摘要：
Introduction: Recently, accumulating studies have reported the roles of competitive endogenous RNA (ceRNA) networks in ischemia/reperfusion (I/R) injury in several organs, including the liver, kidney, heart, brain, and intestine. However, the functions and mechanisms of long noncoding RNAs (lncRNAs)dwhich serve as ceRNA networks in in-testinal I/R injurydremain elusive.Methods: RNA expression data were retrieved from the National Center for Biotechnology Information-Gene Expression Omnibus database. Differentially expressed microRNAs (miRNAs) (miDEGs) were explored between the sham and intestinal I/R injury samples. Next, targeted lncRNAs and messenger RNAs in the database were matched based on miDEGs. Hub ceRNA networks were constructed and visualized via Cytoscape. Intersection analysis was performed to screen mDEGs between two datasets. Finally, the vital nodes of the ceRNA networks were validated by quantitative PCR.Results: A total of 189 miDEGs were identified. Forty miRNAs were found to be associated with 240 predicted target genes from miRWalk 3.0. The ceRNA network was constructed with 10 miRNAs, including the 1700020114Rik/mmu-miR-7a-5p/Klf4 axis. Furthermore, the expression of lncRNA 1700020114Rik (P < 0.05) and messenger RNA Klf4 (P < 0.01) was markedly decreased in mouse models of intestinal I/R injury, whereas the expression level of mmu-miR-7a-5p was significantly increased (P < 0.05).Conclusions: The results provide novel insights into the molecular mechanism of ceRNA networks in intestinal I/R injury and highlight the potential of the 170002700020114Rik/ mmu-miR-7a-5p/Klf4 axis in the prevention and treatment of intestinal I/R injury.(c) 2022 Elsevier Inc. All rights reserved.
摘要：
Treponema pallidum (T. pallidum), an obligate extracellular bacterium, is the causative agent of sexually transmitted bacterial diseases. In this study, the glycolytic enzyme enolase (Tp Eno) of T. pallidum were injected intramuscularly into C57BL/6 mice, resulting in higher levels of specific anti-Tp Eno antibodies and Tp Eno-specific splenocyte proliferation than those in the mice immunized with recombinant protein Tp Eno. Cytokine (IL-4, IL-6, IL-10, IFN-γ, and TNF-α) analysis of splenocytes showed that the Tp Eno could slightly trigger the Th1-biased immune response. Furthermore, immunization of mice with Tp Eno elicited a significant production of IFN-γ by CD4(+) T-cells in the spleen. Subsequently, mice were inoculated intradermally (between the scapulae), intraperitoneally, intrarectally and via the corpora cavernosa with 2.5×10(6) organisms per site (1×10(7) total organisms). The bacterial organ burden detected in the blood, spleen, liver, testes or brain of immunized mice suggested that Tp Eno enhances protective immunity to inhibit T. pallidum colonization in distal tissues. Therefore, Tp Eno vaccination enhances Tp Eno-specific immunogenicity and provides protection against T. pallidum dissemination.
摘要：
Type 2 diabetes mellitus (T2DM) is frequently associated with diabetic cognitive impairment (DCI), and recent studies have shown a strong association between DCI and hippocampal ferroptosis. In this study, we administered dihydromyricetin (DHM) or JNK inhibitor SP600125, to T2DM rats and monitored changes in blood glucose levels, conducted behavioral tests, and detected changes in JNK, inflammatory factors and ferroptosis-related indicators. Our findings demonstrated that T2DM rats displayed signs of cognitive impairment (CI), with ferrozine assays indicating elevated iron content in the hippocampus. Concurrently, there was an increase in p-JNK activity and inflammatory factors IL-6 and TNF-α in the hippocampal region of these rats. Furthermore, we observed elevated levels of Fe(2+), MDA, ROS, LPO, and ACSL4, along with a decrease in GPX4 and GSH, suggesting the occurrence of hippocampal ferroptosis. SP600125 application reversed these changes in the T2DM rats, although it exhibited no significant effects in the control group. Treatment with high and low doses of DHM led to a reduction in p-JNK expression, inflammatory factor-related proteins, and iron accumulation in the hippocampal region, effectively alleviating hippocampal ferroptosis in T2DM rats. No notable effects of DHM were observed in the control group. To conclude, our study suggests that DHM can potentially alleviate hippocampal ferroptosis of T2DM cognitive impairment rats, primarily by suppressing the JNK-inflammatory factor pathway in the hippocampus.
作者机构：
[Huang, Zhixin; Lu, Haike; Dai, Yingyi; Zhang, Wenli; Huang, Ying] Guangdong Second Prov Gen Hosp, Dept Neurol, 466 Middle Xingang Rd, Guangzhou 510317, Peoples R China.;[Huang, Zhixin] Jinan Univ, Dept Neurol, Fac Med Sci, Guangzhou, Peoples R China.;[Huang, Zhixin] Univ South China, Dept Neurol, Hengyang, Peoples R China.;[Chen, Zhenru] Univ Missouri, Dept Mech & Aerosp Engn, Columbia, MO USA.;[Zou, Fengyuan] Guangzhou AID Cloud Technol, Dept Data Sci, Guangzhou, Peoples R China.
通讯机构：
[Zhixin Huang] D;Department of Neurology, Guangdong Second Provincial General Hospital, Guangzhou, China<&wdkj&>Department of Neurology, Jinan University Faculty of Medical Science, Guangzhou, China<&wdkj&>Department of Neurology, University of South China, Hengyang, China
摘要：
OBJECTIVES: To determine the factors that affect recurrent stroke after acute ischemic stroke, specifically between male and female groups. METHODS: We examined relative factors associated with recurrent stroke in Chinese patients with first-ever ischemic stroke. LASSO (least absolute shrinkage and selection operator) Cox regression were used to determine the predictors of recurrent stroke in the male and female groups. Next, We used Kaplan-Meier survival curves and interactions among these predictors to assess the association between relapse-related factors and recurrent stroke. RESULTS: During one year of follow-up, we documented 42 incidents of recurrent stroke in males and 15 in females. There was no significant difference in the overall recurrence rate between men and women. We finally identified three variables in males and one variable in females associated considerably with recurrent stroke by LASSO Cox regression. In females, good sleep appeared to be the most significant protective factor against recurrent stroke(hazard ratio [HR], 0.21; 95% CI, 0.08-0.57). In the male group, we found two risk factors: atherosclerotic burden (HR, 2.42; 95% CI, 1.30-4.51) and coronary heart disease (HR, 2.98; 95% CI, 1.16-7.66); and one protective factor: domestic/physical activities (HR, 0.45; 95% CI, 0.24-0.83). We also found an interaction between good sleep and domestic/physical activities in males (P(interaction) = 0.016). DISCUSSION: Our data indicate that the factors for recurrent stroke may differ by sex. Engaging in domestic/physical activities may substantially lower recurrent strokes in Chinese adult males. And good sleep in females appears to be more important in preventing stroke recurrence.
摘要：
Syphilis, a sexually transmitted disease (STD) caused by Treponema pallidum (T. pallidum), has had a worldwide resurgence in recent years and remains a public health threat. As such, there has been a great deal of research into clinical strategies for the disease, including diagnostic biomarkers and possible strategies for treatment and prevention. Although serological testing remains the predominant laboratory diagnostic method for syphilis, it is worth noting that investigations pertaining to the DNA of T. pallidum, non-coding RNAs (ncRNAs), chemokines, and metabolites in peripheral blood, cerebrospinal fluid, and other bodily fluids have the potential to offer novel perspectives on the diagnosis of syphilis. In addition, the global spread of antibiotic resistance, such as macrolides and tetracyclines, has posed significant challenges for the treatment of syphilis. Fortunately, there is still no evidence of penicillin resistance. Hence, penicillin is the recommended course of treatment for syphilis, whereas doxycycline, tetracycline, ceftriaxone, and amoxicillin are viable alternative options. In recent years, efforts to discover a vaccine for syphilis have been reignited with better knowledge of the repertoire of T. pallidum outer membrane proteins (OMPs), which are the most probable syphilis vaccine candidates. However, research on therapeutic interventions and vaccine development for human subjects is limited due to practical and ethical considerations. Thus, the preclinical model is ideal for conducting research, and it plays an important role in clinical transformation. Different preclinical models have recently emerged, such as in vitro culture and mouse models, which will lay a solid foundation for clinical treatment and prevention of syphilis. This review aims to provide a comprehensive summary of the most recent syphilis tactics, including detection, drug resistance treatments, vaccine development, and preclinical models in clinical practice.
通讯作者：
Fengrui Yang<&wdkj&>Fengrui Yang Fengrui Yang Fengrui Yang
作者机构：
[Chen, Ji] First Peoples Hosp Huaihua, Dept Endocrinol, Huaihua, Peoples R China.;[Guo, Peng; Yang, Fengrui] First Peoples Hosp Huaihua, Dept Anesthesiol, Huaihua, Peoples R China.;[Han, Mingming] Univ Sci & Technol China, Affiliated Hosp USTC 1, Dept Anesthesiol, Div Life Sci & Med, Hefei, Peoples R China.;[Qin, Jie; Chen, Kemin; Yang, Fengrui] Univ South China, Affiliated Hosp 1, Dept Anesthesiol, Hengyang, Peoples R China.;[Yang, Fengrui] First Peoples Hosp Huaihua, Dept Anesthesiol, 144 Jinxi South Rd, Huaihua 418000, Hunan, Peoples R China.
通讯机构：
[Fengrui Yang; Fengrui Yang Fengrui Yang Fengrui Yang] D;Department of Anesthesiology, The First People's Hospital of Huaihua, Huaihua, P.R. China<&wdkj&>Department of Anesthesiology, The First Affiliated Hospital, University of South China, Hengyang, P.R. China
摘要：
Recent years have witnessed a growing research interest in traditional Chinese medicine as a neuroprotective nutrient in the management of diabetic cognitive dysfunction. However, the underlying molecular mechanisms of sinomenine in mediating ferroptosis of hippocampal neurons have been poorly understood. This study sought to decipher the potential effect and molecular mechanism of sinomenine in the cognitive dysfunction following type 2 diabetes mellitus (T2DM). Multi-omics analysis was conducted to identify the microbiota-gut-brain axis in T2DM patient samples obtained from the publicly available database. In HT-22 cells, erastin was utilized to create a ferroptosis model, and streptozotocin was injected intraperitoneally to create a rat model of DM. It was noted that intestinal flora imbalance occurred in patients with T2DM-associated cognitive dysfunction. Sinomenine could reduce Erastin-induced hippocampus neuronal ferroptosis by increasing EGF expression. EGF protected hippocampal neurons against ferroptosis by activating the Nrf2/HO-1 signaling pathway. Furthermore, in vivo results confirmed that sinomenine blocked ferroptosis of hippocampal neurons and alleviated cognitive dysfunction in T2DM rats. Collectively, these results suggest that sinomenine confers neuroprotective effects by curtailing hippocampal neuron ferroptosis via the EGF/Nrf2/HO-1 signaling and microbiota-gut-brain axis. It may be a candidate for the treatment of diabetic cognitive dysfunction.
期刊：
JOURNAL OF INFECTIOUS DISEASES,2023年228(4):453-463 ISSN：0022-1899
通讯作者：
Aihua Lei
作者机构：
[Wu, Yimou; Luo, Ying; Lei, Aihua; Wang, Chuan; Wang, Cui; Du, Zhaoxiang] Univ South China, Inst Pathogen Biol, Sch Basic Med Sci, Hengyang Med Sch, Hengyang, Hunan, Peoples R China.;[Wu, Yimou; Luo, Ying; Lei, Aihua; Wang, Chuan; Wang, Cui; Du, Zhaoxiang] Univ South China, Hunan Prov Key Lab Special Pathogens Prevent & Con, Hengyang, Hunan, Peoples R China.;[Lei, Aihua] Inst Pathogen Biol, 28 Changsheng Western Rd, Hengyang, Peoples R China.
通讯机构：
[Aihua Lei] I;Institute of Pathogenic Biology, School of Basic Medical Sciences, Hengyang Medical School, University of South China , Hengyang, Hunan , China<&wdkj&>Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, University of South China , Hengyang, Hunan , China
关键词：
polymorphonuclear neutrophils;Chlamydia psittaci;inducible NO synthase;lung infection;nitric oxide
摘要：
BACKGROUND: Whether polymorphonuclear neutrophils (PMN) exert a protective role upon chlamydial infection by expressing inducible nitric oxide (NO) synthase (iNOS) and producing NO remains unclear. METHODS: This issue was addressed using BALB/c mice infected with Chlamydia psittaci 6BC strain. Methods included flow cytometry, immunofluorescence, qRT-PCR, and western blot. RESULTS: The number of PMN was significantly increased during C. psittaci infection, which was accompanied by increased iNOS expression and NO production in the mouse lungs. PMN were the major source of NO during pulmonary C. psittaci infection and inhibited C. psittaci multiplication in an iNOS/NO-dependent manner. Depletion of PMN aggravated C. psittaci-induced disease and increased C. psittaci burden. Nuclear factor-κB (NF-κB) and STAT1 signaling pathways, but not MAPK signaling pathways, were required for the induction of iNOS expression and NO production in PMN by C. psittaci infection. Thus, our findings highlight the protective role of NO-producing PMN in C. psittaci infection. CONCLUSIONS: NO-producing PMN confer a protective role during pulmonary C. psittaci infection in mice, and thus our study sheds new light on PMN function during Chlamydia infection.
摘要：
Located in the frontline against the largest population of microbiota, the intestinal mucosa of mammals has evolved to become an effective immune system. ?d T cells, a unique T cell subpopulation, are rare in circulation blood and lymphoid tissues, but rich in the intestinal mucosa, particularly in the epithelium. Via rapid production of cytokines and growth factors, intestinal ?d T cells are key contributors to epithelial homeostasis and immune surveillance of infection. Intriguingly, recent studies have revealed that the intestinal ?d T cells may play novel exciting functions ranging from epithelial plasticity and remodeling in response to carbohydrate diets to the recovery of ischemic stroke. In this review article, we update regulatory molecules newly defined in lymphopoiesis of the intestinal ?d T cells and their novel functions locally in the intestinal mucosa, such as epithelial remodeling, and distantly in pathological setting, e.g., ischemic brain injury repair, psychosocial stress responses, and fracture repair. The challenges and potential revenues in intestinal ?d T cell studies are discussed.
作者机构：
[Ye, Feng; Tang, Hailin] Sun Yat Sen Univ, State Key Lab Oncol South China, Canc Ctr, Guangzhou, Peoples R China.;[Dewanjee, Saikat] Jadavpur Univ, Dept Pharmaceut Technol, Adv Pharmacognosy Res Lab, Kolkata 700032, India.;[Li, Yuehua] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Med Oncol, Hengyang, Peoples R China.;[Li, Yuehua] Univ South China, Inst Pathogen Biol, Hengyang Med Coll, Hengyang, Peoples R China.;[Jha, Niraj Kumar; Jha, SK; Jha, Saurabh Kumar] Sharda Univ, Sch Engn & Technol, Dept Biotechnol, Greater Noida, India.
通讯机构：
[Tang, HL ; Jha, SK ] S;[Behl, T ] U;Sun Yat Sen Univ, State Key Lab Oncol South China, Canc Ctr, Guangzhou, Peoples R China.;Sharda Univ, Sch Engn & Technol, Dept Biotechnol, Greater Noida, India.;Univ Petr & Energy Studies, Sch Hlth Sci & Technol, Dehra Dun, Uttaranchal, India.
关键词：
Breast cancer;Clinical trials;Immune-checkpoint Inhibitors;Immunotherapy;Targeted therapies
摘要：
Breast cancer is the second leading cause of death for women worldwide. The heterogeneity of this disease presents a big challenge in its therapeutic management. However, recent advances in molecular biology and immunology enable to develop highly targeted therapies for many forms of breast cancer. The primary objective of targeted therapy is to inhibit a specific target/molecule that supports tumor progression. Ak strain transforming, cyclin-dependent kinases, poly (ADP-ribose) polymerase, and different growth factors have emerged as potential therapeutic targets for specific breast cancer subtypes. Many targeted drugs are currently undergoing clinical trials, and some have already received the FDA approval as monotherapy or in combination with other drugs for the treatment of different forms of breast cancer. However, the targeted drugs have yet to achieve therapeutic promise against triple-negative breast cancer (TNBC). In this aspect, immune therapy has come up as a promising therapeutic approach specifically for TNBC patients. Different immunotherapeutic modalities including immune-checkpoint blockade, vaccination, and adoptive cell transfer have been extensively studied in the clinical setting of breast cancer, especially in TNBC patients. The FDA has already approved some immune-checkpoint blockers in combination with chemotherapeutic drugs to treat TNBC and several trials are ongoing. This review provides an overview of clinical developments and recent advancements in targeted therapies and immunotherapies for breast cancer treatment. The successes, challenges, and prospects were critically discussed to portray their profound prospects.
期刊：
International Immunopharmacology,2023年118:110035 ISSN：1567-5769
通讯作者：
Zhongyu Li
作者机构：
[Li, Zhongyu; Shi, Keliang; Shu, Mingyi; Zhao, Lanhua; Tang, Shuangyang] Univ South China, Inst Pathogen Biol, Hengyang Med Coll, Sch Nuring,Hunan Prov Key Lab Special Pathogens Pr, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Zhongyu Li] I;Institute of Pathogenic Biology, Hengyang Medical College, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, the School of Nuring, University of South China, Hengyang, 421001 Hunan, PR China
作者机构：
[Xiao, Hao; Wu, Yinyin; Fu, Qian; Tang, Li; Li, Na; Li, Zelong; Liu, Fen; Tan, Xiaofeng; Zhou, Wei; Wang, Wenjie; Lin, Nanyun; Wang, Feirong; Wang, Cheng-kun; Yang, Qinglai; Kang, Qiang; Tan, XF; Wu, Gui-long; Yang, Sha] Univ South China, Ctr Mol Imaging Probe, Hunan Prov Key Lab Tumor Cellular & Mol Pathol, Canc Res Inst,Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;[Chen, Guodong; Yang, Qinglai] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Hepatopancreatobiliary Surg, Hengyang 421001, Hunan, Peoples R China.;[Tan, Xiaofeng; Yang, Qinglai; Tan, XF] Hunan Prov Maternal & Child Hlth Care Hosp, Key Lab Birth Defect Res & Prevent, Natl Hlth Commiss, Changsha 410008, Hunan, Peoples R China.;[Tang, Li] Hainan Normal Univ, Coll Chem & Chem Engn, Key Lab Trop Med Plant Chem, Minist Educ, Haikou 571158, Hainan, Peoples R China.;[Tan, Xiaofeng; Yang, Qinglai; Tan, XF] Univ South China, Hengyang Med Sch, MOE Key Lab Rare Pediat Dis, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Tan, XF; Yang, QL ; Chen, GD] U;Univ South China, Ctr Mol Imaging Probe, Hunan Prov Key Lab Tumor Cellular & Mol Pathol, Canc Res Inst,Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Hepatopancreatobiliary Surg, Hengyang 421001, Hunan, Peoples R China.;Hunan Prov Maternal & Child Hlth Care Hosp, Key Lab Birth Defect Res & Prevent, Natl Hlth Commiss, Changsha 410008, Hunan, Peoples R China.;Univ South China, Hengyang Med Sch, MOE Key Lab Rare Pediat Dis, Hengyang 421001, Hunan, Peoples R China.
关键词：
activatable fluorescence imaging;chemodynamic therapy;gas therapy;glutathione depletion;hypothermal photothermal therapy (HPTT);near-infrared II;photoinduced electron transfer
摘要：
Tumor microenvironment (TME)-triggered phototheranostic platform offers a feasible strategy to improve cancer diagnosis accuracy and minimize treatment side effects. Developing a stable and biocompatible molecular phototheranostic platform for TME-activated second near-infrared (NIR-II) fluorescence imaging-guided multimodal cascade therapy is a promising strategy for creating desirable anticancer agents. Herein, a new NIR-II fluorescence imaging-guided activatable molecular phototheranostic platform (IR-FEP-RGD-S-S-S-Fc) is presented for actively targeted tumor imaging and hydrogen sulfide (H2S) gas-enhanced chemodynamic-hypothermal photothermal combined therapy (CDT/HPTT). It is revealed for the first time that the coupling distance between IR-FE and ferrocene is proportional to the photoinduced electron transfer (PET), and the aqueous environment is favorable for PET generation. The part of Cyclic-RGDfK (cRGDfk) peptides can target the tumor and benefit the endocytosis of nanoparticles. The high-concentration glutathione (GSH) in the TME will separate the fluorescence molecule and ferrocene by the GSH-sensitive trisulfide bond, realizing light-up NIR-II fluorescence imaging and a cascade of trimodal synergistic CDT/HPTT/gas therapy (GT). In addition, the accumulation of hydroxyl radicals (center dot OH) and down-regulation of glutathione peroxidase 4 (GPX4) can produce excessive harmful lipid hydroperoxides, ultimately leading to ferroptosis. Trisulfide bond-mediated molecular phototheranostic platform for "activatable" NIR-II imaging-guided enhanced gas-chemo-hypothermal photothermal therapy. A new phototheranostic platform is developed, utilizing cyclic-RGDfk (cRGDfk) peptide for active tumor cell targeting and achieving glutathione (GSH)-rich tumor environment photoinduced electron transfer (PET) blockade for fluorescence-specific illumination and therapy. image
摘要：
A core transcription regulatory circuitry (CRC) is an interconnected self-regulatory circuitry that is formed by a group of core transcription factors (TFs). These core TFs collectively regulate gene expression by binding not only to their own super enhancers (SEs) but also to the SEs of one another. For most human tissue/cell types, a global view of CRCs and core TFs has not been generated. Here, we identified numerous CRCs using two identification methods and detailed the landscape of the CRCs driven by SEs in large cell/tissue samples. The comprehensive biological analyses, including sequence conservation, CRC activity and genome binding affinity were conducted for common TFs, moderate TFs, and specific TFs, which exhibit different biological features. The local module located from the common CRC network highlighted the essential functions and prognostic performance. The tissue-specific CRC network was highly related to cell identity. Core TFs in tissue-specific CRC networks exhibited disease markers, andhad regulatory potential for cancer immunotherapy. Moreover, a user-friendly resource named CRCdb (http://www.licpathway.net/crcdb/index.html) was developed, which contained the detailed information of CRCs and core TFs used in this study, as well as other interesting results, such as the most representative CRC, frequency of TFs, and indegree/outdegree of TFs.
摘要：
This study was designed to investigate paclitaxel's total efficiency and safety combined with cisplatin in treating advanced esophageal cancer patients. Eighty-eight patients with advanced esophageal cancer were were divided into two groups with different treatment regimens: the control group was treated with 5-fluorouracil combined with cisplatin while the study group was treated with paclitaxel combined with cisplatin. The observed indexes include, the time of tumor progression and median survival between the two groups, the changes in pain score, vertical tumor diameter, and tumor diameter before and after treatment, the total efficiency of treatment as well as the safety of the two groups. Compared with the control group, the time to tumor progression and median survival were longer in the study group (p < 0.05). The total efficien-cy of treatment was higher in the study group (p < 0.05) as compared to control group similarly compared to the control group, all adverse effects were less severe in the study group. The use of paclitaxel combined with cisplatin in the treatment of advanced esophageal cancer patients can further prolong the survival time of patients compared with 5-fluorouracil combined with cisplatin, with higher total clinical efficiency, fewer adverse reactions, and certain safety, which is worthy of clinical promotion.
摘要：
Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder characterized by widespread intranuclear inclusions in the nervous system as well as multiple visceral organs. In 2019, expanded GGC repeats within the 5′ untranslated region of the NOTCH2NLC gene was identified as the causative factor. NIID is a heterogeneous disorder with variable clinical manifestations including cognitive impairment, cerebellar ataxia, parkinsonism, paroxysmal symptoms, autonomic dysfunction, and muscle weakness. Although NIID primarily affects the central and peripheral nervous systems, growing evidence suggests potential cardiac abnormalities in NIID. However, the link between expanded GGC repeats within NOTCH2NLC and cardiac dysfunction remains uncertain. In this study, we utilized two transgenic mouse models, expressing NOTCH2NLC-(GGC)98 ubiquitously or specifically in cardiomyocytes, and identified p62 (also known as sequestosome 1, SQSTM1)-positive intranuclear NOTCH2NLC-polyG inclusions in cardiomyocytes in two mouse models. We observed that both models exhibited cardiac-related pathological and echocardiographic changes, albeit exhibiting varying degrees of severity. Transcriptomic analysis revealed shared downregulation of genes related to ion channels and mitochondria in both models, with the cardiomyocyte-specific mice showing a more pronounced downregulation of mitochondria and energy metabolism-related pathways. Further investigations revealed decreased expression of mitochondria-related genes and electron transport chain activity. At last, we conducted a retrospective review of cardiac-related examination results from NIID patients at our hospital and also identified some cardiac abnormalities in NIID patients. Our study provided the first in vivo evidence linking GGC repeat expansions within NOTCH2NLC to cardiac abnormalities and highlighted the contribution of mitochondrial dysfunction in the development of cardiac abnormalities.
摘要：
Background: Ischemic stroke is the obstruction of cerebral blood flow with a high morbidity. Microglial polarization is a contributing factor for ischemic strokeinduced injury. Here, we focused on function and mechanism of RNA binding protein RPS3 in microglial polarization after ischemic stroke. Methods: Transient middle cerebral artery occlusion (tMCAO) was conducted in SD rats. Infarct area was detected by TTC staining and neurological score was assessed. Fluorescence staining tested neuronal apoptosis and microglial differentiation. Oxygen and glucose deprivation/reoxygenation (OGD/R) was applied for treating microglia. Levels of RPS3, SIRT1, M1 and M2 polarization markers (CD86, iNOS, CD206, Arg-1) were determined by RT-qPCR. Western blot detected RPS3, SIRT1, NLRP3, ASC and Cleaved-caspase-1 expression. RIP assay validated that RPS3 interacted with SIRT1. CCK-8 measured cell viability. Flow cytometry and ELISA assessed M1 and M2 polarization markers. LDH release was detected using colorimetric CytoTox 96 Cytotoxicity kit. Results: RPS3 depletion improved neurological dysfunction and reduced infarction area in rats after tMCAO. Knockdown of RPS3 resulted in increased SIRT1 expression and decreased NLRP3 inflammasome activation, and induced microglia M2 polarization after ischemia-reperfusion (I/R). Besides, RPS3 directly targeted SIRT1 and reduced its expression in microglia. RPS3 silencing suppressed OGD/R-triggered neuronal and microglial cell death through SIRT1. Moreover, RPS3 activated NLRP3 inflammasome and regulated microglial polarization via SIRT1. Conclusion: RPS3 regulates microglial polarization and neuronal injury through SIRT1/NLRP3 pathway, suggesting a novel target for ischemic stroke treatment.Keywords: Ischemic stroke-Microglial polarization-NLRP3 inflammasome-(c) 2023 Elsevier Inc. All rights reserved.
摘要：
High altitude exposure leads to various cognitive impairments. The cerebral vasculature system plays an integral role in hypoxia-induced cognitive defects by reducing oxygen and nutrition supply to the brain. RNA N6-methyladenosine (m6A) is susceptible to modification and regulates gene expression in response to environmental changes, including hypoxia. However, the biological significance of m6A in endothelial cell performance under hypoxic conditions is unknown. Using m6A-seq, RNA immunoprcipitation-seq, and transcriptomic co-analysis, the molecular mechanism of vascular system remodeling under acute hypoxia is investigated. A novel m6A reader protein, proline-rich coiled-coil 2B (PRRC2B), exists in endothelial cells. PRRC2B knockdown promoted hypoxia-induced endothelial cell migration by regulating alternative splicing of the alpha 1 chain of collagen type XII in an m6A-dependent manner and the decay of matrix metallopeptidase domain 14 and ADAM metallopeptidase domain 19 mRNA in an m6A-independent manner. In addition, conditional knockout of PRRC2B in endothelial cells promotes hypoxia-induced vascular remodeling and cerebral blood flow redistribution, thus alleviating hypoxia-induced cognitive decline. Therefore, PRRC2B is integral in the hypoxia-induced vascular remodeling process as a novel RNA-binding protein. These findings provide a new potential therapeutic target for hypoxia-induced cognitive decline.
通讯机构：
[Huan He; Pingkun Zhou] D;Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China<&wdkj&>NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, China<&wdkj&>Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China<&wdkj&>School of Medicine, University of South China, Hengyang, China
关键词：
TAB182;EGFR;Cell invasion;Cell migration;EMT;Lung cancer cells
摘要：
BACKGROUND: TAB182 is overexpressed in cancerous tissues and correlated with poor overall survival in lung cancer patients. Mechanistically, TAB182 participates in DNA damage repair and endows tumour cells with radio- and chemoresistance. However, its role in non-small cell lung cancer (NSCLC) remains unclear. METHODS AND RESULTS: Cells with stable TAB182 knockdown (KD) were generated using A549 NSCLC cells, and we demonstrated that depleting TAB182 inhibits cell EMT, proliferation, colony formation, migration and invasion. Analysis of the TCGA database showed a positive correlation between TAB182 and EGFR, a well-established NSCLC oncoprotein. Then, we verified that silencing TAB182 decreases EGFR expression at both the mRNA and protein levels. Moreover, both TAB182 and EGFR were reported to restore ionizing radiation (IR)-triggered DNA damage. We validated that IR elevates the protein level of EGFR and that silencing TAB182 can alleviate IR-induced EGFR upregulation. Furthermore, overexpressing EGFR abrogates the inhibitory effects of TAB182 KD on EMT, migration, and invasion in A549 cells. CONCLUSIONS: Our data demonstrated that EGFR expression is regulated by TAB182 and downregulation of TAB182 has a novel function to repress EMT, migration and invasion by decreasing EGFR, indicating TAB182 could regulate the malignant progression of NSCLC.
作者机构：
[Li, Weiwei; Wu, Yimou; Yu, Maoying; Liu, Zhaoping; Li, Sijia; He, Zhangping; Tang, Yuanyuan; Xu, Man; Liu, Jie; Xu, M; Guo, Ningyuan; Yang, Hongyu; Wang, Jianye; Wu, YM] Univ South China, Inst Pathogen Biol, Hengyang Med Coll, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang, Peoples R China.;[Li, Weiwei; Xie, Dongde] Second Peoples Hosp Foshan, Dept Clin Lab, Foshan, Peoples R China.;[Wang, Jianye] Tianjin Med Univ, Sch Basic Med Sci, Dept Immunol, Key Lab Immune Microenvironm & Dis,Minist Educ, Tianjin, Peoples R China.;[Zheng, Kang] Hengyang Cent Hosp, Dept Clin Lab, Hengyang, Peoples R China.
通讯机构：
[Xu, M; Wu, YM ] U;Univ South China, Inst Pathogen Biol, Hengyang Med Coll, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang, Peoples R China.
摘要：
Tp92 impedes the activation of procaspase‐3 via the ERK MAPK, PI3K/Akt, and NF‐κB signaling pathways, consequently suppressing caspase‐3 activity within hPMNs, and thereby preventing hPMNs apoptosis. These findings provide valuable insights into the molecular mechanisms underlying Treponema pallidum infection and suggest potential therapeutic targets for syphilis treatment. Abstract Syphilis is a persistent sexually transmitted disease caused by infiltration of the elusive pathogen Treponema pallidum. Despite the prevalence of human polymorphonuclear neutrophils (hPMNs) within cutaneous lesions, which are characteristic of incipient syphilis, their role in T. pallidum infection remains unclear. Tp92 is the only T. pallidum helical outer membrane protein that exhibits structural features similar to those of outer membrane proteins in other gram‐negative bacteria. However, the functional mechanism of this protein in immune cells remains unclear. Neutrophils are short‐lived cells that undergo innate apoptosis in response to external stimuli that typically influence this process. In this study, we determined that Tp92 impedes the activation of procaspase‐3 via the ERK MAPK, PI3K/Akt, and NF‐κB signaling pathways, consequently suppressing caspase‐3 activity within hPMNs, and thereby preventing hPMNs apoptosis. Furthermore, Tp92 could also modulate hPMNs apoptosis by enhancing the expression of the anti‐apoptotic protein Mcl‐1, stimulating IL‐8 secretion, and preserving the mitochondrial membrane potential. These findings provide valuable insights into the molecular mechanisms underlying T. pallidum infection and suggest potential therapeutic targets for syphilis treatment.
期刊：
JMIR PUBLIC HEALTH AND SURVEILLANCE,2023年9(1):e49291- ISSN：2369-2960
通讯作者：
Wang, J
作者机构：
[Wang, Jian; Guo, Qulian; Song, Zongbin; Hou, Xinran; Zhu, Maoen; Wang, J] Cent South Univ, Xiangya Hosp, Dept Anesthesiol, 87 Xiangya Rd, Changsha 410008, Peoples R China.;[Wang, Jian; Guo, Qulian; Song, Zongbin; Zhang, Chengliang; Hou, Xinran; Zhu, Maoen] Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Changsha, Peoples R China.;[Xu, Wei] Univ South China, Hunan Prov Maternal & Child Hlth Care Hosp, Dept Anesthesiol, Changsha, Peoples R China.;[Zhang, Chengliang] Cent South Univ, Xiangya Hosp, Dept Cardiovasc Surg, Changsha, Peoples R China.
通讯机构：
[Wang, J ] C;Cent South Univ, Xiangya Hosp, Dept Anesthesiol, 87 Xiangya Rd, Changsha 410008, Peoples R China.
关键词：
serum chloride;all-cause mortality;cause-specific mortality;National Health and Nutrition Examination Survey;National Death Index
摘要：
BACKGROUND: Chloride is the most abundant anion in the human extracellular fluid and plays a crucial role in maintaining homeostasis. Previous studies have demonstrated that hypochloremia can act as an independent risk factor for adverse outcomes in various clinical settings. However, the association of variances of serum chloride with long-term mortality risk in general populations has been rarely investigated. OBJECTIVE: This study aims to assess the association of serum chloride with all-cause and cause-specific mortality in the general American adult population. METHODS: Data were collected from 10 survey cycles (1999-2018) of the National Health and Nutrition Examination Survey. All-cause mortality, cardiovascular disease (CVD) mortality, cancer mortality, and respiratory disease mortality data were obtained by linkage to the National Death Index through December 31, 2019. After adjusting for demographic factors and relevant lifestyle, laboratory items, and comorbid factors, weighted Cox proportional risk models were constructed to estimate hazard ratios and 95% CIs for all-cause and cause-specific mortality. RESULTS: A total of 51,060 adult participants were included, and during a median follow-up of 111 months, 7582 deaths were documented, 2388 of CVD, 1639 of cancer, and 567 of respiratory disease. The weighted Kaplan-Meier survival analyses showed consistent highest mortality risk in individuals with the lowest quartiles of serum chloride. The multivariate-adjusted hazard ratios from lowest to highest quartiles of serum chloride (≤101.2, 101.3-103.2, 103.2-105.0, and ≥105.1 mmol/L) were 1.00 (95% CI reference), 0.77 (95% CI 0.67-0.89), 0.72 (95% CI 0.63-0.82), and 0.77 (95% CI 0.65-0.90), respectively, for all-cause mortality (P for linear trend<.001); 1.00 (95% CI reference), 0.63 (95% CI 0.51-0.79), 0.56 (95% CI 0.43-0.73), and 0.67 (95% CI 0.50-0.89) for CVD mortality (P for linear trend=.004); 1.00 (95% CI reference), 0.67 (95% CI 0.54-0.84), 0.65 (95% CI 0.50-0.85), and 0.65 (95% CI 0.48-0.87) for cancer mortality (P for linear trend=.004); and 1.00 (95% CI reference), 0.68 (95% CI 0.41-1.13), 0.59 (95% CI 0.40-0.88), and 0.51 (95% CI 0.31-0.84) for respiratory disease mortality (P for linear trend=.004). The restricted cubic spline analyses revealed the nonlinear and L-shaped associations of serum chloride with all-cause and cause-specific mortality (all P for nonlinearity<.05), in which lower serum chloride was prominently associated with higher mortality risk. The associations of serum chloride with mortality risk were robust, and no significant additional interaction effect was detected for all-cause mortality and CVD mortality (P for interaction>.05). CONCLUSIONS: In American adults, decreased serum chloride concentrations were independently associated with increased all-cause mortality, CVD mortality, cancer mortality, and respiratory disease mortality. Our findings suggested that serum chloride may serve as a promising cost-effective health indicator in the general adult population. Further studies are warranted to explore the potential pathophysiological mechanisms underlying the association between serum chloride and mortality.
