Effect of Chinese Medicine in Patients with COVID-19: A Multi-center Retrospective Cohort Study.

OBJECTIVE: To evaluate the effectiveness and safety of Chinese medicine (CM) in the treatment of coronavirus disease 2019 (COVID-19) in China. METHODS: A multi-center retrospective cohort study was carried out, with cumulative CM treatment period of ⩾3 days during hospitalization as exposure. Data came from consecutive inpatients from December 19, 2019 to May 16, 2020 in 4 medical centers in Wuhan, China. After data extraction, verification and cleaning, confounding factors were adjusted by inverse probability of treatment weighting (IPTW), and the Cox proportional hazards regression model was used for statistical analysis. RESULTS: A total of 2,272 COVID-19 patients were included. There were 1,684 patients in the CM group and 588 patients in the control group. Compared with the control group, the hazard ratio (HR) for the deterioration rate in the CM group was 0.52 [95% confidence interval (CI): 0.41 to 0.64, P<0.001]. The results were consistent across patients of varying severity at admission, and the robustness of the results were confirmed by 3 sensitivity analyses. In addition, the HR for all-cause mortality in the CM group was 0.29 (95% CI: 0.19 to 0.44, P<0.001). Regarding of safety, the proportion of patients with abnormal liver function or renal function in the CM group was smaller. CONCLUSION: This real-world study indicates that the combination of a full-course CM therapy on the basic conventional treatment, may safely reduce the deterioration rate and all-cause mortality of COVID-19 patients. This result can provide the new evidence to support the current treatment of COVID-19. Additional prospective clinical trial is needed to evaluate the efficacy and safety of specific CM interventions. (Registration No. ChiCTR2200062917).

Gross Hematuria Does not Affect the Selection of Nephrectomy Types for Clinical Stage 1 Clear Cell Renal Cell Carcinoma: A Multicenter, Retrospective Cohort Study.

PURPOSE: This study aimed to discuss the correlation between gross hematuria and postoperative upstaging (from T1 to T3a) in patients with cT1 clear cell renal cell carcinoma (ccRCC) and to compare oncologic outcomes of partial nephrectomy (PN) and radical nephrectomy (RN) in patients with gross hematuria. METHODS: A total of 2145 patients who met the criteria were enrolled in the study (including 363 patients with gross hematuria). The least absolute selection and shrinkage operator logistic regression was used to evaluate the risk factor of postoperative pathological upstaging. The propensity score matching (PSM) and stable inverse probability of treatment weighting (IPTW) analysis were used to balance the confounding factors. The Kaplan-Meier analysis and multivariate Cox proportional risk regression model were used to assess the prognosis. RESULTS: Gross hematuria was a risk factor of postoperative pathological upstaging (odds ratio [OR] = 3.96; 95% confidence interval [CI] 2.44-6.42; P < 0.001). After PSM and stable IPTW adjustment, the characteristics were similar in corresponding patients in the PN and RN groups. In the PSM cohort, PN did not have a statistically significant impact on recurrence-free survival (hazard ratio [HR] = 1.48; 95% CI 0.25-8.88; P = 0.67), metastasis-free survival (HR = 1.24; 95% CI 0.33-4.66; P = 0.75), and overall survival (HR = 1.46; 95% CI 0.31-6.73; P = 0.63) compared with RN. The results were confirmed in sensitivity analyses. CONCLUSIONS: Although gross hematuria was associated with postoperative pathological upstaging in patients with cT1 ccRCC, PN should still be the preferred treatment for such patients.

Management of biologics in pregnant, lactating patients with inflammatory bowel disease and the impact on neonatal vaccination: A systematic review of clinical practice guidelines and consensus statements.

WHAT IS KNOWN AND OBJECTIVE: The management of biological agents during pregnancy poses challenges as maternal and infant safety must be addressed. This study aims to compare the recommendations of existing guidelines on managing the use of biologics during pregnancy, lactation for patients with inflammatory bowel disease, and the influence on neonatal vaccination. METHODS: The PubMed, EMBASE, China National Knowledge Infrastructure, Wanfang database, China Science and Technology Journal Database and China Biomedical Database were systematically searched from the inception date to 11 May 2022, to screen all relevant guidelines. Quality assessment was performed using the guideline methodology reporting tool AGREE II. RESULTS AND DISCUSSION: Fourteen guidelines and consensus statements with detailed recommendations were included. All guidance documents cover management comments during pregnancy, and most consider that biologics can be given safely during pregnancy but require suspension at the right time to protect the foetus. However, the roles of vedolizumab and ustekinumab are disputed. Five documents guide lactation and the use of most biologics during lactation is safe, but no guidelines recommend vedolizumab. Six papers provide recommendations for newborns' vaccination, suggesting a delay in infants' live vaccination schedule if their mothers are treated with biologics. WHAT IS NEW AND CONCLUSION: Our study concluded that future guidelines could consider incorporating newer, more robust evidence to update recommendations. The development of future guidelines needs to consider the involvement of multidisciplinary experts, adequately report on the evidence retrieval process, and provide strategies for implementation. Besides, more research is needed to explore the use of biologics during pregnancy and lactation in patients with inflammatory bowel disease.

SIRT6 Promotes the Progression of Prostate Cancer via Regulating the Wnt/ß-Catenin Signaling Pathway.

Sirtuin 6 (SIRT6), a DNA repair-related gene, has undergone an extremely thorough study for its involvement in the development of many different cancers. The objective of our study was to explore the function and mechanism of SIRT6-induced regulation of prostate cancer (PCa). RT-PCR was performed to validate the levels of SIRT6 in PCa cell lines. Cell proliferation, migration, and invasion of cells with SIRT6 knockdown were assessed using CCK-8 assay, colony formation assay, wound-healing assay, and transwell assay. Western blot was applied to assess the related proteins. We found that SIRT6 expression was distinctly upregulated in PCa specimens and cells. Loss-of-functional assays revealed that SIRT6 silence suppressed the proliferation and metastasis of PCa cells. Mechanistic studies revealed that SIRT6 silence inhibited Wnt/ß-catenin signaling and EMT progress. Overall, the study confirmed the upregulation of SIRT6 in patients with PCa and its association with the progression. SIRT6 promoted PCa progression by regulating Wnt/ß-catenin signaling, providing a promising biomarker and treatment approach for preventing PCa.

Serum creatinine levels and risk of nonalcohol fatty liver disease in a middle-aged and older Chinese population: A cross-sectional analysis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is now regarded as the hepatic manifestation of metabolic syndrome (MetS). Recent research has suggested that serum creatinine (SCr) may be an indicator of MetS and its related diseases. We aimed to investigate the association between SCr and NAFLD in Chinese adults. METHODS: A cross-sectional sample of 8862 subjects aged 40 years or older (40-73 years) from China were analysed in this study. The anthropometric measurements, laboratory tests, and hepatic ultrasonography were conducted. NAFLD presence was defined by hepatic ultrasound in the absence of other liver diseases. RESULTS: NAFLD subjects had higher SCr than those without NAFLD (66.8 µmol/L vs. 65.6 µmol/L, p < 0.001). Moreover, SCr levels were correlated with alanine aminotransferase (ß = 0.099, p < 0.001), aspartate aminotransferase (ß = 0.135, p < 0.001), γ-glutamyltransferase (ß = 0.039, p < 0.001), and insulin resistance (ß = 0.027, p = 0.014) after adjusted for potential covariates. In the multivariable-adjusted logistic regression analyses, compared to the first SCr quintile, the odds ratio for NAFLD was 1.35 (95% confidence interval 1.14-1.60, p < 0.001) for the fifth quintile after adjusting multiple measured confounders. CONCLUSION: SCr concentration is independently associated with NAFLD in a middle aged and older Chinese population. Elevated SCr levels, even within normal ranges, were associated with higher risk of NAFLD.

Evaluation of hepatotoxicity induced by 2-ethylhexyldiphenyl phosphate based on transcriptomics and its potential metabolism pathway in human hepatocytes.

Increasing use of organophosphorus flame retardants (OPFRs) has aroused great concern to their uncertain environment risk, especially to human health risk. In our study, hepatotoxicity screening of six aryl-OPFRs, potential hepatotoxicity mechanism of 2-ethylhexyldiphenyl phosphate (EHDPP) using RNA-sequencing and its metabolites were investigated in human hepatocytes (L02). The toxicity results demonstrated that EHDPP should be prioritized for further research with the highest toxicity. Further RNA-seq results through GO and KEGG enrichment analysis indicated that exposure to 10 mg/L of EHDPP significantly affected energy homeostasis, endoplasmic reticulum (ER) stress, apoptosis, cell cycle, and inflammation response in cells. The top 12 hub genes were validated by RT-qPCR and conformed to be mainly related to glycolysis and ER stress, followed by cell cycle and inflammation response. Western blot, apoptosis detection, glycolysis stress test, and cell cycle analysis were further performed to verify the above main pathways. Additionally, it was found in the metabolism experiment that detoxification of EHDPP by phase I and phase II metabolism in cells wasn't significant until 48 h with a metabolic rate of 6.12%. EHDPP was stable and still dominated the induction of toxicity. Overall, this study provided valuable information regarding the toxicity and potential metabolism pathway of EHDPP.

Cytotoxic Screening and Transcriptomics Reveal Insights into the Molecular Mechanisms of Trihexyl Phosphate-Triggered Hepatotoxicity.

Mounting evidence shows that organophosphate flame retardants (OPFRs), especially aryl- and halogenated-OPFRs, exert various adverse health effects on living organisms. This study evaluated the hepatotoxic effect of trihexyl phosphate (THP) as a long-chain alkyl-OPFR on human hepatocyte cells (LO2) and mouse hepatocyte cells (AML12) by performing screening of cytotoxicity in vitro. In combination with transcriptomic analysis, toxicological mechanisms in vitro were further investigated. Results showed that THP triggered hepatotoxicity in vitro by altering four signaling pathways: endoplasmic reticulum (ER) stress, apoptosis, cell cycle, and the glycolysis signaling pathway. Exposure of LO2 and AML12 liver cells to THP (25 µg/mL) significantly induced ER stress-mediated apoptosis and cell cycle arrest. Meanwhile, downregulation of glycolysis caused the blockage of energy metabolism. Furthermore, the high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS/MS) revealed that much of THP was absorbed into the cells and displayed stability in the two liver cell lines. In vivo assays using a mouse model demonstrated that exposure to THP at 400 mg/kg induced the ballooning degeneration of hepatocytes in liver tissue, whereas exposure to THP at 800 mg/kg caused acute liver injury with high alanine aminotransferase levels. This study provides novel insights into the impact of THP on hepatotoxicity in vitro and in vivo and uncovers the underlying toxicological mechanisms, which may serve as a guide for further ecological risk assessment and reasonable application of alkyl-OPFRs.

Association of circulating CEACAM1 levels and insulin sensitivity in gestational diabetes mellitus.

BACKGROUND: The aim of this study was to estimate the levels of circulating carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in subjects with gestational diabetes mellitus (GDM) and investigate the relationships between CEACAM1 and GDM. METHODS: Circulating CEACAM1 levels were measured by ELISA kit in 70 women with GDM and 70 normal glucose tolerance (NGT) pregnant women. Blood samples were collected to detect fasting plasma glucose (FPG), fasting insulin (FINS) and glycosylated hemoglobin (HbA1c) levels in all participants. Insulin sensitivity index (ISOGTT) was calculated to assess insulin sensitivity. Correlation analysis was performed between serum CEACAM1 levels and other parameters. RESULTS: Circulating CEACAM1 levels were higher in the GDM group than that in the NGT pregnant group, however, the difference showed no statistical significance (1889.82 ± 616.14 vs 1758.92 ± 433.15 pg/ml, p > 0.05). In GDM group, CEACAM1 was positively correlated with ISOGTT (R = 0.39, P = 0.001), while negatively with 1 h post-meal plasma insulin level (1hPINS) (R = -0.32, P = 0.008), 2 h post-meal plasma insulin level (2hPINS) (R = -0.33, P = 0.006) and area under curve of insulin (AUCI) (R = -0.36, P = 0.002) when adjusting for maternal age and gestational age. CONCLUSIONS: The present study showed that circulating CEACAM1 levels did not differ in both GDM and NGT groups. However, we found a significant positively correlation between CEACAM1 and insulin sensitivity in the GDM group.

A selective c-Met and Trks inhibitor Indo5 suppresses hepatocellular carcinoma growth.

BACKGROUND: Human hepatocellular carcinoma (HCC) lacks effective curative therapy and there is an urgent need to develop a novel molecular-targeted therapy for HCC. Selective tyrosine kinase inhibitors have shown promise in treating cancers including HCC. Tyrosine kinases c-Met and Trks are potential therapeutic targets of HCC and strategies to interrupt c-Met and Trks cross-signaling may result in increased effects on HCC inhibition. METHODS: The effects of Indo5 on c-Met and Trks activity were determined with in vitro kinase activity assay, cell-based signaling pathway activation, and kinases-driven cell transformation. The in vivo anti-tumor activity was determined with xenograft mice and liver orthotopic mice models. The co-expression of c-Met and TrkB in 180 pairs of HCC and adjacent normal tissues were detected using immunohistochemical staining. RESULTS: Indo5, a novel lead compound displayed biochemical potency against both c-Met and Trks with selectivity over 13 human kinases. Indo5 abrogated HGF-induced c-Met signaling activation and BDNF/NGF-induced Trks signal activation, c-Met or TrkB-mediated cell transformation and migration. Furthermore, Indo5 significantly decreased the growth of HCC cells in xenograft mice and improved the survival of mice with liver orthotopic tumors. In addition, co-expression of c-Met and TrkB in HCC patients was a predictor of poor prognosis, and combined inhibition of c-Met and TrkB exerted a synergistic suppressive effect on HCC. CONCLUSIONS: These findings indicate that Indo5 is associated with marked suppression of c-Met and Trks co-expressing HCC, supporting its clinical development as an antitumor treatment for HCC patients with co-active c-Met and Trks signaling.

Advanced treatment of landfill leachate membrane concentrates: performance comparison, biosafety and toxic residue analysis.

With the improvement of people's consciousness about health, more attention has been paid to the biosafety of effluent reaching conventional discharge standard. In this contribution, removal efficiency of chemical oxygen demand (COD), acute toxicity, genotoxicity and estrogenicity in landfill leachate membrane concentrates (MCs) among UV-Fenton, Fenton and activated carbon adsorption process were compared. Daphnia magna acute toxicity assay, comet assay, cytokinesis-block micronucleus and E-screen assay were performed to assess whether the effluent reaching the main parameters of Chinese Discharge Standard (GB 16889-2008) still had toxic residues. Under the conditions that COD of effluents treated by the three processes were up to the discharge standard, no obvious toxic residue was found in the effluent of UV-Fenton treatment, but effluent from Fenton or activated carbon adsorption process showed genotoxicity or estrogenicity to some extent. Dynamic analysis of UV-Fenton degradation process for estrogen simulation solutions was also conducted, and the formation of intermediates was detected by gas chromatography-mass spectrometry (GC/MS). Toxic residues might be caused by the lack of treatment duration and the formation of more toxic intermediates. UV-Fenton was found to be efficient for the treatment of MCs. Biosafety should be concerned when a new wastewater discharge standard is being established.

Resting heart rate and impaired glucose regulation in middle-aged and elderly Chinese people: a cross-sectional analysis.

BACKGROUND: Elevated resting heart rate (RHR) has been reported to be associated with metabolic syndrome and type 2 diabetes. The aim of this study was to explore whether a positive relationship exists between RHR and impaired glucose regulation (IGR) among middle-aged and older Chinese individuals. METHODS: We conducted a cross-sectional analysis that included a total of 9898 subjects (3194 men and 6704 women) in a Chinese population. The RHRs were derived from ECG recordings, and the subjects were stratified based on RHR quartiles. RESULTS: RHR levels were significantly higher in the subjects with isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), IFG + IGT and diabetes than in those with normal glucose regulation. When multivariate logistic regression analyses were performed, the odds ratios were substantially higher for the subjects with IGR (odds ratio 2.19, 95% confidence interval 1.85-2.58) in the fourth RHR quartile compared with those in the first quartile after adjustment for potential confounding covariates, and the corresponding OR for the combined IGR and type 2 diabetes group was 2.56 (95% CI 2.20-2.98, p < 0.001). Multiple regression analyses demonstrated that RHR was significantly associated with fasting plasma glucose, 2-h OGTT plasma glucose and A1c. CONCLUSIONS: Our cross-sectional findings provide evidence that high RHR is associated with existing IGR among middle-aged and older Chinese individuals.

Association of calf circumference with insulin resistance and non-alcohol fatty liver disease: the REACTION study.

BACKGROUND: The feature of nonalcoholic fatty liver disease (NAFLD) is pathological excessive liver lipid accumulation of subjects who without history of alcohol abuse. Calf circumference is a proxy for lower-body fat and screening method for the identification of subjects with acatastatic lipid accumulation. The objective of this study was to examine the association between calf circumference and NAFLD. METHODS: The study was a cross-sectional analysis including 8850 middle-aged and elderly individuals. NAFLD was examined by hepatic ultrasound and without alcohol abuse and other liver diseases. Calf circumference was measured on the lower right leg at the point of maximal circumference. RESULTS: The mean of calf circumference were 35.7 cm for male and 34.6 cm for female (P < 0.001), respectively. Compared with the lowest calf circumference quartile, the odds ratio for NAFLD in the highest quartile was 2.73 (95% CI 2.34-3.19, P trend <0.001) after adjusted for potential cofounders. There were also significant positive correlation between calf circumference and HOMA-IR, liver enzyme levels and triglycerides. In addition, we found significant positive correlation of calf circumference with the HOMA-IR and fasting insulin level in overweight and obese subjects (BMI ≥ 24 kg/m2) but not in lean subjects (test for interaction: P both less than 0.001 for insulin and HOMA-IR). CONCLUSION: High calf circumference is significantly associated with elevated prevalence of NAFLD and increasing insulin resistance.

Estrogenicity assessment of membrane concentrates from landfill leachate treated by the UV-Fenton process using a human breast carcinoma cell line.

Membrane concentrates (MCs) are generated when membranes are used to concentrate landfill leachate. It contains high concentrations of inorganic and organic environmental pollutants, which are highly toxic and carcinogenic. In this paper, the proliferation effect (PE) from MC before and after treatment with the UV-Fenton process was assessed using the human breast carcinoma cell line MCF-7. The highest value of 116% was found at 5% (v/v) concentration after a 10 min reaction. Phthalic acid esters (PAEs) play an important role in the MC estrogenicity. Estrogen simulation solutions (ESS) of PAEs were prepared to simulate the changes in estrogenic active substances during the UV-Fenton process. The ESS degradation conformed to the first-order kinetics model. The estrogenicity decreased after an initial increase until it acted in a non-estrogenic manner. Convincingly, the intermediates were determined by GC/MS, and the estrogenicity was assessed during the degradation process. The estrogenicity was highly related to the generation of intermediates and the PAE concentration. The results provide guidance for UV-Fenton application in MC estrogenicity reduction.

Circulating periostin in relation to insulin resistance and nonalcoholic fatty liver disease among overweight and obese subjects.

Recent study showed periostin play a pivotal role in abnormal liver triglyceride (TG) accumulation and in the development of obesity-related liver fat accumulation. However, little is known regarding whether periostin plays a key role in the heightened prevalence of NAFLD and other metabolic phenotypes among large-scale populations. A cross-sectional sample of 8850 subjects aged 40 yr or older from China were evaluated in this study. Serum periostin was measured by ELISA methods. The diagnosis of NAFLD by liver ultrasonic examination. Among overweight and obese subjects, NAFLD subjects had higher serum periostin levels than those without NAFLD (126.75 ng/ml vs. 75.96 ng/ml, p < 0.001). Periostin was associated with a higher risk for NAFLD (OR 1.75 for each SD increase in periostin, 95% CI 1.04-3.37, p < 0.001) among overweight and obese subjects after confounder adjustment. Furthermore, periostin levels among overweight and obese subjects were correlated with aspartate aminotransferase (r = 0.102, p = 0.004), alanine aminotransferase (r = 0.108, p = 0.003), waist circumference (r = 0.111, p = 0.002), homeostasis model assessment index-insulin resistance (r = 0.154, p < 0.001) and fasting plasma insulin (r = 0.098, p = 0.006), TG (r = 0.117, p = 0.001). Elevated circulating periostin level was associated with an increased risk of having NAFLD and insulin resistance among overweight and obese individuals.

Metabolic syndrome and osteoporotic fracture: a population-based study in China.

BACKGROUND: Associations between metabolic syndrome (MetS) and osteoporotic fracture have been reported. However, the epidemiological studies are not conclusive. The objective of the study was to determine whether metabolic syndrome associates with osteoporotic fracture. METHODS: This was a cross-sectional study of 9930 Chinese adults aged 40 year or older in the Chongming District, Shanghai, China. A questionnaire, anthropometric measurements and laboratory tests were conducted. MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian-Americans. A history of fractures was collected with an interviewer-assisted questionnaire. Osteoporotic fractures were defined as fractures that occurred due to low-trauma in 2 years prior to the study. RESULTS: Among women, the prevalence of osteoporotic fractures was significantly higher in those with MetS (3.5 vs. 2.6 %, P =0.028). However, the difference was not found in men (2.6 vs. 2.4 %, P =0.737). The presence of Mets was significantly associated with increased odds of osteoporotic fracture among women (odds ratio 1.22; 95 % confidence interval 1.12-1.54; P = 0.039) after controlling for potential confounders. The significant associations were not detected in men. CONCLUSIONS: The presence of MetS was significantly associated with a recent history of osteoporotic fracture in middle-aged and elderly Chinese women.

Association of osteoprotegerin with impaired glucose regulation and microalbuminuria: the REACTION study.

BACKGROUND: High osteoprotegerin (OPG) has been reported in association with insulin resistance and type 2 diabetes. We aimed to evaluate the association of serum OPG with impaired glucose regulation (IGR) and microalbuminuria among middle-aged and older Chinese. METHODS: Serum OPG was measured in 599 individuals with normal glucose regulation, 730 with impaired glucose regulation and 327 newly diagnosed patients with diabetes. Serum OPG was measured using ELISA methods and urine albumin/creatinine ratio was used to determine the urinary albumin excretion. RESULTS: Serum OPG levels were significantly higher in subjects with isolated impaired fasting glucose, isolated impaired glucose tolerance, combined impaired fasting glucose/impaired glucose tolerance and diabetes than in those with normal glucose regulation, whereas serum OPG levels were not different in the four groups with dysregulation of glucose metabolism. OPG was associated with a higher risk for IGR (OR 1.108 for each 0.1 µg/l increase in OPG, 95% CI 1.009-1.117, p = 0.01) after adjustment for gender, age, BMI, current smoking and alcohol intake, family history of diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), lipid profile; the corresponding OR of combined impaired glucose regulation and type 2 diabetes was 1.121 (95% CI 1.101-1.141, p = 0.0005). OPG was associated with the risk of microalbuminuria (OR 1.025, 95% CI 1.006-1.044, p = 0.02) after adjustment for gender, age, current smoking, current alcohol intake, family history of diabetes, BMI, waist/hip ratio, HOMA-IR, eGFR and lipid profile. CONCLUSIONS: Serum OPG level is closely and independently associated with IGR and is an independent risk factor for microalbuminuria.