Comparison of the effect between cefazolin/cefuroxime and broad-spectrum antibiotics in preventing post-operative pulmonary infections for smoking patients receiving video-assisted thoracoscopic lung surgery: a propensity score-matched retrospective cohort study.

BACKGROUND: The selection of prophylactic antibiotics for preventing post-operative pulmonary infections in smoking patients undergoing video-assisted thoracoscopic lung surgery (VATLS) is not clear. METHODS: In this retrospective cohort study, the outcomes of 572 smoking patients undergoing VATLS with prophylactic cefazolin/cefuroxime or other antibiotics were analyzed. Patients were classified as cefazolin/cefuroxime group and the control group. A 1:1 propensity score matching was also performed. RESULTS: The primary outcome of the incidence of post-operative pulmonary infection did not differ significantly between the two groups (23.7% vs 30.5%, RR = 0.777, 95%CI 0.564 ~ 1.070 p = 0.113). Similarly, secondary outcomes including the incidence of post-operative fever, the white blood cell count and neutrophils on the 3rd day after the surgery, and time for blood routine test recovery were all found without significant difference between the two groups. In the multivariate logistic regression model, no association was found between prophylactic use of cefazolin/cefuroxime and post-operative pulmonary infections after controlling other possible confounding factors (OR = 0.685, 95%CI 0.441 ~ 1.065, p = 0.093). CONCLUSIONS: Prophylactic use of cefazolin/cefuroxime was not associated with more adverse clinical outcomes among smoking populations undergoing VATLS when compared with broad-spectrum antibiotics and the two drugs are still feasible for peri-operative prophylactic use for smoking population before the surgery.

Does the Anionic Surfactant Isopropylamine Dodecylbenzene Sulfonate Induce Hepatic Oxidative Stress and Impairment in Carassius auratus gibelio?

Isopropylamine dodecylbenzene sulfonate (IDS) is a new kind of anionic surfactant (ANS). To preliminarily evaluate the aquatic toxicity of IDS, this study took gibel carp (Carassius auratus gibelio) as the research object. The well-acclimatized fish were divided into six groups and exposed to 0 mg/L, 0.5 mg/L, 1.0 mg/L, 2.0 mg/L, 4.0 mg/L, or 8.0 mg/L of IDS for 7, 14, 21 or 28 days. Our results showed that the superoxide dismutase (SOD) activity and malondialdehyde (MDA) content of the liver were unaffected by IDS exposure, while glutathione peroxidase (GSH-Px) activity was significantly inhibited. Hepatic tissue exhibited pathological damage, characterized by nuclear migration and dissolution and cell boundary blurring. The results suggest that IDS does not cause oxidative stress in the liver, but cause hepatic histopathological damage. GSH-Px can be considered as a biomarker of IDS exposure in gibel carp.

The availability, price and affordability of essential antibacterials in Hubei province, China.

BACKGROUND: China ranks first amongst the countries for the abuse of antibacterials. Essential antibacterials could help solve the problem. The aim of the work is to evaluate the availability, price and affordability of essential antibacterials in Hubei province, China. METHOD: The standardized methodology developed by the World Health Organization and Health Action International was used to collect data on the availability and prices of 16 antibacterials in 5 cities of Hubei province, China. RESULTS: First, in total, the median availability of originator brands and lowest-priced generics for the essential antibacterials was low, 3.0% (0.0, 18.2%) and 33.3% (0.0, 87.9%) for each, respectively. Second, the median price ratio of originator brands for the antibacterials was 20.30 (4.71, 35.80), while for generics, it was 0.49 (0.07, 1.18). Third, the affordability of originator brands for the antibacterials was 28.14 (21.70, 41.90) times the daily wages of an unskilled government worker, while for generics, the affordability was 0.35 (0.04, 6.11). Finally, we found that in Hubei province, lowest-priced generics for essential antibacterials with (fairly) high availability and relatively low price included Amoxicillin/Clavulanic Acid, Ceftazidime, Metronidazole, Gentamicin Sulfate and Ceftriaxone. CONCLUSION: The prices of lowest-priced generics for essential antibacterials in Hubei province were reasonable, and in tertiary hospitals the availability was the highest, while in secondary and primary hospitals, it was relatively lower. Originator brands were not only extremely expensive but also difficult to obtain. Measures should be taken to improve the availability of essential antibacterials and the affordability of originator brands.

A novel mechanism of action for salidroside to alleviate diabetic albuminuria: effects on albumin transcytosis across glomerular endothelial cells.

Salidroside (SAL) is a phenylethanoid glycoside isolated from the medicinal plant Rhodiola rosea. R. rosea has been reported to have beneficial effects on diabetic nephropathy (DN) and high-glucose (HG)-induced mesangial cell proliferation. Given the importance of caveolin-1 (Cav-1) in transcytosis of albumin across the endothelial barrier, the present study was designed to elucidate whether SAL could inhibit Cav-1 phosphorylation and reduce the albumin transcytosis across glomerular endothelial cells (GECs) to alleviate diabetic albuminuria as well as to explore its upstream signaling pathway. To assess the therapeutic potential of SAL and the mechanisms involved in DN albuminuria, we orally administered SAL to db/db mice, and the effect of SAL on the albuminuria was measured. The albumin transcytosis across GECs was explored in a newly established in vitro cellular model. The ratio of albumin to creatinine was significantly reduced upon SAL treatment in db/db mice. SAL decreased the albumin transcytosis across GECs in both normoglycemic and hyperglycemic conditions. SAL reversed the HG-induced downregulation of AMP-activated protein kinase and upregulation of Src kinase and blocked the upregulation Cav-1 phosphorylation. Meanwhile, SAL decreased mitochondrial superoxide anion production and moderately depolarized mitochondrial membrane potential. We conclude that SAL exerts its proteinuria-alleviating effects by downregulation of Cav-1 phosphorylation and inhibition of albumin transcytosis across GECs. These studies provide the first evidence of interference with albumin transcytosis across GECs as a novel approach to the treatment of diabetic albuminuria.

Secreted Clusterin Inhibits Tumorigenesis by Modulating Tumor Cell and Macrophage in Human Meningioma.

BACKGROUND: Meningioma is the most common primary intracranial tumor with high frequency of postoperative recurrence, yet the biology of meningioma malignancy process is still obscure. METHODS: To identify potential therapeutic targets and tumor suppressors, we performed single-cell transcriptome analysis through meningioma malignancy, which included 18 samples spanning normal meninges, benign and high grade in situ tumors, and lung metastases, for extensive transcriptome characterization. Tumor suppressor candidate gene and molecular mechanism were functionally validated at animal model and cellular level. RESULTS: Comprehensive analysis and validation in mice and clinical cohorts indicated Clusterin (CLU) had suppressive function for meningioma tumorigenesis and malignancy by inducing mitochondria damage and triggering type I interferon pathway dependent on its secreted isoform, and the inhibition effect was enhanced by TNFα as TNFα also induced type I interferon pathway. The expression of CLU was upregulated by histone deacetylase inhibition. Meanwhile, both intra- and extra-cellular CLU overexpression enhanced macrophage polarization towards M1 phenotype and TNFα production, thus promoted tumor killing and phagocytosis. CONCLUSIONS: CLU might be a key brake of meningioma malignance by synchronous modulating tumor cells and their microenvironment. Our work provides comprehensive insights into meningioma malignancy and a potential therapeutic strategy.

Smoking is associated with elevated blood level of volatile organic compounds: a population-based analysis of NHANES 2017-2018.

BACKGROUND: The study aims to explore the association between cigarette smoking with blood exposure to volatile organic compounds using population data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018. METHODS: Based on the data of NHANES 2017-2018, we identified 1117 participants aged 18 to 65 years, who had complete VOCs testing data and filled out the Smoking-Cigarette Use and Volatile Toxicant questionnaires. The participants consisted of 214 dual-smoking persons, 41 E-cigarette smokers, 293 combustible-cigarette smokers and 569 non-smokers. We used One-way ANOVA and Welch's ANOVA to compare differences of VOCs concentration among 4 groups and multivariable regression model to confirm the factors associated with VOCs concentration. RESULTS: In dual-smoking and combustible-cigarette smokers, blood concentration of 2,5-Dimethylfuran, Benzene, Benzonitrile, Furan, Isobutyronitrile were higher than non-smokers. When compared with people who never smoked, E-cigarette smokers had similar blood concentrations of VOCs. Blood concentrations of Benzene, Furan, and Isobutyronitrile were significant higher in combustible-cigarette smokers than in E-cigarette smokers. In the multivariable regression model, dual-smoking and combustible-cigarette smoking were associated with elevated blood concentrations of several VOCs except 1,4-Dichlorobenzene, while E-cigarette smoking was only associated with elevated 2,5-Dimethylfuran concentration. CONCLUSIONS: Smoking, mainly dual-smoking and combustible-cigarette smoking, is associated with elevated blood concentration of VOCs, while the effect is weak in E-cigarette smoking.

Characteristics and risk factors of secondary bacterial infections in COVID-19 patients.

Objective: To describe the characteristics and find out risk factors of COVID-19 patients infected with different categories of bacteria. Design: Case-control. Methods: We conducted a retrospective study including 129 COVID-19 patients admitted to a tertiary hospital between October 13, 2022 and December 31, 2022. Patients' data were collected from the hospital information system. Patients were classified as having or not having confirmed secondary bacterial infections, or gram-positive and gram-negative bacterial infections for analysis. Categories and sources of isolated bacteria, characteristics of the patients, and the risk factors for developing secondary bacterial infections were analyzed. Results: Gram-negative bacteria accounted for the majority of secondary bacterial infections of the included patients. Critical type of COVID-19 (OR = 12.98, 95%CI 3.43∼49.18, p < 0.001), invasive therapy (OR = 9.96, 95%CI 3.01∼32.95, p < 0.001), and previous antibiotics use (OR = 17.23, 95%CI 1.38∼215.69, p = 0.027) were independent risk factors of secondary bacterial infections in COVID-19 patients. Ceftriaxone/cefotaxime use (OR = 15.45, 95%CI 2.72∼87.79, p = 0.002) was associated with gram-positive bacterial infections while age over 70 (OR = 3.30, 95%CI 1.06∼10.26, p = 0.039), invasive therapy (OR = 4.68, 95%CI 1.22∼17.93, p = 0.024), and carbapenems use (OR = 8.48, 95%CI 2.17∼33.15, p = 0.002) were associated with gram-negative bacterial infections. Conclusions: Critical patients with invasive therapy and previous antibiotics use should be cautious with secondary bacterial infections. Third-generation cephalosporins and carbapenems should be used carefully because both are risk factors for gram-positive or gram-negative bacterial infections.

Is Halving Maintenance of Voriconazole Safe and Efficient in Patients Suffering from Invasive Fungal Infections with Serious Hepatic Dysfunction?

Background: There is a wide debate about the efficacy and safety of voriconazole in patients with impaired hepatic function at Child-Pugh C level. Objective: The purpose of this study was to investigate the safety and efficacy between the two groups treated with different dosages of voriconazole (400mg/day vs 200mg/day) in the treatment of invasive fungal infections (IFIs) in patients with hepatic dysfunction. Methods: A retrospective study enrolling patients with hepatic dysfunction receiving intravenous voriconazole for IFIs from January 1st, 2017, to December 30th, 2021 was conducted. Patients were enrolled in the 400mg per day dose group and 200mg per day dose group. In patients with the same degree of hepatic impairment, factors affecting prognosis were screened and differences in steady-state blood trough concentrations (Cmin) of voriconazole, positive G/GM tests and adverse effects (AEs) were compared between the two groups described above. Results: In total, 308 patients with IFIs were enrolled. For Child-Pugh C class, patients receiving the halved maintenance dose had a lower Cmin and AEs rate but higher recovered rate compared to those receiving maintenance dose, and significant predictors of recovery were dosage (OR, 5.131; 95% CI, 1.599-16.464; p = 0.006) and diabetes (OR, 0.111; 95% CI, 0.020-0.597; p = 0.010). For patients of Child-Pugh A & B class, chronic liver disease (OR, 0.334; 95% CI, 0.159-0.704; p = 0.004) was a prognosis-related factor. Conclusion: Halving maintenance dose ensure the efficacy and safety of voriconazole in patients suffering from invasive fungal infections with serious hepatic dysfunction.

Hepatic metabolism-related effects of polysaccharides from red kidney bean and small black soybean on type 2 diabetes.

In our previous study, two crude polysaccharides from red kidney bean and small black soybean (RK, SB) have shown the alleviative effect on type 2 diabetic mice. Meanwhile, hepatic dysfunction usually accompanied with type 2 diabetes mellitus (T2DM), and closely related to glucose and lipid homeostasis. Therefore, this time we further investigated the protective effect on hepatic dysfunction of RK and SB. Results found that both crude polysaccharides had the protective effects. In addition, investigation on purified polysaccharides identified that the polysaccharide was the biofunctional component basis in crude RK and SB. Subsequently, further research investigated the regulating mechanism of two pure polysaccharides (RKPH and SBPH) on hepatic metabolism and lipid metabolism. The results showed the improved different metabolites of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) by RKPH and SBPH to affect glycerophospholipid metabolism pathway might be involved in the improvement of the glucose, lipids homeostasis and liver function in T2DM.

Treatment of Central Nervous System Infection Caused by Multidrug-Resistant Acinetobacter baumannii with Intravenous and Intraventricular Colistin Sulfate: A Case Report and Literature Review.

Purpose: Due to the spread of antimicrobial-resistant bacteria and poor penetration of many antimicrobial drugs across the blood-brain barrier following intravenous administration, treatment of central nervous system (CNS) infections is challenging, especially infections caused by carbapenem-resistant organisms (CRO). Intraventricular (IVT) infusion of antimicrobial drugs could be a choice. This report aims to describe a patient with CNS infection caused by carbapenem-resistant Acinetobacter baumannii (CRAB) which was successfully treated with IVT combined with intravenous (IV) colistin sulfate. Methods: A case of CNS infection caused by CRAB after a craniocerebral injury was presented. The patient was treated with IVT together with IV colistin sulfate. Moreover, literature on the regimens and safety of colistin sulfate were also reviewed and summarized. Results: Intraventricular (50,000 U, qd/100,000 U, qd) combined with IV (500,000 U, q12h/500,000 U, q8h) colistin sulfate was given to the patient, and the CNS infection was successfully controlled. The patient was finally transferred back to a local hospital for rehabilitation treatment. No nephrotoxicity or neurotoxicity was observed during the therapy. Conclusion: IV combined with IVT colistin sulfate is effective in the treatment of CNS infections caused by CRAB. IVT concomitant IV colistin sulfate might be a therapeutic option worth considering in the treatment of CNS infections caused by CRO.

Polysaccharides from red kidney bean alleviating hyperglycemia and hyperlipidemia in type 2 diabetic rats via gut microbiota and lipid metabolic modulation.

Crude polysaccharides extracted from red kidney bean (RK) display significant antidiabetic activity in type 2 diabetic mice, but the underlying mechanism and the core functional component has not been elucidated. In this study, the antidiabetic effect and mechanism of RK are investigated by serum metabolomics and high-throughput sequencing. In addition, the key component was identified by evaluating the improvement on glucose and lipid homeostasis in type 2 diabetic rats. Our data indicated that RK relieved the symptoms of hyperglycemia, hyperlipidemia in STZ-induced diabetic rats. RK not only improved the metabolic disturbance by regulating the biosynthesis of unsaturated fatty acids, but also modified gut microbiota composition by selectively enriching in key genera of Bacteroides, Phascolarctobacterium, Succinivibrio, Blautia. We further found the purified polysaccharides (RKP) were identified as the core biofunctional component in RK. Our present studies provide evidence that RKP are potential effective dietary supplement for type 2 diabetic individuals.

Prolonged duration of lymphocyte deficiency, high-grade CRS, and ventilation are linked to fungal breakthrough in patients with hematologic malignancies 60 days after CAR-T infusion: A single center case-control study.

BACKGROUND: Risk factors for invasive fungal infections (IFIs) after chimeric antigen receptor-modified T cells (CAR-T) treatment have been poorly studied. Here we are investigating the risk factors and prognosis of IFIs following CAR-T therapy. MATERIAL AND METHODS: A case-control study was conducted on the medical records of CAR-T patients admitted to our center between June 2018 and December 2020. The case group (32) consisted of patients who developed IFIs within 60 days after CAR-T infusion, while the control group (298) consisted of patients who did not develop IFIs. The Cox Proportional Hazard Regression model was utilized to analyze the risk factors for the occurrence of IFIs, as well as the factors affecting the 1-year survival rate of patients. RESULT: Cumulatively, 364 patients were included. Inflammatory cytokine release syndrome (CRS) grade (hazard ratio (HR) 2.34 confidential interval (CI)（1.03-5.30) P = 0.042), ventilation (HR 3.23 CI (1.20-8.71) P = 0.020) and lymphocyte deficiency duration (HR 1.06 CI (1.01-1.10) P = 0.015) were associated with IFIs. IFIs (HR 1.12 CI (0.52-2.41) P = 0.767) did not affect a patient's one-year survival, which was associated with lymphocyte deficiency (HR 1.04 CI (1.01-1.07) P = 0.004) and treatment with broad-spectrum antibacterial (HR 1.80 CI (1.03-3.11) P = 0.038) within 30 days prior to CAR-T infusion. CONCLUSION: There is an increased risk of IFIs in patients with hematologic malignancies due to ventilation, high-grade CRS, and prolonged lymphocyte deficiency within 60 days after CAR-T infusion. Invasive fungal infection was not a risk factor for death within 1 year of CAR-T therapy, while broad-spectrum antibacterial therapy prior to infusion and prolonged lymphocyte deficiency were risk factors.

Does COVID-19 have an impact on influenza vaccine knowledge, attitude and practice among medical students: a 2-year prospective cohort study.

OBJECTIVES: To explore the main factors affecting the knowledge, attitude and practice about influenza and influenza vaccine as well as the intention to receive influenza vaccination among the same group of medical students before (2019) and after (2021) the COVID-19 outbreak. DESIGN: A population-based prospective cohort study. SETTING: A longitudinal cohort study of a selected medical school in Chongqing, China, which ran from 2019 to 2021. PARTICIPANTS: A total of 803 medical students participated in the study in 2019 and only 484 students responded in 2021. The response rate for our survey was only 60.27% due to graduation, emails being abandoned, etc. RESULTS: The influenza vaccination rate of students at this medical school was 6.7% in 2019, compared with 25.8% in 2021. The awareness rate of medical students about influenza and influenza vaccine was 82.8% in 2019 and 86% in 2021, and there was no significantly statistical difference between the 2 years (p=0.134); the number of medical students with supportive attitude towards influenza vaccine was 95.1% in 2019 and 97.1% in 2021, and there was no statistically significant difference between the 2 years (p=0.078); the number of students who actively learnt about knowledge related to influenza vaccine rose from 183 (22.8%) in 2019 to 195 (40.3%) in 2021. CONCLUSIONS: The COVID-19 outbreak prompted an increase in influenza vaccination rates among medical students in Chongqing, with almost all students (96.0%) believing that the spread of COVID-19 promoted their knowledge about influenza and influenza vaccine, and the vast majority (74.8%) believing that the spread of COVID-19 promoted their willingness to receive influenza vaccine.

Phase separation in epigenetics and cancer stem cells.

Accumulating evidence indicates that liquid-liquid phase separation (LLPS) is the basis of the formation of membrane-less compartments in cells. This biomolecular condensate represented by phase separation may influence epigenetics in cancer stem cells (CSCs), a small subpopulation of cancer cells responding to the initiation, maintenance, metastasis, and therapy resistance of cancer. Understanding the underlying biophysical principles and the specific characteristics of biocondensates would provide insights into the precise blocking of potential tumor targets, thereby fundamentally curbing tumor occurrence, recurrence and metastasis. In this review, we summarized the key phenomenon and experimental detection of phase separation and the possibility of regulating the stemness of CSCs through phase separation. We believe that the mechanism of phase separation in CSCs will open up new avenues for the mystery of tumor formation, and modulating phase separation will be a great strategy for CSC-targeted tumor therapy.

Availability and Affordability of Therapeutic Monoclonal Antibodies After the New Medical Reform in Hubei Province, China.

OBJECTIVE: In 2017, China launched a new round of medical reform (NMR) to address the inaccessibility of high-priced drugs for patients with serious diseases. This study explored the impact of the NMR on the accessibility and affordability of high-priced monoclonal antibodies (mAbs), and the effective promotion policies after the NMR. METHODS: We used a standard method developed by the World Health Organization to conduct two surveys on the availability of mAbs and their prices before and after the NMR in the public hospitals in Hubei province, China. By interviewing hospital pharmacy experts, we identified the potential value of the current NMR in improving the access to therapeutic mAbs. RESULTS: The average availability of 13 mAbs increased by 8.1% in the surveyed hospitals of Hubei province after the NMR. The median unit price of 10 mAbs dropped by 34.3%. The average affordability of a treatment cycle of 10 mAbs dropped from 680 days to 298 days of the disposable daily income for a middle-income resident (56.2% reduction). The drug price negotiation of medical insurance inclusion and the promotion of consistent evaluation of generic and original drugs could effectively promote the accessibility of mAbs. However, the zero markup of drug pricing and the limit on the proportion of drug revenues in public hospitals showed certain negative effects on the availability of mAbs. CONCLUSION: Not all current NMR policies play a positive role in promoting the accessibility of mAbs. To further improve the accessibility of mAbs in the future in China, it is therefore critical to increase the investment in independent research and development of high-quality mAbs, establish localized guidelines for the rational use of mAbs in clinical practice, and have a cost-sharing mechanism for high-priced drugs with multiple stakeholders.

Glaucoma Is Not Associated With Alzheimer's Disease or Dementia: A Meta-Analysis of Cohort Studies.

Background: Previous studies evaluating the relationships of glaucoma with Alzheimer's disease (AD) and dementia showed inconsistent results. We performed a meta-analysis of cohort studies to evaluate the association between glaucoma with incidence of AD, all-cause dementia, and non-AD dementia. Methods: Cohort studies which evaluated the association between glaucoma with incidence of AD, all-cause dementia, and non-AD dementia in adult population with multivariate analyses were identified by systematic search of PubMed, Embase, and Cochrane's Library databases. A random-effects model incorporating the potential intra-study heterogeneity was used for the meta-analysis. Results: Eleven cohort studies including 4,645,925 participants were included. Results showed that compared to those without glaucoma at baseline, adult patients with glaucoma was not independently associated with increased incidence of AD [adjusted risk ratio (RR): 1.03, 95% confidence interval (CI): 0.93-1.05, P = 0.55; I 2 = 83%], all-cause dementia (adjusted RR: 1.08, 95% CI: 0.97-1.19, P = 0.15; I 2 = 79%), or non-AD dementia (adjusted RR: 1.05 95% CI: 0.91-1.21, P = 0.49; I 2 = 82%). Sensitivity analyses by excluding one study at a time did not significantly affect the results of the meta-analyses. Moreover, subgroup analyses showed consistent results in meta-analysis of prospective or retrospective cohort studies, and in meta-analysis of patients with primary open-angle glaucoma or primary angle-closure glaucoma (P-values for subgroup difference all > 0.05). Conclusions: Current evidence from cohort studies did not support that glaucoma is an independent risk factor of AD, all-cause dementia, or non-AD dementia in adult population.

Comparative study on antidiabetic function of six legume crude polysaccharides.

The antidiabetic function of polysaccharides prepared from six legumes: soybean, white kidney bean, red kidney bean, small black soybean, field bean, lentil were studied. Six legume polysaccharides' antidiabetic function in high-fat diet and streptozotocin-induced type II diabetic mice were compared. Their effects on body weight, fasting blood glucose (FBG), glycosylated serum protein (GSP), serum insulin levels (HOMA-IR), blood lipids (including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c)) were tested. Results showed that red kidney bean polysaccharides (RK) could alleviate the symptoms of emaciation, decreased the levels of FBG, GSP, TC, LDL-c and obviously reduced the concentration of TG and HOMA-IR (p < 0.05). RK exhibited greater antidiabetic potential in type II diabetic mice, compared with other legume polysaccharides. The chemical composition of six legume polysaccharides were determined. Composition analysis indicated that the six legume polysaccharides were obviously different in moisture, ash, neutral sugar, uronic acid, total phenolic content, total flavonoid content, amino acid composition and monosaccharide composition. Results indicated that the antidiabetic activities of RK might due to its higher content and specific structure of polysaccharide.

Protective effect of hydrogen sulfide on endothelial cells through Sirt1-FoxO1-mediated autophagy.

BACKGROUND: As a new member of the vasculoprotective gasotransmitter family, hydrogen sulfide (H2S) functions similar to nitric oxide (NO) and carbon monoxide (CO). Endothelial cell (EC) death and autophagy enable cells to cope with the progression of cardiovascular diseases. However, the impacts and underlying mechanisms of H2S in the autophagic process in ECs are not completely understood. Here, we investigated the effects of H2S on autophagy in human vascular ECs. METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to different concentrations (0, 50, 100, 200, 500 and 1,000 µmol/L) GYY4137 (H2S donor) for indicated times (0, 0.5, 1, 2, 4 and 8 h), with or without pre-treatment with the autophagy inhibitor 3-methyladenine (3-MA) or bafilomycin A1. HUVECs were transfected with sirtuin 1 (Sirt1) overexpression plasmids (PIRES-Sirt1), Sirt1-siRNAs or forkhead box O1 (FoxO1)-siRNA using Lipofectamine 2000. Cell autophagy was evaluated via Western blotting and fluorescence microscopy. Co-immunoprecipitation assay was used to measure acetylation level of FoxO1. The distribution of FoxO1 in the cytoplasm and nucleus was observed using Western blotting and immunofluorescence. Western blotting, flow cytometric analysis, and cell count kit-8 assay were conducted to evaluate the effect of H2S on the oxidized low-density lipoprotein (Ox-LDL) induced apoptosis of HUVECs. RESULTS: Using both gain- and loss-of-function experiments, we showed that Sirt1-dependent activation of FoxO1, including its nuclear translocation and deacetylation, was critical for mediating H2S-induced autophagy in ECs. Furthermore, H2S-induced autophagy protected ECs from Ox-LDL-induced apoptosis by activating Sirt1. CONCLUSIONS: These results suggest that Sirt1-mediated autophagy in ECs is a novel mechanism by which H2S exerts vascular-protective actions.

CAV1-CAVIN1-LC3B-mediated autophagy regulates high glucose-stimulated LDL transcytosis.

Diabetes is a recognized high-risk factor for the development of atherosclerosis, in which macroautophagy/autophagy is emerging to play essential roles. The retention of low-density lipoprotein (LDL) particles in subendothelial space following transcytosis across the endothelium is the initial step of atherosclerosis. Here, we identified that high glucose could promote atherosclerosis by stimulating transcytosis of LDL. By inhibiting AMPK-MTOR-PIK3C3 pathway, high glucose suppresses the CAV-CAVIN-LC3B-mediated autophagic degradation of CAV1; therefore, more CAV1 is accumulated in the cytosol and utilized to form more caveolae in the cell membrane and facilitates the LDL transcytosis across endothelial cells. For a proof of concept, higher levels of lipids were accumulated in the subendothelial space of umbilical venous walls from pregnant women with gestational diabetes mellitus (GDM), compared to those of pregnant women without GDM. Our results reveal that high glucose stimulates LDL transcytosis by a novel CAV1-CAVIN1-LC3B signaling-mediated autophagic degradation pathway. ABBREVIATIONS: 3-MA: 3-methyladenine; ACTB: actin beta; AMPK: AMP-activated protein kinase; Bafi: bafilomycin A1; CAV1: caveolin-1; CAVIN1: caveolae associated protein 1; CSD: the CAV1 scaffolding domain; GDM: gestational diabetes mellitus; IMD: intramembrane domain; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule- associated protein 1 light chain 3; MFI: mean fluorescence intensity; MTOR: mechanistic target of rapamycin kinase; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; SQSTM1/p62: sequestosome 1.

Rhodiola and salidroside in the treatment of metabolic disorders.

Over the past three decades, the knowledge gained about the mechanisms that underpin the potential use of Rhodiola in stress- and ageing-associated disorders has increased, and provided a universal framework for studies that focused on the use of Rhodiola in preventing or curing metabolic diseases. Of particular interest is the emerging role of Rhodiola in the maintenance of energy homeostasis. Moreover, over the last two decades, great efforts have been undertaken to unravel the underlying mechanisms of action of Rhodiola in the treatment of metabolic disorders. Extracts of Rhodiola and salidroside, the most abundant active compound in Rhodiola, are suggested to provide a beneficial effect in mental, behavioral, and metabolic disorders. Both in vivo and ex vivo studies, Rhodiola extracts and salidroside ameliorate metabolic disorders when administered acutely or prior to experimental injury. The mechanism involved includes multi-target effects by modulating various synergistic pathways that control oxidative stress, inflammation, mitochondria, autophagy, and cell death, as well as AMPK signaling that is associated with possible beneficial effects on metabolic disorders. However, evidence-based data supporting the effectiveness of Rhodiola or salidroside in treating metabolic disorders is limited. Therefore, a comprehensive review of available trials showing putative treatment strategies of metabolic disorders that include both clinical effective perspectives and fundamental molecular mechanisms is warranted. This review highlights studies that focus on the potential role of Rhodiola extracts and salidroside in type 2 diabetes and atherosclerosis, the two most common metabolic diseases.