Differentially Altered Metabolic Pathways in the Amygdala of Subjects with Schizophrenia, Bipolar Disorder and Major Depressive Disorder.

Background and hypothesis: A growing number of studies implicate a key role for metabolic processes in psychiatric disorders. Recent studies suggest that ketogenic diet may be therapeutically effective for subgroups of people with schizophrenia (SCZ), bipolar disorder (BPD) and possibly major depressive disorder (MDD). Despite this promise, there is currently limited information regarding brain energy metabolism pathways across these disorders, limiting our understanding of how brain metabolic pathways are altered and who may benefit from ketogenic diets. We conducted gene expression profiling on the amygdala, a key region involved in in the regulation of mood and appetitive behaviors, to test the hypothesis that amygdala metabolic pathways are differentially altered between these disorders. Study Design: We used a cohort of subjects diagnosed with SCZ, BPD or MDD, and non-psychiatrically ill control subjects (n=15/group), together with our bioinformatic 3-pod analysis consisting of full transcriptome pathway analysis, targeted pathway analysis, leading-edge gene analysis and iLINCS perturbagen analysis. Study Results: We identified differential expression of metabolic pathways in each disorder. Subjects with SCZ displayed downregulation of mitochondrial respiration and nucleotide metabolism pathways. In comparison, we observed upregulation of mitochondrial respiration pathways in subjects with MDD, while subjects with BPD displayed enrichment of pathways involved in carbohydrate metabolism. Several pathways associated with brain metabolism including immune system processes and calcium ion transport were also differentially altered between diagnosis groups. Conclusion: Our findings suggest metabolic pathways are differentially altered in the amygdala in these disorders, which may impact approaches for therapeutic strategies.

Effect of dental chew on reducing dental plaque, dental calculus and halitosis in beagle dogs.

Periodontosis is the most common clinical disease in adult dogs, which is mainly caused by plaque accumulation and seriously endangers the oral health of dogs and even cause kidney, myocardial, and liver problems in severe cases. The aim of this study was to determine the clinical efficacy of dental chew (Cature Brushing Treats product) with mechanical and chemical properties in beagles. The dogs in the experimental group were fed with a dental chew twice a day after meals; The control group had no treatment. Dental plaque was evaluated on the 14th day and 29th day, respectively. The concentration of volatile sulfur compounds (VSC) in the breath and dental calculus were also evaluated on the 29th day. The results showed that there was no significant difference in the indexes of dental plaque on the 14th day. While they had significantly reduced accumulation of plaque (37.63%), calculus (37.61%), and VSC concentration (81.08%) compared to when receiving no chew on the 29th day.

Astrocyte modulation in cerebral ischemia-reperfusion injury: A promising therapeutic strategy.

Cerebral ischemia-reperfusion injury (CIRI) poses significant challenges for drug development due to its complex pathogenesis. Astrocyte involvement in CIRI pathogenesis has led to the development of novel astrocyte-targeting drug strategies. To comprehensively review the current literature, we conducted a thorough analysis from January 2012 to December 2023, identifying 82 drugs aimed at preventing and treating CIRI. These drugs target astrocytes to exert potential benefits in CIRI, and their primary actions include modulation of relevant signaling pathways to inhibit neuroinflammation and oxidative stress, reduce cerebral edema, restore blood-brain barrier integrity, suppress excitotoxicity, and regulate autophagy. Notably, active components from traditional Chinese medicines (TCM) such as Salvia miltiorrhiza, Ginkgo, and Ginseng exhibit these important pharmacological properties and show promise in the treatment of CIRI. This review highlights the potential of astrocyte-targeted drugs to ameliorate CIRI and categorizes them based on their mechanisms of action, underscoring their therapeutic potential in targeting astrocytes.

Copper-Catalyzed Multicomponent Coupling Reaction of Primary Aromatic Amines, Rongalite, and Alkynes: Access to N-Aryl Propargylamines.

In this work, a practical copper-catalyzed multicomponent coupling reaction of primary aromatic amines, rongalite, and alkynes for the direct synthesis of N-aryl propargylamines has been developed. This method could overcome the substrate limitation in A3 coupling reactions of primary aromatic amines, formaldehyde, and alkynes. Mechanistic studies revealed that rongalite acts as not only the active C1 unit but also the accelerator to activate the in situ-generated N-arylmethanimines for the coupling reaction with alkynes. This coupling reaction is highly efficient and features a broad substrate scope, as well as utility with scale-up synthesis and converting the corresponding product N-aryl propargylamines into useful heterocyclic skeletons.

Analysis of clinical characteristics of infections caused by shewanella species.

PURPOSE: The Shewanella genus is a rare pathogen of marine origin. In recent years, there has been a continuous increase in infection cases caused by this bacterium, and we have observed the uniqueness of infections caused by this microorganism. MATERIALS AND METHODS: This study conducted a retrospective analysis of the medical history and laboratory examination data of patients infected with the Shewanella genus over the past decade. Additionally, it employed bioinformatics methods to analyze the relevant virulence factors and antibiotic resistance genes associated with the Shewanella genus. RESULTS: Over the past 10 years, we have isolated 51 cases of Shewanella, with 68.82% being Shewanella putrefaciens (35/51 cases) and 31.37% being Shewanella algae (16/51 cases). Infected individuals often had underlying diseases, with 39.22% (20/51) having malignant tumors and 25.49% (13/51) having liver and biliary system diseases primarily characterized by stones. The majority of patients, 62.74% (32/51), exhibited mixed infections, including one case with a combination of infections from three other types of bacteria and five cases with a combination of infections from two other types of bacteria. The identified microorganisms were commonly resistant to ticarcillin-clavulanic acid (23.5%), followed by cefoperazone-sulbactam (19.6%), ciprofloxacin (17.6%), and cefotaxime (17.6%). Bioinformatics analysis indicates that Shewanella can express bile hydrolysis regulators and fatty acid metabolism regulators that aid in adapting to the unique environment of the biliary tract. Additionally, it expresses abundant catalase, superoxide dismutase, and two-component signal transduction system proteins, which may be related to environmental adaptation. Shewanella also expresses various antibiotic resistance genes, including beta-lactamases and aminoglycoside modification enzymes. Iron carriers may be one of its important virulence factors. CONCLUSIONS: We speculate that the Shewanella genus may exist as a specific colonizer in the human body, and under certain conditions, it may act as a pathogen, leading to biliary infections in the host.

Characteristics and functions of memory regulatory T cells in normal pregnancy cycle and pregnancy complications.

Regulatory T cells (Tregs) are activated and expanded after exposure to fetal-specific (paternal) antigens. A proportion of Tregs differentiate into memory Tregs (mTregs), exhibiting immune memory function and exerting more potent immunosuppression than naive Tregs (nTregs). However, it is unclear how mTregs are regulated during normal and pathological pregnancies (e.g., gestational diabetes mellitus (GDM) and preeclampsia (PE)). In this study, PD-1, HLA-G, and HLA-DR expressions on memory CD4+ T cells, naive CD4+ T cells, Tregs, mTregs, and nTregs in healthy non-pregnant women (n=20), healthy first (n=20), second (n=20), and third-trimester women (n=20), postpartum women (n=20), GDM (n=20), and PE patients (n=20) were analyzed. The proportion of mTregs out of Tregs was increased (P<0.05) in the first trimester compared with that in non-pregnancy and reduced in the second and third trimesters. The proportions of PD-1+ Tregs and mTregs were significantly increased during the first trimester compared to those of non-pregnancy (P<0.01), reached their maximum in the second trimester. Moreover, the proportions of HLA-G+ memory CD4+ T cells, Tregs, and mTregs were increased in the first and second trimesters (P<0.01), reached their maximum in the third trimester. GDM patients were characterized by significantly lower percentages of PD-1+ and HLA-G+ mTregs (P<0.01), while PE patients were characterized by significantly lower percentages of HLA-G+ mTregs (P<0.01), compared with the healthy third-trimester women. In general, as demonstrated by this study, mTregs increase in number and enhance maternal-fetal immunoregulation during pregnancy, and their dysfunction can result in pregnancy complications such as GMD or PE.

Genus Shewanella: A Potential Intestinal Colonizer Associated With Post-Operative Surgical Site Infections in Coastal Regions.

Background: This study aims to elucidate the clinical characteristics of Shewanella-related surgical site infections (SSIs) and assess the risk of mortality in patients by establishing a predictive model. Patients and Methods: A retrospective analysis of medical history and laboratory data of Shewanella-related SSI patients over the past decade was conducted via the electronic medical record (EMR) system. A predictive model for mortality risk in Shewanella-related SSI patients was established using plasma interleukin-6 (IL-6) levels combined with the Howell-PIRO scoring system. Results: Over the past 10 years, 45 strains of Shewanella were isolated from specimens such as bile, drainage fluid, and whole blood in patients with digestive tract SSIs. Among them, 21 of 45 (46.67%) patients underwent malignant tumor resection of the digestive system, 14 of 45 (31.11%) underwent endoscopic retrograde cholangiopancreatography (ERCP) common bile duct exploration or the stone removal, and seven of 45 (15.56%) were trauma repair patients with fractures and abdominal injuries. Among the 45 Shewanella-related SSI patients, 10 died within 30 days of infection, six cases involved infections with more than two other types of bacteria. The combined use of IL-6 and Howell-PIRO scores for mortality risk assessment yielded an receiver operating characteristic (ROC) curve with an area under the curve (AUC) of 0.9350, a positive predictive value of 92.71%, a negative predictive value of 94.58%, a diagnostic sensitivity of 95.35%, and a diagnostic specificity of 92.14%-all higher than the model using IL-6 or Howell-PIRO scores alone. Conclusions: We found that residents in coastal areas faced an increased risk of Shewanella-related SSI. Moreover, the higher the number of concurrent microbial infections occurring alongside Shewanella-related SSI, the greater the mortality rate among patients. The combined application of plasma IL-6 levels and the Howell-PIRO scoring system is beneficial for assessing patient mortality risk and guiding timely and proactive clinical interventions.

Transcutaneous auricular vagus nerve stimulation enhanced emotional inhibitory control via increasing intrinsic prefrontal couplings.

Background: Inhibitory control represents a core executive function that critically facilitates adaptive behavior and survival in an ever-changing environment. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has been hypothesized to improve behavioral inhibition performance, however the neurocomputational mechanism of taVNS-induced neuroenhancement remains elusive. Method: In the current study, we investigated the efficacy of taVNS in a sham-controlled between-subject functional near infrared spectroscopy (fNIRS) experiment with an emotional face Go/No-Go paradigm in ninety healthy young adults. Results: After a data quality check, eighty-two subjects were included in the final data analysis. Behaviorally, the taVNS improved No-Go response accuracy, together with computational modeling using Hierarchical Bayesian estimation of the Drift Diffusion Model (HDDM) indicating that it specifically reduced the information accumulation rate for Go responses, and this was negatively associated with increased accuracy of No-Go responses. On the neural level, taVNS enhanced engagement of the bilateral inferior frontal gyrus (IFG) during inhibition of angry expression faces and modulated functional couplings (FCs) within the prefrontal inhibitory control network. Mediation models revealed that taVNS-induced facilitation of inhibitory control was critically mediated by a decreased information accumulation for Go responses and concomitantly enhanced neurofunctional coupling between the inferior and orbital frontal cortex. Discussion: Our findings demonstrate a potential for taVNS to improve emotional inhibitory control via reducing pre-potent responses and enhancing FCs within prefrontal inhibitory control networks, suggesting a promising therapeutic role in treating specific disorders characterized by inhibitory control deficits.

Analysis of heavy metal and polycyclic aromatic hydrocarbon pollution characteristics of a typical metal rolling industrial site based on data mining.

With the transformation and upgrading of industries, the environmental problems caused by industrial residual contaminated sites are becoming increasingly prominent. Based on actual investigation cases, this study analyzed the soil pollution status of a remaining sites of the copper and zinc rolling industry, and found that the pollutants exceeding the screening values included Cu, Ni, Zn, Pb, total petroleum hydrocarbons and 6 polycyclic aromatic hydrocarbon monomers. Based on traditional analysis methods such as the correlation coefficient and spatial distribution, combined with machine learning methods such as SOM + K-means, it is inferred that the heavy metal Zn/Pb may be mainly related to the production history of zinc rolling. Cu/Ni may be mainly originated from the production history of copper rolling. PAHs are mainly due to the incomplete combustion of fossil fuels in the melting equipment. TPH pollution is speculated to be related to oil leakage during the industrial use period and later period of vehicle parking. The results showed that traditional analysis methods can quickly identify the correlation between site pollutants, while SOM + K-means machine learning methods can further effectively extract complex hidden relationships in data and achieve in-depth mining of site monitoring data.

Interactions between integrin α9ß1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT.

ABSTRACT: Venous thromboembolic events are significant contributors to morbidity and mortality in patients with stroke. Neutrophils are among the first cells in the blood to respond to stroke and are known to promote deep vein thrombosis (DVT). Integrin α9 is a transmembrane glycoprotein highly expressed on neutrophils and stabilizes neutrophil adhesion to activated endothelium via vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, the causative role of neutrophil integrin α9 in poststroke DVT remains unknown. Here, we found higher neutrophil integrin α9 and plasma VCAM-1 levels in humans and mice with stroke. Using mice with embolic stroke, we observed enhanced DVT severity in a novel model of poststroke DVT. Neutrophil-specific integrin α9-deficient mice (α9fl/flMrp8Cre+/-) exhibited a significant reduction in poststroke DVT severity along with decreased neutrophils and citrullinated histone H3 in thrombi. Unbiased transcriptomics indicated that α9/VCAM-1 interactions induced pathways related to neutrophil inflammation, exocytosis, NF-κB signaling, and chemotaxis. Mechanistic studies revealed that integrin α9/VCAM-1 interactions mediate neutrophil adhesion at the venous shear rate, promote neutrophil hyperactivation, increase phosphorylation of extracellular signal-regulated kinase, and induce endothelial cell apoptosis. Using pharmacogenomic profiling, virtual screening, and in vitro assays, we identified macitentan as a potent inhibitor of integrin α9/VCAM-1 interactions and neutrophil adhesion to activated endothelial cells. Macitentan reduced DVT severity in control mice with and without stroke, but not in α9fl/flMrp8Cre+/- mice, suggesting that macitentan improves DVT outcomes by inhibiting neutrophil integrin α9. Collectively, we uncovered a previously unrecognized and critical pathway involving the α9/VCAM-1 axis in neutrophil hyperactivation and DVT.

Pelvic bone tumor segmentation fusion algorithm based on fully convolutional neural network and conditional random field.

Background and objective: Pelvic bone tumors represent a harmful orthopedic condition, encompassing both benign and malignant forms. Addressing the issue of limited accuracy in current machine learning algorithms for bone tumor image segmentation, we have developed an enhanced bone tumor image segmentation algorithm. This algorithm is built upon an improved full convolutional neural network, incorporating both the fully convolutional neural network (FCNN-4s) and a conditional random field (CRF) to achieve more precise segmentation. Methodology: The enhanced fully convolutional neural network (FCNN-4s) was employed to conduct initial segmentation on preprocessed images. Following each convolutional layer, batch normalization layers were introduced to expedite network training convergence and enhance the accuracy of the trained model. Subsequently, a fully connected conditional random field (CRF) was integrated to fine-tune the segmentation results, refining the boundaries of pelvic bone tumors and achieving high-quality segmentation. Results: The experimental outcomes demonstrate a significant enhancement in segmentation accuracy and stability when compared to the conventional convolutional neural network bone tumor image segmentation algorithm. The algorithm achieves an average Dice coefficient of 93.31 %, indicating superior performance in real-time operations. Conclusion: In contrast to the conventional convolutional neural network segmentation algorithm, the algorithm presented in this paper boasts a more intricate structure, proficiently addressing issues of over-segmentation and under-segmentation in pelvic bone tumor segmentation. This segmentation model exhibits superior real-time performance, robust stability, and is capable of achieving heightened segmentation accuracy.

Chrysin inhibits ferroptosis of cerebral ischemia/reperfusion injury via regulating HIF-1α/CP loop.

Chrysin is a natural flavonoid with powerful neuroprotective capacity. Cerebral ischemia/reperfusion injury (CIRI) is associated with oxidative stress and ferroptosis. Hypoxia-inducible factor 1α (HIF-1α) and ceruloplasmin (CP) are the critical targets for oxidation reactions and iron transport. But the regulatory mechanism between them is still unclear. Transient middle cerebral artery occlusion (tMCAO) model in rats and oxygen and glucose deprivation/re-oxygenation (OGD/R) model in PC12 cells were applied. Pathological tissue staining and biochemical kit were used to evaluate the effect of chrysin. The relationship between HIF-1α and CP was verified by transcriptomics, qRT-PCR and Western blot. In CIRI, HIF-1α/CP loop was discovered to be the regulatory pathway of ferroptosis. CIRI led to activation and nuclear translocation of HIF-1α, which promoted CP transcription and translation, and downstream ferroptosis. Inhibition of HIF-1α had opposite effect on CP and ferroptosis regulation. Overexpression of CP increased the expression of HIF-1α, nevertheless, inhibited the nuclear translocation of HIF-1α and alleviated CIRI. Silencing CP promoted HIF-1α elevation in nucleus and aggravated CIRI. Mechanistically, chrysin restrained HIF-1α nuclear translocation, thereby inhibiting CP transcription and translation, which in turn reduced downstream HIF-1α expression and mitigated ferroptosis in CIRI. Our results highlight chrysin restrains ferroptosis in CIRI through HIF-1α/CP loop.

Post translational modifications of connexin 43 in ventricular arrhythmias after myocardial infarction.

Ventricular arrhythmias are the leading cause of sudden cardiac death in patients after myocardial infarction (MI). Connexin43 (Cx43) is the most important gap junction channel-forming protein in cardiomyocytes. Dysfunction of Cx43 contributes to impaired myocardial conduction and the development of ventricular arrhythmias. Following an MI, Cx43 undergoes structural remodeling, including expression abnormalities, and redistribution. These alterations detrimentally affect intercellular communication and electrical conduction within the myocardium, thereby increasing the susceptibility to post-infarction ventricular arrhythmias. Emerging evidence suggests that post-translational modifications play essential roles in Cx43 regulation after MI. Therefore, Cx43-targeted management has the potential to be a promising protective strategy for the prevention and treatment of post infarction ventricular arrhythmias. In this article, we primarily reviewed the regulatory mechanisms of Cx43 mediated post-translational modifications on post-infarction ventricular arrhythmias. Furthermore, Cx43-targeted therapy have also been discussed, providing insights into an innovative treatment strategy for ventricular arrhythmias after MI.

Olanzapine's effects on hypothalamic transcriptomics and kinase activity.

Olanzapine is a second-generation antipsychotic that disrupts metabolism and is associated with an increased risk of type 2 diabetes. The hypothalamus is a key region in the control of whole-body metabolic homeostasis. The objective of the current study was to determine how acute peripheral olanzapine administration affects transcription and serine/threonine kinase activity in the hypothalamus. Hypothalamus samples from rats were collected following the pancreatic euglycemic clamp, thereby allowing us to study endpoints under steady state conditions for plasma glucose and insulin. Olanzapine stimulated pathways associated with inflammation, but diminished pathways associated with the capacity to combat endoplasmic reticulum stress and G protein-coupled receptor activity. These pathways represent potential targets to reduce the incidence of type 2 diabetes in patients taking antipsychotics.

Synovia tissue-specific exosomes participate in the dual variation of the osteoarthritis microenvironment via miR-182.

Osteoarthritis (OA) is the most common type of joint disease and the leading cause of chronic disability among older adults. As an important component of the joint, synovium influences the inflammatory and degenerative process of OA. This study found that miRNA 182 (miR-182) in synovium-specific exosomes can modulate inflammation and apoptotic signaling. It also regulated different biological functions to promote the progression of OA. Experiments based on rat OA model and synovium samples from OA patients, we found that synovium-derived miR-182 regulates inflammatory response in the early stage of OA by regulating the expression level of forkhead box O-3 (FOXO3). However, the expression of miR-182 was significantly increased in synovial tissue of advanced OA, which was involved in the apoptotic signal of severe OA. These findings suggest that miR-182 may directly regulate OA progression by modulating FOXO3 production inflammation, and apoptosis.

Sustained exposure to Helicobacter pylori induces immune tolerance by desensitizing TLR6.

Helicobacter pylori (H. pylori, Hp) has been designated a class I carcinogen and is closely associated with severe gastric diseases. During colonization in the gastric mucosa, H. pylori develops immune escape by inducing host immune tolerance. The gastric epithelium acts as the first line of defense against H. pylori, with Toll-like receptors (TLRs) in gastric epithelial cells being sensitive to H. pylori components and subsequently activating the innate immune system. However, the mechanism of immune tolerance induced by H. pylori through the TLR signalling pathway has not been fully elucidated. In this research, we detected the expression of TLRs and inflammatory cytokines in GES-1 cells upon sustained exposure to H. pylori or H. pylori lysate from 1 to 30 generations and in Mongolian gerbils infected with H. pylori for 5 to 90 weeks. We found that the levels of TLR6 and inflammatory cytokines first increased and then dropped during the course of H. pylori treatment in vitro and in vivo. The restoration of TLR6 potentiated the expression of IL-1ß and IL-8 in GES-1 cells, which recruited neutrophils and reduced the colonization of H. pylori in the gastric mucosa of gerbils. Mechanistically, we found that persistent infection with H. pylori reduces the sensitivity of TLR6 to bacterial components and regulates the expression of inflammatory cytokines in GES-1 cells through TLR6/JNK signaling. The TLR6 agonist obviously alleviated inflammation in vitro and in vivo. Promising results suggest that TLR6 may be a potential candidate immunotherapy drug for H. pylori infection.

Tiaogan daozhuo formula attenuates atherosclerosis via activating AMPK -PPARγ-LXRα pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Tiaogan Daozhuo Formula (TGDZF) is a common formulation against atherosclerosis, however, there is limited understanding of its therapeutic mechanism. AIM OF THIS STUDY: To examine the effectiveness of TGDZF in the treatment of atherosclerosis and to explore its mechanisms. MATERIALS AND METHODS: In ApoE-/- mice, atherosclerosis was induced by a high-fat diet for 12 weeks and treated with TGDZF at different doses. The efficacy of TGDZF in alleviating atherosclerosis was evaluated by small animal ultrasound and histological methods. Lipid levels were measured by biochemical methods. The capacity of cholesterol efflux was tested with a cholesterol efflux assay in peritoneal macrophage, and the expression of AMPKα1, PPARγ, LXRα, and ABCA1 was examined at mRNA and protein levels. Meanwhile, RAW264.7-derived macrophages were induced into foam cells by ox-LDL, and different doses of TGDZF-conducting serum were administered. Similarly, we examined differences in intracellular lipid accumulation, cholesterol efflux rate, and AMPKα1, PPARγ, LXRα, and ABCA1 levels following drug intervention. Finally, changes in the downstream molecules were evaluated following the inhibition of AMPK by compound C or PPARγ silencing by small interfering RNA. RESULTS: TGDZF administration reduced aortic plaque area and lipid accumulation in aortic plaque and hepatocytes, and improved the serum lipid profiles of ApoE-/- mice. Further study revealed that its efficacy was accompanied by an increase in cholesterol efflux rate and the expression of PPARγ, LXRα, and ABCA1 mRNA and protein, as well as the promotion of AMPKα1 phosphorylation. Moreover, similar results were caused by the intervention of TGDZF-containing serum in vitro experiments. Inhibition of AMPK and PPARγ partially blocked the regulatory effect of TGDZF, respectively. CONCLUSIONS: TGDZF alleviated atherosclerosis and promoted cholesterol efflux from macrophages by activating the AMPK-PPARγ-LXRα-ABCA1 pathway.

Empagliflozin Induces Vascular Relaxation in Rat Coronary Artery Due to Activation of BK Channels.

Purpose: The aim of this study was to investigate the effects and mechanisms of SGLT2 inhibitor empagliflozin on diabetic coronary function. Methods: A rat diabetic model was established by injection of streptozotocin. Rats in the treated group were administered empagliflozin by gavage and rat coronary vascular tensions were measured after eight weeks. Large conductance calcium activated K+ channel currents were recorded using a patch clamp technique, while human coronary artery smooth muscle cells were used to explore the underlying mechanisms. Results: After incubation with empagliflozin (10, 30, 100, 300, 1000 µmol/L), the Δ relaxation % of rat coronary arteries were 2.459 ± 1.304, 3.251 ± 1.119, 6.946 ± 3.407, 28.36 ± 11.47, 86.90 ± 3.868, respectively. Without and with empagliflozin in the bath solution, BK channel opening probabilities at a membrane potential of +60 mV were 0.0458 ± 0.0517 and 0.3413 ± 0.2047, respectively (p < 0.05, n = 4 cells). After incubation with iberiotoxin, the Δ tensions of rat coronary arteries in the control (Ctrl), untreated (DM), low empagliflozin (10 mg/kg/d)-treated (DM+L-EMPA) and high empagliflozin (30mg/kg/d)-treated (DM+H-EMPA) group were 103.20 ± 5.85, 40.37 ± 22.12, 99.47 ± 28.51, 78.06 ± 40.98, respectively (p < 0.01 vs Ctrl, n = 3-7; p < 0.001 vs DM+L-EMPA, n = 5-7). Empagliflozin restored high glucose-induced downregulation of Sirt1, Nrf2, and BK-ß1, while the effect of empagliflozin disappeared in the presence of EX-527, a Sirt1 selective inhibitor. Conclusion: Empagliflozin has a vasodilation effect on the coronary arteries in a concentration-dependent manner and can activate BK channels via the Sirt1-Nrf2 mechanism.

Validation of China Health-Related Outcomes Measures-Cardiovascular Disease.

OBJECTIVES: China Health-Related Outcomes Measures (CHROME) was an initiative aimed at developing a system of preference-based health-related quality of life instruments for China. CHROME-cardiovascular disease (CVD) is a CVD-specific instrument with 14 items developed under this initiative. This study aimed to test the psychometric properties of CHROME-CVD. METHODS: This validation study was conducted using cross-sectional questionnaire survey in China. Eligible patients with CVD were recruited and asked to complete the CHROME-CVD, the EQ-5D-5L, and a CVD-specific nonpreference-based health-related quality of life instrument selected according to the confirmed diagnosis of the patients. Item evaluation, internal consistency, measurement invariance, test-retest reliability, structural validity, and construct validity were tested using classic test theory. Item response theory was used to evaluate item-level performance. RESULTS: A total of 444 patients with CVD (coronary artery disease, n = 276, heart failure, n = 104, angina, n = 33, and atrial fibrillation, n = 16) from 6 provinces in China were enrolled for the validation. Exploratory factor analysis identified 4 factors: chest pain, other symptoms, physical health, and mental and social health. Cronbach's alpha and intraclass correlation coefficient were >0.8. A total of 20 of 26 (76.9%), and 90 of 95 (94.7%) predefined hypotheses were met for convergent and discriminant validities, respectively. No important difference was identified between subgroups of gender and residency. Response options of 10 items were found overlapped based on categorical response curves, which led to modification to 4-level response options. Wording of 3 items were modified by referring wordings of reference instruments. CONCLUSION: The validation of the CHROME-CVD demonstrated generally good psychometric properties. Further validation on the modified CHROME-CVD is needed.