Apilarnil exerts neuroprotective effects and alleviates motor dysfunction by rebalancing M1/M2 microglia polarization, regulating miR-155 and miR-124 expression in a rotenone-induced Parkinson's disease rat model.

Microglial activation contributes to the neuropathology of Parkinson's disease (PD). Inhibiting M1 while simultaneously boosting M2 microglia activation may therefore be a potential treatment for PD. Apilarnil (API) is a bee product produced from drone larvae. Recent research has demonstrated the protective effects of API on multiple body systems. Nevertheless, its impact on PD or the microglial M1/M2 pathway has not yet been investigated. Thus, we intended to evaluate the dose-dependent effects of API in rotenone (ROT)-induced PD rat model and explore the role of M1/M2 in mediating its effect. Seventy-two Wistar rats were equally grouped as; control, API, ROT, and groups in which API (200, 400, and 800 mg/kg, p.o.) was given simultaneously with ROT (2 mg/kg, s.c.) for 28 days. The high dose of API (800 mg/kg) showed enhanced motor function, higher expression of tyrosine hydroxylase and dopamine levels, less dopamine turnover and α-synuclein expression, and a better histopathological picture when compared to the ROT group and the lower two doses. API's high dose exerted its neuroprotective effects through abridging the M1 microglial activity, illustrated in the reduced expression of miR-155, Iba-1, CD36, CXCL10, and other pro-inflammatory markers' levels. Inversely, API high dose enhanced M2 microglial activity, witnessed in the elevated expression of miR-124, CD206, Ym1, Fizz1, arginase-1, and other anti-inflammatory indices, in comparison to the diseased group. To conclude, our study revealed a novel neuroprotective impact for API against experimentally induced PD, where the high dose showed the highest protection via rebalancing M1/M2 polarization.

Regulation of NOX/p38 MAPK/PPARα pathways and miR-155 expression by boswellic acids reduces hepatic injury in experimentally-induced alcoholic liver disease mouse model: novel mechanistic insight.

Alcoholic liver disease (ALD) refers to hepatic ailments induced by excessive alcohol intake. The pathogenesis of ALD comprises a complex interplay between various mechanistic pathways, among which inflammation and oxidative stress are key players. Boswellic acids (BAs), found in Boswellia serrata, have shown hepatoprotective effects owing to their antioxidant and anti-inflammatory activities, nevertheless, their therapeutic potential against ALD has not been previously investigated. Hence, this study was performed to depict the possible protective effect of BAs and detect their underlying mechanism of action in an experimentally-induced ALD mouse model. Male BALB/c mice were equally categorized into six groups: control, BAs-treated, ALD, and ALD that received BAs at three-dose levels (125, 250, and 500 mg/kg) by oral gavage for 14 days. Results showed that the high dose of BAs had the most protective impact against ALD according to histopathology examination, blood alcohol concentration (BAC), and liver function enzymes. Mechanistic investigations revealed that BAs (500 mg/kg) caused a significant decrease in cytochrome P450 2E1(CYP2E1), nicotine adenine dinucleotide phosphate oxidase (NOX) 1/2/4, p38 mitogen-activated protein kinase (MAPK), and sterol regulatory element-binding protein-1c (SREBP-1c) levels, and the expression of miR-155, yet increased peroxisome proliferator-activated receptor alpha (PPARα) levels. This led to an improvement in lipid profile and reduced hepatic inflammation, oxidative stress, and apoptosis indices. In summary, our study concludes that BAs can protect against ethanol-induced hepatic injury, via modulating NOX/p38 MAPK/PPARα pathways and miR-155 expression.

Gastroprotective effect of dapagliflozin in ethanol-induced gastric lesions in rats: Crosstalk between HMGB1/RAGE/PTX3 and TLR4/MyD88/VEGF/PDGF signaling pathways.

Alcohol abuse may lead to the development of gastric mucosal lesions. Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 inhibitor, is clinically used to treat type 2 diabetes mellitus. However, studies showed protective effect of DAPA under various experimental conditions by alleviating oxidative stress and inflammation. The effect of DAPA on experimental gastric ulcer has not been studied yet. Therefore, we attempted to investigate DAPA's protective effect against ethanol (EtOH)-induced gastric lesions. Fifty-six (8-week-old) male Wistar rats were divided into seven groups. DAPA (1, 5, and 10 mg/kg/day; p.o.) was given for seven days, plus a single dose of absolute EtOH (5 ml/kg) on day 8. According to hematoxylin and eosin, and Alcian blue staining of gastric tissue sections, titratable acidity, and macroscopic assessments, DAPA high dose (10 mg/kg) was the most protective, with lesser ulcerations, and higher mucin, relative to the lower two doses and the standard treatment omeprazole (OME). In rats pre-treated with DAPA high dose, colorimetric and ELISA analyses revealed significantly decreased oxidative stress, pro-inflammatory, and apoptosis indices and increased levels of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Western blot analysis revealed reduced pentraxin-3 (PTX3), high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), and myeloid differentiation factor 88 (MyD88) expression. These results were comparable in DAPA (10 mg/kg) and OME pre-treated groups. Overall, DAPA exerted a dose-dependent protective effect against EtOH-induced gastric injury. Gastroprotective effects of DAPA (10 mg/kg) may be associated with influencing HMGB1/RAGE/PTX3 and TLR4/MyD88/VEGF/PDGF pathways.

Anti-fibrotic impact of Carvedilol in a CCl-4 model of liver fibrosis via serum microRNA-200a/SMAD7 enhancement to bridle TGF-ß1/EMT track.

Circulating microRNAs (miRNAs) play a role in modulating the prevalence of fibrosis and have been a target of the cardiac anti-fibrotic effect of Carvedilol. However, the impact of miRNAs on the hepatoprotective effect of this non-selective ß-blocker has not been yet elucidated. Hence, the current goal is to evaluate the potential role of circulating miR-200a in the hepatic anti-fibrotic pathway of Carvedilol. Male Wistar rats were randomized into normal, CCl4 (2 ml/kg, i.p, twice weekly for 8 weeks), and CCl4 + Carvedilol (10 mg/kg, p.o, daily). Carvedilol over-expressed the circulating miR-200a to modulate epithelial mesenchymal transition (EMT) markers (vimentin, E-Cadherin). In turn, Carvedilol increased SMAD7 gene expression and protein content to attenuate the pro-fibrogenic marker transforming growth factor ß1 (TGF-ß1) and the inflammatory markers (p-38 MAPK and p-S536-NF-κB p65). The anti-fibrotic potential was reflected on the decreased expression of the mesenchymal product and EMT marker α-SMA, besides the improved histopathological examination, and the fibrosis scores/collagen quantification to enhance liver functions (AST, ALT, ALP, and AST/platelet ratio index; APRI). In conclusion, circulating miR-200a/SMAD7/TGF-ß1/EMT/MAPK axis is crucial in the hepatic anti-fibrotic mechanism of Carvedilol.