Youcai Tang

The occurrence and progression of gastric cancer (GC) are closely associated with dysbiosis of the gastric microbiota and alteration in host microenvironments. However, the interaction between intratumoral bacteria and gastric microenvironments remains incompletely understood. In this study, we characterized the biological profiles of intratumoral bacteria, metabolome, and proteome in 20 GC tumors and paired non-tumor tissues, in combination with 6 independent datasets (comprising 477 gastric tissue biopsies and 534 normal tissues), as well as mucosal tissues from 10 individuals without GC. We found that the diversity and richness of gastric microbiota were significantly higher in tumor tissues than in non-tumor tissues. In contrast, the lowest biodiversity, at both the genus and species levels, was found in the microbiota of individuals without GC. Specifically, tumors were enriched with Bacteroides thetaiotaomicron, Lactobacillus parabrevis, Brevundimonas nasdae, and Brevundimonas vesicularis. We also identified 39 human immunity-related proteins, particularly in the tryptophan metabolic pathway, which were differentially expressed across various microenvironments (tumor and non-tumor). Furthermore, we found that several pathways involved in the human immune system and associated with the gastric microbiota, such as thiazole biosynthesis II, pyrimidine deoxyribonucleoside salvage, superpathway of pyrimidine deoxyribonucleoside salvage, and superpathway of heme biosynthesis from uroporphyrinogen-III, hold potential as biomarkers for early detection of GC. Our results provide a comprehensive framework for investigating the complex interactions between the tumor immune microenvironment and intratumoral bacterial community.

Metabolic‑associated fatty liver disease (MAFLD) is widely recognized as the most common type of chronic liver disease. As a member of the perilipin (PLIN) family, PLIN5 serves an important role in the regulation of lipid metabolism. Ferroptosis is a form of iron‑dependent non‑apoptotic cell death characterized by lipid peroxidation. Notably, knockout of PLIN5 can attenuate high‑fat diet (HFD)‑induced MAFLD; however, the specific underlying mechanism remains unclear. The present study induced PLIN5 overexpression by transfecting AML12 cells with a pcDNA3.1‑PLIN5 plasmid, and PLIN5 knockdown was achieved using short hairpin RNA‑mediated interference. Subsequently, intracellular ferrous iron (Fe²⁺) levels were assessed via immunofluorescence staining. Furthermore, a MAFLD model was established in C57BL/6J mice by feeding them a HFD. To establish an in vitro model of hepatic steatosis, AML12 hepatocytes were treated with palmitic acid and oleic acid to induce intracellular lipid accumulation. To further explore the effects of PLIN5 on ferroptosis, liver single‑cell sequencing was conducted and cellular experiments were performed to assess changes in redox and ferroptosis‑related proteins. The current study investigated the effects of PLIN5 on MAFLD in animal and cellular experiments, including the changes in lipid accumulation, redox and ferroptosis‑related markers. The results revealed that genetic knockdown of PLIN5 significantly attenuated lipid accumulation and intracellular Fe²⁺ levels in AML12 hepatocytes, whereas PLIN5 overexpression markedly exacerbated these parameters. In addition, PLIN5 deficiency substantially reduced malondialdehyde content while enhancing glutathione levels, indicating attenuated oxidative stress. The results of the in vivo studies demonstrated that PLIN5 knockout effectively ameliorated MAFLD progression in mice by suppressing ferroptosis. In conclusion, PLIN5 knockout may delay the progression of MAFLD in mice via ferroptosis inhibition. Therefore, targeting PLIN5 could offer a novel therapeutic strategy to address MAFLD by modulating lipid metabolism and ferroptosis pathways.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and restricted, repetitive behaviors (RRBs). These symptoms may stem from cognitive flexibility deficits, with dysfunction in the prefrontal cortex (PFC) and related neural circuits proposed as underlying mechanisms.Objectives: This study examined whether transcranial direct current stimulation (tDCS) could enhance PFC activity and functional connectivity, thereby improving cognitive flexibility in a valproic acid (VPA)-induced ASD rat model.Methods: Pregnant Sprague-Dawley rats were administered VPA (600 mg/kg, E12.5) or saline. VPA-exposed offspring exhibiting curved tails received tDCS and underwent behavioral tests, including the three-chamber social interaction test and cross-maze rule-shifting task, while local field potentials (LFPs) were recorded. Immunohistochemistry was performed to evaluate microglial activation (Iba1 +) and synaptic density (PSD95).Results: Valproic acid -exposed offspring displayed significant social interaction deficits and impaired cognitive flexibility, alongside disrupted functional connectivity in frontal-striato-hippocampal circuits. Neuroinflammatory analysis revealed elevated Iba1+ microglial density (p < 0.05) and increased PSD95 expression (p < 0.05). After tDCS intervention, VPA rats exhibited restored sociability and cognitive performance, normalized functional connectivity, and significantly reduced microglial activation (p < 0.05), though PSD95 levels were unaffected.Conclusion: Our results indicate that tDCS ameliorates ASD-like phenotypes in VPA rats, potentially through microglial suppression and PFC network synchronization. These findings support neuromodulation as a promising therapeutic approach for ASD-related cognitive dysfunction.

Background: Tumor‐associated neutrophils (TANs), a major immune cell type in the tumor microenvironment (TME), are associated with antitumor or pro‐tumor phenotypes. A wealth of evidence evidences demonstrated that the content of TANs has been implicated in the pathogenesis of cancer and may be ideal targets for cancer therapy. In this study, we identified TANs‐related genes to construct a prognostic model and evaluated its potential as a biomarker for predicting prognosis and immunotherapeutic response in colorectal carcinoma (CRC). Methods: Kaplan–Meier survival curves were used to assess the impact of TANs infiltration on patient survival. Weighted Gene Co‐Expression Network Analysis (WGCNA) identified genes associated with TANs. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression were applied to filter TANs‐related risk signatures. A prognostic model was constructed using data from The Cancer Genome Atlas (TCGA) and validated with the GSE39582 dataset. Immune cell infiltration levels and immunotherapy responses were compared between high‐ and low‐risk groups. Functional enrichment analysis was performed to identify relevant Gene Ontology (GO) terms and pathways. Results: Patients with elevated TANs levels have a low survival rate. Fourteen risk signature genes were identified, and a risk model was constructed based on these genes. Patients in the high‐risk group had worse survival outcomes and improved responsiveness to immunotherapy. Conclusions: This study comprehensively analyzed the role of TANs in CRC progression and developed a prognostic model based on TANs‐related genes, which holds significant potential for predicting prognosis and immunotherapy outcomes in CRC patients.

α1-antitrypsin deficiency (AATD) is a well-known genetic disease. No effective medical therapy is currently available for the liver disease. 24-norursodeoxycholic acid (norUDCA) has shown potent anti-cholestatic, anti-inflammatory, and anti-fibrotic properties in experimental and human cholestatic liver diseases. In this minireview, we discuss the role of exogenous norUDCA in reducing accumulation of a1-antitrypsin mutant Z proteins (AATZ) in the livers of PiZ mice and the in vitro model, HTOZ cells. In these model systems, norUDCA reduces AATZ accumulation and reduces the associated toxicity, but human trials will be needed to explore further use.

Background: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that has been found to be associated with dysregulation of gastrointestinal functions and gut microbial homeostasis (the so-called “gut-brain axis”). ASD is often accompanied by poor performances in social interaction and repetitive behaviors. Studies on the gut-brain axis provide novel insights and candidate targets for ASD therapeutics and diagnosis. Based on the ASD mice model, this work aims to reveal the mechanisms behind the interaction of intestinal barrier function and probiotics in ASD mouse models. Results: We found an altered intestinal barrier in both BTBR T⁺ Itpr3^tf/J (BTBR) and valproic acid (VPA) mice, including increased intestinal permeability, decreased expression of intestinal tight junction proteins (claudin1, claudin3, and occludin), and increased levels of IL-6, TNF-α, and IFN-γ. Based on intestinal microbial alternation, C. butyricum can drive reduced expression of histone deacetylases 1 (HDAC1) and enhanced intestinal barrier function, significantly promoting behavioral abnormalities of ASD in BTBR mice. In parallel, we confirmed that C. butyricum was involved in the regulation of intestinal function by the Trek1 channel, indicating that it is a target of C. butyricum/butyric acid to improve intestinal barrier function in ASD mice. Conclusions: Our finding provides solid evidence for the gut microbiota involved in ASD through the brain-gut axis. In addition, the probiotics C. butyricum hold promise to improve gut health and ameliorate behavioral abnormalities associated with ASD.