Liver pyruvate kinase (PKL) has recently emerged as a new target for non-alcoholic fatty liver disease (NAFLD), and inhibitors of this enzyme could represent a new therapeutic option. However, this breakthrough is complicated by selectivity issues since pyruvate kinase exists in four different isoforms. In this work, we report that ellagic acid (EA) and its derivatives, present in numerous fruits and vegetables, can inhibit PKL potently and selectively. Several polyphenolic analogues of EA were synthesized and tested to identify the chemical features responsible for the desired activity. Molecular modelling studies suggested that this inhibition is related to the stabilization of the PKL inactive state. This unique inhibition mechanism could potentially herald the development of new therapeutics for NAFLD.

Background and Objectives: The plant Muscari Mill. is employed in both raw and cooked forms for the treatment of gastric diseases, as an expectorant, and for the treatment of warts and the enhancement of urine. A review of the scientific literature revealed no studies investigating the effect of Muscari neglectum (MN) water extract on gastric diseases. The objective of this study was to determine the effect of a water extract of the MN plant on indomethacin-induced gastric ulcer in rats, using a series of biochemical (SOD, CAT, GSH and MDA levels) and histopathological parameters. Methods: 60 male Sprague Dawley rats were utilized for the purposes of evaluating the acute toxicity and gastric ulcer models, with a total of 36 rats employed for these experiments (n = 6). The rats were divided into six groups: intact; indomethacin; famotidine; indomethacin and MN (100, 200, 400 mg/kg). Results: The Gastric tissue examinations at biochemical, macroscopic and pathological levels showed that MN extracts effectively prevented indo-methacin-induced gastric mucosal damage. The 400 mg/kg dose exhibited the most effective antiulcer effect, with a 69% protective efficacy. This dose caused an increase in the SOD, CAT and GSH levels and a decrease in the MDA levels compared to the IND group. Furthermore, an LC-MS/MS analysis was conducted on the water extract of MN, resulting in the identification of 14 phenolic compounds. Conclusions: Biochemical analyses and histopathological examinations demonstrated that the water extract of MN exhibited a beneficial protective effect against gastric ulceration due to its high antioxidant content.

Sepsis is a life-threatening systemic inflammatory condition marked by a dysregulated host response to infection. The intestinal microbiota plays a pivotal role in maintaining immune homeostasis and epithelial barrier integrity, whereas dysbiosis significantly contributes to the pathogenesis of sepsis. This study investigates the effects of the Pseudomonas aeruginosa-derived metabolite Pyocyanin and the probiotic Saccharomyces boulardii (S. boulardii) on microbial composition and the TLR4/MyD88/NF-κB/NLRP3 signaling axis in a cecal ligation and puncture (CLP)-induced rat model of sepsis. The experimental design assessed the synergistic or antagonistic effects of single and combined treatments using molecular, microbiome, and immunohistochemical parameters to evaluate histopathological damage and microbial ecological dynamics. Seven experimental groups were established following CLP. Intra-abdominal Pyocyanin (10 nmol/g) and oral probiotic (10⁶ CFU/kg) treatments were administered either individually or in combination. Focused Ion Beam - Scanning Electron Microscopy (FIB-SEM) analyses revealed that the amorphous structure of Pyocyanin interacted with the surface of S. boulardii. Western blot analysis showed a 2.3-fold increase in TLR4/NF-κB expression in the CLP group (p ≤ 0.05), which synergistically rose to 4.5-fold with Pyocyanin (p ≤ 0.001), whereas probiotic treatment decreased expression levels by 35%. According to 16 S rRNA sequencing, Pyocyanin reduced α-diversity by increasing Lactobacillaceae abundance to 32.66% (Shannon index: 3.598 vs. 4.433 in control), while S. boulardii enhanced β-diversity by elevating Coriobacteriaceae (5.85%) and Prevotellaceae (10.63%) levels (Tables 2, 3 and 4). PCoA confirmed 41.7% Bray-Curtis dissimilarity between groups at the species level (PERMANOVA R²=0.38, p = 0.002). Histopathologically, severe hepatocyte necrosis (73.2 ± 6.1%, p = 0.0022) and a 4.2-fold increase in hepatic TGF-β expression were observed in the CLP group, whereas epithelial barrier damage was significantly attenuated in the probiotic groups. Immunofluorescence analysis revealed that combined treatment reduced Caspase-8 and TLR4 expression by 28% compared to Pyocyanin alone (p ≤ 0.05). In conclusion, S. boulardii supported microbiota homeostasis by suppressing TLR4/NF-κB signaling, whereas Pyocyanin exacerbated the inflammatory response via NLRP3 activation. These findings provide molecular evidence supporting probiotic-assisted immunomodulatory strategies in sepsis therapy.

Purpose: To investigate the effect of intraperitoneal treatment with low- and high-dose methotrexate (MTX) on wound healing in rats.

Aims: We examined the protective effect of the natural product osajin against sepsis-induced brain damage by targeting the 8-hydroxydeoxyguanosine (8-OHdG)/Bcl-2-associated×protein (Bax)/caspase-3 pathway in the brain tissue of septic rats. Methods: Osajin was isolated from Maclura pomifera fruit, the structure was confirmed, and a rat model of brain damage was established by the cecal ligation and puncture (CLP) method. Osajin was administered to the animals with sepsis-associated brain damage at 150 and 300 mg/kg. Following euthanasia, histopathological examination, detection of 8-OHdG by immunohistochemistry, and the estimation of Bax and caspase-3 expression using an immunofluorescent technique in the brain tissue were performed. Results: Histopathological examination revealed the presence of severe inflammation, marked degeneration, and necrosis in the brains of rats with sepsis. The results of immunohistochemical and immunofluorescent assays revealed that the CLP technique induced marked 8-OHdG, Bax, and caspase-3 expression in the brain tissues of septic rats compared with those in healthy rats. Osajin administration at a dose of 150 mg/kg (p