摘要：
Hyperhomocysteinemia can cause severe damage to kidney. Ferroptosis represents a critical mechanism in the initiation and development of kidney disorders. We focus on the beta-catenin/GPX4 signaling pathway to explore how homocysteine influences ferroptosis regulation in renal tubular epithelial cells. C57BL/6J mice were administered drinking water with high level of homocysteine to establish a hyperhomocysteinemia model. In the cell experiments, HKC-8 cells were exposed to homocysteine for a duration of 12 h. Active beta-catenin, beta-catenin, GPX4, FTH1, and KIM-1 were detected using Western blotting; Biochemical assays were conducted to measure lipid ROS, Fe2+, and GSH; GPX4 and beta-catenin were detected through immunohistochemistry and immunofluorescence techniques; Mitochondrial damage was examined using transmission electron microscopy; ChIP analysis, coupled with dual-luciferase reporter gene assays, was employed to investigate the relationship between beta-catenin protein and GPX4 gene promoter. Our findings revealed that homocysteine disrupted beta-catenin signaling, inhibited GPX4 expression in renal tubular epithelial cells, subsequently promoted ferroptosis. Overexpression of beta-catenin or GPX4 inhibited ferroptosis induced by homocysteine, and beta-catenin regulated GPX4 expression in renal tubular epithelial cells. Further assays demonstrated that GPX4 acted as a target gene of beta-catenin. In conclusion, homocysteine elicits ferroptosis in renal tubular epithelial cells by disrupting beta-catenin signaling and inhibiting its target gene, GPX4.
摘要：
Persistent and maladaptive drug-related memories represent a key component in drug addiction. Converging evidence from both preclinical and clinical studies has demonstrated the potential efficacy of the memory reconsolidation updating procedure (MRUP), a non-pharmacological strategy intertwining two distinct memory processes: reconsolidation and extinction-alternatively termed "the memory retrieval-extinction procedure". This procedure presents a promising approach to attenuate, if not erase, entrenched drug memories and prevent relapse. The present review delineates the applications, molecular underpinnings, and operational boundaries of MRUP in the context of various forms of substance dependence. Furthermore, we critically examine the methodological limitations of MRUP, postulating potential refinement to optimize its therapeutic efficacy. In addition, we also look at the potential integration of MRUP and neurostimulation treatments in the domain of substance addiction. Overall, existing studies underscore the significant potential of MRUP, suggesting that interventions predicated on it could herald a promising avenue to enhance clinical outcomes in substance addiction therapy.
摘要：
Ferroptosis, a form of iron-dependent regulated cell death, has emerged as a critical mechanism in the pathogenesis of organ fibrosis. This review aims to provide an overview of the molecular mechanisms underlying ferroptosis and its contribution to fibrosis in various organs, including the liver, lung, heart, and kidneys. We explore how dysregulated iron metabolism, lipid peroxidation, and oxidative stress contribute to ferroptosis and subsequent tissue damage, promoting the progression of fibrosis. In addition, we highlight the complex interplay between ferroptosis and other cellular processes such as apoptosis, necrosis, and inflammation in the fibrotic microenvironment. Furthermore, this review discusses current therapeutic strategies targeting ferroptosis, including iron chelation, antioxidants, and modulators of lipid peroxidation. We also examine ongoing clinical and preclinical studies aimed at translating these findings into viable treatments for fibrotic diseases. Understanding the role of ferroptosis in organ fibrosis offers novel therapeutic opportunities, with the potential to mitigate disease progression and improve patient outcomes.
Ferroptosis, a form of iron-dependent regulated cell death, has emerged as a critical mechanism in the pathogenesis of organ fibrosis. This review aims to provide an overview of the molecular mechanisms underlying ferroptosis and its contribution to fibrosis in various organs, including the liver, lung, heart, and kidneys. We explore how dysregulated iron metabolism, lipid peroxidation, and oxidative stress contribute to ferroptosis and subsequent tissue damage, promoting the progression of fibrosis. In addition, we highlight the complex interplay between ferroptosis and other cellular processes such as apoptosis, necrosis, and inflammation in the fibrotic microenvironment. Furthermore, this review discusses current therapeutic strategies targeting ferroptosis, including iron chelation, antioxidants, and modulators of lipid peroxidation. We also examine ongoing clinical and preclinical studies aimed at translating these findings into viable treatments for fibrotic diseases. Understanding the role of ferroptosis in organ fibrosis offers novel therapeutic opportunities, with the potential to mitigate disease progression and improve patient outcomes.
作者机构：
[Yao, Xiang-Rong; He, Jun-Yan] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Oncol, Hengyang, Peoples R China.;[Yao, Xiang-Rong; Xiao, Fang-Zhu] Univ South China, Sch Publ Hlth, Hengyang, Peoples R China.;[Xiao, Wen-Tao] Nantong Univ, Affiliated Hosp, Med Sch, Dept Radiat Oncol, Nantong, Peoples R China.;[Huang, Cui-Qin] Univ South China, Hengyang Med Sch, Affiliated Hosp 1, Dept Pathol, Hengyang, Peoples R China.
通讯机构：
[He, JY ; Huang, CQ ] U;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Oncol, Hengyang, Peoples R China.;Univ South China, Hengyang Med Sch, Affiliated Hosp 1, Dept Pathol, Hengyang, Peoples R China.
摘要：
Head and neck squamous cell carcinoma (HNSC) is a prevalent and aggressive malignancy with poor prognosis, underscoring the need for novel biomarkers and therapeutic strategies. This study investigates the role of C16orf74 as a potential diagnostic and prognostic biomarker in HNSC. Bioinformatics analyses revealed that C16orf74 is significantly overexpressed in HNSC and is associated with advanced disease stages, therapy resistance, and shorter overall and progression-free survival. A prognostic nomogram integrating C16orf74 expression with clinicopathological features demonstrated robust predictive performance. Functional enrichment and immune infiltration analyses suggest that high C16orf74 expression might contribute to an immunosuppressive tumor microenvironment by reducing key immune cell populations, such as B cells, T cells, and natural killer cells, which are critical for anti-tumor immunity. Moreover, C16orf74 expression was inversely associated with immune checkpoint expression and immunotherapy response, highlighting its potential as a predictive biomarker for immune checkpoint blockade (ICB) efficacy. Drug sensitivity analyses identified potential therapeutic agents, including arsenic trioxide, carmustine, vincristine, quercetin, and carboplatin for patients with high C16orf74 expression. These findings highlight the potential of C16orf74 as a biomarker and therapeutic target to improve HNSC management.
摘要：
One‑carbon metabolism plays an important role in cancer progression. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial enzyme in one‑carbon metabolism, is dysregulated in several cancer types. However, the precise role and mechanisms of MTHFD2 in esophageal squamous cell carcinoma (ESCC) remain unclear. The present study unravels the multifaceted mechanisms by which MTHFD2 contributes to ESCC pathogenesis. Bioinformatics analyses revealed significant upregulation of MTHFD2 in ESCC tumor tissues, which was associated with advanced disease stage and poor patient prognosis. Validating these findings in clinical samples, MTHFD2 overexpression was confirmed through immunohistochemistry, Reverse transcription‑quantitative PCR and western blotting. Knockdown of MTHFD2 inhibited ESCC cell viability, colony formation, invasion, and tumor growth in vivo, indicating its oncogenic potential. Mechanistically, the present study elucidated a novel regulatory axis involving N6‑methyladenosine modification and MTHFD2 mRNA stability. Specifically, methyltransferase‑like 3 (METTL3) and insulin‑like growth factor 2 mRNA binding protein 2 (IGF2BP2) were identified as key mediators of m6A‑dependent stabilization of MTHFD2 mRNA, contributing to its elevated expression in ESCC. Furthermore, MTHFD2 was found to activate PI3K/AKT and ERK signaling pathways by modulating interaction between phosphatidylethanolamine‑binding protein 1 (PEBP1) and raf‑1 proto‑oncogene (RAF1). This modulation was achieved through direct binding of MTHFD2 to PEBP1, disrupting the inhibitory effect of PEBP1 on RAF1 and promoting downstream pathway activation. The oncogenic functions of MTHFD2 were attenuated upon PEBP1 knockdown, underscoring the role of the MTHFD2‑PEBP1 axis in ESCC progression. In summary, the present study uncovers a novel regulatory mechanism involving m6A modification and the MTHFD2‑PEBP1 axis, unveiling potential therapeutic avenues for targeting MTHFD2 in ESCC.
作者机构：
[Wang, Lihua] Hengyang Maternal and Child Health Hospital, Hengyang, China;[Zheng, Qinwen; Wei, Dangheng"] Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, China;[Liu, Yue] Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China;Department of Vascular Surgery, the Second Xiangya Hospital, Central South University, Changsha, China;["Xia, Dexiang] Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, China<&wdkj&>Department of Vascular Surgery, the Second Xiangya Hospital, Central South University, Changsha, China
通讯机构：
[Lihua Wang] H;[Dangheng Wei] I;Hengyang Maternal and Child Health Hospital, Hengyang, China<&wdkj&>Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, China
摘要：
Cardiovascular disease (CVD) is a leading cause of morbidity and mortality globally. Recent groundbreaking preclinical and clinical research underscores the pivotal role of metabolite remodelling in the pathology of CVD. This metabolic transformation not only directly fuels the progression of CVD but also profoundly influences the immune response within the cardiovascular system. In this review, we focused on the complex interactions between cardiovascular metabolic alterations and immune responses during the course of CVD. Furthermore, we explore the potentialtherapeutic interventions that could be developed based on the understanding of metabolic alterations and immune dysregulation in CVD. By targeting these metabolic and immunological pathways, novel strategies for the prevention and treatment of CVDs might be developed to improve patient outcomes and reduce the global burden of this disease.
期刊：
JOURNAL OF GLOBAL HEALTH,2025年15:04001 ISSN：2047-2978
通讯作者：
Zhang, YP
作者机构：
[Zhuang, Xinqi; Lei, Xiaoyu; Zhang, Yin-Ping; Zhang, YP; Zhang, Dandan; Zhang, Jianzhong] Xi An Jiao Tong Univ, Hlth Sci Ctr, Sch Nursing, West Yanta Rd 76, Xian 710061, Shaanxi, Peoples R China.;[Zhang, Dandan] Univ South China, Affiliated Nanhua Hosp, Inst Clin Res, Hengyang Med Sch, Hengyang, Hunan, Peoples R China.;[Liu, Fen] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Gynecol & Obstet, Hengyang, Hunan, Peoples R China.;[Cui, Tianxin] Univ Edinburgh, Sch Hlth Social Sci, Edinburgh, Scotland.
通讯机构：
[Zhang, YP ] X;Xi An Jiao Tong Univ, Hlth Sci Ctr, Sch Nursing, West Yanta Rd 76, Xian 710061, Shaanxi, Peoples R China.
摘要：
BACKGROUND: As fertility rates decline and population ageing intensifies, the conflict between career and childbearing continues to impact clinicians, especially women. Exploring gender differences in the fertility intentions of male and female clinicians could help with identifying barriers to childbearing, developing effective policies to support work-life balance, and addressing the gap in research on gender disparities in this field. METHODS: We conducted a cross-sectional survey among health care personnel in Chinese public hospitals. Through cluster sampling from highly active WeChat groups, we gathered 698 responses from clinicians to the third fertility intention questionnaire online. We then used descriptive statistics and χ(2) tests for analysis. RESULTS: Men (28.28%) had higher intentions of having a third child than women (20.71%) (P = 0.013). In terms of reasons, female clinicians were more concerned than male clinicians about the impact on their career development (P = 0.002), difficulties in job hunting (P = 0.039), and physical injuries caused by multiple births (P < 0.001), and whether the elderly can help (P = 0.001). Conversely, men's apprehensions centred on economic factors such as real house costs (P < 0.001), policy support (P = 0.036), and wives' disagreement (P < 0.001). In discussing governmental interventions, men showed a higher level of interest in policies related to child care (P < 0.001), employment stability for women (P < 0.001), extended maternity leave (P < 0.001), and financial assistance than women (P < 0.001). CONCLUSIONS: Our findings show substantial gender-specific differences in third-child fertility intentions among clinicians. To address this, the government should consider divisions in family roles, future societal needs, and women's career development. Policies should focus on balancing work and family by offering affordable childcare, flexible parenting leave, financial incentives, and career support, ensuring childbirth does not negatively impact women's professional growth, and fostering gender equality in parenting.
作者机构：
[Jiaxin Chen; Yalan Jiang; Yifei Wang; Gao Zeng; Peng Liu; Jindou She; Keming Zhong; Baihuan Duan; Hong Huang; Yating Wen; Wenxin Chen] Institute of Pathogenic Biology, Basic Medical School, Hengyang Medical School, University of South China, Hengyang Central Hospital, Hengyang, China
通讯机构：
[Wenxin Chen] I;Institute of Pathogenic Biology, Basic Medical School, Hengyang Medical School, University of South China, Hengyang Central Hospital, Hengyang, China
摘要：
Mycoplasma represents a unique genus of prokaryotic bacteria distinguished by the absence of a cell wall, a characteristic that sets it apart from other bacteria. Within the Mollicutes class, phylogenetic analysis reveals three distinct categories: Spiroplasma, Mycoplasma and Acholeplasma. Mycoplasmas within Pneumoniae are recognized for their capacity to induce a range of diseases in both humans and animals, frequently impacting respiratory and reproductive health. The representative strains in Pneumoniae group, particularly the M. pneumoniae clusters, have garnered significant attention due to their remarkable ability to adhere to, invade, and traverse host cells. This ability is facilitated by specialized structures known as attachment organelles, which possess a unique cytoskeletal structure that supports a distinctive gliding motility mechanism. This mode of motility is distinct from that observed in eukaryotes and the majority of bacteria. The gliding machinery of Mycoplasma is a complex assembly consisting of both surface and internal components, including a terminal button, paired plates, and a structure resembling a bowl or wheel. The internal architecture of the attachment organelles provides the essential scaffold for the operation of this sophisticated motility system. Mycoplasma's gliding motility is crucial for its infection process and its capacity to evade the host immune defenses. Understanding the role of this motility to immune evasion can offer profound insights into the pathogenesis of these bacteria, could pave the way for the development of more effective therapeutic strategies against diseases caused by Mycoplasma and related species.
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS,2025年1870(7):159681 ISSN：1388-1981
通讯作者：
Duo Gong
作者机构：
[Zhou, Jing; Zhou, Qin-Yi; Li, Zhao-Bing] Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, The Affiliated Nanhua Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China;[Zhou, Jing] Chongqing Creation Vocational College, Yongchuan 402160, Chongqing, China;[Wang, Qun] Department of Cardiology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China;[Gong, Duo] Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, The Affiliated Nanhua Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China. Electronic address: gong-duo@usc.edu.cn;[Liu, Wang] Department of Gastrointestinal Surgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China. Electronic address: 1377621039@qq.com
通讯机构：
[Duo Gong] I;Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, The Affiliated Nanhua Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
摘要：
Macrophage cholesterol efflux, a critical step in reverse cholesterol transport, plays a pivotal role in the attenuation of atherosclerosis. Echinacoside, a natural compound with anti-inflammatory, antioxidant, and antitumor properties, has emerged as a potential therapeutic agent for atherosclerosis. However, the mechanisms underlying its anti-atherosclerotic effects remain unclear. In this study, we aimed to investigate the effects of echinacoside on lipid accumulation in macrophage-derived foam cells and on atherosclerotic progression in apoE −/− mice. Our key findings indicated that echinacoside upregulated ABCA1 expression, enhanced macrophage cholesterol efflux, and reduced lipid accumulation by modulating MDM2/PPARγ signaling. Additionally, echinacoside alleviated atherosclerotic progression in high-fat diet-fed apoE −/− mice. MDM2 overexpression with pcDNA3.1-MDM2 eliminated the effects of echinacoside on ABCA1 and PPARγ upregulation, macrophage cholesterol efflux, and lipid accumulation. In conclusion, echinacoside inhibits macrophage lipid accumulation and alleviates atherosclerotic progression via the MDM2/PPARγ/ABCA1 signaling pathway.
Macrophage cholesterol efflux, a critical step in reverse cholesterol transport, plays a pivotal role in the attenuation of atherosclerosis. Echinacoside, a natural compound with anti-inflammatory, antioxidant, and antitumor properties, has emerged as a potential therapeutic agent for atherosclerosis. However, the mechanisms underlying its anti-atherosclerotic effects remain unclear. In this study, we aimed to investigate the effects of echinacoside on lipid accumulation in macrophage-derived foam cells and on atherosclerotic progression in apoE −/− mice. Our key findings indicated that echinacoside upregulated ABCA1 expression, enhanced macrophage cholesterol efflux, and reduced lipid accumulation by modulating MDM2/PPARγ signaling. Additionally, echinacoside alleviated atherosclerotic progression in high-fat diet-fed apoE −/− mice. MDM2 overexpression with pcDNA3.1-MDM2 eliminated the effects of echinacoside on ABCA1 and PPARγ upregulation, macrophage cholesterol efflux, and lipid accumulation. In conclusion, echinacoside inhibits macrophage lipid accumulation and alleviates atherosclerotic progression via the MDM2/PPARγ/ABCA1 signaling pathway.
作者机构：
[Zeng, Chenlu; Xie, Hailong; Li, Junru; Song, Ge; Liu, Jiajia; Xie, HL] Univ South China, Canc Res Inst Hengyang Med Coll, Key Lab Canc Cellular & Mol Pathol Hunan Prov, Hengyang 421001, Hunan, Peoples R China.;[Zhao, Juanxia] Univ South China, Affiliated Nanhua Hosp, Hengyang Med Coll, Dept Pathol, Hengyang, Hunan, Peoples R China.;[Liu, Bin] Hunan Univ, Coll Biol, Changsha, Hunan, Peoples R China.;[Fan, Jialong; Fan, JL] Changsha Med Univ, Hunan Prov Key Lab Res & Dev Novel Pharmaceut Prep, Changsha 410219, Peoples R China.
通讯机构：
[Fan, JL ] C;[Xie, HL ] U;Univ South China, Canc Res Inst Hengyang Med Coll, Key Lab Canc Cellular & Mol Pathol Hunan Prov, Hengyang 421001, Hunan, Peoples R China.;Changsha Med Univ, Hunan Prov Key Lab Res & Dev Novel Pharmaceut Prep, Changsha 410219, Peoples R China.
关键词：
Exosomes;digestive system tumors;drug delivery;tumor therapy;exosome source
摘要：
Digestive system tumors constitute a major subset of malignancies, consistently ranking among the leading causes of mortality globally. Despite limitations inherent in current therapeutic modalities, recent advancements in targeted therapy and drug delivery systems have led to significant improvements in the efficacy of pharmacotherapy for digestive system tumors. In this context, exosomes - naturally occurring nanoscale vesicles - have emerged as promising drug delivery candidates due to their intrinsic molecular transport capabilities, superior biocompatibility, and targeted recognition of tumor cells. The integration of exosomes into cancer therapeutics represents a novel and potentially transformative approach for treating digestive system tumors, which may drive further progress in this field. This review comprehensively examines the sources, loading mechanisms, and therapeutic efficacy of exosomes in the context of digestive system tumor treatment. Furthermore, it discusses the opportunities and challenges associated with exosomes, offering insights into their future role within the therapeutic armamentarium against digestive tumors.
作者机构：
[Liu, Ying; Deng, Min; Zhai, Zibo; He, Longwei; Wang, Peipei; Li, Songjiao; Cheng, Dan; He, LW] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang Med Sch, Dept Pharm & Pharmacol, Hengyang 421002, Peoples R China.;[Cheng, Dan] Univ South China, Affiliated Nanhua Hosp, Clin Res Inst, Hengyang Med Sch,Dept Gastroenterol, Hengyang 421002, Peoples R China.;[He, LW; He, Longwei] Henan Normal Univ, Sch Chem & Chem Engn, Xinxiang 453007, Peoples R China.
通讯机构：
[He, LW ] H;[Li, SJ ; He, LW] U;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang Med Sch, Dept Pharm & Pharmacol, Hengyang 421002, Peoples R China.;Henan Normal Univ, Sch Chem & Chem Engn, Xinxiang 453007, Peoples R China.
摘要：
Revealing changes in the tumor microenvironment is crucial for understanding cancer and developing sensitive methods for precise cancer imaging and diagnosis. Intracellular hydrogen peroxide (H(2)O(2)) and microenvironmental factors (e.g., viscosity and polarity) are closely linked to various physiological and pathological processes, making them potential biomarkers for cancer. However, a triple-response theranostic probe for precise tumor imaging and therapy has not yet been achieved due to the lack of effective tools. Herein, we present a mitochondria-targeting near-infrared (NIR) fluorescent probe, VPH-5DF, capable of simultaneously monitoring H(2)O(2), viscosity, and polarity through dual NIR channels. The probe specifically detects H(2)O(2) via NIR emission (λ(em) = 650 nm) and shows high sensitivity to microenvironmental viscosity/polarity in the deep NIR channel (λ(em) ≈ 750 nm). Furthermore, the probe not only monitors mitochondrial polarity, viscosity, and fluctuations in endogenous/exogenous H(2)O(2) levels but also distinguishes cancer cells from normal cells through multiple parameters. Additionally, VPH-5DF can be employed to monitor alterations in H(2)O(2) levels, as well as changes in viscosity and polarity, during drug-induced pyroptosis in living cells. After treatment with VPH-5DF, chemotherapy-induced oxidative damage to the mitochondria in tumor cells activated the pyroptosis pathway, leading to a robust antitumor response, as evidenced in xenograft tumor models. Thus, this triple-response theranostic prodrug offers a new platform for precise in vivo cancer diagnosis and anticancer chemotherapy.
通讯机构：
[Tang, BS ; Qiu, J ; Qiu, J] C;Cent South Univ, Xiangya Hosp, Dept Neurol, Dept Geriatr, Changsha 410008, Peoples R China.;Cent South Univ, Xiangya Hosp, Hunan Key Lab Mol Precis Med, Changsha 41008, Peoples R China.
摘要：
OBJECTIVE: Despite substantial advancements in uncovering the genetic basis of Parkinson's disease (PD), a significant portion of cases characterized by familial PD remain genetically elusive. Here, we reported that biallelic variants in EPG5, a key autophagy gene responsible for Vici syndrome, are associated with PD. METHODS: Whole-exome sequencing (WES) was performed in the first cohort including 171 pedigrees with autosomal recessive PD (ARPD), 1,746 cases of sporadic early-onset PD (sEOPD, age at onset ≤ 50 years) and 1,652 healthy controls. Whole-genome sequencing (WGS) was performed in the second cohort consisting of 1,947 sporadic late-onset PD (sLOPD, age at onset >50 years) and 2,478 healthy controls. RESULTS: We identified 7 participants harboring compound heterozygous variants within the EPG5 gene across 1 family with ARPD (ARPD-F1), 4 sporadic EOPD cases, and 1 sporadic LOPD individual. A total of 10 novel variants in EPG5 were discovered in the 7 individuals, comprising 3 nonsense variants and 7 missense variants. The compound heterozygous variants in the EPG5 gene led to decreased expression of EPG5 protein, and impaired autophagy-lysosome function in cells derived from EPG5-PD individuals. We also revealed several key pathological features, including abnormal accumulation of autophagic vacuoles, aggregation of α-synuclein in skin tissue from EPG5-PD individuals. In mice, EPG5 deficiency led to progressive dopaminergic neurodegeneration in the substantia nigra of the midbrain. INTERPRETATION: Our results unveil a novel association between biallelic variants in EPG5 gene and PD, providing compelling initial evidence for the involvement of EPG5 and autophagy dysregulation in the development of PD. ANN NEUROL 2025;98:369-385.
摘要：
The Omicron BA.2.86 subvariants, JN.1, KP.2, and KP.3, have become predominant globally, raising concerns about their immune evasion from vaccines and monoclonal antibody (mAb) treatments. These variants harbor more receptor-binding domain (RBD) mutations than the XBB and EG.5 sub-lineages, which are already known to compromise vaccine and therapeutic efficacy. We evaluated sera from individuals vaccinated with inactivated vaccines, with or without breakthrough infections, as well as COVID-19 convalescents. Our results showed a substantial decrease in serum neutralizing activity against the JN.1, KP.2, XBB.1.5, and EG.5.1 variants compared to BA.2. Additionally, we developed 19 neutralizing antibodies from memory B cells, with some retaining efficacy against earlier Omicron variants. However, potency was notably diminished against newer subvariants like BF.7, BQ.1, XBB.1.5, and BA.2.86. Of mAbs, those isolated from COVID-19 convalescents, particularly SA-3, exhibited exceptional potency across ten variants from BA.2 to KP.2, with IC50 values ranging from 0.006 to 2.546 μg/mL. However, SA-3 had lost neutralizing activity against the KP.3 due to the Q493E mutation, but the KP.3 became susceptible to neutralization by the other mAb, SA-6. In contrast, SA-6 was unable to neutralize KP.2 because of the presence of R346T mutation. Our findings underscore the importance of continuous surveillance of viral evolution and the need for updated vaccines and therapeutics to combat the ongoing evolution of SARS-CoV-2, particularly in the context of emerging variants that escape both vaccine-induced immunity and monoclonal antibody treatments.
The Omicron BA.2.86 subvariants, JN.1, KP.2, and KP.3, have become predominant globally, raising concerns about their immune evasion from vaccines and monoclonal antibody (mAb) treatments. These variants harbor more receptor-binding domain (RBD) mutations than the XBB and EG.5 sub-lineages, which are already known to compromise vaccine and therapeutic efficacy. We evaluated sera from individuals vaccinated with inactivated vaccines, with or without breakthrough infections, as well as COVID-19 convalescents. Our results showed a substantial decrease in serum neutralizing activity against the JN.1, KP.2, XBB.1.5, and EG.5.1 variants compared to BA.2. Additionally, we developed 19 neutralizing antibodies from memory B cells, with some retaining efficacy against earlier Omicron variants. However, potency was notably diminished against newer subvariants like BF.7, BQ.1, XBB.1.5, and BA.2.86. Of mAbs, those isolated from COVID-19 convalescents, particularly SA-3, exhibited exceptional potency across ten variants from BA.2 to KP.2, with IC50 values ranging from 0.006 to 2.546 μg/mL. However, SA-3 had lost neutralizing activity against the KP.3 due to the Q493E mutation, but the KP.3 became susceptible to neutralization by the other mAb, SA-6. In contrast, SA-6 was unable to neutralize KP.2 because of the presence of R346T mutation. Our findings underscore the importance of continuous surveillance of viral evolution and the need for updated vaccines and therapeutics to combat the ongoing evolution of SARS-CoV-2, particularly in the context of emerging variants that escape both vaccine-induced immunity and monoclonal antibody treatments.
通讯机构：
[Zi, WJ; Yang, QW ; Qiu, ZM] A;Army Med Univ, Affiliated Hosp 2, Dept Neurol, 183 Xinqiao Main St, Chongqing 400037, Peoples R China.
摘要：
BACKGROUND: The safety and efficacy of treatment with intravenous tenecteplase before endovascular thrombectomy in patients with acute ischemic stroke due to large-vessel occlusion remain uncertain. METHODS: In this open-label trial conducted in China, we randomly assigned patients with acute ischemic stroke due to large-vessel occlusion who had presented within 4.5 hours after onset and were eligible for thrombolysis to receive either intravenous tenecteplase followed by endovascular thrombectomy or endovascular thrombectomy alone. The primary outcome was functional independence (a score of 0 to 2 on the modified Rankin scale; range, 0 to 6, with higher scores indicating more severe disability) at 90 days. Secondary outcomes included successful reperfusion before and after thrombectomy. Safety outcomes included symptomatic intracranial hemorrhage within 48 hours and death within 90 days. RESULTS: A total of 278 patients were randomly assigned to the tenecteplase-thrombectomy group and 272 to the thrombectomy-alone group. Functional independence at 90 days was observed in 147 patients (52.9%) in the tenecteplase-thrombectomy group and in 120 patients (44.1%) in the thrombectomy-alone group (unadjusted risk ratio, 1.20; 95% confidence interval, 1.01 to 1.43; P = 0.04). A total of 6.1% of the patients in the tenecteplase-thrombectomy group and 1.1% of those in the thrombectomy-alone group had successful reperfusion before thrombectomy, and 91.4% and 94.1%, respectively, had successful reperfusion after thrombectomy. Symptomatic intracranial hemorrhage within 48 hours occurred in 8.5% of the patients in the tenecteplase-thrombectomy group and in 6.7% of those in the thrombectomy-alone group; mortality at 90 days was 22.3% and 19.9%, respectively. CONCLUSIONS: Among patients with acute ischemic stroke due to large-vessel occlusion who had presented within 4.5 hours after onset, the percentage of patients with functional independence at 90 days was higher with intravenous tenecteplase plus endovascular thrombectomy than with endovascular thrombectomy alone. (Funded by the Chongqing Science and Health Joint Medical Research Project and others; BRIDGE-TNK ClinicalTrials.gov number, NCT04733742.).
通讯机构：
[Tan, XF; Yang, QL ; Chen, GD; Wu, GL] U;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Hepatopancreatobiliary Surg, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Inst Pharm & Pharmacol, Hengyang Med Sch, Sch Pharmaceut Sci, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Hengyang Med Sch, NHC Key Lab Birth Defect Res & Prevent, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Hengyang Med Sch, MOE Key Lab Rare Pediat Dis, Hengyang 421001, Hunan, Peoples R China.
摘要：
The advancement of mitochondria-targeted near-infrared-II (NIR-II) excitable phototheranostics constitutes a promising strategy for improving fluorescence-image-guided cancer phototherapy. However, developing phototheranostic agents that simultaneously combine high-contrast NIR-II fluorescence imaging with effective multimodal therapeutic techniques remains a substantial challenge. Herein, we reported a shielding-donor–acceptor–donor-shielding structured NIR-II phototheranostic (FCD-T) by a molecular engineering strategy, followed by self-assembly with glutathione-responsive copolymer to form FCD-T nanoparticles. The introduction of functional bithiophene endows FCD-T with significant electron-donating properties and reduces intermolecular π-π stacking interactions. The robust π-conjugation of fluorene with good rigidity would enhance the intramolecular charge transfer capability. Therefore, FCD-T NPs exhibited an NIR-II absorption peak at 1075 nm and an emission peak at 1280 nm. Upon NIR-II light excitation, such nanoparticles could generate excellent photothermal and photodynamic performances with good biocompatibility. Moreover, the NIR-II mitochondria-targeted phototherapy further facilitated mitochondrial apoptosis-related pathways, activating antitumor immunity and inhibiting tumor growth with single irradiation at low doses.
The advancement of mitochondria-targeted near-infrared-II (NIR-II) excitable phototheranostics constitutes a promising strategy for improving fluorescence-image-guided cancer phototherapy. However, developing phototheranostic agents that simultaneously combine high-contrast NIR-II fluorescence imaging with effective multimodal therapeutic techniques remains a substantial challenge. Herein, we reported a shielding-donor–acceptor–donor-shielding structured NIR-II phototheranostic (FCD-T) by a molecular engineering strategy, followed by self-assembly with glutathione-responsive copolymer to form FCD-T nanoparticles. The introduction of functional bithiophene endows FCD-T with significant electron-donating properties and reduces intermolecular π-π stacking interactions. The robust π-conjugation of fluorene with good rigidity would enhance the intramolecular charge transfer capability. Therefore, FCD-T NPs exhibited an NIR-II absorption peak at 1075 nm and an emission peak at 1280 nm. Upon NIR-II light excitation, such nanoparticles could generate excellent photothermal and photodynamic performances with good biocompatibility. Moreover, the NIR-II mitochondria-targeted phototherapy further facilitated mitochondrial apoptosis-related pathways, activating antitumor immunity and inhibiting tumor growth with single irradiation at low doses.
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作者机构：
[Shen, Xiangyu; Wu, Wei; Zhong, Xiaoxiao; Li, Jun; Pang, Jin; Ding, Boni; Qian, Liyuan; Chen, Ting; Zhong, XX] Cent South Univ, Dept Breast & Thyroid Surg, Xiangya Hosp 3, Changsha 410000, Hunan, Peoples R China.;[Zhong, Xiaoxiao; Zhong, XX] Cent South Univ, Xiangya Hosp 3, Dept Gen Surg, Changsha 410000, Hunan, Peoples R China.;[Han, Jiaxuan] Cent South Univ, Xiangya Hosp 2, Dept Ophthalmol, Changsha 410000, Hunan, Peoples R China.;[Li, Huan] Cent South Univ, Xiangya Hosp 3, Dept Gastroenterol, Changsha 410000, Hunan, Peoples R China.;[Yu, Bowen] Cent S Univ, Xiangya Hosp 3, Dept Gastrointestinal Surg, Changsha 410000, Hunan, Peoples R China.
通讯机构：
[Ding, BN ; Tong, XL ; Zhong, XX; Zhong, XX ] C;Cent South Univ, Dept Breast & Thyroid Surg, Xiangya Hosp 3, Changsha 410000, Hunan, Peoples R China.;Cent South Univ, Xiangya Hosp 3, Dept Gen Surg, Changsha 410000, Hunan, Peoples R China.;Cent South Univ, Xiangya Hosp 3, Dept Hematol, Changsha 410000, Peoples R China.
关键词：
Breast cancer;Tumor microenvironment;Prognostic mode;Glycosylation;Glycosyltransferases;KLRB1
摘要：
The tumor microenvironment (TME) and aberrant glycosylation have been suggested to play key roles in cancer. This study integrated differentially expressed genes (DEGs) and weighted gene coexpression network analysis (WGCNA) to identify tumor microenvironment-related genes and construct a TME-risk prognostic signature (TMERS) through LASSO Cox regression. After batch effect removal, 44 TME-prognosis-related genes (TMEPGs) were identified and classified into three molecular subtypes via K-means clustering. The finalized 22-gene TMERS model demonstrated robust prognostic predictive capacity in GEO datasets. The results revealed distinct immune profiles and prognostic stratifications among genetic subtypes and risk groups, confirming that the TMERS is an independent prognostic indicator for breast cancer (BRCA). Glycosyltransferase genes (GTs) have potential therapeutic relevance through immune regulation, with TMEPG member killer cell lectin like receptor B1 (KLRB1) significantly correlated with BRCA prognosis. Cellular experiments demonstrated that KLRB1 overexpression suppressed BRCA cell proliferation and migration. This work establishes a novel prognostic model for BRCA while highlighting KLRB1 as a potential biomarker, providing new insights into TME-targeted therapeutic strategies.
作者机构：
[Li, Pian; He, Junyan; Yang, Dong] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Oncol, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Xiaoli] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Pathol, Hengyang 421001, Hunan, Peoples R China.;[Tan, Yini; Li, Yi] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Obstet & Gynecol, 69 Chuanshan Rd, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Li, Y ] U;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Obstet & Gynecol, 69 Chuanshan Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
Endometrial carcinoma;Estrogen receptor;Lymphovascular space invasion;Myometrial invasion;Progesterone receptor
摘要：
Background It is crucial to identify the high-risk factors associated with the recurrence and metastasis of endometrial cancer (EC) in order to implement more precise clinical stratification and management strategies for EC patients. Methods A total of 336 patients with stage I-III EC were retrospectively analyzed. According to the recurrence site, they were divided into locoregional recurrence (LR) and poor-prognosis recurrence (PPR). The factors that may affect the prognosis of EC were analyzed and the subgroups were analyzed. Results Among the no recurrence(NR), LR and PPR groups, 5-year OS were 89.4%, 60.2% and 46.8%, 5-year RFS were 100%, 15.4% and 6.4%. The FIGO stage, molecular classification, lymphovascular space invasion (LVSI) and smoking history were independent risk factors affecting 5-year OS and 5-year RFS in EC patients (p < 0.05). Pathological type and progesterone receptor (PR) were independent risk factors affecting 5-year OS (p < 0.05). Histologic Grade and adjuvant therapy were independent risk factors affecting 5-year RFS (p < 0.05). Myometrial invasion, LVSI and FIGO stage were independent risk factors in the LR subgroup (p < 0.05), FIGO stage, ER and PR were independent risk in the PPR subgroup (p < 0.05). Conclusions Patients with myometrial invasion ≥ 1/2 and substantial LVSI may be more likely to have LR, while patients with positive ER and PR are more likely to have PPR. We need to pay attention to these factors to help us judge the prognosis of EC patients.
摘要：
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is characterized by systemic insulin resistance and metabolic dysfunction. MASLD/NAFLD elevates the risk of developing cardiovascular disease (CVD). As a quantitative method, bibliometric analysis, illuminates the trajectory of research within a particular field and offers insights into its current state and future directions. In the present study, Citespace (version 6.3.1) was used to comprehensively review the relevant literature for a detailed characterization of the association between MASLD/NAFLD and CVD. This analysis aimed to delineate the historical progression, current research hotspots, and future development trends of MASLD/NAFLD and its relationship with CVD. Our findings highlight a notable surge in research interest in MASLD/NAFLD and CVD over the past 19 years, reflecting an increasing depth of exploration into their interrelationship. In addition to established factors, such as alanine aminotransferase (ALT) and metabolic syndrome, previously overlooked aspects, such as inflammation, gut microbiota, and oxidative stress, have gained significant attention as notable contributors to the pathogenesis of MASLD/NAFLD. By elucidating the intricate association between MASLD/NAFLD and CVD, this study provides prospects for pathophysiological mechanism and preventive strategies for both conditions and provides research insights regarding potential future avenues and focal areas for future investigations.
期刊：
Journal of Ethnopharmacology,2025年352:120146 ISSN：0378-8741
通讯作者：
Xiao, ZJ;Kang, X;Wen, G
作者机构：
[Li, Xun; Xiao, Zi-Jian; Xiao, ZJ] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Neurol, Hengyang 421001, Hunan, Peoples R China.;[Yang, San-Qiao] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Anesthesiol, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Hai-Jun] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Cardiol, Hengyang 421001, Hunan, Peoples R China.;[Kang, Xuan] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Metab & Endocrinol, Hengyang 421001, Hunan, Peoples R China.;[Wen, Ge; Zhong, Yuan] TUS PHARMA Grp Co Ltd, Hengyang, Peoples R China.
通讯机构：
[Kang, X ; Xiao, ZJ ] U;[Wen, G ] T;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Neurol, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Metab & Endocrinol, Hengyang 421001, Hunan, Peoples R China.;TUS PHARMA Grp Co Ltd, Hengyang, Peoples R China.
关键词：
AKT1/p65 signaling pathway;Gu Han Yang Sheng Jing;Major depressive disorder;Network pharmacology;Neuroinflammation
摘要：
Ethnopharmacological relevance Previous studies indicate that Gu Han Yang Sheng Jing (GHYSJ) exhibits neuroprotective properties in the central nervous system, but the protective effect of GHYSJ on major depressive disorder (MDD) and the precise mechanism underlying its protective effects remains unclear.
Previous studies indicate that Gu Han Yang Sheng Jing (GHYSJ) exhibits neuroprotective properties in the central nervous system, but the protective effect of GHYSJ on major depressive disorder (MDD) and the precise mechanism underlying its protective effects remains unclear.
Aim of the study : This study aimed to clarify the antidepressant role of GHYSJ in MDD and the precise mechanism underlying via network pharmacology and experimental evaluations.
: This study aimed to clarify the antidepressant role of GHYSJ in MDD and the precise mechanism underlying via network pharmacology and experimental evaluations.
Materials and methods Compounds-target-disease and protein-protein interaction network were constructed by network pharmacology to predict the potential targets of GHYSJ for the treatment of MDD. Molecular docking was used to predict the binding affinity between active components and pivotal targets. Protein expression levels were quantified via western blot analysis. The levels of proinflammatory factor were measured using ELISA kits. Immunofluorescence staining was performed to quantify Iba-1-positive cells. The antidepressant role of GHYSJ in MDD was tested by depression-like behavioral tests.
Compounds-target-disease and protein-protein interaction network were constructed by network pharmacology to predict the potential targets of GHYSJ for the treatment of MDD. Molecular docking was used to predict the binding affinity between active components and pivotal targets. Protein expression levels were quantified via western blot analysis. The levels of proinflammatory factor were measured using ELISA kits. Immunofluorescence staining was performed to quantify Iba-1-positive cells. The antidepressant role of GHYSJ in MDD was tested by depression-like behavioral tests.
Results This study identified a total of 94 active compounds and 185 targets of GHYSJ associated with MDD. Functional enrichment analyses revealed that inflammatory-related signalling pathways may be involved in GHYSJ-against MDD. Molecular docking demonstrated high-affinity binding between quercetin and TNF receptors. Furthermore, GHYSJ attenuated depressive-like behaviors of chronic unpredictable mild stress (CUMS)-exposed rats, reduced neuroinflammation, and inhibited the AKT1/p65 signaling pathway in the hippocampus of CUMS-exposed rats, which was reversed by the treatment of SC97 (AKT1 activator).
This study identified a total of 94 active compounds and 185 targets of GHYSJ associated with MDD. Functional enrichment analyses revealed that inflammatory-related signalling pathways may be involved in GHYSJ-against MDD. Molecular docking demonstrated high-affinity binding between quercetin and TNF receptors. Furthermore, GHYSJ attenuated depressive-like behaviors of chronic unpredictable mild stress (CUMS)-exposed rats, reduced neuroinflammation, and inhibited the AKT1/p65 signaling pathway in the hippocampus of CUMS-exposed rats, which was reversed by the treatment of SC97 (AKT1 activator).
Conclusion Taken together, These results suggest that GHYSJ improves MDD via attenuating neuroinflammation by inhibiting AKT1/p65 signaling pathway.
Taken together, These results suggest that GHYSJ improves MDD via attenuating neuroinflammation by inhibiting AKT1/p65 signaling pathway.
作者机构：
[Zhong, Jing; Zhao, Hu; Zhong, J; Xiao, Qian] Univ South China, Affiliated Hosp 1, Canc Res Inst, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;[Xiao, Qian] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Clin Lab Med, Hengyang 421001, Hunan, Peoples R China.;[An, Yangfang] Yiyang Cent Hosp, Yiyang 413099, Hunan, Peoples R China.;[Wang, Mu] Univ South China, Affiliated Nanhua Hosp, Clin Res Inst, Clin Mass Spectrometry Lab, Hengyang, Peoples R China.;[Zhong, Jing] Univ South China, Affiliated Hosp 1, Inst Clin Med, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Zhong, J ; Wang, M ] U;Univ South China, Affiliated Hosp 1, Canc Res Inst, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Affiliated Nanhua Hosp, Clin Res Inst, Clin Mass Spectrometry Lab, Hengyang, Peoples R China.
摘要：
Phospholipids, complex lipids prevalent in the human body, play crucial roles in various pathophysiological processes. Beyond their synthesis and degradation, phospholipids can influence chemoresistance by participating in ferroptosis. Extensive evidence highlights the significant link between tumor drug resistance and phospholipids. Therefore, drugs targeting phospholipid metabolism itself or the synthesis of corresponding composite materials will effectively overcome the difficulties of clinical tumor treatment.
Phospholipids, complex lipids prevalent in the human body, play crucial roles in various pathophysiological processes. Beyond their synthesis and degradation, phospholipids can influence chemoresistance by participating in ferroptosis. Extensive evidence highlights the significant link between tumor drug resistance and phospholipids. Therefore, drugs targeting phospholipid metabolism itself or the synthesis of corresponding composite materials will effectively overcome the difficulties of clinical tumor treatment.
