期刊：
Frontiers in Pharmacology,2025年16:1524159 ISSN：1663-9812
通讯作者：
Lai, QY;Lian, YX
作者机构：
[Gao, Yuan; Lai, Quanyou; Wang, Shangyu; Jia, Peng] Air Force Mil Med Univ, Xijing Hosp, Dept Hepatobiliary & Pancreato Splen Surg, Xian, Peoples R China.;[Zhou, Yusen; Yin, Jiangliu] Univ South China, Affiliated Nanhua Hosp, Dept Neurosurg, Changsha, Peoples R China.;[Lian, Yixiang] Univ South China, Affiliated Changsha Cent Hosp, Dept Pathol, Changsha, Peoples R China.
通讯机构：
[Lian, YX ] U;[Lai, QY ] A;Air Force Mil Med Univ, Xijing Hosp, Dept Hepatobiliary & Pancreato Splen Surg, Xian, Peoples R China.;Univ South China, Affiliated Changsha Cent Hosp, Dept Pathol, Changsha, Peoples R China.
关键词：
FAERS;adverse events;carbapenem;imipenem/cilastatin;pharmacovigilance;real-world data analysis
摘要：
BACKGROUND: Although imipenem/cilastatin (IMI/CIL) has demonstrated favorable therapeutic efficacy against various infections, the incidence of potential adverse events (AEs) has escalated in parallel with its increased utilization and has been documented in clinical trials. However, a comprehensive understanding of real-world implications remains lacking. METHODS: By conducting a comprehensive search in the FDA Adverse Event Reporting System (FAERS) database, AE reports associated with IMI/CIL as the primary suspect (PS) were selected for analysis, spanning from the first quarter of 2004 to the fourth quarter of 2023. Utilizing disproportionality analysis techniques, potential signals of AE s were identified through reported odds ratio (ROR), proportional report ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM). The obtained results were systematically classified using Medical Dictionary for Regulatory Activities (MedDRA). RESULT: From the first quarter of 2004 to the fourth quarter of 2023, a total of 2,574 reports documenting AEs associated with IMI/CIL were obtained, with more than half (n = 1,517, 58.94%) involving individuals aged over 60years old. Descriptive analysis was conducted based on age groups and time to onset, revealing that the majority of AEs occurred within 3days. Adverse drug reactions caused by IMI/CIL were classified into 24 system organ classes (SOCs) at the preferred term (PT) level. Furthermore, previously unreported and clinically significant AEs such as cerebral atrophy, and delirium were also identified at the PT level. CONCLUSION: This study offers a more comprehensive insight into the monitoring, supervision, and management of adverse drug reactions associated with IMI/CIL. Clinicians should pay further attention to the implications of numerous AEs and their corresponding signal intensities, as well as unrecorded signals of severe AEs. This holds significant value in enhancing the clinical safety profile of IMI/CIL.
摘要：
BACKGROUND: Destruction of the blood-spinal cord barrier (BSCB) following spinal cord injury (SCI) can result in various harmful cytokines, neutrophils, and macrophages infiltrating into the injured site, causing secondary damage. Growing evidence shows that M2 macrophages and their small extracellular vesicles (sEVs) contribute to tissue repair in various diseases. METHODS AND RESULTS: In our previous proteomics-based analysis of protein expression profiles in M2 macrophages and their sEVs (M2-sEVs), the proteoglycan perlecan, encoded by HSPG2, was found to be upregulated in M2-sEVs. Perlecan is a crucial component of basement membranes, playing a vital role in stabilising BSCB homeostasis and functions through its interactions with other matrix components, growth factors, and receptors. Here, we verified the high levels and remarkable therapeutic effect of M2-sEV-derived perlecan on the permeability of spinal cord microvascular endothelial cells exposed to oxygen glucose deprivation and reoxygenation in vitro. We also decorated the surface of M2-sEVs with a fusion protein comprising the N-terminus of Lamp2 and arginine glycine aspartic acid (RGD) peptides, which have an affinity for integrin αvβ3 and are primarily present on neovascular endothelium surfaces. In SCI model mice, these RGD-M2-sEVs accumulated at injured sites, promoting BSCB restoration. Finally, we identified M2-sEV-derived perlecan as a key player in regulating BSCB integrity and functional recovery post-SCI. CONCLUSION: Our results indicate that RGD-M2-sEVs promote BSCB restoration by transporting perlecan to neovascular endothelial cells, representing a potential strategy for SCI treatment. KEY POINTS: Perlecan, a crucial component of basement membranes that plays a vital role in stabilising BSCB homeostasis and functions, was found to be upregulated in M2-sEVs. M2-sEVs decorated with RGD peptide can effectively target the neovascular endothelium surfaces at the injured spinal cord site. RGD-M2-sEVs promote BSCB restoration by transporting perlecan to neovascular endothelial cells, representing a potential strategy for SCI treatment.
作者机构：
[Li, Min; Zhang, Fengying; Pan, Zhao; Zhang, Ping; Tang, Yonghong; Jiang, Li] Univ South China, Nanhua Hosp, Hengyang Med Sch, Dept Neurol, 336 Dongfeng South Rd, Hengyang 421001, Hunan, Peoples R China.;[Li, Min; Zhang, Fengying; Pan, Zhao; Quan, Xiajie; Zhang, Ping; Tang, Yonghong; Jiang, Li; Ouyang, Bo] Univ South China, Nanhua Hosp, Dept Sleep Med Ctr, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;[Li, Yao] Jinzhou Med Univ, Dept Physiol, Jinzhou 121000, Peoples R China.;[Wang, Yingbin] Cent Hosp, Shenyang Med Coll, Dept Neurosurg, Shenyang 110024, Peoples R China.;[Ouyang, Bo] Univ South China, Nanhua Hosp, Hengyang Med Sch, Dept Tradit Chinese Med, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Chen, KY ] C;[Zhang, P ] U;Univ South China, Nanhua Hosp, Hengyang Med Sch, Dept Neurol, 336 Dongfeng South Rd, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Nanhua Hosp, Dept Sleep Med Ctr, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;China Med Univ, Lab Anim Sci, 77 Puhe Rd, Shenyang 110122, Liaoning, Peoples R China.
摘要：
BACKGROUND: The prefrontal cortex (PFC) plays a pronounced role in cognitive and emotional functions, which may be compromised by dismal sleep quality. This study intended to clarify the impact of Slc1a2 ectopic expression in the PFC on sleep deprivation (SD)-induced disturbances in the glutamate (Glu)/GABA-glutamine cycle and the role of astrocyte (AC)-neuron (Neu) communication. METHODS: Single-cell RNA sequencing was adopted to illuminate cell-specific changes in the brainstem, cortex, and hypothalamus of mice under NS, SD, and post-SD conditions. Cell communication analysis was applied to study interactions between ACs and Neus, which altered after the SD. Slc1a2 was ectopically expressed in the PFC and subjected to SD, followed by electrophysiological, immunofluorescence staining, and [(1)H-(13)C]-nuclear magnetic resonance (NMR) assays to examine neural activity and metabolic status. Behavioral tests, including the open field, novel object recognition, and Y-maze, were conducted to examine cognitive functions and emotional states. RESULTS: SD caused notable changes in cellular distribution and downregulation of metabolic and synaptic genes in affected brain regions. Cell communication studies highlighted a reduction in AC-Neu interactions, with corresponding metabolic disruptions in the Glu/GABA-glutamine cycle as depicted by [(1)H-(13)C]-NMR results. Behavior tests confirmed anxiety and cognitive deficits in SD mice, which were substantially alleviated by Slc1a2 ectopic expression in the PFC. CONCLUSIONS: Slc1a2 ectopic expression in the PFC negates SD-induced GABA dysfunction through vital AC-Neu communication. This study sheds light on the mechanisms through which SD affects neural function and suggesting potential treatments for sleep-related disorders.
期刊：
Food Safety and Health,2025年3(1):89-99 ISSN：2835-1096
通讯作者：
Xiangheng Niu
作者机构：
[Ziyu Zhang; Lina Tang; Wenjie Sheng; Youyi Yang; Guolin Lai; Jinjin Liu] School of Public Health, Hengyang Medical School, University of South China, Hengyang, China;Shandong Key Laboratory of Biochemical Analysis, Qingdao University of Science and Technology, Qingdao, China;[Xiangheng Niu] School of Public Health, Hengyang Medical School, University of South China, Hengyang, China<&wdkj&>Shandong Key Laboratory of Biochemical Analysis, Qingdao University of Science and Technology, Qingdao, China
通讯机构：
[Xiangheng Niu] S;School of Public Health, Hengyang Medical School, University of South China, Hengyang, China<&wdkj&>Shandong Key Laboratory of Biochemical Analysis, Qingdao University of Science and Technology, Qingdao, China
摘要：
AbstractAs a common food additive, excessive nitrite poses a great threat to human health, and monitoring its content in food products is of importance for healthy diet. Currently, the detection of nitrite content in food is primarily focused on fresh dishes, and there is a lack of research on monitoring the variations of nitrite in different foods under various storage conditions. In this study, we cascaded nanozyme catalysis with diazotization reaction and developed a ratiometric colorimetric assay to dynamically analyze nitrite in leftovers. First, nanoscale MnFe2O4 was synthesized as an oxidase mimic to catalyze colorless 3,3′,5,5′‐tetramethylbenzidine (TMB) oxidation to blue TMBox. Then, a diazotization process of the produced TMBox took place under the stimulation of nitrite, lowering the ultraviolet‐visible absorption signal (652 nm) assigned to TMBox and simultaneously generating a new signal at 445 nm ascribed to diazotized TMBox. Thus, a ratiometric colorimetric method could be constructed based on the above reversed variations of the two signals for high‐selectivity nitrite determination, providing a linear range of 1.76–180 μM and a detection limit of 0.12 μM. By employing the established assay to dynamically monitor nitrite in food products, it was found that the nitrite content in overnight leftovers was higher than that in fresh dishes, presenting an increasing trend with storage time. In addition, potential impacts of storage factors on the dynamics of nitrite content were investigated, providing some implications for food preservation and daily consumption.
摘要：
Vaccine development targeting Mycoplasma pneumoniae began in the 1960s, but achieving safe and effective immunization is still challenging. Careful consideration of the immunization pathway is one of the critical aspects of vaccine development. In this investigation, C57BL/6 J mice were intragastrically vaccinated with live M. pneumoniae , and the short-term safety and resultant immune effects were evaluated. Oral administration likely demonstrated intestinal clearance with restricted systemic dissemination and no tissue pathogenicity in both the intestinal and pulmonary tracts. Furthermore, the oral vaccination with live M. pneumoniae effectively reduced the pathogen burden in the lung, alleviated pulmonary inflammation, and reduced the pulmonary secretion of IL-1β and TNF-α after intranasal bacterial infection 3 or 15 weeks after the last dose. Moreover, Airway exposure to M. pneumoniae in live pathogen intragastric vaccinated mice triggered robust recall responses, marked by the elevation of systemic mycoplasma-specific IgG and IgM, alongside pulmonary mucosal IgA, paralleled by clonal expansion of Th1, Th2, and CTL. In conclusion, oral delivery presents a promising route for developing M. pneumoniae vaccines.
Vaccine development targeting Mycoplasma pneumoniae began in the 1960s, but achieving safe and effective immunization is still challenging. Careful consideration of the immunization pathway is one of the critical aspects of vaccine development. In this investigation, C57BL/6 J mice were intragastrically vaccinated with live M. pneumoniae , and the short-term safety and resultant immune effects were evaluated. Oral administration likely demonstrated intestinal clearance with restricted systemic dissemination and no tissue pathogenicity in both the intestinal and pulmonary tracts. Furthermore, the oral vaccination with live M. pneumoniae effectively reduced the pathogen burden in the lung, alleviated pulmonary inflammation, and reduced the pulmonary secretion of IL-1β and TNF-α after intranasal bacterial infection 3 or 15 weeks after the last dose. Moreover, Airway exposure to M. pneumoniae in live pathogen intragastric vaccinated mice triggered robust recall responses, marked by the elevation of systemic mycoplasma-specific IgG and IgM, alongside pulmonary mucosal IgA, paralleled by clonal expansion of Th1, Th2, and CTL. In conclusion, oral delivery presents a promising route for developing M. pneumoniae vaccines.
摘要：
Beryllium (Be) is a recognised environmental toxicant associated with pulmonary fibrosis. Epithelial-mesenchymal transition (EMT), a critical process in cell phenotype conversion, plays a key role in its pathophysiology. Methyltransferase-like 3 (METTL3), a major N6-methyladenosine methyltransferase, regulates gene expression and cellular functions. However, its role in Be-induced EMT remains unclear. In this study, human bronchial epithelial cell line (16HBE cells) were exposed to varying concentrations of beryllium sulphate (BeSO(4)) to assess changes in METTL3 expression. METTL3 overexpression vectors were constructed, and quantitative reverse transcription-polymerase chain reaction, western blotting and immunofluorescence were used to detect METTL3, EMT markers and Wingless/Integrated (Wnt)/β-catenin pathway proteins. The Wnt/β-catenin pathway inhibitor ICG-001 was also employed to explore the role of the Wnt/β-catenin pathway in BeSO(4)-induced EMT. The study demonstrated that BeSO(4) suppressed METTL3 expression, induced EMT and activated the Wnt/β-catenin pathway in 16HBE cells. Both METTL3 overexpression and ICG-001 pretreatment mitigated BeSO(4)-induced EMT and Wnt/β-catenin pathway activation. These findings suggest that METTL3 inhibits BeSO(4)-induced EMT by suppressing the Wnt/β-catenin pathway, offering novel mechanistic insights into beryllium toxicity and a potential therapeutic target for Be-related pulmonary fibrosis.
摘要：
Simple Summary Acinetobacter baumannii is often recognized for its resistance to antibiotics, posing a serious threat in healthcare environments. In this study, we investigated a clinical isolate, HKAB-1, that despite being highly sensitive to many antibiotics, exhibits pronounced virulence-associated traits. Compared to the reference strain ATCC 19606, HKAB-1 demonstrates enhanced survival in serum and under desiccating conditions. HKAB-1 also forms robust biofilm and displays greater motility, phenotypes associated with persistence and pathogenicity. Genomic and transcriptomic analyses revealed that HKAB-1 harbours active iron acquisition and heme utilization systems, which are highly responsive to host-like conditions. Moreover, we found that genes associated with biofilm formation were highly induced in biofilm-forming cells. Conversely, the expression of adeB was markedly reduced, potentially explaining its antibiotic susceptibility despite harbouring multiple resistance genes. These findings reflect a potential evolutionary trade-off in certain A. baumannii strains, favoring virulence-associated traits over the expression of antimicrobial resistance mechanisms. This result highlights the need for continuous genomic surveillance to monitor emerging virulent but drug-susceptible strains like HKAB-1, which may serve as reservoirs for resistance development under selective pressures.Abstract Acinetobacter baumannii is an opportunistic pathogen notable for multidrug resistance and environmental persistence. We characterized a clinical isolate, HKAB-1, which exhibits pronounced virulence-associated traits despite being highly susceptible to all tested antibiotics. HKAB-1 exhibited superior growth in MH2B, serum and desiccating conditions, robust biofilm formation, and active motility. Whole-genome sequencing identified two heme utilization clusters, multiple siderophore biosynthesis pathways, and other virulence-associated genes. Gene expression analysis revealed significant upregulation of heme utilization and siderophore biosynthetic gene clusters under serum exposure, indicating activation of iron uptake pathways under host-like conditions. Biofilm-associated genes, including bap, PNAG biosynthetic genes, and type IV pili components, were notably upregulated in biofilm-forming cells, supporting their role in driving the enhanced biofilm phenotype. Conversely, adeB, encoding a major RND efflux pump, was markedly downregulated, potentially explaining its drug-susceptible phenotype. Comparative genomic analysis highlighted differences in genes related to nutrient transport, metabolic pathways, and membrane biogenesis that may underpin its enhanced growth. These findings point to a potential trade-off between antibiotic resistance and virulence, underscoring the importance of monitoring antibiotic-susceptible yet highly virulent A. baumannii isolates as potential reservoirs for resistance evolution. Further investigation is warranted to elucidate the mechanisms underlying this phenotypic balance.
期刊：
Journal of Inflammation Research,2025年18:5727-5739 ISSN：1178-7031
通讯作者：
He, J;Deng, Zhongliang
作者机构：
[Li, Yuan; He, Jun; Yang, Xue; Li, Chao; Huang, Ying; Liao, Daoyong] Univ South China, Affiliated Nanhua Hosp, Hengyang Med Sch, Dept Clin Lab, Hengyang, Peoples R China.;[Deng, Zhongliang; He, Jun; Yang, Xue] Univ South China, Sch Publ Hlth, Hengyang Med Sch, Dept Publ Hlth Lab Sci, Hengyang, Hunan, Peoples R China.
通讯机构：
[He, J ; Deng, ZL] U;Univ South China, Affiliated Nanhua Hosp, Hengyang Med Sch, Dept Clin Lab, Hengyang, Peoples R China.;Univ South China, Sch Publ Hlth, Hengyang Med Sch, Dept Publ Hlth Lab Sci, Hengyang, Hunan, Peoples R China.
关键词：
M. pneumoniae;CCL20;EMT;AKT-ERK1/2-AP1;cell migration
摘要：
PURPOSE: Mycoplasma pneumoniae, a clinically significant respiratory pathogen, primarily causes community-acquired pneumonia and contributes to asthma development, with its persistent infection frequently resulting in fibrotic pulmonary changes and structural airway abnormalities. This study investigates the signaling pathways regulating CCL20 expression in THP-1 cells following M. pneumoniae infection and its impact on cell migration and epithelial-mesenchymal transition (EMT). METHODS: THP-1 cells were infected with M. pneumoniae, and the expression of CCL20 was measured over time and at various doses. In addition, co-culture experiments were performed using M. pneumoniae-infected THP-1 cells and bronchial epithelial cells to assess EMT and cell migration. RESULTS: M. pneumoniae infection significantly upregulated CCL20 production in THP-1 cells via the AKT-ERK1/2-AP1 pathway, a process that was both time- and dose-dependent. Furthermore, co-culturing M. pneumoniae-infected THP-1 cells with 16HBE cells promoted EMT and increased cell migration, a process that is believed to be associated with CCL20. CONCLUSION: This study provides insights into the molecular mechanisms linking CCL20 to cell migration, highlighting potential therapeutic targets for M. pneumoniae-related lung diseases.
通讯机构：
[Zhao, W; Zhao, SP ] C;Cent South Univ, Xiangya Hosp 2, Dept Cardiovasc Med, Changsha 410011, Peoples R China.
关键词：
Hypercholesterolemia;Fixed-dose combination of rosuvastatin/ezetimibe;Rosuvastatin alone;Efficacy;Safety
摘要：
OBJECTIVE: Rosuvastatin plus ezetimibe improves the lipid-lowering effect through different mechanisms of action. This study intended to compare the efficacy and safety of the fixed-dose combination (FDC) of rosuvastatin/ezetimibe vs. rosuvastatin alone in hypercholesterolemia patients. METHODS: ROSE-CH (ROSuvastatin and Ezetimibe in Chinese Hypercholesterolemia patients) was a multicenter, randomized, double-blind, positive drug-controlled, superiority-tested phase III clinical trial; 743 patients were randomized into rosuvastatin/ezetimibe 10/10mg, 5/10mg, and 2.5/10mg groups, as well as rosuvastatin 10mg and 5mg groups at a 1:1:1:1:1 ratio. A total of 143, 127, 263, and 137 patients had low, intermediate, high, and very-high baseline atherosclerotic cardiovascular disease (ASCVD) risks. The study period spanned from December 24, 2021, to December 6, 2022. RESULTS: Efficacy and safety assessments were conducted in 670 and 696 patients. Percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to week (W)12 was greater in the rosuvastatin/ezetimibe 10/10mg group vs. rosuvastatin 10mg group [least-squares means (LSmean): -51.48% vs. -42.47%], rosuvastatin/ezetimibe 5/10 group vs. rosuvastatin 5mg group (LSmean: -50.08% vs. -40.17%), and rosuvastatin/ezetimibe 2.5/10mg group vs. the rosuvastatin 5mg group (LSmean: -48.47% vs. -40.17%) (all P < 0.001). The same trend was observed for the percentage change in LDL-C from baseline to W4 and W8 (all P < 0.001). In patients with baseline very high ASCVD risk, the achievement of LDL-C target at W12 was higher in rosuvastatin/ezetimibe 10/10mg vs. rosuvastatin 10mg groups and rosuvastatin/ezetimibe 2.5/10mg vs. rosuvastatin 5mg groups (both P < 0.05). The incidence of adverse events was 36.0%, 38.7%, 25.2%, 31.4%, and 38.6% in each group. Regarding serious adverse events, the incidence was 2.2%, 2.9%, 0.7%, 3.6%, and 0.7% in each group. The incidence of drug-related adverse events was relatively high, which was 26.6%, 31.4%, 18.5%, 23.6%, and 29.0% in each group, respectively, irrespective of the absence of serious drug-related adverse events. CONCLUSION: The FDC of rosuvastatin/ezetimibe has superior LDL-C-lowering effects over rosuvastatin alone, with good safety profiles in hypercholesterolemia patients.
摘要：
Background Patients with Parkinson's disease (PD) tend to have a shorter life expectancy compared to the general population. While the genetic architecture significantly influences individual variability in survival among these patients with PD, the contributions of most genetic variations to this heterogeneity remain unclear. Methods The study included 2365 living and 1575 deceased unrelated White European PD patients from the UK Biobank, of whom 503 had PD as the primary cause of death and 423 had PD as the secondary cause of death. Consequently, a genome-wide time-to-event analysis, utilizing a saddle point approximation implementation based on the Cox proportional hazards regression model, was performed to identify variants associated with the survival time of PD patients across three distinct cohorts as follows: (I) PD as the primary cause of death, (II) PD as the primary or secondary cause of death, and (III) all-cause mortality. To investigate the impact of APOE epsilon 4 on cell viability, SH-SY5Y cells overexpressing different APOE isoforms were treated with rotenone to model PD-related stress. Cell viability, flow cytometry, immunofluorescence, and western blotting were used to assess APOE epsilon 4 related effects and underlying mechanisms. Results In the time-to-event analysis, rs429358 (APOE epsilon 4) was found to be significantly associated with reduced patients' survival time across all three cohorts (P < 1.6 x 10(-8)). Concurrently, we observed that both dementia symptoms (P < 5.6 x 10(-42), hazard ratio > 2) and the rs429358 (APOE epsilon 4) (P < 2.4 x 10(-5), hazard ratio > 1.2) were significant risk factors for the survival time of PD patients in the same multivariate survival analysis with Cox proportional hazards regression across all three cohorts. More importantly, we also constructed PD model using SH-SY5Y cells to validate the screened genetic variant and noticed that expressing APOE epsilon 4 allele (rs429358) significantly reduced cell activity exclusively under the pathological state of PD. This was accompanied by impaired mitochondrial function, increased DNA damage, and activation of ER stress primarily through the PERK signaling pathway. Conclusions In summary, we found that rs429358 (APOE epsilon 4) may influence the survival time of patients with PD not only through its association with dementia but also independently.
摘要：
BACKGROUND: Proteus spp. have long been recognized for their role in urinary tract infections, while recent evidence disclosed their implications in gastrointestinal diseases. Despite this, the taxonomy of clinically-derived Proteus spp., particularly those from gastrointestinal samples, remains understudied and is frequently mis-assigned, which limits our understanding of infections caused by these species. RESULTS: Four Proteus strains (i.e., DFP240708, LHD240705, TSJ240517 and WDL240414) were isolated from the appendiceal pus of patients with acute appendicitis, whole-genome average nucleotide identity (ANI) analysis identified all of them as Proteus genomosp. 6, different from that identified using the automated bacterial identification instrument (VITEK(®)-32). Based on ANI and the core-genomic phylogenetic tree, we found that 87.5% of clinically-related strains previously identified as P. columbae should be re-classified as Proteus genomosp. 6. Additionally, the Proteus genomosp. 6 genomes all carry one or more beta-lactam resistance genes, but none carry aminoglycoside resistance genes, and antibiotic susceptibility testing conducted on the four strains isolated in this study confirmed these findings. Among the genomes analyzed, only four (two from this study (TSJ240517 and WDL240414)) carried virulence genes, specifically the hlyA, hlyB, and hlyD genes encoding hemolysin. CONCLUSION: Our study highlights inaccuracies in the taxa classification of Proteus species under clinical settings, underscoring the necessity of using genomic-based taxonomic assignment methods. We revealed that the prevalence of Proteus genomosp. 6 in clinical infections has likely been underestimated. Furthermore, given the resistance-gene absence and their sensitivity to aminoglycosides, aminoglycosides may serve as a promising first-line treatment option for infections caused by this species.
摘要：
Pulmonary hypertension (PH) is an incurable disease, pulmonary arterial smooth muscle cells (PASMCs) senescence induces PASMCs proliferation by secreting interleukin 6 (IL-6), thereby promoting vascular remodeling. Accumulation of prelamin A is an important initial event at the onset of cellular senescence. Studies have shown that prelamin A has played a crucial role in the senescence-associated cardiovascular disease. However, the role of prelamin A in PH remains to be elucidated. This study aimed to elucidate how prelamin A accelerates PASMCs senescence and its regulatory mechanisms in hypoxia-induced pulmonary hypertension (HPH). Our findings demonstrated increased vascular remodeling and PASMCs senescence in HPH rats, notably, we observed upregulation of prelamin A and histone lactylation in these rats. Inhibiting histone lactylation resulted in decreased prelamin A expression, which consequently mitigated PASMCs senescence and alleviated vascular remodeling in HPH rats. And in 2-DG-treated HPH rats, overexpression of prelamin A reversed defective PASMCs senescence and vascular remodeling. These findings suggest that prelamin A accelerates PASMCs senescence, senescent PASMCs can promote PASMCs proliferation by secreting IL-6, and its upstream regulatory mechanism involves the up-regulation of lactylation modification of histone.
Pulmonary hypertension (PH) is an incurable disease, pulmonary arterial smooth muscle cells (PASMCs) senescence induces PASMCs proliferation by secreting interleukin 6 (IL-6), thereby promoting vascular remodeling. Accumulation of prelamin A is an important initial event at the onset of cellular senescence. Studies have shown that prelamin A has played a crucial role in the senescence-associated cardiovascular disease. However, the role of prelamin A in PH remains to be elucidated. This study aimed to elucidate how prelamin A accelerates PASMCs senescence and its regulatory mechanisms in hypoxia-induced pulmonary hypertension (HPH). Our findings demonstrated increased vascular remodeling and PASMCs senescence in HPH rats, notably, we observed upregulation of prelamin A and histone lactylation in these rats. Inhibiting histone lactylation resulted in decreased prelamin A expression, which consequently mitigated PASMCs senescence and alleviated vascular remodeling in HPH rats. And in 2-DG-treated HPH rats, overexpression of prelamin A reversed defective PASMCs senescence and vascular remodeling. These findings suggest that prelamin A accelerates PASMCs senescence, senescent PASMCs can promote PASMCs proliferation by secreting IL-6, and its upstream regulatory mechanism involves the up-regulation of lactylation modification of histone.
作者机构：
[Zhang, Yuexin; Li, Ye; Yin, Mingxue; Li, Chunquan; Wang, Xuan; Song, Chao; Yu, Zhengmin] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Hengyang 421001, Peoples R China.;[Zhang, Yuexin; Li, Ye; Yin, Mingxue; Li, Chunquan; Wang, Xuan; Song, Chao; Yu, Zhengmin] Univ South China, Hengyang Med Sch, Key Lab Birth Defect Res & Prevent, Natl Hlth Commiss, Hengyang 421001, Peoples R China.;[Zhang, Yuexin; Li, Ye; Yin, Mingxue; Li, Chunquan; Yu, Zhengmin] Univ South China, Hengyang Med Coll, Inst Biochem & Mol Biol, Hengyang 421001, Peoples R China.;[Zhang, Yuexin; Li, Ye; Yin, Mingxue; Li, Chunquan; Wang, Xuan; Song, Chao; Yu, Zhengmin] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Cardiovasc Lab Big Data & Imaging Artificial Intel, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Yuexin; Li, Ye; Yin, Mingxue; Li, Chunquan; Wang, Xuan; Song, Chao; Yu, Zhengmin] Univ South China, Hengyang Med Sch, Hengyang 421001, Peoples R China.
通讯机构：
[Li, CQ ] U;[Guo, MZ ] B;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Hengyang 421001, Peoples R China.;Univ South China, Hengyang Med Sch, Key Lab Birth Defect Res & Prevent, Natl Hlth Commiss, Hengyang 421001, Peoples R China.;Univ South China, Hengyang Med Coll, Inst Biochem & Mol Biol, Hengyang 421001, Peoples R China.
关键词：
genes;genome-wide association study;rna, small cytoplasmic;datasets
摘要：
Identifying cell populations associated with risk variants is essential for uncovering cell-specific mechanisms that drive disease development and progression. Integrating genome-wide association studies (GWAS) with single-cell RNA sequencing (scRNA-seq) has become an effective strategy for detecting trait-cell relationships. The accumulation of trait-related single cell data has led to an urgent need for its comprehensively processing. To address this, we developed sc2GWAS (https://bio.liclab.net/sc2GWAS/), which aims to document large-scale GWAS trait-cell regulatory pairs at single-cell resolution and provide comprehensive annotations and enrichment analyses for these related pairs. The current version of sc2GWAS curates a total of 15 078 310 candidate trait-cell pairs from > 6 300 000 individual cells, offering a valuable resource for exploring complex regulatory relationships between traits and cells. We applied strict quality control measures on both scRNA-seq data and GWAS data, ensuring the reliability and accuracy of the datasets for the identification of trait-relevant cells and genes. In addition, sc2GWAS provides ranked lists of trait-relevant genes and extensive (epi) genetic annotations, making it a valuable resource for downstream analyses. We demonstrate the utility of the platform by investigating Alzheimer's disease, where we identified significant associations between the disease and microglial cells, with the APOE gene emerging as particularly significant. This platform facilitates detailed research into complex trait-cell and trait-gene interactions, we anticipate that sc2GWAS will become a comprehensive and valuable platform for exploring GWAS trait-cell regulatory mechanisms.<br /> [GRAPHICS] .
摘要：
Mucinous adenocarcinoma (MAC) is a unique histological subtype of colorectal cancer (CRC), which usually occurs in the right-sided colon with poor prognosis. Our previous studies reveled unique clinicopathological characteristic of MAC, but the distinct molecular features and tumor microenvironment (TME) characteristics remain clarify systematically. In this study, we conducted a single nuclear RNA sequencing (snRNA-seq) analysis for CRC tissues with different histological subtypes, including MAC, partial mucinous adenocarcinoma (pMAC) and non-specific adenocarcinoma (AC). Our results show that MAC has a unique transcriptome profile and a distinct single-cell characteristic. It exhibited a higher degree of tumor purity but a lower composition of TME. MAC had a distinct cell-cell communication microenvironment and a particular evolutionary trajectory. The EpithelialCells of MAC closely interacted with fibroblasts, endothelial cells, and mural cells clusters. Furthermore, molecular functional characteristics analysis revealed that MAC enriched EpithelialCells, Fibroblasts, and Endothelial cells clusters have a high active in glycolysis, inflammation, and angiogenesis respectively. This comprehensive study first demonstrated that MAC is a unique histological subtype of right-sided CRC in the single cell level, and elucidated its tumor microenvironment composition and biological function characteristics, which will help us better understand the intrinsic feature of MAC.
Mucinous adenocarcinoma (MAC) is a unique histological subtype of colorectal cancer (CRC), which usually occurs in the right-sided colon with poor prognosis. Our previous studies reveled unique clinicopathological characteristic of MAC, but the distinct molecular features and tumor microenvironment (TME) characteristics remain clarify systematically. In this study, we conducted a single nuclear RNA sequencing (snRNA-seq) analysis for CRC tissues with different histological subtypes, including MAC, partial mucinous adenocarcinoma (pMAC) and non-specific adenocarcinoma (AC). Our results show that MAC has a unique transcriptome profile and a distinct single-cell characteristic. It exhibited a higher degree of tumor purity but a lower composition of TME. MAC had a distinct cell-cell communication microenvironment and a particular evolutionary trajectory. The EpithelialCells of MAC closely interacted with fibroblasts, endothelial cells, and mural cells clusters. Furthermore, molecular functional characteristics analysis revealed that MAC enriched EpithelialCells, Fibroblasts, and Endothelial cells clusters have a high active in glycolysis, inflammation, and angiogenesis respectively. This comprehensive study first demonstrated that MAC is a unique histological subtype of right-sided CRC in the single cell level, and elucidated its tumor microenvironment composition and biological function characteristics, which will help us better understand the intrinsic feature of MAC.
摘要：
The global incidence of metabolic dysfunction-associated fatty liver disease (MAFLD) has risen sharply. This condition is strongly associated with the risk of cardiovascular disease (CVD), but how MAFLD affects the development and progression of CVD, particularly concerning vascular calcification, remains unclear. Herein, extracellular vesicles (EVs) are identified from steatotic hepatocytes as a trigger that accelerated the progression of both vascular intimal and medial calcification. Steatotic hepatocytes are found to release more EVs, which are able to reach the vascular tissue, be taken up by vascular smooth muscle cells (VSMCs), and promote their osteogenic differentiation. Within these toxic vesicles, a protein cargo is identified called lectin galactoside-binding soluble 3 binding protein (Lgals3bp) that acted as a potent inducer of osteochondrogenic transformation in VSMCs. Both the inhibition of EV release and the liver-specific knockdown of Lgals3bp profoundly attenuated vascular calcification. This work partially explains the reason for the high incidence of vascular calcification in MAFLD and unveils a novel mechanism that may be used to prevent or treat cardiovascular complications in patients with MAFLD.
作者机构：
[Tan, Hui; Jiang, Xinmiao] Univ South China, Affiliated Hosp 1, Dept Hepatobiliary & Pancreat Surg, Hengyang 421001, Peoples R China.;[Tan, Hui] Univ South China, Affiliated Hosp 1, Dept Pathol, 69 Chuanshan Rd, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Tan, H ] U;Univ South China, Affiliated Hosp 1, Dept Pathol, 69 Chuanshan Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
Intrahepatic cholangiocarcinoma;Invasion and migration;METTL3;Proliferation;m6A modification
摘要：
Intrahepatic cholangiocarcinoma (ICC) is a primary invasive malignant tumor. This study was conducted to explore the role of methyltransferase-like 3 (METTL3)-mediated m6A modification in ICC cells and provide novel targets for ICC treatment. Levels of METTL3/YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)/Nedd4 family interacting protein 1 (NDFIP1) in cells were determined. Cell viability, proliferation, invasion, and migration were evaluated. The enrichments of METTL3, YTHDF2, and m6A on NDFIP1 mRNA were analyzed. The mRNA stability was determined. Inhibition of YTHDF2 or NDFIP1 was combined with si-METTL3 to confirm the mechanism. The role of METTL3 in vivo was verified. METTL3 was overexpressed in ICC cells. METTL3 silencing suppressed ICC cell malignant behaviors, which were reversed by METTL3 overexpression. METTL3 increased m6A modification on NDFIP1 mRNA, facilitated YTHDF2 recognition of m6A, and promoted NDFIP1 mRNA degradation, thereby suppressing NDFIP1 expression. YTHDF2 inhibition increased NDFIP1 mRNA levels. NDFIP1 downregulation partially reversed the inhibitory effects of si-METTL3 on ICC cell behaviors, while NDFIP1 overexpression partially reversed the promotive effects of METTL3 on ICC cell behaviors. METTL3 downregulation suppressed ICC growth by increasing NDFIP1 expression. In conclusion, METTL3 aggravates ICC cell proliferation, invasion, and migration by promoting the degradation of NDFIP1 mRNA in a YTHDF2-dependent manner.
Intrahepatic cholangiocarcinoma (ICC) is a primary invasive malignant tumor. This study was conducted to explore the role of methyltransferase-like 3 (METTL3)-mediated m6A modification in ICC cells and provide novel targets for ICC treatment. Levels of METTL3/YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)/Nedd4 family interacting protein 1 (NDFIP1) in cells were determined. Cell viability, proliferation, invasion, and migration were evaluated. The enrichments of METTL3, YTHDF2, and m6A on NDFIP1 mRNA were analyzed. The mRNA stability was determined. Inhibition of YTHDF2 or NDFIP1 was combined with si-METTL3 to confirm the mechanism. The role of METTL3 in vivo was verified. METTL3 was overexpressed in ICC cells. METTL3 silencing suppressed ICC cell malignant behaviors, which were reversed by METTL3 overexpression. METTL3 increased m6A modification on NDFIP1 mRNA, facilitated YTHDF2 recognition of m6A, and promoted NDFIP1 mRNA degradation, thereby suppressing NDFIP1 expression. YTHDF2 inhibition increased NDFIP1 mRNA levels. NDFIP1 downregulation partially reversed the inhibitory effects of si-METTL3 on ICC cell behaviors, while NDFIP1 overexpression partially reversed the promotive effects of METTL3 on ICC cell behaviors. METTL3 downregulation suppressed ICC growth by increasing NDFIP1 expression. In conclusion, METTL3 aggravates ICC cell proliferation, invasion, and migration by promoting the degradation of NDFIP1 mRNA in a YTHDF2-dependent manner.
通讯机构：
[Hu, YJ; Liu, ZY ] H;Hunan Normal Univ, Hunan Prov Peoples Hosp, Affiliated Hosp 1, Dept Cardiol, Changsha, Peoples R China.;Hunan Prov Peoples Hosp, Inst Cardiovasc Epidemiol, Changsha, Hunan, Peoples R China.;Hunan Prov Peoples Hosp, Inst Epidemiol, Changsha, Hunan, Peoples R China.;Clin Res Ctr Heart Failure Hunan Prov, Changsha, Hunan, Peoples R China.
关键词：
Berberine;Cardiovascular-kidney metabolic syndrome (CKM);HFpEF;animal model;network pharmacology;“two-hit” model
摘要：
BACKGROUND: Cardiovascular, Kidney and metabolic syndrome (CKM) is a complex disease, for which current therapeutic approaches have limited efficacy. This study aims to screen for potential targets and novel drugs for treating CKM using network pharmacology. METHODS: Using reverse network pharmacology, core targets and potential drugs for CKM were identified. Candidate compounds were screened from a natural product library. Male C57BL/6J mice were fed a high-fat L-NAME diet for 12weeks to induce CKM and confirm successful model establishment, followed by 4weeks of BBR (Berberine) treatment. Metabolic parameters, as well as cardiac and renal structural and functional indices, were assessed. Key targets and potential drugs identified through network pharmacology and bioinformatics were validated using pathological analysis, RT-qPCR, and Western blotting (WB), collectively demonstrating the therapeutic effects of BBR on CKM. RESULTS: Network pharmacology identified multiple core targets of CKM, and reverse pharmacology discovered the potential drug BBR (Berberine) from a natural product library. In vivo experiments demonstrated that the "two-hit" HFpEF model, which is induced by a high-fat diet combined with L-NAME treatment for 12weeks and is characterized by metabolic disorders, cardiac diastolic dysfunction, and renal fibrosis, can be used as a new model of CKM. BBR improved metabolic disorders, cardiac diastolic function, and renal damage in CKM mice by regulating lipid metabolism, glucose metabolism, and fibrosis-related pathways. CONCLUSION: The "two-hit" HFPEF model can be used as a new model of CKM, and BBR may become a new candidate drug for the treatment of CKM through multiple targets.
作者机构：
[Gan, Ni; Cui, Yuting; Li, Hengjuan; Li, Man; Peng, Juan; Chen, Yanyu; Xiang, Qiong; Tang, Zhihan; Xia, Mengdie; Zhang, Huayu; Zhou, Yating] Univ South China, Inst Cardiovasc Dis, Sch Basic Med Sci,Hunan Int Sci & Technol Cooperat, Hengyang Med Sch,Key Lab Arteriosclerol Hunan Prov, Hengyang 421001, Peoples R China.;[Cui, Yuting] Sun Yat Sen Univ, Sch Med, Dept Pathophysiol, Shenzhen 518107, Peoples R China.;[Chen, Yanyu; Dai, Xiaoyan] Univ South China, Affiliated Hosp 2, Dept Cardiovasc Med, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Weizheng] Second Peoples Hosp Hunan Prov, Brain Hosp Hunan Prov, Changsha 410007, Hunan, Peoples R China.;[Wang, Xin] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Metab & Endocrinol, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Peng, J; Tang, ZH ; Dai, XY ] U;Univ South China, Inst Cardiovasc Dis, Sch Basic Med Sci,Hunan Int Sci & Technol Cooperat, Hengyang Med Sch,Key Lab Arteriosclerol Hunan Prov, Hengyang 421001, Peoples R China.;Univ South China, Affiliated Hosp 2, Dept Cardiovasc Med, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Affiliated Hosp 2, Clin Res Inst, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Affiliated Nanhua Hosp, Hengyang Med Sch, Dept Cardiol, Hengyang 421001, Hunan, Peoples R China.
摘要：
Atherosclerosis persists as a principal driver of global cardiovascular mortality and morbidity, and its sustained prevalence surge fuels the incidence of major adverse cardiovascular events (MACE). Plaque instability is a critical determinant of MACE, as fissure formation or rupture of vulnerable plaques can precipitate thromboembolic complications. In this study, we investigate a noncanonical role of proprotein convertase subtilisin/kexin type 9 (PCSK9) beyond its lipid regulatory function, focusing on its impact on vascular smooth muscle cells (VSMCs) in the context of plaque instability. Our results demonstrate that PCSK9 overactivity markedly promotes ferroptotic cell death in VSMCs, thereby exacerbating plaque vulnerability. Furthermore, we delineate the underlying mechanism: PCSK9 physically interacts with Yes-associated protein 1 and targets it for lysosomal degradation, which, in turn, suppresses the expression of nuclear protein 1. In conclusion, our findings unveil a novel role of PCSK9 in promoting plaque instability by driving ferroptosis in VSMCs, suggesting that targeting PCSK9 presents a potential avenue for plaque stabilization, thereby mitigating the incidence of major MACE.
摘要：
Herein, the Nd@g-C 3 N 4 dual-functional photocatalysis enabled fluoroalkylative heteroarylation of alkenes with R f SO 2 Cl under visible-light and ultrasound conditions was firstly reported. The photogenerated electron-driven reductive production of fluoroalkyl radical paired with photogenerated hole-driven oxidative production of chloride radical resulted in the full utilization of photogenerated carrier for bond formation. A wide range of N -heteroarenes, alkenes and R f SO 2 Cl, were well compatible for this reaction to access valuable fluoroalkylated N -heteroarenes with diverse structural features. The antitumor potential of synthesized fluoroalkylated N -heterocycles against Glioma 261 cells was evaluated by CCK8 assay. Notably, compound 4aka demonstrated remarkable efficacy, exhibiting approximately sevenfold greater potency than temozolomide, a widely used chemotherapeutic agent.
Herein, the Nd@g-C 3 N 4 dual-functional photocatalysis enabled fluoroalkylative heteroarylation of alkenes with R f SO 2 Cl under visible-light and ultrasound conditions was firstly reported. The photogenerated electron-driven reductive production of fluoroalkyl radical paired with photogenerated hole-driven oxidative production of chloride radical resulted in the full utilization of photogenerated carrier for bond formation. A wide range of N -heteroarenes, alkenes and R f SO 2 Cl, were well compatible for this reaction to access valuable fluoroalkylated N -heteroarenes with diverse structural features. The antitumor potential of synthesized fluoroalkylated N -heterocycles against Glioma 261 cells was evaluated by CCK8 assay. Notably, compound 4aka demonstrated remarkable efficacy, exhibiting approximately sevenfold greater potency than temozolomide, a widely used chemotherapeutic agent.
