Decreased Left Ventricular Mass is Associated with Sarcopenia and its Severity in Elderly Inpatients.

Objective: Skeletal muscle mass and cardiac structure change with age. It is unclear whether the loss of skeletal muscle mass (SMM) is accompanied by a decrease in heart mass loss. The aim of this study is to investigate the relationship of left ventricular mass (LVM) with sarcopenia and its severity in elderly inpatients. Methods: Seventy-one sarcopenia subjects and 103 non-sarcopenia controls were enrolled in this study. Bioelectrical impedance analysis, handgrip strength, and 5-time chair stand test were used to evaluate SMM, muscle strength, and physical performance, respectively. Myocardial structure and function were assessed by echocardiography. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia criteria 2019. Results: Sarcopenic patients had smaller left ventricular sizes and LVM than non-sarcopenic controls. Severe sarcopenic patients had smaller left ventricular sizes and LVM than non-severe sarcopenic patients. In univariate regression analysis, body mass index (BMI), cardiac size, and LVM were positively correlated with SMM or SMI. In multivariate regression analysis, BMI and LVM were independently correlated with SMM and SMI. The combined measurement of LVM and BMI predicts sarcopenia with 66.0% sensitivity and 88.7% specificity (AUC: 0.825; 95% CI: (0.761, 0.889); p < 0.001). Conclusion: In hospitalized elderly patients, decreased left ventricular mass is associated with sarcopenia and its severity, and the combined measurement of LVM and BMI has a predictive value for sarcopenia.

[Methods for traditional Chinese medicine syndrome-based efficacy evaluation: a review].

Traditional Chinese medicine(TCM) syndrome-based efficacy is an evaluation index which is unique to TCM and can reflect the advantages of TCM. The development of the methods and measurement tools for evaluating TCM syndrome-based efficacy can provide objective and quantitative evidence for the clinical efficacy evaluation of TCM and the development of new Chinese medicine preparations, being the exploration direction of innovative methods and technologies for evaluating TCM efficacy. The conventional evaluation methods are subjective and limited to the mitigation of symptoms and the improvement of physical signs, which make it difficult to form a unified evaluation standard. In addition, the evaluation methods lack unity, objectivity, and quantitative research. The scientific connotation, evaluation ideas and methods, and key technologies of the evaluation for the therapeutic effect on syndromes remain unclear, which leads to diverse evaluation modes, methods, and indexes. The syndrome-based efficacy scale provides a new idea for the objective quantification and standardization of TCM syndromes. This review systematically summarizes the methods and problems, introduces the research progress in the evaluation scales, and puts forward some thoughts on the characteristics of TCM syndrome-based efficacy evaluation, aiming to provide insights for the research in this field.

Target genes regulated by CLEC16A intronic region associated with common variable immunodeficiency.

BACKGROUND: CLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID). OBJECTIVES: This study sought to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID. METHODS: The investigators performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-sequencing to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using circular chromosome conformation capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-sequencing and reverse phase protein array. RESULTS: This study showed that the CLEC16A locus is an enhancer regulating expression of multiple target genes including a distant gene ATF7IP2 through chromatin interactions. Distinct transcription factor complexes mediate the chromatin interactions in an allele-specific manner. Disruption of the CLEC16A locus affects the AKT signaling pathway, as well as the molecular response of CD4+ T cells to immune stimulation. CONCLUSIONS: Through multiomics and targeted experimental approaches, this study elucidated the underlying target genes and signaling pathways involved in the genetic association of CLEC16A with CVID, and highlighted plausible molecular targets for developing novel therapeutics.

Eupatilin inhibits pulmonary fibrosis by activating Sestrin2/PI3K/Akt/mTOR dependent autophagy pathway.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive chronic inflammatory disease with poor clinical outcomes and ineffective drug treatment options. Eupatilin is a major component extracted from the traditional herbal medicine Artemisia asiatica Nakai. Notably, it was demonstrated to have an anti-fibrosis effect in endometrial fibrosis, vocal fold, and hepatic fibrosis. Its role and mechanism in IPF remain unclear. METHODS: This study used the TGF-ß1-induced human embryonic lung fibroblasts (MRC-5) activation, IPF lung fibroblasts, and bleomycin-induced lung fibrosis mice model. Western blot, immunofluorescence staining, quantitative real time-PCR, hematoxylin and eosin staining, Masson's trichrome staining, and immunohistochemistry were used to evaluate the effects of eupatilin on fibroblast activation, pulmonary fibrosis, and autophagy. The autophagosomes were observed with a transmission electron microscope (TEM). RNA sequencing was used to determine the signaling pathway and key regulator related to autophagy. RESULTS: Eupatilin significantly decreased the expression of Col1A1, fibronectin, α-SMA, and SQSTM1/p62. In contrast, it increased the expression of LC3B II/I and the number of autophagosomes in TGF-ß1 treated MRC-5, IPF lung fibroblasts, and bleomycin-induced lung fibrosis mice model; it also alleviated bleomycin-induced lung fibrosis. The KEGG pathway mapping displayed that PI3K/Akt and Sestrin2 were associated with the enhanced fibrogenic process. Eupatilin suppressed the phosphorylation of PI3K/Akt/mTOR. Autophagy inhibitor 3-methyladenine (3-MA) and Akt activator SC-79 abrogated the anti-fibrotic effect of eupatilin. Sestrin2 expression was also downregulated in TGF-ß1 treated lung fibroblasts and lung tissues of the bleomycin-induced pulmonary fibrosis mice model. Furthermore, eupatilin promoted Sestrin2 expression, and the knockdown of Sestrin2 significantly aggravated the degree of fibrosis, increased the phosphorylation of PI3K/Akt/mTOR, and decreased autophagy. CONCLUSION: These findings indicate that eupatilin ameliorates pulmonary fibrosis through Sestrin2/PI3K/Akt/mTOR-dependent autophagy pathway.

Research Progress of Exosomal Non-Coding RNAs in Cardiac Remodeling.

Exosomes are vesicles with a size range of 50 to 200 nm and released by different cells, which are essential for the exchange of information between cells. They have attracted a lot of interest from medical researchers. Exosomal non-coding RNAs play an important part in pathological cardiac remodelings, such as cardiomyocyte hypertrophy, cardiomyocyte apoptosis, and cardiac fibrosis. This review summarizes the origins and functions of exosomes, the role of exosomal non-coding RNAs in the process of pathological cardiac remodeling, as well as their theoretical basis for clinical application.

Serum Sema7A is increased in patients with acute aortic dissection.

BACKGROUND: To observe the level of serum Sema7A in acute aortic dissection (AAD) and its diagnostic value for AAD. RESEARCH DESIGN AND METHODS: Patients with sudden chest pain including AAD, acute myocardial infarction (AMI) or pulmonary embolism (PE) were enrolled. Patients without chest pain or cardiovascular diseases were included as the controls. Serum Sema7A and plasma D-dimer were detected and compared in each group. RESULTS: 85 AAD patients, 55 AMI patients, 15 PE patients, and 30 controls were enrolled. The concentration of Serum Sema7A in the AAD group was significantly higher than that in the control, AMI and PE group. Serum Sema7A was positively correlated with D-dimer. In AAD patients who underwent invasive intervention therapy, serum Sema7A levels were significantly decreased after the intervention. Serum Sema7A was an independent risk factor for the presence of AAD. The areas under the ROC curve of Sema7A and D-dimer for differential diagnosis of AAD from other chest pain disorders were 0.842 (0.776, 0.909) and 0.788 (0.714, 0.862), respectively. CONCLUSIONS: Sema7A is highly expressed in patients with AAD. Sema7A might be a valuable biomarker for the early diagnosis of AAD and has the potential to differentiate AAD from AMI and PE.

[Network Meta-analysis of oral Chinese patent medicine in adjuvant treatment of rotavirus gastroenteritis in children].

This study aimed to evaluate the efficacy and safety of various oral Chinese patent medicines in the adjuvant treatment of rotavirus gastroenteritis(RVGE) in children based on network Meta-analysis. Randomized controlled trial(RCT) of oral Chinese patent medicine in the adjuvant treatment of RVGE in children was retrieved from the databases such as CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane Library, EMbase, and Web of Science from database inception to October 22, 2022. The quality of the included RCT was evaluated according to the Cochrane risk-of-bias tool, and the data were analyzed by RevMan 5.4 and Stata 16 software. Sixty-three RCTs were included, with 11 oral Chinese patent medicines involved, including Xingpi Yanger Granules, Weichang'an Pills, Qiuxieling Mixture, Erxieting Granules, and Changyanning Granules/Syrup. The results of the network Meta-analysis showed that in terms of clinical total effective rate, the top 3 optimal interventions were Changyanning Granules/Syrup, Xiaoer Guangpo Zhixie Oral Liquid, and Xiaoer Shuangjie Zhixie Granules combined with conventional western medicine. In terms of the anti-diarrheal time, the top 3 optimal interventions were Shenling Baizhu Granules, Qiuxieling Mixture, and Shuangling Zhixie Oral Liquid combined with conventional western medicine. In terms of the antiemetic time, the top 3 optimal interventions were Changyanning Granules/Syrup, Xingpi Yanger Granules, and Xiaoer Shuangjie Zhixie Granules combined with conventional western medicine. In terms of the antipyretic time, the top 3 optimal interventions were Shenling Baizhu Granules, Xiaoer Shuangjie Zhixie Granules, and Qiuxieling Mixture combined with conventional western medicine. In terms of the negative conversion rate of rotavirus, the top 3 optimal interventions were Xingpi Yanger Granules, Erxieting Granules, and Cangling Zhixie Oral Liquid combined with conventional western medicine. In terms of reducing creatine kinase isoenzyme MB(CK-MB) level, the top 3 optimal interventions were Weichang'an Pills, Xingpi Yanger Granules, and Xiaoer Shuangjie Zhixie Granules combined with conventional western medicine. In terms of adverse reactions, no se-rious adverse reactions were reported in all studies. Oral Chinese patent medicines in the adjuvant treatment of children with RVGE have their own advantages, Specifically, Changyanning Granules/Syrup + conventional western medicine focuses on improving the clinical total effective rate and shortening the antiemetic time, Shenling Baizhu Granules + conventional western medicine on shortening the anti-diarrheal time and antipyretic time, Xingpi Yanger Granules + conventional western medicine on improving the negative conversion rate of rotavirus, and Weichang'an Pills + conventional western medicine on reducing the CK-MB level. Limited by the quantity and quality of literature included in this study, the results need to be verified by high-quality RCT with a larger sample size.

Single-cell transcriptome analysis profiles cellular and molecular alterations in submandibular gland and blood in IgG4-related disease.

OBJECTIVES: The aim of this study is to profile the transcriptional landscapes of affected tissues and peripheral blood mononuclear cells (PBMCs) at the single-cell level in IgG4-related disease (IgG4-RD). Identifying the cell populations and crosstalk between immune cells and non-immune cells will assist us in understanding the aetiology of IgG4-RD. METHODS: We performed single-cell RNA sequencing analysis on submandibular glands (SMGs) and PBMCs from patients with IgG4-RD and matched controls. Additionally, bulk RNA sequencing of PBMCs was used to construct the immune repertoire. Furthermore, multiplex immunofluorescence staining was performed to validate the transcriptomic results. RESULTS: We identified three novel subsets of tissue-resident immune cells in the SMGs of patients with IgG4-RD. TOP2A_B cells and TOP2A_T cells had stemness signatures, and trajectory analysis showed that TOP2A_B cells may differentiate into IgG4+plasma cells and that TOP2A_T cells may differentiate into T follicular helper (Tfh) cells. ICOS_PD-1_B cells with Tfh-like characteristics appeared to be an intermediate state in the differentiation from B cells to IgG4+plasma cells. The cellular communication patterns within immune cells and between immune cells and non-immune cells were altered in IgG4-RD compared with controls. Consistently, infection-related pathways were shared in B cells and T cells from SMGs and PBMCs. Furthermore, immune clonotype analysis of PBMC samples showed the complementary determining region 3 amino acid CQQSYSTPYTF was expanded in patients with IgG4-RD. CONCLUSION: Our data revealed the cellular and molecular changes at the single-cell resolution of IgG4-RD and provide valuable insights into the aetiology and novel therapeutic targets of the autoimmune disease.

Integrated strategies for chemotherapy cycles in nasopharyngeal carcinoma patients: Real-world data from two epidemic centers guiding decision-making.

Objective: Two cycles of induction chemotherapy (IC) followed by 2 cycles of platinum-based concurrent chemoradiotherapy (CCRT) (2IC+2CCRT) for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is widely adopted but not evidence-confirmed. This study aimed to determine the clinical value of 2IC+2CCRT regarding efficacy, toxicity and cost-effectiveness. Methods: This real-world study from two epidemic centers used propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses. The enrolled patients were divided into three groups based on treatment modality: Group A (2IC+2CCRT), Group B (3IC+2CCRT or 2IC+3CCRT) and Group C (3IC+3CCRT). Long-term survival, acute toxicities and cost-effectiveness were compared among the groups. We developed a prognostic model dividing the population into high- and low-risk cohorts, and survivals including overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRRFS) were compared among the three groups according to certain risk stratifications. Results: Of 4,042 patients, 1,175 were enrolled, with 660, 419, and 96 included in Groups A, B and C, respectively. Five-year survivals were similar among the three groups after PSM and confirmed by IPTW. Grade 3-4 neutropenia and leukocytopenia were significantly higher in Groups C and B than in Group A (52.1% vs. 41.5% vs. 25.2%; 41.7% vs. 32.7% vs. 25.0%) as were grade 3-4 nausea/vomiting and oral mucositis (29.2% vs. 15.0% vs. 6.1%; 32.3% vs. 25.3% vs. 18.0%). Cost-effective analysis suggested that 2IC+2CCRT was the least expensive, while the health benefits were similar to those of the other groups. Further exploration showed that 2IC+2CCRT tended to be associated with a shorter PFS in high-risk patients, while 3IC+3CCRT potentially contributed to poor PFS in low-risk individuals, mainly reflected by LRRFS. Conclusions: In LA-NPC patients, 2IC+2CCRT was the optimal choice regarding efficacy, toxicity and cost-effectiveness; however, 2IC+2CCRT and 3IC+3CCRT probably shortened LRRFS in high- and low-risk populations, respectively.

P66Shc is increased in peripheral blood mononuclear cells of the patients with obstructive sleep apnea.

Objective: Obstructive sleep apnea (OSA) is characterized by nocturnal intermittent hypoxemia and linked to oxidative stress. Evidence demonstrated that p66Shc plays a key role in regulating oxidative stress. This study aimed to investigate the expression of p66Shc in peripheral blood mononuclear cells (PBMCs) of patients with OSA and the association with polysomnographic parameters. Methods: Fifty-four OSA subjects and 19 no OSA controls were enrolled in this study. All the subjects underwent standard polysomnography. P66Shc mRNA and protein levels in the PBMCs were detected by quantitative real-time polymerase chain reaction and western blotting. Plasma 3-nitrotyrosine (3-NT), oxidized low density lipoprotein (oxLDL), and advanced oxidation protein products (AOPP) were measured by ELISA method. Results: P66Shc mRNA and protein levels in PBMCs were significantly higher in OSA patients than in controls. P66Shc mRNA was positively correlated with plasma 3-NT, oxLDL, AOPP, hypopnea index (AHI), oxygen desaturation index (ODI), percentage of total sleep time with oxygen saturation (SaO2) below 90% (CT90), epworth sleepiness scale (ESS) and lymphocytes; negatively correlated with lowest SaO2 (LSaO2) and mean SaO2 (MSaO2). Further multivariate linear regression analysis showed that p66Shc mRNA levels were independently associated with AHI, MSaO2 and CT90. Conclusions: Oxidative stress regulator p66Shc may play a role in the pathophysiology of OSA and might serve as a potential biomarker for this disease.

Characteristics of the fecal microbiome and metabolome in older patients with heart failure and sarcopenia.

Background: Increasing evidence supports that gut microbiota plays an important role in the development of cardiovascular diseases. The prevalence of sarcopenia is increasing in patients with heart failure. Muscle wasting is an independent predictor of death in heart failure patients. Aims: In this study, we aimed to explore the characteristics of gut microbiota and metabolites in heart failure patients with or without sarcopenia. Methods: Fecal samples of 33 heart failure patients without sarcopenia, 29 heart failure patients with sarcopenia, and 15 controls were collected. The intestinal microbiota was analyzed using 16S rRNA sequencing and the metabolites were detected using the gas chromatography-mass spectrometry method. Results: There were significant differences in the overall microbial community structure and diversity between control and heart failure patients with or without sarcopenia. However, no clear clustering of samples was observed in heart failure with and without sarcopenia patients. Several bacterial, particularly Nocardiaceae, Pseudonocardiaceae, Alphaproteobacteria, and Slackia were significantly enriched in the heart failure patients without sarcopenia, while Synergistetes was more abundant in the heart failure patients with sarcopenia. Isobutyric acid, isovaleric acid, and valeric acid were lower in heart failure patients with sarcopenia than that without sarcopenia but lacked significance. Conclusions: This study demonstrates that there are differences in the gut microbiota between control individuals and heart failure patients with or without sarcopenia. Modulating the gut microbiota may be a new target for the prevention and treatment of sarcopenia in heart failure patients.

Aspirin alleviates pulmonary fibrosis through PI3K/AKT/mTOR-mediated autophagy pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible lung disease with limited therapeutic options. Aspirin can alleviate liver, kidney, and cardiac fibrosis. However, its role in lung fibrosis is unclear. This study aims to investigate the effects of aspirin on lung fibroblast differentiation and pulmonary fibrosis. TGF-ß1-induced human embryonic lung fibroblasts, IPF lung fibroblasts, and bleomycin-induced lung fibrosis mouse model were used in this study. The results showed that aspirin significantly decreased the expression of Collagen 1A1, Fibronectin, Alpha-smooth muscle actin, and equestosome1, and increased the ratio of light chain 3 beta II/I and the number of autophagosome in vivo and in vitro; reduced bleomycin-induced lung fibrosis. Aspirin also decreased the ratios of phosphorylated phosphatidylinositol 3 kinase (p-PI3K)/PI3K, protein kinase B (p-AKT)/AKT, and mechanistic target of rapamycin (p-mTOR)/mTOR in vitro. Autophagy inhibitor 3-methyladenine, bafilomycin-A1, and AKT activator SC-79 abrogated the effects of aspirin. These findings indicate that aspirin ameliorates pulmonary fibrosis through a PI3K/AKT/mTOR-dependent autophagy pathway.

Neutrophil extracellular traps drive lupus flares with acute skin and kidney inflammation triggered by ultraviolet irradiation.

Sunlight triggers lupus flares causing both local skin and systemic inflammation, including lupus nephritis, through poorly understood mechanisms. To address this knowledge gap, we found that UVB irradiation of asymptomatic, young female lupus-prone mice induced skin and kidney inflammation with proteinuria, accompanied by neutrophil infiltration and neutrophil extracellular trap (NET) formation. Furthermore, UVB irradiation induced co-expression of CXCR4 and cytokines/C3 by neutrophils in vitro and in vivo, in the skin and kidneys of lupus-prone mice, indicating their transmigratory and pro-inflammatory potentials. A causality study demonstrated that inhibiting CXCR4 attenuated renal neutrophil infiltration, accumulation of NETs, NET-associated cytokines/C3, and proteinuria in UVB-irradiated lupus-prone mice. Remarkably, inhibiting NETosis through a novel strategy targeting nuclear envelope integrity reduced deposition of NET-associated cytokines/C3 in skin and kidneys, attenuating proteinuria in UVB-irradiated MRL/lpr·lmnB1 Tg mice. Our investigation unveils a new mechanism by which neutrophil NETs drive the early onset of lupus flares triggered by UVB-irradiation. Targeting neutrophil transmigration and NETosis could be promising therapeutic strategies.

Emerging story of gut dysbiosis in spondyloarthropathy: From gastrointestinal inflammation to spondyloarthritis.

As a set of inflammatory disorders, spondyloarthritis (SpA) exhibits distinct pathophysiological, clinical, radiological, and genetic characteristics. Due to the extra-articular features of this disorder, early recognition is crucial to limiting disability and improving outcomes. Gut dysbiosis has been linked to SpA development as evidence grows. A pathogenic SpA process is likely to occur when a mucosal immune system interacts with abnormal local microbiota, with subsequent joint involvement. It is largely unknown, however, how microbiota alterations predate the onset of SpA within the "gut-joint axis". New microbiome therapies, such as probiotics, are used as an adjuvant therapy in the treatment of SpA, suggesting that the modulation of intestinal microbiota and/or intestinal barrier function may contribute to the prevention of SpA. In this review, we highlight the mechanisms of SpA by which the gut microbiota impacts gut inflammation and triggers the activation of immune responses. Additionally, we analyze the regulatory role of therapeutic SpA medication in the gut microbiota and the potential application of probiotics as adjunctive therapy for SpA.

Add-on individualizing prediction of nasopharyngeal carcinoma using deep-learning based on MRI: A multicentre, validation study.

In nasopharyngeal carcinoma, deep-learning extracted signatures on MR images might be correlated with survival. In this study, we sought to develop an individualizing model using deep-learning MRI signatures and clinical data to predict survival and to estimate the benefit of induction chemotherapy on survivals of patients with nasopharyngeal carcinoma. Two thousand ninety-seven patients from three independent hospitals were identified and randomly assigned. When the deep-learning signatures of the primary tumor and clinically involved gross cervical lymph nodes extracted from MR images were added to the clinical data and TNM staging for the progression-free survival prediction model, the combined model achieved better prediction performance. Its application is among patients deciding on treatment regimens. Under the same conditions, with the increasing MRI signatures, the survival benefits achieved by induction chemotherapy are increased. In nasopharyngeal carcinoma, these prediction models are the first to provide an individualized estimation of survivals and model the benefit of induction chemotherapy on survivals.

Increased Levels of CHI3L1 and HA Are Associated With Higher Occurrence of Liver Damage in Patients With Obstructive Sleep Apnea.

Background: Obstructive sleep apnea-hypopnea syndrome (OSA) may cause liver fibrosis, and liver fibrosis serum biomarkers plays an important role on the diagnosis of liver fibrosis. In addition, this study aimed to observe the changes of 4 serum markers and Chitinase 3-like protein 1 (CHII3L1) levels in OSA patients with different disease severity and explore their interactions. And then, we examined whether intermittent hypoxia (IH) exposure can activate hepatic stellate cell. Methods: 74 OSA patients in Second Xiangya hospital from January 2021 to October 2021 was selected and categorized into mild, moderate, and severe groups according to AHI. In addition, 20 subjects were selected as the control group. Serum levels of liver fibrosis markers were determined by electrochemiluminescence immunoassay. Hepatic stellate cells were exposed to intermittent IH or normoxia (RA). Results were analyzed using the SPSS software. Results: There was a significant increase in serum hyaluronic acid (HA), collagen type IV (CIV) and CHI3L1 levels in OSA patients compared with control group. Specifically, serum liver fibrosis markers HA, CIV and CHI3L1 levels were positively correlated with apnea-hypopnea index (AHI), but negatively correlated with the lowest saturation oxygen (LSaO2) respectively. The LX-2 cells (human hepatic stellate cell line) exposed to IH showed significant increases in fibrotic protein expression. Conclusion: OSA might either directly or indirectly trigger or exacerbate liver fibrosis, possibly via IH-related pathways.

Obstructive Sleep Apnea Impacts Cardiac Function in Dilated Cardiomyopathy Patients Through Circulating Exosomes.

Background: Obstructive sleep apnea (OSA) is common and independently associated with heart failure. This study aimed to investigate the impact of OSA on heart function in patients with dilated cardiomyopathy (DCM) as well as the possible mechanism related to exosomes regulated autophagy. Methods and Results: A total of 126 patients with DCM who underwent sleep evaluations were analyzed retrospectively. Cardiomyocytes were treated with exosomes isolated from untreated OSA patients and healthy controls. Fibrotic and hypertrophic markers were evaluated, and Akt/mTOR pathway-mediated autophagy was investigated. DCM patients with severe OSA had larger right ventricular end-diastolic diameter (RVEDd) and right atrial diameter (RAD) and increased N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels than DCM patients without OSA. Moreover, NT-proBNP and diabetes mellitus were independently correlated with the apnea-hypopnea index in multiple linear regression analysis. Treatment with OSA-derived exosomes significantly increased Col1A1, ANP, and BNP protein expression and decreased the expression of the autophagy markers LC3B II/I and beclin1. Rapamycin treatment significantly increased the decreased autophagy markers and attenuated the increased expression of Col1A1, ANP and BNP induced by OSA-derived exosomes. Conclusion: The severity of OSA is significantly associated with cardiac injury and remodeling. The underlying mechanism may be related to changed autophagy levels, which are regulated by circulating exosomes via the Akt/mTOR signaling pathway. This study may provide a new clue for the treatment of heart failure with OSA.

Rho Kinase regulates neutrophil NET formation that is involved in UVB-induced skin inflammation.

Objective: Ultraviolet B (UVB) is an important trigger of skin inflammation and lupus with leukocyte recruitment to inflamed skin. We recently reported the involvement of neutrophil NETosis in UVB-induced skin inflammation, and that NETotic nuclear envelope rupture is driven by PKCα-mediated nuclear lamin B disassembly. To address the role of Actin cytoskeleton in NETosis, we investigated the effects of Rho kinase (ROCK) and its downstream actomyosin cytoskeletal networks on PKCα nuclear translocation and NET formation, as well as their involvement in UVB-induced skin inflammation. Methods: We studied the dynamic changes of ROCK and actomyosin cytoskeletal networks during NETosis induction and their involvement in PKCα nuclear translocation. Using mice with hematopoietic-specific ROCK1 deficiency, we investigated the effects of ROCK1 deficiency on NETosis, and its involvement in UVB-induced skin inflammation. Results: Our time course studies demonstrated the dynamic changes of actin polymerization and ROCK activation, support the role of actin cytoskeleton in nuclear translocation of cytosolic PKCα in early stage of NETosis induction. Inhibition of actin polymerization or key molecules of the ROCK/MLCK/myosin pathway decreased PKCα nuclear translocation and NET formation. Genetic deficiency of ROCK1, inhibited NETosis ex vivo and in vivo, decreased extracellular display of NET-associated IL-17A, TNFα, IFNγ, and IFNα in inflamed skin, which were correlated with the ameliorated skin inflammation in UVB-irradiated mice with hematopoietic-specific ROCK1 deficiency. Conclusions: ROCK regulated NETosis through modulation of PKCα nuclear translocation via actomyosin cytoskeletal networks in neutrophils. ROCK1 deficiency ameliorated UVB-induced skin inflammation by attenuation of NETosis and NET-associated cytokines.

Recent progress in the mechanistic understanding of NET formation in neutrophils.

Neutrophils are the most abundant circulating white blood cells and one of the major cell types of the innate immune system. Neutrophil extracellular traps (NETs) are a result of the extracellular release of nuclear chromatin from the ruptured nuclear envelope and plasma membrane. The externalized chromatin is an ancient defense weapon for animals to entrap and kill microorganisms in the extracellular milieu, thus protecting animals ranging from lower invertebrates to higher vertebrates. Although the externalized chromatin has the advantage of acting as anti-infective to protect against infections, extracellular chromatin might be problematic in higher vertebrate animals as they have an adaptive immune system that can trigger further immune or autoimmune responses. NETs and their associated nuclear and/or cytoplasmic components may induce sterile inflammation, immune, and autoimmune responses, leading to various human diseases. Though important in human pathophysiology, the cellular and molecular mechanisms of NET formation (also called NETosis) are not well understood. Given that nuclear chromatin forms the backbone of NETs, the nucleus is the root of the nuclear DNA extracellular traps. Thus, nuclear chromatin decondensation, along with the rupture of nuclear envelope and plasma membrane, is required for nuclear chromatin extracellular release and NET formation. So far, most of the literature focuses on certain signaling pathways, which are involved in NET formation but without explanation of cellular events and morphological changes described above. Here, we have summarized emerging evidence and discuss new mechanistic understanding, with our perspectives, in NET formation in neutrophils.

Lipoprotein subfractions in patients with sarcopenia and their relevance to skeletal muscle mass and function.

OBJECTIVE: Loss of skeletal muscle mass is a characteristic of aging. Growing evidence suggests the role of fatty acids and their derived lipid intermediates in the regulation of skeletal muscle and function. However, the exact association between lipoprotein subfractions and sarcopenia in elderly individuals remains unclear. In this study, we aimed to investigate the levels of lipoprotein subfractions in sarcopenia patients and their relationship with skeletal muscle mass and function. METHODS: A total of 84 elderly Chinese subjects aged ≥65 years who did not have diseases that obviously affected lipid metabolism were included. Concentrations of lipoprotein subfractions, including total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), HDL2, HDL3, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), VLDL3, LDL-particle (LDL-P), lipoprotein(a) and remnant-like particle cholesterol (RLP-C), were determined by vertical auto profile. Triglyceride (TG) was measured by an enzymatic colorimetric assay. The skeletal muscle index (SMI) was assessed by bioelectrical impedance analysis. Handgrip strength was measured using a hand-held dynamometer. RESULTS: The levels of TC, TG, LDL-C, LDL-P, IDL, VLDL, VLDL3, RLP-C and C-reactive protein were significantly higher in sarcopenia patients than in controls (p < 0.05). Pearson Product-Moment Correlation Coefficient analysis showed that the TC, TG, LDL-C, IDL, VLDL, VLDL3, and RLP-C levels were negatively associated with the SMI; The TG, IDL, VLDL, VLDL3, and RLP-C were negatively correlated with handgrip strength. In multivariate stepwise regression analysis, the VLDL and RLP-C levels were significantly correlated with the SMI. The sensitivity and specificity of the combined measurement of VLDL and RLP-C in predicting sarcopenia were 69.8% and 92.5% (AUC: 0.831; 95% CI:(0.739, 0.924); p < 0.05). CONCLUSION: The occurrence of sarcopenia is associated with disorders of lipid metabolism, particularly VLDL and RLP-C.