摘要：
OBJECTIVE: To investigate the risk factors for all-cause mortality of previously untreated pulmonary tuberculosis patients complicated by hypertension and construct a predictive model. METHODS: We retrospectively analyzed the clinical data of inpatients with previously untreated pulmonary tuberculosis complicated by hypertension from 2019 to 2021 in Changsha Central Hospital. Patients' survival status and cardiovascular events were collected through telephone follow-up. LASSO regression was utilized to screen predictive variables, and binary logistic regression identified mortality risk factors. A predictive nomogram model was developed using R software, and its precision and reliability were verified. RESULTS: Among the 1,014 patients, there were 100 (9.86%) deaths and 82 (8.09%) cardiovascular events. LASSO regression screened out 13 predictive variables. Multivariate logistic regression analysis revealed that smoking history, sputum bacteriology, pleural effusion, coronary heart disease, and chronic kidney disease were independent risk factors. Based on the training set data, a nomogram prognostic model was developed, showing an AUC of 0.712 (95% CI: 0.777-0.847), with 50.0% sensitivity and 84.3% specificity. The model's fit was confirmed through internal and external validations. CONCLUSION: The prediction model constructed in this study has high predictive ability and satisfactory clinical efficacy, and can provide an effective individualized prediction tool for assessing all-cause mortality risk in patients with previously untreated pulmonary tuberculosis complicated by hypertension.
期刊：
Molecular and Cellular Biochemistry,2025年480(4):2143-2157 ISSN：0300-8177
通讯作者：
Wang, J
作者机构：
[Jiang, Tingting] Univ South China, Hengyang Med Sch, Affiliated Nanhua Hosp, Dept Clin Lab, Hengyang 421000, Peoples R China.;[Zeng, Qun] Univ South China, Hengyang Med Sch, Dept Biochem & Mol Biol, Hengyang 421000, Peoples R China.;[Wang, Jing] Changsha Med Univ, Hunan Prov Key Lab Tradit Chinese Med Agr Biogenom, Changsha 410219, Peoples R China.;[Wang, Jing] Changsha Med Univ, Hunan Prov Univ Key Lab Fundamental & Clin Res Fun, Changsha 410219, Peoples R China.;[Wang, Jing] Changsha Med Univ, Clin Coll 1, Changsha 410219, Peoples R China.
通讯机构：
[Wang, J ] C;Changsha Med Univ, Hunan Prov Key Lab Tradit Chinese Med Agr Biogenom, Changsha 410219, Peoples R China.;Changsha Med Univ, Hunan Prov Univ Key Lab Fundamental & Clin Res Fun, Changsha 410219, Peoples R China.;Changsha Med Univ, Clin Coll 1, Changsha 410219, Peoples R China.
摘要：
FHL2 (Four-and-a-half LIM domain protein 2) is a crucial factor involved in cardiac morphogenesis, the process by which the heart develops its complex structure. It is expressed in various tissues during embryonic development, including the developing heart, and has been shown to play important roles in cell proliferation, differentiation, and migration. FHL2 interacts with multiple proteins to regulate cardiac development as a coactivator or a corepressor. It is involved in cardiac specification and determination of cell fate, cardiomyocyte growth, cardiac remodeling, myofibrillogenesis, and the regulation of HERG channels. Targeting FHL2 has therapeutic implications as it could improve cardiac function, control arrhythmias, alleviate heart failure, and maintain cardiac integrity in various pathological conditions. The identification of FHL2 as a signature gene in atrial fibrillation suggests its potential as a diagnostic marker and therapeutic target for this common arrhythmia.
关键词：
Drug reposition;Enrichment score;Immunoregulation;LINCS;Lenalidomide;Radioprotection
摘要：
Ionizing radiation induces DNA damage and impairs genomic integrity, leading to cell death and tissue injuries or carcinogenesis. Medical radiation protectors are essential and necessary. However, there are limited radioprotectors in clinics, which can't meet the growing demand for countering radiation emergencies. Traditional drug discovery approach has been proven expensive and risky. Computational drug repositioning provides an attractive strategy for radioprotector discovery. Here we constructed a systematic workflow to identify repositioning radioprotectors by comparison of biosimilarity between γ-ray and known medicines characterized by gene expression signatures from GEO and LINCS. Using enrichment scoring, medicines with negative scores were considered as candidates of revising or mitigating radiation injuries. Seven approved medicines were identified, and their targets enriched in steroid and estrogen metabolic, chemical carcinogenesis associated pathways. Lenalidomide, an approved medicine for multiple myeloma and anemia, was further verified as a promising potential radioprotector. It increases survival of mice after lethal doses of irradiation by alleviating bone marrow and intestinal injury in vivo, and inhibits apoptosis of cultured irradiated AHH- 1 and IEC- 6 cells in vitro. This study introduces rational drug repositioning to radiation medicine and provides viable candidates for radioprotective therapeutic regimens.
摘要：
Biased µ-opioid receptor (MOR) agonists enhance pain relief by selectively activating G protein-coupled receptor signaling and minimizing β-arrestin-2 activation, resulting in fewer side effects. This multicenter Phase II/III trial evaluated the optimal dosage, efficacy, and safety of SHR8554, a biased MOR agonist, for postoperative pain management following orthopedic surgery. In Phase II, 121 patients were divided into four groups to receive varying patient-controlled analgesia (PCA) doses of SHR8554 or morphine. Phase III involved 320 patients with similar groupings, including a placebo group. The primary outcome was the resting summed pain intensity difference over 24 hours (rSPID 24 ). Secondary outcomes included rSPID and active-SPID (aSPID) at other time points, rescue analgesia received, cumulative dose of analgesics, and satisfaction scores. Safety endpoints included treatment-emergent adverse events (TEAEs) and AE of special interest (AESIs). In both phases, SHR8554 demonstrated significant analgesic efficacy. In Phase II, the least squares (LS) mean differences in rSPID 24 compared to morphine for the 0.05 mg,0.1 mg, and 0.2 mg SHR8554 groups were 16.8 (p = 0.01), 7.4 (p = 0.27), and 0.2 (p = 0.98), respectively. Phase III confirmed the efficacy of the 0.05 mg and 0.1 mg SHR8554 doses compared to placebo, with LS mean differences of 15.4 (p = 0.0001) and −19.8 (p < 0.0001), respectively. Trends in other secondary outcomes mirrored these findings. Safety analysis revealed that the 0.2 mg SHR8554 group had higher incidences of TEAEs (83.3 %) and AESIs (33.3 %) compared to other groups in Phase II. Similarly, in Phase III, the incidences of TEAEs were 81.0 %, 73.4 %, and 74.1 % in the 0.05 and 0.1 mg SHR8554 and morphine groups, respectively, compared with 61.3 % in the placebo group, while the AESIs were 29.1 %, 20.3 %, and 24.7 % compared with 12.5 % in the placebo group. In conclusion, SHR8554 exhibited efficacy compared to placebo and safety comparable to morphine for patients experiencing moderate-to-severe acute pain following unilateral total knee replacement or knee ligament reconstruction surgery.
Biased µ-opioid receptor (MOR) agonists enhance pain relief by selectively activating G protein-coupled receptor signaling and minimizing β-arrestin-2 activation, resulting in fewer side effects. This multicenter Phase II/III trial evaluated the optimal dosage, efficacy, and safety of SHR8554, a biased MOR agonist, for postoperative pain management following orthopedic surgery. In Phase II, 121 patients were divided into four groups to receive varying patient-controlled analgesia (PCA) doses of SHR8554 or morphine. Phase III involved 320 patients with similar groupings, including a placebo group. The primary outcome was the resting summed pain intensity difference over 24 hours (rSPID 24 ). Secondary outcomes included rSPID and active-SPID (aSPID) at other time points, rescue analgesia received, cumulative dose of analgesics, and satisfaction scores. Safety endpoints included treatment-emergent adverse events (TEAEs) and AE of special interest (AESIs). In both phases, SHR8554 demonstrated significant analgesic efficacy. In Phase II, the least squares (LS) mean differences in rSPID 24 compared to morphine for the 0.05 mg,0.1 mg, and 0.2 mg SHR8554 groups were 16.8 (p = 0.01), 7.4 (p = 0.27), and 0.2 (p = 0.98), respectively. Phase III confirmed the efficacy of the 0.05 mg and 0.1 mg SHR8554 doses compared to placebo, with LS mean differences of 15.4 (p = 0.0001) and −19.8 (p < 0.0001), respectively. Trends in other secondary outcomes mirrored these findings. Safety analysis revealed that the 0.2 mg SHR8554 group had higher incidences of TEAEs (83.3 %) and AESIs (33.3 %) compared to other groups in Phase II. Similarly, in Phase III, the incidences of TEAEs were 81.0 %, 73.4 %, and 74.1 % in the 0.05 and 0.1 mg SHR8554 and morphine groups, respectively, compared with 61.3 % in the placebo group, while the AESIs were 29.1 %, 20.3 %, and 24.7 % compared with 12.5 % in the placebo group. In conclusion, SHR8554 exhibited efficacy compared to placebo and safety comparable to morphine for patients experiencing moderate-to-severe acute pain following unilateral total knee replacement or knee ligament reconstruction surgery.
Trial Registration Trial Name: Study on the Efficacy and Safety of SHR8554 Injection for Postoperative Analgesia in Orthopedics: Multicenter, Randomized, Double Blind, Dose Exploration, Placebo/Positive Control, Phase II/III Clinical Trial Registered on: chinadrugtrials.org.cn Identifier: CTR20220639.
Trial Name: Study on the Efficacy and Safety of SHR8554 Injection for Postoperative Analgesia in Orthopedics: Multicenter, Randomized, Double Blind, Dose Exploration, Placebo/Positive Control, Phase II/III Clinical Trial Registered on: chinadrugtrials.org.cn Identifier: CTR20220639.
摘要：
Acute kidney injury (AKI) is associated with poor prognosis. New biomarkers, like neutrophil gelatinase-associated lipocalin (NGAL), are helpful for early warning of AKI. This study aims to investigate the accuracy of NGAL in evaluating the perioperative AKI of liver transplantation. The four databases, PubMed, Web of Science, Embase, and Cochrane Library, were searched for relevant studies published from database inception to August 2023. Results were pooled using random-effects models, and heterogeneity was examined. A total of 16 case-control studies with 1271 patients were included. The results showed that both preoperative [standardized mean difference (SMD) = 0.53; 95% confidence interval (CI): 0.15, 0.91; P < 0.001] and postoperative NGAL levels (SMD = 0.63; 95% CI: 0.24, 1.03; P < 0.001) were higher in the AKI group compared with the non-AKI group. Subgroup analysis by continents showed higher preoperative NGAL levels in AKI patients in the European population (SMD = 1.63; 95% CI: 0.55, 0.27; P = 0.003), but no differences in Asian, African, North American, and South American. Subgroup analysis by continents revealed higher postoperative NGAL levels in the European (SMD = 1.63; 95% CI: 0.55, 0.27; P = 0.002) and Asian populations (SMD = 0.42; 95% CI: 0.04, 0.81; P = 0.039). Higher postoperative NGAL levels in plasma and urine were observed in AKI patients compared with non-AKI patients [plasma (SMD = 1.29; 95% CI: 0.21, 2.38; P = 0.011), urine (SMD = 0.88; 95% CI: 0.18, 1.59; P = 0.035)], while there was no difference in African, North American, South American, and serum NGAL. NGAL level may be an important biomarker for early detection of AKI in the perioperative period of liver transplantation.
摘要：
The recent elucidation of disulfidptosis, a unique form of cell death, has opened new paths for the development of targeted cancer therapies. However, a thorough examination of disulfidptosis-related genes (DRGs) across various cancer types has been lacking. Our extensive analysis of DRGs through genomic, transcriptional, and immune profiling has yielded substantial insights. Utilizing The Cancer Genome Atlas (TCGA), we have identified key changes in gene expression, including alterations in copy number and DNA methylation, and evaluated their impact on cancer prognosis. We constructed a disulfidptosis-related signature (DFRS) using LASSO regression and multivariate Cox regression analysis, which demonstrated a strong prognostic connection across diverse cancer types. The DFRS score is linked with poorer clinical outcomes, reflects the immune characteristics of the tumor microenvironment (TME), and predicts responsiveness to immunotherapy and other treatments. Notably, the DFRS score interacts with critical oncogenic pathways, highlighting the potential benefits of targeting disulfidptosis in cancer treatment. Our findings underscore the critical influence of disulfidptosis on cancer prognosis and therapeutic response, offering meaningful clinical insights.
作者机构：
[Tang, Jingjing; Tang, Wei; Li, Yanlin; Li, Zhenkui] Univ South China, Inst Pathogen Biol, Sch Basic Med Sci, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;[Tang, Jingjing; Tang, Wei; Li, Yanlin; Li, Zhenkui] Univ South China, Sch Basic Med Sci, Hengyang Med Sch, Key Lab Special Pathogen Prevent & Control Hunan P, Hengyang 421001, Hunan, Peoples R China.;[Liu, Cong] Univ South China, Sch Publ Hlth, Hengyang Med Sch, Dept Hlth Inspect & Quarantine, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Li, ZK ] U;Univ South China, Inst Pathogen Biol, Sch Basic Med Sci, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Sch Basic Med Sci, Hengyang Med Sch, Key Lab Special Pathogen Prevent & Control Hunan P, Hengyang 421001, Hunan, Peoples R China.
摘要：
Malaria, a severe parasitic disease caused by Plasmodium infections, remains a major global health challenge. Efforts to eradicate malaria are complicated by the parasite’s intricate life cycle, which alternates between vertebrate hosts and mosquito vectors. Host-derived factors and parasite-sourced components exert crucial roles in regulating this biological process. This review explores the critical role of host-derived factors in shaping Plasmodium sexual differentiation and transmission. We examine how vertebrate and mosquito host-specific factors either promote or restrict parasite development, influencing the transition from vertebrates to mosquitoes. Understanding these host-mediated mechanisms is crucial for developing novel transmission-blocking strategies to reduce malaria prevalence. By highlighting key interactions between hosts and parasites, this review provides insights into potential interventions that could disrupt Plasmodium transmission and contribute to malaria control efforts.
Malaria, a severe parasitic disease caused by Plasmodium infections, remains a major global health challenge. Efforts to eradicate malaria are complicated by the parasite’s intricate life cycle, which alternates between vertebrate hosts and mosquito vectors. Host-derived factors and parasite-sourced components exert crucial roles in regulating this biological process. This review explores the critical role of host-derived factors in shaping Plasmodium sexual differentiation and transmission. We examine how vertebrate and mosquito host-specific factors either promote or restrict parasite development, influencing the transition from vertebrates to mosquitoes. Understanding these host-mediated mechanisms is crucial for developing novel transmission-blocking strategies to reduce malaria prevalence. By highlighting key interactions between hosts and parasites, this review provides insights into potential interventions that could disrupt Plasmodium transmission and contribute to malaria control efforts.
摘要：
Objectives Dysregulated inflammatory responses during sepsis often result in acute lung injury (ALI). Neutrophils activated at the primary site of injury can re-enter the circulation through reverse transendothelial migration (rTEM), subsequently infiltrating other organs and contributing to systemic inflammation and multi-organ damage. The specialized pro-resolving lipid mediator (SPM) maresin conjugate in tissue regeneration 1 (MCTR1) has been shown to mitigate organ injury in sepsis. This study investigated the role of neutrophil rTEM in ALI and examined whether MCTR1 can alleviate ALI by modulating neutrophil rTEM.
Dysregulated inflammatory responses during sepsis often result in acute lung injury (ALI). Neutrophils activated at the primary site of injury can re-enter the circulation through reverse transendothelial migration (rTEM), subsequently infiltrating other organs and contributing to systemic inflammation and multi-organ damage. The specialized pro-resolving lipid mediator (SPM) maresin conjugate in tissue regeneration 1 (MCTR1) has been shown to mitigate organ injury in sepsis. This study investigated the role of neutrophil rTEM in ALI and examined whether MCTR1 can alleviate ALI by modulating neutrophil rTEM.
Methods Lung injury was induced in mice by administrating lipopolysaccharide (LPS). Lung damage was assessed using H&E staining, lung wet-to-dry ratio, inflammatory mediator levels, and protein content in the bronchoalveolar lavage fluid. Neutrophil infiltration in lung tissue was evaluated by immunofluorescence, and flow cytometry was used to quantify rTEM neutrophils. Protein expression of neutrophil elastase (NE) and junctional adhesion molecule-C (JAM-C) was analyzed to assess rTEM activity. The role of CXCR4 in neutrophil rTEM was investigated using the CXCR4 inhibitor AMD3100. Additionally, bone marrow-derived neutrophils were isolated to evaluate the effects of MCTR1 on CXCR4 and GRK2 expression.
Lung injury was induced in mice by administrating lipopolysaccharide (LPS). Lung damage was assessed using H&E staining, lung wet-to-dry ratio, inflammatory mediator levels, and protein content in the bronchoalveolar lavage fluid. Neutrophil infiltration in lung tissue was evaluated by immunofluorescence, and flow cytometry was used to quantify rTEM neutrophils. Protein expression of neutrophil elastase (NE) and junctional adhesion molecule-C (JAM-C) was analyzed to assess rTEM activity. The role of CXCR4 in neutrophil rTEM was investigated using the CXCR4 inhibitor AMD3100. Additionally, bone marrow-derived neutrophils were isolated to evaluate the effects of MCTR1 on CXCR4 and GRK2 expression.
Results MCTR1 alleviated lung injury and inhibited neutrophils rTEM in LPS-induced lung injury. MCTR1 also decreased NE expression and increased JAM-C expression. The CXCR4 inhibitor AMD3100 effectively suppressed neutrophil rTEM and alleviated lung injury. Furthermore, MCTR1 inhibited CXCR4 expression and enhanced GRK2 expression.
MCTR1 alleviated lung injury and inhibited neutrophils rTEM in LPS-induced lung injury. MCTR1 also decreased NE expression and increased JAM-C expression. The CXCR4 inhibitor AMD3100 effectively suppressed neutrophil rTEM and alleviated lung injury. Furthermore, MCTR1 inhibited CXCR4 expression and enhanced GRK2 expression.
Conclusions MCTR1 reduces lung damage by upregulating GRK2 to inhibit CXCR4 expression, thereby suppressing neutrophil rTEM in LPS-induced lung injury.
MCTR1 reduces lung damage by upregulating GRK2 to inhibit CXCR4 expression, thereby suppressing neutrophil rTEM in LPS-induced lung injury.
摘要：
Sepsis-associated acute respiratory distress syndrome (ARDS) is a heterogeneous disease with high morbidity and mortality. Lactylation plays a crucial role in sepsis and sepsis-induced lung injury. This study aimed to identify distinct lactylation-based phenotypes in patients with sepsis-associated ARDS and determine relevant molecular biomarkers. We analyzed blood transcriptome and clinical data from patients with sepsis-associated ARDS and calculated the lactylation activity. KEGG pathway analysis, drug sensitivity prediction, and immune cell infiltration analysis were performed. Candidate molecular biomarkers were identified by intersecting the feature genes extracted from four machine learning models. Lactylation activity showed significant heterogeneity among patients with sepsis-associated ARDS, which enabled the classification into low- and high-lactylation activity phenotypes. Patients with high-lactylation experienced longer hospital stays and higher mortality rates, as well as distinct signaling pathways, drug responses, and circulating immune cell abundances. Six key markers (ALDOB, CCT5, EP300, PFKP, PPIA, and SIRT1) were identified to differentiate the two lactylation activity phenotypes, all significantly correlated with circulating immune cell populations. This study revealed significant heterogeneity in lactylation activity phenotypes among patients with sepsis-associated ARDS and identified potential biomarkers to facilitate the application of these phenotypes in clinical practice.
摘要：
Peptides exhibit various biological activities, including biorecognition, cell targeting, and tumor penetration, and can stimulate immune cells to elicit immune responses for tumor immunotherapy. Peptide self-assemblies and peptide-functionalized nanocarriers can reduce the effect of various biological barriers and the degradation by peptidases, enhancing the efficiency of peptide delivery and improving antitumor immune responses. To date, the design and development of peptides with various functionalities have been extensively reviewed for enhanced chemotherapy; however, peptide-mediated tumor immunotherapy using peptides acting on different immune cells, to the knowledge, has not yet been summarized. Thus, this work provides a review of this emerging subject of research, focusing on immunomodulatory anticancer peptides. This review introduces the role of peptides in the immunomodulation of innate and adaptive immune cells, followed by a link between peptides in the innate and adaptive immune systems. The peptides are discussed in detail, following a classification according to their effects on different innate and adaptive immune cells, as well as immune checkpoints. Subsequently, two delivery strategies for peptides as drugs are presented: peptide self-assemblies and peptide-functionalized nanocarriers. The concluding remarks regarding the challenges and potential solutions of peptides for tumor immunotherapy are presented. This work introduces the role of peptides in immune regulation of innate and adaptive immune cells, as well as immune checkpoints. Then this work introduces two strategies for delivering polypeptides: peptide self-assemblies, and peptide-functionalized nanocarriers. Finally, the challenges and prospects of peptides in tumor immunotherapy are summarized. image
摘要：
The major facilitator superfamily (MFS) type efflux pumps of Acinetobacter baumannii play important roles in antibiotic resistance. However, the molecular mechanism of these transporters remains poorly understood. To address the molecular basis of substrate polyspecificity mediated by multidrug MFS transporters, we compared the substrate binding modes of A. baumannii CraA with its well-studied homolog, Escherichia coli MdfA. MdfA and CraA share similar structural features, including a cavity accessible to drugs from the cytoplasm when these transporters adopt the inside-out conformation. This predominantly hydrophobic cavity contains several distinct titratable and hydrophilic residues. Through substitution analysis, we demonstrate that these polar residues within the CraA drug binding cavity contribute to the transport of all tested drugs, whereas mutations of hydrophobic residues result in altered drug recognition profiles. In addition to the known titratable residues E38 and D46, we identified E338 as the only titratable residue that plays a substrate-specific role, as it is required for efficient transport of norfloxacin, but not ethidium. Substitution of E338 with asparagine or glutamine changes substrate specificity, enabling specific recognition of phenicols and mitomycin C. Furthermore, we show that the aromaticity of Y42 is crucial for phenicol recognition, while general hydrophobicity at this position is critical for mitomycin C specificity. We propose that E338 and Y42 function as key substrate selectivity determinants in CraA. IMPORTANCE Multidrug efflux transporters of the major facilitator superfamily (MFS) are key contributors to antibiotic resistance, mediating the export of structurally diverse compounds across bacterial membranes. While homologous transporters such as Escherichia coli MdfA and Acinetobacter baumannii CraA share high structural similarity and overlapping substrate profiles, the molecular basis of their substrate specificity remains poorly understood. In this study, we show that structural homology among MFS transporters does not inherently imply mechanistic conservation, as species-specific variations can give rise to distinct substrate recognition profiles. Our findings reveal that CraA utilizes unique residues Y42 and E338 for substrate selectivity, while R124 and Y73 contribute to its transport activity. These findings enhance our understanding of efflux pump specificity and underscore the need to consider organism-specific features when targeting multidrug transporters in antimicrobial therapy.
The major facilitator superfamily (MFS) type efflux pumps of Acinetobacter baumannii play important roles in antibiotic resistance. However, the molecular mechanism of these transporters remains poorly understood. To address the molecular basis of substrate polyspecificity mediated by multidrug MFS transporters, we compared the substrate binding modes of A. baumannii CraA with its well-studied homolog, Escherichia coli MdfA. MdfA and CraA share similar structural features, including a cavity accessible to drugs from the cytoplasm when these transporters adopt the inside-out conformation. This predominantly hydrophobic cavity contains several distinct titratable and hydrophilic residues. Through substitution analysis, we demonstrate that these polar residues within the CraA drug binding cavity contribute to the transport of all tested drugs, whereas mutations of hydrophobic residues result in altered drug recognition profiles. In addition to the known titratable residues E38 and D46, we identified E338 as the only titratable residue that plays a substrate-specific role, as it is required for efficient transport of norfloxacin, but not ethidium. Substitution of E338 with asparagine or glutamine changes substrate specificity, enabling specific recognition of phenicols and mitomycin C. Furthermore, we show that the aromaticity of Y42 is crucial for phenicol recognition, while general hydrophobicity at this position is critical for mitomycin C specificity. We propose that E338 and Y42 function as key substrate selectivity determinants in CraA.
IMPORTANCE
Multidrug efflux transporters of the major facilitator superfamily (MFS) are key contributors to antibiotic resistance, mediating the export of structurally diverse compounds across bacterial membranes. While homologous transporters such as Escherichia coli MdfA and Acinetobacter baumannii CraA share high structural similarity and overlapping substrate profiles, the molecular basis of their substrate specificity remains poorly understood. In this study, we show that structural homology among MFS transporters does not inherently imply mechanistic conservation, as species-specific variations can give rise to distinct substrate recognition profiles. Our findings reveal that CraA utilizes unique residues Y42 and E338 for substrate selectivity, while R124 and Y73 contribute to its transport activity. These findings enhance our understanding of efflux pump specificity and underscore the need to consider organism-specific features when targeting multidrug transporters in antimicrobial therapy.
Multidrug efflux transporters of the major facilitator superfamily (MFS) are key contributors to antibiotic resistance, mediating the export of structurally diverse compounds across bacterial membranes. While homologous transporters such as Escherichia coli MdfA and Acinetobacter baumannii CraA share high structural similarity and overlapping substrate profiles, the molecular basis of their substrate specificity remains poorly understood. In this study, we show that structural homology among MFS transporters does not inherently imply mechanistic conservation, as species-specific variations can give rise to distinct substrate recognition profiles. Our findings reveal that CraA utilizes unique residues Y42 and E338 for substrate selectivity, while R124 and Y73 contribute to its transport activity. These findings enhance our understanding of efflux pump specificity and underscore the need to consider organism-specific features when targeting multidrug transporters in antimicrobial therapy.
Multidrug efflux transporters of the major facilitator superfamily (MFS) are key contributors to antibiotic resistance, mediating the export of structurally diverse compounds across bacterial membranes. While homologous transporters such as Escherichia coli MdfA and Acinetobacter baumannii CraA share high structural similarity and overlapping substrate profiles, the molecular basis of their substrate specificity remains poorly understood. In this study, we show that structural homology among MFS transporters does not inherently imply mechanistic conservation, as species-specific variations can give rise to distinct substrate recognition profiles. Our findings reveal that CraA utilizes unique residues Y42 and E338 for substrate selectivity, while R124 and Y73 contribute to its transport activity. These findings enhance our understanding of efflux pump specificity and underscore the need to consider organism-specific features when targeting multidrug transporters in antimicrobial therapy.
摘要：
This study aimed to create a personalized risk assessment model for asymptomatic intracerebral hemorrhage (aICH) following endovascular thrombectomy (ET) to aid clinical decision-making.Between 2019 and 2023, 469 inpatients with acute ischemic stroke (AIS) who received ET treatment within 24h of onset were recruited from three centers. Patients were randomly assigned to either a training or validation cohort. Univariate and multivariate logistic regression analyses were conducted to identify independent factors for aICH. A nomogram-based model was developed for personalized risk assessment for aICH following ET. The model's usability was evaluated using the receiver operating characteristic (ROC) curve, and a calibration curve was plotted to compare predicted probabilities with actual occurrences. The feasibility of the model for practical clinical application was assessed using decision curve analysis.Four independent risk factors for aICH in patients with AIS following ET were identified: preoperative Alberta Stroke Program Early Computed Tomography score [odds ratio (OR) = 0.686, 95% confidence interval (CI): 0.581-0.811], time from onset to surgery completion (OR = 1.186, 95% CI: 1.097-1.282), intraoperative arterial thrombolysis (OR = 2.405, 95% CI: 1.289-4.487), and Careggi collateral score (OR = 0.560, 95% CI: 0.422-0.743). ROC analysis indicated that the model demonstrated excellent accuracy and discrimination with area under the curve values of 0.812 (95% CI: 0.763-0.861) and 0.896 (95% CI, 0.843-0.949) for the training and validation cohorts, respectively.This nomogram-based model is a reliable personalized tool for evaluating the risk of aICH in patients with AIS after ET.
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：
[Yifei Wang; Jiaxin Chen; Baihuan Duan; Jindou She; Keming Zhong; Peng Liu; Yating Wen; Yalan Jiang; Gao Zeng; Hong Huang] Institute of Pathogenic Biology, Basic Medical School, Hengyang Medical School, University of South China, Hengyang Central Hospital, Hengyang, 421001, China;[Wenxin Chen] Institute of Pathogenic Biology, Basic Medical School, Hengyang Medical School, University of South China, Hengyang Central Hospital, Hengyang, 421001, China. cwx0905299299@163.com
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.
