Role of liver sinusoidal endothelial cell in metabolic dysfunction-associated fatty liver disease.

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that represent the interface between blood cells on one side and hepatocytes on the other side. LSECs not only form a barrier within the hepatic sinus, but also play important physiological functions such as regulating hepatic vascular pressure, anti-inflammatory and anti-fibrotic. Pathologically, pathogenic factors can induce LSECs capillarization, that is, loss of fenestra and dysfunction, which are conducive to early steatosis, lay the foundation for the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), and accelerate metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. The unique localization, phenotype, and function of LSECs make them potential candidates for reducing liver injury, inflammation, and preventing or reversing fibrosis in the future.

Leukocyte telomere length and sarcopenia-related traits: A bidirectional Mendelian randomization study.

Accumulating evidence indicated that leukocyte telomere length (LTL) was related to sarcopenia. However, it is still not clear whether the association of changes in LTL with sarcopenia is likely to be causal, or could be explained by reverse causality. Thus, we carried on bidirectional Mendelian randomization (MR) and multivariable MR analyses to identify the causal relationship between LTL and sarcopenia-related traits. Summary-level data and independent variants used as instruments came from large genome-wide association studies of LTL (472,174 participants), appendicular lean mass (450,243 participants), low grip strength (256,523 participants), and walking pace (450,967 participants). We identified suggestive association of longer LTL with larger appendicular lean mass [odds ratio (OR) = 1.053; 95% confidence interval (CI), 1.009-1.099; P = 0.018], and causal association of longer LTL with a lower risk of low grip strength (OR = 0.915; 95% CI, 0.860-0.974; P = 0.005). In the reverse MR analysis, we also observed a positive causal association between walking pace and LTL (OR = 1.252; 95% CI, 1.121-1.397; P < 0.001). Similar results can be repeated in sensitivity analyses. While in the multivariable MR analysis, the estimate of the impact of walking pace on LTL underwent a transformation after adjusting for T2DM (OR = 1.141; 95%CI: 0.989-1.317; P = 0.070). The current MR analysis supported a causal relationship between shorter telomere length and both low muscle mass and strength. Additionally, walking pace may affect LTL through T2DM.

Depression and sarcopenia-related traits: A Mendelian randomization study.

BACKGROUND: Observational studies have suggested that depression is associated with sarcopenia. However, the causal relationship between depression and sarcopenia remains unclear. AIM: To investigate the causal relationship between depression and sarcopenia. METHODS: We performed a Mendelian randomization (MR) analysis to identify the bidirectional relationship between depression and sarcopenia-related traits. Summary-level data and independent variants used as instrumental variables came from large genome-wide association studies of depression (414055 cases and 892299 controls), of appendicular lean mass (ALM, 450243 participants), and of hand grip strength (exposure: 360000 participants; outcome: 334925 participants). RESULTS: We identified a negative association of depression with lower ALM [odds ratio (OR): 0.932, 95% confidence interval (95%CI): 0.889-0.979, P = 0.005]. In the reverse MR analysis, we also observed an inverse association of hand grip strength with depression (OR: 0.200, 95%CI: 0.108-0.370, P < 0.001). Similar results were obtained in sensitivity analyses. CONCLUSION: Depression was causally related to decreased muscle mass, and declined muscle strength might lead to a higher risk of depression.

Coupling of Adhesion and Anti-Freezing Properties in Hydrogel Electrolytes for Low-Temperature Aqueous-Based Hybrid Capacitors.

Solid-state zinc-ion capacitors are emerging as promising candidates for large-scale energy storage owing to improved safety, mechanical and thermal stability and easy-to-direct stacking. Hydrogel electrolytes are appealing solid-state electrolytes because of eco-friendliness, high conductivity and intrinsic flexibility. However, the electrolyte/electrode interfacial contact and anti-freezing properties of current hydrogel electrolytes are still challenging for practical applications of zinc-ion capacitors. Here, we report a class of hydrogel electrolytes that couple high interfacial adhesion and anti-freezing performance. The synergy of tough hydrogel matrix and chemical anchorage enables a well-adhered interface between hydrogel electrolyte and electrode. Meanwhile, the cooperative solvation of ZnCl2 and LiCl hybrid salts renders the hydrogel electrolyte high ionic conductivity and mechanical elasticity simultaneously at low temperatures. More significantly, the Zn||carbon nanotubes hybrid capacitor based on this hydrogel electrolyte exhibits low-temperature capacitive performance, delivering high-energy density of 39 Wh kg-1 at -60 °C with capacity retention of 98.7% over 10,000 cycles. With the benefits of the well-adhered electrolyte/electrode interface and the anti-freezing hydrogel electrolyte, the Zn/Li hybrid capacitor is able to accommodate dynamic deformations and function well under 1000 tension cycles even at -60 °C. This work provides a powerful strategy for enabling stable operation of low-temperature zinc-ion capacitors.

Ginsenoside Rg3 Sensitizes Nasopharyngeal Carcinoma Cells to Radiation by Suppressing Epithelial Mesenchymal Transition.

Radioresistance restrains the therapeutic effect of nasopharyngeal carcinoma (NPC). Ginsenoside Rg3 (Rg3), an active pharmaceutical component extracted from ginseng, shows antitumor effects in various cancers. In this study, we aimed to determine whether Rg3 sensitized NPC cells to radiation and to explore the possible mechanisms. Our results revealed that Rg3 increased radiosensitivity in both HNE1 and CNE2 cell lines. Radiation induced epithelial mesenchymal transition (EMT) in NPC cells and Rg3 blocked this effect. In addition, Rg3 attenuated radiation-induced epidermal growth factor receptor (EGFR) nuclear transport and DNA-dependent protein kinase expression. What's more, Rg3 significantly accelerated the apoptosis rates in irradiated NPC cells. In summary, our data suggested that Rg3 sensitized NPC cells to radiation and suppressed radiation-induced EMT. This effect is mediated through restrained EGFR nuclear translocation and increased cell apoptosis. Thus, Rg3 may be a potential radiation sensitizing agent for NPC.

Prognostic Value of Pentraxin-3 Change After Primary Percutaneous Coronary Intervention in Patients with ST-Segment Elevation Myocardial Infarction.

Purpose: So far, ST-segment elevation myocardial infarction (STEMI) is still the main cause of morbidity and mortality of cardiovascular diseases worldwide. Recent studies showed that pentraxin-3 (PTX3) was related to the early diagnosis and prognosis of coronary heart disease. This study aimed to investigate the dynamical change of PTX3 after primary percutaneous coronary intervention (pPCI) in STEMI patients and its prognostic value. Patients and methods: In this prospective cohort study, a total of 350 patients were enrolled. The plasma level of PTX3 was measured at admission, 24-hour and 5-day after pPCI. The primary endpoint was the incidence of major adverse cardiac cerebral events (MACCEs) during 1-year follow-up. Results: Compared with the admission, PTX3 levels were significantly increased at 24 hours, and decreased at 5 days after pPCI in the whole cohort. PTX3 levels at these three time points were not significantly different between the patients with and without MACCEs. Notably, the change in PTX3 from admission to post-pPCI 24-hour (ΔPTX3) was higher in patients with MACCEs (112.83 vs 17.94 ng/dl, P = 0.001). The ROC curves showed that the cut-off value was 29.22 ng/dl and the area under curves was 0.622 (95% CI: 0.554-0.690, p = 0.001). Multivariable cox regression models revealed that the high ΔPTX3 group was an independent predictor of MACCEs (adjusted HR = 2.010, 95% CI = 1.280-3.186, p = 0.003). The higher ΔPTX3 group had significantly higher incidences of revascularization (HR = 2.094, 95% CI: 1.056-4.150, p = 0.034) and composite MACCEs (HR = 2.219, 95% CI: 1.425-3.454, p < 0.001). However, the change of PTX3 level from admission to post-pPCI 5-day had no independently predictive value. Conclusion: The higher increase of PTX3 level 24-hour after pPCI appeared to have a potential value in independently predicting the incidence of 1-year MACCEs in STEMI patients, especially for coronary revascularization.

Association between brain structures and migraine: A bidirectional Mendelian randomization study.

Background: Accumulating evidence of clinical and neuroimaging studies indicated that migraine is related to brain structural alterations. However, it is still not clear whether the associations of brain structural alterations with migraine are likely to be causal, or could be explained by reverse causality confounding. Methods: We carried on a bidirectional Mendelian randomization analysis in order to identify the causal relationship between brain structures and migraine risk. Summary-level data and independent variants used as instruments came from large genome-wide association studies of total surface area and average thickness of cortex (33,992 participants), gray matter volume (8,428 participants), white matter hyperintensities (50,970 participants), hippocampal volume (33,536 participants), and migraine (102,084 cases and 771,257 controls). Results: We identified suggestive associations of the decreased surface area (OR = 0.85; 95% CI, 0.75-0.96; P = 0.007), and decreased hippocampal volume (OR = 0.74; 95% CI, 0.55-1.00; P = 0.047) with higher migraine risk. We did not find any significant association of gray matter volume, cortical thickness, or white matter hyperintensities with migraine. No evidence supporting the significant association was found in the reverse MR analysis. Conclusion: We provided suggestive evidence that surface area and hippocampal volume are causally associated with migraine risk.

The dysregulation of plasma miR-497/FGF23 axis, and its association with clinical characteristics and major adverse cardiovascular event in female premature acute coronary syndrome patients.

AIM: MicroRNA-497 (miR-497) directly targets fibroblast growth factor 23 (FGF23) to participate in the pathology of acute coronary syndrome (ACS) by regulating atherosclerosis, inflammatory response, lipid metabolism, etc. This study intended to investigate the dysregulation of the miR-497/FGF23 axis, and its association with the major adverse cardiovascular event (MACE) in female premature ACS. METHODS: MiR-497 and FGF23 from plasma samples were detected by RT-qPCR and ELISA in 979 newly diagnosed female premature ACS patients and 100 healthy controls (HCs). MACE was recorded during follow-up (median: 27.0, range: 1.0-54.0 months) in female premature ACS patients. RESULTS: MiR-497/FGF23 axis was reduced in female premature ACS patients versus HCs [median (interquartile range): 0.7 (0.1-1.2) versus 1.9 (1.1-3.4)] (P < 0.001). Meanwhile, miR-497 negatively correlated with FGF23 in femal e premature ACS patients (P < 0.001), but not in HCs (P = 0.157). In female premature ACS patients, the miR-497/FGF23 axis was negatively associated with serum creatinine (P < 0.001), serum uric acid (P = 0.003), high-sensitivity C-reactive protein (P < 0.001), total cholesterol (P = 0.031), and low-density lipoprotein cholesterol (P = 0.003). The 1-year, 2-year, 3-year, and 4-year accumulating MACE rate was 2.9%, 8.6%, 16.7%, and 26.0%, respectively. Interestingly, a high level of miR-497/FGF23 axis predicted decreased accumulating MACE risk (P < 0.001). After adjustment by multivariate Cox's regression analysis, the high miR-497/FGF23 axis (hazard ratio (HR) = 0.005, P = 0.001) independently correlated with reduced accumulating MACE risk. CONCLUSION: The plasma miR-497/FGF23 axis represents favorable kidney function, decreased inflammation, and reduced lipid level; meanwhile, this axis possesses prognostic value in predicting decreased accumulating MACE risk in female premature ACS patients.

Multi-target regulation of intestinal microbiota by berberine to improve type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) and its complications are major public health problems that seriously affect the quality of human life. The modification of intestinal microbiota has been widely recognized for the management of diabetes. The relationship between T2DM, intestinal microbiota, and active ingredient berberine (BBR) in intestinal microbiota was reviewed in this paper. First of all, the richness and functional changes of intestinal microbiota disrupt the intestinal environment through the destruction of the intestinal barrier and fermentation/degradation of pathogenic/protective metabolites, targeting the liver, pancreas, visceral adipose tissue (VAT), etc., to affect intestinal health, blood glucose, and lipids, insulin resistance and inflammation. Then, we focus on BBR, which protects the composition of intestinal microbiota, the changes of intestinal metabolites, and immune regulation disorder of the intestinal environment as the therapeutic mechanism as well as its current clinical trials. Further research can analyze the mechanism network of BBR to exert its therapeutic effect according to its multi-target compound action, to provide a theoretical basis for the use of different phytochemical components alone or in combination to prevent and treat T2DM or other metabolic diseases by regulating intestinal microbiota.

Dynamic changes in soluble suppression of tumorigenicity 2 levels predict major adverse cardiovascular events in patients with ST­segment elevation myocardial infarction.

Introduction：The predictive value of soluble suppression of tumorigenicity 2 (sST2) for the occurrence of major adverse cardiovascular events (MACEs) in patients with ST­segment elevation myocardial infarction (STEMI) remains unclear. OBJECTIVES: We aimed to investigate the role of sST2 in predicting MACEs in STEMI patients after primary percutaneous coronary intervention (pPCI). PATIENTS AND METHODS: A total of 350 patients were enrolled in this study. The levels of sST2, N­terminal pro-B­type natriuretic peptide (NT­proBNP), cardiac troponin I (TnI), and creatine kinase-MB (CK­MB) were measured on admission as well as 24 hours and 5 days after pPCI. The end point was the incidence of MACEs. RESULTS: Compared with the values on admission, sST2 levels increased 24 hours post pPCI and decreased significantly at day 5 after the procedure in the whole cohort. The pattern of sST2 level changes between the 3 time points was similar in the MACE and MACE­free groups. Notably, the change in the sST2 level from admission to 24 hours post pPCI (Δ1sST2) was significantly higher in the MACE group. After multivariable adjustment, Δ1sST2 was an independent risk factor for MACEs, with an area under the curve of 0.621 (95% CI, 0.547-0.695). Patients with a greater Δ1sST2 had a significantly higher incidence of composite MACEs, coronary revascularization, and cardiac rehospitalization. However, the change in sST2 levels from admission to 5 days post pPCI, as well as the dynamic changes in NT­proBNP, TnI, and CK­MB levels had no predictive value. CONCLUSIONS: The increase in plasma sST2 levels from admission to 24 hours post pPCI has a potential value for independently predicting the incidence of coronary revascularization and cardiac rehospitalization at 1 year in patients with STEMI.

Turmeric and curcuminiods ameliorate disorders of glycometabolism among subjects with metabolic diseases: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Metabolic diseases are globally popular, and a systematic review and meta-analysis of turmeric and curcuminoids on glucose metabolism among people with metabolic diseases was performed. DESIGN: We comprehensively searched Web of Science, PubMed, Ovid (including EMBASE and MEDLINE), Scopus, the Cochrane Library and two Chinese databases, Wanfang and CNKI for RCTs that focused on the effects of turmeric and curcuminoids on fasting blood glucose (FBG), hemoglobin A1C (HbA1c), fasting serum insulin (FSI) and HOMA-IR among patients with metabolic diseases. The FBG and HbA1c were the main outcomes to be analyzed. With random-effects models, separate meta-analyses were conducted by inverse-variance and reported as WMD with 95% CIs. RESULTS: Evidence from 17 RCTs including 22 trials showed that turmeric and curcuminoids lowered FBG by - 7.86 mg/dL (95% CI: -12.04, -3.67 mg/dL; P = 0.0002), HbA1c by - 0.38% (95% CI: -0.52%, -0.23%; P < 0.00001) and HOMA-IR by - 1.01 (95% CI: -1.6, -0.42; P = 0.0008). Moreover, they decreased fasting serum insulin by - 1.69 mU/L (95% CI: -3.22, -0.16 mU/L; P = 0.03) after more than 8 weeks of intervention in a subgroup analysis. CONCLUSIONS: Turmeric and curcuminiods decrease FBG, HbA1c and HOMA-IR significantly among subjects with metabolic disease. Additionally, they may have an effect on FSI concentrations if the intervention period is more than 8 weeks. However, attention should be paid to these outcomes due to the significant heterogeneity.

Proanthocyanidins Promote Endothelial Cell Viability and Angiogenesis.

ABSTRACT: Botanic drugs are reportedly effective in treating ischemic conditions by improving vascular circulation. However, it has been very rare for biomaterial researchers to look into the possibility of using such products in the context of tissue regeneration. This work studied 4 botanic drugs to explore their effects on vascular endothelial cell growth. Human umbilical endothelial cells were cultured in the presence of different doses of astragalus powder extract, astragalus injection, puerarin injection, and proanthocyanidin (PAC). Among the 4 drugs, PAC showed a potent effect on cell viability and stimulated cell growth in a dose-dependent manner. In particular, the PAC under test was able to maintain a high level of cell viability/proliferation comparable with the cells supplemented with the endothelial cell growth medium, at both low and normal serum conditions. Blocking either endothelial cell growth factor receptors or epithelial cell growth factor receptors was ineffective in reducing the stimulatory effect. The PAC released from polyvinyl alcohol cryogels stimulated HUVECs proliferation. The chick embryo chorioallantoic membrane model was further used to test the angiogenicity of PAC, showing that this botanic drug was potent in stimulating vasculature development. This work therefore demonstrates for the first time that PAC is capable of upregulating endothelial cell activity and growth in vitro in the absence of growth factors and that PAC can be loaded and released from drug carriers and can stimulate angiogenesis. These findings suggest the application of PAC in angiogenesis and tissue regeneration.

Berberine Ameliorates Glucose Metabolism in Diabetic Rats through the alpha7 Nicotinic Acetylcholine Receptor-Related Cholinergic Anti-Inflammatory Pathway.

Berberine is an isoquinoline derivative alkaloid extracted from Chinese herbs. Recent studies have demonstrated the therapeutic effect of berberine on glucose metabolic disorders. However, its specific mechanism is still unclear. Our study aimed to research the glucose-lowering effect of berberine in diabetic rats and to reveal the possible role of the cholinergic anti-inflammatory pathway. Diabetic rats induced by administration of a high-calorie diet and streptozocin tail vein injection were assessed by the oral glucose tolerance test. Then, the diabetic rats were divided into two groups, those with or without the alpha7 nicotinic acetylcholine receptor gene downregulated, respectively, followed by treatment including berberine for 6 weeks. Results of this study show that the administration of berberine downregulated levels of fasting blood glucose and fasting insulin, and ameliorated insulin resistance in diabetic rats. Treatment with berberine inhibited acetylcholinesterase activity, and upregulated acetylcholine levels in the serum and alpha7 nicotinic acetylcholine receptor gene expression in the liver tissue. Meanwhile, berberine reversed elevated expression of cytokines interleukin-1ß and TNF-α in the serum and downregulated nuclear factor κB expression. However, berberine administration showed no glucose-lowering or anti-inflammatory effect in diabetic rats in which alpha7 nicotinic acetylcholine receptor gene expression was downregulated, and acetylcholinesterase activity was also significantly inhibited. In conclusion, berberine may ameliorate glucose metabolism by activating the alpha7 nicotinic acetylcholine receptor-mediated cholinergic anti-inflammatory pathway.

Berberine Alleviates Insulin Resistance and Inflammation via Inhibiting the LTB4-BLT1 Axis.

Background: Chronic low-grade inflammation is recognized as a key pathophysiological mechanism of insulin resistance. Leukotriene B4 (LTB4), a molecule derived from arachidonic acid, is a potent neutrophil chemoattractant. The excessive amount of LTB4 that is combined with its receptor BLT1 can cause chronic low-grade inflammation, aggravating insulin resistance. Berberine (BBR) has been shown to relieve insulin resistance due to its anti-inflammatory properties. However, it is not clear whether BBR could have any effects on the LTB4-BLT1 axis. Methods: Using LTB4 to induce Raw264.7 and HepG2 cells, we investigated the effect of BBR on the LTB4-BLT1 axis in the progression of inflammation and insulin resistance. Results: Upon exposure to LTB4, intracellular insulin resistance and inflammation increased in HepG2 cells, and chemotaxis and inflammation response increased in RAW264.7 cells. Interestingly, pretreatment with BBR partially blocked these changes. Our preliminary data show that BBR might act on BLT1, modulating the LTB4-BLT1 axis to alleviate insulin resistance and inflammation. Conclusions: Our study demonstrated that BBR treatment could reduce intracellular insulin resistance and inflammation of hepatic cells, as well as chemotaxis of macrophages induced by LTB4. BBR might interact with BLT1 and alter the LTB4-BLT1 signaling pathway. This mechanism might be a novel anti-inflammatory and anti-diabetic function of BBR.

Relationship between Plasma Trimethylamine N-Oxide Levels and Renal Dysfunction in Patients with Hypertension.

INTRODUCTION: Trimethylamine N-oxide (TMAO) is a metabolite produced by gut bacteria. Although increased TMAO levels have been linked to hypertension (HTN) and chronic kidney disease (CKD) with poor prognosis, no clinical studies have directly addressed the relationship between them. In this study, we investigated the relationship between TMAO and renal dysfunction in hypertensive patients. METHODS: We included healthy controls (n = 50), hypertensive patients (n = 46), and hypertensive patients with renal dysfunction (n = 143). Their blood pressure values were taken as the highest measured blood pressure. Renal function was evaluated using the estimated glomerular filtration rate. Plasma TMAO levels were measured using high-performance liquid chromatography tandem mass spectrometry. RESULTS: We found significant differences in plasma TMAO levels among the 3 groups (p < 0.01). The plasma TMAO of patients with HTN was significantly higher than that of healthy people, and the plasma TMAO of patients with HTN complicated by renal dysfunction was significantly higher than either of the other groups. Patients in the highest TMAO quartile were at a higher risk of developing CKD stage 5 than those in the lowest quartile. In the receiver operating characteristic curve, the area under the curve of TMAO combined with ß 2-macroglobulin for predicting renal dysfunction in patients with HTN was 0.85 (95% confidence interval 0.80-0.90). CONCLUSION: An elevated TMAO level reflects higher levels of HTN and more severe renal dysfunction. TMAO, combined with ß 2-macroglobulin levels, may assist in diagnosing CKD in hypertensive patients. Plasma TMAO has predictive value for early kidney disease in hypertensive patients.

Prognostic significance of low TSH concentration in patients with COVID-19 presenting with non-thyroidal illness syndrome.

BACKGROUND: Low free triiodothyronine (FT3) levels are related to a poor prognosis deterioration in patients with COVID-19 presenting with non-thyroidal illness syndrome (NTI). This study was designed to explore whether free thyroxin (FT4) or thyroid stimulating hormone (TSH) levels affected the mortality of patients with COVID-19 presenting with NTI. METHODS: Patients with COVID-19 complicated with NTI who were treated at our hospital were included in this retrospective study. Patients were divided into low TSH and normal TSH groups, as well as low and normal-high FT4 group, according to the reference range of TSH or FT4 levels. The 90-day mortality and critical illness rates were compared among patients with low and normal TSH levels, as well as among patients with low FT4 levels and normal-high FT4 levels; in addition, differences in demographic and laboratory data were compared. A Kaplan-Meier analysis and Cox proportional hazards models were used to assess the associations of TSH and FT4 levels with mortality. RESULTS: One hundred fifty patients with low FT3 levels and without a history of thyroid disease were included, 68% of whom had normal FT4 and TSH levels. Critical illness rates (74.07% VS 37.40%, P = 0.001) and mortality rates (51.85% VS 22.76%, P = 0.002) were significantly higher in the low TSH group than in the normal TSH group. Although no significant difference in the critical illness rate was found (P = 0.296), the mortality rate was significantly higher in the low FT4 group (P = 0.038). Low TSH levels were independently related to 90-day mortality (hazard ratio = 2.78, 95% CI:1.42-5.552, P = 0.003). CONCLUSIONS: Low FT4 and TSH concentrations were associated with mortality in patients with COVID-19 presenting with NTI; moreover, low TSH levels were an independent risk factor for mortality in these patients.

Characteristics of Viral Shedding in Respiratory Samples and Specific Antibodies Production in 564 COVID-19 Patients.

Positive nucleic acid (NA) results have been found in recovered and discharged COVID-19 patients, but the proportion is unclear. This study was designed to analyze the recurrent positive rate of NA results after consecutively negative results, and the relationship between the specific antibody production and positive NA rate. According to Strengthening the Reporting of Observational Studies in Epidemiology guidelines, data of inpatients in Sino-French New City Branch of Tongji Hospital between Jan. 28 and Mar. 6, 2020 were collected. A total of 564 COVID-19 patients over 14 years old who received the examinations of NA and antibodies against SARS-CoV-2 were included. Days of viral shedding and specific antibodies were recorded and assessed. Among NA tests in respiratory samples (throat swabs, nasopharyngeal swabs, sputum and flushing fluid in alveoli), the patients with all-negative NA results accounted for 17.20%, those with single-positive results for 46.63%, and those with multiple-positive results for 36.17% respectively. Besides, the recurrent positive NA results after consecutively negative results appeared in 66 patients (11.70%). For multiple-positive patients, median viral shedding duration was 20 days (range: 1 to 57 days). Of the 205 patients who received 2 or more antibody tests, 141 (68.78%) had decreased IgG and IgM concentrations. IgM decreased to normal range in 24 patients, with a median of 44 days from symptom onset. Viral shedding duration was not significantly correlated with gender, age, disease severity, changes in pulmonary imaging, and antibody concentration. It is concluded that antibody level and antibody change had no significant correlation with the positive rate of NA tests and the conversion rate after continuous negative NA tests. In order to reduce the recurrent positive proportion after discharge, 3 or more consecutive negative NA test results with test interval more than 24 h every time are suggested for the discharge or release from quarantine.

A bioinformatics and transcriptomics based investigation reveals an inhibitory role of Huanglian-Renshen-Decoction on hepatic glucose production of T2DM mice via PI3K/Akt/FoxO1 signaling pathway.

BACKGROUND: Excessive hepatic glucose production (HGP) largely promotes the development of type 2 diabetes mellitus (T2DM), and the inhibition of HGP significantly ameliorates T2DM. Huanglian-Renshen-Decoction (HRD), a classic traditional Chinese herb medicine, is widely used for the treatment of diabetes in clinic for centuries and proved effective. However, the relevant mechanisms of HRD are not fully understood. PURPOSE: Based on that, this study was designed to identify the potential effects and underlying mechanisms of HRD on HGP by a comprehensive investigation that integrated in vivo functional experiments, network pharmacology, molecular docking, transcriptomics and molecular biology. METHODS: After confirming the therapeutic effects of HRD on T2DM mice, the inhibitory role of HRD on HGP was evaluated by pyruvate and glucagon tolerance tests, liver positron emission tomography (PET) imaging and the detection of gluconeogenic key enzymes. Then, network pharmacology and transcriptomics approaches were used to clarify the underlying mechanisms. Molecular biology, computational docking analysis and in vitro experiments were applied for final mechanism verification. RESULTS: Here, our results showed that HRD can decrease weight gain and blood glucose, increase fasting insulin, glucose clearance and insulin sensitivity in T2DM mice. Dysregulated lipid profile was also corrected by HRD administration. Pyruvate, glucagon tolerance tests and liver PET imaging all indicated that HRD inhibited the abnormal HGP of T2DM, and the expressions of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) were significantly suppressed by HRD as expected. Network pharmacology and transcriptomics approaches illustrated that PI3K/Akt/FoxO1 signaling pathway may be responsible for the inhibitory effect of HRD on HGP. Afterward, further western blot and immunoprecipitation found that HRD did activate PI3K/Akt/FoxO1 signaling pathway in T2DM mice, which confirmed previous results. Additionally, the conclusion was further supported by molecular docking and in vitro experiments, in which identified HRD compound, oxyberberine, was proven to exert an obvious effect on Akt. CONCLUSION: Our data demonstrated that HRD can treat T2DM by inhibiting hepatic glucose production, the underlying mechanisms were associated with the activation of PI3K/Akt/FoxO1 signaling pathway.

Correlation analysis between disease severity and inflammation-related parameters in patients with COVID-19: a retrospective study.

BACKGROUND: COVID-19 is highly contagious, and the crude mortality rate could reach 49% in critical patients. Inflammation concerns on disease progression. This study analyzed blood inflammation indicators among mild, severe and critical patients, helping to identify severe or critical patients early. METHODS: In this cross-sectional study, 100 patients were included and divided into mild, severe or critical groups according to disease condition. Correlation of peripheral blood inflammation-related indicators with disease criticality was analyzed. Cut-off values for critically ill patients were speculated through the ROC curve. RESULTS: Significantly, disease severity was associated with age (R = -0.564, P < 0.001), interleukin-2 receptor (IL2R) (R = -0.534, P < 0.001), interleukin-6 (IL-6) (R = -0.535, P < 0.001), interleukin-8 (IL-8) (R = -0.308, P < 0.001), interleukin-10 (IL-10) (R = -0.422, P < 0.001), tumor necrosis factor α (TNFα) (R = -0.322, P < 0.001), C-reactive protein (CRP) (R = -0.604, P < 0.001), ferroprotein (R = -0.508, P < 0.001), procalcitonin (R = -0.650, P < 0.001), white cell counts (WBC) (R = -0.54, P < 0.001), lymphocyte counts (LC) (R = 0.56, P < 0.001), neutrophil count (NC) (R = -0.585, P < 0.001) and eosinophil counts (EC) (R = 0.299, P < 0.001). With IL2R > 793.5 U/mL or CRP > 30.7 ng/mL, the progress of COVID-19 to critical stage should be closely observed and possibly prevented. CONCLUSIONS: Inflammation is closely related to severity of COVID-19, and IL-6 and TNFα might be promising therapeutic targets.

The expression of Cav3.1 on T-type calcium channels of rats with subarachnoid hemorrhage.

To study delayed cerebral vasospasm (DCVS) induced by subarachnoid hemorrhage (SAH), 60 healthy Sprague Dawley (SD) rats were randomly divided into 5 groups (12 rats in each group), namely sham operation group, blood injection model group, nimodipine group, flunarizine hydrochloride group, and normal group. Then, the physiological parameters were detected, and after the rats were killed under anesthesia, the degree of nerve injury, vasospasm as well as the therapeutic effect of drugs were evaluated by Western Blot (WB). Neurological impairment (NI), endothelial contraction and spasm were obvious in rats following blood injection. The expression of Cav3.1 on T-type calcium channels was significantly higher in the blood injection model group than in the sham operation group along with the normal group. Moreover, Cav3.1 mRNA was expressed in all groups. The Cav3.1 expression in blood injection model group and two drug groups were significantly higher than that in sham operation group and lower than that in blood injection model group. Vasospasm was improved in two drug groups, which indicated that calcium channel antagonists nimodipine and flunarizine hydrochloride had a certain therapeutic effect on DCVS in rats. The decrease in body weight and food intake of the two groups of rats treated with drugs decreased, and the delayed vasospasm was improved, but the expression of Cav3.1 was not changed significantly, indicating nimodipine and flunarizine hydrochloride had a therapeutic effect on delayed vasospasm in rats, but Cav3.1 expression on calcium channels was not affected.