Military Medical Research最新文献

{"title":"Interleukin-1 receptor associated kinase 2 is a functional downstream regulator of complement factor D that controls mitochondrial fitness in diabetic cardiomyopathy","authors":"Stanislovas S. Jankauskas, Fahimeh Varzideh, Pasquale Mone, Urna Kansakar, Francesco Di Lorenzo, Angela Lombardi, Gaetano Santulli","doi":"10.1186/s40779-023-00506-3","DOIUrl":"https://doi.org/10.1186/s40779-023-00506-3","url":null,"abstract":"<p>Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes. The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown, but several factors have been implicated in the pathogenesis of the disease and its progression towards heart failure, including endothelial dysfunction, autonomic neuropathy, metabolic alterations, oxidative stress, and alterations in ion homeostasis, especially calcium transients [1]. In <i>Military Medical Research</i>, Jiang et al. [2] sought to determine the functional role of complement factor D (Adipsin) in the pathophysiology of diabetic cardiomyopathy.</p><p>Complement factor D is a protein secreted into the bloodstream mainly by adipocytes. It is also known as Adipsin, C3 pro-activator convertase, or properdin factor D esterase. The protein is a member of the trypsin family of serine proteases and has a high level of expression in fat, implying a functional role for adipose tissue in immune system biology. Complement factor D is involved in the alternative pathway of the complement system where it cleaves factor B1 [3].</p><p>HFD feeding is usually used to obtain animal models of type 2 diabetes mellitus (T2DM), because chronic HFD feeding is capable of inducing hyperglycemia, insulin resistance and glucose intolerance, and similar manifestations of T2DM. Animal models that can nicely recapitulate human T2DM are crucial to examine the pathogenesis and intervention strategies for diabetes and diabetic complications [4, 5].</p><p>In their experimental setting, Jiang et al. [2] observed that HFD feeding for 6 months induced a pronounced hyperglycemia as well as diastolic and systolic cardiac dysfunction. They detected reduced serum levels of complement factor D starting at the 2nd month of HFD feeding, which is consistent with previous observations showing that circulating levels of complement factor D decreased in obese patients [6]; such reduction may be due to high activity or resistance, albeit the exact causes are not fully known.</p><p>Mass spectrometry (MS) analysis was used to screen the potential proteins that directly interact with complement factor D in cardiomyocytes [2]. The top 5 proteins with high MS scores were interleukin-1 receptor-associated kinase like 2 (Irak2), hemoglobin subunit beta-1 (Hbb-b1), hemoglobin subunit alpha (Hb-α), myosin regulatory light chain 2 (Myl2), and myosin light chain 3 (Myl3). After reviewing the functions of these proteins, Jiang et al. [2] noticed that Irak2 is known to participate in the regulation of cardiomyocyte apoptosis in models of diabetic cardiomyopathy. Additionally, mitochondrial translocation of Irak2 regulates oxidative metabolism in adipocytes [7].</p><br/><p>Irak2 is one of the two putative serine/threonine kinases that are associated with the IL-1 receptor upon stimulation. It is involved in the IL-1 receptor/Toll-like receptor (TLR) signaling cascade and is known to act as an adaptor in the TLR-MyD88-TN","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"225 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139083862","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":"Disentangling the effects of PTSD from Gulf War Illness in male veterans via a systems-wide analysis of immune cell, cytokine, and symptom measures","authors":"Esha Sultana, Nandan Shastry, Rishabh Kasarla, Jacob Hardy, Fanny Collado, Kristina Aenlle, Maria Abreu, Emily Sisson, Kimberly Sullivan, Nancy Klimas, Travis J. A. Craddock","doi":"10.1186/s40779-023-00505-4","DOIUrl":"https://doi.org/10.1186/s40779-023-00505-4","url":null,"abstract":"One-third of veterans returning from the 1990–1991 Gulf War reported a myriad of symptoms including cognitive dysfunction, skin rashes, musculoskeletal discomfort, and fatigue. This symptom cluster is now referred to as Gulf War Illness (GWI). As the underlying mechanisms of GWI have yet to be fully elucidated, diagnosis and treatment are based on symptomatic presentation. One confounding factor tied to the illness is the high presence of post-traumatic stress disorder (PTSD). Previous research efforts have demonstrated that both GWI and PTSD are associated with immunological dysfunction. As such, this research endeavor aimed to provide insight into the complex relationship between GWI symptoms, cytokine presence, and immune cell populations to pinpoint the impact of PTSD on these measures in GWI. Symptom measures were gathered through the Multidimensional fatigue inventory (MFI) and 36-item short form health survey (SF-36) scales and biological measures were obtained through cytokine & cytometry analysis. Subgrouping was conducted using Davidson Trauma Scale scores and the Structured Clinical Interview for Diagnostic and statistical manual of mental disorders (DSM)-5, into GWI with high probability of PTSD symptoms (GWIH) and GWI with low probability of PTSD symptoms (GWIL). Data was analyzed using Analysis of variance (ANOVA) statistical analysis along with correlation graph analysis. We mapped correlations between immune cells and cytokine signaling measures, hormones and GWI symptom measures to identify patterns in regulation between the GWIH, GWIL, and healthy control groups. GWI with comorbid PTSD symptoms resulted in poorer health outcomes compared with both Healthy control (HC) and the GWIL subgroup. Significant differences were found in basophil levels of GWI compared with HC at peak exercise regardless of PTSD symptom comorbidity (ANOVA F = 4.7, P = 0.01,) indicating its potential usage as a biomarker for general GWI from control. While the unique identification of GWI with PTSD symptoms was less clear, the GWIL subgroup was found to be delineated from both GWIH and HC on measures of IL-15 across an exercise challenge (ANOVA F > 3.75, P < 0.03). Additional differences in natural killer (NK) cell numbers and function highlight IL-15 as a potential biomarker of GWI in the absence of PTSD symptoms. We conclude that disentangling GWI and PTSD by defining trauma-based subgroups may aid in the identification of unique GWI biosignatures that can help to improve diagnosis and target treatment of GWI more effectively.","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"25 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139077474","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":"Elevated FBXL6 activates both wild-type KRAS and mutant KRASG12D and drives HCC tumorigenesis via the ERK/mTOR/PRELID2/ROS axis in mice","authors":"Hao-Jun Xiong, Hong-Qiang Yu, Jie Zhang, Lei Fang, Di Wu, Xiao-Tong Lin, Chuan-Ming Xie","doi":"10.1186/s40779-023-00501-8","DOIUrl":"https://doi.org/10.1186/s40779-023-00501-8","url":null,"abstract":"Kirsten rat sarcoma (KRAS) and mutant KRASG12D have been implicated in human cancers, but it remains unclear whether their activation requires ubiquitination. This study aimed to investigate whether and how F-box and leucine-rich repeat 6 (FBXL6) regulates KRAS and KRASG12D activity in hepatocellular carcinoma (HCC). We constructed transgenic mouse strains LC (LSL-Fbxl6KI/+;Alb-Cre, n = 13), KC (LSL-KrasG12D/+;Alb-Cre, n = 10) and KLC (LSL-KrasG12D/+;LSL-Fbxl6KI/+;Alb-Cre, n = 12) mice, and then monitored HCC for 320 d. Multiomics approaches and pharmacological inhibitors were used to determine oncogenic signaling in the context of elevated FBXL6 and KRAS activation. Co‑immunoprecipitation (Co-IP), Western blotting, ubiquitination assay and RAS activity detection assay were employed to investigate the underlying molecular mechanism by which FBXL6 activates KRAS. The pathological relevance of the FBXL6/KRAS/extracellular signal-regulated kinase (ERK)/mammalian target of rapamycin (mTOR)/proteins of relevant evolutionary and lymphoid interest domain 2 (PRELID2) axis was evaluated in 129 paired samples from HCC patients. FBXL6 is highly expressed in HCC as well as other human cancers (P < 0.001). Interestingly, FBXL6 drives HCC in transgenic mice. Mechanistically, elevated FBXL6 promotes the polyubiquitination of both wild-type KRAS and KRASG12D at lysine 128, leading to the activation of both KRAS and KRASG12D and promoting their binding to the serine/threonine-protein kinase RAF, which is followed by the activation of mitogen-activated protein kinase kinase (MEK)/ERK/mTOR signaling. The oncogenic activity of the MEK/ERK/mTOR axis relies on PRELID2, which induces reactive oxygen species (ROS) generation. Furthermore, hepatic FBXL6 upregulation facilitates KRASG12D to induce more severe hepatocarcinogenesis and lung metastasis via the MEK/ERK/mTOR/PRELID2/ROS axis. Dual inhibition of MEK and mTOR effectively suppresses tumor growth and metastasis in this subtype of cancer in vivo. In clinical samples, FBXL6 expression positively correlates with p-ERK (χ2 = 85.067, P < 0.001), p-mTOR (χ2 = 66.919, P < 0.001) and PRELID2 (χ2 = 20.891, P < 0.001). The Kaplan–Meier survival analyses suggested that HCC patients with high FBXL6/p-ERK levels predicted worse overall survival (log‑rank P < 0.001). FBXL6 activates KRAS or KRASG12D via ubiquitination at the site K128, leading to activation of the ERK/mTOR/PRELID2/ROS axis and tumorigenesis. Dual inhibition of MEK and mTOR effectively protects against FBXL6- and KRASG12D-induced tumorigenesis, providing a potential therapeutic strategy to treat this aggressive subtype of liver cancer.","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"7 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138820594","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":"Apoptosis-resistant megakaryocytes produce large and hyperreactive platelets in response to radiation injury","authors":"Chang-Hong Du, Yi-Ding Wu, Ke Yang, Wei-Nian Liao, Li Ran, Chao-Nan Liu, Shu-Zhen Zhang, Kuan Yu, Jun Chen, Yong Quan, Mo Chen, Ming-Qiang Shen, Hong Tang, Shi-Lei Chen, Song Wang, Jing-Hong Zhao, Tian-Min Cheng, Jun-Ping Wang","doi":"10.1186/s40779-023-00499-z","DOIUrl":"https://doi.org/10.1186/s40779-023-00499-z","url":null,"abstract":"The essential roles of platelets in thrombosis have been well recognized. Unexpectedly, thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of biological, physical and chemical origins, which could be suffered by military personnel and civilians during chemical, biological, radioactive, and nuclear events. Especially, thrombosis is considered a major cause of mortality from radiation injury-induced thrombocytopenia, while the underlying pathogenic mechanism remains elusive. A mouse model of radiation injury-induced thrombocytopenia was built by exposing mice to a sublethal dose of ionizing radiation (IR). The phenotypic and functional changes of platelets and megakaryocytes (MKs) were determined by a comprehensive set of in vitro and in vivo assays, including flow cytometry, flow chamber, histopathology, Western blotting, and chromatin immunoprecipitation, in combination with transcriptomic analysis. The molecular mechanism was investigated both in vitro and in vivo, and was consolidated using MK-specific knockout mice. The translational potential was evaluated using a human MK cell line and several pharmacological inhibitors. In contrast to primitive MKs, mature MKs (mMKs) are intrinsically programmed to be apoptosis-resistant through reprogramming the Bcl-xL-BAX/BAK axis. Interestingly, mMKs undergo minority mitochondrial outer membrane permeabilization (MOMP) post IR, resulting in the activation of the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway via the release of mitochondrial DNA. The subsequent interferon-β (IFN-β) response in mMKs upregulates a GTPase guanylate-binding protein 2 (GBP2) to produce large and hyperreactive platelets that favor thrombosis. Further, we unmask that autophagy restrains minority MOMP in mMKs post IR. Our study identifies that megakaryocytic mitochondria-cGAS/STING-IFN-β-GBP2 axis serves as a fundamental checkpoint that instructs the size and function of platelets upon radiation injury and can be harnessed to treat platelet pathologies.","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"1 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138745372","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":"The applied principles of EEG analysis methods in neuroscience and clinical neurology","authors":"Hao Zhang, Qing-Qi Zhou, He Chen, Xiao-Qing Hu, Wei-Guang Li, Yang Bai, Jun-Xia Han, Yao Wang, Zhen-Hu Liang, Dan Chen, Feng-Yu Cong, Jia-Qing Yan, Xiao-Li Li","doi":"10.1186/s40779-023-00502-7","DOIUrl":"https://doi.org/10.1186/s40779-023-00502-7","url":null,"abstract":"Electroencephalography (EEG) is a non-invasive measurement method for brain activity. Due to its safety, high resolution, and hypersensitivity to dynamic changes in brain neural signals, EEG has aroused much interest in scientific research and medical fields. This article reviews the types of EEG signals, multiple EEG signal analysis methods, and the application of relevant methods in the neuroscience field and for diagnosing neurological diseases. First, three types of EEG signals, including time-invariant EEG, accurate event-related EEG, and random event-related EEG, are introduced. Second, five main directions for the methods of EEG analysis, including power spectrum analysis, time–frequency analysis, connectivity analysis, source localization methods, and machine learning methods, are described in the main section, along with different sub-methods and effect evaluations for solving the same problem. Finally, the application scenarios of different EEG analysis methods are emphasized, and the advantages and disadvantages of similar methods are distinguished. This article is expected to assist researchers in selecting suitable EEG analysis methods based on their research objectives, provide references for subsequent research, and summarize current issues and prospects for the future.","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"30 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138745652","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":"Pre-hospital application of REBOA for life-threatening hemorrhage","authors":"Xiao-Mei Tian, Wei Hu, Feng-Yong Liu","doi":"10.1186/s40779-023-00504-5","DOIUrl":"https://doi.org/10.1186/s40779-023-00504-5","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Most battlefield casualties occur prior to the arrival of medical facilities. Uncontrollable hemorrhage accounts for more than 90% of those potentially survivable battlefield casualties [1]. In both military and civilian conditions, non-compressible torso hemorrhage always caused rapid exsanguination and high mortality rates before definitive treatment [2]. More than half of the deaths due to non-compressible torso hemorrhage occur before hospital care can be provided [2]. Therefore, early and rapid pre-hospital hemorrhage control is essential to reduce mortality.&lt;/p&gt;&lt;p&gt;Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a life-saving procedure for patients with non-compressible hemorrhage and severe hemorrhagic shock [3]. In addition to in-hospital REBOA, urgent REBOA can be rapidly completed in grim pre-hospital situations for patients [4]. Thus, pre-hospital REBOA application for the treatment of life-threatening hemorrhages has attracted increasing attention. In patients who receive timely pre-hospital REBOA treatment, the mortality can be reduced to less than 40% [5]. In this letter, we focus on the pre-hospital application of REBOA for managing life-threatening traumatic hemorrhages in both military and civilian settings.&lt;/p&gt;&lt;p&gt;REBOA was first introduced by the US Army in the Korean War to treat intraabdominal hemorrhages. With significant improvements in endovascular equipment and techniques, pre-hospital REBOA has attracted renewed clinical interest. Recently, the US Army reported the use of pre-hospital REBOA in treating modern combat casualties [6]. After pre-hospital REBOA treatment, the patients were finally hemodynamically stabilized and safely evacuated without any apparent complications. Furthermore, the Russian Army have also validated the effectiveness of pre-hospital REBOA on the battlefield [7]. When combined with other resuscitation strategies like blood transfusion, pre-hospital REBOA can further enhance survival rates. Therefore, it is evident that pre-hospital REBOA is an effective method for acute care of massive hemorrhage and can be safely performed in the battlefield setting as an emergency treatment option for individuals at risk of cardiovascular failure due to injuries sustained in combat situations. On the battlefield, frontline implementation of REBOA allows temporary hemorrhage control and facilitates timely evacuation to the hospital, thereby reducing mortality rate and improving overall treatment outcomes, simultaneously saving lives among military personnel. This technology is of great significance for military applications and may become an essential skill for military training programs and medical practices in the future.&lt;/p&gt;&lt;p&gt;In addition to the battlefield environment, pre-hospital REBOA is also suitable for trauma patients in civilian conditions. Uncontrolled hemorrhagic shock or cardiac arrest accounts for a significant percentage of trauma patients. Some of these pa","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"22 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138580886","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":"ADP-dependent glucokinase controls metabolic fitness in prostate cancer progression","authors":"Hang Xu, Yi-Fan Li, Xian-Yan-Ling Yi, Xiao-Nan Zheng, Yang Yang, Yan Wang, Da-Zhou Liao, Jia-Peng Zhang, Ping Tan, Xing-Yu Xiong, Xi Jin, Li-Na Gong, Shi Qiu, De-Hong Cao, Hong Li, Qiang Wei, Lu Yang, Jian-Zhong Ai","doi":"10.1186/s40779-023-00500-9","DOIUrl":"https://doi.org/10.1186/s40779-023-00500-9","url":null,"abstract":"Cell metabolism plays a pivotal role in tumor progression, and targeting cancer metabolism might effectively kill cancer cells. We aimed to investigate the role of hexokinases in prostate cancer (PCa) and identify a crucial target for PCa treatment. The Cancer Genome Atlas (TCGA) database, online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase (ADPGK) in PCa. The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo. Quantitative proteomics, metabolomics, and extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) tests were performed to evaluate the impact of ADPGK on PCa metabolism. The underlying mechanisms were explored through ADPGK overexpression and knockdown, co-immunoprecipitation (Co-IP), ECAR analysis and cell counting kit-8 (CCK-8) assays. ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival (OS) in prostate adenocarcinoma (PRAD). Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs. non-PCa tissues. High ADPGK expression indicates worse survival outcomes, and ADPGK serves as an independent factor of biochemical recurrence. In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration, and ADPGK inhibition suppressed malignant phenotypes. Metabolomics, proteomics, and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa. Mechanistically, ADPGK binds aldolase C (ALDOC) to promote glycolysis via AMP-activated protein kinase (AMPK) phosphorylation. ALDOC was positively correlated with ADPGK, and high ALDOC expression was associated with worse survival outcomes in PCa. In summary, ADPGK is a driving factor in PCa progression, and its high expression contributes to a poor prognosis in PCa patients. ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling, suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"9 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138576328","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 NR1D1 in organ injury: challenges and prospects","authors":"Zi-Yin Zhang-sun, Xue-Zeng Xu, Germaine Escames, Wang-Rui Lei, Lin Zhao, Ya-Zhe Zhou, Ye Tian, Ya-Nan Ren, Darío Acuña-Castroviejo, Yang Yang","doi":"10.1186/s40779-023-00495-3","DOIUrl":"https://doi.org/10.1186/s40779-023-00495-3","url":null,"abstract":"Nuclear receptor subfamily 1, group D, member 1 (NR1D1, also known as REV-ERBα) belongs to the nuclear receptor (NR) family, and is a heme-binding component of the circadian clock that consolidates circadian oscillators. In addition to repressing the transcription of multiple clock genes associated with circadian rhythms, NR1D1 has a wide range of downstream target genes that are intimately involved in many physiopathological processes, including autophagy, immunity, inflammation, metabolism and aging in multiple organs. This review focuses on the pivotal role of NR1D1 as a key transcription factor in the gene regulatory network, with particular emphasis on the milestones of the latest discoveries of NR1D1 ligands. NR1D1 is considered as a promising drug target for treating diverse diseases and may contribute to research on innovative biomarkers and therapeutic targets for organ injury-related diseases. Further research on NR1D1 ligands in prospective human trials may pave the way for their clinical application in many organ injury-related disorders.","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"29 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138567863","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":"Adipsin inhibits Irak2 mitochondrial translocation and improves fatty acid β-oxidation to alleviate diabetic cardiomyopathy","authors":"Meng-Yuan Jiang, Wan-Rong Man, Xue-Bin Zhang, Xiao-Hua Zhang, Yu Duan, Jie Lin, Yan Zhang, Yang Cao, De-Xi Wu, Xiao-Fei Shu, Lei Xin, Hao Wang, Xiao Zhang, Cong-Ye Li, Xiao-Ming Gu, Xuan Zhang, Dong-Dong Sun","doi":"10.1186/s40779-023-00493-5","DOIUrl":"https://doi.org/10.1186/s40779-023-00493-5","url":null,"abstract":"Diabetic cardiomyopathy (DCM) causes the myocardium to rely on fatty acid β-oxidation for energy. The accumulation of intracellular lipids and fatty acids in the myocardium usually results in lipotoxicity, which impairs myocardial function. Adipsin may play an important protective role in the pathogenesis of DCM. The aim of this study is to investigate the regulatory effect of Adipsin on DCM lipotoxicity and its molecular mechanism. A high-fat diet (HFD)-induced type 2 diabetes mellitus model was constructed in mice with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg). Liquid chromatography-tandem mass spectrometry (LC–MS/MS), glutathione-S-transferase (GST) pull-down technique, Co-immunoprecipitation (Co-IP) and immunofluorescence colocalization analyses were used to investigate the molecules which can directly interact with Adipsin. The immunocolloidal gold method was also used to detect the interaction between Adipsin and its downstream modulator. The expression of Adipsin was significantly downregulated in the HFD-induced DCM model (P < 0.05). Adipose tissue-specific overexpression of Adipsin significantly improved cardiac function and alleviated cardiac remodeling in DCM (P < 0.05). Adipsin overexpression also alleviated mitochondrial oxidative phosphorylation function in diabetic stress (P < 0.05). LC–MS/MS analysis, GST pull-down technique and Co-IP studies revealed that interleukin-1 receptor-associated kinase-like 2 (Irak2) was a downstream regulator of Adipsin. Immunofluorescence analysis also revealed that Adipsin was co-localized with Irak2 in cardiomyocytes. Immunocolloidal gold electron microscopy and Western blotting analysis indicated that Adipsin inhibited the mitochondrial translocation of Irak2 in DCM, thus dampening the interaction between Irak2 and prohibitin (Phb)-optic atrophy protein 1 (Opa1) on mitochondria and improving the structural integrity and function of mitochondria (P < 0.05). Interestingly, in the presence of Irak2 knockdown, Adipsin overexpression did not further alleviate myocardial mitochondrial destruction and cardiac dysfunction, suggesting a downstream role of Irak2 in Adipsin-induced responses (P < 0.05). Consistent with these findings, overexpression of Adipsin after Irak2 knockdown did not further reduce the accumulation of lipids and their metabolites in the cardiac myocardium, nor did it enhance the oxidation capacity of cardiomyocytes expose to palmitate (PA) (P < 0.05). These results indicated that Irak2 may be a downstream regulator of Adipsin. Adipsin improves fatty acid β-oxidation and alleviates mitochondrial injury in DCM. The mechanism is related to Irak2 interaction and inhibition of Irak2 mitochondrial translocation.","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"65 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138568341","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 the epigenome to reinvigorate T cells for cancer immunotherapy.","authors":"Dian Xiong, Lu Zhang, Zhi-Jun Sun","doi":"10.1186/s40779-023-00496-2","DOIUrl":"10.1186/s40779-023-00496-2","url":null,"abstract":"<p><p>Cancer immunotherapy using immune-checkpoint inhibitors (ICIs) has revolutionized the field of cancer treatment; however, ICI efficacy is constrained by progressive dysfunction of CD8⁺ tumor-infiltrating lymphocytes (TILs), which is termed T cell exhaustion. This process is driven by diverse extrinsic factors across heterogeneous tumor immune microenvironment (TIME). Simultaneously, tumorigenesis entails robust reshaping of the epigenetic landscape, potentially instigating T cell exhaustion. In this review, we summarize the epigenetic mechanisms governing tumor microenvironmental cues leading to T cell exhaustion, and discuss therapeutic potential of targeting epigenetic regulators for immunotherapies. Finally, we outline conceptual and technical advances in developing potential treatment paradigms involving immunostimulatory agents and epigenetic therapies.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"10 1","pages":"59"},"PeriodicalIF":21.1,"publicationDate":"2023-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10694991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138478136","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}