摘要：
Introduction Glucosylceramidase beta 1 (GBA1) mutations are a genetic risk factor for Parkinson's disease (PD), though most carriers do not develop the disease. This study aimed to identify exposure factors linked to PD in GBA1 carriers and assess clinical features and the probability of prodromal PD in non-manifesting carriers.
Glucosylceramidase beta 1 (GBA1) mutations are a genetic risk factor for Parkinson's disease (PD), though most carriers do not develop the disease. This study aimed to identify exposure factors linked to PD in GBA1 carriers and assess clinical features and the probability of prodromal PD in non-manifesting carriers.
Methods Data from the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network in China was used, including 59 GBA1 non-manifesting carriers, 62 controls, and 107 GBA1-associated PD, of whom 81 were in the early stage. Exposure factors included pesticide/solvent exposure, smoking, alcohol, and tea consumption. Logistic regression assessed the association between exposure factors and PD. Clinical characteristics were evaluated using multiple scales, relevant markers were collected based on the Movement Disorders Society criteria. A naive Bayesian classifier method determined the probability of prodromal PD in GBA1 non-manifesting carriers and controls.
Data from the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network in China was used, including 59 GBA1 non-manifesting carriers, 62 controls, and 107 GBA1-associated PD, of whom 81 were in the early stage. Exposure factors included pesticide/solvent exposure, smoking, alcohol, and tea consumption. Logistic regression assessed the association between exposure factors and PD. Clinical characteristics were evaluated using multiple scales, relevant markers were collected based on the Movement Disorders Society criteria. A naive Bayesian classifier method determined the probability of prodromal PD in GBA1 non-manifesting carriers and controls.
Results After adjusting for sociodemographic variables, pesticide/solvent exposure was positively associated with PD in GBA1 carriers (OR 8.40; 95 % CI 2.50–28.20), while smoking was inversely associated with PD (OR 0.18; 95 % CI 0.05–0.62). Rapid eye movement sleep behavior disorder, constipation, hyposmia, and cognitive deficits were more severe in early-stage GBA1-associated PD than in carriers and controls. Clinical symptoms and the probability of prodromal PD were similar between carriers and controls.
After adjusting for sociodemographic variables, pesticide/solvent exposure was positively associated with PD in GBA1 carriers (OR 8.40; 95 % CI 2.50–28.20), while smoking was inversely associated with PD (OR 0.18; 95 % CI 0.05–0.62). Rapid eye movement sleep behavior disorder, constipation, hyposmia, and cognitive deficits were more severe in early-stage GBA1-associated PD than in carriers and controls. Clinical symptoms and the probability of prodromal PD were similar between carriers and controls.
Conclusions PD in GBA1 carriers is closely linked to exposure factors. Early-stage GBA1-associated PD shows significant prodromal symptoms, which are not evident in carriers. The probability of prodromal PD in carriers is similar to that in controls.
PD in GBA1 carriers is closely linked to exposure factors. Early-stage GBA1-associated PD shows significant prodromal symptoms, which are not evident in carriers. The probability of prodromal PD in carriers is similar to that in controls.
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.
通讯机构：
[Tan, XF; Yang, QL ; Wu, GL] U;Univ South China, Affiliated Hosp 1, Dept Hepatopancreatobiliary Surg, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Canc Res Inst, Ctr Mol Imaging Probe, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;Univ South China, NHC Key Lab Birth Defect Res & Prevent, Hengyang 421001, Hunan, Peoples R China.;Univ South China, MOE Key Lab Rare Pediat Dis, Hengyang 421001, Hunan, Peoples R China.
关键词：
NIR-II;Phototheranostics;Endoplasmic reticulum;Triple-negative breast cancer;Intermolecular π–π stacking interaction
摘要：
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by an extremely poor prognosis. Photoimmunotherapy has emerged as a promising strategy for the treatment of TNBC. This approach works by selectively destroying tumor cells, releasing tumor-associated antigens, activating the immune system, and effectively inhibiting tumor proliferation and metastasis. However, the majority of current phototheranostic approaches are hindered by limited tissue penetration in the first near-infrared (NIR-I) and ultraviolet-visible (UV-Vis) regions. Additionally, due to the lack of specific subcellular targets, it may be difficult to effectively treat deep-seated lesions with ambiguous and extensive boundaries caused by TNBC metastases. Consequently, the development of effective, deep-penetrating, organelle-targeted phototheranostics is essential for enhancing treatment outcomes in TNBC. This work proposes a novel molecular design strategy of NIR-II phototheranostics to realize planar rigid conjugation and alkyl chain functionalization. The di-hexaalkyl chains in a vertical configuration on the donor (4H-cyclopenta[2,1-b:3,4-b'] dithiophene) and shielding units (fluorene) are introduced to construct a S-D-A-D-S type NIR-II phototheranostics (IR-FCD). The planar and rigid structure of IR-FCD exhibits a robust intramolecular charge transfer capability, a lower band gap, enhanced photon absorption properties, and significant steric hindrance from vertically arranged alkyl chains to minimize non-radiative energy loss. By incorporating N-(but-3-yn-1-yl)-4-methylbenzenesulfonamide at the terminus of an elongated alkyl chain, followed by self-assembly into DSPE-S-S-PEG2000, NIR-II excitable phototheranostics (IR-FCD-Ts NPs) with endoplasmic reticulum (ER) targeting capability were successfully synthesized for imaging-guided photoimmunotherapy of TNBC. The IR-FCD-Ts NPs demonstrate exceptional optical characteristics, with maximum absorption at 1068nm (extending to 1300nm) and emission at 1273nm (extending to 1700nm), along with a high molar absorption coefficient of 2.76*10(4)L/mol·c at 1064nm in aqueous solution. Under exposure to 1064nm laser irradiation, IR-FCD-Ts NPs exhibit superior photothermal properties and have the potential for photodynamic therapy. By targeting ER, thereby inducing ER stress and significantly enhancing immunogenic cell death (ICD) in tumor cells, it triggers a strong antitumor immune response and inhibits the proliferation and metastasis of TNBC.
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：
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.
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.
期刊：
Tremor and Other Hyperkinetic Movements,2025年15:43 ISSN：2160-8288
通讯作者：
Sun, QY
作者机构：
[Zhang, Hainan; He, Runcheng; Wang, Chunyu] Department of Neurology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China;[Zhang, Hainan; He, Runcheng; Wang, Chunyu] Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China;[Li, Mingqiang] Department of Neurology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, 421001, China;[Sun, Qiying; Zhou, Xun; Liu, Lanqing] Department of Geriatric Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China;[Sun, Qiying] National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
通讯机构：
[Sun, QY ] C;Cent South Univ, Xiangya Hosp, Dept Geriatr Neurol, Changsha 410008, Hunan, Peoples R China.
关键词：
Essential tremor;Essential tremor plus;Medication adherence;Real world study
摘要：
BACKGROUND: Medication adherence in essential tremor (ET) remains poorly characterized. This real world study aimed to investigate adherence rates, clinical correlates, and predictors among ET patients in China. METHODS: A prospective cohort of 318 ET patients (116 pure ET, 202 ET-plus) was followed for a mean of 22.91 ± 3.86 months. Standardized assessments included the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Non-Motor Symptoms Scale (NMSS). Adherence was defined as daily use of prescribed tremor medications. Logistic regression identified predictors. RESULTS: Only 27.4% (87/318) maintained daily adherence. ET-plus patients showed higher adherence than pure ET (32.2% vs 19.0%, P = 0.011). Arotinolol was the most common medication. Compared to non-adherent patients, adherent patients showed higher urban residency (P = 0.026), head tremor prevalence (P = 0.002), mild cognitive impairment (P = 0.038), higher TETRAS-I (P = 0.047) and TETRAS-II scores (P = 0.008), as well as lower MoCA scores (P = 0.021). Multivariable analysis showed better medication adherence was significantly associated with higher TETRAS-II score (OR = 1.041, 95% CI = 1.001-1.082, P = 0.047), urban residence (OR = 1.775, 95% CI = 1.066-2.957, P = 0.028), and the presence of head tremor (OR = 1.936, 95% CI = 1.125-3.332, P = 0.017). No significant association was found between ET subtypes and adherence (P > 0.05). CONCLUSION: Medication adherence is alarmingly low in Chinese ET patients, especially in pure ET. Greater tremor severity, presence of head tremor, and urban residence were independently associated with better medication adherence. HIGHLIGHT: Medication adherence among Chinese essential tremor (ET) patients remains suboptimal (only 27.4% in our cohort). ET plus patients showed higher adherence (32.2%) than pure ET (19.0%). Predictors of adherence included severe tremor (TETRAS-II), urban residence, and head tremor. Arotinolol was the predominant treatment. Findings emphasize the need for personalized interventions.
作者机构：
[Li, Pian; He, Junyan; Yang, Dong] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Oncol, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Xiaoli] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Pathol, Hengyang 421001, Hunan, Peoples R China.;[Tan, Yini; Li, Yi] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Obstet & Gynecol, 69 Chuanshan Rd, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Li, Y ] U;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Obstet & Gynecol, 69 Chuanshan Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
Endometrial carcinoma;Estrogen receptor;Lymphovascular space invasion;Myometrial invasion;Progesterone receptor
摘要：
Background It is crucial to identify the high-risk factors associated with the recurrence and metastasis of endometrial cancer (EC) in order to implement more precise clinical stratification and management strategies for EC patients. Methods A total of 336 patients with stage I-III EC were retrospectively analyzed. According to the recurrence site, they were divided into locoregional recurrence (LR) and poor-prognosis recurrence (PPR). The factors that may affect the prognosis of EC were analyzed and the subgroups were analyzed. Results Among the no recurrence(NR), LR and PPR groups, 5-year OS were 89.4%, 60.2% and 46.8%, 5-year RFS were 100%, 15.4% and 6.4%. The FIGO stage, molecular classification, lymphovascular space invasion (LVSI) and smoking history were independent risk factors affecting 5-year OS and 5-year RFS in EC patients (p < 0.05). Pathological type and progesterone receptor (PR) were independent risk factors affecting 5-year OS (p < 0.05). Histologic Grade and adjuvant therapy were independent risk factors affecting 5-year RFS (p < 0.05). Myometrial invasion, LVSI and FIGO stage were independent risk factors in the LR subgroup (p < 0.05), FIGO stage, ER and PR were independent risk in the PPR subgroup (p < 0.05). Conclusions Patients with myometrial invasion ≥ 1/2 and substantial LVSI may be more likely to have LR, while patients with positive ER and PR are more likely to have PPR. We need to pay attention to these factors to help us judge the prognosis of EC patients.
摘要：
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.
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.
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：
N-acetyltransferase 10 (NAT10) is a key enzyme for N4-acetylcytidine (ac4C) modification of mRNA, but its functions in the central nervous system remain unclear. In this study, we explored the spatial localization of NAT10 and observed the alterations of it in the brain of l ipopolysaccharide (LPS) treated mice. Meanwhile, we observed the changes of depression-like behaviors after blocking NAT10 systematically with its inhibitor Remodelin or knockdown hippocampal NAT10 in LPS treated mice and explored its potential mechanism. After having showed the NAT10 is highly expressed in the mouse brain and mainly co-localized with the neuron, we found that LPS elicited hippocammpal NAT10 expression, and chronic administration of NAT10 inhibitor Remodelin, instead of acute administration, prevented LPS-induced depression-like behavior without affecting acute sickness behavior . Consistently, viral-mediated NAT10 knock-down in the hippocampus could also relieve depression-like behaviors in the mice challenged with LPS. And we identified that hippocampal microglia represented a cellular target of NAT10 inhibitor. The role of both pharmacological agents and viral tool in the block of NAT10 to alleviate depressive-like behavior suggests that NAT10 may be a valuable target for drug discovery in depression.
N-acetyltransferase 10 (NAT10) is a key enzyme for N4-acetylcytidine (ac4C) modification of mRNA, but its functions in the central nervous system remain unclear. In this study, we explored the spatial localization of NAT10 and observed the alterations of it in the brain of l ipopolysaccharide (LPS) treated mice. Meanwhile, we observed the changes of depression-like behaviors after blocking NAT10 systematically with its inhibitor Remodelin or knockdown hippocampal NAT10 in LPS treated mice and explored its potential mechanism. After having showed the NAT10 is highly expressed in the mouse brain and mainly co-localized with the neuron, we found that LPS elicited hippocammpal NAT10 expression, and chronic administration of NAT10 inhibitor Remodelin, instead of acute administration, prevented LPS-induced depression-like behavior without affecting acute sickness behavior . Consistently, viral-mediated NAT10 knock-down in the hippocampus could also relieve depression-like behaviors in the mice challenged with LPS. And we identified that hippocampal microglia represented a cellular target of NAT10 inhibitor. The role of both pharmacological agents and viral tool in the block of NAT10 to alleviate depressive-like behavior suggests that NAT10 may be a valuable target for drug discovery in depression.
通讯机构：
[Zi, WJ; Yang, QW ; Qiu, ZM] A;Army Med Univ, Affiliated Hosp 2, Dept Neurol, 183 Xinqiao Main St, Chongqing 400037, Peoples R China.
摘要：
BACKGROUND The safety and efficacy of treatment with intravenous tenecteplase before endovascular thrombectomy in patients with acute ischemic stroke due to large-vessel occlusion remain uncertain. METHODS In this open-label trial conducted in China, we randomly assigned patients with acute ischemic stroke due to large-vessel occlusion who had presented within 4.5 hours after onset and were eligible for thrombolysis to receive either intravenous tenecteplase followed by endovascular thrombectomy or endovascular thrombectomy alone. The primary outcome was functional independence (a score of 0 to 2 on the modified Rankin scale; range, 0 to 6, with higher scores indicating more severe disability) at 90 days. Secondary outcomes included successful reperfusion before and after thrombectomy. Safety outcomes included symptomatic intracranial hemorrhage within 48 hours and death within 90 days. RESULTS A total of 278 patients were randomly assigned to the tenecteplase-thrombectomy group and 272 to the thrombectomy-alone group. Functional independence at 90 days was observed in 147 patients (52.9%) in the tenecteplase-thrombectomy group and in 120 patients (44.1%) in the thrombectomy-alone group (unadjusted risk ratio, 1.20; 95% confidence interval, 1.01 to 1.43; P=0.04). A total of 6.1% of the patients in the tenecteplase-thrombectomy group and 1.1% of those in the thrombectomy-alone group had successful reperfusion before thrombectomy, and 91.4% and 94.1%, respectively, had successful reperfusion after thrombectomy. Symptomatic intracranial hemorrhage within 48 hours occurred in 8.5% of the patients in the tenecteplase-thrombectomy group and in 6.7% of those in the thrombectomy-alone group; mortality at 90 days was 22.3% and 19.9%, respectively. CONCLUSIONS Among patients with acute ischemic stroke due to large-vessel occlusion who had presented within 4.5 hours after onset, the percentage of patients with functional independence at 90 days was higher with intravenous tenecteplase plus endovascular thrombectomy than with endovascular thrombectomy alone. Tenecteplase before Thrombectomy in Stroke Among 550 patients with stroke due to large-vessel occlusion who had presented within 4.5 hours after onset, 90-day functional outcomes were better with intravenous tenecteplase before thrombectomy than with thrombectomy alone.
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：
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：
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：
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.
作者机构：
[Shen, Xiangyu; Wu, Wei; Zhong, Xiaoxiao; Li, Jun; Pang, Jin; Ding, Boni; Qian, Liyuan; Chen, Ting; Zhong, XX] Cent South Univ, Dept Breast & Thyroid Surg, Xiangya Hosp 3, Changsha 410000, Hunan, Peoples R China.;[Zhong, Xiaoxiao; Zhong, XX] Cent South Univ, Xiangya Hosp 3, Dept Gen Surg, Changsha 410000, Hunan, Peoples R China.;[Han, Jiaxuan] Cent South Univ, Xiangya Hosp 2, Dept Ophthalmol, Changsha 410000, Hunan, Peoples R China.;[Li, Huan] Cent South Univ, Xiangya Hosp 3, Dept Gastroenterol, Changsha 410000, Hunan, Peoples R China.;[Yu, Bowen] Cent S Univ, Xiangya Hosp 3, Dept Gastrointestinal Surg, Changsha 410000, Hunan, Peoples R China.
通讯机构：
[Ding, BN ; Tong, XL ; Zhong, XX; Zhong, XX ] C;Cent South Univ, Dept Breast & Thyroid Surg, Xiangya Hosp 3, Changsha 410000, Hunan, Peoples R China.;Cent South Univ, Xiangya Hosp 3, Dept Gen Surg, Changsha 410000, Hunan, Peoples R China.;Cent South Univ, Xiangya Hosp 3, Dept Hematol, Changsha 410000, Peoples R China.
关键词：
Breast cancer;Tumor microenvironment;Prognostic mode;Glycosylation;Glycosyltransferases;KLRB1
摘要：
The tumor microenvironment (TME) and aberrant glycosylation have been suggested to play key roles in cancer. This study integrated differentially expressed genes (DEGs) and weighted gene coexpression network analysis (WGCNA) to identify tumor microenvironment-related genes and construct a TME-risk prognostic signature (TMERS) through LASSO Cox regression. After batch effect removal, 44 TME-prognosis-related genes (TMEPGs) were identified and classified into three molecular subtypes via K-means clustering. The finalized 22-gene TMERS model demonstrated robust prognostic predictive capacity in GEO datasets. The results revealed distinct immune profiles and prognostic stratifications among genetic subtypes and risk groups, confirming that the TMERS is an independent prognostic indicator for breast cancer (BRCA). Glycosyltransferase genes (GTs) have potential therapeutic relevance through immune regulation, with TMEPG member killer cell lectin like receptor B1 (KLRB1) significantly correlated with BRCA prognosis. Cellular experiments demonstrated that KLRB1 overexpression suppressed BRCA cell proliferation and migration. This work establishes a novel prognostic model for BRCA while highlighting KLRB1 as a potential biomarker, providing new insights into TME-targeted therapeutic strategies.
作者机构：
[Zhou, Jie; He, Longmei; Jiang, Binyuan; Deng, Jiali; Liu, Sisi] Univ South China, Affiliated Changsha Cent Hosp, Hengyang Med Sch, Dept Clin Lab, Changsha, Hunan, Peoples R China.;[He, Longmei] Univ South China, Affiliated Changsha Cent Hosp, Med Res Ctr, Hengyang Med Sch, Changsha, Hunan, Peoples R China.;[Jiang, Binyuan] Univ South China, Affiliated Changsha Cent Hosp, Hengyang Med Sch, Clin Trials Off, Changsha, Hunan, Peoples R China.
通讯机构：
[Jiang, BY ] U;Univ South China, Affiliated Changsha Cent Hosp, Hengyang Med Sch, Dept Clin Lab, Changsha, Hunan, Peoples R China.;Univ South China, Affiliated Changsha Cent Hosp, Hengyang Med Sch, Clin Trials Off, Changsha, Hunan, Peoples R China.
摘要：
3-Methyladenine (3-MA) is widely recognized as a PI3K inhibitor involved in autophagy regulation. However, it is also a byproduct of DNA damage repair, and its role in modulating DNA damage response (DDR) mechanisms remains largely unexplored. Cisplatin (CDDP), a cornerstone chemotherapeutic agent for nasopharyngeal carcinoma (NPC), exerts its cytotoxic effects by inducing DNA damage in tumor cells. This study investigates the combined effects of CDDP and 3-MA on NPC cells. Cell viability and the half-maximal inhibitory concentration (IC50) were assessed using the Cell Counting Kit-8 (CCK-8) assay. Flow cytometry was employed to analyze cell cycle distribution, mitochondrial membrane potential (MMP) alterations, and apoptosis. γ-H2AX foci formation and morphological changes were examined via fluorescence microscopy, while Western blotting was used to evaluate proteins associated with the DNA damage response. The combination treatment significantly reduced cell viability and lowered the IC50 compared to CDDP alone. While both treatments induced Sub-G1 phase arrest, the combination resulted in greater MMP loss and apoptosis. Western blot analysis further revealed that 3-MA enhanced CDDP cytotoxicity by suppressing ATM/ATR/p53-mediated DNA damage repair and promoting apoptotic signaling. These findings suggest that 3-MA sensitizes NPC cells to CDDP by disrupting DNA repair processes, offering a promising therapeutic strategy.
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.
