Ursolic acid alleviates cancer cachexia by inhibiting STAT3 signaling pathways in C2C12 myotube and CT26 tumor-bearing mouse model.

Cancer cachexia, a multi-organ disorder resulting from tumor and immune system interactions, prominently features muscle wasting and affects the survival of patients with cancer. Ursolic acid (UA) is known for its antioxidant, anti-inflammatory, and anticancer properties. However, its impact on cancer cachexia remains unexplored. This study aimed to assess the efficacy of UA in addressing muscle atrophy and organ dysfunction in cancer cachexia and reveal the mechanisms involved. UA dose-dependently ameliorated C2C12 myotube atrophy. Mechanistically, it inhibited the expression of muscle-specific RING finger containing protein 1 (MURF1) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3), and upregulated the mRNA or protein levels of myogenic differentiation antigen and myogenin in cultured C2C12 myotubes treated with conditioned medium. In vivo, UA protected CT26 tumor-bearing mice against loss of body weight, as well as increased skeletal muscle and epididymal fat without affecting tumor growth. Additionally, UA increased food intake in CT26 tumor-bearing mice. The mRNA expression of tumor necrosis-α and interleukin 6 was significantly downregulated in the intestine, gastrocnemius, and heart tissues following 38 d UA administration. UA treatment reversed the levels of myocardial function indicators, including creatine kinase, creatine kinase-MB, lactate dehydrogenase, car-dial troponin T, and glutathione. Finally, UA treatment significantly inhibited the expression of MURF1, the phosphorylation of nuclear factor kappa-B p65, and STAT3 in the gastrocnemius muscle and heart tissues of cachexic mice. Our findings suggest that UA is a promising natural compound for developing dietary supplements for cancer cachexia therapy owing to its anti-catabolic effects.

DMC (2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone) enhances exercise tolerance via the AMPK-SIRT1-PGC-1α pathway in mice fed a high-fat diet.

Obesity is caused by an imbalance between energy intake and energy expenditure. This study aimed to determine the effects and mechanisms of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) on exercise tolerance in high-fat diet (HFD)-fed mice. Male C57BL/6J mice were randomly divided into two categories (7 groups [n = 8]): sedentary (control [CON], HFD, 200 mg/kg DMC, and 500 mg/kg DMC) and swimming (HFD, 200 mg/kg DMC, and 500 mg/kg DMC). Except the CON group, all other groups were fed HFD with or without DMC intervention for 33 days. The swimming groups were subjected to exhaustive swimming (three sessions/week). Changes in swimming time, glucolipid metabolism, body composition, biochemical indicators, histopathology, inflammation, metabolic mediators, and protein expression were assessed. DMC combined with regular exercise improved endurance performance, body composition, glucose and insulin tolerance, lipid profile, and the inflammatory state in a dose-dependent manner. Further, DMC alone or combined with exercise could restore normal tissue morphology, reduce fatigue-associated markers, and boost whole-body metabolism and the protein expression of phospho-AMP-activated protein kinase alpha/total-AMP-activated protein kinase alpha (AMPK), sirtuin-1 (SIRT1), peroxisome-proliferator-activated receptor gamma coactivator 1alpha (PGC-1α), and peroxisome proliferator-activated receptor alpha in the muscle and adipose tissues of HFD-fed mice. DMC exhibits antifatigue effects by regulating glucolipid catabolism, inflammation, and energy homeostasis. Furthermore, DMC exerts a synergistic exercise-related metabolic effect via the AMPK-SIRT1-PGC-1α signaling pathway, suggesting that DMC is a potential natural sports supplement with mimicked or augmented exercise effects for obesity prevention.

Mulberry Leaf Extract Alleviates Staphylococcus aureus-Induced Conjunctivitis in Rabbits via Downregulation of NLRP3 Inflammasome and Upregulation of the Nrf2 System and Suppression of Pro-Inflammatory Cytokines.

INTRODUCTION: Mulberry (Morus alba L.) leaves are widely used in traditional Chinese medicine for their antioxidant, anti-inflammatory, antibacterial, anti-obesity, antidiabetic, antiatherosclerotic, and anticancer properties. The current study aimed to investigate the effect of mulberry leaf extract (MLE) on Staphylococcus aureus (S. aureus)-induced conjunctivitis (5 × 109 colony-forming units, 0.5 mL/eye) in a rabbit model. METHODS: Rabbits were treated with MLE (5 mL/kg·d-1 and 10 mL/kg·d-1), 0.9% saline, pearl bright eye (PBE) drops, or erythromycin eye ointment (EEO) group for 5 days. The ocular infection symptoms, bacterial negative conversion rate, and conjunctival histopathological changes of rabbits in each group were observed. The expression of caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, NOD-like receptor leucine-rich pyrin domain-containing protein 3 (NLRP3), interleukin (IL)-18, IL-6, IL-1ß, TNFα, Keap1, and nuclear factor erythroid 2-related factor 2 (Nrf2) in conjunctival tissue of rabbits were detected by quantitative real-time reverse transcription PCR and/or Western blot analysis. RESULTS: The results showed that MLE treatment significantly reduced the clinical sign scores of conjunctivitis, alleviated clinical signs, and decreased bacterial load, and histological damage in a time- and dose-dependent manner was compared to that in the control group. The antibacterial and anti-inflammatory activities of MLE (10 mL/kg·d-1) were similar to those of the positive control drug PBE and EEO. In addition, MLE significantly decreased the levels of pro-inflammatory cytokines, downregulated the NLRP3 inflammasome, and upregulated the Nrf2 system. CONCLUSIONS: MLE is effective in alleviating S. aureus-induced conjunctivitis in rabbits, and this mechanism is associated with the inhibition of the NLRP3 inflammasome and activation of the Nrf2 system to regulate pro-inflammatory signaling.