When resveratrol was given with half the dose of fenofibrate it improved NASH-related fructose-induced disturbances in gene expression similar to a full dose of fenofibrate.

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Disruption of Th17/Tregs homeostasis plays a crucial role in governing the immune response during myocardial fibrosis and its progression to heart failure. The present study aimed to assess for the first time the possible protection afforded by rupatadine against isoproterenol-induced heart failure in rats. It also explored the role of PI3k/Akt as a possible mechanistic pathway, through which rupatadine could modulate Th17/Tregs balance to display its effect. Isoproterenol (85 and 170 mg/kg/day) was injected subcutaneously for 2 successive days, respectively and rupatadine (4 mg/kg/day) was then given orally for 14 days with or without wortmannin (PI3K/Akt inhibitor). Rupatadine succeeded to completely ameliorate isoproterenol-induced cardiac dysfunction as demonstrated by improvements of electrocardiographic and echocardiographic measurements. Moreover, rupatadine prevented the marked elevation of PAF and oxidative stress in addition to Th17 promoting cytokines (IL-6, IL-23, and TGF-β). Accordingly, rupatadine prevented Th17 stimulation or expansion as indicated by increased Foxp3/RORγt ratio and decreased production of its pro-inflammatory cytokine (IL-17). Rupatadine treatment mitigated isoproterenol-induced activation of STAT-3 signaling and the imbalance in p-Akt/total Akt ratio affording marked decrease in atrogin-1 and apoptotic biomarkers. Finally, this therapy was effective in averting cardiac troponin loss and reverting the histological alterations as assessed by myocardial fibrosis and hypertrophy grading. Contrariwise, co-administration of wortmannin mostly attenuated the protective effects of rupatadine affording more or less similar results to that of isoproterenol-untreated rats. In conclusion, rupatadine could be an effective therapy against the development of isoproterenol-induced heart failure where PI3K/Akt pathway seems to play a crucial role in its protective effect.

Background: There is a causative relation between the increased hepatic steatohepatitis prevalence and sweeteners intake, fructose in particular. Despite an increasing understanding of the mechanisms of nonalcoholic steatohepatitis (NASH) pathogenesis, there are no drugs approved for it. Objectives: Evaluate the effect of bee venom (BV) treatment on the fructose-induced NASH in rats and demonstrate its possible molecular mechanisms. Methods: NASH was induced in rats by 10% fructose in drinking water for 8 weeks. BV was administered (0.1 mg/kg, i.p.) 3 times per week during the last 2 weeks of the experiment. Sera were used for the determination of lipids, cholesterol, glucose, insulin, and liver enzymes. Hepatic gene expressions of farnesoid X receptor (FXR)α and the liver X receptor (LXR) were determined. Hepatic sterol regulatory element-binding protein (SREBP)1/2, oxidative stress, and inflammation parameters were measured. Liver parts were used for histopathological examination. Small intestine was removed for the determination of tight junction proteins. Results: Fructose caused overt histological damage in the liver, and this was associated with parallel changes in all parameters measured. BV effectively prevented these changes, presumably through amelioration of hepatic SREBP1/2, LXR, and FXRα expression as well as intestinal tight junction proteins. Conclusion: These findings support the therapeutic usefulness of BV, a remedy with a favorable safety profile, in the prevention of fructose-induced NASH.

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Tamoxifen (TAM) is a life-saving and cost-effective drug widely used in the prevention and treatment of breast cancer. However, the adverse effects of tamoxifen can lead to non-adherence and poor patient outcomes. Therefore, exploring novel strategies to improve TAM safety profile is crucial. Given the key role that vitamin D (VD) plays in modulating lipid metabolism and inflammation, in addition to its benefits in reducing risk and progression of breast cancer, we evaluated the protective potential of VD against TAM-induced hepatotoxicity focusing on lipid metabolism and microRNAs (miRNAs) regulation. Female rats were pretreated with VD as cholecalciferol (500 IU/kg/day, po) for 4 weeks before receiving TAM (40 mg/kg/day, po) concurrently with VD during the fifth and sixth weeks. Liver histology, lipid profile and expression of genes, proteins, and miRNAs involved in lipid metabolism and inflammation were examined. TAM-induced steatohepatitis was evidenced by elevated liver triglycerides and cholesterol contents, increased serum miRNA-122 level, and ALT activity, in parallel with accumulation of lipid droplets, focal necrosis, and inflammatory cells infiltration in hepatocytes. Prophylactic use of VD mitigated TAM-induced steatohepatitis by modulating key transcription factors in the liver: PPAR-α, Srebf1, and NF-κB and their downstream genes/proteins Fas, CPT-1A, and TNF-α resulting in reduced hepatic lipids and suppressed pro-inflammatory signaling. Notably, VD pretreatment mitigated TAM-induced alterations in the expression of serum miRNA-122, hepatic miRNA-21, and miRNA-33. The combination therapy of VD and TAM has complementary benefits in terms of safety and not only efficacy and should be further investigated clinically.