Inhibition of ferroptosis: A new direction in the treatment of ulcerative colitis by traditional Chinese medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a chronic idiopathic intestinal disease of unknown cause and has been classified as one of the modern intractable diseases by the World Health Organization (WHO). Ferroptosis, as an iron-ion-dependent mode of programmed cell death, is closely related to iron metabolism, lipid peroxidation, and imbalance of the antioxidant system, and plays an important role in the development of UC. In this paper, we will review the regulatory pathways of ferroptosis, the relationship between ferroptosis and the pathogenesis of UC, and the treatment of UC by TCM from the perspective of ferroptosis inhibition, and summarize the mechanism of action of the active ingredients of TCM and TCM compounds to improve UC through ferroptosis inhibition, and look forward to the prospect of the application of ferroptosis inhibition by TCM in the treatment of UC. AIM OF THIS REVIEW: This paper aims to elucidate the mechanism of action of TCM active ingredients and TCM combinations in the treatment of UC by inhibiting ferroptosis. The active ingredients of TCM have the significant advantages of multi-targets and multi-pathways, and ferroptosis is the current research hotspot in the prevention and treatment of UC, so the inhibition of ferroptosis by TCM is a key direction for future research. MATERIALS AND METHODS: The keywords "ferroptosis", "ulcerative colitis" and "TCM" were searched in Pubmed, CNKI, and Wed of Science databases. Papers related to clinical trials and pharmacological research up to August 2023 were screened for inclusion. Combined with the theory of TCM, we systematically summarized the effects of TCM active ingredients and TCM combinations in inhibiting ferroptosis and thus preventing UC. RESULTS: A large number of studies have shown that TCM active ingredients and TCM combinations inhibit the inflammatory response and oxidative stress in the course of UC mainly by interfering with iron metabolism, correcting lipid metabolism and peroxidative accumulation, and regulating the processes of glutathione (GSH) and glutathione peroxidase 4 (GPX4), to improve colonic mucosal damage and promote the repair of colonic mucosal tissue. CONCLUSION: Since the study of ferroptosis in UC is still in the exploratory stage, many issues still deserve attention in the future. This paper reviews the mechanism of ferroptosis inhibition by TCM active ingredients and TCM combinations to prevent and treat UC. In the future, we should also further increase the number of clinical experimental studies to explore whether more TCM medicines can play a therapeutic role in UC by inhibiting ferroptosis, and explore more pathways and genes targeting the inhibition of ferroptosis, to seek more TCM therapies for UC. We believe that the use of TCM active ingredients and TCM combinations to regulate ferroptosis is an important direction for future UC prevention and treatment.

Adjuvant activity of cordycepin, a natural derivative of adenosine from Cordyceps militaris, on an inactivated rabies vaccine in an animal model.

Vaccination is the most feasible way of preventing rabies, an ancient zoonosis that remains a major public health concern globally. However, administration of inactivated rabies vaccination without adjuvants is always inefficient and necessitates four to five injections. In the current study, we explored the adjuvant characteristics of cordycepin, a major bioactive component of Cordyceps militaris, to boost immune responses against a commercially available rabies vaccine. We found that cordycepin could stimulate stronger phenotypic and functional maturation of dendritic cells (DCs). For animal experiments, mice were immunized 3 times with rabies vaccine in the presence or absence of cordycepin at 1-week interval. Analysis of T cell differentiation and serum antibody isotypes showed that humoral immunity was dominant with a Th2 biased immune response. These results were also supported by the raised ratio of follicular helper T cells (TFH) and germinal center B cells (GCB). Thus, titer of rabies virus neutralizing antibody (RVNAb) and rabies virus-specific memory B cells were both raised as a result. Furthermore, administration of cordycepin did not cause pathological phenomena or body weight loss. The findings indicate that cordycepin could be used as a promising adjuvant for rabies vaccines to get a higher range of protection without any side effects.

Intestinal uric acid excretion contributes to serum uric acid decrease during acute gout attack.

OBJECTIVE: Spontaneous serum uric acid (SUA) decrease has been found in many patients during acute gout attacks, but its mechanism remains unclear. METHODS: The spontaneous regulation of SUA during a gout attack and its possible causes were evaluated in patients with gout. The mechanism of the spontaneous SUA decrease was further studied in Caco2 cells and a monosodium urate (MSU)-induced gout model of wild-type mice and ABCG2-/- mice. The urate transport function of intestinal epithelial cells was detected by transwell culture of Caco2 cells. Expression of ATP-binding cassette super-family G member 2 (ABCG2), IL-1ß and phosphoinositide 3-kinase (PI3K)/Akt was analysed using real-time PCR, western blotting, or immunofluorescence assays. RESULTS: SUA decreased during acute gout attacks in both the gout patients and MSU-induced gouty mice. Increased serum CRP and IL-1ß levels were correlated with the SUA decrease. Intestinal uric acid excretion and expression of ABCG2 were upregulated in the mice during acute gout attacks. In the ABCG2-/- mice, intestinal uric acid excretion significantly decreased during gout attacks. In an in vitro study of a transwell culture, ABCG2 and its upstream PI3K/Akt pathway were significantly upregulated in intestinal epithelial cells. However, ABCG2 expression and its associated intestinal uric acid transport were inhibited when PI3K/Akt was blocked by a PI3K inhibitor, LY294002. CONCLUSIONS: Increased intestinal urate excretion resulted in spontaneous SUA downregulation during acute gout attacks. Inflammation-induced PI3K/Akt activation and ABCG2 expression in epithelial cells might contribute to the upregulation of intestinal uric acid excretion.

SULT2B1b promotes epithelial-mesenchymal transition through activation of the ß-catenin/MMP7 pathway in hepatocytes.

Epithelial-mesenchymal transition (EMT) occurs in the progression of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The hydroxysteroid sulfotransferase 2B1b (SULT2B1b) promotes the proliferation of hepatocarcinoma cells both in vitro and in vivo. However, the correlation between SULT2B1b and the EMT in hepatocytes has not yet been addressed. The present study demonstrated that the SULT2B1b overexpression promoted the EMT process in mouse primary hepatocytes in the absence or presence of TGF-ß1 treatment. Moreover, SULT2B1b interference suppressed the EMT and attenuated the migration and invasion abilities of human hepatocarcinoma BEL-7402 cells by inhibiting the activation of the ß-catenin/MMP-7 pathway. In summary, SULT2B1b enhanced the EMT of hepatocytes and promoted the migration and invasion abilities of BEL-7402 cells by activing the ß-catenin/MMP-7 pathway. Therefore, inhibition of SULT2B1b has therapeutic potential for the treatment of HCC.