Drug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer.

Constipation, a gastrointestinal function disorder, is one of the side effects of paclitaxel (PTX) chemotherapy. Shenhuang plaster (SHP) application on the Shenque acupoint promotes gut motility in clinical settings. In this study, we elucidated the ingredients in SHP and evaluated its effects on PTX‐induced constipation using a tumour‐bearing mouse model. SHP was prepared using the traditional Chinese plaster preparation method. The ingredients were analysed using UPLC‐MS/MS and identified via screening in a standard drug database. The gastrointestinal transit was evaluated by the movement of a fluorescein‐labelled dextran in the gastrointestinal tract. A histological study of the mucosa was carried out after haematoxylin and eosin staining. mRNA expression was assessed using real‐time RT‐PCR, and the foetal microbiota composition was elucidated through 16 s rDNA sequencing and BLAST analysis. Our results indicate that the application of SHP attenuated weight gain inhibition by PTX; however, no inhibitory effect was observed on tumour growth. PTX‐induced sluggish intestine, villus, and mucosal base layer damage were significantly improved following the application of SHP. Further, SHP enhanced the stimulation efficiency of PTX on TLR4 and its downstream cytokines, as well as on IL‐1 β in intestinal cells. SHP combined with PTX reshaped the microbiota, which showed beneficial effects on health. Hence, these results provide evidence that SHP alleviates PTX‐induced constipation and intestinal morphological damage but augments the effects of PTX on the expression of cytokines in the TLR4 pathway and IL‐1 β . Therefore, we propose that SHP stimulates the host immune response to eradicate cancer cells.

Postoperative ileus (POI), a gastrointestinal function disorder, is a complication that arises from surgery. Shenhuang plaster (SHP) application to the Shenque acupoint (CV8) to promote the recovery of gastrointestinal function has achieved definite curative effects in clinical settings; however, the underlying pharmacological mechanism remains unknown. In this study, we evaluated the effects of SHP using a Sprague Dawley rat POI model. Then, gastrointestinal transit in different rat groups was evaluated by the movement of fluorescein-labelled dextran. Ghrelin, obestatin, motilin (MTL), and vasoactive intestinal peptide (VIP) plasma concentrations were measured via a radioimmunoassay. The expression of the ghrelin and obestatin receptors (GHS-R1α and GPR39) in the intestinal muscularis of rats in different groups was comparatively identified via western blotting. The results indicated that SHP application improved gastrointestinal motility in POI model rats. SHP application significantly increased ghrelin concentration and the expression of its receptor and inhibited obestatin concentration and the expression of its receptor in blood. Further, ghrelin concentration and the capability of gastrointestinal transit were positively correlated. Simultaneously, SHP application also promoted the secretion of other gastrointestinal motility hormones, such as MTL and VIP. Hence, these results provide evidence that SHP can promote the recovery of gastrointestinal transmission in POI rat models through regulation of ghrelin and other intestinal hormones.

Wei X, et al. Immune Netw. 2023 Aug;23(4):e34. https://doi.org/10.4110/in.2023.23.e34

Breast cancer remains the most commonly diagnosed cancer among women worldwide, and multiple studies now link its development and progression to disturbances in metabolic and immune regulation. Among these factors, the gut microbiota is increasingly recognized as a modulator of host physiology through its metabolism of dietary tryptophan (Trp). Here we focus on the current understanding of the microbial metabolism of Trp, which primarily generates bioactive metabolites through the kynurenine (Kyn) pathway and the indole pathway. These metabolites can serve as endogenous ligands, activating the aryl hydrocarbon receptor (AhR) signaling pathway. They can also promote tumor stem cell characteristics, epithelial-mesenchymal transition (EMT), and metastasis via serotonin receptors (such as HTR1B/1D, HTR2B). The activation of such pathways contributes to the remodeling of the tumor immune microenvironment, alters the functions of immune cells, and directly influences the proliferation, invasion, and metastatic behavior of breast cancer cells. By integrating findings from preclinical and clinical studies, this review organizes current evidence around the “gut microbiota-Trp metabolism-breast cancer” axis and discusses clinical implications and current limitations. Targeting this metabolic network may provide new opportunities for breast cancer prevention and therapeutic intervention.