Military Medical Research最新文献

{"title":"Endophilin A2 controls touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking","authors":"Man-Xiu Xie, Ren-Chun Lai, Yi-Bin Xiao, Xi Zhang, Xian-Ying Cao, Xiao-Yu Tian, An-Nan Chen, Zi-Yi Chen, Yan Cao, Xiao Li, Xiao-Long Zhang","doi":"10.1186/s40779-024-00520-z","DOIUrl":"https://doi.org/10.1186/s40779-024-00520-z","url":null,"abstract":"Tactile and mechanical pain are crucial to our interaction with the environment, yet the underpinning molecular mechanism is still elusive. Endophilin A2 (EndoA2) is an evolutionarily conserved protein that is documented in the endocytosis pathway. However, the role of EndoA2 in the regulation of mechanical sensitivity and its underlying mechanisms are currently unclear. Male and female C57BL/6 mice (8–12 weeks) and male cynomolgus monkeys (7–10 years old) were used in our experiments. Nerve injury-, inflammatory-, and chemotherapy-induced pathological pain models were established for this study. Behavioral tests of touch, mechanical pain, heat pain, and cold pain were performed in mice and nonhuman primates. Western blotting, immunostaining, co-immunoprecipitation, proximity ligation and patch-clamp recordings were performed to gain insight into the mechanisms. The results showed that EndoA2 was primarily distributed in neurofilament-200-positive (NF200+) medium-to-large diameter dorsal root ganglion (DRG) neurons of mice and humans. Loss of EndoA2 in mouse NF200+ DRG neurons selectively impaired the tactile and mechanical allodynia. Furthermore, EndoA2 interacted with the mechanically sensitive ion channel Piezo2 and promoted the membrane trafficking of Piezo2 in DRG neurons. Moreover, as an adaptor protein, EndoA2 also bound to kinesin family member 5B (KIF5B), which was involved in the EndoA2-mediated membrane trafficking process of Piezo2. Loss of EndoA2 in mouse DRG neurons damaged Piezo2-mediated rapidly adapting mechanically activated currents, and re-expression of EndoA2 rescued the MA currents. In addition, interference with EndoA2 also suppressed touch sensitivity and mechanical hypersensitivity in nonhuman primates. Our data reveal that the KIF5B/EndoA2/Piezo2 complex is essential for Piezo2 trafficking and for sustaining transmission of touch and mechanical hypersensitivity signals. EndoA2 regulates touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking in sensory neurons. Our findings identify a potential new target for the treatment of mechanical pain.","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"115 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140106874","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":"Targeting vulnerable microcircuits in the ventral hippocampus of male transgenic mice to rescue Alzheimer-like social memory loss.","authors":"Hui-Yang Lei, Gui-Lin Pi, Ting He, Rui Xiong, Jing-Ru Lv, Jia-Le Liu, Dong-Qin Wu, Meng-Zhu Li, Kun Shi, Shi-Hong Li, Na-Na Yu, Yang Gao, Hui-Ling Yu, Lin-Yu Wei, Xin Wang, Qiu-Zhi Zhou, Pei-Lin Zou, Jia-Yang Zhou, Ying-Zhou Liu, Nai-Ting Shen, Jie Yang, Dan Ke, Qun Wang, Gong-Ping Liu, Xi-Fei Yang, Jian-Zhi Wang, Ying Yang","doi":"10.1186/s40779-024-00512-z","DOIUrl":"10.1186/s40779-024-00512-z","url":null,"abstract":"<p><strong>Background: </strong>Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease (AD), which is closely related to tau pathology and hippocampal impairment. Due to the heterogeneity of brain neurons, the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear. Therefore, further investigation is necessary.</p><p><strong>Methods: </strong>We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis, social behavioural tests, hippocampal electrophysiology, immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine the effects of these agents on social memory in mice.</p><p><strong>Results: </strong>The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, vCA1, especially its excitatory and parvalbumin (PV) neurons, were fully filled with mislocated and phosphorylated tau (p-Tau). This finding was not observed for dorsal hippocampal CA1 (dCA1). The overexpression of human tau (hTau) in excitatory and PV neurons mimicked AD-like tau accumulation, significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory. Notably, 1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB (TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory.</p><p><strong>Conclusion: </strong>This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"16"},"PeriodicalIF":21.1,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10926584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140094306","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":"Emerging roles of ADP-dependent glucokinase in prostate cancer.","authors":"Xu Zhang","doi":"10.1186/s40779-024-00518-7","DOIUrl":"10.1186/s40779-024-00518-7","url":null,"abstract":"","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"15"},"PeriodicalIF":21.1,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10898003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139972636","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":"CT whole lung radiomic nomogram: a potential biomarker for lung function evaluation and identification of COPD.","authors":"Tao-Hu Zhou, Xiu-Xiu Zhou, Jiong Ni, Yan-Qing Ma, Fang-Yi Xu, Bing Fan, Yu Guan, Xin-Ang Jiang, Xiao-Qing Lin, Jie Li, Yi Xia, Xiang Wang, Yun Wang, Wen-Jun Huang, Wen-Ting Tu, Peng Dong, Zhao-Bin Li, Shi-Yuan Liu, Li Fan","doi":"10.1186/s40779-024-00516-9","DOIUrl":"10.1186/s40779-024-00516-9","url":null,"abstract":"<p><strong>Background: </strong>Computed tomography (CT) plays a great role in characterizing and quantifying changes in lung structure and function of chronic obstructive pulmonary disease (COPD). This study aimed to explore the performance of CT-based whole lung radiomic in discriminating COPD patients and non-COPD patients.</p><p><strong>Methods: </strong>This retrospective study was performed on 2785 patients who underwent pulmonary function examination in 5 hospitals and were divided into non-COPD group and COPD group. The radiomic features of the whole lung volume were extracted. Least absolute shrinkage and selection operator (LASSO) logistic regression was applied for feature selection and radiomic signature construction. A radiomic nomogram was established by combining the radiomic score and clinical factors. Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) were used to evaluate the predictive performance of the radiomic nomogram in the training, internal validation, and independent external validation cohorts.</p><p><strong>Results: </strong>Eighteen radiomic features were collected from the whole lung volume to construct a radiomic model. The area under the curve (AUC) of the radiomic model in the training, internal, and independent external validation cohorts were 0.888 [95% confidence interval (CI) 0.869-0.906], 0.874 (95%CI 0.844-0.904) and 0.846 (95%CI 0.822-0.870), respectively. All were higher than the clinical model (AUC were 0.732, 0.714, and 0.777, respectively, P < 0.001). DCA demonstrated that the nomogram constructed by combining radiomic score, age, sex, height, and smoking status was superior to the clinical factor model.</p><p><strong>Conclusions: </strong>The intuitive nomogram constructed by CT-based whole-lung radiomic has shown good performance and high accuracy in identifying COPD in this multicenter study.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"14"},"PeriodicalIF":21.1,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10877876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139906019","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":"Biomaterial-based mechanical regulation facilitates scarless wound healing with functional skin appendage regeneration.","authors":"Ying-Ying Li, Shuai-Fei Ji, Xiao-Bing Fu, Yu-Feng Jiang, Xiao-Yan Sun","doi":"10.1186/s40779-024-00519-6","DOIUrl":"10.1186/s40779-024-00519-6","url":null,"abstract":"<p><p>Scar formation resulting from burns or severe trauma can significantly compromise the structural integrity of skin and lead to permanent loss of skin appendages, ultimately impairing its normal physiological function. Accumulating evidence underscores the potential of targeted modulation of mechanical cues to enhance skin regeneration, promoting scarless repair by influencing the extracellular microenvironment and driving the phenotypic transitions. The field of skin repair and skin appendage regeneration has witnessed remarkable advancements in the utilization of biomaterials with distinct physical properties. However, a comprehensive understanding of the underlying mechanisms remains somewhat elusive, limiting the broader application of these innovations. In this review, we present two promising biomaterial-based mechanical approaches aimed at bolstering the regenerative capacity of compromised skin. The first approach involves leveraging biomaterials with specific biophysical properties to create an optimal scarless environment that supports cellular activities essential for regeneration. The second approach centers on harnessing mechanical forces exerted by biomaterials to enhance cellular plasticity, facilitating efficient cellular reprogramming and, consequently, promoting the regeneration of skin appendages. In summary, the manipulation of mechanical cues using biomaterial-based strategies holds significant promise as a supplementary approach for achieving scarless wound healing, coupled with the restoration of multiple skin appendage functions.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"13"},"PeriodicalIF":21.1,"publicationDate":"2024-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10874556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139900137","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":"ADP-dependent glucokinase: the ancient, archaeal key to prostate cancer.","authors":"Marcin M Kamiński","doi":"10.1186/s40779-024-00514-x","DOIUrl":"10.1186/s40779-024-00514-x","url":null,"abstract":"","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"10"},"PeriodicalIF":21.1,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10860298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139717730","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":"Deciphering the molecular interplay and tumorigenesis in hepatocellular carcinoma through insights into FBXL6 and KRAS^G12D.","authors":"Qiang Cai, Quazi T H Shubhra","doi":"10.1186/s40779-024-00515-w","DOIUrl":"10.1186/s40779-024-00515-w","url":null,"abstract":"","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"9"},"PeriodicalIF":21.1,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10851466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139702897","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":"In situ genetic engineering of host T-cells based on acellular scaffold strategy: a big but also small step for solid tumor immunotherapy","authors":"Shu-Yan Han, Zi-Xuan Zhao, Jun Wu","doi":"10.1186/s40779-024-00517-8","DOIUrl":"https://doi.org/10.1186/s40779-024-00517-8","url":null,"abstract":"&lt;p&gt;The advent of targeted T-cell therapy, with chimeric antigen receptor (CAR) T-cell therapy as the most prominent example, has yielded significant clinical efficacy for both relapsed and refractory hematological malignancies. However, this form of T-cell immunotherapy is often accompanied by severe systemic toxicities, suboptimal response rates, and host immune rejection in clinical settings, which detracts from its therapeutic utility. Additional concerns, such as the time-intensive ex vivo manufacturing process and the substantial treatment costs, also require resolution. Beyond these limitations, the use of CAR T-cell therapy against solid tumors presents an ongoing and formidable challenge. The extensive heterogeneity and complex spatial organization of solid tumors, along with their associated microenvironments, have impeded the broader clinical adoption of T-cell-based tumor immunotherapies [1, 2].&lt;/p&gt;&lt;p&gt;In the work of Dandia et al. [3], a novel strategy was reported that utilizes an acellular three-dimensional scaffold-based localized approach to program host T cells in situ, thus addressing several major challenges faced by traditional T-cell therapies and offering new hope for the elimination of solid tumors. The polyethylene glycol (PEG) scaffolds, conjugated with poly-L-lysine (PLL) and loaded with ovalbumin (OVA)-specific T-cell receptors (TCRs) lentiviruses (LVs), were implanted in B16-OVA melanoma-bearing mice and demonstrated significant anti-solid tumor efficacy. These bioactive scaffolds effectively recruited host T cells to the tumor site, transduced them with OVA-specific TCRs, and enabled them to home to tumors and draining lymph nodes. This facilitated in vivo T-cell genetic engineering and solid tumor immunotherapy. On one hand, this approach circumvented the need for in vitro manipulation and large-scale expansion of allogeneic T cells by directly utilizing host cells, thereby reducing the common risks associated with traditional adoptive cell therapies. On the other hand, unlike systemic delivery, the scaffold-based in situ localized administration minimized the incidence of “on-target, off-tumor” effects and enhanced the efficiency of regional immunomodulation, making it particularly effective at overcoming immunosuppression within solid tumors.&lt;/p&gt;&lt;p&gt;As is widely recognized, the ultimate goal of preclinical research is to facilitate successful clinical translation into practical medicine. The unquestionable benefits of this novel in situ immunomodulation strategy include its streamlined one-step, one-day process, as well as its high-efficiency targeting and programming of solid tumors, which engender considerable optimism for the immunotherapy of solid tumors with its ease of operation, reduced cost, and exceptional efficacy. However, the promising results of the current proof-of-concept study represent merely the beginning, and numerous considerations must be addressed before this approach can be applied clinically.&lt;/","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"300 2 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139668057","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":"Alleviating mitochondrial dysfunction in diabetic cardiomyopathy through the Adipsin and Irak2 pathways","authors":"Mabel L. Cummins, Grace Delmonte, Skylar Wechsler, Joseph J. Schlesinger","doi":"10.1186/s40779-024-00513-y","DOIUrl":"https://doi.org/10.1186/s40779-024-00513-y","url":null,"abstract":"&lt;p&gt;Diabetic cardiomyopathy (DCM) is a major cause of heart failure in diabetic patients. It progresses asymptomatically prior to the onset of severe cardiac symptoms [1]; therefore, elucidating the underlying mechanisms of DCM is critical to providing early treatment options. This commentary elaborates on the findings of Jiang et al. [2], who investigated the role of adipokine hormone, Adipsin, as a cardioprotective factor in DCM. We provide an exposition and alternative treatment considerations, like Fisetin, and discuss the potential of investigating other cellular targets implicated in cardiac dysfunction, like the interleukin-1 receptor-associated kinase-like 2 (Irak2) protein [3] and protein kinase R [4].&lt;/p&gt;&lt;p&gt;Elevated circulation of fatty acids (FAs) in diabetes leads to their ectopic accumulation in other organs, like the heart. This accumulation causes lipotoxicity, exacerbates oxidative stress and leads to cell and organ dysfunction [1]. When the excess utilization and uptake of lipids exceeds the adaptation of the heart, myocardial contractile function decreases, leading to heart failure. A treatment to reverse myocardial lipotoxicity and treat damaged mitochondrial tissue is currently unknown [5]. However, Adipsin (an adipokine implicated in poor cardiovascular function resulting from diabetes mellitus) may regulate myocardial metabolism and function.&lt;/p&gt;&lt;p&gt;Jiang et al. [2] measured cardiac function, lipid accumulation, and FAs oxidation in myocardial cells treated with Adipsin overexpression or &lt;i&gt;Irak2&lt;/i&gt; knockdown (a protein downstream of Adipsin). Adipsin is a metabolic hormone used to control metabolism and fat homeostasis [1]. Overall, they found significant improvement in myocardial function, FAs oxidation, and electron transport chain activity, and decreased lipid accumulation in these cells, suggesting that Adipsin and Irak2 may be used to treat damaged mitochondrial tissue and alleviate myocardial lipotoxicity in patients with DCM. This research illuminates a novel mechanism of Adipsin alteration in DCM, revealing a potential method to reduce mitochondrial dysfunction.&lt;/p&gt;&lt;p&gt;First, Jiang et al. [2] established how Adipsin induces myocardial protection through interactions with the Irak2 protein in cardiomyocytes. In the mouse model, they found that Adipsin overexpression inhibited Irak2 translocation to the mitochondria, which increased prohibitin (Phb) and optic atrophy protein 1 (Opa1) levels, improving mitochondrial structure and mitochondrial electron transport chain activity. Jiang et al. [2] also induced DCM through a high-fat diet, which mimics only the early stages of diabetes, as the animals do not develop β-cell failure [6]. The combination of streptozotocin and a high-fat diet induces the onset and development into later stages of diabetes, including the organ damage observed in DCM [7]. To account for the pathology of DCM more thoroughly, we suggest that further work confirm the role of Adipsin through this meth","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"23 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139657633","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":"Nickel's carcinogenicity: the need of more studies to progress.","authors":"Consolato M Sergi","doi":"10.1186/s40779-024-00509-8","DOIUrl":"10.1186/s40779-024-00509-8","url":null,"abstract":"","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"8"},"PeriodicalIF":16.7,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10809529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139546850","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}