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.

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.

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.

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.

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.

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.

Electricity production and key exoelectrogens in a mixed-culture psychrophilic microbial fuel cell at 4 °C.

The electricity production via psychrophilic microbial fuel cell (PMFC) for wastewater treatment in cold regions offers an alternative to avoid the unwanted methane dissolution of traditional anaerobic fermentation. But, it is seldom reported by mixed-culture, especially closed to 0 °C. Thus, a two-chamber mixed-culture PMFC at 4 °C was successfully operated in this study using acetate as an electron donor. The main results demonstrated a good performance of PMFC, including the maximum voltage of 513 mV at 1000 Ω, coulombic efficiency of 53%, and power density of 689 mW/m2. The cyclic voltammetry curves of enriched biofilm showed a direct electron transfer pathway. These good performances of mixed-culture PMFC were due to the high psychrophilic activity of enriched biofilm, including exoelectrogens genera of Geobacter (6.1%), Enterococcus (17.5%), and Clostridium_sensu_stricto_12 (3.8%). Consequently, a mixed-culture PMFC provides a reasonable strategy to enrich exoelectrogens with high activity. For low-temperature regions, the mixed-culture PMFC involved biotechnologies shall benefit energy generation and valuable chemical production in the future. KEY POINTS: • PMFC showed a maximum voltage of around 513 mV under a resistance of 1000 Ω. • The coulombic efficiency was 53% and the max power density was 689 mW/m2. • Geobacter, Enterococcus, and Clostridium_sensu_stricto_12 were key exoelectrogens.

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.

Activation of AMPK inhibits Galectin-3-induced pulmonary artery smooth muscle cells proliferation by upregulating hippo signaling effector YAP.

Galectin-3(Gal-3) is an effective regulator in the pathological process of pulmonary arterial hypertension (PAH). However, the detailed mechanisms underlying Gal-3 contribution to PAH are not yet entirely clear. The aim of the present study was to explore these issues. Proliferation of rat pulmonary arterial smooth muscle cells (PASMCs) was determined using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Small interfering RNA (siRNA) was applied to silence the expression of yes-associated protein (YAP) and Forkhead box M1 (FOXM1). The protein expression and phosphorylation were measured by immunoblotting. The subcellular location of YAP was determined using immunoblotting and immunofluorescence. Gal-3-stimulated PASMCs proliferation in a time- and dose-dependent manner, this was accompanied with, YAP upregulation, dephosphorylation, and nucleus translocation. Gal-3 further increased FOXM1 and cyclinD1 expression via YAP activation. Interfering YAP/FOXM1 axis suppressed Gal-3-induced PASMCs proliferation. Activation of AMPK also inhibited Gal-3-triggered cells proliferation by targeting YAP/FOXM1/cyclinD1 pathway. Gal-3 induced PASMCs proliferation by regulating YAP/FOXM1/cyclinD1 signaling cascade, and activation of AMPK targeted on this axis and suppressed Gal-3-stimulated PASMCs proliferation. Our study provides novel therapeutic targets for prevention and treatment of PAH.

The association between cystatin C and COPD: a meta-analysis and systematic review.

BACKGROUND: In recent years, many studies have discovered that cystatin C (Cys C) may play an important role in respiratory diseases, especially in chronic obstructive pulmonary disease (COPD). However, the findings of these studies were inconsistent. This systematic review and meta-analysis aimed to assess the relationship between serum Cys C and COPD. METHODS: We conducted a systematic literature search in PubMed, Embase, Web of Science, Wanfang databases, and the China National Knowledge Infrastructure. The standardized mean difference (SMD), Fisher's Z-value and 95% confidence interval (CI) were calculated to investigate the effect sizes. Subgroup analyses were performed on disease status, ethnicity, assay method, and study design. Sensitivity was performed, and publication bias was assessed. RESULTS: A total of 15 studies, including 4079 COPD patients and 5949 controls, were included in this meta-analysis. The results showed that serum Cys C levels in patients with COPD were significantly higher than those in controls (SMD = 0.99, 95% CI =0.62-1.37, P < 0.001), especially in AECOPD (SMD = 1.59, 95% CI =1.05-2.13, P < 0.001), and there were statistically different among AECOPD and SCOPD (SMD = 0.35, 95% CI =0.10-0.59, P = 0.005). The serum Cys C levels were negatively correlated with FEV1%pre (Z = - 0.45, 95%CI = -0.58--0.32, P = 0.011) and FEV1/FVC (Z = - 0.32, 95%CI = -0.50--0.14, P = 0.006). The serum Cys C levels were independent of ethnicity, assay method, and study design. CONCLUSION: Serum Cys C levels were associated with COPD and COPD exacerbation, and they were inversely correlated with FEV1%pre and FEV1/FVC.

S1P induces pulmonary artery smooth muscle cell proliferation by activating calcineurin/NFAT/OPN signaling pathway.

The upregulation of osteopontin(OPN) has been found to contribute to the proliferation of pulmonary artery smooth muscle cells(PASMCs), and activation of PPARγ has been shown to suppress OPN expression in THP-1 cells. However, the molecular mechanisms underlying the upregulation of OPN expression and PPARγ agonist modulation of OPN expression in PASMCs remain largely unclear. Here we found that S1P stimulated PASMCs proliferation and up-regulated OPN expression in rat PASMCs, which was accompanied with the activation of phospholipase C(PLC), calcineurin and translocation of NFATc3 to nucleus. Further study showed that inhibition of PLC by U73122, suppression of calcineurin activity by cyclosporine A(CsA) or knockdown of NFATc3 using small interfering RNA suppressed S1P-induced OPN up-regulation. Activation of PPARγ by pioglitazone suppressed S1P-induced activation of calcineurin/NFATc3 signaling pathway and followed OPN up-regulation. Taken together, our study indicates that S1P stimulates OPN expression by activation of PLC/calcineurin/NFATc3 signaling pathway, and activation of PPARγ suppresses calcineurin/NFATc3-mediated OPN expression in PASMCs.

COP9 signalosome subunit 6 mediates PDGF -induced pulmonary arterial smooth muscle cells proliferation.

Up-regulation of mammalian COP9 signalosome subunit 6 (CSN6) and consequent reduction of SCF ubiquitin ligase substrate receptor ß-transduction repeat-containing protein (ß-TrCP) have been shown to be associated with cancer cells proliferation. However, it is unclear whether CSN6 and ß-TrCP are also involved in PDGF-induced pulmonary arterial smooth muscle cells (PASMCs) proliferation. This study aims to address this issue and further explore its potential mechanisms. Our results indicated that PDGF phosphorylated Akt, stimulated PASMCs proliferation; while inhibition of PDGF receptor (PDGFR) by imatinib prevented these effects. PDGF further up-regulated CSN6 protein expression, this was accompanied with ß-TrCP reduction and increase of Cdc25A. Inhibition of PDGFR/PI3K/Akt signaling pathway reversed PDGF-induced such changes and cell proliferation. Prior transfection of CSN6 siRNA blocked PDGF-induced ß-TrCP down-regulation, Cdc25A up-regulation and cell proliferation. Furthermore, pre-treatment of cells with MG-132 also abolished PDGF-induced ß-TrCP reduction, Cdc25A elevation and cell proliferation. In addition, pre-depletion of Cdc25A by siRNA transfection suppressed PDGF-induced PASMCs proliferation. Taken together, our study indicates that up-regulation of CSN6 by PDGFR/PI3K/Akt signaling pathway decreases ß-TrCP by increasing its ubiquitinated degradation, and thereby increases the expression of Cdc25A, which promotes PDGF-induced PASMCs proliferation.

SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway.

BACKGROUND/AIMS: The underlying molecular mechanisms involved in sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate (S1P) mediation of platelet-derived growth factor (PDGF)-induced pulmonary arterial smooth muscle cell (PASMC) proliferation are still unclear, and the present study aims to address this issue. METHODS: Small interfering RNA (siRNA) and microRNA inhibitor transfection was performed to block the expression of SphK1, bone morphogenetic protein receptor II (BMPRII) and microRNA-21 (miR-21). Gene expression levels of SphK1, BMPRII and inhibitor of DNA binding 1 (Id1) were detected by immunoblotting, miR-21 expression level was examined with qRT-PCR, and S1P production was measured by ELISA. Additionally, PASMC proliferation was determined by BrdU incorporation assay. RESULTS: Our results indicated that PDGF increased the expression of SphK1 protein and S1P production, up-regulated miR-21 expression, reduced BMPRII and Id1 expression, and promoted PASMCs proliferation. Pre-silencing of SphK1 with siRNA reversed PDGF-induced S1P production, miR-21 up-regulation, BMPRII and Id1 down-regulation, as well as PASMC proliferation. Pre-inhibition of miR-21 also blocked BMPRII and Id1 down-regulation as well as PASMC proliferation caused by PDGF. Knockdown of BMPRII down-regulated Id1 expression in PASMCs. We further found that inhibition of PI3K/Akt and ERK signaling pathways, particularly ERK cascade, suppressed PDGF-induced above changes. CONCLUSION: Our study indicates that SphK1/S1P pathway plays an important role in PDGF-induced PASMC proliferation via miR-21/BMPRII/Id1 axis and targeting against SphK1/S1P axis might be a novel strategy in the prevention and treatment of pulmonary arterial hypertension (PAH).

Association between psoriasis and asthma risk: A meta-analysis.

BACKGROUND: Psoriasis has been shown to be related to an increased risk of asthma, although the results remain inconclusive. Therefore, we performed a meta-analysis to determine whether psoriasis increases the risk of asthma. METHODS: A comprehensive search of medical literature data bases was conducted through May 2017. The pooled odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated. RESULTS: A total of six studies with 66,772 psoriasis cases and 577,415 controls were included. Our meta-analysis showed that psoriasis was significantly associated with the increased risk of asthma (OR 1.32 [95% CI, 1.20-1.46]). The older age patients with psoriasis (≥50 years) (OR 1.64 [95% CI, 1.44-1.88]) had a higher risk of asthma susceptibility compared with the younger patients (20-49 years old) (OR 1.25 [95% CI 1.09-1.44]). Subgroup analysis by ethnicity indicated a significant increase in asthma risk in both Asian populations (OR 1.35 [95% CI, 1.18-1.54]) and white populations (OR 1.27 [95% CI, 1.05-1.54]) with psoriasis compared with those without psoriasis. CONCLUSION: Results of this meta-analysis indicated that the patients with psoriasis had a higher risk of asthma susceptibility, especially among the older patients with psoriasis.

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.

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.

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.

Identification and degradation of structural extracellular polymeric substances in waste activated sludge via a polygalacturonate-degrading consortium.

By maintaining the cell integrity of waste activated sludge (WAS), structural extracellular polymeric substances (St-EPS) resist WAS anaerobic fermentation. This study investigates the occurrence of polygalacturonate in WAS St-EPS by combining chemical and metagenomic analyses that identify ∼22% of the bacteria, including Ferruginibacter and Zoogloea, that are associated with polygalacturonate production using the key enzyme EC 5.1.3.6. A highly active polygalacturonate-degrading consortium (GDC) was enriched and the potential of this GDC for degrading St-EPS and promoting methane production from WAS was investigated. The percentage of St-EPS degradation increased from 47.6% to 85.2% after inoculation with the GDC. Methane production was also increased by up to 2.3 times over a control group, with WAS destruction increasing from 11.5% to 28.4%. Zeta potential and rheological behavior confirmed the positive effect which GDC has on WAS fermentation. The major genus in the GDC was identified as Clostridium (17.1%). Extracellular pectate lyases (EC 4.2.2.2 and 4.2.2.9), excluding polygalacturonase (EC 3.2.1.15), were observed in the metagenome of the GDC and most likely play a core role in St-EPS hydrolysis. Dosing with GDC provides a good biological method for St-EPS degradation and thereby enhances the conversion of WAS to methane.

Yiqi Yangjing recipe stimulates apoptosis while suppressing the energy metabolism via under-expression of PFKFB3 in A549 cells.

Background: Lung cancer is a malignant tumor associated with high morbidity and mortality. Yiqi Yangjing recipe (YYR) is a formula of traditional Chinese medicine (TCM) that is commonly used for the treatment of lung cancer with good clinical efficacy. The specific anti-cancer mechanism of YYR is still unknown. We need to embark on a more in-depth pharmacological study of YYR to determine the complex compound ingredients, which could be promoted in clinical practice to achieve efficacy in prolonging recurrent metastasis of lung cancer. Methods: The cytotoxic effects of YYR on A549 cells were evaluated by Cell Counting Kit-8 (CCK-8) assay. The PFKFB3-under-expressed and overexpressed A549 cell lines were constructed via PFK15 treatment and transfection, respectively. The effects of YYR on PFKFB3 messenger RNA (mRNA) and protein expression were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. The pro-apoptotic and anti-glycolytic abilities of YYR were measured using flow cytometry assay and hippocampal XF96 extracellular flux analyzer. An in vivo tumorigenicity assay was performed on nude mice to confirm the anti-cancer effects of YYR. Results: YYR has a noticeable cytotoxic activity on A549 cells, with the treatment with both YYR and PFK15 significantly inducing apoptosis. YYR and PFK15 treatment reduced the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in A549 cells. Similar to PFK15, YYR can down-regulate PFKFB3 expression, and PFKFB3 overexpression suppressed the apoptosis, which was reversed by YYR. Animal experiments confirmed that YYR was able to inhibit tumor growth, induce tumor cell apoptosis, and down-regulate PFKFB3 in tumor tissues. Conclusions: This study demonstrated that YYR promoted lung cancer cell apoptosis and inhibited energy metabolism by targeting PFKFB3. Furthermore, we believe that YYR may be a suitable supplement or alternative drug for lung cancer treatment.