Benjie Zhou

Ulcerative Colitis (UC) refers to multifaceted disorders in the intestinal microenvironment and microbiota homeostasis, which are exacerbated by increased reactive oxygen species (ROS). As a natural acyclic monoterpene alcohol abundant, geraniol exhibits outstanding antioxidant and anti-inflammatory bioactivity. However, its poor biocompatibility and low stability limit its further applications. This study leveraged the ROS-responsive properties of the thiolketone bond to construct a delivery platform, thereby enhancing geraniol's biocompatibility, stability, and targeted transport characteristics. The TKG@NPs exhibited ROS-responsive release characteristics and released within the oxidative microenvironment of an inflamed colon. In vitro studies, TKG@NPs improved geraniol internalization and significantly suppressed oxidative stress-induced excessive ROS production and macrophage polarization toward the M1 type. In vivo studies, it showed that TKG@NPs effectively alleviated colitis brought on by dextran sodium sulfate and preserved the integrity of colonic tissue structure, characterized by suppressing pro-inflammatory mediators coinciding with facilitating anti-inflammatory mediators. Furthermore, TKG@NPs not only help maintain ZO-1 and Occludin expression but also support intestinal homeostasis by promoting the growth of beneficial bacteria while suppressing pathogenic populations. In conclusion, the geraniol delivery system offers potential applications for oral administration of hydrophobic bioactivators in ulcerative colitis interventions.

Background: The mechanism of Dendrobium officinale polysaccharide-based nanocarriers in enhancing photodynamic immunotherapy in colorectal cancer (CRC) remains poorly understood. Methods: The effects of TPA-3BCP-loaded cholesteryl hemisuccinate–Dendrobium officinale polysaccharide nanoparticles (DOP@3BCP NPs) and their potential molecular mechanism of action in a tumor-bearing mouse model of CRC were investigated using non-targeted metabolomics and transcriptomics. Meanwhile, a histopathological analysis (H&E staining, Ki67 staining, and TUNEL assay) and a qRT-PCR analysis revealed the antitumor effects of DOP@3BCP NPs with and without light activation. Results: Through metabolomics and transcriptomics analysis, we found an alteration in the metabolome and functional pathways in the examined tumor tissues. The metabolic analysis showed 69 and 60 differentially expressed metabolites (DEMs) in positive- and negative-ion modes, respectively, in the treated samples compared to the Control samples. The transcriptomics analysis showed that 1352 genes were differentially expressed among the three groups. The differentially regulated functional pathways were primally related to the antitumor immune response. The results of the pathological histology assay and qRT-PCR analysis verified the findings of the integrated metabolomics and transcriptomics analysis. Conclusions: Overall, our findings elucidate the potential antitumor mechanisms of the D. officinale polysaccharide-based nanocarrier in enhancing photodynamic immunotherapy in CRC.

The impairment of the blood-brain barrier (BBB) has been increasingly recognised as a critical element in the early pathogenesis of Alzheimer’s disease (AD), prompting a focus on brain endothelial cells (BECs), which serve as the primary constituents of the BBB. Death receptor 6 (DR6) is highly expressed in brain vasculature and acts downstream of the Wnt/β-catenin pathway to promote BBB formation during development. Here, we found that brain endothelial DR6 levels were significantly reduced in a murine model of AD (APP_swe/PS1_dE9 mice) at the onset of amyloid-β (Aβ) accumulation. Toxic Aβ_25-35 oligomer treatment recapitulated the reduced DR6 in cultured BECs. We further showed that suppressing DR6 resulted in BBB malfunction in the presence of Aβ_25-35 oligomers. In contrast, overexpressing DR6 increased the level of BBB functional proteins through the activation of the Wnt/β-catenin and JNK pathways. More importantly, DR6 overexpression in BECs was sufficient to rescue BBB dysfunction in vitro. In conclusion, our findings provide new insight into the role of endothelial DR6 in AD pathogenesis, highlighting its potential as a therapeutic target to tackle BBB dysfunction in early-stage AD progression.

Non-alcoholic fatty liver disease (NAFLD) is a type of metabolic stress liver injury closely related to insulin resistance (IR) and genetic susceptibility without alcohol consumption, which encompasses a spectrum of liver disorders ranging from simple hepatic lipid accumulation, known as steatosis, to the more severe form of steatohepatitis (NASH). NASH can progress to cirrhosis and hepatocellular carcinoma (HCC), posing significant health risks. As a multisystem disease, NAFLD is closely associated with systemic insulin resistance, central obesity, and metabolic disorders, which contribute to its pathogenesis and the development of extrahepatic complications, such as cardiovascular disease (CVD), type 2 diabetes mellitus, chronic kidney disease, and certain extrahepatic cancers. Recent evidence highlights the indispensable roles of intestinal barrier dysfunction and gut microbiota in the onset and progression of NAFLD/NASH. This review provides a comprehensive insight into the role of intestinal barrier dysfunction and gut microbiota in NAFLD, including intestinal barrier function and assessment, inflammatory factors, TLR4 signaling, and the gut–liver axis. Finally, we conclude with a discussion on the potential therapeutic strategies targeting gut permeability and gut microbiota in individuals with NAFLD/NASH, such as interventions with medications/probiotics, fecal transplantation (FMT), and modifications in lifestyle, including exercise and diet.

肝纤维化是一种肝脏组织在长期炎症状态下持续损伤和自我修复形成纤维化瘢痕的过程, 以细胞外基质过度沉积为特征的病理综合征. 目前肝纤维化常见的病因包括酒精性脂肪肝炎、非酒精性肝炎、胆汁淤积性肝病、化学性肝损伤、病毒性肝炎等. 肝纤维化是肝硬化和肝功能衰竭的主要前期阶段, 在持续炎症刺激下, 若不加以控制, 可能会进一步发展成肝硬化, 乃至肝癌, 对患者的治疗负担和生存质量产生重要影响. 近年来, 研究表明色氨酸及其代谢产物在肝纤维化的发生和进展中起着重要的调控作用, 本文将综述色氨酸代谢与肝纤维化的相关研究进展, 以期深入了解其潜在的治疗价值.

Background: Endoplasmic reticulum (ER) stress, promoting lipid metabolism disorders and steatohepatitis, contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Hugan Qingzhi tablets (HQT) has a definite effect in the clinical treatment of NAFLD patients, but its mechanism is still unclear. This study aims to investigate the effects of HQT on ER stress in the liver tissues of NAFLD rats and explore the underlying mechanism. Methods: The NAFLD rat model was managed with high-fat diet (HFD) for 12weeks. HQT was administrated in a daily basis to the HFD groups. Biochemical markers, pro-inflammatory cytokines, liver histology were assayed to evaluate HQT effects in HFD-induced NAFLD rats. Furthermore, the expression of ER stress-related signal molecules including glucose regulating protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), p-PERK, eukaryotic translation initiation factor 2α (EIF2α), p-EIF2α, activating transcription factor 4 (ATF4), acetyl-coenzyme A-carboxylase (ACC), activating transcription factor (ATF6), and nuclear factor-kappa B-p65 (NF-κB-p65) were detected by western blot and/or qRT-PCR. Results: The histopathological characteristics and biochemical data indicated that HQT exhibited protective effects on HFD-induced NAFLD rats. Furthermore, it caused significant reduction in the expression of ERS markers, such as GRP78, PERK, p-PERK, and ATF6, and subsequently downregulated the expression of EIF2α, p-EIF2α ATF4, ACC, and NF-κB-p65. Conclusions: The results suggested that HQT has protective effect against hepatic steatosis and inflammation in NAFLD rats by attenuating ER stress, and the potential mechanism is through inhibition of PERK and ATF6 pathways.