Military Medical Research最新文献

{"title":"Effect of early administration of tetracosactide on mortality and host response in critically ill patients requiring rescue surgery: a sensitivity analysis of the STOPSHOCK phase 3 randomized controlled trial.","authors":"Giorgio Noera, Alfio Bertolini, Laura Calzà, Mercedes Gori, Annalisa Pitino, Graziella D'Arrigo, Colin Gerard Egan, Giovanni Tripepi","doi":"10.1186/s40779-024-00555-2","DOIUrl":"10.1186/s40779-024-00555-2","url":null,"abstract":"<p><strong>Background: </strong>Undifferentiated shock is recognized as a criticality state that is transitional in immune-mediated topology for casual risk of lethal microcirculatory dysfunction. This was a sensitivity analysis of a drug (tetracosactide; TCS10) targeting melanocortin receptors (MCRs) in a phase 3 randomized controlled trial to improve cardiovascular surgical rescue outcome by reversing mortality and hemostatic disorders.</p><p><strong>Methods: </strong>Sensitivity analysis was based on a randomized, two-arm, multicenter, double-blind, controlled trial. The Naïve Bayes classifier was performed by density-based sensitivity index for principal strata as proportional hazard model of 30-day surgical risk mortality according to European System for Cardiac Operative Risk Evaluation inputs-outputs in 100 consecutive cases (from August to September 2013 from Emilia Romagna region, Italy). Patients included an agent-based TCS10 group (10 mg, single intravenous bolus before surgery; n = 56) and control group (n = 44) and the association with cytokines, lactate, and bleeding-blood transfusion episodes with the prior-risk log-odds for mortality rate in time-to-event was analyzed.</p><p><strong>Results: </strong>Thirty-day mortality was significantly improved in the TCS10 group vs. control group (0 vs. 8 deaths, P < 0.0001). Baseline levels of interleukin (IL)-6, IL-10, and lactate were associated with bleeding episodes, independent of TCS10 treatment [odds ratio (OR) = 1.90, 95% confidence interval (CI) 1.39-2.79; OR = 1.53, 95%CI 1.17-2.12; and OR = 2.92, 95%CI 1.40-6.66, respectively], while baseline level of Fms-like tyrosine kinase 3 ligand (Flt3L) was associated with lower bleeding rates in TCS10-treated patients (OR = 0.31, 95%CI 0.11-0.90, P = 0.03). For every 8 TCS10-treated patients, 1 bleeding case was avoided. Blood transfusion episodes were significantly reduced in the TCS10 group compared to the control group (OR = 0.32, 95%CI 0.14-0.73, P = 0.01). For every 4 TCS10-treated patients, 1 transfusion case was avoided.</p><p><strong>Conclusions: </strong>Sensitivity index underlines the quality target product profile of TCS10 in the runway of emergency casualty care. To introduce the technology readiness level in real-life critically ill patients, further large-scale studies are required.</p><p><strong>Trial registration: </strong>European Union Drug Regulating Authorities Clinical Trials Database (EudraCT Number: 2007-006445-41 ).</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"56"},"PeriodicalIF":16.7,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"National age-specific mortality trends for cervical and breast cancers in urban-rural areas of China from 2009 to 2021: a population-based analysis.","authors":"Meng-Long Li, Jin-Lei Qi, Ya-Qi Ma, Wen Shu, Hui-Di Xiao, Li-Jun Wang, Peng Yin, Hao-Yan Guo, Sten H Vermund, Mai-Geng Zhou, Yi-Fei Hu","doi":"10.1186/s40779-024-00561-4","DOIUrl":"10.1186/s40779-024-00561-4","url":null,"abstract":"<p><strong>Background: </strong>Cervical and breast cancers are among the top 4 leading causes of cancer-related mortality in women. This study aimed to examine age-specific temporal trends in mortality for cervical and breast cancers in urban and rural areas of China from 2009 to 2021.</p><p><strong>Methods: </strong>Age-specific mortality data for cervical and breast cancers among Chinese women aged 20-84 years were obtained from China's National Disease Surveillance Points system spanning the years 2009 to 2021. Negative binomial regression models were utilized to assess urban-rural differences in mortality rate ratios, while Joinpoint models with estimated average annual percent changes (AAPC) and slopes were employed to compare temporal trends and the acceleration of mortality rates within different age groups.</p><p><strong>Results: </strong>From 2009 to 2021, there was a relative increase in age-specific mortality associated with the two cancers observed in rural areas compared with urban areas. A rising trend in the screening age of 35-64 [AAPC: 4.0%, 95% confidence interval (CI) 0.5-7.6%, P = 0.026] for cervical cancer was noted in rural areas, while a stable trend (AAPC: - 0.7%, 95% CI - 5.8 to 4.6%, P = 0.78) was observed in urban areas. As for breast cancer, a stable trend (AAPC: 0.3%, 95% CI - 0.3 to 0.9%, P = 0.28) was observed in rural areas compared to a decreasing trend (AAPC: - 2.7%, 95% CI - 4.6 to - 0.7%, P = 0.007) in urban areas. Urban-rural differences in mortality rates increased over time for cervical cancer but decreased for breast cancer. Mortality trends for both cervical and breast cancers showed an increase with age across 4 segments, with the most significant surge in mortality observed among the 35-54 age group across urban and rural areas, periods, and regions in China.</p><p><strong>Conclusions: </strong>Special attention should be given to women aged 35-54 years due to mortality trends and rural-urban disparities. Focusing on vulnerable age groups and addressing rural-urban differences in the delivery of cancer control programs can enhance resource efficiency and promote health equity.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"55"},"PeriodicalIF":16.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Congenital hydrocephalus: a review of recent advances in genetic etiology and molecular mechanisms","authors":"Xiu-Yun Liu, Xin Song, Marek Czosnyka, Chiara Robba, Zofia Czosnyka, Jennifer Lee Summers, Hui-Jie Yu, Guo-Yi Gao, Peter Smielewski, Fang Guo, Mei-Jun Pang, Dong Ming","doi":"10.1186/s40779-024-00560-5","DOIUrl":"https://doi.org/10.1186/s40779-024-00560-5","url":null,"abstract":"The global prevalence rate for congenital hydrocephalus (CH) is approximately one out of every five hundred births with multifaceted predisposing factors at play. Genetic influences stand as a major contributor to CH pathogenesis, and epidemiological evidence suggests their involvement in up to 40% of all cases observed globally. Knowledge about an individual’s genetic susceptibility can significantly improve prognostic precision while aiding clinical decision-making processes. However, the precise genetic etiology has only been pinpointed in fewer than 5% of human instances. More occurrences of CH cases are required for comprehensive gene sequencing aimed at uncovering additional potential genetic loci. A deeper comprehension of its underlying genetics may offer invaluable insights into the molecular and cellular basis of this brain disorder. This review provides a summary of pertinent genes identified through gene sequencing technologies in humans, in addition to the 4 genes currently associated with CH (two X-linked genes L1CAM and AP1S2, two autosomal recessive MPDZ and CCDC88C). Others predominantly participate in aqueduct abnormalities, ciliary movement, and nervous system development. The prospective CH-related genes revealed through animal model gene-editing techniques are further outlined, focusing mainly on 4 pathways, namely cilia synthesis and movement, ion channels and transportation, Reissner’s fiber (RF) synthesis, cell apoptosis, and neurogenesis. Notably, the proper functioning of motile cilia provides significant impulsion for cerebrospinal fluid (CSF) circulation within the brain ventricles while mutations in cilia-related genes constitute a primary cause underlying this condition. So far, only a limited number of CH-associated genes have been identified in humans. The integration of genotype and phenotype for disease diagnosis represents a new trend in the medical field. Animal models provide insights into the pathogenesis of CH and contribute to our understanding of its association with related complications, such as renal cysts, scoliosis, and cardiomyopathy, as these genes may also play a role in the development of these diseases. Genes discovered in animals present potential targets for new treatments but require further validation through future human studies.","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"41 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141947241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in the mechanism of small nucleolar RNA and its role in DNA damage response.","authors":"Li-Ping Shen, Wen-Cheng Zhang, Jia-Rong Deng, Zhen-Hua Qi, Zhong-Wu Lin, Zhi-Dong Wang","doi":"10.1186/s40779-024-00553-4","DOIUrl":"10.1186/s40779-024-00553-4","url":null,"abstract":"<p><p>Small nucleolar RNAs (snoRNAs) were previously regarded as a class of functionally conserved housekeeping genes, primarily involved in the regulation of ribosome biogenesis by ribosomal RNA (rRNA) modification. However, some of them are involved in several biological processes via complex molecular mechanisms. DNA damage response (DDR) is a conserved mechanism for maintaining genomic stability to prevent the occurrence of various human diseases. It has recently been revealed that snoRNAs are involved in DDR at multiple levels, indicating their relevant theoretical and clinical significance in this field. The present review systematically addresses four main points, including the biosynthesis and classification of snoRNAs, the mechanisms through which snoRNAs regulate target molecules, snoRNAs in the process of DDR, and the significance of snoRNA in disease diagnosis and treatment. It focuses on the potential functions of snoRNAs in DDR to help in the discovery of the roles of snoRNAs in maintaining genome stability and pathological processes.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"53"},"PeriodicalIF":16.7,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11308251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guidance of development, validation, and evaluation of algorithms for populating health status in observational studies of routinely collected data (DEVELOP-RCD).","authors":"Wen Wang, Ying-Hui Jin, Mei Liu, Qiao He, Jia-Yue Xu, Ming-Qi Wang, Guo-Wei Li, Bo Fu, Si-Yu Yan, Kang Zou, Xin Sun","doi":"10.1186/s40779-024-00559-y","DOIUrl":"10.1186/s40779-024-00559-y","url":null,"abstract":"<p><strong>Background: </strong>In recent years, there has been a growing trend in the utilization of observational studies that make use of routinely collected healthcare data (RCD). These studies rely on algorithms to identify specific health conditions (e.g. diabetes or sepsis) for statistical analyses. However, there has been substantial variation in the algorithm development and validation, leading to frequently suboptimal performance and posing a significant threat to the validity of study findings. Unfortunately, these issues are often overlooked.</p><p><strong>Methods: </strong>We systematically developed guidance for the development, validation, and evaluation of algorithms designed to identify health status (DEVELOP-RCD). Our initial efforts involved conducting both a narrative review and a systematic review of published studies on the concepts and methodological issues related to algorithm development, validation, and evaluation. Subsequently, we conducted an empirical study on an algorithm for identifying sepsis. Based on these findings, we formulated specific workflow and recommendations for algorithm development, validation, and evaluation within the guidance. Finally, the guidance underwent independent review by a panel of 20 external experts who then convened a consensus meeting to finalize it.</p><p><strong>Results: </strong>A standardized workflow for algorithm development, validation, and evaluation was established. Guided by specific health status considerations, the workflow comprises four integrated steps: assessing an existing algorithm's suitability for the target health status; developing a new algorithm using recommended methods; validating the algorithm using prescribed performance measures; and evaluating the impact of the algorithm on study results. Additionally, 13 good practice recommendations were formulated with detailed explanations. Furthermore, a practical study on sepsis identification was included to demonstrate the application of this guidance.</p><p><strong>Conclusions: </strong>The establishment of guidance is intended to aid researchers and clinicians in the appropriate and accurate development and application of algorithms for identifying health status from RCD. This guidance has the potential to enhance the credibility of findings from observational studies involving RCD.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"52"},"PeriodicalIF":16.7,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Poor sleep and decreased cortical thickness in veterans with mild traumatic brain injury and post-traumatic stress disorder.","authors":"Murray J Andrews, David H Salat, William P Milberg, Regina E McGlinchey, Catherine B Fortier","doi":"10.1186/s40779-024-00557-0","DOIUrl":"10.1186/s40779-024-00557-0","url":null,"abstract":"<p><strong>Background: </strong>Poor sleep quality has been associated with changes in brain volume among veterans, particularly those who have experienced mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). This study sought to investigate (1) whether poor sleep quality is associated with decreased cortical thickness in Iraq and Afghanistan war veterans, and (2) whether these associations differ topographically depending on the presence or absence of mTBI and PTSD.</p><p><strong>Methods: </strong>A sample of 440 post-9/11 era U.S. veterans enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders study at VA Boston, MA from 2010 to 2022 was included in the study. We examined the relationship between sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI), and cortical thickness in veterans with mTBI (n = 57), PTSD (n = 110), comorbid mTBI and PTSD (n = 129), and neither PTSD nor mTBI (n = 144). To determine the topographical relationship between subjective sleep quality and cortical thickness in each diagnostic group, we employed a General Linear Model (GLM) at each vertex on the cortical mantle. The extent of topographical overlap between the resulting statistical maps was assessed using Dice coefficients.</p><p><strong>Results: </strong>There were no significant associations between PSQI and cortical thickness in the group without PTSD or mTBI (n = 144) or in the PTSD-only group (n = 110). In the mTBI-only group (n = 57), lower sleep quality was significantly associated with reduced thickness bilaterally in frontal, cingulate, and precuneus regions, as well as in the right parietal and temporal regions (β = -0.0137, P < 0.0005). In the comorbid mTBI and PTSD group (n = 129), significant associations were observed bilaterally in frontal, precentral, and precuneus regions, in the left cingulate and the right parietal regions (β = -0.0094, P < 0.0005). Interaction analysis revealed that there was a stronger relationship between poor sleep quality and decreased cortical thickness in individuals with mTBI (n = 186) compared to those without mTBI (n = 254) specifically in the frontal and cingulate regions (β = -0.0077, P < 0.0005).</p><p><strong>Conclusions: </strong>This study demonstrates a significant relationship between poor sleep quality and lower cortical thickness primarily within frontal regions among individuals with both isolated mTBI or comorbid diagnoses of mTBI and PTSD. Thus, if directionality is established in longitudinal and interventional studies, it may be crucial to consider addressing sleep in the treatment of veterans who have sustained mTBI.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"51"},"PeriodicalIF":16.7,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing adherence for total body skin examination in post-surgical veterans: an interventional study at an urban Veterans Affairs center.","authors":"Vignesh Ramachandran, Efe Kakpovbia, Michelle C Juarez, Neil Jairath, Andjela Nemcevic, Christine C Akoh, Ian M Ahearn, Ian W Tattersall, Nayoung Lee, Jo-Ann M Latkowski, John G Zampella","doi":"10.1186/s40779-024-00552-5","DOIUrl":"10.1186/s40779-024-00552-5","url":null,"abstract":"","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"50"},"PeriodicalIF":16.7,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippocampal PACAP signaling activation triggers a rapid antidepressant response.","authors":"Hai-Lou Zhang, Yan Sun, Zhang-Jie Wu, Ying Yin, Rui-Yi Liu, Ji-Chun Zhang, Zhang-Jin Zhang, Suk-Yu Yau, Hao-Xin Wu, Ti-Fei Yuan, Li Zhang, Miroslav Adzic, Gang Chen","doi":"10.1186/s40779-024-00548-1","DOIUrl":"10.1186/s40779-024-00548-1","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The development of ketamine-like rapid antidepressants holds promise for enhancing the therapeutic efficacy of depression, but the underlying cellular and molecular mechanisms remain unclear. Implicated in depression regulation, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is investigated here to examine its role in mediating the rapid antidepressant response.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The onset of antidepressant response was assessed through depression-related behavioral paradigms. The signaling mechanism of PACAP in the hippocampal dentate gyrus (DG) was evaluated by utilizing site-directed gene knockdown, pharmacological interventions, or optogenetic manipulations. Overall, 446 mice were used for behavioral and molecular signaling testing. Mice were divided into control or experimental groups randomly in each experiment, and the experimental manipulations included: chronic paroxetine treatments (4, 9, 14 d) or a single treatment of ketamine; social defeat or lipopolysaccharides-injection induced depression models; different doses of PACAP (0.4, 2, 4 ng/site; microinjected into the hippocampal DG); pharmacological intra-DG interventions (CALM and PACAP6-38); intra-DG viral-mediated PACAP RNAi; and opotogenetics using channelrhodopsins 2 (ChR2) or endoplasmic natronomonas halorhodopsine 3.0 (eNpHR3.0). Behavioral paradigms included novelty suppressed feeding test, tail suspension test, forced swimming test, and sucrose preference test. Western blotting, ELISA, or quantitative real-time PCR (RT-PCR) analysis were used to detect the expressions of proteins/peptides or genes in the hippocampus.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Chronic administration of the slow-onset antidepressant paroxetine resulted in an increase in hippocampal PACAP expression, and intra-DG blockade of PACAP attenuated the onset of the antidepressant response. The levels of hippocampal PACAP expression were reduced in both two distinct depression animal models and intra-DG knockdown of PACAP induced depression-like behaviors. Conversely, a single infusion of PACAP into the DG region produced a rapid and sustained antidepressant response in both normal and chronically stressed mice. Optogenetic intra-DG excitation of PACAP-expressing neurons instantly elicited antidepressant responses, while optogenetic inhibition induced depression-like behaviors. The longer optogenetic excitation/inhibition elicited the more sustained antidepressant/depression-like responses. Intra-DG PACAP infusion immediately facilitated the signaling for rapid antidepressant response by inhibiting calcium/calmodulin-dependent protein kinase II (CaMKII)-eukaryotic elongation factor 2 (eEF2) and activating the mammalian target of rapamycin (mTOR). Pre-activation of CaMKII signaling within the DG blunted PACAP-induced rapid antidepressant response as well as eEF2-mTOR-brain-derived neurotrophic factor (BDNF) signaling. Finally, acute ketamine ","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"49"},"PeriodicalIF":16.7,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11265467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TGF-β1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson's disease models and patients.","authors":"Yi Zhuo, Wen-Shui Li, Wen Lu, Xuan Li, Li-Te Ge, Yan Huang, Qing-Tao Gao, Yu-Jia Deng, Xin-Chen Jiang, Zi-Wei Lan, Que Deng, Yong-Heng Chen, Yi Xiao, Shuo Lu, Feng Jiang, Zuo Liu, Li Hu, Yu Liu, Yu Ding, Zheng-Wen He, De-An Tan, Da Duan, Ming Lu","doi":"10.1186/s40779-024-00550-7","DOIUrl":"10.1186/s40779-024-00550-7","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients.</p><p><strong>Results: </strong>A functional assay identified that transforming growth factor-β1 (TGF-β1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-β1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD.</p><p><strong>Conclusions: </strong>These findings provide compelling evidence for the involvement of TGF-β1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-β1 may be used alone or combined with hOM-MSCs therapy for treating PD.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"48"},"PeriodicalIF":16.7,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11265117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial complex I: the key to sustained microglia activation and neuroinflammation maintenance.","authors":"Hua Wang, Sheng-Yuan Yu, Sofus Nielsen, Xing Wang, Wei-Wei Zhao","doi":"10.1186/s40779-024-00554-3","DOIUrl":"10.1186/s40779-024-00554-3","url":null,"abstract":"","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"47"},"PeriodicalIF":16.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11264769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}