Activation of CaMKII/HDAC4 by SDF1 contributes to pulmonary arterial hypertension via stabilization Runx2.

Stromal derived factor 1 (SDF1) has been shown to be involved in the pathogenesis of pulmonary artery hypertension (PAH). However, the detailed molecular mechanisms remain unclear. To address this, we utilized primary cultured rat pulmonary artery smooth muscle cells (PASMCs) and monocrotaline (MCT)-induced PAH rat models to investigate the mechanisms of SDF1 driving PASMCs proliferation and pulmonary arterial remodeling. SDF1 increased runt-related transcription factor 2 (Runx2) acetylation by Calmodulin (CaM)-dependent protein kinase II (CaMKII)-dependent HDAC4 cytoplasmic translocation, elevation of Runx2 acetylation conferred its resistance to proteasome-mediated degradation. The accumulation of Runx2 further upregulated osteopontin (OPN) expression, finally leading to PASMCs proliferation. Blocking SDF1, suppression of CaMKII, inhibition the nuclear export of HDAC4 or silencing Runx2 attenuated pulmonary arterial remodeling and prevented PAH development in MCT-induced PAH rat models. Our study provides novel sights for SDF1 induction of PASMCs proliferation and suggests that targeting SDF1/CaMKII/HDAC4/Runx2 axis has potential value in the management of PAH.

The global burden of ischemic heart disease attributed to high fasting plasma glucose: Data from 1990 to 2019.

Background: Ischemic heart disease (IHD) is the leading cause of death worldwide. High fasting plasma glucose (FPG) is an increasing risk factor for IHD. We aimed to explore the long-term trends of high FPG-attributed IHD mortality during 1990-2019. Methods: Data were obtained from the Global Burden of Disease Study 2019 database. Deaths, disability-adjusted life-years (DALYs), the age-standardized mortality rate (ASMR) and age-standardized DALY rate (ASDR) of IHD attributable to high FPG were estimated by sex, socio-demographic index (SDI), regions and age. Estimated annual percentage changes (EAPCs) were calculated to assess the trends of ASMR and ASDR of IHD attributable to high FPG. Results: IHD attributable to high FPG deaths increased from 1.04 million (0.62-1.63) in 1990 to 2.35 million (1.4-3.7) in 2019, and the corresponding DALYs rose from 19.82 million (12.68-29.4) to 43.3 million (27.8-64.2). In 2019, ASMR and ASDR of IHD burden attributable to high FPG were 30.45 (17.09-49.03) and 534.8 (340.7-792.2), respectively. The highest ASMR and ASDR of IHD attributable to high FPG occurred in low-middle SDI quintiles, with 39.28 (22.40-62.76) and 742.3 (461.5-1117.5), respectively, followed by low SDI quintiles and middle SDI quintiles. Males had higher ASMR and ASDR compared to females across the past 30 years. In addition, ASRs of DALYs and deaths were highest in those over 95 years old. Conclusion: High FPG-attributed IHD mortality and DALYs have increased dramatically and globally, particularly in low, low-middle SDI quintiles and among the elderly. High FPG remains a great concern on the global burden of IHD and effective prevention and interventions are urgently needed to curb the ranking IHD burden, especially in lower SDI regions.

Global burden of MDR-TB and XDR-TB attributable to high fasting plasma glucose from 1990 to 2019: a retrospective analysis based on the global burden of disease study 2019.

PURPOSE: High fasting plasma glucose (HFPG) has been identified as a risk factor for drug-resistant tuberculosis incidence and mortality. However, the epidemic characteristics of HFPG-attributable multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) remain unclear. We aimed to analyze the global spatial patterns and temporal trends of HFPG-attributable MDR-TB and XDR-TB from 1990 to 2019. METHODS: Utilizing data from the Global Burden of Disease 2019 project, annual deaths and disability-adjusted life years (DALYs) of HFPG-attributable MDR-TB and XDR-TB were conducted from 1990 to 2019. Joinpoint regression was employed to quantify trends over time. RESULTS: From 1990 to 2019, the deaths and DALYs due to HFPG-attributable MDR-TB and XDR-TB globally showed an overall increasing trend, with a significant increase until 2003 to 2004, followed by a gradual decline or stability thereafter. The low sociodemographic index (SDI) region experienced the most significant increase over the past 30 years. Regionally, Sub-Saharan Africa, Central Asia and Oceania remained the highest burden. Furthermore, there was a sex and age disparity in the burden of HFPG-attributable MDR-TB and XDR-TB, with young males in the 25-34 age group experiencing higher mortality, DALYs burden and a faster increasing trend than females. Interestingly, an increasing trend followed by a stable or decreasing pattern was observed in the ASMR and ASDR of HFPG-attributable MDR-TB and XDR-TB with SDI increasing. CONCLUSION: The burden of HFPG-attributable MDR-TB and XDR-TB rose worldwide from 1990 to 2019. These findings emphasize the importance of routine bi-directional screening and integrated management for drug-resistant TB and diabetes.

NAMPT mediates PDGF-induced pulmonary arterial smooth muscle cell proliferation by TLR4/NF-κB/PLK4 signaling pathway.

Nicotinamide phosphoribosyltransferase (NAMPT), a pleiotropic protein, promotes the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), which is associated with the genesis and progression of pulmonary arterial hypertension (PAH). NAMPT is highly increased in PAH patient's plasma and highly relevant to PAH severity. The mRNA and protein levels of NAMPT are elevated in PAH animal models. However, the underlying molecular mechanisms how NAMPT mediated platelet-derived growth factor (PDGF)-induced PASMCs proliferation are still unclear. The present study aimed to address these issues. Primary cultured PASMCs were attained from male Sprague-Dawley (SD) rats. Western blotting, RT-PCR, ELISA, cell transfection, Cell Counting Kit-8 (CCK-8) and EdU incorporation assays were used in the experiments. We showed that PDGF upregulated NAMPT expression through the activation of signal transducers and activators of transcription 5 (STAT5), and elevated extracellular NAMPT further promoted the activation of NF-κB through Toll-like receptor 4 (TLR4), which ultimately upregulated polo-like kinase 4 (PLK4) expression leading to PASMCs proliferation. Knockdown of STAT5, NAMPT or PLK4, and inhibition of TLR4 or NF-κB suppressed PDGF-induced PASMCs proliferation. Our study suggests that NAMPT plays an essential role in PDGF-induced PASMCs proliferation via TLR4/NF-κB/PLK4 pathway, suggesting that targeting NAMPT might be valuable in ameliorating pulmonary arterial hypertension.

Macrophage migration inhibitory factor exacerbates asthmatic airway remodeling via dynamin-related protein 1-mediated autophagy activation.

BACKGROUND: Macrophage migration inhibitory factor (MIF) and GTPase dynamin-related protein 1 (Drp1)-dependent aberrant mitochondrial fission are closely linked to the pathogenesis of asthma. However, it is unclear whether Drp1-mediated mitochondrial fission and its downstream targets mediate MIF-induced proliferation of airway smooth muscle cells (ASMCs) in vitro and airway remodeling in chronic asthma models. The present study aims to clarify these issues. METHODS: In this study, primary cultured ASMCs and ovalbumin (OVA)-induced asthmatic rats were applied. Cell proliferation was detected by CCK-8 and EdU assays. Western blotting was used to detect extracellular signal-regulated kinase (ERK) 1/2, Drp1, autophagy-related markers and E-cadherin protein phosphorylation and expression. Inflammatory cytokines production, airway reactivity test, histological staining and immunohistochemical staining were conducted to evaluate the development of asthma. Transmission electron microscopy was used to observe the mitochondrial ultrastructure. RESULTS: In primary cultured ASMCs, MIF increased the phosphorylation level of Drp1 at the Ser616 site through activation of the ERK1/2 signaling pathway, which further activated autophagy and reduced E-cadherin expression, ultimately leading to ASMCs proliferation. In OVA-induced asthmatic rats, MIF inhibitor 4-iodo-6-phenylpyrimidine (4-IPP) treatment, suppression of mitochondrial fission by Mdivi-1 or inhibiting autophagy with chloroquine phosphate (CQ) all attenuated the development of airway remodeling. CONCLUSIONS: The present study provides novel insights that MIF promotes airway remodeling in asthma by activating autophagy and degradation of E-cadherin via ERK/Drp1 signaling pathway, suggesting that targeting MIF/ERK/Drp1 might have potential therapeutic value for the prevention and treatment of asthma.

Epidemiological features and temporal trends of HIV-negative tuberculosis burden from 1990 to 2019: a retrospective analysis based on the Global Burden of Disease Study 2019.

OBJECTIVE: This study aimed to analyse the burden and temporal trends of tuberculosis (TB) incidence and mortality globally, as well as the association between mortality-to-incidence ratio (MIR) and Socio-Demographic Index (SDI). DESIGN: A retrospective analysis of TB data from 1990 to 2019 was conducted using the Global Burden of Disease Study database. RESULTS: Between 1990 and 2019, there was a declining trend in the global incidence and mortality of TB. High SDI regions experienced a higher declining rate than in low SDI regions during the same period. Nearly half of the new patients occurred in South Asia. In addition, there is a sex-age imbalance in the overall burden of TB, with young males having higher incidence and mortality than females. In terms of the three subtypes of TB, drug-sensitive (DS)-TB accounted for more than 90% of the incidents and deaths and experienced a decline over the past 30 years. However, drug-resistant TB (multidrug-resistant (MDR)-TB and extensively drug-resistant (XDR)-TB) showed an overall increasing trend in age-standardised incidence rates and age-standardised mortality rates, with an inflection point after the year 2000. At the regional level, South Asia and Eastern Europe remained a high burden of drug-resistant TB incidence and mortality. Interestingly, a negative correlation was found between the MIR and SDI for TB, including DS-TB, MDR-TB and XDR-TB. Notably, central sub-Saharan Africa had the highest MIR, which indicated a higher-than-expected burden given its level of sociodemographic development. CONCLUSION: This study provides comprehensive insights into the global burden and temporal trends of TB incidence and mortality, as well as the relationship between MIR and SDI. These findings contribute to our understanding of TB epidemiology and can inform public health strategies for prevention and management.

Downregulation of PDCD4 through STAT3/ATF6/autophagy mediates MIF-induced PASMCs proliferation/migration and vascular remodeling.

To address the molecular mechanisms underlying macrophage migration inhibitory factor (MIF) induced pulmonary artery smooth muscle cells (PASMCs) proliferation, migration and vascular remodeling in pulmonary hypertension (PH), primary cultured rat PASMCs and monocrotaline (MCT)-induced rats with PH were applied in the present study. The results showed that MIF increased signal transducer and activator of transcription 3 (STAT3) phosphorylation, and then stimulated activating transcription factor 6 (ATF6) activation, subsequently triggered autophagy activation, which further led to programmed cell death factor 4 (PDCD4) lysosomal degradation, and eventually promoted PASMCs proliferation/migration. In lung tissues of MCT rats, MIF protein expression was elevated, phosphorylation of STAT3 and activation of ATF6 were increased, activation of autophagy was evident, and reduction of PDCD4 was observed. Intervention with MIF inhibitor 4-Iodo-6-phenylpyrimidine (4-IPP), ATF6 blocker melatonin or autophagy inhibitor chloroquine, confirmed the in vitro interaction among MIF, STAT3, ATF6, autophagy and PDCD4 in MCT induced rats with PH. Targeting MIF/STAT3/ATF6/autophagy/PDCD4 axis effectively prevented the development of PH by suppressing PASMCs proliferation and vascular remodeling. In conclusions, we demonstrate that MIF activates the STAT3/ATF6/autophagy cascade and then degrades PDCD4 leading to PASMCs proliferation/migration and pulmonary vascular remodeling, suggesting that intervention this axis might have potential value in management of PH.

HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo.

BACKGROUND: HMGB1 and ER stress have been considered to participate in the progression of pulmonary artery hypertension (PAH). However, the molecular mechanism underlying HMGB1 and ER stress in PAH remains unclear. This study aims to explore whether HMGB1 induces pulmonary artery smooth muscle cells (PASMCs) functions and pulmonary artery remodeling through ER stress activation. METHODS: Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. Cell proliferation and migration were determined by CCK-8, EdU and transwell assay. Western blotting was conducted to detect the protein levels of protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor-4 (ATF4), seven in absentia homolog 2 (SIAH2) and homeodomain interacting protein kinase 2 (HIPK2). Hemodynamic measurements, immunohistochemistry staining, hematoxylin and eosin staining were used to evaluate the development of PAH. The ultrastructure of ER was observed by transmission electron microscopy. RESULTS: In primary cultured PASMCs, HMGB1 reduced HIPK2 expression through upregulation of ER stress-related proteins (PERK and ATF4) and subsequently increased SIAH2 expression, which ultimately led to PASMC proliferation and migration. In MCT-induced PAH rats, interfering with HMGB1 by glycyrrhizin, suppression of ER stress by 4-phenylbutyric acid or targeting SIAH2 by vitamin K3 attenuated the development of PAH. Additionally, tetramethylpyrazine (TMP), as a component of traditional Chinese herbal medicine, reversed hemodynamic deterioration and vascular remodeling by targeting PERK/ATF4/SIAH2/HIPK2 axis. CONCLUSIONS: The present study provides a novel insight to understand the pathogenesis of PAH and suggests that targeting HMGB1/PERK/ATF4/SIAH2/HIPK2 cascade might have potential therapeutic value for the prevention and treatment of PAH.

Association Between Red Blood Cell Distribution Width-Albumin Ratio and Hospital Mortality in Chronic Obstructive Pulmonary Disease Patients Admitted to the Intensive Care Unit: A Retrospective Study.

Purpose: High levels of red blood cell distribution width (RDW) and hypoalbuminemia are markers of poor prognosis in chronic obstructive pulmonary disease (COPD) patients. However, few studies have shown that the red blood cell distribution width-albumin ratio (RAR) is related to the mortality of COPD. This study aimed to explore the relationship between RAR and hospital mortality in COPD patients admitted to the intensive care unit (ICU). Patients and Methods: Patients were retrospectively incorporated from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database and divided into two groups by a cutoff value of RAR. Propensity score matching (PSM) was performed to adjust for the imbalance of covariates. Logistic regression models and subgroup analyses were carried out to investigate the relationship between RAR and hospital mortality. The receiver operating characteristic (ROC) curve was used to evaluate the predictive performance of RAR and decision curve analysis (DCA) to assess the clinical utility. Results: In total, 1174 patients were finally identified from the MIMIC-IV database. The cutoff value for RAR was 5.315%/g/dL. After PSM at a 1:1 ratio, 638 patients were included in the matched cohort. In the original and matched cohorts, the high RAR group had higher hospital mortality and longer hospital stays. Logistic regression analysis suggested that RAR was an independent risk factor for hospital mortality. The areas under the ROC curve in the original and matched cohorts were 0.706 and 0.611, respectively, which were larger than applying RDW alone (the original cohort: 0.600, the matched cohort: 0.514). The DCA indicated that RAR had a clinical utility. Conclusion: A higher RAR (>5.315%/g/dL) was associated with hospital mortality in COPD patients admitted to ICU. As an easily available peripheral blood marker, RAR can predict hospital mortality in critically ill patients with COPD independently.

Global burden of asthma associated with high body mass index from 1990 to 2019.

BACKGROUND: High body mass index (BMI) plays a key role in the progression of asthma and asthma related to high BMI resulted in a high burden of disease globally. OBJECTIVE: To explore the geographic and temporal trends in the global burden of asthma associated with high BMI from 1990 to 2019. METHODS: This is a retrospective analysis with data based on the Global Burden of Disease Study 2019 database. Deaths, disability-adjusted life-years (DALYs), age-standardized mortality rate (ASMR), and age-standardized DALY rate (ASDR) were estimated according to sex, age, and sociodemographic index levels. The estimated annual percentage change was used to evaluate the variation trends of ASMR and ASDR from 1990 to 2019. RESULTS: In 2019, the number of global asthma deaths and DALYs related to high BMI increased by 69.69% and 63.91%, respectively, compared with 1990, among which more deaths and DALYs occurred in women. The corresponding ASMR and ASDR exhibited a slightly decreasing tendency globally. South Asia accounted for the highest number of deaths and DALYs, with India ranking first worldwide in 2019. The number of deaths and DALYs were mainly seen in individuals 60 to 79 years old and 55 to 69 years old, respectively, from 1990 to 2019. The heaviest burden existed in the low-middle sociodemographic index region. CONCLUSION: The global asthma burden associated with obesity increased in absolute value but the standardized burden decreased slightly. Large variations existed in the high BMI-related asthma burdens among sexes, ages, and regions.

Clinicopathological and prognostic role of ROC1 in neoplasms: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: Regulator of cullins 1 (ROC1) is frequently overexpressed in multiple tumors, and many pieces of research demonstrate that ROC1 is associated with the prognosis and development of a diversity of neoplasms and it is able to serve as a promising prognostic biomarker. Here we performed this meta-analysis to evaluate the prognostic and clinicopathological significance of ROC1 in patients suffering from cancer. METHODS: We searched Pubmed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and WanFang database. The role of ROC1 in cancers was evaluated by pooled hazard ratios (HRs), odd ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In total, 9 studies including 1002 patients were enrolled in this analysis. The pooled results showed that patients with high expression of ROC1 had poor overall survival (OS) (HR: 2.04, 95% CI: 1.48-2.60, P < 0.001) and recurrence-free survival (RFS) (HR: 1.727, 95% CI: 0.965-2.488, P < 0.001). Additionally, elevated expression of ROC1 was significantly correlated with advanced clinical Tumor Node Metastasis stage (OR: 2.708, 95% CI: 1.856-3.951, P < 0.001), positive lymph node metastasis (OR: 1.968; 95% CI: 1.294-2.993, P = .002), large tumor size (OR: 1.522, 95% CI: 1.079-2.149, P = .017) and poor tumor differentiation (OR: 2.448, 95% CI: 1.793-3.344, P < 0.001). CONCLUSIONS: Elevated ROC1 expression predicted worse prognosis and advanced pathological parameters in various cancers. ROC1 was a significant prognostic biomarker for poor survival in human cancers.

Nomograms for Predicting Coexisting Cardiovascular Disease and Prognosis in Chronic Obstructive Pulmonary Disease: A Study Based on NHANES Data.

Background: Chronic obstructive pulmonary disease (COPD) is a common chronic disease. Progression is further exacerbated by the coexistence of cardiovascular disease (CVD). We aim to construct a diagnostic nomogram for predicting the risk of coexisting CVD and a prognostic nomogram for predicting long-term survival in COPD. Methods: The 540 eligible participants selected from the NHANES 2005-2010 were included in this study. Logistic regression analysis was used to construct a diagnostic nomogram for the diagnosis of coexisting CVD in COPD. Cox regression analyses were used to construct a prognostic nomogram for COPD. A risk stratification system was developed based on the total score generated from the prognostic nomogram. We used C-index and ROC curves to evaluate the discriminant ability of the newly built nomograms. The models were also validated utilizing calibration curves. Survival curves were made using the Kaplan-Meier method and compared by the Log-rank test. Results: Logistic regression analysis showed that gender, age, neutrophil, RDW, LDH, and HbA1c were independent predictors of coexisting CVD and were included in the diagnostic model. Cox regression analysis indicated that CVD, gender, age, BMI, RDW, albumin, LDH, creatinine, and NLR were independent predictors of COPD prognosis and were incorporated into the prognostic model. The C-index and ROC curves revealed the good discrimination abilities of the models. And the calibration curves implied that the predicted values by the nomograms were in good agreement with the actual observed values. In addition, we found that coexisting with CVD had a worse prognosis compared to those without CVD, and the prognosis of the low-risk group was better than that of the high-risk group in COPD. Conclusions: The nomograms we developed can help clinicians and patients to identify COPD coexisting CVD early and predict the 5-year and 10-year survival rates of COPD patients, which has some clinical practical values.

CEMIP as a prognostic biomarker for cancers: a meta- and bioinformatic analysis.

OBJECTIVE: Cell migration-inducing and hyaluronan-binding protein (CEMIP) is overexpressed in several cancers and is related to prognosis in cancer patients. Here, we conducted a meta-analysis to explore the prognostic effects of CEMIP in cancer patients. METHODS: Relevant published studies were systematically searched in four databases. The role of CEMIP was evaluated using pooled hazard ratios (HRs), odd ratios (ORs), and 95% confidence intervals (95% CIs). The Cancer Genome Atlas (TCGA) was used to investigate the prognostic value of CEMIP in various cancers. RESULTS: 11 literatures with 1355 patients were included in this meta-analysis. The results showed that overexpression of CEMIP was significantly associated with poor OS (HR = 3.03; 95% CI: 2.00-4.59; p < 0.001), DFS (HR = 3.38; 95% CI: 2.41-4.74; p < 0.001). Elevated CEMIP expression is associated with advanced clinical stage, lymph node metastasis, and poor histological grade. In addition, TCGA datasets were used to verify that CEMIP was found highly expressed in multiple cancers and was associated with poorer survival. CONCLUSION: The results demonstrated that CEMIP could be a novel prognostic biomarker for cancer patients. However, because the included studies mainly focused on Asian populations, further research is needed to verify its applicability.

Quantitative CT parameters correlate with lung function in chronic obstructive pulmonary disease: A systematic review and meta-analysis.

Objective: This study aimed to analyze the correlation between quantitative computed tomography (CT) parameters and airflow obstruction in patients with COPD. Methods: PubMed, Embase, Cochrane and Web of Knowledge were searched by two investigators from inception to July 2022, using a combination of pertinent items to discover articles that investigated the relationship between CT measurements and lung function parameters in patients with COPD. Five reviewers independently extracted data, and evaluated it for quality and bias. The correlation coefficient was calculated, and heterogeneity was explored. The following CT measurements were extracted: percentage of lung attenuation area <-950 Hounsfield Units (HU), mean lung density, percentage of airway wall area, air trapping index, and airway wall thickness. Two airflow obstruction parameters were extracted: forced expiratory volume in the first second as a percentage of prediction (FEV1%pred) and FEV1 divided by forced expiratory volume lung capacity. Results: A total of 141 studies (25,214 participants) were identified, which 64 (6,341 participants) were suitable for our meta-analysis. Results from our analysis demonstrated that there was a significant correlation between quantitative CT parameters and lung function. The absolute pooled correlation coefficients ranged from 0.26 (95% CI, 0.18 to 0.33) to 0.70 (95% CI, 0.65 to 0.75) for inspiratory CT and 0.56 (95% CI, 0.51 to 0.60) to 0.74 (95% CI, 0.68 to 0.80) for expiratory CT. Conclusions: Results from this analysis demonstrated that quantitative CT parameters are significantly correlated with lung function in patients with COPD. With recent advances in chest CT, we can evaluate morphological features in the lungs that cannot be obtained by other clinical indices, such as pulmonary function tests. Therefore, CT can provide a quantitative method to advance the development and testing of new interventions and therapies for patients with COPD.