Preventive empagliflozin activity on acute acetic acid-induced ulcerative colitis in rats via modulation of SIRT-1/PI3K/AKT pathway and improving colon barrier.

BACKGROUND: Ulcerative colitis (UC) is a chronic colon inflammation that is linked to exposure to environmental factors leading to improper immune responses to enteric microbes in genetically susceptible individuals. This study was designed to explore the possible protective impact of Empagliflozin (EMPA), an anti-diabetic sodium-glucose cotransporter-2 (SGLT2) inhibitor, on acetic acid (AA)-induced UC in rats. METHOD: Intrarectal instillation of AA (2 ml, 3% v/v) was used to induce UC. EMPA (10 & 30 mg/kg) was administered orally for 11 days. RESULTS: EMPA successfully counteracted AA-induced UC that was manifested by improving colonic histopathological architecture concomitant with a marked decrease in disease activity index (DAI), colon weight, weight/length ratio, serum lactate dehydrogenase (LDH) activity, and C-reactive protein (CRP) level. Additionally, EMPA successfully restored the disrupted oxidant/antioxidants balance induced by AA. Moreover, EMPA significantly induced silent information regulator-1(SIRT-1) expression along with a significant reduction in phosphatidylinositol-3-Kinase (PI3K), Protein Kinase B (AKT), nuclear factor kappa B (NF-κB), tumor necrosis factor (TNF)-α and interleukins (IL-1ß and IL-6) expression in colonic tissues. Furthermore, EMPA successfully improved the colonic barrier that was appeared from the marked induction of tight junction proteins level (occludin and claudin-1). CONCLUSION: EMPA successfully counteracted AA-induced UC in rats via the modulation of SIRT1/PI3K/AKT/NF-κB inflammatory pathway, normalizing oxidant/antioxidants balance, and improving the integrity of colon barrier.

Beneficial effect of trimetazidine on folic acid-induced acute kidney injury in mice: Role of HIF-1α/HO-1.

Acute kidney injury (AKI) is a complex syndrome associated with a decrease in renal function and a significant impact on patient outcomes. Injection of folic acid (FA) in mice is used for studying the pathogenesis of AKI. This study investigated the impact of trimetazidine (a metabolic modulator-antianginal drug; TMZ), against FA-induced AKI. AKI was induced by FA (250 mg/kg, ip) in mice. Two doses of TMZ were administered orally for 10 days. Administration of TMZ at a high dose (20 mg/kg) exhibited significant decreases in the renal somatic index (RSI), serum levels of lactate dehydrogenase (LDH), creatinine (Cr), blood urea nitrogen (1), and proteins level in urine. Moreover, TMZ significantly increased creatinine clearance (CCr), serum albumin, urine creatinine, and urine urea levels. This improvement in markers of kidney damage was associated with marked renal antioxidant effects (↓NO and ↓lipid peroxidation, normalized reduced glutathione (GSH) level and superoxide dismutase (SOD) activity, and increased HIF-1α/HO-1 level). Furthermore, TMZ significantly decreased FA-induced expression of MPO and inflammatory cytokine IL-18, TNF-α, and NF-κB p65 subunit. Renal apoptosis, along with apoptotic markers, were enhanced by FA injection and suppressed by TMZ administration (↓Caspase-3, ↓Bax, and ↑Bcl2 expression). Finally, TMZ amended FA-induced histopathological changes in kidneys. By mitigating functional alteration, oxidative stress, and preventing the development of inflammatory and apoptosis signals, TMZ provides dose-dependent defense against FA-induced AKI mainly via stimulation of hypoxia-inducible factor-1 alpha (HIF-1α)/heme oxygenase-1 (HO-1) pathway.

Targeting HMGB1/TLR4/NF-κB signaling pathway by protocatechuic acid protects against l-arginine induced acute pancreatitis and multiple organs injury in rats.

Acute pancreatitis (AP) is a common pancreatic inflammation associated with substantial morbidity and mortality. AP may be mild or severe which can spread systemically causing multiple organs failure (MOF) and even death. In the current study, protocatechuic acid (PCA), a natural phenolic acid, was investigated for its possible protective potential against L-arginine induced AP and multiple organs injury (MOI) in rats. AP was induced by L-arginine (500 mg/100 g, ip). Two dose levels of PCA were tested (50 and 100 mg/kg, oral, 10 days before L-arginine injection). PCA successfully protected against L-arginine induced AP and MOI that was manifested by normalizing pancreatic, hepatic, pulmonary, and renal tissue architecture and restoring the normal values of pancreatic enzymes (amylase and lipase), serum total protein, liver enzymes (alanine transaminase (ALT) and aspartate transaminase (AST)) and kidney function biomarkers (blood urea nitrogen (BUN) and serum creatinine (Cr)) that were significantly elevated upon L-arginine administration. Additionally, PCA restored balanced oxidant/antioxidants status that was disrupted by L-arginine and normalized pancreatic levels of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) content. Moreover, PCA significantly decreased L-arginine induced elevation in pancreatic high motility group box protein 1 (HMGB1), toll like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor kappa B (NF-κB), tumor necrosis factor- α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) expression. PCA significantly ameliorated L-arginine-induced AP and MOI through its anti-inflammatory and antioxidant effects. HMGB1/TLR4/NF-κB was the major pathway involved in the observed protective potential.

Mycophenolate mofetil attenuates concanavalin A-induced acute liver injury through modulation of TLR4/NF-κB and Nrf2/HO-1 pathways.

BACKGROUND: Acute liver injury (ALI) is a serious health condition associated with rising morbidity and sudden progression. This study was designed to investigate the possible hepatocurative potential of two dose levels (30 and 60 mg/kg) of Mycophenolate mofetil (MMF), an immune-suppressant agent, against Concanavalin A (Con A)-induced ALI in mice. METHOD: A single dose of Con A (20 mg/kg, IV) was used to induce ALI in mice. MMF (30 mg/kg and 60 mg/kg) was administered orally for 4 days post Con A injection. RESULTS: MMF (30 mg/kg) failed to cause significant amelioration in Con A-induced ALI while MMF (60 mg/kg) significantly alleviated Con A-induced ALI. Administration of MMF (60 mg/kg) significantly decreased Con A-induced increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Additionally, MMF significantly restored the disrupted oxidant/antioxidants status induced by Con A. MMF caused marked increase in hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels. Moreover, MMF significantly reduced Con A-induced increase in the expression of hepatic toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ) and interleukin-1ß (Il-1ß). Also, MMF administration significantly decreased Con A-induced increase in the immune-expression of pro-apoptotic Bcl-2-associated X protein (Bax) and markedly increased Con A-induced decrease in the anti-apoptotic B-cell lymphoma 2 protein (Bcl2). CONCLUSION: The observed ameliorative effect of MMF against Con A-induce ALI may be contributed to its anti-inflammatory, anti-oxidant and anti-apoptotic potentials taking into consideration that TLR4/NF-κB and Nrf2/HO-1 are the main implicated pathways. Schematic diagram summarizing the possible mechanisms underlying the ameliorative potential of Mycophenolate Mofetil against Con A-induced acute liver injury. Bax Bcl-2-associated X protein, Bcl2 B-cell lymphoma 2, MMF Mycophenolate mofetil, Con A Concanavalin A, GSH reduced glutathione, HO-1 Heme oxygenase-1, IL-1ß Interleukin-1ß, IFN-γ Interferon-γ, MDA Malondialdehyde, NF-κB Nuclear Factor Kappa B, Nrf2 Nuclear factor erythroid 2-related factor 2, NO Nitric Oxide, SOD Superoxide Dismutase, TLR4 Toll-like receptor 4, TNF-α tumor necrosis factor-α.

Nilotinib ameliorates folic acid-induced acute kidney injury through modulation of TWEAK and HSP-70 pathways.

PURPOSE: Acute Kidney Injury (AKI) is a global health concern associated with high morbidity and mortality. Experimental folic acid-induced AKI is comparable to human AKI and is repeatedly reported to study the pathogenic pathway of human AKI and study the therapeutic efficacy of different agents against AKI. In the present study, nilotinib has been investigated for its possible ameliorative potential against folic acid-induced AKI. METHODS: AKI was induced by IP injection of single dose (250 mg/kg) folic acid in mice. Nilotinib (15 mg/kg and 25 mg/kg) was administered orally by different treatment regimens (pre, post, and pre + post). RESULTS: Folic acid injection induced marked AKI in mice. Nilotinib (25 mg/kg) successfully alleviated folic acid-induced AKI. Nilotinib significantly decreased folic acid-induced elevation in serum Cr, BUN, LDH and urine MTP, kidney MDA content and significantly increased folic acid-induced reduction in serum albumin, CrC, urine urea, kidney SOD activity and GSH content. Kidney TWEAK, IL-18, IL-1ß, TNF-α, NF-κB, Caspase 3 and Bax contents significantly decreased upon nilotinib administration while, kidney contents of Bcl2 and HSP-70 significantly increased. CONCLUSION: Anti-inflammatory, anti-apoptotic and anti-oxidant potentials are the main mechanisms by which nilotinib can ameliorate folic acid-induced AKI. Modulation of TWEAK and HSP 70 pathways are thought to be the main contributor to the observed ameliorative potential.

Crocin attenuates lung inflammation and pulmonary vascular dysfunction in a rat model of bleomycin-induced pulmonary fibrosis.

Amongst the various forms of lung injury; pulmonary fibrosis remains the most intricate form with limited therapeutic options to both the patient and the physicians. Bleomycin (BLM) is a chemotherapeutic agent used for the treatment of various carcinomas; however, its therapeutic value is significantly limited by its associated pulmonary fibrosis. The current study highlights the prominent antioxidant, anti-inflammatory and anti-fibrotic effect of crocin against BLM-induced pulmonary fibrosis. Intratracheal BLM instillation induced significant biochemical, structural, functional and vascular pulmonary injury. BLM instillation increased oxidant load with quenching of antioxidant defenses together with increase inflammatory and fibrotic cytokines expression. Crocin significantly attenuated BLM-induced lung injury and its effect was comparable to the standard anti-fibrotic; halofuginone. The observed anti-inflammatory and anti-fibrotic and antioxidant impacts are thought to be embroiled in the therapeutic impacts of crocin. Down-regulation of TLR4, IL-10 expression is the major pathway involved in the observed anti-inflammatory effects and finally, down-regulation of tissue expression of TNF-α and TGF-ß1 is the major pathways implicated in the observed anti-fibrotic activities and modulation of Nrf2 and HO-1 pathways is the main mechanism involved in the observed antioxidant effects.