Deficiency of neutral cholesterol ester hydrolase 1 (NCEH1) impairs endothelial function in diet-induced diabetic mice.

BACKGROUND: Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored. METHODS: The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured. RESULTS: Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1. CONCLUSIONS: NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes.

Hydrogen sulfide in health and diseases: cross talk with noncoding RNAs.

Hydrogen sulfide (H2S) is previously described as a potentially lethal toxic gas. However, this gasotransmitter is also endogenously generated by the actions of cystathionine-ß-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) in mammalian systems, thus belonging to the family of gasotransmitters after nitric oxide (NO) and carbon monoxide (CO). The physiological or pathological significance of H2S has been extensively expanded for decades. Growing evidence has revealed that H2S exerts cytoprotective functions in the cardiovascular, nervous, and gastrointestinal systems by modulating numerous signaling pathways. With the continuous advancement of microarray and next-generation sequencing technologies, noncoding RNAs (ncRNAs) have gained recognition as key players in human health and diseases due to their considerable potential as predictive biomarkers and therapeutic targets. Coincidentally, H2S and ncRNAs are not independent regulators but interact with each other during the development and progression of human diseases. Specifically, ncRNAs might serve as downstream mediators of H2S or act on H2S-generating enzymes to govern endogenous H2S production. The purpose of this review is to summarize the interactive regulatory roles of H2S and ncRNAs in the initiation and development of various diseases and explore their potential health and therapeutic benefits. This review will also highlight the importance of cross talk between H2S and ncRNAs in disease therapy.

[Effect of Ropivacaine Combined with Dexmedetomidine for Serratus Anterior Plane Block Plus Patient-Controlled Intravenous Analgesia on Postoperative Recovery Quality of Patients Undergoing Thoracoscopic Radical Resection of Lung Cancer].

Objective: To study the postoperative analgesic effect of ropivacaine combined with dexmedetomidine for serratus anterior plane block (SAPB) under ultrasound visualization plus patient-controlled intravenous analgesia (PCIA) in patients undergoing thoracoscopic radical resection of lung cancer. Methods: A total of 129 patients undergoing elective thoracoscopic surgery were enrolled. The patients were randomly assigned to three groups ( n=43 in each group), a normal saline group (control group), a ropivacaine mesylate group (Group R) and a ropivacaine mesylate combined with dexmetomidine hydrochloride group (Group RD). After operation, ultrasound-guided SAPB was performed and patients in the three groups received the injection of 0 mL of 0.9% normal saline, 25 mL of 0.5% ropivacaine, and 25 mL of 0.5% ropivacaine+1 µg/kg dextrometomidine hydrochloride mixture, respectively. In addition, PCIA was used for all the patients. The button on the PCIA pump was pressed when the postoperative pain visual analogue score (VAS)≥4 on coughing, and rescue analgesic of sufentanil was given intravenously at 2.5 µg/bolus. The primary outcome was the VAS scores at rest and on coughing at 10 min (T 1), 6 h (T 2), 12 h (T 3), 24 h (T 4), and 48 h (T 5) after extubation. The secondary outcomes included hemodynamics, the quality of sleep for the first 3 nights after operation, number of times the button on the PCIA pump was pressed, intraoperative and postoperative opioid dosage, time of first postoperative rescue analgesic, duraion of intubation, length of stay at the hospital, adverse reactions, etc. Results: Compared with those of the control group, the VAS scores of the Group R and Group RD were significantly lower at 10 min, 6 h, and 12 h after extubation ( P<0.05). In comparison with Group R, the number of patients requiring rescue analgesia, the time of first postoperative rescue analgesic, the number of times the button on the PCIA pump was pressed, and the total dose of rescue sufentanil were all significantly lower ( P<0.05) in the Group RD. Patients in the Group RD had better sleep quality in the second and third nights after operation and lower incidence of nausea and vomiting ( P<0.05). Conclusion: 0.5% ropivacaine and 1 µg/kg dexmedetomidine SAPB combined with PCIA can significantly reduce postoperative pain and improve postoperative recovery quality in patients undergoing thoracoscopic radical resection of lung cancer.

Extracellular Vesicle-Mediated Vascular Cell Communications in Hypertension: Mechanism Insights and Therapeutic Potential of ncRNAs.

Hypertension, a chronic and progressive disease, is an outstanding public health issue that affects nearly 40% of the adults worldwide. The increasing prevalence of hypertension is one of the leading causes of cardiovascular morbidity and mortality. Despite of the available treatment medications, an increasing number of hypertensive individuals continues to have uncontrolled blood pressure. In the vasculature, endothelial cells, vascular smooth muscle cells (VSMCs), and adventitial fibroblasts play a fundamental role in vascular homeostasis. The aberrant interactions between vascular cells might lead to hypertension and vascular remodeling. Identification of the precise mechanisms of vascular remodeling may be highly required to develop effective therapeutic approaches for hypertension. Recently, extracellular vesicle-mediated transfer of proteins or noncoding RNAs (ncRNAs) between vascular cells holds promise for the treatment of hypertension. Especially, extracellular vesicle-packaging ncRNAs have gained enormous attention of basic and clinical scientists because of their tremendous potential to act as novel clinical biomarkers and therapeutic targets of hypertension. Here we will discuss the current findings focusing on the emerging roles of extracellular vesicle-carrying ncRNAs in the pathologies of hypertension and its associated vascular remodeling. Furthermore, we will highlight the potential of extracellular vesicles and ncRNAs as biomarkers and therapeutic targets for hypertension. The future research directions on the challenges and perspectives of extracellular vesicles and ncRNAs in hypertensive vascular remodeling are also proposed.

Frailty is an independent risk factor for postoperative pulmonary complications in elderly patients undergoing video-assisted thoracoscopic pulmonary resections.

BACKGROUND: Although frailty as a common geriatric syndrome is associated with postoperative complications, its relationship with postoperative pulmonary complications (PPCs) following pulmonary resections in elderly patients is unclear. AIMS: To investigate the relationship between frailty and PPCs in elderly patients undergoing video-assisted thoracoscopic pulmonary resections and explore the effect of the addition of frailty assessment to PPC risk index and ASA on their predictive ability. METHODS: In a prospective cohort study, we measured frailty status using the FRAIL scale in elderly patients undergoing video-assisted thoracoscopic pulmonary resections. Multivariate analysis was used to identify the relationship between frailty and PPCs. Receiver operating characteristic curves were used to examine the predictive power of frailty and other assessment tools. RESULTS: 227 patients were analyzed in the study. The prevalence of PPCs was 24.7%. Significant differences between patients with and without PPCs were observed in the following aspects: BMI, smoking, COPD, respiratory infection within the last month, FEV1/FVC ratio, creatinine, ASA, frailty and PPC risk index (p < 0.05, respectively). After adjusting for all covariates, frailty was significantly related to PPCs in elderly patients (odds ratio: 6.33, 95% confidence interval: 2.45-16.37). Combined with frailty assessment, the area under the curve for ASA class and PPC risk index was increased to 0.759 (95% CI 0.687-0.831) and 0.821 (95% CI 0.758-0.883). CONCLUSIONS: Frailty was associated with PPCs in elderly patients undergoing video-assisted thoracoscopic pulmonary resections. Combined with the frailty assessment, the predictive power of the PPC risk index and ASA class was improved.

A sensitive H2O2 biosensor based on carbon nanotubes/tetrathiafulvalene and its application in detecting NADH.

Reduced nicotinamide adenine dinucleotide (NADH) plays a pivotal role in the electron-transfer chain of biological system. Analysis of many biological markers is based on the detection of the enzymatically generated NADH. In this paper, a sensitive hydrogen peroxide (H2O2) biosensor, fabricated by carbon nanotubes (CNTs)/tetrathiafulvalene (TTF)/horseradish peroxidase (HRP), was applied for detecting the NADH in a buffer containing methylene blue (MB) at low operating potential of - 0.3 V (vs. Ag/AgCl). Since the NADH could be oxidized by MB to release H2O2, the electrochemical biosensor enables to detect the NADH in the MB buffer. And the low working potential made the biosensor avoid the interference from other electroactive substances. Linear response ranges from 10 µM to 790 µM, with a sensitivity of 4.76 µA mM-1 and a detection limit of 1.53 µM were obtained under the optimum conditions. The proposed sensor provided a promising approach for sensitively detecting the NADH.

LncRNAs and circular RNAs as endothelial cell messengers in hypertension: mechanism insights and therapeutic potential.

Endothelial cells are major constituents in the vasculature, and they act as important players in vascular homeostasis via secretion/release of vasodilators and vasoconstrictors. In healthy arteries, endothelial cells play a key role in the regulation of vascular tone, cellular adhesion, and angiogenesis. A shift in the functions of the blood vessels toward vasoconstriction, proinflammatory state, oxidative stress and deficiency of nitric oxide (NO) might lead to endothelial dysfunction, a key event implicated in the pathophysiology of cardiovascular metabolic diseases, including diabetes, atherosclerosis, arterial hypertension and pulmonary arterial hypertension (PAH). Thus, reversibility of endothelial dysfunction may be beneficial for maintaining vascular homeostasis. In recent years, accumulative evidence has documented that noncoding RNAs (ncRNAs) are critically involved in endothelial homeostasis. Specifically, long noncoding RNAs (lncRNAs) and circular RNAs are highly expressed in endothelial cells where they serve as important mediators in normal endothelial functions. Dysregulation of lncRNAs and circular RNAs has been tightly associated with hypertension-related endothelial dysfunction. In this review, we will summarize the current progression and underlying mechanisms of lncRNA and circular RNA in endothelial cell biology under hypertensive conditions. We will also highlight their potential as biomarkers or therapeutic targets for hypertension and its associated endothelial dysfunction.

Remote Ischaemic Preconditioning and Sevoflurane Postconditioning Synergistically Protect Rats from Myocardial Injury Induced by Ischemia and Reperfusion Partly via Inhibition TLR4/MyD88/NF-κB Signaling Pathway.

BACKGROUND/AIMS: A combination sevoflurane postconditioning (SPC) and remote ischemic preconditioning (RIPC) is proved effective in an ex vivo rat heart perfusion model. However, the combined effect of those two interventions is not tested in rat myocardial ischemia/reperfusion (I/R) model, and the underlying mechanisms remain to be elucidated. This study aimed to investigate the effect in vivo using a rat myocardial I/R model and illuminate the related mechanisms. METHODS: Forty male Sprague-Dawley rats were randomly divided into the following 5 groups: i) sham-operated control; ii) I/R; iii) I/R + RIPC; iv) I/R + SPC; v) I/R + RIPC + SPC. The hemodynamic parameters were recorded at the end of reperfusion. The histological changes including the infarct size were assessed using Triphenyltetrazolium chloride (TTC) staining and H&E staining. In addition, the circulating levels of cardiac enzymes (CK-MB, hs-cTnT, and cTnT) inflammatory cytokines (IL-6, IL-8, and TNF-α) were detected. The expression levels of apoptosis-related proteins (C-Caspase 3, PARP, Bax, and Bcl-2), proinflammatory factors (TLR4, HMGB-1, MyD88, and p65), and IKB-α were measured by Western blot analysis. Real-time PCR was performed to detect mRNA levels of the proinflammatory factors. RESULTS: Both SPC and RIPC significantly reduced the infarct size, cardiac enzyme release, inflammatory cytokine secretion, and proinflammatory factor expression, and increased IKB-α expression compared to I/R group. Furthermore, the combination of those two strategies had synergic infarct size limiting and anti-inflammatory effects. CONCLUSIONS: The finding of this study suggested that the combination of SPC and RIPC had a potentially cardioprotective effect through inhibiting TLR4/MyD88/NF-κB signaling.

[Dexmedetomidine improves function of lung oxygenation in patients with moderate chronic obstructive pulmonary disease underwent lung cancer surgery].

OBJECTIVE: To determine whether dexmedetomidine (Dex) improves oxygenation and lung mechanics in patients with moderate chronic obstructive pulmonary disease (COPD) during lung cancer surgery.
 Methods: Fifty-six patients with moderate COPD were randomly allocated to a control group and a Dex group (n=28 each). In the Dex group, dexmedetomidine was given as an initial loading dose at 1.0 µg/kg lasting for 10 min followed by a maintenance dose at 0.5 µg/(kg.h) during OLV while the control group was administered an equal volume of 0.9% saline accordingly.
 Results: Patients in the Dex group had a significantly higher oxygenation index (P<0.05) and higher dynamic lung compliance at Dex-30 and Dex-60 (P<0.05) compared with those in the control group. In the Dex group, oxygenation index in the postoperative period was significantly higher (P= 0.025) and postoperative complications were lower than those in the control group.
 Conclusion: Dex administration may provide clinically relevant benefits by improving o xygenation index and lung mechanics, and reducing postoperative pulmonary complications in patients with moderate COPD underwent lung cancer surgery.

Adam17, a Target of Mir-326, Promotes Emt-Induced Cells Invasion in Lung Adenocarcinoma.

BACKGROUND/AIMS: A disintegrin and metalloprotease (ADAM) 17 has been reported to be implicated in cancer cells invasion. Nevertheless, its potential role in lung adenocarcinoma has not been addressed clearly. METHODS: RT-PCR and Western blot were used to detect the expression of miR-326 and ADAM17 in lung adenocarcinoma samples (n=73). miR-326 mimics and inhibitor were tansfected in human A549 and SPCA1 cell lines. The transwell assay was used to detect the cell invasive ability. The regulation mechanism was evaluated by luciferase reporter assay. The markers of (epithelial-to-mesenchymal transition) EMT were detected by using Western blot assay. RESULTS: We found increased expression of ADAM17 in lung adenocarcinoma and cell lines. In vitro, up-regulation of ADAM17 promoted cells invasion, while silencing of ADAM17 inhibited cells invasion. Meanwhile, ADAM17 could affect the markers of EMT. Furthermore, we confirmed that ADAM17 is a target of miR-326, which is involved in EMT and cells invasion. CONCLUSIONS: These findings revealed that ADAM17, a target of miR-326, promoted EMT-induced cells invasion in lung adenocarcinoma.

[Risk analysis of cardiovascular events in elderly hypertensive patients with different risk stratification during the perioperative period].

OBJECTIVE: To study the risks of cardiovascular events of elderly hypertensive patients with different risk stratification during the perioperative period. METHODS: 126 elderly hypertensive patients without cardiac surgery were selected and divided into following 3 groups: group I (in danger), group II (high-risk), group III (very high-risk), each group with 42 cases. Control group was randomly selected 42 elderly patients without hypertension and other cardiovascular risk factors. Sevoflurane, Etomidate, Propofol, Cisatracurium Besilate for Injection, Fentanyl were used to induction and maintenance of anesthesia. Patients' cardiac index (CI), cardiac output (CO), stroke volume (SV), systemic vascular resistance (SVR), peak velocity (Vpk), heart rate (HR), mean arterial pressure (MAP) were monitored by ultrasonic cardiac output monitor (ultrasonic cardiac output monitor, USCOM). Pre- and post-operative myocardial ischemia and arrhythmia were monitored by dynamic electrocardiogram (dynamic electrocardiography, DCG). RESULTS: Incidence myocardial（9.5%, 31.0%, 40.5%), ischemia frequency [(10.4 ± 1.7) time, 13.3 ± 1.9) time, 17.4 ± 2.3) time], ischemic time [(116.4 ± 9.7) min, (174.3 ± 19.8) min, (212.4 ± 20.5) min] and arrhythmias incidence (28.6%, 52.4%, 92.9%) were specially more significant for group I, group II and group III patients within the postoperative 24 hours (P < 0.05). Comparison between group I, group II and group III each other, myocardial ischemia incidence (11.9%, 21.4%, 31.0%), ischemia frequency [(9.5 ± 1.5) time, (11.6 ± 2.0) time, (15.0 ± 2.2) time], ischemic time [(98.5 ± 9.4) min, (158.3 ± 16.7) min, (198.0 ± 18.1) min] and arrhythmias incidence (16.7%, 45.2%, 81.0%) gradually increased for 3 groups within the postoperative 48 hours (P < 0.05). CONCLUSION: Risk of cardiovascular events significantly increases for elderly patients with cardiovascular high-risk factors in the perioperation period, and especially cardiovascular function is inhibited most obviously in the general anesthesia intubation immediately before and after 24 hours and is prone to cardiovascular events, such as myocardial ischemia and arrhythmia.

Factors affecting major morbidity after video-assisted thoracic surgery for lung cancer.

BACKGROUND: Video-assisted thoracic surgery (VATS) has been widely applied in the treatment of lung cancer. However, few studies have focused on the clinical factors predicting the major postoperative complications. METHODS: Clinical data from 525 patients who underwent resection of primary lung cancer with VATS from January 2007-August 2011 were retrospectively analyzed. Risk factors related to major postoperative complications were assessed by univariate and multivariate analyses with logistic regression. RESULTS: Major complications occurred in 36 (6.86%) patients, of which seven died (1.33%) within 30 d, postoperatively. Major complications included respiratory failure, hemothorax, myocardial infarction, heart failure, bronchial fistula, cerebral infarction, and pulmonary embolism. Univariate and multivariate logistic regression analyses demonstrated that age >70 y (odds ratio [OR], 2.105; 95% confidence interval [CI] 1.205-3.865), forced expiratory volume during the first second expressed as a percentage of predicted ≤70% (OR, 2.106; 95% CI 1.147-3.982) combined with coronary heart disease (OR, 2.257; 95% CI 1.209-4.123) were independent prognostic factors for major complications. CONCLUSIONS: Age >70 and forced expiratory volume during the first second expressed as a percentage of predicted ≤70% combined with coronary heart disease are independent prognostic factors for postoperative major complications. Patients in these groups should undergo careful preoperative evaluation and perioperative management.

Female travellers in hospitality and tourism industry: A systematic literature review.

Female tourism is gaining momentum in the world. Thus, a review of female tourism is essential to explore future research directions. The paper discusses the evolution of female tourism research from the early 1980s to 2022 through different analytical methods. The 116 articles published in the list of Social Science Citation Index (SSCI) journals were collected. A systematic quantitative assessment of 116 articles was conducted using HistCite, and research themes were identified using VOSviewer. Qualitative content analysis was conducted to trace the growth of research, understand the past research development of each research theme, and identify research gaps for further research. The results show that current female tourism research can be divided into three research themes: motivation, risk, and sexuality. The motivations for young female travellers, solo female travellers, and middle-aged female travellers are discussed. In the atmosphere of gender equality, current female tourism research in risk and sexuality contains contradictory viewpoints with past studies as a result of changing times. A research agenda in four potential research areas is recommended. This review contributes to female tourism research by providing researchers with literature to guide and support further research.

Chicoric acid ameliorates sepsis-induced cardiomyopathy via regulating macrophage metabolism reprogramming.

BACKGROUND: Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury. PURPOSE: This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved. METHODS/RESULTS: From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD+/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury. CONCLUSION: These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.

Cichoric acid ameliorates sepsis-induced acute kidney injury by inhibiting M1 macrophage polarization.

Cichoric acid (CA), a widely utilized polyphenolic compound in medicine, has garnered significant attention due to its potential health benefits. Sepsis-induced acute kidney disease (AKI) is related with an elevated risk of end-stage kidney disease (ESKD). However, it remains unclear whether CA provides protection against septic AKI. The aim of this study is to investigated the protective effect and possible mechanisms of CA against LPS-induced septic AKI. Sepsis-induced AKI was induced in mice through intraperitoneal injection of lipopolysaccharide (LPS), and RAW264.7 macrophages were incubated with LPS. LPS exposure significantly increased the levels of M1 macrophage biomarkers while reducing the levels of M2 macrophage indicators. This was accompanied by the release of inflammatory factors, superoxide anion production, mitochondrial dysfunction, activation of succinate dehydrogenase (SDH), and subsequent succinate formation. Conversely, pretreatment with CA mitigated these abnormalities. CA attenuated hypoxia-inducible factor-1α (HIF-1α)-induced glycolysis by lifting the NAD+/NADH ratio in macrophages. Additionally, CA disrupted the K (lysine) acetyltransferase 2A (KAT2A)/α-tubulin complex, thereby reducing α-tubulin acetylation and subsequently inactivating the NLRP3 inflammasome. Importantly, administration of CA ameliorated LPS-induced renal pathological damage, apoptosis, inflammation, oxidative stress, and disturbances in mitochondrial function in mice. Overall, CA restrained HIF-1α-mediated glycolysis via inactivation of SDH, leading to NLRP3 inflammasome inactivation and the amelioration of sepsis-induced AKI.

Vaccarin alleviates septic cardiomyopathy by potentiating NLRP3 palmitoylation and inactivation.

BACKGROUND: Sepsis often leads to significant morbidity and mortality due to severe myocardial injury. As is known, the activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome crucially contributes to septic cardiomyopathy (SCM) by facilitating the secretion of interleukin (IL)-1ß and IL-18. The removal of palmitoyl groups from NLRP3 is a crucial step in the activation of the NLRP3 inflammasome. Thus, the potential inhibitors that regulate the palmitoylation and inactivation of NLRP3 may significantly diminish sepsis-induced cardiac dysfunction. PURPOSE: The present study sought to explore the effects of the prospective flavonoid compounds targeting NLRP3 on SCM and to elucidate the associated underlying mechanisms. STUDY DESIGN: The palmitoylation and activation of NLRP3 were detected in H9c2 cells and C57BL/6 J mice. METHODS/RESULTS: Echocardiography, histological staining, western blotting, co-immunoprecipitation, qPCR, ELISA and network pharmacology were used to assess the impact of vaccarin (VAC) on SCM in mice subjected to lipopolysaccharide (LPS) injection. From the collection of 74 compounds, we identified that VAC had the strongest capability to suppress NLRP3 luciferase report gene activity in cardiomyocytes, and the anti-inflammatory characteristics of VAC were further ascertained by the network pharmacology. Exposure of LPS triggered apoptosis, inflammation, oxidative stress, mitochondrial disorder in cardiomyocytes. The detrimental alterations were significantly reversed upon VAC treatment in both septic mice and H9c2 cells exposed to LPS. In vivo experiments demonstrated that VAC treatment alleviated septic myocardial injury, indicated by enhanced cardiac function parameters, preserved cardiac structure, and reduced inflammation/oxidative response. Mechanistically, VAC induced NLRP3 palmitoylation to inactivate NLRP3 inflammasome by acting on zDHHC12. In support, the NLRP3 agonist ATP and the acylation inhibitor 2-bromopalmitate (2-BP) prevented the effects of VAC. CONCLUSION: Our findings suggest that VAC holds promise in protecting against SCM by mitigating cardiac oxidative stress and inflammation via priming NLRP3 palmitoylation and inactivation. These results lay the solid basis for further assessment of the therapeutic potential of VAC against SCM.

Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy.

INTRODUCTION: Meteorin-like hormone (Metrnl) is ubiquitously expressed in skeletal muscle, heart, and adipose with beneficial roles in obesity, insulin resistance, and inflammation. Metrnl is found to protect against cardiac hypertrophy and doxorubicin-induced cardiotoxicity. However, its role in diabetic cardiomyopathy (DCM) is undefined. OBJECTIVES: We aimed to elucidate the potential roles of Metrnl in DCM. METHODS: Gain- andloss-of-function experimentswere utilized to determine the roles of Metrnl in the pathological processes of DCM. RESULTS: We found that plasma Metrnl levels, myocardial Metrnl protein and mRNA expressions were significantly downregulated in both streptozotocin (STZ)-induced (T1D) mice and leptin receptor deficiency (db/db) (T2D) mice. Cardiac-specific overexpression (OE) of Metrnl markedly ameliorated cardiac injury and dysfunction in both T1D and T2D mice. In sharp contrast, specific deletion of Metrnl in the heart had the opposite phenotypes. In parallel, Metrnl OE ameliorated, whereas Metrnl downregulation exacerbated high glucose (HG)-elicited hypertrophy, apoptosis and oxidative damage in primary neonatal rat cardiomyocytes. Antibody-induced blockade of Metrnl eliminated the effects of benefits of Metrnl in vitro and in vivo. Mechanistically, Metrnl activated the autophagy pathway and inhibited the cGAS/STING signaling in a LKB1/AMPK/ULK1-dependent mechanism in cardiomyocytes. Besides, Metrnl-induced ULK1 phosphorylation facilitated the dephosphorylation and mitochondrial translocation of STING where it interacted with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase that was responsible for ubiquitination and degradation of STING, rendering cardiomyocytes sensitive to autophagy activation. CONCLUSION: Thus, Metrnl may be an attractive therapeutic target or regimen for treating DCM.

Dexmedetomidine post-conditioning alleviates myocardial ischemia-reperfusion injury in rats by ferroptosis inhibition via SLC7A11/GPX4 axis activation.

The SLC7A11/GPX4 axis plays an important role in ferroptosis during cardiac ischemia/reperfusion injury (IRI). The present study was designed to evaluate the impact of dexmedetomidine (DEX) post-conditioning on cardiac IRI and to explore whether the effect was achieved by SLC7A11/GPX4 signaling pathway regulation. Rat myocardial IRI was established by occluding the left anterior descending artery for 30 min followed by 2-h reperfusion. The infarct area was detected by diphenyltetrazolium chloride (TTC) staining; the cardiac function was evaluated by echocardiography. The levels of lipid peroxide biomarkers were measured to estimate the injury caused by lipid peroxide. HE staining and Sirius staining were utilized to assess myocardial damage and fibrosis. The mitochondrial morphology was observed by electron micrography. Western blot and quantitative real-time polymerase chain reaction were employed to measure the relative molecular characteristics. Our results showed that DEX administration at the beginning of reperfusion attenuated IRI-induced myocardial injury, alleviated mitochondrial dysfunction, decreased the level of reactive oxygen species (ROS), alleviated mitochondrial dysfunction, inhibited the activation of SLC7A11/GPX4, and modulated the expression of ferroptosis-related proteins, including SLC7A11, glutathione peroxidase 4 (GPX4), ferritin heavy chain (FTH), and cyclooxygenase-2 (COX-2). Conversely, the ferroptosis activator erastin partly suppressed the DEX-mediated cardio protection. Altogether, these results reveal that DEX inhibits ferroptosis by enhancing the expression of SLC7A11 and GPX4, thereby preventing cardiac I/R injury.

MiRNAs, lncRNAs, and circular RNAs as mediators in hypertension-related vascular smooth muscle cell dysfunction.

Hypertension is a multifactorial disorder that involves complex genetic and environmental factors. Vascular smooth muscle cells (VSMCs) are important components of blood vessels, and their dysregulation has been shown to be involved in vascular remodeling during the development of systemic hypertension and pulmonary arterial hypertension (PAH) via multiple mechanisms, such as aberrant apoptosis, phenotype conversion, proliferation, and migration of VSMCs. With increasing advances in microarrays and next-generation sequencing, nonprotein-coding RNAs (ncRNAs) have attracted much attention due to their numerous functions in health and diseases. Among ncRNAs, microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs are emerging as novel modulators in the biological behaviors of VSMCs, especially in systemic hypertension and PAH. Studies have recommended miRNAs, lncRNAs, and circular RNAs as predictive biomarkers and therapeutic targets for systemic hypertension and PAH. In this review, we summarize the current studies focusing on the roles of VSMC-derived miRNAs, lncRNAs and circular RNAs in the pathologies of systemic hypertension and PAH. MiRNAs, lncRNAs, and circular RNAs might serve as attractive targets for the prevention and treatment of VSMC dysfunction-linked systemic hypertension and PAH.

Itaconate ameliorates methicillin-resistant Staphylococcus aureus-induced acute lung injury through the Nrf2/ARE pathway.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) are a critical predisposing factor of sepsis in the clinic. As a product of human energy metabolism and immune response, itaconate can effectively reduce inflammation in the body. This research employed 4-octyl itaconate (4-OI) to illustrate that itaconate exerted anti-inflammatory effects to protect the body from acute lung injury (ALI) induced by MRSA. METHODS: HE staining and immunohistochemistry are used to evaluate the MRSA-induced ALI in mice. WB and qPCR were used to verify the effect of 4-OI on inflammation and oxidative stress caused by MRSA. Molecular docking was used to verify the binding sites of 4-OI and Keap1. RESULTS: We demonstrated that 4-OI treatment increased the survival ratio, attenuated the pathological damage, inhibited neutrophil infiltration, and reduced lung bacterial burden in the mouse MRSA pneumonia model. 4-OI decreased the expression of inflammatory factors by stimulating the Nrf2 in vivo and in vitro. Furthermore, 4-OI exerted its effect by promoting nuclear transport of Nrf2 in vitro. The results of molecular docking indicated that 4-OI bound to the pocket of Keap1 and exerted a stable interaction. Both Nrf2 inhibitors (ML385) and Nrf2-/- mice abolished the protective effect of 4-OI on MRSA-induced inflammation both in vitro and in vivo. CONCLUSIONS: 4-OI prevents lung damage caused by MRSA bacteremia via activating Nrf2/ARE pathway.