Early metastasis of pancreatic cancer (PC) leads to high mortality, and the underlying mechanism of metastasis remains unclear. Tumor necrosis factor superfamily member 9 (TNFSF9) is associated with poor prognosis in PC. Here, we investigated the effect of TNFSF9 on PC proliferation and apoptosis, and focused on the effect of TNFSF9 on PC metastasis and its potential mechanism. We found that TNFSF9 promotes PC metastasis in vivo and in vitro, and may be partially dependent on the Wnt/Snail signaling pathway. In addition, TNFSF9 also regulates the release of cytokines IL-10 and transforming growth factor-β (TGF-β) in pancreatic cancer cells through Wnt signaling to induce the M2 polarization of macrophages and promote the migration of PC cells. Overall, our study found that TNFSF9 may directly promote PC metastasis or indirectly promote PC metastasis through macrophage M2 polarization. Our study provides a new costimulatory target for the treatment of PC.

Viral vectors for vaccine delivery are challenged by recently reported safety issues like immunogenicity and risk for cancer development, and thus there is a growing need for the development of non-viral vectors. Cell penetrating peptides (CPPs) are non-viral vectors that can enter plasma membranes efficiently and deliver a broad range of cargoes. Our bioinformatic prediction and wet-lab validation data suggested that peptide P1 derived from MARCKS protein phosphorylation site domain is a new potential CPP candidate. We found that peptide P1 can efficiently internalize into various cell lines in a concentration-dependent manner. Receptor-mediated endocytosis pathway is the major mechanism of P1 penetration, although P1 also directly penetrates the plasma membrane. We also found that peptide P1 has low cytotoxicity in cultured cell lines as well as mouse red blood cells. Furthermore, peptide P1 not only can enter into cultured cells itself, but it also can interact with plasmid DNA and mediate the functional delivery of plasmid DNA into cultured cells, even in hard-to-transfect cells. Combined, these findings indicate that P1 may be a promising vector for efficient intracellular delivery of bioactive cargos.

Autosomal dominant polycystic kidney disease (ADPKD) is a predominant genetic disease, which is caused by mutations in PKD genes and is associated with DNA damage in cystic cells. The intrinsic stimulator of interferon genes (STING) pathway is crucial for recognizing damaged DNA in the cytosol, triggering the expression of inflammatory cytokines to activate defense mechanisms. However, the precise roles and mechanisms of STING in ADPKD remain elusive. In this study, we show that Pkd1 mutant mouse kidneys show upregulation of STING, which is stimulated by the DNAs of nuclear and mitochondrial origin. The activation of STING promotes cyst growth through increasing (1) the activation of NF-κB in Pkd1 mutant cells and (2) the recruitment of macrophages in the interstitial and peri-cystic regions in Pkd1 mutant mouse kidneys via NF-κB mediating the upregulation of TNF-α and MCP-1. Targeting STING with its specific inhibitor C-176 delays cyst growth in an early-stage aggressive Pkd1 conditional knockout mouse model and a milder long-lasting Pkd1 mutant mouse model. Targeting STING normalizes mitochondrial structure and function, decreases the formation of micronuclei, induces Pkd1 mutant renal epithelial cell death via p53 signaling, and decreases renal fibrosis in Pkd1 mutant mouse kidneys. These results support that STING is a novel therapeutic target for ADPKD treatment.

The common kidney disease diabetic nephropathy (DN) accounts for significant morbidity and mortality in patients with diabetes, and its effective diagnosis in incipient stages is still lacking. Renal fibrosis is the main pathological feature of DN. Cell division autoantigen 1 (CDA1), a phosphorylated protein encoded by TSPYL2 on the X chromosome, plays a fibrogenic role by modulating the transforming growth factor‐β (TGF‐β) signaling, but the exact mechanism remains unclear. TGF‐β signaling has been recognized as the key factor in promoting the development and progression of DN. At present, strict control of blood sugar and blood pressure can significantly lower the development and progression of DN in the early stages, and many studies have shown that blocking TGF‐β signaling can delay the progress of DN. However, TGF‐β is a multifunctional cytokine. Its direct intervention may result in increased side effects. Therefore, the targeted intervention of CDA1 not only can block the TGF‐β signaling pathway but also can reduce these side effects. In this article, we review the main physiological roles of CDA1, with particular attention to its effect and potential mechanism in the renal fibrosis of DN.

This Mendelian randomization (MR) study investigates the causal relationships between circulating inflammatory proteins, blood metabolites, and Clostridium difficile colitis (CDC), with a focus on potential metabolic mediation. Bidirectional and mediation MR analyses were performed using genome-wide association study (GWAS) summary statistics from 3384 CDC cases and 406,048 controls. The primary MR methods included inverse variance weighting (IVW) and MR-Egger regression, with MR-PRESSO applied to detect and correct horizontal pleiotropy. Sensitivity analyses, including leave-one-out tests, were conducted to ensure the robustness of the findings. Mediation analysis was performed using a two-step MR framework to estimate the causal effects of inflammatory proteins on metabolites and, subsequently, the impact of these metabolites on CDC risk. Bidirectional MR identified 2 inflammatory proteins associated with CDC risk. Higher IL-2 receptor subunit beta (IL-2RB) levels were protective against CDC (OR = 0.827, 95% CI = 0.718–0.953, P < .01), whereas increased IL-22 receptor subunit alpha-1 (IL-22RA1) levels elevated CDC risk (OR = 1.300, 95% CI = 1.078–1.570, P < .01). Unidirectional MR identified 11 plasma metabolites associated with CDC, including a positive correlation with spermidine-to-choline ratio. Mediation MR analysis suggested that 17.4% (−6.21%, 41%) of IL-2RB’s protective effect on CDC was mediated through this metabolite. Sensitivity analyses confirmed the robustness of these associations. Our findings suggest that higher IL-2RB levels were protective against CDC, while increased IL-22RA1 levels were associated with higher risk. The Spermidine-to-choline ratio partially mediated the protective effect of IL-2RB, suggesting a metabolic link between inflammation and CDC.