Pub Date : 2026-03-01Epub Date: 2025-06-14DOI: 10.1016/j.jare.2025.06.029
Jing Peng , Fengming Pan , Yu Xu , Yizhong Yan , Min Gao , HongJing Zang , Ge Lin , Lamei Cheng , Yu Zhou
<div><h3>Introduction</h3><div>Traumatic brain injury (TBI) affects millions of people worldwide and often results in significant extracranial complications, particularly acute respiratory distress syndrome (ARDS). The mechanisms underlying TBI-induced lung damage remain poorly understood, and current treatment options are limited.</div></div><div><h3>Objectives</h3><div>This study aimed to investigate the therapeutic potential and mechanisms of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) transplantation for alleviating TBI-induced lung injury and improving neurological function. Specifically, we sought to determine the role of neutrophil extracellular traps (NETs) in TBI-induced lung injury and whether hUC-MSCs improve acute lung injury (ALI) by inhibiting NET formation.</div></div><div><h3>Methods</h3><div>TBI-associated ARDS in patients was diagnosed based on chest computed tomography (CT) imaging and relevant physiological and biochemical parameters. Bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) samples from TBI patients were collected to evaluate neutrophil activation and its correlation with the severity of pulmonary injury. A TBI mouse model was established using the Controlled Cortical Impact (CCI) method. 12 h post-injury, hUC-MSCs were administered via intravenous injection. Neurological function was assessed using the modified Neurological Severity Score (mNSS) and balance beam test. Lung and brain tissue injury were evaluated by histological staining, oxygen saturation monitoring, and micro-CT. Neutrophil infiltration and NET formation were detected in PB, BALF, and lung tissue by flow cytometry, immunofluorescence, and Western blotting. To further elucidate the direct regulatory effects of hUC-MSCs on neutrophils in vitro, neutrophils isolated from the PB of TBI patients were co-cultured with hUC-MSCs. The formation of NETs and reactive oxygen species (ROS) was subsequently quantified.</div></div><div><h3>Results</h3><div>We initially assessed neutrophil activation and NET formation in PB and BALF from TBI patients. The results revealed that neutrophils in PB were activated, with even more pronounced activation observed in BALF. Simultaneously, NET formation in PB was significantly elevated. A strong positive correlation was identified between the extent of neutrophil infiltration in BALF and the severity of pulmonary injury. In the CCI-induced TBI mouse model, hUC-MSC transplantation notably improved neurological function and alleviated pathological brain damage. Additionally, hUC-MSC administration increased SpO2, reduced lung injury scores, and partially restored the ultrastructural integrity of type II alveolar epithelial cells. Mechanistic studies demonstrated that hUC-MSC transplantation effectively suppressed neutrophil infiltration, NET formation, and the expression of peptidyl arginine deiminase 4 (PAD4), a crucial enzyme involved in NETosis. Remarkably, hUC-MSCs showed superior efficacy in
{"title":"Mesenchymal stem cell transplantation alleviated TBI-induced lung injury by inhibiting PAD4-dependent NET formation","authors":"Jing Peng , Fengming Pan , Yu Xu , Yizhong Yan , Min Gao , HongJing Zang , Ge Lin , Lamei Cheng , Yu Zhou","doi":"10.1016/j.jare.2025.06.029","DOIUrl":"10.1016/j.jare.2025.06.029","url":null,"abstract":"<div><h3>Introduction</h3><div>Traumatic brain injury (TBI) affects millions of people worldwide and often results in significant extracranial complications, particularly acute respiratory distress syndrome (ARDS). The mechanisms underlying TBI-induced lung damage remain poorly understood, and current treatment options are limited.</div></div><div><h3>Objectives</h3><div>This study aimed to investigate the therapeutic potential and mechanisms of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) transplantation for alleviating TBI-induced lung injury and improving neurological function. Specifically, we sought to determine the role of neutrophil extracellular traps (NETs) in TBI-induced lung injury and whether hUC-MSCs improve acute lung injury (ALI) by inhibiting NET formation.</div></div><div><h3>Methods</h3><div>TBI-associated ARDS in patients was diagnosed based on chest computed tomography (CT) imaging and relevant physiological and biochemical parameters. Bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) samples from TBI patients were collected to evaluate neutrophil activation and its correlation with the severity of pulmonary injury. A TBI mouse model was established using the Controlled Cortical Impact (CCI) method. 12 h post-injury, hUC-MSCs were administered via intravenous injection. Neurological function was assessed using the modified Neurological Severity Score (mNSS) and balance beam test. Lung and brain tissue injury were evaluated by histological staining, oxygen saturation monitoring, and micro-CT. Neutrophil infiltration and NET formation were detected in PB, BALF, and lung tissue by flow cytometry, immunofluorescence, and Western blotting. To further elucidate the direct regulatory effects of hUC-MSCs on neutrophils in vitro, neutrophils isolated from the PB of TBI patients were co-cultured with hUC-MSCs. The formation of NETs and reactive oxygen species (ROS) was subsequently quantified.</div></div><div><h3>Results</h3><div>We initially assessed neutrophil activation and NET formation in PB and BALF from TBI patients. The results revealed that neutrophils in PB were activated, with even more pronounced activation observed in BALF. Simultaneously, NET formation in PB was significantly elevated. A strong positive correlation was identified between the extent of neutrophil infiltration in BALF and the severity of pulmonary injury. In the CCI-induced TBI mouse model, hUC-MSC transplantation notably improved neurological function and alleviated pathological brain damage. Additionally, hUC-MSC administration increased SpO2, reduced lung injury scores, and partially restored the ultrastructural integrity of type II alveolar epithelial cells. Mechanistic studies demonstrated that hUC-MSC transplantation effectively suppressed neutrophil infiltration, NET formation, and the expression of peptidyl arginine deiminase 4 (PAD4), a crucial enzyme involved in NETosis. Remarkably, hUC-MSCs showed superior efficacy in","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 849-864"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-06-18DOI: 10.1016/j.jare.2025.06.043
Tao Gao , Qingye Jiang , Bin Zhang , Shenglin Hu , Meijing Ye , Tianyi Cao , Dong Peng , Zonghua Zhao , Zizhong Tang , Yanger Chen , Shu Yuan , Xiaorong Yan , Ming Yuan
Introduction
Nasal spray films, an innovative formulation in recent years, have garnered significant acclaim from patients with nasal mucosal injury because it integrate the benefits of spray and film formulation, offering ease of application while reducing the risk of droplet formation and further inhalation into the throat. Furthermore, Lithospermum erythrorhizon is a traditional Chinese medicine frequently employed in the management of dermal injuries, and our previous work suggested its major compound, shikonin, possesses the capacity to promote the repair of nasal mucosal injury. Notwithstanding these encouraging results, research on the development of shikonin nasal spray film preparation (SNSF) and its bioactivity mechanism remains limited.
Objectives
This work aimed to formulate SNSF and examine its mechanisms and pharmacokinetic properties in facilitating the repair of nasal mucosal injury, thereby offering insights for its subsequent clinical application.
Methods
The SNSF was prepared, and its structural properties were characterized through particle size analysis, thermogravimetric analysis, scanning electron microscopy, and its material properties, including viscosity, film-forming duration, moisture absorption, moisture retention, breathability, and transdermal permeation efficacy, were evaluated. Simultaneously, the repair mechanism of SNSF was explored with RNA-seq, western blotting, RT-PCR, bio-layer interferometry, ultrafiltration affinity, and molecular simulation. Additionally, the pharmacokinetics of SNSF were revealed by HPLC-MS/MS to further demonstrate its clinical application potential.
Results
Shikonin successfully adsorbs on the surface of spray film to obtain SNSF without affecting its material properties. Meanwhile, SNSF treatment significantly alleviated the inflammatory response and facilitated the repair of nasal mucosal injury. This therapeutic effect might be attributed to its active compound, shikonin, which binds to IL-6 and subsequently activates the IL-17 signaling pathway. Additionally, SNSF possessed the characteristics of fast absorption, short half-life, and further enhanced bioavailability of shikonin.
Conclusion
SNSF is a novel candidate drug with great clinical potential for patients with nasal mucosal injury.
{"title":"Shikonin nasal spray film preparation promoted the repair of nasal mucosal injury by the interaction of shikonin with interleukin-6","authors":"Tao Gao , Qingye Jiang , Bin Zhang , Shenglin Hu , Meijing Ye , Tianyi Cao , Dong Peng , Zonghua Zhao , Zizhong Tang , Yanger Chen , Shu Yuan , Xiaorong Yan , Ming Yuan","doi":"10.1016/j.jare.2025.06.043","DOIUrl":"10.1016/j.jare.2025.06.043","url":null,"abstract":"<div><h3>Introduction</h3><div>Nasal spray films, an innovative formulation in recent years, have garnered significant acclaim from patients with nasal mucosal injury because it integrate the benefits of spray and film formulation, offering ease of application while reducing the risk of droplet formation and further inhalation into the throat. Furthermore, <em>Lithospermum erythrorhizon</em> is a traditional Chinese medicine frequently employed in the management of dermal injuries, and our previous work suggested its major compound, shikonin, possesses the capacity to promote the repair of nasal mucosal injury. Notwithstanding these encouraging results, research on the development of shikonin nasal spray film preparation (SNSF) and its bioactivity mechanism remains limited.</div></div><div><h3>Objectives</h3><div>This work aimed to formulate SNSF and examine its mechanisms and pharmacokinetic properties in facilitating the repair of nasal mucosal injury, thereby offering insights for its subsequent clinical application.</div></div><div><h3>Methods</h3><div>The SNSF was prepared, and its structural properties were characterized through particle size analysis, thermogravimetric analysis, scanning electron microscopy, and its material properties, including viscosity, film-forming duration, moisture absorption, moisture retention, breathability, and transdermal permeation efficacy, were evaluated. Simultaneously, the repair mechanism of SNSF was explored with RNA-seq, western blotting, RT-PCR, bio-layer interferometry, ultrafiltration affinity, and molecular simulation. Additionally, the pharmacokinetics of SNSF were revealed by HPLC-MS/MS to further demonstrate its clinical application potential.</div></div><div><h3>Results</h3><div>Shikonin successfully adsorbs on the surface of spray film to obtain SNSF without affecting its material properties. Meanwhile, SNSF treatment significantly alleviated the inflammatory response and facilitated the repair of nasal mucosal injury. This therapeutic effect might be attributed to its active compound, shikonin, which binds to IL-6 and subsequently activates the IL-17 signaling pathway. Additionally, SNSF possessed the characteristics of fast absorption, short half-life, and further enhanced bioavailability of shikonin.</div></div><div><h3>Conclusion</h3><div>SNSF is a novel candidate drug with great clinical potential for patients with nasal mucosal injury.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 1065-1077"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-06-18DOI: 10.1016/j.jare.2025.06.040
Guanglin Cui , Jiali Nie , Huihui Li, Luyun Wang, Kun Miao, Chunxia Zhao, Jiangang Jiang, Dao Wen Wang
Background
Fulminant myocarditis (FM) is the most severe form of myocarditis, characterized by rapid clinical progression and circulatory instability. However, its pathological features and their relationship to clinical presentation are not well understood.
Objectives
This study aims to provide an overview of the clinicopathologic features of FM.
Methods
A total of 80 patients with FM were enrolled between January 2021 and September 2022 in Wuhan, China. Endomyocardial biopsies and subsequent histochemical staining were performed on all patients who were followed up for 3 months. The pathological features of the myocardium were described. The relationship between myocardial inflammatory cell infiltration and clinical presentation was analyzed.
Results
According to hematoxylin and eosin staining, 76 out of 80 patients with FM were diagnosed with lymphocytic myocarditis, while 4 were diagnosed with eosinophilic myocarditis. Microscopically, various forms of cell degeneration were observed, especially myocardial edema and cardiomyocyte necrosis. Histochemical analysis indicated that innate immune cells (primarily macrophages and neutrophils) predominated in the acute stage of FM. Proper treatment with immunomodulatory agents, such as glucocorticoids and immunoglobulin, promoted macrophage polarization into the M2 subtype. A high density of total inflammatory cell infiltration was associated with elevated levels of inflammatory biomarkers (hs-CRP and ESR) and more severe circulatory deterioration, which necessitated more frequent use of IABP, ECMO, and pacemakers.
Conclusions
To date, this largest cohort of histochemical analyses of FM, based on endomyocardial biopsy samples, has revealed dominant infiltration of innate immune cells in the early stage, followed by lymphocytes. This finding suggests that the activation of innate immunity is the initial mechanism triggering the cytokine storm in FM. The results also support the beneficial effects of immunomodulatory therapy using glucocorticoids and immunoglobulins rather than immunosuppression by promoting M2 macrophage polarization. This study was registered at https://clinicaltrials.gov/study/NCT03268642.
{"title":"The clinicopathologic features of fulminant myocarditis","authors":"Guanglin Cui , Jiali Nie , Huihui Li, Luyun Wang, Kun Miao, Chunxia Zhao, Jiangang Jiang, Dao Wen Wang","doi":"10.1016/j.jare.2025.06.040","DOIUrl":"10.1016/j.jare.2025.06.040","url":null,"abstract":"<div><h3>Background</h3><div>Fulminant myocarditis (FM) is the most severe form of myocarditis, characterized by rapid clinical progression and circulatory instability. However, its pathological features and their relationship to clinical presentation are not well understood.</div></div><div><h3>Objectives</h3><div>This study aims to provide an overview of the clinicopathologic features of FM.</div></div><div><h3>Methods</h3><div>A total of 80 patients with FM were enrolled between January 2021 and September 2022 in Wuhan, China. Endomyocardial biopsies and subsequent histochemical staining were performed on all patients who were followed up for 3 months. The pathological features of the myocardium were described. The relationship between myocardial inflammatory cell infiltration and clinical presentation was analyzed.</div></div><div><h3>Results</h3><div>According to hematoxylin and eosin staining, 76 out of 80 patients with FM were diagnosed with lymphocytic myocarditis, while 4 were diagnosed with eosinophilic myocarditis. Microscopically, various forms of cell degeneration were observed, especially myocardial edema and cardiomyocyte necrosis. Histochemical analysis indicated that innate immune cells (primarily macrophages and neutrophils) predominated in the acute stage of FM. Proper treatment with immunomodulatory agents, such as glucocorticoids and immunoglobulin, promoted macrophage polarization into the M2 subtype. A high density of total inflammatory cell infiltration was associated with elevated levels of inflammatory biomarkers (hs-CRP and ESR) and more severe circulatory deterioration, which necessitated more frequent use of IABP, ECMO, and pacemakers.</div></div><div><h3>Conclusions</h3><div>To date, this largest cohort of histochemical analyses of FM, based on endomyocardial biopsy samples, has revealed dominant infiltration of innate immune cells in the early stage, followed by lymphocytes. This finding suggests that the activation of innate immunity is the initial mechanism triggering the cytokine storm in FM. The results also support the beneficial effects of immunomodulatory therapy using glucocorticoids and immunoglobulins rather than immunosuppression by promoting M2 macrophage polarization. This study was registered at <span><span>https://clinicaltrials.gov/study/NCT03268642</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 945-953"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01DOI: 10.1016/j.jare.2026.02.051
Yong-Heng Lu, Xiu-Ping Zhu, Song Li, Feng-Ning Zhang, Chuan-Bin Cai, Mao Tian, Yu-Hang Zhu, Ling-Hui Zeng, Jun Tan, Chang-Yin Yu, Jiang Chen
Background
Neurodegenerative disorders impose a growing global burden, yet disease-modifying therapies remain limited. Glial fibrillary acidic protein (GFAP) has shifted from a passive astrocytic marker to an active effector shaping neurodegenerative pathology.
Aim
of Review: This review synthesizes mechanistic and translational evidence that defines GFAP as a proteoform-governed hub and highlights its value for biomarker-guided precision intervention.Key Scientific Concepts of Review: An extensive literature search across major databases was conducted using predefined keywords and strict inclusion criteria, covering mechanistic, pathological, and clinical studies. Evidence supports a GFAP proteoform code in which alternative splicing generates functionally distinct isoforms and PTMs encode context-dependent assembly dynamics and signaling outputs. We summarize how GFAP proteoforms integrate cytoskeletal remodeling with inflammatory transcriptional programs (notably STAT3 and NF-κB), proteostasis stress, and mitochondrial dysfunction, thereby coupling astrocyte state transitions to neuronal vulnerability and synaptic impairment. Disease trajectories are context specific: GFAP dysfunction drives primary toxicity in Alexander disease (AxD); in Alzheimer’s disease (AD), isoform-specific mechanisms intersect with amyloidogenic machinery and track early preclinical astrocyte activation; and in frontotemporal dementia (FTD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), GFAP reflects inflammatory–metabolic coupling during progression. Translationally, ultrasensitive plasma assays reveal GFAP elevation years to decades before symptom onset, complementing NfL and amyloid/tau within AT(N)-oriented diagnostic frameworks. Therapeutically, we evaluate precision strategies beyond global suppression, including ASO-based modulation, targeting STAT3/NF-κB-driven reactive programs, and restoring proteostasis via chaperone/autophagy pathways. Future progress hinges on isoform-/PTM-specific probes, conformational sensors, and spatial proteomic atlases validated in prospective longitudinal cohorts. In conclusion, GFAP represents both a mechanistic driver and a scalable biomarker, offering a translationally actionable axis to advance precision medicine in neurodegeneration.
{"title":"From scaffold to effector: reframing GFAP in neurodegeneration","authors":"Yong-Heng Lu, Xiu-Ping Zhu, Song Li, Feng-Ning Zhang, Chuan-Bin Cai, Mao Tian, Yu-Hang Zhu, Ling-Hui Zeng, Jun Tan, Chang-Yin Yu, Jiang Chen","doi":"10.1016/j.jare.2026.02.051","DOIUrl":"https://doi.org/10.1016/j.jare.2026.02.051","url":null,"abstract":"<h3>Background</h3>Neurodegenerative disorders impose a growing global burden, yet disease-modifying therapies remain limited. Glial fibrillary acidic protein (GFAP) has shifted from a passive astrocytic marker to an active effector shaping neurodegenerative pathology.<h3>Aim</h3><strong>of Review:</strong> This review synthesizes mechanistic and translational evidence that defines GFAP as a proteoform-governed hub and highlights its value for biomarker-guided precision intervention.<strong>Key Scientific Concepts of Review:</strong> An extensive literature search across major databases was conducted using predefined keywords and strict inclusion criteria, covering mechanistic, pathological, and clinical studies. Evidence supports a GFAP proteoform code in which alternative splicing generates functionally distinct isoforms and PTMs encode context-dependent assembly dynamics and signaling outputs. We summarize how GFAP proteoforms integrate cytoskeletal remodeling with inflammatory transcriptional programs (notably STAT3 and NF-κB), proteostasis stress, and mitochondrial dysfunction, thereby coupling astrocyte state transitions to neuronal vulnerability and synaptic impairment. Disease trajectories are context specific: GFAP dysfunction drives primary toxicity in Alexander disease (AxD); in Alzheimer’s disease (AD), isoform-specific mechanisms intersect with amyloidogenic machinery and track early preclinical astrocyte activation; and in frontotemporal dementia (FTD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), GFAP reflects inflammatory–metabolic coupling during progression. Translationally, ultrasensitive plasma assays reveal GFAP elevation years to decades before symptom onset, complementing NfL and amyloid/tau within AT(N)-oriented diagnostic frameworks. Therapeutically, we evaluate precision strategies beyond global suppression, including ASO-based modulation, targeting STAT3/NF-κB-driven reactive programs, and restoring proteostasis via chaperone/autophagy pathways. Future progress hinges on isoform-/PTM-specific probes, conformational sensors, and spatial proteomic atlases validated in prospective longitudinal cohorts. In conclusion, GFAP represents both a mechanistic driver and a scalable biomarker, offering a translationally actionable axis to advance precision medicine in neurodegeneration.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"25 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147329727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-05-26DOI: 10.1016/j.jare.2025.05.052
Xiaohan Xu , Wanlin Liu , Bo Pang , Yu Wang , Hongying Zhen , Quan Jiang , Yuening Chen , Kun Yang , Jinjie Shi , Jie Ma , Hongxiao Liu
Introduction
Ankylosing spondylitis (AS) is a systemic inflammatory disorder that predominantly involves the axial skeleton, often leading to irreversible structural damage and disability. Although several therapeutic measurements are available, limitations in efficacy and long-term outcomes remain significant. Therefore, identifying novel biomarkers and therapeutic targets is of critical importance for optimizing clinical management and prognostic evaluation in AS patients.
Objectives
This study aims to elucidate the immune features and discover potential biomarkers for AS by the integration of deep plasma proteomics and deep learning strategies.
Methods
The deep quantitative proteomics was applied to analyze the plasma samples from 104 participants of AS patients with active and stable stages, along with healthy controls. The immune and functional features of AS patients in different stages were assessed. By integrating random forest (RF) with orthogonal partial least squares discriminant analysis (OPLS-DA), a machine learning model-based score matrix was constructed to identify biomarkers. ELISA experiments were performed on an independent cohort of 79 participants to confirm the potential biomarkers for AS.
Results
Patients with AS exhibit significant dysregulation in the distributions and characteristics of immune cells. Several key proteins involved in integrin signaling pathway were significantly differentially expressed in patients with AS, highlighting the pathway’s role in the pathogenesis of AS. Four proteins including SAA1, FERMT3, ILK, and TLN1, were identified as potential biomarkers for AS and further verified by ELISA experiments.
Conclusions
By integrating the machine learning-based method with deep proteomics analysis, we explored the pathological mechanism and identified biomarkers for AS. Our study provides insights into the distinct protein expression patterns and pathogenesis of AS and may contribute to diagnosis, long-term monitoring, and therapy for this disease.
{"title":"Characterization of immune features and discovery of potential biomarkers for ankylosing spondylitis using deep plasma proteomics","authors":"Xiaohan Xu , Wanlin Liu , Bo Pang , Yu Wang , Hongying Zhen , Quan Jiang , Yuening Chen , Kun Yang , Jinjie Shi , Jie Ma , Hongxiao Liu","doi":"10.1016/j.jare.2025.05.052","DOIUrl":"10.1016/j.jare.2025.05.052","url":null,"abstract":"<div><h3>Introduction</h3><div>Ankylosing spondylitis (AS) is a systemic inflammatory disorder that predominantly involves the axial skeleton, often leading to irreversible structural damage and disability. Although several therapeutic measurements are available, limitations in efficacy and long-term outcomes remain significant. Therefore, identifying novel biomarkers and therapeutic targets is of critical importance for optimizing clinical management and prognostic evaluation in AS patients.</div></div><div><h3>Objectives</h3><div>This study aims to elucidate the immune features and discover potential biomarkers for AS by the integration of deep plasma proteomics and deep learning strategies.</div></div><div><h3>Methods</h3><div>The deep quantitative proteomics was applied to analyze the plasma samples from 104 participants of AS patients with active and stable stages, along with healthy controls. The immune and functional features of AS patients in different stages were assessed. By integrating random forest (RF) with orthogonal partial least squares discriminant analysis (OPLS-DA), a machine learning model-based score matrix was constructed to identify biomarkers. ELISA experiments were performed on an independent cohort of 79 participants to confirm the potential biomarkers for AS.</div></div><div><h3>Results</h3><div>Patients with AS exhibit significant dysregulation in the distributions and characteristics of immune cells. Several key proteins involved in integrin signaling pathway were significantly differentially expressed in patients with AS, highlighting the pathway’s role in the pathogenesis of AS. Four proteins including SAA1, FERMT3, ILK, and TLN1, were identified as potential biomarkers for AS and further verified by ELISA experiments.</div></div><div><h3>Conclusions</h3><div>By integrating the machine learning-based method with deep proteomics analysis, we explored the pathological mechanism and identified biomarkers for AS. Our study provides insights into the distinct protein expression patterns and pathogenesis of AS and may contribute to diagnosis, long-term monitoring, and therapy for this disease.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 223-234"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-06-05DOI: 10.1016/j.jare.2025.06.006
Hongyan Zhang , Hongyi Wei , Sijia Han , Lufeng Zheng , Xiaodong Chen , Ziwei Li , Lanbo Wang
Background
Lung cancer is a leading cause of death worldwide, with environmental factors playing critical roles in its development and progression. Respirable and food-borne contaminants are major contributors to lung cancer onset, influencing various physiological pathways that lead to lung injury and tumor formation.
Aim of Review
This review aims to examine the effects of common environmental pollutants on lung cancer development, highlighting the role of specific contaminants, such as PM2.5 (particulate matter with aerodynamic diameter less than 2.5 µm) and nitrogen oxides, and warning people to pay more attention to environmental pollutants.
Key Scientific Concepts of Review
Environmental pollutants play a significant role in increasing the susceptibility to lung cancer by triggering various biological mechanisms that lead to lung injury and tumorigenesis. Excessive PM2.5 exposure contributes to the overall burden of lung cancer via Wnt/β-catenin, Reactive oxygen species-DNA methyltransferases (ROS-DNMT), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt), Janus kinase/signal transducers and activators of transcription (JAK/STAT) signalling pathways. The primary mechanisms by which NO contributes to the occurrence and development of pulmonary neoplasm revolve around the production and regulation of ROS. Occupational exposure and ecosystem pollution to hazardous substances, including microplastics, pesticides, asbestos, cadmium, and nickel, are the well-established risk factors for the development of lung cancer via DNA damage, oxidative stress, and inflammation pathways. This review emphasizes the importance of effective prevention strategies for lung cancer by reducing environmental pollution levels.
{"title":"A comprehensive examination of the impact of environmental pollution on lung cancer: A review","authors":"Hongyan Zhang , Hongyi Wei , Sijia Han , Lufeng Zheng , Xiaodong Chen , Ziwei Li , Lanbo Wang","doi":"10.1016/j.jare.2025.06.006","DOIUrl":"10.1016/j.jare.2025.06.006","url":null,"abstract":"<div><h3>Background</h3><div>Lung cancer is a leading cause of death worldwide, with environmental factors playing critical roles in its development and progression. Respirable and food-borne contaminants are major contributors to lung cancer onset, influencing various physiological pathways that lead to lung injury and tumor formation.</div></div><div><h3>Aim of Review</h3><div>This review aims to examine the effects of common environmental pollutants on lung cancer development, highlighting the role of specific contaminants, such as PM2.5 (particulate matter with aerodynamic diameter less than 2.5 µm) and nitrogen oxides, and warning people to pay more attention to environmental pollutants.</div></div><div><h3>Key Scientific Concepts of Review</h3><div>Environmental pollutants play a significant role in increasing the susceptibility to lung cancer by triggering various biological mechanisms that lead to lung injury and tumorigenesis. Excessive PM2.5 exposure contributes to the overall burden of lung cancer via Wnt/β-catenin, Reactive oxygen species-DNA methyltransferases (ROS-DNMT), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt), Janus kinase/signal transducers and activators of transcription (JAK/STAT) signalling pathways. The primary mechanisms by which NO contributes to the occurrence and development of pulmonary neoplasm revolve around the production and regulation of ROS. Occupational exposure and ecosystem pollution to hazardous substances, including microplastics, pesticides, asbestos, cadmium, and nickel, are the well-established risk factors for the development of lung cancer via DNA damage, oxidative stress, and inflammation pathways. This review emphasizes the importance of effective prevention strategies for lung cancer by reducing environmental pollution levels.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 273-286"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144228719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-06-12DOI: 10.1016/j.jare.2025.05.065
Yunchang Liu , Liping Zeng , Qi Cai , Yunfei Zeng , Shuo Zheng , Xue Gong , Lu Zhou , Miao Tian , Lianglong Chen , Gengze Wu , Chunyu Zeng
Introduction
Arterial pathological remodeling, central to arterial diseases including atherosclerosis and aortic aneurysms, is characterized by vascular smooth muscle cell (VSMC) phenotypic switching with concomitant loss of contractile markers. Uncovering the molecular changes initiating phenotypic transition may advance the understanding of vascular pathogenesis and provide new therapeutic strategies.
Objectives
To construct a cross-species integrative model of VSMC transition in arterial diseases including atherosclerosis and aortic aneurysm, identify key genes regulating phenotypic switching in the trajectory from contractile to other phenotypes, and further validate their function in arterial remodeling models.
Methods
Public single-cell RNA-seq datasets were analyzed to map VSMC transcriptional dynamics and identify regulated gene expression patterns during transition. The changes were further checked using experimental animal aneurysm samples and PDGF-BB treated VSMCs. Functional validation included in vitro siRNA-mediated knockdown using primary VSMCs and in vivo gene-manipulated (AAv-shRNA/Adv-overexpression) wire-injury models.
Results
Dysregulation of cytoskeletal-related genes (Fblim1, Tns1, and Synpo2) may cause disarrangement of actin cytoskeleton, and were identified as checkpoint process before VSMCs transition initiation. Knockdown of target genes suppressed contractile markers, enhanced proliferation, migration, and disrupted cytoskeleton architecture in VSMCs. In animal models, gene down-regulation exacerbated pathological remodeling while over-expression partially reverted these effects.
Conclusion
The findings highlight the critical role of cytoskeleton-related genes in arterial diseases that function as a critical checkpoint in preventing VSMC pathological phenotypic switching.
动脉病理性重构是动脉粥样硬化和主动脉瘤等动脉疾病的核心，其特征是血管光滑。
{"title":"Cytoskeletal-related genes function as checkpoints for the maintenance of VSMC contractile phenotype and prevent pathological remodeling in arterial diseases","authors":"Yunchang Liu , Liping Zeng , Qi Cai , Yunfei Zeng , Shuo Zheng , Xue Gong , Lu Zhou , Miao Tian , Lianglong Chen , Gengze Wu , Chunyu Zeng","doi":"10.1016/j.jare.2025.05.065","DOIUrl":"10.1016/j.jare.2025.05.065","url":null,"abstract":"<div><h3>Introduction</h3><div>Arterial pathological remodeling, central to arterial diseases including atherosclerosis and aortic aneurysms, is characterized by vascular smooth muscle cell (VSMC) phenotypic switching with concomitant loss of contractile markers. Uncovering the molecular changes initiating phenotypic transition may advance the understanding of vascular pathogenesis and provide new therapeutic strategies.</div></div><div><h3>Objectives</h3><div>To construct a cross-species integrative model of VSMC transition in arterial diseases including atherosclerosis and aortic aneurysm, identify key genes regulating phenotypic switching in the trajectory from contractile to other phenotypes, and further validate their function in arterial remodeling models.</div></div><div><h3>Methods</h3><div>Public single-cell RNA-seq datasets were analyzed to map VSMC transcriptional dynamics and identify regulated gene expression patterns during transition. The changes were further checked using experimental animal aneurysm samples and PDGF-BB treated VSMCs. Functional validation included <em>in vitro</em> siRNA-mediated knockdown using primary VSMCs and <em>in vivo</em> gene-manipulated (AAv-shRNA/Adv-overexpression) wire-injury models.</div></div><div><h3>Results</h3><div>Dysregulation of cytoskeletal-related genes (<em>Fblim1</em>, <em>Tns1</em>, and <em>Synpo2</em>) may cause disarrangement of actin cytoskeleton, and were identified as checkpoint process before VSMCs transition initiation. Knockdown of target genes suppressed contractile markers, enhanced proliferation, migration, and disrupted cytoskeleton architecture in VSMCs. In animal models, gene down-regulation exacerbated pathological remodeling while over-expression partially reverted these effects.</div></div><div><h3>Conclusion</h3><div>The findings highlight the critical role of cytoskeleton-related genes in arterial diseases that function as a critical checkpoint in preventing VSMC pathological phenotypic switching.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 689-707"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-06-11DOI: 10.1016/j.jare.2025.06.021
Jian Xu , Jingyu Liu , Xiaowei Li, Liang Zhao, Jianzhong Shen, Xi Xia
Introduction
Antimicrobial resistance (AMR) has emerged as a critical health challenge; however, there is a paucity of in-depth reports outlining its burden and trends in China.
Objectives
This study aimed to systematically assess the burden of bacterial AMR in China from 1990 to 2021 and project future trends up to 2050, providing critical insights for AMR control and policy-making.
Methods
We analyzed data from the Global Burden of Disease Study 2021, encompassing 12 infectious syndromes, 64 pathogens (including 22 with AMR), and 84 pathogen-drug combinations. The burden was quantified by deaths and disability-adjusted life years under two counterfactual scenarios: those associated with AMR and those attributable to AMR. Trends were assessed using joinpoint regression analysis, and future projections up to 2050 were modeled using an autoregressive integrated moving average approach.
Results
In 2021, AMR was attributable to approximately 160,268 (95% uncertainty intervals [UI]: 132,375–188,160) deaths in China, with up to 711,852 (95% UI: 586,447–837,256) fatalities associated with AMR. The most lethal infectious syndrome was bloodstream infections, with key pathogen-drug combinations including methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Streptococcus pneumoniae, and carbapenem-resistant Acinetobacter baumannii. Between 1990 and 2021, there was a substantial decrease in the burden among children under the age of five, primarily due to a decline in fatalities caused by carbapenem-resistant S. pneumoniae. In contrast, the burden increased among individuals aged 45 and older, with MRSA identified as the principal contributor. Projections indicate that by 2050, AMR could be associated with 769,432 deaths in China, of which 180,123 directly attributable to AMR.
Conclusion
Our findings provide a comprehensive evaluation of AMR burden in China, highlighting the urgent need for targeted interventions to prevent and control resistant infections, particularly among older adults.
{"title":"Burden of bacterial antimicrobial resistance in China: a systematic analysis from 1990 to 2021 and projections to 2050","authors":"Jian Xu , Jingyu Liu , Xiaowei Li, Liang Zhao, Jianzhong Shen, Xi Xia","doi":"10.1016/j.jare.2025.06.021","DOIUrl":"10.1016/j.jare.2025.06.021","url":null,"abstract":"<div><h3>Introduction</h3><div>Antimicrobial resistance (AMR) has emerged as a critical health challenge; however, there is a paucity of in-depth reports outlining its burden and trends in China.</div></div><div><h3>Objectives</h3><div>This study aimed to systematically assess the burden of bacterial AMR in China from 1990 to 2021 and project future trends up to 2050, providing critical insights for AMR control and policy-making.</div></div><div><h3>Methods</h3><div>We analyzed data from the Global Burden of Disease Study 2021, encompassing 12 infectious syndromes, 64 pathogens (including 22 with AMR), and 84 pathogen-drug combinations. The burden was quantified by deaths and disability-adjusted life years under two counterfactual scenarios: those associated with AMR and those attributable to AMR. Trends were assessed using joinpoint regression analysis, and future projections up to 2050 were modeled using an autoregressive integrated moving average approach.</div></div><div><h3>Results</h3><div>In 2021, AMR was attributable to approximately 160,268 (95% uncertainty intervals [UI]: 132,375–188,160) deaths in China, with up to 711,852 (95% UI: 586,447–837,256) fatalities associated with AMR. The most lethal infectious syndrome was bloodstream infections, with key pathogen-drug combinations including methicillin-resistant <em>Staphylococcus aureus</em> (MRSA), carbapenem-resistant <em>Streptococcus pneumoniae</em>, and carbapenem-resistant <em>Acinetobacter baumannii</em>. Between 1990 and 2021, there was a substantial decrease in the burden among children under the age of five, primarily due to a decline in fatalities caused by carbapenem-resistant <em>S. pneumoniae</em>. In contrast, the burden increased among individuals aged 45 and older, with MRSA identified as the principal contributor. Projections indicate that by 2050, AMR could be associated with 769,432 deaths in China, of which 180,123 directly attributable to AMR.</div></div><div><h3>Conclusion</h3><div>Our findings provide a comprehensive evaluation of AMR burden in China, highlighting the urgent need for targeted interventions to prevent and control resistant infections, particularly among older adults.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 809-822"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-06-16DOI: 10.1016/j.jare.2025.06.038
Fei Liu , Lan Li , Longhui Yuan , Jingchao Yang , Xi Tang , Jingping Liu , Shuyun Liu , Younan Chen , Yanrong Lu , Jingqiu Cheng , Yujia Yuan
Background
Hydrogen sulfide (H2S) and hydrogen polysulfide-induced S-sulfhydration are critical posttranslational modifications that specifically target cysteine residues within proteins. Degenerative diseases are often characterized by oxidative stress and inflammaging, ultimately leading to progressive organ dysfunction. Emerging evidence underscores the essential role of S-sulfhydration in modulating mitochondrial synthesis, energy metabolism, and cellular homeostasis during aging. However, the intricate pathways and molecular regulators that connect S-sulfhydration to degenerative pathologies remain insufficiently elucidated.
Aim of review
This review aims to delineate the biological significance of S-sulfhydration in the context of age-associated degenerative disorders especially in redox balance and inflammatory response, including neurodegenerative diseases, osteoarthrosis, osteoporosis, and age-related renal pathologies. In addition, the redox-adaptive S-sulfhydration and clinical applications based on S-sulfhydration-related delivery strategies are proposed, which may reveal novel therapeutic interventions in combating aging.
Key scientific concepts of review
This review provides a detailed synthesis of the cellular and molecular mechanisms by which S-sulfhydrated target proteins mitigate senescence phenotypes through antioxidative and anti-inflammatory pathways. Nonetheless, the dual role of S-sulfhydration highly depends on threshold-dependent signaling correlated with H2S synthetase. Moreover, the dynamic compensatory mechanism of S-sulfhydration plays a critical role in the interaction between oxidative stress and inflammatory stress during the aging process, which identifies S-sulfhydration-mediated redox homeostasis as a promising avenue for therapeutic interventions aimed at mitigating the progression of degenerative diseases.
{"title":"S-sulfhydration: Novel insights into the antioxidant and antiinflammation in age-related diseases","authors":"Fei Liu , Lan Li , Longhui Yuan , Jingchao Yang , Xi Tang , Jingping Liu , Shuyun Liu , Younan Chen , Yanrong Lu , Jingqiu Cheng , Yujia Yuan","doi":"10.1016/j.jare.2025.06.038","DOIUrl":"10.1016/j.jare.2025.06.038","url":null,"abstract":"<div><h3>Background</h3><div>Hydrogen sulfide (H<sub>2</sub>S) and hydrogen polysulfide-induced S-sulfhydration are critical posttranslational modifications that specifically target cysteine residues within proteins. Degenerative diseases are often characterized by oxidative stress and inflammaging, ultimately leading to progressive organ dysfunction. Emerging evidence underscores the essential role of S-sulfhydration in modulating mitochondrial synthesis, energy metabolism, and cellular homeostasis during aging. However, the intricate pathways and molecular regulators that connect S-sulfhydration to degenerative pathologies remain insufficiently elucidated.</div></div><div><h3>Aim of review</h3><div>This review aims to delineate the biological significance of S-sulfhydration in the context of age-associated degenerative disorders especially in redox balance and inflammatory response, including neurodegenerative diseases, osteoarthrosis, osteoporosis, and age-related renal pathologies. In addition, the redox-adaptive S-sulfhydration and clinical applications based on S-sulfhydration-related delivery strategies are proposed, which may reveal novel therapeutic interventions in combating aging.</div></div><div><h3>Key scientific concepts of review</h3><div>This review provides a detailed synthesis of the cellular and molecular mechanisms by which S-sulfhydrated target proteins mitigate senescence phenotypes through antioxidative and anti-inflammatory pathways. Nonetheless, the dual role of S-sulfhydration highly depends on threshold-dependent signaling correlated with H<sub>2</sub>S synthetase. Moreover, the dynamic compensatory mechanism of S-sulfhydration plays a critical role in the interaction between oxidative stress and inflammatory stress during the aging process, which identifies S-sulfhydration-mediated redox homeostasis as a promising avenue for therapeutic interventions aimed at mitigating the progression of degenerative diseases.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 915-933"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-06-19DOI: 10.1016/j.jare.2025.06.045
Nan Li , Jianpeng Zhuang , Jiayi Wu, Zhuoti Xue, Jiayi Xu, Zuye Fang, Yundan Zheng, Yun Liu, Yunpeng Yang, Xinyu Ye, Qing-Yu He, Xuesong Sun
Introduction
To cope with the host’s stressful environment and immune clearance, some drug-resistant bacteria have reduced their virulence. Protein post-translational modifications (PTMs) are known to regulate numerous critical biological processes; however, their specific role in modulating bacterial virulence remains poorly understood.
Objective
This study seeks to elucidate the mechanistic role of lysine crotonylation (Kcr) in modulating Streptococcus pneumoniae virulence and adaptive survival.
Methods
This study employed quantitative differential proteomics combined with animal models to delineate the critical role of Kcr in the adaptive survival of clinically multidrug-resistant bacterial strains. A crotonyltransferase was identified via knockout/overexpression screening, and its regulatory role was characterized using multi-omics characterization methods, including biochemical and molecular biology assays. Antibody-based enrichment coupled with proteomic techniques was utilized to map the enzyme-substrate network of the crotonyltransferase while comprehensive biochemical analyses-including isothermal titration calorimetry (ITC), hemolysis assays, immunoblotting, circular dichroism (CD) spectroscopy and molecular docking, deciphered its mechanism in modulating the virulence effector pneumolysin (PLY).
Results
Our results reveal that mice infected with clinically multidrug-resistant S.pn strains exhibit enhanced invasiveness but attenuated virulence. Quantitative proteomics reveal that Kcr serves as a critical regulator of bacterial virulence and host adaptation. SPD_0839 functions as a crotonyltransferase in S.pn, with Phe93 as its critical catalytic residue. SPD_0839 upregulates 205 Kcr sites on 153 substrates, enhancing the Kcr levels of key enzymes involved in energy metabolism, thereby regulating ATP production. Notably, SPD_0839 modulates the function of the key virulence factor PLY by catalyzing Kcr at Lys171 and Lys442, increases its pore-forming activity and ultimately enhances bacterial hemolysis activity and virulence.
Conclusion
Our findings shed light on the molecular mechanisms underlying PLY hemolytic activity regulated by Kcr, revealing its importance in bacterial survival and virulence. Overall, this research provides valuable insights into the important biological roles of Kcr in S.pn and offers potential theoretical foundations for developing new antibacterial drugs.
{"title":"Crotonylation driving Streptococcus pneumoniae adaption and virulence","authors":"Nan Li , Jianpeng Zhuang , Jiayi Wu, Zhuoti Xue, Jiayi Xu, Zuye Fang, Yundan Zheng, Yun Liu, Yunpeng Yang, Xinyu Ye, Qing-Yu He, Xuesong Sun","doi":"10.1016/j.jare.2025.06.045","DOIUrl":"10.1016/j.jare.2025.06.045","url":null,"abstract":"<div><h3>Introduction</h3><div>To cope with the host’s stressful environment and immune clearance, some drug-resistant bacteria have reduced their virulence. Protein post-translational modifications (PTMs) are known to regulate numerous critical biological processes; however, their specific role in modulating bacterial virulence remains poorly understood.</div></div><div><h3>Objective</h3><div>This study seeks to elucidate the mechanistic role of lysine crotonylation (Kcr) in modulating <em>Streptococcus pneumoniae</em> virulence and adaptive survival.</div></div><div><h3>Methods</h3><div>This study employed quantitative differential proteomics combined with animal models to delineate the critical role of Kcr in the adaptive survival of clinically multidrug-resistant bacterial strains. A crotonyltransferase was identified via knockout/overexpression screening, and its regulatory role was characterized using multi-omics characterization methods, including biochemical and molecular biology assays. Antibody-based enrichment coupled with proteomic techniques was utilized to map the enzyme-substrate network of the crotonyltransferase while comprehensive biochemical analyses-including isothermal titration calorimetry (ITC), hemolysis assays, immunoblotting, circular dichroism (CD) spectroscopy and molecular docking, deciphered its mechanism in modulating the virulence effector pneumolysin (PLY).</div></div><div><h3>Results</h3><div>Our results reveal that mice infected with clinically multidrug-resistant <em>S.pn</em> strains exhibit enhanced invasiveness but attenuated virulence. Quantitative proteomics reveal that Kcr serves as a critical regulator of bacterial virulence and host adaptation. SPD_0839 functions as a crotonyltransferase in <em>S.pn</em>, with Phe93 as its critical catalytic residue. SPD_0839 upregulates 205 Kcr sites on 153 substrates, enhancing the Kcr levels of key enzymes involved in energy metabolism, thereby regulating ATP production. Notably, SPD_0839 modulates the function of the key virulence factor PLY by catalyzing Kcr at Lys171 and Lys442, increases its pore-forming activity and ultimately enhances bacterial hemolysis activity and virulence.</div></div><div><h3>Conclusion</h3><div>Our findings shed light on the molecular mechanisms underlying PLY hemolytic activity regulated by Kcr, revealing its importance in bacterial survival and virulence. Overall, this research provides valuable insights into the important biological roles of Kcr in <em>S.pn</em> and offers potential theoretical foundations for developing new antibacterial drugs.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 453-468"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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