Chemerin Enhances Migration and Invasion of OC Cells via CMKLR1/RhoA/ROCK-Mediated EMT.

Chemerin is a newly described adipokine with significant effects on obesity, metabolic disorders, and immune trafficking. Recently, chemerin has gained prominence for its potential roles in cancer and tumorigenesis with pro- or antitumor effects. To date, most referenced multifunctions of chemerin are attributed to the chemokine-like receptor 1 (CMKLR1), distributing broadly in many tissues. This study investigates the in vitro roles of chemerin treatment on migration and invasion of ovarian carcinoma cells (OVCAR-3 and SK-OV-3) and potential underlying mechanisms. Herein, exogenous chemerin treatment promotes growth and invasion of SK-OV-3 cells but has no significant effects on OVCAR-3 cells. SK-OV-3 cells undergo morphological elongation characterized by epithelial-to-mesenchymal transition (EMT) and Ras homologous genome members A (RhoA)/Rho protein-related curl spiral kinase-1 (ROCK1) activation. Furthermore, chemerin-enhanced invasion and EMT of SK-OV-3 cells are effectively blocked by C3 transferase (C3T) and Y27632 and RhoA and ROCK1 inhibitor, respectively. More importantly, RhoA/ROCK1-EMT-mediated SK-OV-3 cell invasion is orchestrated by CMKLR1 upregulation after chemerin treatment (50 ng/mL). The silencing of CMKLR1 significantly (P < 0.0001) reverses the chemerin-enhanced invasion, EMT, and RhoA/ROCK1 activation of SK-OV-3 cells. Our study indicates that chemerin promotes invasion of OC cells via CMKLR1-RhoA/ROCK1-mediated EMT, offering a novel potential target for metastasis of OC.

Data Flow Construction and Quality Evaluation of Electronic Source Data in Clinical Trials: Pilot Study Based on Hospital Electronic Medical Records in China.

Background: The traditional clinical trial data collection process requires a clinical research coordinator who is authorized by the investigators to read from the hospital's electronic medical record. Using electronic source data opens a new path to extract patients' data from electronic health records (EHRs) and transfer them directly to an electronic data capture (EDC) system; this method is often referred to as eSource. eSource technology in a clinical trial data flow can improve data quality without compromising timeliness. At the same time, improved data collection efficiency reduces clinical trial costs. Objective: This study aims to explore how to extract clinical trial-related data from hospital EHR systems, transform the data into a format required by the EDC system, and transfer it into sponsors' environments, and to evaluate the transferred data sets to validate the availability, completeness, and accuracy of building an eSource dataflow. Methods: A prospective clinical trial study registered on the Drug Clinical Trial Registration and Information Disclosure Platform was selected, and the following data modules were extracted from the structured data of 4 case report forms: demographics, vital signs, local laboratory data, and concomitant medications. The extracted data was mapped and transformed, deidentified, and transferred to the sponsor's environment. Data validation was performed based on availability, completeness, and accuracy. Results: In a secure and controlled data environment, clinical trial data was successfully transferred from a hospital EHR to the sponsor's environment with 100% transcriptional accuracy, but the availability and completeness of the data could be improved. Conclusions: Data availability was low due to some required fields in the EDC system not being available directly in the EHR. Some data is also still in an unstructured or paper-based format. The top-level design of the eSource technology and the construction of hospital electronic data standards should help lay a foundation for a full electronic data flow from EHRs to EDC systems in the future.

Determination of ED90s of Phenylephrine and Norepinephrine Infusion for Prevention of Spinal Anesthesia-Induced Hypotension in Patients with Preeclampsia During Cesarean Delivery.

Background: Vasopressors remain an important strategy for managing spinal anesthesia-induced hypotension in women with preeclampsia. The aim of this study was to investigate the ED90s and efficacy ratio of phenylephrine and norepinephrine in managing spinal anesthesia-induced hypotension in women with preeclampsia during cesarean delivery. Methods: 60 women with preeclampsia, who underwent cesarean delivery, were randomly assigned to receive either a continuous intravenous infusion of phenylephrine or norepinephrine following spinal anesthesia. The initial dosage of phenylephrine or norepinephrine for the first women was 0.5 or 0.05 µg/kg/min, respectively, and subsequent infusion dosages were adjusted based on their efficacy in preventing spinal anesthesia-induced hypotension (defined as a systolic blood pressure less than 80% of the baseline level). The incremental or decremental doses of phenylephrine or norepinephrine were set at 0.1 or 0.01 µg/kg/min. The primary outcomes were the ED90s and efficacy ratio of phenylephrine and norepinephrine infusions for preventing spinal anesthesia-induced hypotension prior to delivery. Results: The results obtained from isotonic regression analysis revealed that the ED90 values of the phenylephrine and norepinephrine group for preventing spinal anesthesia-induced hypotension were 0.597 (95% CI: 0.582-0.628) and 0.054 (95% CI: 0.053-0.056) µg/kg/min, respectively, with an efficacy ratio of 11.1:1. The results of Probit regression analysis revealed that the ED90 values were determined to be 0.665 (95% CI: 0.576-1.226) and 0.055 (95% CI: 0.047-0.109) µg/kg/min, respectively, with an efficacy ratio of 12.1:1. Conclusion: The administration of 0.6 µg/kg/min phenylephrine and 0.05 µg/kg/min norepinephrine has been found to effectively manage a 90% incidence of spinal anesthesia-induced hypotension in women with preeclampsia.

FTY720 ameliorates experimental MPO-ANCA-associated vasculitis by regulating fatty acid oxidation via the neutrophil PPARα-CPT1a pathway.

OBJECTIVES: Increasing studies demonstrated the importance of C5a and anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation in the pathogenesis of ANCA-associated vasculitis (AAV). Sphingosine-1-phosphate (S1P) acts as a downstream effector molecule of C5a and enhances neutrophil activation induced by C5a and ANCA. The current study investigated the role of a S1P receptor modulator FTY720 in experimental autoimmune vasculitis (EAV) and explored the immunometabolism-related mechanisms of FTY720 in modulating ANCA-induced neutrophil activation. METHODS: The effects of FTY720 in EAV were evaluated by quantifying hematuria, proteinuria, crescent formation, tubulointerstitial injury and pulmonary hemorrhage. RNA sequencing of renal cortex and gene enrichment analysis were performed. The proteins of key identified pathways were analyzed in neutrophils isolated from peripheral blood of patients with active AAV and normal controls. We assessed the effects of FTY720 on ANCA-induced neutrophil respiratory burst and neutrophil extracellular traps formation (NETosis). RESULTS: FTY720 treatment significantly attenuated renal injury and pulmonary hemorrhage in EAV. RNA sequencing analyses of renal cortex demonstrated enhanced fatty acid oxidation (FAO) and peroxisome proliferators-activated receptors (PPAR) signalling in FTY720-treated rats. Compared with normal controls, patients with active AAV showed decreased FAO in neutrophils. FTY720-treated differentiated HL-60 cells showed increased expression of carnitine palmitoyltransferase 1A (CPT1a) and PPARα. Blocking or knockdown of CPT1a or PPARα in isolated human neutrophils and HL-60 cells reversed the inhibitory effects of FTY720 on ANCA-induced neutrophil respiratory burst and NETosis. CONCLUSION: FTY720 attenuated renal injury in EAV through upregulating FAO via the PPARα-CPT1a pathway in neutrophils, offering potential immunometabolic targets in AAV treatment.

Socioeconomic support, quality of life, and prognosis of frailty among the older adults.

Background: Although socioeconomic support is recommended for frailty management, its association with the prognosis of frailty is unclear. Methods: Using data from participants aged ≥65 years in the Chinese Longitudinal Healthy Longevity Survey (2008-2018), the associations between socioeconomic support (source of income, medical insurance, community support, living status), onset of prefrailty/frailty, and worsening of prefrailty, were analyzed using multinominal logistic regression models. The associations between self-reported low quality of life (QoL) and reversion of prefrailty/frailty were analyzed using multivariate logistic regression models. Associations with mortality risk were analyzed using Cox proportional hazard regression models. Results: A total of 13,859 participants (mean age: 85.8 ± 11.1 years) containing 2056 centenarians were included. Financial dependence was a risk factor for low QoL among prefrail/frail individuals, but not among robust individuals. Having commercial or other insurance, and receiving social support from the community were protective factors for low QoL among prefrail/frail individuals and for the worsening of prefrailty. Continuing to work was a risk factor for low QoL, but a protective factor for worsening of prefrailty. A negative association between continuing to work and mortality existed in prefrail individuals aged <85 years and ≥85 years. Living alone was a risk factor for low QoL, but was not significantly associated with frailty prognosis. Conclusions: Prefrail and frail individuals were vulnerable to changes in socioeconomic support and more sensitive to it compared with robust individuals. Preferential policies regarding financial support, social support, and medical insurance should be developed for individuals with frailty.

CAR-T therapy for ovarian cancer: Recent advances and future directions.

Ovarian cancer (OC) is a common gynecological tumor with high mortality, which is difficult to control its progression with conventional treatments and is prone to recurrence. Recent studies have identified OC as an immunogenic tumor that can be recognized by the host immune system. Immunotherapy for OC is being evaluated, but approaches such as immune checkpoint inhibitors have limited efficacy, adoptive cell therapy is an alternative therapy, in which CAR(chimeric antigen receptor)-T therapy has been applied to the clinical treatment of hematological malignancies. In addition, CAR-NK and CAR-macrophage (CAR-M) have also shown great potential in the treatment of solid tumors. Here, we discuss recent advances in preclinical and clinical studies of CAR-T for OC treatment, introduce the efforts made by researchers to modify the structure of CAR in order to achieve effective OC immunotherapy, as well as the research status of CAR-NK and CAR-M, and highlight emerging therapeutic opportunities that can be utilized to improve the survival of patients with OC using CAR-based adoptive cell therapy.

Protective Role of TRPC3 Gene Polymorphism (rs10518289) in Obstructive Sleep Apnea Hypopnea Syndrome Among Hypertensive Patients.

BACKGROUND Obstructive sleep apnea-hypopnea syndrome (OSAHS) presents a significant health concern, particularly among individuals with essential hypertension (EH). Understanding the genetic underpinnings of this association is crucial for effective management and intervention. We investigated the relationship between TRPC3 gene polymorphisms and susceptibility to OSAHS in patients with EH. MATERIAL AND METHODS We enrolled 373 patients with EH hospitalized at the First Affiliated Hospital of Xinjiang Medical University between April 2015 and November 2017. Patients were categorized into EH (n=74) and EH+OSAHS (n=299) groups according to the apnea-hypopnea index. Sequenom detection technology was used for TRPC3 gene single-nucleotide polymorphism genotyping, including genotypes at rs953691, rs10518289, rs2292232, rs4995894, rs951974, and rs4292355. RESULTS Sex, smoking history, alcohol history, hypertension duration, fasting blood glucose, urea, creatinine, total cholesterol, HDL-C, LDL-C, glycosylated hemoglobin, 24-h mean systolic BP, and 24-h mean diastolic BP were not significantly different between the 2 groups (P>0.05); however, age, BMI, triglyceride levels differed significantly (P<0.05). No significant difference was detected in distribution frequency of polymorphisms of TRPC3 gene between the 2 groups (P>0.05), while genotype, dominant genotype, and recessive genotype at rs10518289 and alleles at rs4292355 differed significantly (P<0.05). Logistic regression analysis showed age, BMI, and CG+GG genotypes at rs10518289 were risk factors for OSAHS in patients with EH. Interaction between TRPC3 (rs10518289) and obesity was not a risk of OSAHS with EH (P>0.05). CONCLUSIONS CC genotype of rs10518289 in the TRPC3 gene could be a protective genetic marker of OSAHS, and CG+GG genotype may be a risk genetic marker of OSAHS with EH.

Revealing core functional microorganisms in the fermentation process of Qicaipaojiao (Capsicum annuum L.) based on microbial metabolic network.

Paojiao, a typical Chinese traditional fermented pepper, is favored by consumers for its unique flavor profile. Microorganisms, organic acids, amino acids, and volatile compounds are the primary constituents influencing the development of paojiao's flavor. To elucidate the key flavor compounds and core microorganisms of Qicaipaojiao (QCJ), this study conducted a comprehensive analysis of the changes in taste substances (organic acids and amino acids) and volatile flavor compounds during QCJ fermentation. Key flavor substances in QCJ were identified using threshold aroma value and odor activity value and the core microorganisms of QCJ were determined based on the correlation between dominant microorganisms and the key flavor substances. During QCJ fermentation, 16 key taste substances (12 free amino acids and 4 organic acids) and 12 key aroma substances were identified. The fermentation process involved 10 bacteria and 7 fungal genera, including Lactiplantibacillus, Leuconostoc, Klebsiella, Pichia, Wickerhamomyces, and Candida. Correlation analysis revealed that the core functional microorganisms encompassed representatives from 8 genera, including 5 bacterial genera (Lactiplantibacillus, Weissella, Leuconostoc, Klebsiella, and Kluyvera) and 3 fungal genera (Rhodotorula, Phallus, and Pichia). These core functional microorganisms exhibited significant correlations with approximately 70 % of the key flavor substances (P < 0.05). This study contributes to an enhanced understanding of flavor formation mechanisms and offers valuable insight into flavor quality control in food fermentation processes.

Palladium-Catalyzed (4 + 1) Annulation of 4-Vinylbenzodioxinones with Sulfur Ylides: Diastereoselective Synthesis of Dihydrobenzofuran Derivatives.

Palladium-catalyzed (4 + 1) annulation of 4-vinylbenzodioxinones with sulfur ylides has been developed to afford various dihydrobenzofuran derivatives in moderate to high yields with excellent diastereoselectivities. The scale-up reaction and further derivations of the product worked well, demonstrating the application potential of the current reaction in organic synthesis.

Epidemiological survey and risk factor analysis of high-risk human papillomavirus in women in Longgang District, Shenzhen.

Objective: The objective of this study was to assess the prevalence of high-risk HPV infection in married women in Longgang District, Shenzhen, and to analyze the distribution of HPV subtypes across different age groups while identifying risk factors associated with HPV infection. Methods: 1. From January 2018 to December 2020, 209,627 married women in Longgang District were selected as study subjects, using high-risk HPV testing as the primary screening means. HPV 16 or 18 positive directly referred to colposcopy, other types positive continued liquid-based thin-layer cytology (TCT) examination, if ≥ ASCUS, referred to colposcopy, and biopsy if necessary. 2. 210 female patients who came to our hospital for HPV testing from January 2018 to December 2020 were used for the study, including 130 HPV-positive patients and 80 HPV-negative patients. The risk factors of HPV infection were studied by questionnaire. Results: The HPV infection rate in 2018 was 13.17%, including LSIL 6.87%, HSIL 3.57%, the single type infection rate was 79.83%, top5 monotypes were 52, 53, 16, 58, 81, multiple types infection rate was 20.17%, top5 multiple types were 52/ 53, 52/68, 16/52 52/58, 52/81; 2019 HPV positivity rate was 10.23%, including LSIL 5.98%, HSIL 5.81%, the monotypic infection rate was 82.5%, top5 monotypic were: 52, 16, 58, 51, 53, multi heavy sex infection rate was 17.5%, top5 multi typic were: 52/53, 52/58, 52/68, 16/52, 51/52; HPV positive rate in 2020 was 11.28%, including LSIL 6 %, HSIL 4.84%, monotypic infection rate was 79.89%, top5 monotypic were: 52, 16, 53, 58, 51, multiheavy category infection rate was 20.11%, top5 multitypic were: 52/58, 16/52, 52/68, 52/53, 51/52. 30-50 years old is the high prevalence age of HPV susceptibility, followed by 50-60 years old, and HPV52 is the most common type. 2. 210 female patients were surveyed by filling out questionnaires: Smoking history, age at first sex, age at first pregnancy, abortion, number of sexual partners, contraceptive method, bleeding during intercourse, cervicitis, vaginitis, sleeping habits, and mental status totaling 11 factors were significant between infected and control (P < .05). Dichotomous logistic regression analysis with these 11 factors as independent variables and HPV infection as dependent variable revealed that abortion (OR=2.117, 95% CI: 1.337-3.354), number of sexual partners (OR=2.562, 95% CI: 1.222-5.373), cervicitis (OR=2.873, 95% CI: 1.407-5.868), vaginitis (OR=2.413, 95% CI: 1.158-5.026) staying up late (OR=2.408, 95% CI: 1.134-5.115) and mental status (OR=3.139, 95% CI: 1.470-6.703) were six factors that were risk factors for HPV infection. Conclusion: The common HPV infection types among women in Longgang district were mainly 52, 16, 58, 53, and 51, with a predominance of a single type of infection. The positive rate and pathogenicity of HPV 52 were higher than HPV 16. Women aged 30-60 years should be included in priority screening for cervical lesions. The six factors of miscarriage, number of sexual partners, cervicitis, vaginitis, staying up late, and mental status were risk factors for HPV infection occurrence.

Effects and safety of Ginkgo biloba on depression: a systematic review and meta-analysis.

Background: Because depression is a major factor contributing to the global disease burden, we tried to analyze the effects and safety of Ginkgo biloba (GKB) on patients with depression. Methods: We conducted a literature search for articles published between January 2002 and May 2022 in seven online databases (PubMed, Scopus, Embase, Google Scholar, Web of Sciences, Cochrane Library, and China National Knowledge Infrastructure). A systematic literature review and meta-analysis were performed to compare the effects and safety of GKB on patients with depression, including subjective and objective indicators of depression evaluation. Results: In total, 21 eligible articles with nine indicators among 2074 patients were included. Several outcomes showed a difference, and the GKB group had better results than the control group, including the Hamilton Depression Scale (HAMD), after taking GKB for 4 weeks (MD = -2.86, 95%CI [-4.27, -1.46], p < 0.01), 6 weeks (mean difference (MD) = -3.36, 95%CI [-4.05, -2.67], p < 0.01), and 8 weeks (MD = -4.58, 95% CI [-6.11, -3.05], p < 0.01), modified Barthel index (MBI) (MD = 14.86, 95%CI [12.07, 17.64], p < 0.01), modified Edinburgh-Scandinavian stroke scale (MESSS) (MD = -4.57, 95%CI [-6.34, -2.79], p < 0.01), brain-derived neurotrophic factor (BDNF) (MD = 16.35, 95%CI [7.34, 25.36], p < 0.01), 5-hydroxytryptamine (5-HT) (MD = 4.57, 95%CI [3.08, 6.05], p < 0.01), and clinical efficacy (risk ratio, RR = 1.24, 95%CI [1.17, 1.32], p < 0.01). However, there were no differences in adverse events between GKB and controls. Conclusion: In conclusion, the main finding was that patients treated with GKB had better MBI, MESSS, BDNF, 5-HT, and HAMD values after 4 weeks, 6 weeks, and 8 weeks than the control group. GKB might reduce the risk of depression or depressive symptoms with safe clinical efficacy. Systematic Review Registration: identifier (INPLASY2023100052).

Clinicopathological characteristics and gene mutations in 11 patients with lipoprotein glomerulopathy.

OBJECTIVE: Lipoprotein glomerulopathy (LPG) is a rare disorder characterized by the development of glomerular lipoprotein thrombosis. LPG exhibits familial aggregation, with mutations in the apolipoprotein E (APOE) gene identified as the leading cause of this disease. This study aimed to investigate APOE gene mutations and the clinicopathological features in eleven LPG patients. METHODS: Clinicopathological and follow-up data were obtained by extracting DNA, followed by APOE coding region sequencing analysis. This study analyzed clinical and pathological manifestations, gene mutations, treatment and prognosis. RESULTS: The mean age of the eleven patients was 33.82 years. Among them, five had a positive family history for LPG, ten presented with proteinuria, four exhibited nephrotic syndrome, and six presented with microscopic hematuria. Dyslipidemia was identified in ten patients. In all renal specimens, there was evident dilation of glomerular capillary lumens containing lipoprotein thrombi, and positive oil red O staining was observed in frozen sections of all samples. APOE gene testing revealed that one patient had no mutations, while the remaining ten patients exhibited mutations in the APOE gene, with three patients presenting with multiple mutations simultaneously. Following the confirmation of LPG diagnosis, treatment with angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) was initiated, and the disease progressed slowly. CONCLUSION: LPG is histologically characterized by lamellated lipoprotein thrombi in glomeruli, and kidney biopsy is essential for diagnosis. Mutations in the APOE gene are the leading cause of LPG. This study revealed clinicopathological characteristics and APOE gene mutations in patients with LPG, which helps us better understand the disease.

Role of Radiation-related Lung Function Genes in Prognosis and Immune Infiltration of Lung Adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is a common malignant tumor with no obvious clinical symptoms in its early stages. Patients can be divided into radiotherapysensitive groups (RS) and radiotherapy-resistant groups (RR) due to their varying conditions. The therapeutic effect of radiotherapy is quite different between the two groups. Therefore, this paper explores the role of radiation-related lung function genes in LUAD and its immune landscape. METHODS: Firstly, we divided LUAD samples from the TCGA cohort into RS and RR groups and analyzed differential expression to obtain differentially expressed genes (DEGs). Then, DEGs and patients' grouping information were input into the weighted co-expression network, and the genes in the radiotherapy-related modules were identified. Furthermore, after the intersection of DEGs and lung function-related genes, the prognosis-related genes were obtained through univariate Cox and Lasso-Cox analyses, respectively, and the risk model was constructed. Finally, the differences in prognosis and immunity of the samples in the risk model were explored. Additionally, we also performed a qPCR experiment on lung function-related genes. RESULTS: In this paper, radiation-related genes of LUAD were identified through a series of bioinformatics analyses. By conducting enrichment analysis on these genes, several pathways related to LUAD radiation were identified, and DEGs associated with significant prognosis were determined. Furthermore, a radiation-related risk model of LUAD was developed. All samples were divided into high-risk and low-risk groups based on the risk score, and the differences in immune cell infiltration abundance and immune function between these groups were evaluated. The qPCR experimental results demonstrated a significant difference in the expression of genes related to lung function. CONCLUSION: The prognosis-related genes identified in this paper and the risk model created can serve as a reference for diagnosing and treating LUAD.

Association of lipid-modifying therapy with risk of obstructive sleep apnea: A drug-target mendelian randomization study.

BACKGROUND: Obstructive sleep apnea (OSA) is considered to be an important contributor of dyslipidemia. However, there lacks observational studies focusing on the potential effect of lipid management on OSA risk. Thus, we aimed to investigate the genetic association of lipid-modifying therapy with risk of OSA. METHODS: A drug-target mendelian randomization (MR) study using both cis-variants and cis-expression quantitative trait loci (eQTLs) of lipid-modifying drug targets was performed. The MR analyses used summary-level data of genome wide association studies (GWAS). Primary MR analysis was conducted using inverse-variance-weighted (IVW) method. Sensitivity analysis was performed using weighted median (WM) and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. RESULTS: Genetically proxied low-density lipoprotein cholesterol (LDL-C)-lowering effect of cholesteryl ester transfer protein (CETP) was associated with reduced risk of OSA (odds ratio [OR] =0.75, 95% confidence interval [CI]: 0.60-0.94, false discovery rate [FDR] q value = 0.046). A significant MR association with risk of OSA was observed for CETP expression in subcutaneous adipose tissue (OR = 0.94, 95%CI: 0.89-1.00, FDR q value = 0.049), lung (OR = 0.94, 95%CI: 0.89-1.00, FDR q value = 0.049) and small intestine (OR = 0.96, 95%CI: 0.93-1.00, FDR q value = 0.049). No significant effects of high-density lipoprotein cholesterol (HDL-C)-raising effect of CETP inhibition, LDL-C-lowering and triglycerides-lowering effect of other drug targets on OSA risk were observed. CONCLUSIONS: The present study presented genetic evidence supporting the association of LDL-C-lowering therapy by CETP inhibition with reduced risk of OSA. These findings provided novel insights into the role of lipid management in patients with OSA and encouraged further clinical validations and mechanistic investigations.

Sorbs2 Deficiency and Vascular BK Channelopathy in Diabetes.

BACKGROUND: Vascular large conductance Ca2+-activated K+ (BK) channel, composed of the α-subunit (BK-α) and the ß1-subunit (BK-ß1), is a key determinant of coronary vasorelaxation and its function is impaired in diabetic vessels. However, our knowledge of diabetic BK channel dysregulation is incomplete. The Sorbs2 (Sorbin homology [SoHo] and Src homology 3 [SH3] domains-containing protein 2), is ubiquitously expressed in arteries, but its role in vascular pathophysiology is unknown. METHODS: The role of Sorbs2 in regulating vascular BK channel activity was determined using patch-clamp recordings, molecular biological techniques, and in silico analysis. RESULTS: Sorbs2 is not only a cytoskeletal protein but also an RNA-binding protein that binds to BK channel proteins and BK-α mRNA, regulating BK channel expression and function in coronary smooth muscle cells. Molecular biological studies reveal that the SH3 domain of Sorbs2 is necessary for Sorbs2 interaction with BK-α subunits, while both the SH3 and SoHo domains of Sorbs2 interact with BK-ß1 subunits. Deletion of the SH3 or SoHo domains abolishes the Sorbs2 effect on the BK-α/BK-ß1 channel current density. Additionally, Sorbs2 is a target gene of the Nrf2 (nuclear factor erythroid-2-related factor 2), which binds to the promoter of Sorbs2 and regulates Sorbs2 expression in coronary smooth muscle cells. In vivo studies demonstrate that Sorbs2 knockout mice at 4 months of age display a significant decrease in BK channel expression and function, accompanied by impaired BK channel Ca2+-sensitivity and BK channel-mediated vasodilation in coronary arteries, without altering their body weights and blood glucose levels. Importantly, Sorbs2 expression is significantly downregulated in the coronary arteries of db/db type 2 diabetic mice. CONCLUSIONS: Sorbs2, a downstream target of Nrf2, plays an important role in regulating BK channel expression and function in vascular smooth muscle cells. Vascular Sorbs2 is downregulated in diabetes. Genetic knockout of Sorbs2 manifests coronary BK channelopathy and vasculopathy observed in diabetic mice, independent of obesity and glucotoxicity.

Recent advances in tissue repair of the blood-brain barrier after stroke.

The selective permeability of the blood-brain barrier (BBB) enables the necessary exchange of substances between the brain parenchyma and circulating blood and is important for the normal functioning of the central nervous system. Ischemic stroke inflicts damage upon the BBB, triggering adverse stroke outcomes such as cerebral edema, hemorrhagic transformation, and aggravated neuroinflammation. Therefore, effective repair of the damaged BBB after stroke and neovascularization that allows for the unique selective transfer of substances from the BBB after stroke is necessary and important for the recovery of brain function. This review focuses on four important therapies that have effects of BBB tissue repair after stroke in the last seven years. Most of these new therapies show increased expression of BBB tight-junction proteins, and some show beneficial results in terms of enhanced pericyte coverage at the injured vessels. This review also briefly outlines three effective classes of approaches and their mechanisms for promoting neoangiogenesis following a stroke.

Optimization and characterization of pectin extracted from hawthorn by deep eutectic solvent.

In this study, hawthorn pectin was extracted from dried hawthorn with deep eutectic solvent(DES) and compared with the traditional extraction methods such as acid extraction (AE) and ultrasonic-assisted extraction (UAE). Under optimal conditions, with a molar ratio of choline chloride to urea at 1:3, a water content of 30 %, a liquid-to-solid ratio of 30:1 (mL/g), an extraction temperature of 80 °C, an extraction time of 60 min, and a pH of 1, the yield of hawthorn pectin was 4.33 % ± 0.02 %. The measured results were consistent with the prediction. In addition, compared with AE and UAE, the experimental results showed that DES had a higher yield, a lower degree of esterification, and a slightly different monosaccharide composition from other extraction methods. The results of infrared spectroscopy and scanning electron microscopy showed that DES had a fine microstructure and coarser surface, and the main chemical structure of DES didn't change. The rheological analysis showed that DES had lower apparent viscosity than AE and UAE. These results represent a green source for pectin extraction with high pectin yield and good performance. In conclusion, the deep eutectic solvent has good application prospects in extracting hawthorn pectin.

Early Impact of Proton Beam Therapy on Electrophysiological Characteristics in a Porcine Model.

BACKGROUND: Particle therapy is a noninvasive, catheter-free modality for cardiac ablation. We previously demonstrated the efficacy for creating ablation lesions in the porcine heart. Despite several earlier studies, the exact mechanism of early biophysical effects of proton and photon beam delivery on the myocardium remain incompletely resolved. METHODS: Ten normal and 9 infarcted in situ porcine hearts received proton beam irradiation (40 Gy) delivered to the left ventricular myocardium with follow-up for 8 weeks. High-resolution electroanatomical mapping of the left ventricular was performed at baseline and follow-up. Bipolar voltage amplitude, conduction velocity, and connexin-43 were determined within the irradiated and nonirradiated areas. RESULTS: The irradiated area in normal hearts showed a significant reduction of bipolar voltage amplitude (10.1±4.9 mV versus 5.7±3.2, P<0.0001) and conduction velocity (85±26 versus 55±13 cm/s, P=0.03) beginning at 4 weeks after irradiation. In infarcted myocardium after irradiation, bipolar voltage amplitude of the infarct scar (2.0±2.9 versus 0.8±0.7 mV, P=0.008) was significantly reduced as well as the conduction velocity in the infarcted heart (43.7±15.7 versus 26.3±11.4 cm/s, P=0.02). There were no significant changes in bipolar voltage amplitude and conduction velocity in nonirradiated myocardium. Myocytolysis, capillary hyperplasia, and dilation were seen in the irradiated myocardium 8 weeks after irradiation. Active caspase-3 and reduction of connexin-43 expression began in irradiated myocardium 1 week after irradiation and decreased over 8 weeks. CONCLUSIONS: Irradiation of the myocardium with proton beams reduce connexin-43 expression, conduction velocity, and bipolar conducted electrogram amplitude in a large porcine model. The changes in biomarkers preceded electrophysiological changes after proton beam therapy.

Pathogenesis of anti-neutrophil cytoplasmic antibody-associated vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) encompasses a group of potentially life-threatening disorders characterized by necrotizing small vessel vasculitis with positive serum ANCA. To date, the pathogenesis of AAV has not been fully elucidated, but remarkable progress has been achieved in the past few decades. In this review, we summarize the mechanism of AAV. The pathogenesis of AAV involves various factors. ANCA, neutrophils, and the complement system play key roles in disease initiation and progression, forming a feedback amplification loop leading to vasculitic injury. Neutrophils activated by ANCA undergo respiratory burst and degranulation, as well as releasing neutrophils extracellular traps (NETs), thus causing damage to vascular endothelial cells. Activated neutrophils could further activate the alternative complement pathway, leading to the generation of complement 5a (C5a), which amplifies the inflammatory response by priming neutrophils for ANCA-mediated overactivation. Neutrophils stimulated with C5a and ANCA could also activate the coagulation system, generate thrombin, and subsequently cause platelet activation. These events in turn augment complement alternative pathway activation. Moreover, disturbed B-cell and T-cell immune homeostasis is also involved in disease development. In-depth investigation in pathogenesis of AAV might help to offer more effective targeted therapies.