Background: Around 80% of patients with advanced cancer have cancer cachexia (CC), a serious complication for which there are currently no FDA‐approved treatments. Nuciferine (NF) is the main active ingredient of lotus leaf, which has anti‐inflammatory, anti‐tumour and other effects. The purpose of this work was to explore the target and mechanism of NF in preventing cancer cachexia‐induced muscle atrophy. Methods: The action of NF against CC‐induced muscle atrophy was determined by constructing an animal model with a series of behavioural tests, H&E staining and related markers. Network pharmacology and molecular docking were used to preliminarily determine the mechanism and targets of NF against CC‐induced muscle atrophy. The mechanisms of NF in treating CC‐induced muscle atrophy were verified by western blotting. Molecular dynamics simulation (MD), drug affinity responsive target stability (DARTS) and surface plasmon resonance (SPR) were used to validate the key target of NF. Results: After 13 days of NF treatment, the reduction of limb grip strength and hanging time in LLC model mice increased by 29.7% and 192.2% ( p ≤ 0.01; p ≤ 0.001). Gastrocnemius and quadriceps muscles weight/initial body weight (0.98 ± 0.11 and 1.20 ± 0.17) and cross‐sectional area of muscle fibres (600–1600 μm ² ) of NF‐treated mice were significantly higher than those of the model group (0.84 ± 0.10, 0.94 ± 0.09, 400–800 μm ² , respectively) ( p ≤ 0.01; p ≤ 0.01; p ≤ 0.001). NF treatment also decreased the MyHC (myosin heavy chain) degradation and the protein levels of muscle‐specific E3 ubiquitin ligases Atrogin1 and MuRF1 in the model group ( p ≤ 0.001; p ≤ 0.01; p ≤ 0.05). Network pharmacology revealed that NF majorly targeted AKT1, TNF and HSP90AA1 to regulate PI3K‐Akt and inflammatory pathways. Molecular docking predicted that NF bound best to HSP90AA1. Mechanism analysis demonstrated that NF regulated NF‐κB and AKT–mTOR pathways for alleviating muscle wasting in tumour bearing mice. The results of MD, DARTS and SPR further confirmed that HSP90AA1 was the direct target of NF. Conclusions: Overall, we first discovered that NF retards CC‐induced muscle atrophy by regulating AKT–mTOR and NF‐κB signalling pathways through directly binding HSP90AA1, suggesting that NF may be an effective treatment for cancer cachexia.

Ulcerative colitis (UC) is a chronic and recurrent gastrointestinal disease that affects millions of humans worldwide and imposes a huge social and economic burden. It is necessary to find safe and efficient drugs for preventing and treating UC. The aim of this study was to determine whether ganoderic acid (GA), the main bioactive components of Ganoderma lucidum, has preventive and therapeutic effect on UC in a dextran sulfate sodium (DSS)-induced UC mouse model. Our experimental results showed that GA significantly ameliorated the body weight loss and disease activity index (DAI) of UC mice. GA significantly restored 11% of the colon length and 69% of the spleen index compared to UC mice. GA significantly decreased the intestinal inflammatory response and improved the barrier function of the intestine by upregulating the tight junction proteins Zonula occludens-1 (ZO-1), occludin and claudin-1. A co-housing experiment showed that gut microbiota accounted for the therapeutic activity of GA on UC, which was confirmed by fecal microbiota transplantation from GA-treated mice to the UC mice. Furthermore, 16S rDNA high-throughput sequencing of fecal bacteria showed that GA significantly enriched the abundance of Lactobacillus, Oscillospira, Odoribacter and Ruminococcus, which were positively correlated with colon length. Furthermore, this study found the functional metabolites, including Indole-3-acetaldehyde (IAAld), Glutamine (Gln) and Glutathione (GSH), reduced barrier damage in the Caco-2 cell model. In conclusion, this study suggests that GA could ameliorate UC by improving intestinal barrier function via modulating gut microbiota and associated metabolites.

80% of advanced cancer patients suffer from cachexia, but there are no FDA-approved drugs. Therefore, it is imperative to discover potential drugs. Objective: This study aims at exploring the effect and targets of Aloin A against cancer cachexia (CC)-induced muscle atrophy. Methods: Network pharmacology, molecular docking, molecular dynamics (MD) and animal model of CC-induced muscle atrophy with a series of behavior tests, muscle quality, HE staining and RT-PCR were performed to investigate the anticachectic effects and targets of Aloin A and its molecular mechanism. Results: Based on network pharmacology, 51 potential targets of Aloin A on CC-induced muscle atrophy were found, and then 10 hub genes were predicted by the PPI network. Next, KEGG and GO enrichment analysis showed that the anticachectic effect of Aloin A is associated with PI3K-AKT, MAPK, TNF, TLR, etc., pathways, and biological processes like inflammation, apoptosis and cell proliferation. Molecular docking and MD results showed good binding ability between the Aloin A and key targets. Moreover, experiments in vivo demonstrated that Aloin A effectively rescued muscle function and wasting by improving muscle quality, mean CSA, and distribution of muscle fibers by regulating HSP90AA1/AKT signaling in tumor-bearing mice. Conclusion: This study offers new insights for researchers to understand the effect and mechanism of Aloin A against CC using network pharmacology, molecular docking, MD and experimental validation, and Aloin A retards CC-induced muscle wasting through multiple targets and pathways, including HSP90AA1/AKT signaling, which provides evidence for Aloin A as a potential therapy for cancer cachexia in clinic.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder with limited treatment options. This study investigated the therapeutic potential of water extract of Ajania fruticulosa (WEAF) against NAFLD in cellular and animal models. WEAF significantly attenuated obesity, lipid accumulation, liver injury, and inflammation in NAFLD mice. Next, UPLC-MS/MS-based network pharmacology and molecular biology revealed that WEAF alleviated NAFLD by TLR2-mediated MYD88/NF-κB and SREBP1/PPAR-γ pathways, with 3,4-dihydroxyphenylpropionic acid, glycitein, and isorhapontigenin identified as the primary bioactive compounds. Finally, molecular docking, molecular dynamics, drug affinity responsive target stability, and cellular thermal shift assay confirmed that glycitein and isorhapontigenin directly bind to TLR2 to modulate the NF-κB/PPAR-γ signaling, and their anti-NAFLD effects were abolished by TLR2 agonist Pam3CSK4. In conclusion, WEAF and its key active compounds, glycitein and isorhapontigenin, effectively ameliorate obesity-induced NAFLD via the NF-κB/PPAR-γ signaling pathway by targeting TLR2, supporting their potential as therapeutic target and agents for NAFLD.