Berberine-loaded nanostructured lipid carriers mitigate warm hepatic ischemia/reperfusion-induced lesion through modulation of HMGB1/TLR4/NF-κB signaling and autophagy.

OBJECTIVE: Berberine (BBR) is a known alkaloid that has verified its protective effects against ischemia/reperfusion (I/RN) lesion in multiple organs but its poor oral bioavailability limited its use. Despite the previous works, its possible impact on the warm hepatic I/RN-induced lesion is not clear. Accordingly, a nanostructured lipid carrier of BBR (NLC BBR) was developed for enhancing its efficiency and to inspect its protective mechanistic against warm hepatic I/RN. METHODS: NLC BBR formula was evaluated pharmaceutically. Wistar rats were orally pre-treated with either BBR or NLC BBR (100 mg/kg) for 2 weeks followed by hepatic I/RN (30 min/24 h). Biochemical, ELISA, qPCR, western blot, histopathological, and immunohistochemical studies were performed. KEY FINDINGS: Optimized NLC BBR was prepared with a particle size of 130 ± 8.3 nm. NLC BBR divulged its aptitude to safeguard the hepatic tissues partly due to anti-inflammatory capacity through downsizing the HMGB1/TLR4/NF-κB trajectory with concomitant rebating of TNF-α, iNOS, COX-2, and MPO content. Furthermore, NLC BBR antiapoptotic trait was confirmed by boosting the prosurvival protein (Bcl-2) and cutting down the pro-apoptotic marker (Bax). Moreover, its antioxidant nature was confirmed by TAC uplifting besides MDA subsiding. On the other hand, NLC BBR action embroiled autophagy flux spiking merit exemplified in Beclin-1 and LC3-II enhancement. Finally, NLC BBR administration ascertained its hepatocyte guarding action by recovering the histopathological ailment and diminishing serum transaminases. CONCLUSION: NLC BBR purveyed reasonable shielding mechanisms and subsided incidents contemporaneous to warm hepatic I/RN lesion in part, by moderating HMGB1/TLR4/NF-κB inflammatory signaling, autophagy, and apoptosis.

Dipeptedyl peptidase-4 (DPP-4) inhibitor downregulates HMGB1/TLR4/NF-κB signaling pathway in a diabetic rat model of non-alcoholic fatty liver disease.

CONTEXT: Inflammatory and immune pathways play a crucial role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD). Sitagliptin blocks the dipeptidyl peptidase-4 (DPP-4) enzyme, mechanisms that alter inflammatory pathways and the innate immune system, and by which Sitagliptin affects the pathogenesis of NAFLD weren't previously discussed. OBJECTIVE: This study aims to understand the interaction between Sitagliptin and innate immune response in order to meliorate NAFLD. METHODS: Thirty- two Wistar male albino rats were categorised into four groups. Rats have received a standard diet or a high-fat diet either with or without Sitagliptin. Serum HMGB1, protein and mRNA expressions of hepatic TLR4 and NF-κB, inflammatory cytokines, and histopathological changes were analysed. RESULTS: An ameliorative action of Sitagliptin in NAFLD was demonstrated via decreasing HMGB1-mediated TLR4/NF-κB signalling in order to suppress inflammation and reduce insulin resistance. CONCLUSION: Sitagliptin may in fact prove to be a beneficial therapeutic intervention in NAFLD.

Adipose mesenchymal stem cells combined with platelet-rich plasma accelerate diabetic wound healing by modulating the Notch pathway.

BACKGROUND: Diabetic foot ulceration is a serious chronic complication of diabetes mellitus characterized by high disability, mortality, and morbidity. Platelet-rich plasma (PRP) has been widely used for diabetic wound healing due to its high content of growth factors. However, its application is limited due to the rapid degradation of growth factors. The present study aimed to evaluate the efficacy of combined adipose-derived mesenchymal stem cells (ADSCs) and PRP therapy in promoting diabetic wound healing in relation to the Notch signaling pathway. METHODS: Albino rats were allocated into 6 groups [control (unwounded), sham (wounded but non-diabetic), diabetic, PRP-treated, ADSC-treated, and PRP+ADSCs-treated groups]. The effect of individual and combined therapy was evaluated by assessing wound closure rate, epidermal thickness, dermal collagen, and angiogenesis. Moreover, gene and protein expression of key elements of the Notch signaling pathway (Notch1, Delta-like canonical Notch ligand 4 (DLL4), Hairy Enhancer of Split-1 (Hes1), Hey1, Jagged-1), gene expression of angiogenic marker (vascular endothelial growth factor and stromal cell-derived factor 1) and epidermal stem cells (EPSCs) related gene (ß1 Integrin) were assessed. RESULTS: Our data showed better wound healing of PRP+ADSCs compared to their individual use after 7 and 14 days as the combined therapy caused reepithelialization and granulation tissue formation with a marked increase in area percentage of collagen, epidermal thickness, and angiogenesis. Moreover, Notch signaling was significantly downregulated, and EPSC proliferation and recruitment were enhanced compared to other treated groups and diabetic groups. CONCLUSIONS: These data demonstrated that PRP and ADSCs combined therapy significantly accelerated healing of diabetic wounds induced experimentally in rats via modulating the Notch pathway, promoting angiogenesis and EPSC proliferation.

Exendin-4, a glucagon-like peptide-1 receptor agonist downregulates hepatic receptor for advanced glycation end products in non-alcoholic steatohepatitis rat model.

CONTEXT: Exendin-4, a glucagon-like peptide-1 receptor agonist has been shown to have curative effects on hepatic steatosis in murine models. OBJECTIVE: The present study aimed to elucidate the effect of Exendin-4 on hepatic receptor for advanced glycation end products (RAGE) mRNA expression in non-alcoholic steatohepatitis (NASH) rat model induced by high-fat diet. METHODS: NASH was induced by high-fat diet intake, and Exendin-4 was given in two different doses. After 12 weeks, liver enzyme levels, hepatic triglycerides, antioxidant enzymes and malondialdehyde (MDA) levels, and mRNA RAGE was detected using RT-PCR. RESULTS: Exendin-4 in high dose reduced significantly liver enzymes activity, hepatic triglycerides, MDA levels and hepatic mRNA RAGE expression levels with significantly higher antioxidant enzymes activity. CONCLUSIONS: Our results give further insights into the mechanisms underlying the curative role of Exendin-4 in NASH, suggesting that interference with RAGE may be a useful therapeutic approach to NASH.

Gastroprotective effect of ghrelin against indomethacin-induced gastric injury in rats: possible role of heme oxygenase-1 pathway.

Ghrelin has been shown to ameliorate gastric injury by several mechanisms in experimental animal models. The present study aimed to investigate the effect of pretreatment with ghrelin on indomethacin-induced gastric injury in rats and the role of heme oxygenase-1(HO-1) pathway as a novel mechanism underlying the gastroprotective effect of ghrelin. In all groups studied, ulcer score (U.S), ulcer index (U.I) and preventive index (P.I) were evaluated and the gastric inflammatory biomarkers including levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and myeloperoxidase (MPO) activity as well as prostaglandin E2 (PGE2), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), HO-1 and bilirubin as an indicator of heme oxygenase activity were measured. Indomethacin induced significant elevation in U.S and U.I as well as the inflammatory and the oxidative markers and reduced the PGE2 in addition to HO-1 level and activity. Pretreatment with ghrelin reversed these results. In order to elucidate the possible role of HO-1 in mediating the protective effects of ghrelin, tin protoporphyrin (SnPP) HO-1 blocker was administrated; it significantly attenuated the gastroprotective effect of ghrelin. In conclusion HO-1 activity significantly contributes toward ghrelin-mediated gastroprotection.