Accumulating evidence indicates that gut microbiota participates in the pathogenesis and progression of liver diseases. The severity of immune-mediated liver injury is associated with different microbial communities. Akkermansia muciniphila can regulate immunologic and metabolic functions. However, little is known about its effects on gut microbiota structure and function. This study investigated the effect of A. muciniphila on immune-mediated liver injury and potential underlying mechanisms. Twenty-two C57BL/6 mice were assigned to three groups (N=7-8 per group) and continuously administrated A. muciniphila MucT or PBS by oral gavage for 14 days. Mouse feces were collected for gut microbiota analysis on the fifteenth day, and acute liver injury was induced by Concanavalin A (Con A, 15 mg/kg) injection through the tail vein. Samples (blood, liver, ileum, colon) were assessed for liver injury, systemic inflammation, and intestinal barrier function. We found that oral administration of A. muciniphila decreased serum ALT and AST and alleviated liver histopathological damage induced by Con A. Serum levels of pro-inflammatory cytokines and chemokines (IL-2, IFN-γ, IL-12p40, MCP-1, MIP-1a, MIP-1b) were substantially attenuated. A. muciniphila significantly decreased hepatocellular apoptosis; Bcl-2 expression increased, but Fas and DR5 decreased. Further investigation showed that A. muciniphila enhanced expression of Occludin and Tjp-1 and inhibited CB1 receptor, which strengthened intestinal barriers and reduced systemic LPS level. Fecal 16S rRNA sequence analysis indicated that A. muciniphila increased microbial richness and diversity. The community structure of the Akk group clustered distinctly from that of mice pretreated with PBS. Relative abundance of Firmicutes increased, and Bacteroidetes abundance decreased. Correlation analysis showed that injury-related factors (IL-12p40, IFN-, DR5) were negatively associated with specific genera (Ruminococcaceae_UCG−009, Lachnospiraceae_UCG−001, Akkermansia), which were enriched in mice pretreated with A. muciniphila. Our results suggested that A. muciniphila MucT had beneficial effects on immune-mediated liver injury by alleviating inflammation and hepatocellular death. These effects may be driven by the protective profile of the intestinal community induced by the bacteria. The results provide a new perspective on the immune function of gut microbiota in host diseases.

Background: The morbidity and mortality of pancreatic cancer vary considerably around the world. The aim of this study was to characterize and evaluate recent changes in incidence and incidence-based mortality in the USA. Methods: Incidence and incidence-based mortality data were based on the 18 Surveillance, Epidemiology, and End Results (SEER) registries through SEER*Stat software. We adopted joinpoint regression to analyze the temporal trends stratified by age, gender, ethnicity, stage, tumor site, and size. Results: Based on 18 SEER data sets, the age-adjusted incidence of pancreatic cancer increased from 11.85/100,000 in 2000 to 14.70/100,000 in 2014, increasing by an average annual percentage change (AAPC) of 1.6 (95% CI 1.5–1.8, p<0.05). The incidence-based mortality also increased, from 9.96/100,000 in 2001 to 12.96/100,000 in 2014, increasing by an AAPC of 1.9 (95% CI 1.3–2.5, p<0.05). However, we observed a deceleration in mortality since 2005, with the annual percentage change decreasing from 4.1 (2001–2005) to 1.0 (2005–2014). These increasing trends in pancreatic cancer were observed in most subgroups (stratified by age, gender, ethnicity, stage, tumor site, and size). Conclusion: The incidence and mortality rates of pancreatic cancer in the USA have increased significantly since 2000, highlighting the need for increased preventive, screening, and surveillance efforts.

FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2⁺ tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2⁺ pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. FGF-2⁺ tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2⁺ breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRβ ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers.

Objective: The objective of this study was to explore the potential correlation between the composite dietary antioxidant index (CDAI) and biological aging, addressing the insufficient epidemiological evidence in this area. Methods: Participants meeting eligibility criteria were selected from the National Health and Nutrition Examination Surveys (NHANES) conducted between 2001 and 2018. CDAI was determined based on dietary antioxidants obtained from 24-hour dietary recalls. Biological age was determined using PhenoAge algorithms incorporating various clinical features. Weighted multiple models were employed to investigate and assess the association between CDAI and biological age. Results: Analysis of the CDAI quartile revealed disparities in terms of age, gender, ethnicity, educational level, marital status, poverty, dietary calories intakes, smoking, drinking status, BMI, physical activity, and PhenoAge. After adjusting for potential confounding factors, a significant inverse relationship was found between CDAI and Phenotypic Age, with each standard deviation increase in CDAI score correlating with a 0.18-year decrease in Phenotypic Age. These negative correlations between CDAI and PhenoAge advancement were observed regardless of age, gender, physical activity status, smoking status, and body mass index. Conclusions: Our findings demonstrate a positive relationship between higher CDAI scores and delayed biological aging. These results have significant implications for public health initiatives aimed at promoting healthy aging through dietary interventions.