Nuciferine alleviates collagen-induced arthritic in rats by inhibiting the proliferation and invasion of human arthritis-derived fibroblast-like synoviocytes and rectifying Th17/Treg imbalance.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by persistent synovial inflammation and joint degradation, posing challenges in the development of effective treatments. Nuciferine, an alkaloid found in lotus leaf, has shown promising anti-inflammatory and anti-tumor effects, yet its efficacy in RA treatment remains unexplored. This study investigated the antiproliferative effects of nuciferine on the MH7A cell line, a human RA-derived fibroblast-like synoviocyte, revealing its ability to inhibit cell proliferation, promote apoptosis, induce apoptosis, and cause G1/S phase arrest. Additionally, nuciferine significantly reduced the migration and invasion capabilities of MH7A cells. The therapeutic potential of nuciferine was further evaluated in a collagen-induced arthritis (CIA) rat model, where it markedly alleviated joint swelling, synovial hyperplasia, cartilage injury, and inflammatory infiltration. Nuciferine also improved collagen-induced bone erosion, decreased pro-inflammatory cytokines and serum immunoglobulins (IgG, IgG1, IgG2a), and restored the balance between T helper (Th) 17 and regulatory T cells in the spleen of CIA rats. These results indicate that nuciferine may offer therapeutic advantages for RA by decreasing the proliferation and invasiveness of FLS cells and correcting the Th17/Treg cell imbalance in CIA rats.

Gastrodin Attenuates Colitis and Prevents Tumorigenesis in Mice by Interrupting TLR4/MD2/NF-κB Signaling Transduction.

INTRODUCTION: Chronic inflammation is one of the causative factors for tumorigenesis. Gastrodin is a main active ingredient isolated from Gastrodia elata Blume, a famous medicinal herb with a long edible history. AIM: This study aimed to explore the effects of gastrodin on colitis-associated carcinogenesis (CRC) in mice and to elucidate its potential molecular mechanisms. METHODS: Balb/c mice were induced with azoxymethane (AOM) and dextran sulfate sodium (DSS) for 12 weeks. Gastrodin (50 mg/kg) was administered via oral gavage three times per week until the end of the experiment. Disease indexes, including body weight, bloody diarrhea, colon length, histopathological score, and tumor size, were measured. Tumor cell proliferation was evaluated by BrdU incorporation assay and tumor cell cytotoxicity was assessed by cell counting kit (CCK-8). The expression levels of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling molecules, NF-κB luciferase, and pro-inflammatory cytokines were determined by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), immunoblotting, immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), or reporter gene assays. The binding affinity between gastrodin and myeloid differentiation protein-2 (MD2) was analyzed by molecular docking and cellular thermal shift assay (CETSA). RESULTS: Gastrodin administration was demonstrated to mitigate various CRC-related symptoms in mice, including weight loss, diarrhea, and tissue abnormalities. Notably, gastrodin suppressed tumor cell growth during colitis- associated tumorigenesis, resulting in fewer and smaller adenomas in the colon. Unlike irinotecan, a broadspectrum antitumor drug, gastrodin did not exhibit apparent cytotoxicity in various colorectal adenocarcinoma cell lines. Additionally, gastrodin downregulated TLR4/NF-κB signaling molecules and pro-inflammatory mediators in mice and macrophages. Molecular docking and CETSA experiments suggested that gastrodin binds to the MD2 protein, potentially interfering with the recognition of lipopolysaccharide (LPS) by TLR4, leading to NF-κB pathway inhibition. CONCLUSION: This study provides evidence for the first time that gastrodin attenuated colitis and prevented colitisrelated carcinogenesis in mice, at least partially, by diminishing tumor-promoting cytokines through the interruption of TLR4/MD2/NF-κB signaling transduction.

Microbiota-Host-Irinotecan Axis: A New Insight Toward Irinotecan Chemotherapy.

Irinotecan (CPT11) and its active metabolite ethyl-10-hydroxy-camptothecin (SN38) are broad-spectrum cytotoxic anticancer agents. Both cause cell death in rapidly dividing cells (e.g., cancer cells, epithelial cells, hematopoietic cells) and commensal bacteria. Therefore, CPT11 can induce a series of toxic side-effects, of which the most conspicuous is gastrointestinal toxicity (nausea, vomiting, diarrhea). Studies have shown that the gut microbiota modulates the host response to chemotherapeutic drugs. Targeting the gut microbiota influences the efficacy and toxicity of CPT11 chemotherapy through three key mechanisms: microbial ecocline, catalysis of microbial enzymes, and immunoregulation. This review summarizes and explores how the gut microbiota participates in CPT11 metabolism and mediates host immune dynamics to affect the toxicity and efficacy of CPT11 chemotherapy, thus introducing a new concept that is called "microbiota-host-irinotecan axis". Also, we emphasize the utilization of bacterial ß-glucuronidase-specific inhibitor, dietary interventions, probiotics and strain-engineered interventions as emergent microbiota-targeting strategies for the purpose of improving CPT11 chemotherapy efficiency and alleviating toxicity.

Berberine Improves Irinotecan-Induced Intestinal Mucositis Without Impairing the Anti-colorectal Cancer Efficacy of Irinotecan by Inhibiting Bacterial ß-glucuronidase.

Irinotecan (CPT11), a broad-spectrum cytotoxic anticancer agent, induces a series of toxic side-effects. The most conspicuous side-effect is gastrointestinal mucositis, including nausea, vomiting, and diarrhea. A growing body of evidence indicates that bacteria ß-glucuronidase (GUS), an enzyme expressed by intestinal microbiota, converts the inactive CPT11 metabolite SN38G to the active metabolite SN38 to ultimately induce intestinal mucositis. We sought to explore the potential efficacy and underlying mechanisms of berberine on CPT11-induced mucositis. Our study showed that berberine (50 mg/kg; i. g.) mitigated the CPT11-induced loss of mucosal architecture, ulceration, and neutrophil infiltration. Meanwhile, berberine improved mucosal barrier function by increasing the number of globlet cells, protecting trans-endothelial electrical resistance (TEER), reducing permeability and increasing tight junction proteins expression. LC-MS analysis showed that berberine decreased the content of SN38 in feces, which correlated with decreases in both GUS activity and GUS-producing bacteria. Further molecular docking and Lineweaver-Burk plots analyses suggested that berberine functions as a potential non-competitive inhibitor against GUS enzyme. Of note, berberine maintained the anti-tumor efficacy of CPT11 in a tumor xenograft model while abrogating the intestinal toxicity of CPT11. Overall, we identified for the first time the remission effects of berberine on intestinal mucositis induced by CPT11 without impairing the anti-colorectal cancer efficacy of CPT11 partially via inhibiting bacterial GUS enzyme.