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.

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.

Associations between long-term blood pressure trajectory and all-cause and CVD mortality among old people in China.

Background: Optimal blood pressure (BP) management strategy among the elderly remains controversial, with insufficient consideration of long-term BP trajectory. This study aimed to identify BP trajectory patterns as well as terminal BP trajectory among the Chinese elderly and to explore the relationships between BP trajectories and all-cause mortality and cardiovascular disease (CVD) mortality. Methods: We included 11,181 participants older than 60 at baseline (mean age, 80.98 ± 10.71) with 42,871 routine BP measurements from the Chinese Longitudinal Healthy Longevity Survey. Latent class trajectory analysis and Cox proportional hazard model were conducted to identify trajectory patterns and their associations with mortality. Furthermore, we also applied mixed-effects model to identify terminal BP trajectories among the elderly. Results: Compared with stable at normal high level trajectory, excess systolic BP (SBP) trajectory with decreasing trend was associated with a 34% (HR = 1.34, 95% CI: 1.23-1.45) higher risk of all-cause mortality. Considering the competing risk of non-CVD death, excess BP trajectory with decreasing trend had a more pronounced effect on CVD mortality, in which HR (95% CI) was 1.67 (1.17, 2.37). Similar results were also found in diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP) trajectories. We further conducted a mixed-effects model and observed that SBP and PP trajectories first increased and began to decline slightly six years before death. In contrast, DBP and MAP showed continuous decline 15 years before death. Conclusion: Long-term BP trajectory was associated with all-cause mortality, especially CVD mortality. Keeping a stable BP over time may be an important way for CVD prevention among the elderly.

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.

OsPEX1, an extensin-like protein, negatively regulates root growth in a gibberellin-mediated manner in rice.

Leucine-rich repeat extensins (LRXs) are required for plant growth and development through affecting cell growth and cell wall formation. LRX gene family can be classified into two categories: predominantly vegetative-expressed LRX and reproductive-expressed PEX. In contrast to the tissue specificity of Arabidopsis PEX genes in reproductive organs, rice OsPEX1 is also highly expressed in roots in addition to reproductive tissue. However, whether and how OsPEX1 affects root growth is unclear. Here, we found that overexpression of OsPEX1 retarded root growth by reducing cell elongation likely caused by an increase of lignin deposition, whereas knockdown of OsPEX1 had an opposite effect on root growth, indicating that OsPEX1 negatively regulated root growth in rice. Further investigation uncovered the existence of a feedback loop between OsPEX1 expression level and GA biosynthesis for proper root growth. This was supported by the facts that exogenous GA3 application downregulated transcript levels of OsPEX1 and lignin-related genes and rescued the root developmental defects of the OsPEX1 overexpression mutant, whereas OsPEX1 overexpression reduced GA level and the expression of GA biosynthesis genes. Moreover, OsPEX1 and GA showed antagonistic action on the lignin biosynthesis in root. OsPEX1 overexpression upregulated transcript levels of lignin-related genes, whereas exogenous GA3 application downregulated their expression. Taken together, this study reveals a possible molecular pathway of OsPEX1mediated regulation of root growth through coordinate modulation of lignin deposition via a negative feedback regulation between OsPEX1 expression and GA biosynthesis.

Activation of PPAR-γ prevents TERT-mediated pulmonary vascular remodeling in MCT-induced pulmonary hypertension.

Background: It has been demonstrated that elevated telomerase reverse transcriptase (TERT) expression or activity is implicated in pulmonary hypertension (PH). In addition, activation of peroxisome-proliferator-activated receptor γ (PPAR-γ) has been found to prevent PH progression. However, the molecular mechanism responsible for the protective effect of PPAR-γ activation on TERT expression in the pathogenesis of PH remains unknown. This study was performed to address these issues. Methods: Intraperitoneal injection of monocrotaline (MCT) was used to establish PH. BIBR1532 was applied to inhibit the activity of telomerase. The right ventricular systolic pressure (RVSP) and histological analysis were used to detect the development of PH. The protein levels of p-Akt, t-Akt, c-Myc and TERT were determined by western blotting. Pharmacological inhibition of TERT by BIBR1532 effectively suppressed RVSP, RVHI and the WT% in MCT-induced PH rats. Results: Pharmacological inhibition of Akt/c-Myc pathway by LY294002 diminished TERT upregulation, RVSP, RVHI and WT% in MCT-PH rats. Activation of PPAR-γ by pioglitazone inhibited p-Akt and c-Myc expressions and further downregulated TERT, thus to reduced RVSP, RVHI and WT% in MCT-treated PH rats. Conclusions: In conclusion, TERT upregulation contributes to PH development in MCT-treated rats. Activation of PPAR-γ prevents pulmonary arterial remodeling through Akt/c-Myc/TERT axis suppression.

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.

Induction of GLI1 by miR-27b-3p/FBXW7/KLF5 pathway contributes to pulmonary arterial hypertension.

Glioma-associated oncogene homolog 1 (GLI1), a zinc-finger transcription factor, is upregulated in tumors and promotes cancer cell proliferation and migration. However, whether GLI1 involves in pulmonary artery smooth muscle cells (PASMCs) proliferation and migration and the detailed molecular mechanisms underlying GLI1 in pulmonary arterial hypertension (PAH) are not yet clear. Primary cultured rat PASMCs and monocrotaline (MCT)-induced PAH rats model were applied to address these issues in the present study. We found that the expression of GLI1 was significantly increased in endothelin-1 (ET-1) treated PASMCs, accompanied with the activation of microRNA (miR)-27b-3p/F-box and WD repeat domain containing 7 (FBXW7)/kruppel-like factor 5 (KLF5)/GLI1 pathway through endothelin-1 receptor type A (ETAR). Elevated miR-27b-3p suppressed FBXW7 expression, which led to KLF5 accumulation by decreasing its ubiquitinated degradation, KLF5 further induced GLI1 upregulation leading to PASMCs proliferation and migration. In addition, in MCT-induced PAH rats, targeting ETAR/miR-27b-3p/FBXW7/KLF5/GLI1 pathway effectively prevented the pulmonary vascular remodeling and the development of PAH in rats. Our study indicates that interfering ETAR/miR-27b-3p/FBXW7/KLF5/GLI1 signaling axis might have a potential value in the prevention and treatment of PAH.

PPARγ activation inhibits PDGF-induced pulmonary artery smooth muscle cell proliferation and migration by modulating TERT.

Vascular remodeling is a significant feature of pulmonary artery hypertension (PAH), and is characterized by abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Telomerase reverse transcriptase (TERT), as a determining factor for controlling telomerase activity, has been proven to be associated with cell proliferation. This study aims to explore whether TERT mediates the proliferation and migration of PASMCs and the underlying molecular mechanism. Primary PASMCs from Sprague-Dawley (SD) rats were used in this experiment. Cell proliferation and migration were evaluated by Cell Counting Kit-8, EdU incorporation assay and transwell assay, respectively. Telomerase activity was assessed with a rat TE ELISA kit. Small interfering RNA (siRNA) transfection was conducted to silence c-MYC expression. The protein levels of p-Akt, c-MYC, PPARγ and TERT were determined through western blotting. Our work demonstrates that PDGF upregulated TERT expression and telomerase activation by activating Akt and upregulating of c-MYC in PASMCs. Inhibition of Akt with LY294002, knockdown of c-MYC by siRNA or suppression of telomerase activity with BIBR1532 repressed PDGF-induced PASMC proliferation and migration. Furthermore, activation of peroxisome proliferator-activated receptor γ (PPARγ) with pioglitazone suppressed PDGF-induced TERT expression and telomerase activation, leading to inhibition of PASMC proliferation and migration.

Overexpression of Pennisetum purpureum CCoAOMT Contributes to Lignin Deposition and Drought Tolerance by Promoting the Accumulation of Flavonoids in Transgenic Tobacco.

Elephant grass (Pennisetum purpureum) is a fast-growing and low-nutrient demand plant that is widely used as a forage grass and potential energy crop in tropical and subtropical regions of Asia, Africa, and the United States. Transgenic tobacco with the PpCCoAOMT gene from Pennisetum purpureum produces high lignin content that is associated with drought tolerance in relation to lower accumulation of reactive oxygen species (ROS), along with higher antioxidant enzyme activities and osmotic adjustment. In this study, transgenic tobacco plants revealed no obvious cost to plant growth when expressing the PpCCoAOMT gene. Metabolomic studies demonstrated that tobacco plants tolerant to drought stress accumulated flavonoids under normal and drought conditions, which likely explains the observed tolerance phenotype in wild-type tobacco. Our results suggest that plants overexpressing PpCCoAOMT were better able to cope with water deficit than were wild-type controls; metabolic flux was redirected within primary and specialized metabolism to induce metabolites related to defense to drought stress. These results could help to develop drought-resistant plants for agriculture in the future.

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.

An SETD1A/Wnt/ß-catenin feedback loop promotes NSCLC development.

BACKGROUND: SETD1A, a member of SET1/MLL family H3K4 methyltransferases, is involved in the tumorigenesis of numerous cancers. However, the biological role and mechanism of SETD1A in non-small cell lung cancer (NSCLC) remain to be elucidated. METHODS: The expression of SETD1A, NEAT1, EZH2, and ß-catenin in NSCLC tissues and cell lines was detected by qRT-PCR, immunohistochemistry and western blotting. The regulatory mechanisms were validated by chromatin immunoprecipitation, co-immunoprepitation and luciferase reporter assay. The self-renewal, cisplatin sensitivity and tumorigenesis of NSCLC cells were analyzed using sphere formation, CCK-8, colony formation assays and xenograft tumor models. RESULTS: SETD1A expression was significantly increased in NSCLC and its overexpression predicted a poor prognosis of patients with NSCLC. Functional experiments showed that SETD1A positively regulated cancer stem cell property and negatively regulated cisplatin sensitivity in NSCLC cells via the Wnt/ß-catenin pathway. Next, we found that SETD1A positively regulated the Wnt/ß-catenin pathway via interacting with and stabilizing ß-catenin. The SET domain is dispensable for the interaction between SETD1A and ß-catenin. Furthermore, we identified that SETD1A bound to the promoters of NEAT1 and EZH2 to activate gene transcription by inducing H3K4me3 enrichment. Rescue experiments showed that SETD1A promoted the Wnt/ß-catenin pathway and exerted its oncogenic functions in NSCLC, at least, partly through NEAT1 and EZH2 upregulation. In addition, SETD1A was proven to be a direct target of the Wnt/ß-catenin pathway, thus forming a positive feedback loop in NSCLC cells. CONCLUSION: SETD1A and Wnt/ß-catenin pathway form a positive feedback loop and coordinately contribute to NSCLC progression.

Overexpression of SgGH3.1 from Fine-Stem Stylo (Stylosanthes guianensis var. intermedia) Enhances Chilling and Cold Tolerance in Arabidopsis thaliana.

Stylosanthes (stylo) species are commercially significant tropical and subtropical forage and pasture legumes that are vulnerable to chilling and frost. However, little is known about the molecular mechanisms behind stylos' responses to low temperature stress. Gretchen-Hagen 3 (GH3) proteins have been extensively investigated in many plant species for their roles in auxin homeostasis and abiotic stress responses, but none have been reported in stylos. SgGH3.1, a cold-responsive gene identified in a whole transcriptome profiling study of fine-stem stylo (S. guianensis var. intermedia) was further investigated for its involvement in cold stress tolerance. SgGH3.1 shared a high percentage of identity with 14 leguminous GH3 proteins, ranging from 79% to 93%. Phylogenetic analysis classified SgGH3.1 into Group Ⅱ of GH3 family, which have been proven to involve with auxins conjugation. Expression profiling revealed that SgGH3.1 responded rapidly to cold stress in stylo leaves. Overexpression of SgGH3.1 in Arabidopsis thaliana altered sensitivity to exogenous IAA, up-regulated transcription of AtCBF1-3 genes, activated physiological responses against cold stress, and enhanced chilling and cold tolerances. This is the first report of a GH3 gene in stylos, which not only validated its function in IAA homeostasis and cold responses, but also gave insight into breeding of cold-tolerant stylos.

ERK/Drp1-dependent mitochondrial fission contributes to HMGB1-induced autophagy in pulmonary arterial hypertension.

OBJECTIVES: High-mobility group box-1 (HMGB1) and aberrant mitochondrial fission mediated by excessive activation of GTPase dynamin-related protein 1 (Drp1) have been found to be elevated in patients with pulmonary arterial hypertension (PAH) and critically implicated in PAH pathogenesis. However, it remains unknown whether Drp1-mediated mitochondrial fission and which downstream targets of mitochondrial fission mediate HMGB1-induced pulmonary arterial smooth muscle cells (PASMCs) proliferation and migration leading to vascular remodelling in PAH. This study aims to address these issues. METHODS: Primary cultured PASMCs were obtained from male Sprague-Dawley (SD) rats. We detected RNA levels by qRT-PCR, protein levels by Western blotting, cell proliferation by Cell Counting Kit-8 (CCK-8) and EdU incorporation assays, migration by wound healing and transwell assays. SD rats were injected with monocrotaline (MCT) to establish PAH. Hemodynamic parameters were measured by closed-chest right heart catheterization. RESULTS: HMGB1 increased Drp1 phosphorylation and Drp1-dependent mitochondrial fragmentation through extracellular signal-regulated kinases 1/2 (ERK1/2) signalling activation, and subsequently triggered autophagy activation, which further led to bone morphogenetic protein receptor 2 (BMPR2) lysosomal degradation and inhibitor of DNA binding 1 (Id1) downregulation, and eventually promoted PASMCs proliferation/migration. Inhibition of ERK1/2 cascade, knockdown of Drp1 or suppression of autophagy restored HMGB1-induced reductions of BMPR2 and Id1, and diminished HMGB1-induced PASMCs proliferation/migration. In addition, pharmacological inhibition of HMGB1 by glycyrrhizin, suppression of mitochondrial fission by Mdivi-1 or blockage of autophagy by chloroquine prevented PAH development in MCT-induced rats PAH model. CONCLUSIONS: HMGB1 promotes PASMCs proliferation/migration and pulmonary vascular remodelling by activating ERK1/2/Drp1/Autophagy/BMPR2/Id1 axis, suggesting that this cascade might be a potential novel target for management of PAH.

S1P induces proliferation of pulmonary artery smooth muscle cells by promoting YAP-induced Notch3 expression and activation.

Sphingosine-1-phosphate (S1P), a natural multifunctional phospholipid, is highly increased in plasma from patients with pulmonary arterial hypertension and mediates proliferation of pulmonary artery smooth muscle cells (PASMCs) by activating the Notch3 signaling pathway. However, the mechanisms underpinning S1P-mediated induction of PASMCs proliferation remain unclear. In this study, using biochemical and molecular biology approaches, RNA interference and gene expression analyses, 5'-ethynyl-2'-deoxyuridine incorporation assay, and 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, we demonstrated that S1P promoted the activation of signal transducers and activators of transcription 3 (STAT3) through sphingosine-1-phosphate receptor 2 (S1PR2), and subsequently upregulated the expression of the microRNA miR-135b, which further reduced the expression of E3 ubiquitin ligase ß-transduction repeat-containing protein and led to a reduction in yes-associated protein (YAP) ubiquitinated degradation in PASMCs. YAP is the core effector of the Hippo pathway and mediates the expression of particular genes. The accumulation of YAP further increased the expression and activation of Notch3 and ultimately promoted the proliferation of PASMCs. In addition, we showed that preblocking S1PR2, prior silencing of STAT3, miR-135b, or YAP, and prior inhibition of Notch3 all attenuated S1P-induced PASMCs proliferation. Taken together, our study indicates that S1P stimulates PASMCs proliferation by activation of the S1PR2/STAT3/miR-135b/ß-transduction repeat-containing protein/YAP/Notch3 pathway, and our data suggest that targeting this cascade might have potential value in ameliorating PASMCs hyperproliferation and benefit pulmonary arterial hypertension.

Determinants of ICS therapy adherence in patients with asthma.

OBJECTIVES: This study aimed to evaluate factors affecting adherence to inhaled therapy in patients with asthma to further identify the determinants most closely associated with adherence to inhaled therapy for asthma, especially inhaled glucocorticosteroids (ICS). STUDY DESIGN: A 2-stage study was conducted. In stage 1, we performed nonassumptive deep-dive qualitative scoping to investigate the determinants of poor adherence in patients with asthma, and in stage 2 we developed a new questionnaire for cross-sectional surveys to obtain more accurate information about critical issues related to asthma management. METHODS: Patients with asthma who were 18 years and older in the outpatient clinic of The First Affiliated Hospital of Xi'an Jiaotong University from November 2016 to January 2018 were investigated. RESULTS: In the 350 patients with asthma recruited, 32% of patients showed good adherence, whereas 68% of patients displayed poor adherence to inhaled therapy due to various reasons. Further analysis indicated that inadequate understanding of asthma treatment and control, poor self-management, financial burden, adverse reactions, and the fear of potential adverse reactions were significant independent risk factors for poor ICS inhalation adherence in patients with asthma. CONCLUSIONS: Our research shows that many patients with asthma in western China have poor disease control and poor inhalation therapy adherence. We hope this research can alert clinicians and help them identify patients who may be experiencing uncontrolled asthma due to poor adherence to inhaled therapy, and we suggest that clinicians help those patients obtain appropriate information about asthma control and self-management.

Activation of yes-associated protein mediates sphingosine-1-phosphate-induced proliferation and migration of pulmonary artery smooth muscle cells and its potential mechanisms.

The aims of the present study were to examine the molecular mechanisms underlying sphingosine-1-phosphate (S1P)-induced rat pulmonary artery smooth muscle cells (PASMCs) proliferation/migration and to determine the effect of yes-associated protein (YAP) activation on S1P-induced PASMCs proliferation/migration and its potential mechanisms. S1P induced YAP dephosphorylation and nuclear translocation, upregulated microRNA-130a/b (miR-130a/b) expression, reduced bone morphogenetic protein receptor 2 (BMPR2), and inhibitor of DNA binding 1(Id1) expression, and promoted PASMCs proliferation and migration. Pretreatment of cells with Rho-associated protein kinase (ROCK) inhibitor Y27632 suppressed S1P-induced YAP activation, miR-130a/b upregulation, BMPR2/Id1 downregulation, and PASMCs proliferation/migration. Knockdown of YAP using small interfering RNA also suppressed S1P-induced alterations of miR-130a/b, BMPR2, Id1, and PASMCs behavior. In addition, luciferase reporter assay indicated that miR-130a/b directly regulated BMPR2 expression in PASMCs. Inhibition of miR-130a/b functions by anti-miRNA oligonucleotides attenuated S1P-induced BMPR2/Id1 downregulation and the proliferation and migration of PASMCs. Taken together, our study indicates that S1P induces activation of YAP through ROCK signaling and subsequently increases miR-130a/b expression, which, in turn, downregulates BMPR2 and Id1 leading to PASMCs proliferation and migration.

Zafirlukast prevented ox-LDL-induced formation of foam cells.

Atherosclerosis (AS), a common arterial disease, is one of the main pathological roots of cardiovascular disease. The formation and accumulation of foam cells is an important event in early AS. An imbalance between cholesterol uptake and efflux is the primary cause of foam cell formation. Although research has focused on preventing the formation of foam cells, a safe and effective therapy has to be found. Zafirlukast is a widely useful type 1 cysteinyl leukotriene receptor (CysLT1R) antagonist with a good safety profile. Zafirlukast is the most used for the treatment of asthma and allergic rhinitis. However, the effect of zafirlukast on preventing the formation of foam cells has not been determined. The aim of this study was to investigate whether zafirlukast prevented macrophages from transforming into foam cells. Our data show that zafirlukast reduced the expression of CD36 and lipoprotein receptor-1 (LOX-1), which are responsible for lipid uptake. In addition, zafirlukast enhanced the activity of ATP-Binding Cassette A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1), leading to the acceleration of cholesterol efflux. Furthermore, zafirlukast influenced the activity of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway, which mediates the expression of ABCA1 and ABCG1. In summary, our data indicate that zafirlukast might be a potential treatment strategy for AS by mediating lipid metabolism and preventing the formation of foam cells.

SgRVE6, a LHY-CCA1-Like Transcription Factor From Fine-Stem Stylo, Upregulates NB-LRR Gene Expression and Enhances Cold Tolerance in Tobacco.

Stylosanthes species are economically important tropical and subtropical forage legumes which are generally vulnerable to chilling and frost. Fine-stem stylo (S. guianensis var. intermedia) has the most superior cold tolerance among all stylo species. A REVEILLE (RVE) gene, SgRVE6, was cloned from fine-stem stylo. Bioinformatic analysis suggests that SgRVE6 encodes a transcription factor of 292 amino acid residues, which belongs to the LATE ELONGATED HYPOCOTYL/CIRCADIAN CLOCK ASSOCIATED 1-LIKE (LCL) subgroup of RVE family and contains a SHAQKYF-class MYB domain and a LCL domain. SgRVE6 is universally expressed in root, stem and leaf tissues of fine-stem stylo and is rapidly up-regulated in all tested tissues under cold stress. Over-expressing SgRVE6 affects expression of 21 circadian clock genes, up-regulates expression of 6 nucleotide binding domain leucine-rich repeats (NB-LRR) encoding genes associated with tobacco cold tolerance, improves physiological responses to low temperature, and endows the transgenic tobaccos with higher tolerance to cold stress. This is the first time a study investigates the biological function of RVE6 in cold responses of plant species.