Yilong Zhu

Alzheimer’s disease treatment is shifting from pathology removal to regulating the brain microenvironment. Anti-Aβ monoclonal antibodies, such as lecanemab and donanemab, provide statistically significant disease-modifying effects but offer only modest cognitive improvement and pose safety risks, including amyloid-related imaging abnormalities. These results show that amyloid clearance is clinically relevant but not sufficient for full restoration of neuroimmune, metabolic, synaptic, and neurovascular balance. Microglia are now seen as central to Alzheimer’s disease susceptibility and progression, existing along dynamic, spatially organized, sex-influenced, and genetically determined continua beyond a simple pro- or anti-inflammatory state. This review calls out three key drivers of microglial dysfunction: the TREM2–APOE lipid-sensing axis, complement-mediated synaptic elimination, and immunometabolic reprogramming—including glycolysis, mitochondrial damage, autophagy failure, NAD+ depletion, and innate immune signaling. We examine natural bioactive compounds, metabolic modulators, and biomimetic nanodelivery as promising, yet currently unproven, strategies for adjusting microglial state. Future therapies should incorporate both pathology removal and microenvironment protection, tailored by disease stage, genetic profile, sex, vascular risk, and microglial state-associated biomarkers.

Long-term excessive alcohol intake can directly injure the gastroduodenal mucosa, causing gastric erosions, gastric ulcers, and gastrorrhagia. Fritillaria ussuriensis Maxim is a famous traditional Chinese medicine and health food produced in China. Sipeimine is an alkaloidal component of Fritillaria ussuriensis Maxim. This research aimed to investigate the protective effects of sipeimine on ethanol-induced gastric ulcers in mice. The results displayed that sipeimine could alleviate gastric tissue damage and decrease the levels of SOD, MDA, IL-6, IFN-γ, TNF-α, and IL-1β. Sipeimine treatment also adjusted macrophage polarization and the balance of Th17/Treg cell by reducing the expression of Jak1/2, p-Jak1/2, Stat1/3, and p-Stat1/3. Moreover, sipeimine could increase the abundance of Lactobacillus_johnsonii and decrease the abundance of Bacteroides_vulgatus in the gut microbiota. Meanwhile, sipeimine treatment significantly decreased the abundance of Rodentibacter_heylii and Streptococcus_cuniculi in the gastric microbiota. In conclusion, sipeimine can improve gastric ulcers by suppressing the Jak-Stat pathway, reversing gut-gastro microbiota dysbiosis, inhibiting macrophage M1 polarization, maintaining the balance of Th17/Treg cell, and lessening sustained inflammatory injury.

Purpose: The study was aimed at identifying the pathogenic gene responsible for X‐linked nonsyndromic hearing loss (NSHL) in a five‐generation Chinese family and at elucidating the gene’s function both in vivo using a zebrafish model and in vitro using PRPS1 knockdown HEI‐OC1 cells.Methods: Exome sequencing (ES) and Sanger sequencing were used to identify the pathogenic variants. A transgenic zebrafish model overexpressing the novel PRPS1 variant (c.494G>A: p.Cys165Tyr) was constructed, and PRPS1 was knocked down in HEI‐OC1 cells using siRNA to explore the underlying mechanisms. Hair cell development and behavior were assessed in zebrafish, and mitochondrial function and cell viability were analyzed in HEI‐OC1 cells.Results: A novel missense variant (c.494G>A: p.Cys165Tyr) in the PRPS1 gene was identified as the pathogenic variant causing progressive X‐linked deafness‐1 (DFNX1). The variant led to hair cell death in zebrafish, with disrupted swimming behavior. In HEI‐OC1 cells, PRPS1 knockdown resulted in downregulation of the nicotinamide adenine dinucleotide (NAD⁺)/sirtuin 3 (SIRT3)/superoxide dismutase 2 (SOD2) pathway, increased reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and apoptosis, which were partially rescued by pretreatment with nicotinamide mononucleotide (NMN), a precursor of NAD⁺.Conclusion: The study reports a novel PRPS1 variant contributing to the variant spectrum of PRPS1 and highlights the role of PRPS1 deficiency in increasing oxidative stress‐induced hair cell apoptosis via the NAD⁺/SIRT3/SOD2 pathway. These findings provide new insights into the molecular mechanisms of PRPS1‐related hearing loss and potential therapeutic targets.

Objectives: Inflammatory cytokine secretion and gut microbiota dysbiosis play crucial roles in ulcerative colitis. In this research, the protective effects of peimisine on colitis mice were investigated. Methods: The protective effects were evaluated by the disease activity index, colonic length, hematoxylin–eosin, and AB/PAS Staining. The protective mechanisms were analyzed by ELISA, Western-blot, immunohistochemistry staining, immunofluorescence staining, and 16S rRNA gene analysis. Key findings: The results showed that peimisine treatment could reduce the disease activity index, prevent colonic shortening, and alleviate colon tissue damage. Peimisine treatment also decreased the levels of MCP-1, IL-1β, IL-6, IFN-γ, TNF-α and affected macrophage polarization and Th17/Treg cell balance by downregulating the expression of jak1/2, p-jak1/2, stat1/3, and p-stat1/3. Moreover, peimisine treatment significantly increased the abundances of beneficial microbes (e.g. Ruminococcaceae UCG-014 and Lachnospiraceae_NK4A136_group) and decreased the abundances of harmful microbes (e.g. Bacteroides and Escherichia). Conclusions: Peimisine can ameliorate colitis by inhibiting Jak–Stat signaling pathway, reversing gut microbiota alterations, suppressing macrophage M1 polarization, maintaining the Th17/Treg cell balance, and reducing sustained inflammatory cytokines-related inflammatory injury.

Background: Apoptin is derived from the chicken anemia virus and exhibits specific cytotoxic effects against tumor cells. Herein, we found that Apoptin induced a strong and lasting endoplasmic reticulum (ER) stress response, Ca²⁺imbalance, and triggered the mitochondrial apoptotic pathway. The aim of this study was to explore the mechanisms by which Apoptin exhibited anti‐tumor effects in HepG‐2 cells.Methods: The intracellular levels of calcium (Ca²⁺) were induced by ER stress and determined by electron microscopy, flow cytometry, and fluorescence staining. The mitochondrial injury was determined by mitochondrial membrane potential and electron microscopy. Western blotting was used to investigate the levels of key proteins in ER stress and the apoptotic pathway in mitochondria. The relationship between Ca²⁺levels and apoptosis in Apoptin‐treated cells was analyzed using a Ca²⁺chelator (BAPTA‐AM), flow cytometry, and fluorescence staining. We also investigated the in vivo effects of Ca²⁺imbalance on the mitochondrial apoptotic pathway using tumor tissues xenografted on nude mice.Results: This study showed that Apoptin induced a strong and long‐ lasting ER stress and injury, which subsequently led to an imbalance of cellular Ca²⁺levels, a reduction in the mitochondrial membrane potential, a significant extent image in the mitochondrial structure, and an increase in the expression levels of Smac/Diablo and Cyto‐C.Conclusions: In summary, Apoptin induced apoptosis in HepG‐2 cells via Ca²⁺imbalance and activation of the mitochondrial apoptotic pathway. This study provided a new direction for antitumor research in Apoptin.

Apoptin is derived from the chicken anemia virus and exhibits specific cytotoxic effects against tumor cells. Herein, we found that Apoptin induced a strong and lasting endoplasmic reticulum (ER) stress response and Ca²⁺ imbalance, and triggered the mitochondrial apoptotic pathway. The aim of this study was to explore the mechanisms by which Apoptin exhibited anti-tumor effects on the HepG-2 cells. The intracellular level of calcium (Ca²⁺) was induced by ER stress and determined by electron microscopy, flow cytometry and fluorescence staining. Mitochondrial injury was determined by mitochondrial membrane potential, electron microscopy. Western blotting was used to investigate the levels of key proteins in the ER stress and the apoptotic pathway in the mitochondria. The relationship between Ca²⁺ level and apoptosis on Apoptin-treating cells was analyzed using Ca²⁺ chelator (BAPTA-AM), flow cytometry and fluorescence staining. We also investigated the in vivo effects of Ca²⁺ imbalance on the mitochondrial apoptotic pathway using the tumor tissues xenografted on nude mice. In vitro and in vivo experiments showed that Apoptin caused an imbalance in Ca²⁺, and increased the expression levels of Smac/Diablo and Cyto-C. In summary, Apoptin induced apoptosis in HepG-2 cells via Ca²⁺ imbalance-triggered mitochondrial apoptotic pathway. This study provided a new direction for antitumor research in Apoptin.

Ad-VT (Ad-Apoptin-hTERTp-E1a) is a type of oncolytic adenovirus with dual specific tumor cell death ability. It can effectively induce cell death of breast cancer cells and has better effect when used in combination with chemotherapy drugs. However, it has not been reported whether Ad-VT reduces the resistance of breast cancer cells to chemotherapy drugs. The purpose of this study is to investigate the effect of Ad-VT on drug resistance of Adriamycin-resistant breast cancer cells. For this, the effects of different doses of Ad-VT on the resistance of breast cancer cells to Adriamycin were analyzed using qualitative and quantitative experiments in vitro and in vivo. The Ad-VT can reduce the resistance of MCF-7/ADR to adriamycin, which is caused by the reduction of MRP1 protein level in MCF-7/ADR cells after treatment with Ad-VT, and MRP1 can be interfered with by autophagy inhibitors. Subsequently, the upstream signal of autophagy was analyzed and it was found that Ad-VT reduced the resistance of cells to doxorubicin by reducing the level of mTOR, and then the analysis of the upstream and downstream proteins of mTOR found that Ad-VT increased the sensitivity of MCF-7/ADR cells to adriamycin by activating AMPK-mTOR-eIF4F signaling axis. Ad-VT can not only significantly induce cell death in MCF-7/ADR cells, but also improved their sensitivity to Adriamycin. Therefore, the combination of Ad-VT and chemotherapy drugs may become a new strategy for the treatment of breast cancer in overcoming Adriamycin resistance.