulatory cytokines, serum myeloperoxidase and C-reactive protein as inflammatory biomarkers, as well as malondialdehyde and glutathione reduced (GSH) as oxidative stress biomarkers were assessed. A histopathological study on joints and spleens was performed to support the results of biochemical estimations. Ramipril administration significantly corrected all the measured biomarkers, being restored back to normal levels except for MMP-3, TNF-α and IL-10. Haloperidol administration restored all the measured biomarkers back to normal levels except for TNF-α, IL-10 and GSH. In conclusion, ACE inhibitors represented by ramipril and dopamine receptor blockers represented by haloperidol may represent new promising protective strategies against RA, at least owing to their immunomodulatory, anti-inflammatory and antioxidant potentials.

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