miR-23b-3p Ameliorates LPS-Induced Pulmonary Fibrosis by Inhibiting EndMT via DPP4 Inhibition.

Acute respiratory distress syndrome is a disease triggered by severe pulmonary and systemic inflammation that may lead to fibrosis and the decline of lung function. Lung capillary endothelial-to-mesenchymal transition (EndMT) is one of the primary sources of fibroblasts in pulmonary fibrosis. The role of miRNAs as molecular markers of pulmonary fibrosis, and miRNAs as nucleic acid drugs has attracted increasing attention. To mock EndMT process, Human pulmonary microvascular endothelial cells (HPMECs) were induced with lipopolysaccharide (LPS). Similarly, LPS treatment was used to generate a mouse model of LPS-induced EndMT and pulmonary fibrosis. LPS-induced EndMT in HPMECs resulted in a significant reduction of miR-23b-3p. miR-23b-3p inhibited the interstitial transition of HPMECs, and miR-23b-3p could mediate this process via inhibiting dipeptidyl peptidase-4 (DPP4). Dual-luciferase assays confirmed the regulatory mechanism of miR-23b-3p. In our mouse model of LPS-induced pulmonary fibrosis, miR-23b-3p and a DPP4 inhibitor (sitagliptin) individually alleviated LPS-induced EndMT progression and pulmonary fibrosis, and their combined use achieved the strongest remission effect. To sum up, miR-23b-3p alleviates EndMT in pulmonary fibrosis by inhibiting the expression of DPP4.

Participation of ASK-1 in the cardiomyocyte-protective role of mechanical ventilation in a rat model of myocardial infarction.

Non-invasive positive-pressure ventilation (NIPPV) has been demonstrated to exhibit a cardioprotective function in a rat model of myocardial infarction (MI). However, the mechanism underlying NIPPV-mediated MI progression requires further investigation. We aimed to investigate the effectiveness and corresponding mechanism of NIPPV in an acute MI-induced heart failure (HF) rat model. Thirty each of healthy wild type (WT) and apoptosis signal-regulating kinase 1 (ASK-1)-deficient rats were enrolled in this study. MI models were established via anterior descending branch ligation of the left coronary artery. The corresponding data indicated that NIPPV treatment reduced the heart infarct area, myocardial fibrosis degree, and cardiac function loss in MI rats, and ameliorated apoptosis and reactive oxygen species (ROS) levels in the heart tissue. Furthermore, the expression level of ASK-1 level, a key modulator of the ROS-induced extrinsic apoptosis pathway, was upregulated in the heart tissues of MI rats, but decreased after NIPPV treatment. Meanwhile, the downstream cleavage of caspase-3, caspase-9, and PARP, alongside p38 phosphorylation and FasL expression, exhibited a similar trend to that of ASK-1 expression. The involvement of ASK-1 in NIPPV-treated MI in ASK-1-deficient rats was examined. Although MI modeling indicated that cardiac function loss was alleviated in ASK-1-deficient rats, NIPPV treatment did not confer any clear efficiency in cardiac improvement in ASK-1-knockdown rats with MI modeling. Nonetheless, NIPPV inhibited ROS-induced extrinsic apoptosis in the heart tissues of rats with MI by regulating ASK-1 expression, and subsequently ameliorated cardiac function loss and MI-dependent pathogenic changes in the heart tissue.

Vitamin D, vitamin D supplementation and atrial fibrillation risk in the general population: updated systematic review and meta-analysis of prospective studies.

Background: Since the association of vitamin D with atrial fibrillation (AF) risk is still unclear, we conducted this updated meta-analysis of prospective studies to identify the relationship between vitamin D or vitamin D supplementation and AF in the general population. Methods: We conducted a comprehensive search of multiple databases up to May 2023 for studies reporting vitamin D and AF. The hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled by a random-effects model. Results: A total of seven studies were included in this meta-analysis. Vitamin D deficiency (<20 ng/ml) was associated with increased AF incidence (HR: 1.12, 95% CI: 1.005-1.25). The HR was not significant with vitamin D insufficiency (20-30 ng/ml; HR: 1.09, 95% CI: 0.98-1.21). Each 10 ng/ml increase in serum vitamin D was associated with a significantly decreased AF incidence (HR: 0.95, 95% CI: 0.93-0.97). Two studies reported the effect of vitamin D supplements on AF incidence but reached inconsistent results. Conclusions: Vitamin D deficiency or insufficiency was associated with an increased risk of AF in the general population. The role of vitamin D supplementation in AF prevention needs further investigation.

Toll-like receptor 4 promotes the inflammatory response in septic acute kidney injury by promoting p38 mitogen-activated protein kinase phosphorylation.

Septic acute kidney injury (AKI) contributes to the mortality and morbidity of sepsis patients. Toll-like Receptor 4 (TLR4) has prominent roles in septic AKI. This study investigated the functions of TLR4 in septic AKI. A septic AKI mouse model was established by cecal ligation and puncture surgery. Mouse kidney function and kidney tissue lesion were examined using corresponding kits and H&E staining. The in vitro cell model of septic AKI was established by lipopolysaccharide induction. Cell viability, inflammatory factor (TNF-α, IL-6, IL-4, IL-1ß, IL-18) levels, pyroptotic cell number changes, lactate dehydrogenase (LDH) activity, myeloperoxidase (MOP) concentration, and levels of pyroptosis-associated protein and MyD88, TRIF and p38 MAPK phosphorylation were determined by MTT, ELISA, FAM-FLICA Caspase-1 Detection kit, other corresponding kits, and Western blot. TLR4 was highly expressed in septic AKI mouse kidney tissues and human septic AKI cells. TLR4 knockdown alleviated kidney injury, increased cell viability, and reduced LDH activity and MPO concentration. TLR4 knockdown reduced cell pyroptosis by repressing p38 MAPK phosphorylation through MyD88/TRIF, suppressed pro-inflammatory factor (TNF-α, IL-6, IL-4, IL-1ß, IL-18) levels, promoted anti-inflammatory factor (IL-4) level, and reduced inflammatory response, thus playing a protective role in septic AKI. Briefly, TLR4 promoted the inflammatory response in septic AKI by promoting p38 MAPK phosphorylation through MyD88/TRIF.

Mechanical ventilation reduces myocardial injury in rats with acute heart failure by inhibiting cardiomyocyte apoptosis.

OBJECTIVE: To explore the mechanism by which mechanical ventilation improves myocardial injury in rats with acute heart failure (AHF). METHODS: Thirty-six male Sprague Dawley rats were randomized into a sham group, heart failure (HF) group, and mechanical ventilation (MV) group. The AHF rat model was established by pentobarbital perfusion under right internal jugular vein monitoring. The symptoms of heart failure, changes in hemodynamic parameters, cardiac function, N-terminal pro-B-type natriuretic peptide (NT-proBNP), oxidative stress-related indicators, myocardial apoptosis index, and expression of apoptosis-related proteins were compared in an AHF rat model with or without mechanical ventilation. RESULTS: Compared to the sham group, the hemodynamics and cardiac function of MV and HF groups were markedly reduced (P<0.05), and the serum levels of NT-proBNP of MV and HF groups were elevated (P<0.05). The levels of malondialdehyde (MDA) were lowest in the sham group, followed by the MV group, and highest in the HF group. Glutathione (GSH) and superoxide dismutase (SOD) were lowest in the HF group, inermediate in MV group, and highest in the sham group (P<0.05). Mechanical ventilation improved myocardial injury and reduced apoptosis of myocardial cells in a rat model of AHF. CONCLUSION: Mechanical ventilation in the early stage of heart failure can significantly reduce the excessive occurrence of oxidative stress in rats and significantly improve apoptosis in myocardial cells in AHF rats, so as to effectively improve the symptoms of AHF and reduce the mortality of AHF rats.

Effects of oral anticoagulant therapy in patients with pulmonary diseases.

Background: To evaluate the effect of oral anticoagulants (OACs) therapy, including vitamin K antagonist (VKA) and direct oral anticoagulants (DOAC) in patients with pulmonary diseases. Methods: Literature from PubMed, MEDLINE, and Cochrane Library were screened until June 2022. Studies assessing OACs for pulmonary hypertension (PH), pulmonary embolism (PE), pulmonary fibrosis (PF), or chronic obstructive pulmonary disease (COPD) were evaluated for inclusion. Results: Our study indicated that in patients with PH, PE, and COPD, OACs could significantly reduce the mortality risk, and the effects of VKA and DOACs without statistical difference in reducing the risk of recurrent embolism events. In patients with sclerosis-associated pulmonary arterial hypertension (SSc-PAH) or idiopathic pulmonary fibrosis (IPF), vitamin K antagonist (warfarin) significantly increased the mortality risk, while DOACs were not. As for the safety outcome of OACs, existing studies indicate that compared with patients treated with warfarin, the users of DOAC have a lower risk of major bleeding, while there is no statistical significance between them in non-major bleeding events. In current guidelines, the anticoagulation regimen for patients with pulmonary disease has not been defined. The results of our study confirm that DOACs (apixaban, rivaroxaban, dabigatran, and edoxaban) are superior to VKAs in the efficacy and safety outcomes of patients with pulmonary disease. Conclusions: Oral anticoagulant therapy brings benefits to patients with PH, PE, or COPD, while the anticoagulation regimen for patients with SSc-PAH or IPF requires serious consideration. Compared with VKA, DOAC is a non-inferior option for anticoagulation in pulmonary disease treatment. Further studies are still needed to provide more reliable evidence about the safety outcome of pulmonary disease anticoagulation.

The predictive value of lung ultrasound combined with central venous oxygen saturation variations in the outcome of ventilator weaning in patients after thoracic surgery.

OBJECTIVE: To evaluate the predictive value of lung ultrasound score (LUS) combined with central venous oxygen saturation variations (ΔScvO2) in the outcome of ventilator weaning in patients after thoracic surgery. METHODS: The clinical data of 60 patients who received tracheal intubation ventilator-assisted breathing after thoracic surgery were retrospectively analyzed, and they were divided into successful (n = 35) and failed (n = 25) groups according to the postoperative weaning outcomes. The factors influencing the failure of weaning in patients after thoracic surgery were compared and analyzed, and the values of LUS, ΔScvO2 as well as the combination of both were calculated to predict the failure of weaning in patients after thoracic surgery. RESULTS: The results of logistic regression analysis showed that LUS, ΔScvO2, and partial pressure of carbon dioxide (PaCO2) may be risk factors influencing weaning failure in patients after thoracic surgery (OR = 1.844, 4.006, 1.271, P < 0.001 for all), while diaphragm thickening fraction (DTF) and partial pressure of oxygen (PaO2) may be protective factors (OR = 0.852, 0.674, P = 0.002 for all). Receiver operator characteristic (ROC) curve showed that area under the curves (AUCs) of LUS, ΔScvO2, and the combination of the two was 0.865 (95% CI: 0.766-0.964), 0.874 (95% CI: 0.781-0.967), and 0.925 (95% CI: 0.860-0.990), respectively, in predicting failure of weaning in patients after thoracic surgery. CONCLUSION: LUS and ΔScvO2 were closely related to chest ultrasound index and arterial blood gas index in patients after thoracic surgery, both of which may be risk factors for weaning failure in patients after thoracic surgery, and their combination can effectively predict the occurrence of weaning failure.