KDELR2 is necessary for chronic obstructive pulmonary disease airway Mucin5AC hypersecretion via an IRE1α/XBP-1s-dependent mechanism.

Airway mucus hypersecretion, a crucial pathological feature of chronic obstructive pulmonary disease (COPD), contributes to the initiation, progression, and exacerbation of this disease. As a macromolecular mucin, the secretory behaviour of Mucin5AC (MUC5AC) is highly dependent on a series of modifying and folding processes that occur in the endoplasmic reticulum (ER). In this study, we focused on the ER quality control protein KDEL receptor (KDELR) and demonstrated that KDELR2 and MUC5AC were colocalized in the airway epithelium of COPD patients and COPD model rats. In addition, knockdown of KDELR2 markedly reduced the expression of MUC5AC both in vivo and in vitro and knockdown of ATF6 further decreased the levels of KDELR2. Furthermore, pretreatment with 4µ8C, an IRE1α inhibitor, led to a partial reduction in the expression of KDELR2 and MUC5AC both in vivo and in vitro, which indicated the involvement of IRE1α/XBP-1s in the upstream signalling cascade. Our study revealed that KDELR2 plays a crucial role in airway MUC5AC hypersecretion in COPD, which might be dependent on ATF6 and IRE1α/XBP-1s upstream signalling.

Clinical Characteristics of Overweight Patients With Acute Exacerbation Chronic Obstructive Pulmonary Disease (AECOPD).

INTRODUCTION: Low body weight in patients with COPD is associated with a poor prognosis and more comorbidities. However, the impact of increased body weight in patients with COPD remains controversial. The aim of this study was to explore the clinical features of overweight patients with AECOPD. METHODS: In this multicenter cross-sectional study, a total of 647 AECOPD patients were recruited. Finally, 269 normal weight and 162 overweight patients were included. Baseline characteristics and clinical and laboratory data were collected. The least absolute shrinkage and selection operator (LASSO) regression was performed to determine potential features, which were substituted into binary logistic regression to reveal overweight-associated clinical features. The nomogram and its associated curves were established to visualize and verify the logistic regression model. RESULTS: Six potential overweight-associated variables were selected by LASSO regression. Subsequently, a binary logistic regression model identified that the rates of type 2 diabetes (T2DM) and hypertension and levels of lymphocytes (LYM)%, and alanine aminotransferase (ALT) were independent variables of overweight in AECOPD patients. The C-index and AUC of the ROC curve of the nomogram were 0.671 and 0.666, respectively. The DCA curve revealed that the nomogram had more clinical benefits if the threshold was at a range of 0.22~0.78. CONCLUSIONS: Collectively, we revealed that T2DM and hypertension were more common, and LYM% and ALT were higher in AECOPD patients with overweight than those with normal weight. The result suggests that AECOPD patients with overweight are at risk for additional comorbidities, potentially leading to worse outcomes.

MAPKAP1 orchestrates macrophage polarization and lipid metabolism in fatty liver-enhanced colorectal cancer.

Various factors, including fatty liver and macrophage alterations, influence colorectal cancer (CRC). This study explores the mechanistic role of fatty liver in CRC progression, focusing on macrophage polarization and lipid metabolism. A murine fatty liver model was created with a high-fat diet (HFD), and CRC was induced using AOM and DSS. Single-cell transcriptome sequencing (scRNA-seq) identified MAPKAP1 as a critical gene promoting CRC via M2 macrophage polarization and lipid metabolism reprogramming. Prognosis analysis on the TCGA-CRC dataset confirmed MAPKAP1's significance. In vitro and in vivo experiments demonstrated that EVs from fatty liver cells enhanced MAPKAP1 expression, accelerating CRC development and metastasis. HFD exacerbated CRC, but fatty acid inhibitors delayed progression. Fatty liver upregulates MAPKAP1, driving M2 macrophage polarization and lipid metabolism changes, worsening CRC. These findings suggest potential therapeutic strategies for CRC, particularly targeting lipid metabolism and macrophage-mediated tumor promotion.

Risk factors for hyponatremia in acute exacerbation chronic obstructive pulmonary disease (AECOPD): a multicenter cross-sectional study.

BACKGROUND: Hyponatremia is an independent predictor of poor prognosis, including increased mortality and readmission, in COPD patients. Identifying modifiable etiologies of hyponatremia may help reduce adverse events in patients with AECOPD. Therefore, the aim of this study was to explore the risk factors and underlying etiologies of hyponatremia in AECOPD patients. METHODS: A total of 586 AECOPD patients were enrolled in this multicenter cross-sectional study. Finally, 323 had normonatremia, and 90 had hyponatremia. Demographics, underlying diseases, comorbidities, symptoms, and laboratory data were collected. The least absolute shrinkage and selection operator (LASSO) regression was used to select potential risk factors, which were substituted into binary logistic regression to identify independent risk factors. Nomogram was built to visualize and validate binary logistics regression model. RESULTS: Nine potential hyponatremia-associated variables were selected by LASSO regression. Subsequently, a binary logistic regression model identified that smoking status, rate of community-acquired pneumonia (CAP), anion gap (AG), erythrocyte sedimentation rate (ESR), and serum magnesium (Mg2+) were independent variables of hyponatremia in AECOPD patients. The AUC of ROC curve of nomogram was 0.756. The DCA curve revealed that the nomogram could yielded more clinical benefits if the threshold was between 10% and 52%. CONCLUSIONS: Collectively, our results showed that smoking status, CAP, AG, ESR, and serum Mg2+ were independently associated with hyponatremia in AECOPD patients. Then, these findings indicate that pneumonia, metabolic acidosis, and hypomagnesemia were the underlying etiologies of hyponatremia in AECOPD patients. However, their internal connections need further exploration.

Association between serum cotinine and α-Klotho levels among adults: Findings from the National Health and Nutrition Examination Survey 2007-2016.

INTRODUCTION: Serum cotinine is a sensitive and specific marker of tobacco smoke exposure. α-Klotho is an anti-ageing molecule, which plays an important role in several diseases. We aimed to examine the association between smoke exposure indicated by the serum cotinine and α-Klotho levels, as previous reports regarding the level of α-Klotho in smokers have been inconsistent. METHODS: This secondary dataset analysis included 9833 participants (aged 40-79 years; 47.0% females and 53.0% males) from the US National Health and Nutrition Examination Survey 2007-2016. Independent variables were serum cotinine level, age, sex, race, body mass index (BMI), and alcohol consumption. The outcome variable was serum α-Klotho level. Multiple linear regression analysis was used to examine the association between serum cotinine and α-Klotho levels. RESULTS: The serum cotinine level was negatively associated with the α-Klotho level (ß= -0.107, 95% CI: -0.155 to -0.059, p<0.0001) after adjusting for age, BMI, sex, race, and alcohol consumption. The α-Klotho level in participants with cotinine ≥3 ng/mL decreased by 44.514 pg/mL (p<0.0001) compared to that in participants with cotinine <3 ng/mL. There is a non-linear relationship between serum cotinine and α-Klotho levels. The piecewise linear models indicated a significant threshold effect between serum cotinine and α-Klotho levels. On the left of the inflection point (cotinine <130 ng/mL), the serum cotinine level increased with decreased α-Klotho level (ß= -0.519, 95% CI: -0.682 to -0.356). On the right of the inflection point (cotinine ≥130 ng/mL), the serum cotinine level increased with increased α-Klotho level (ß=0.085, 95% CI: 0.000 to 0.170). CONCLUSIONS: Based on our study results, serum cotinine level was associated with the serum α-Klotho level.

Notoginsenoside R1 Protects Against High Glucose-Induced Cell Injury Through AMPK/Nrf2 and Downstream HO-1 Signaling.

Notoginsenoside R1 (NGR1), the primary bioactive compound found in Panax notoginseng, is believed to have antihypertrophic and antiapoptotic properties, and has long been used to prevent and treat cardiovascular diseases. However, its potential role in prevention of diabetic cardiomyopathy remains unclear. The present study aimed to investigate the mechanism of NGR1 action in high glucose-induced cell injury. H9c2 cardiomyocytes were cultured in a high-glucose medium as an in-vitro model, and apoptotic cells were visualized using TUNEL staining. Expression of Nrf2 and HO-1 was measured using Western blotting or reverse transcription-quantitative PCR (RT-qPCR). The Nrf2 small interfering (si) RNA was transfected into cardiomyocytes using Opti-MEM containing Lipofectamine® RNAiMAX. NGR1 protected H9c2 cardiomyocytes from cell death, apoptosis and hypertrophy induced by high glucose concentration. Expression of auricular natriuretic peptide and brain natriuretic peptide was remarkably reduced in NGR1-treated H9C2 cells. Western blot analysis showed that high glucose concentration markedly inhibited AMPK, Nrf2 and HO-1, and this could be reversed by NGR1 treatment. However, the cardioprotective effect of NGR1 was attenuated by compound C, which reverses Nrf2 and HO-1 expression levels, suggesting that AMPK upregulates Nrf2 and HO-1 gene expression, protein synthesis and secretion. Transfection of H9C2 cells with Nrf2 siRNA markedly reduced the cardioprotective effect of NGR1 via reduced expression of HO-1. These results indicated that NGR1 attenuated high glucose-induced cell injury via AMPK/Nrf2 signaling and its downstream target, the HO-1 pathway. We conclude that the cardioprotective effects of NGR1 result from upregulation of AMPK/Nrf2 signaling and HO-1 expression in cardiomyocytes. Our findings suggest that NGR1 treatment might provide a novel therapy for diabetic cardiomyopathy.

Metformin attenuates angiotensin II-induced cardiomyocyte hypertrophy by upregulating the MuRF1 and MAFbx pathway.

Pathological cardiac hypertrophy induced by aging and neurohumoral activation, such as angiotensin II (Ang II) activation, is an independent risk factor for heart failure. The muscle really interesting new gene-finger protein-1 (MuRF1) and muscle atrophy F-box (MAFbx) pathway has been previously reported to be an important mechanism underlying the pathogenesis of cardiac hypertrophy. Metformin is currently the first-line blood glucose-lowering agent that can be useful for the treatment of cardiovascular diseases. However, the potential role of metformin in the modulation of MuRF1 and MAFbx in cardiomyocyte hypertrophy remains poorly understood. The present study used H9c2 cells, a cardiomyocyte cell model. The surface area of cultured rat H9c2 myoblasts was measured and the expression levels of MuRF1 and MAFbx were quantified using western blot or reverse transcription-quantitative PCR. H9c2 cells were transfected with MuRF1 and MAFbx small interfering (si) RNA. The present study revealed that Ang II treatment significantly increased the cell surface area of model cardiomyocytes. Additionally, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNA and protein expression was increased following this treatment. Ang II also downregulated MuRF1 and MAFbx protein and mRNA expression. In the H9C2, treatment with metformin attenuated hypertrophic remodeling. In addition, expression of ANP and BNP was significantly reduced in metformin-treated H9C2 cells. The results indicated that metformin increased the activity of MuRF1 and MAFbx and upregulated their expression, the knockdown of which resulted in deteriorative Ang II-induced cell hypertrophy, even following treatment with metformin. Taken together, data from the present study suggest that metformin can prevent cardiac hypertrophy through the MuRF1 and MAFbx pathways.

Irisin Enhances Angiogenesis of Mesenchymal Stem Cells to Promote Cardiac Function in Myocardial Infarction via PI3k/Akt Activation.

BACKGROUND AND OBJECTIVES: With the growing incidence of acute myocardial infarction (MI), angiogenesis is vital for cardiac function post-MI. The role of bone marrow mesenchymal stem cells (BMSCs) in angiogenesis has been previously confirmed. Irisin is considered a potential vector for angiogenesis. The objective of the present study was to investigate the potential role of irisin in the angiogenesis of BMSCs. METHODS AND RESULTS: In vivo, irisin-treated BMSCs (BMSCs＋irisin) were transplanted into an MI mouse model. On day 28 post-MI, blood vessel markers were detected, and cardiac function and infarct areas of mice were evaluated. In vitro, paracrine effects were assessed by examining tube formation in human umbilical vein endothelial cells (HUVECs) co-cultured with the BMSCs＋irisin supernatant. The scratch wound-healing assay was performed to evaluate HUVEC migration. Western blotting was performed to determine PI3k/Akt pathway activation in the BMSCs＋irisin group. Transplantation of BMSCs＋irisin promoted greater angiogenesis, resulting in better cardiac function in the MI mouse model than in controls. In the BMSC＋irisin group, HUVECs demonstrated enhanced tube formation and migration. Activation of the PI3k/Akt pathway was found to be involved in mediating the role of irisin in the angiogenesis of BMSCs. CONCLUSIONS: In cardiovascular diseases such as MI, irisin administration can enhance angiogenesis of BMSCs and promote cardiac function via the PI3k/Akt pathway, optimizing the therapeutic effect based on BMSCs transplantation.

Cardiac hemodynamic response to the 6-minute walk test in patients with intestinal carcinoma undergoing bevacizumab treatment.

BACKGROUND: Exercise capacity is evaluated using the 6-minute walk test (6MWT) in various cardiovascular diseases. Bevacizumab (BEV) has been associated with significant risk of cardiovascular complications. The aim of this study was to investigate BEV-related influences on cardiac hemodynamic response to 6MWT. METHODS: We prospectively studied 24 patients with intestinal carcinoma to assess the hemodynamic response during 6MWT, of whom eight underwent BEV treatment. Obtained data was analyzed to identify hemodynamic differences between BEV and non-BEV treated patients. RESULTS: Twenty-four patients with stage IV intestinal carcinoma consented to assessment after the completion of three cycles of BEV-combined chemotherapy (age, 46.4±16.7 years) or standard chemotherapy alone (age, 56.4±13.7 years). In comparison with non-BEV treated patients, BEV-treated patients walked less (484.3±42.4 vs. 503.0±48.2, P=0.339). These two groups manifested similar hemodynamic response during the 6MWT. The change of hemodynamic parameters at 1 minute after completion of 6MWT was defined as hemodynamic parameter recovery. BEV-treated patients had significantly lower change of left cardiac work index (LCWi), cardiac index (CI), cardiac output (CO) and stroke volume (SV) after 6MWT. Interestingly, in BEV-treated patients CI change after 6MWT was predominantly related to the decrease in SV instead of heart rate (HR) as suggested by a higher standardized beta coefficient (0.883 vs. 0.657) and semi-partial correlations (0.821 vs. 0.677). CONCLUSIONS: Estimation of hemodynamic response to 6MWT is feasible, and may provide useful information of myocardial damage in BEV-treated patients.

Association between retinal arterial narrowing and left ventricular diastolic dysfunction in masked hypertensives.

Morphological change in retinal vessel diameters has been reported to be associated with negative cardiovascular outcomes, but its association with left ventricular diastolic dysfunction (LVDD) is not clear. This study aimed to examine the association between echocardiographic markers of LVDD and retinal vascular diameters, in untreated masked hypertension (MH). In this observational study, 105 MH patients without other cardiovascular risks were included (mean age 48.4 ± 5.7, female 72.4%). All individuals underwent extensive clinical and laboratory investigations, including echocardiography, ambulatory blood pressure monitoring, and retinal vascular diameters measured by optical coherence tomography. In the group, LVDD was diagnosed in 36 participants evaluated by left ventricular volume index, E/A and E/e' ratio. Compared to non-LVDD, LVDD subjects displayed narrower retinal arteriolar diameter (139.1 ± 33.8 vs 165.1 ± 29.1; adjusted P = .007) and wider retinal venular diameter (237.9 ± 42.2 vs 214.9 ± 44.8; adjusted P = .045). Significant and independent associations were demonstrated for retinal arteriolar narrowing and E/A ratio (adjusted ß = 0.744, P = .031) and for retinal arteriolar diameter and E/e' ratio (adjusted ß = -0.158, P = .001) after controlling for age, gender, body mass index, ambulatory systolic blood pressure, low-density lipoprotein cholesterol, and retinal venular diameter. In untreated MH subjects, retinal arteriolar diameter, a marker of microvascular damage, was independently associated with echocardiographic markers of diastolic dysfunction. These findings might underscore the hypothesis that microvascular disease could contribute to cardiac remodeling.

Sodium valproate sensitizes non-small lung cancer A549 cells to γδ T-cell-mediated killing through upregulating the expression of MICA.

Major histocompatibility complex (MHC) class I chain-related protein A (MICA) is involved in γδ T-cell recognition of target tumor cells. The aim of this study was to investigate the feasibility of utilization of sodium valproate (VPA), a histone deacetylase inhibitor, to sensitize non-small cell lung cancer A549 cells to γδ T-cell-mediated killing. VPA induced a dose-dependent increase in the mRNA and protein expression of MICA in A549 cells. γδ T cells showed cytotoxicity to A549 cells, which was increased by about 50% in the presence of VPA. The concomitant addition of MICA antibody significantly attenuated the VPA-mediated sensitization to γδ T-cell killing. VPA enhanced the cleavage of caspase-3 and caspase-9 in A549 cells cocultured with γδ T cells, and such enhancement was reversed by the MICA antibody. In conclusion, VPA sensitizes tumor cells to γδ T-cell-mediated cytotoxicity through the upregulation of MICA and may thus have benefits in improving γδ T-cell-based cancer immunotherapy.

The viable Mycobacterium tuberculosis H37Ra strain induces a stronger mouse macrophage response compared to the heat-inactivated H37Rv strain.

Macrophages are the target cells for Mycobacterium tuberculosis (M. tuberculosis) as well as key effector cells for clearance of this pathogen. The aim of the present study was to measure and compare the responses of mouse peritoneal macrophages following exposure to the live M. tuberculosis H37Ra and heat-inactivated H37Rv strains. In vitro phagocytosis assays indicated that the macrophages had a higher capacity to engulf the live H37Ra strain compared to the inactivated H37Rv strain. Enzyme-linked immunosorbent assay (ELISA) demonstrated that H37Ra­stimulated macrophages produced significantly increased concentrations of interleukin­12p40 (IL­12p40), tumor necrosis factor-α (TNF­α) and interferon­Î³ (IFN­Î³) compared to the untreated control cells. However, H37Rv exposure induced little to no increase in the levels of the cytokines examined. The results from ELISA were confirmed by reverse transcription-polymerase chain reaction (RT­PCR) at the mRNA level. There was a dose-dependent increase in nitric oxide (NO) and hydrogen peroxide (H2O2) production from the H37Ra­stimulated macrophages compared to the H37Rv­stimulated ones. Confocal microscopy and flow cytometric analysis indicated that the IFN­Î³­stimulated macrophages from viable H37Ra­immunized mice had an enhanced surface expression of CD40 ligand (CD40L) compared to those from inactivated H37Rv­immunized mice. Our data collectively indicate that exposure to the viable H37Ra strain induces a stronger macrophage response compared to exposure to the heat-inactivated H37Rv strain, which may be associated with the increased surface expression of CD40L in activated macrophages.

Comparison of circumferential pulmonary vein isolation and antiarrhythmic drug therapy in patients with atrial fibrillation.

INTRODUCTION: The aim of this study was to evaluate quality of life after circumferential pulmonary vein isolation (CPVI) compared with antiarrhythmic drug therapy (ADT) in treating atrial fibrillation (AF). CPVI is now a common therapy in AF, but few studies have focused on the effect of CPVI on quality of life. METHODS: A total of 123 AF patients were followed prospectively. Quality of life was evaluated comparing CPVI with ADT as a second-line treatment for patients with AF. The Medical Outcomes Study Short Form (SF)-36 health surveys were conducted to establish a baseline score before initiation and again at 6 months after the intervention. RESULTS: Mean follow-up duration was 12.7 ± 4.3 months. Of 123 patients enrolled, 66 were randomized to receive CPVI and 57 to ADT alone. At the 6-month follow-up, 13 (22.8%) patients in the ADT group and 41 (62.1%) patients in the CPVI group had no recurrence of AF. The SF-36 scales were significantly higher in the CPVI than in the ADT group, as were the physical component summary scores (269.3 ± 58.6 vs. 234.9 ± 66.9) and mental component summary scores (273.6 ± 69.4 vs. 234.1 ± 44.7). Quality of life was significantly higher in the CPVI group (except for body pain). CONCLUSION: In patients with AF, CPVI has superiority over ADT with regards to the maintenance of sinus rhythm and improvements in quality of life.