Octreotide and melatonin alleviate inflammasome-induced pyroptosis through inhibition of TLR4-NF-κB-NLRP3 pathway in hepatic ischemia/reperfusion injury.

BACKGROUND AND AIM: The Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB)/NLRP3 inflammasome signaling pathway is essential in the pathogenesis of hepatic ischemia/ reperfusion (HIR) injury. Pyroptosis is a proinflammatory programmed cell death that is related to several diseases. Thus, the purpose of this study was to examine whether pretreatment with octreotide (somatostatin analogue, OCT) at different doses or OCT at 75µg/kg combined with melatonin (N-acetyl-5-methoxytryptamine, MLT) can alleviate HIR injury via targeting NLRP3 inflammasome-induced pyroptosis in a TLR4/MyD88/NF-κB dependent manner. METHODS: Rats were randomized into sham, HIR, OCT (50, 75, and 100 µg/kg), MLT, and MLT + OCT75 groups. Ischemia was induced via occlusion of the portal triad for 30 min followed by 24 h reperfusion. RESULTS: OCT pretreatment at doses (50 or 75 µg/kg), MLT alone, and MLT + OCT75 significantly ameliorated the biochemical with histopathological changes, oxidative stress, inflammation, apoptosis, then augmented anti-oxidant and anti-apoptotic markers through downregulation of HMGB1, TLR4, MyD88, TRAF-6, p-IκBα (S32), p-NF-κBp65 (S536), NLRP3, ASC, caspase-1(p20), and GSDMD-N expressions compared with HIR group. CONCLUSION: OCT at doses (50 or 75 µg/kg) showed for the first time a hepatoprotective effect against HIR injury via inhibiting TLR4-NLRP3-mediated pyroptosis in rats. As well, OCT75 was more effective than OCT50 or MLT alone, and its effect was not enhanced after the addition of MLT, through downregulation of TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway.

Metformin alleviates inflammation in oxazolone induced ulcerative colitis in rats: plausible role of sphingosine kinase 1/sphingosine 1 phosphate signaling pathway.

OBJECTIVES: Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is associated with high sphingosine kinase 1(SPHK1) expression in the colon, however its role in pathogenesis of UC is not clearly understood so, the aim of the present study was to clarify the role of SPHK1 and investigate whether the anti-inflammatory effects of metformin in UC is mediated by Sphingosine kinase 1/sphingosine 1 phosphate (S1P) signaling pathway. MATERIAL AND METHODS: Colitis was induced in adult male wistar rats by intra rectal administration of oxazolone in the fifth and seventh days from initial presensitization. Oxazolone treated rats were divided into untreated oxazolone group, metformin and mesalazine treated groups both in a dose of 100 mg/kg/day orally for 21 days. Along with these groups normal control and saline groups were used .Colitis was assessed by colon length, disease activity index (DAI) and histological examination of colontissue. Plasma samples were used to measure S1P.SPHK1 activity, signal transducer and activator of transcription -3(STAT-3), interleukin-6 (IL-6), nitric oxide (NO), myeloperoxidase activity (MPO), reduced glutathione (GSH) and tissue expression of intracellular cell adhesion molecule -1(ICAM-1) and caspase-3 genes were measured in tissue. RESULTS: Metformin successfully attenuated oxazolone colitis by increasing colon length, decreasing DAI and improved colon histologic picture. Metformin also induced a significant decrease in Plasma SIP, SPHK1 activity, inflammatory, oxidative stress markers, ICAM-1 and Caspase-3 genes expression compared to oxazolone group. CONCLUSION: It is revealed that metformin alleviated inflammation and underlying mechanism may result from inhibition of SPHK1/S1P signaling pathway.

Evaluation of the effect of direct-acting antiviral agents on melatonin level and lipid peroxidation in chronic hepatitis C patients.

Background: Oxidative stress and its end products, such as malondialdehyde (MDA) play a leading role in the pathogenesis of hepatitis C. Melatonin is a hormone that helps regulate circadian rhythms, which likely play a role in infectious diseases in terms of susceptibility, clinical expression, and outcome. Objective: The present study was conducted to assess serum malondialdehyde and melatonin levels in patients with chronic hepatitis C infection before and after the intake of direct-acting antivirals. Method: Forty hepatitis C patients were the subjects of this study. While ten healthy volunteers who matched in age and socioeconomic status served as the control subjects. Malondialdehyde and melatonin were assayed in the serum of the three groups, and the results were statistically analyzed. Results: Hepatitis C patients had significantly higher malondialdehyde (p < 0.001) but significantly lower melatonin (p < 0.001) as compared to the healthy controls. After 12 weeks of treatment with direct-acting antivirals, the malondialdehyde level decreased significantly (p < 0.001) and the melatonin level increased significantly (p < 0.001). A significant negative correlation between malondialdehyde and melatonin was observed. Conclusion: The present findings suggest that treatment of hepatitis C patients with Direct-acting antivirals improves liver function parameters and antioxidant profiles.

Hepatoprotective effects of carvedilol and crocin against leflunomide-induced liver injury.

Leflunomide-induced liver injury has been an important problem since its approval. Although, severe cases of leflunomide-induced liver injury leading to hospitalization are rare, the risk is higher with concurrent liver disease or use of other hepatotoxic drugs. The current study was conducted to investigate the potential protective effects of carvedilol and crocin alone and in combination against leflunomide-induced hepatic injury and to clarify the possible mechanism(s) through which carvedilol and crocin may elicit their effects. Fifty male albino mice were allocated into five groups: normal control group, leflunomide group, carvedilol group, crocin group, and combination group. These groups were given vehicle, leflunomide, leflunomide plus carvedilol, leflunomide plus crocin, and leflunomide plus combination of carvedilol and crocin, respectively. The study was conducted for 8 weeks, and different parameters were assessed. The results demonstrated that leflunomide significantly increased the serum levels of AST, ALT, ALP, hepatic MDA, nitrite, mTOR gene, PI3K gene, TGF-ß, and the pathological changes alongside with the significant decrease of serum albumin, total protein, hepatic catalase, and GSH. While the coadministration of carvedilol, crocin and their combination with leflunomide significantly decreased the serum levels of AST, ALT, ALP, hepatic MDA, mTOR gene, PI3K gene, TGF-ß, and the pathological changes alongside with the significant elevation of serum albumin, total protein, hepatic catalase, and GSH. This study is suggesting several solutions for Leflunomide-induced hepatotoxicity demonstrated by the protective effect of the antihypertensive drug carvedilol, the natural product crocin, and their combination which was demonstrated to be superior to each drug alone.

Nephroprotective effects of febuxostat and/or mirtazapine against gentamicin-induced nephrotoxicity through modulation of ERK 1/2, NF-κB and MCP1.

OBJECTIVES: This study was conducted to evaluate the potential nephroprotective effects of febuxostat, mirtazapine, and their combination against gentamicin-induced nephrotoxicity. METHODS: Induction of nephrotoxicity was achieved via gentamicin injection (100 mg/kg, I.P., for 7 days). Two different doses of mirtazapine (15-30 mg/kg), febuxostat (5-10 mg/kg), and their combination were administered daily for 14 days prior to gentamicin injection and then concomitantly with gentamicin for additional 7 days. Nephrotoxicity was evaluated histopathologically and biochemically. Renal caspase-3, extracellular signal-regulated protein kinase 1/2 (ERK1/2), nuclear factor-kappa-ß (NF-κß), and monocyte chemoattractant protein (MCP-1) were assayed. RESULTS: Febuxostat and mirtazapine significantly (p < 0.05) alleviated biochemical and histopathological alterations that were induced by gentamicin and, for the first time, significantly decreased the renal levels of ERK1/2 and MCP-1. Conclusion: Febuxostat and mirtazapine were found to have a synergistic impact in reducing gentamicin-induced nephrotoxicity. EXPERT OPINION: The utility of nonpurine xanthine oxidase inhibitor, such as febuxostat and mirtazapine are offering a new potential opportunity for the future nephroprotective effects therapy: Febuxostat and mirtazapine are found to have a synergistic impact in reducing gentamicin-induced nephrotoxicity.

Targeting IL-10, ZO-1 gene expression and IL-6/STAT-3 trans-signaling by a combination of atorvastatin and mesalazine to enhance anti-inflammatory effects and attenuates progression of oxazolone-induced colitis.

Ulcerative colitis (UC) is a chronic inflammatory disease characterized by diffused inflammation of the colon and rectum mucosa. The pathogenesis of UC is multifactorial, and the exact underlying mechanisms remain poorly understood. This study aims to investigate the effect of mesalazine and atorvastatin combination in enhancing anti-inflammatory effects and attenuates progression of oxazolone colitis in rats. In the present study, male albino rats (N = 60) were divided into six groups (10 rats each), the first two groups served as normal control and a control saline group. Colitis was induced by intra-rectal administration of oxazolone in the 5th and 7th days after pre-sensitization. Then, rats were divided into untreated group, groups treated with mesalazine or atorvastatin or their combination. Colitis was assessed by colon length, body weight, and incidence of diarrhea, rectal bleeding, and histopathology of colon tissue. Colon tissues were used for measuring interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), IL-13, signal transducer and activator of transcription-3 (STAT-3), myeloperoxidase activity (MPO), reduced glutathione(GSH), and tissue expression of IL-10, tight junction protein zonula occludens (ZO-1), and caspase-3 genes. The combination therapy significantly attenuated progression of UC by decreasing incidence of diarrhea, rectal bleeding, weight loss, IL-13, IL-6, TNF-α, STAT-3, caspase-3, and MPO activity and significantly increased IL-10, ZO-1, colon length, and GSH content, and these effects were more superior to single drugs. These findings showed that combination therapy was able to ameliorate progression of UC and enhance anti-inflammatory effects possibly by restoring IL-10 and ZO-1 levels and limiting IL-6/STAT-3 trans-signaling.

Gastrointestinal and hepatic diseases during the COVID-19 pandemic: Manifestations, mechanism and management.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is considered the causative pathogen of coronavirus disease 2019 (COVID-19) and has become an international danger to human health. Although respiratory transmission and symptoms are still the essential manifestations of COVID-19, the digestive system could be an unconventional or supplementary route for COVID-19 to be transmitted and manifested, most likely due to the presence of angiotensin-converting enzyme 2 (ACE2) in the gastrointestinal tract. In addition, SARS-CoV-2 can trigger hepatic injury via direct binding to the ACE2 receptor in cholangiocytes, antibody-dependent enhancement of infection, systemic inflammatory response syndrome, inflammatory cytokine storms, ischemia/reperfusion injury, and adverse events of treatment drugs. Gastrointestinal symptoms, including anorexia, nausea, vomiting, and diarrhea, which are unusual in patients with COVID-19, and some digestive signs may occur without other respiratory symptoms. Furthermore, SARS-CoV-2 can be found in infected patients' stool, demonstrating the likelihood of transmission through the fecal-oral route. In addition, liver function should be monitored during COVID-19, particularly in more severe cases. This review summarizes the evidence for extra-pulmonary manifestations, mechanisms, and management of COVID-19, particularly those related to the gastrointestinal tract and liver.

Targeting autophagy to modulate hepatic ischemia/reperfusion injury: A comparative study between octreotide and melatonin as autophagy modulators through AMPK/PI3K/AKT/mTOR/ULK1 and Keap1/Nrf2 signaling pathways in rats.

Hepatic ischemia-reperfusion (HIR) injury is a common pathophysiological process in many clinical settings. This study was designed to compare the protective role of octreotide (somatostatin analogue, OCT) and melatonin (N-acetyl-5-methoxytryptamine, MLT) through the modulation of autophagy against HIR injury in rats. Male albino rats were divided into sham, HIR, OCT at three doses (50, 75, and 100 µg/kg), MLT, MLT + OCT75, compound C (AMPK inhibitor, CC), and CC + OCT75 groups. Ischemia was induced for 30 min followed by 24 h reperfusion. Biochemical, histopathological, immunohistochemical, lipid peroxidation, ELISA, qPCR, and western blot techniques were performed in our study. Liver autophagy was restored by OCT at doses (50 or 75 µg/kg) as indicated by elevating the expressions of Beclin-1, ATG7, and LC3 accompanied by the reduction of p62 expression through induction of AMPK/S317-ULK1 and inhibition of PI3K/AKT/mTOR/S757-ULK1 signaling pathways. As well, OCT maintained the integrity of the Keap1-Nrf2 system for the normal hepatic functions via controlling the Keap1 turnover through autophagy in a p62-dependent manner, resulting in upholding a series of anti-oxidant and anti-inflammatory cascades. These effects were abolished by compound C. On the other hand, MLT showed a decrease in the autophagy markers via inhibiting AMPK/pS317-ULK1 and activating PI3K/AKT/mTOR/pS757-ULK1 pathways. Autophagy inhibition with MLT markedly reversed the hepatoprotective effects of OCT75 after HIR injury. Finally, our results proved for the first time that OCT75 was more effective than MLT as it was sufficient to induce protective autophagy in our HIR model, which led to the induction of Nrf2-dependent AMPK/autophagy pathways.

Therapeutic effect of inhaled budesonide in transient tachypnea of newborn: A placebo-controlled study.

Transient tachypnea of the newborn (TTN) is a chest disease found in neonates. It varies from mild to severe and is accompanied by neonatal morbidity and respiratory complications. This is a prospective placebo-controlled study, identification number is TCTR20200513005, which was done in the neonatal unit of Tanta University Hospital between June 2016 and March 2018. This study comprised 100 neonates with TTN, which were divided into two groups. The first group (inhaled steroid group) consisted of 50 neonates with TTN who were exposed to inhalation of corticosteroids (budesonide 2 ml, 0.25 mg/ml suspension for nebulizer, AstraZeneca AB, Södertälje, Sweden), the first dose was administered within 6 h of birth and the second dose was given 12 h later. The second group (placebo group) consisted of 50 neonates with TTN who were exposed to placebo inhalation (2 ml of distilled sterile water). There was significant difference between both groups regarding Down score (P = 0.001), TTN clinical score (P = 0.001) and Saturation of Peripheral Oxygen (SpO2) measured by pulse oximeter (P = 0.008), while there was nonsignificant difference between both groups regarding PH (P = 0.573), and this showed that clinically the inhaled steroid group is significantly better than the placebo group. Hence, this study concludes that since administration of inhaled budesonide showed improvement in TTN cases, it could be a recommended line of treatment for neonatal TTN.

Role of allopurinol and febuxostat in the amelioration of dextran-induced colitis in rats.

Ulcerative colitis is a chronic auto-inflammatory disorder confined to the colorectal region. It is challenging to find an absolute treatment and current therapy aims to ameliorate symptoms, decrease relapses and prevent prognosis of colorectal cancer. In the present study, we investigated the possible action of xanthine oxidase inhibitors in murine colitis model by measuring different indicative parameters and comparing the results to those of the reference sulfasalazine. Also, we compared the effects of combining sulfasalazine and allopurinol to each drug alone. Dextran Sodium Sulfate (DSS) is used in this study to induce ulcerative colitis in male wistar rats as it is known to be the closest model that mimics human ulcerative colitis. Allopurinol was given prior to colitis induction by four days and febuxostat for six days before induction with DSS (5% w/v) and continue to give them concomitantly during the induction.Il-1ß, malondialdehyde, reduced glutathione (GSH), xanthine oxidase, and superoxide dismutase were measured in colonic tissue. We also measured concentrations of IL-1ß, Il-6 and uric acid in serum. Allopurinol dose-dependently ameliorated biochemical injuries. Febuxostat has shown better results than allopurinol and sulfasalazine, and this is the first study to demonstrate this.

Zinc oxide nanoparticles and a standard antidiabetic drug restore the function and structure of beta cells in Type-2 diabetes.

The aim of this study was to use Zinc oxide nanoparticles and a standard antidiabetic drug to restore the function and structure of beta cells in a rat model of Type-2 diabetes and compare the effects of a DPP-IV inhibitor with or without zinc oxide nanoparticles (ZnONPs) using a model of type 2 diabetes (rats fed a high fat diet that was treated with a low dose of streptozotocin). Ninety male Wistar rats were randomly divided into three groups 10days after the induction of diabetes: group I: non-diabetic animals that received only the chow diet plus 2ml of 0.5% carboxymethyl cellulose sodium; group II: diabetic animals that received only the chow diet plus 2ml of 0.5% carboxymethyl cellulose sodium; group III: diabetic animals were subdivided into 7 equal subgroups; one subgroup was administered Vildagliptin (10mg/kg/day p.o.); three subgroups were administered ZnONPs at doses of 1, 3 and 10mg/kg/day p.o.; and three subgroups were administered ZnONPs in different doses plus Vildagliptin for seven weeks. The DPP-IV inhibitor (Vildagliptin) and ZnONPs alone or in combination significantly decreased microRNA-103 and microRNA-143 expression compared to the diabetic group, indicating antidiabetic effects. ZnONPs improved many of the indices of diabetic dysfunction (glucose tolerance, weight loss, insulin levels, fructosamine levels, pancreatic SOD activity, and pancreas histology), but the addition of the DPP-IV further improved these indices. ZnONPs alone resulted in significant antidiabetic effects, whereas the addition of Vildagliptin resulted in a synergistic effect on the therapy of diabetes.