Regulating bile acids signaling for NAFLD: molecular insights and novel therapeutic interventions.

Nonalcoholic fatty liver disease (NAFLD) emerges as the most predominant cause of liver disease, tightly linked to metabolic dysfunction. Bile acids (BAs), initially synthesized from cholesterol in the liver, undergo further metabolism by gut bacteria. Increasingly acknowledged as critical modulators of metabolic processes, BAs have been implicated as important signaling molecules. In this review, we will focus on the mechanism of BAs signaling involved in glucose homeostasis, lipid metabolism, energy expenditure, and immune regulation and summarize their roles in the pathogenesis of NAFLD. Furthermore, gut microbiota dysbiosis plays a key role in the development of NAFLD, and the interactions between BAs and intestinal microbiota is elucidated. In addition, we also discuss potential therapeutic strategies for NAFLD, including drugs targeting BA receptors, modulation of intestinal microbiota, and metabolic surgery.

Tripterygium glycosides sensitizes cisplatin chemotherapeutic potency by modulating gut microbiota in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is a fatal gynecological malignancy with limited therapeutic options. Previous research has demonstrated that Tripterygium glycosides (GTW) can enhance effectiveness of cisplatin (DDP) chemotherapy against EOC. However, the underlying mechanism of GTW alleviating EOC still remains unclear. In this article, an ID8 cell-derived xenograft mouse model was established to evaluate the anti-tumor efficacy of GTW combined with DDP. Consistent with previous findings, the results suggested that GTW combined with DDP can exhibit a stronger tumor suppressive effect than DDP alone. Additionally, GTW was found can further exert gastrointestinal protection against DDP by reducing pathological damage on colon tissue. Secondly, to verify whether gut microbiota play an instrumental role in GTW's anticancer effect, we treated mice models with antibiotic to eliminate gut microbiota. And our experimental results indicated that all drug groups showed a weaker tumor suppressive effect and more severe gastrointestinal damage post antibiotic supplement. At genus level, the relative abundance of Lactobacillus was dramatically diminished by the antibiotic treatment, while combined treatment of GTW and DDP can significantly restore the level. Moreover, we performed Lactobacillus acidophilus transplantation and healthy mice fecal microbiota transplantation experiments to further investigate the link between the anticancer effect of GTW and gut microbiota. Our results suggested that both cisplatin-sensitizing and intestinal barrier-protecting effects of GTW can be recovered to a different extent. In conclusion, our results indicated that GTW is a promising chemosensitization and intestinal barrier repair drug for EOC, and the potential mechanism may corelate with the restoration of the compromised intestinal microbial balance.

Tripterygium glycosides reverse chemotherapy resistance in ovarian cancer by targeting the NRF2/GPX4 signal axis to induce ferroptosis of drug-resistant human epithelial ovarian cancer cells.

Cisplatin resistance is the main cause of postoperative recurrence and difficulty in the treatment of ovarian cancer. It is urgently needed to identify therapeutic drugs with unique functions to overcome the current challenges in the treatment of ovarian cancer. In this study, we found that TG promoted the accumulation of ROS and MDA in A2780/DDP cells and downregulated the expression of key antioxidant molecules. In vivo, the survival rate of tumor-bearing nude mice was prolonged by TG without significant hepatotoxic reaction. The expression of key antioxidant molecules in tumor tissues was consistent with that in vitro. These findings revealed that TG disrupted homeostasis of redox reactions and induced ferroptosis in A2780/DDP cells, thereby enhancing cisplatin chemosensitivity of ovarian cancer. Overall, TG may be a novel potential therapeutic option for reversing resistance to cisplatin chemotherapy.

GTW inhibits the Epithelial to Mesenchymal Transition of Epithelial Ovarian Cancer via ILK/AKT/GSK3ß/Slug Signalling Pathway.

Background: Epithelial ovarian cancer (EOC) accounts for the most lethal of all gynaecological cancers which is attributed to metastasis, invasiveness and drug resistance. A crucial link has been found between epithelial-mesenchymal transition (EMT) and cancer metastasis and chemo-resistance. Previous studies have confirmed that one of the main components of tripterygium glycosides (GTW)-triptolide (TPL) has anticancer effects. Methods: The purpose of this study is to determine whether GTW could inhibit EMT in A2780/DPP cells in vitro and in vivo, and explore the underlying mechanism. Results: In vitro results showed that GTW inhibited cell proliferation, invasion and migration, and intensified the sensitivity of A2780/DDP cells to cisplatin (DDP). GTW, especially GTW+DDP, significantly inhibited the expression of N-cadherin, integrin-linked kinase (ILK), phospho-protein kinase B/AKT (PKB/p-AKT), phospho-glycogen synthase kinase (p-GSK3ß) and Slug, while it increased E-cadherin levels by inhibiting EMT via the ILK/AKT/GSK3ß/Slug signalling pathway. Animal results indicated that GTW, especially GTW+DDP, significantly reduced tumour burden, prolonged the life span of mice, and down-regulated the levels of tumour markers CA125 and HE4 by regulating EMT through the ILK/AKT/GSK3ß/Slug signalling pathway. Conclusion: Our results highlighted the significance of EMT in EOC metastasis, invasiveness and resistance to DDP and investigated the potential role of GTW as an adjuvant therapeutic agent in chemo-resistant EOC.

Revealing the Disturbed Vaginal Micobiota Caused by Cervical Cancer Using High-Throughput Sequencing Technology.

Cervical cancer is the fourth most prevalent cancer type among all malignancies, so it is of great significance to find its actual pathogenesis mechanisms. In the present study, 90 women were enrolled, and high-throughput sequencing technology was firstly used to analyze the vaginal microbiota of healthy women (C group), cervical intraepithelial neoplasia patients (CIN group) and cervical cancer patients (CER group). Our results indicates that compared with C group, a higher HPV infection rate as well as increased Neutrophil ratio and tumor marker squamous cell carcinoma antigen (SCCA) were obtained, and a decrease in Lymphocyte ratio and Hemoglobin were also present. In addition, the cervical cancer showed a strong association with reduced probiotics Lactobacillus, increased pathogens Prevotella spp., Sneathia spp. and Pseudomonas spp. These results prove that the immunological changes generated by the cervical cancer and the vaginal microbiota can interact with each other. However, further study investigating the key bacteria for cervical cancer is still needed, which can be a clue for the diagnosis or treatment of cervical cancer.

Antitumor activity of triptolide in SKOV3 cells and SKOV3/DDP in vivo and in vitro.

This study was designed to investigate the antitumor activity of triptolide in ovarian cancer inoculated with SKOV3 and SKOV3/cisplatin (DDP) cells, and to assess the mechanisms. In-vivo and in-vitro experiments were designed to evaluate the effects of triptolide on the tumor growth of SKOV3 and SKOV3/DDP cells. The experiments were divided into four groups: a SKOV3 group, a SKOV3 + TP treatment group, a SKOV3/DDP group and a SKOV3/DDP + TP treatment group. The expression of Sorcin, vascular endothelial growth factor and matrix metalloproteinase-2 were detected by western blotting and immunohistochemistry. Tumor cell apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling. In-vitro experiments showed that compared with SKOV3 control group, the level of colony-stimulating factor 1 and expression of Sorcin in SKOV3/DDP was significantly higher. Interestingly, triptolide treatment could reduce colony-stimulating factor 1 level and expression of Sorcin in both SKOV3 and SKOV3/DDP cell lines. In-vivo experiments showed that tissue necrosis area in SKOV3 + TP and SKOV3/DDP + TP was larger than SKOV3 and SKOV3/DDP group, respectively. Triptolide treatment induced apoptosis in both SKOV3 and SKOV3/DDP cells. Compared with SKOV3 group, the size of tumors was large, and the expression of MMP-2, Sorcin and vascular endothelial growth factor was higher in SKOV3/DDP group. Triptolide treatment reduced the size of tumors, and the expression of MMP-2, Sorcin and vascular endothelial growth factor in SKOV3/DDP as well as in SKOV3 tumors. In conclusion, triptolide has antitumor activity in both SKOV3 and SKOV3/DDP cells likely through inducing apoptosis and regulating MMP-2, Sorcin and vascular endothelial growth factor expression.

Triptolide sensitizes cisplatin-resistant human epithelial ovarian cancer by inhibiting the phosphorylation of AKT.

Advanced and chemotherapy-resistant ovarian cancer causes high mortality of ovarian cancer, and it is important to find safe and effective drugs to reduce the chemotherapeutic resistance of ovarian cancer. In our study, we attempted to clarify the resistance mechanisms of SKOV3/DDP cells in vitro and evaluated the sensitization to triptolide (TPL) in vivo. Our results indicated that the overexpression of AKT and p-AKT greatly enhanced the cisplatin (DDP) tolerance of SKOV3/DDP, and the combination of DDP+TPL had a significant tumour inhibition effect compared to DDP treatment (p<0.05), via reducing the expressions of p-PI3K, p-Akt, Survivin, VEGF and MMP-2, and the increase of Caspase-3. Collectively, these results suggest that the synergistic anticancer effect of TPL and DDP warrants their potential clinical applications in further.

Inhibition effect of triptolide on human epithelial ovarian cancer via adjusting cellular immunity and angiogenesis.

Chemotherapy resistance of advanced ovarian cancers is responsible for death of most cancer patients, so it is necessary to seek safe and effective natural ingredients to lower the chemotherapy resistance of ovarian cancer. In the present study, we studied the anticancer effects of triptolide (TPL) and TPL + cisplatin (DDP) in vitro and in vivo using SKOV3/DDP cell line and a mouse model. In vitro results showed that TPL and TPL + DDP inhibited cellular invasion and migration of SKOV3/DDP cells (P<0.05), and significantly reduced the expression of adhesion-related proteins integrin ß1 (ITGß1) and apoptosis-inhibiting proteins survivin, matrix metalloproteinase 2 (MMP-2) and MMP-9 (P<0.05). Animal results demonstrated that TPL and TPL + DDP had significantly enhanced the inflammatory factor-2 (IL-2) and tumor necrosis factor-α (TNF-α) in serum of mice, and significantly increased the NK cell-related protein levels of CD16 and CD56, while significantly inhibited the production of vascular endothelial growth factor (VEGF) related protein clusters of differentiation 31 (CD31) and CD105. Collectively, the combination of TPL and DDP may produce a synergistic anticancer effect on epithelial ovarian cancer (EOC).

Overexpression of Notch3 and pS6 Is Associated with Poor Prognosis in Human Ovarian Epithelial Cancer.

Notch3 and pS6 play important roles in tumor angiogenesis. To assess the expression of Notch3 and pS6 in Chinese ovarian epithelial cancer patients, a ten-year follow-up study was performed in ovarian epithelial cancer tissues from 120 specimens of human ovarian epithelial cancer, 30 specimens from benign ovarian tumors, and 30 samples from healthy ovaries by immunohistochemistry. The results indicate that the expression of Notch3 and pS6 was higher in ovarian epithelial cancer than in normal ovary tissues and in benign ovarian tumor tissues (p < 0.01). In tumor tissues, Notch3 expression and pS6 expression were negatively associated with age (p > 0.05) but positively associated with clinical stage, pathological grading, histologic type, lymph node metastasis, and ascites (p < 0.05 or p < 0.01). A follow-up survey of 64 patients with ovarian epithelial cancer showed that patients with high Notch3 and pS6 expression had a shorter survival time (p < 0.01), in which the clinical stage (p < 0.05) and Notch3 expression (p < 0.01) played important roles. In conclusion, Notch3 and pS6 are significantly related to ovarian epithelial cancer development and prognosis, and their combination represents a potential biomarker and therapeutic target in ovarian tumor angiogenesis.