Background: Increasing evidences show the interconnections of glucose with albumin, and their ratio (GAR) has been reported to be associated with mortality and clinical outcomes in several cardiovascular diseases. However, whether GAR is associated with diabetes, CVD and mortality in the general population remains unknown.Objective: To explore whether GAR is associated with incident diabetes, CVD and mortality and to elucidate their dose‒response association.Methods: This prospective cohort study used data from the US National Health and Nutrition Examination Survey (NHANES) and the UK Biobank. The potential associations between GAR and the risk of incident diabetes, CVD and mortality were evaluated by Cox proportional hazard regression. Restricted cubic spline regressions were applied to estimate possible nonlinear associations.Results: The NHANES documented 7605 deaths over a median follow-up of 9.4 years, and the UK Biobank documented 37753 deaths, 17314 incident diabetes and 30716 CVD cases with over a median follow-up of 13.8 years. In the NHANES, 50699 participants aged 18+ (mean age 48.58 [18.72]) years were included, and the mean GAR was 2.42 (1.01). In the UK Biobank, 429261 participants aged 37+ (mean age 56.55 [8.09]) years were included, and the mean GAR was 2.05 (0.53). An elevated GAR was significantly associated with a greater risk of all-cause mortality (NHANES: hazard ratio [HR]: 1.16, 95% confidence interval [CI]: 1.14-1.18; UK Biobank: HR: 1.19, 95% CI: 1.17-1.20), and incident diabetes (HR: 1.81, 95% CI: 1.79-1.83), heart failure (HR: 1.16, 95% CI: 1.11-1.22), myocardial infarction (HR: 1.08, 95% CI: 1.03-1.13) and stroke (HR: 1.14, 95% CI 1.08-1.20). In addition, a J-shaped relationship was also observed between GAR levels and incident diabetes, CVD and mortality.Conclusions: In this population-based prospective cohort study, a higher baseline GAR was associated with an increased risk of incident diabetes, CVD and mortality. GAR is a promising indicator to identify individuals at high risk of mortality in clinical practice.Funding: This work was supported by grants from the National Natural Science Foundation of China-Youth Science Fund (82301768, 32300533, 32100510), the Key Discipline Construction Project of Pudong Health and Family Planning Commission of Shanghai (PWZxk2022-01), the Shanghai Sailing Program (23YF1430500), the Scientific Research Foundation provided by Pudong Hospital affiliated with Fudan University (YJYJRC202202), and the Talents Training Program of Pudong Hospital affiliated with Fudan University (YQ202201).Declaration of Interest: None declared.Ethical Approval: The UKB study received approval from the National Information Governance Board for Health and Social Care and the National Health Service North West Multi-Centre Research Ethics Committee. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines for cohort studies.
Da Vinci Surgical System is one of the greatest inventions of the 20th century, which represents the development direction of the precise minimally invasive surgical techniques, the aim of this study was to comparing the short-term outcomes between da Vinci robot-assisted lobectomy and video-assisted thoracic surgery (VATS) lobectomy for non-small cell lung cancer.45 pairs of non-small cell lung cancer patients underwent pulmonary lobectomy with da Vinci Robotic assisted thoracoscopic (RATS) and VATS approach during the same period from January 2014 to January 2017. The operative time, estimated blood loss (EBL), total number and total groups of dissected lymph nodes, postoperative duration of drainage, the first day volume of drainage, total volume of drainage were compared.No perioperative death and convertion to thoracotomy occured in both groups. There were significant difference between RATS group and VATS group in EBL [(50.30±32.33) mL vs (208.60±132.63) mL], the first day volume of drainage [(275.00±145.42) mL vs (347.60±125.80) mL], the dissected total number [(22.67±9.67) vs (15.51±5.41)] and total team [(6.31±1.43) vs (4.91±1.04)] of lymph node. There were no significant difference in other outcomes.RATS is safe and effective and took better short-outcomes than VATS in non-small cell lung cancer.背景与目的 作为20世纪最伟大发明之一的达芬奇机器人手术系统代表了精准微创外科的发展方向，本文旨在比较达芬奇机器人与电视胸腔镜辅助肺癌根治术的近期疗效。方法 回顾性分析自2014年1月-2017年1月在我院行达芬奇机器人手术以及行电视胸腔镜辅助手术治疗非小细胞肺癌患者的相关临床资料，两组各纳入45例并进行配对的病例对照研究。比较两组的手术时间、术中失血量、术中淋巴结清扫数量、淋巴结清扫站数、术后带管时间、术后住院天数、术后第1日胸引液的量以及术后胸引液的总量。结果 两组均无中转开胸及围术期死亡病例。机器人组与胸腔镜组的术中失血量[（50.30±32.33）mL vs（208.60±132.63）mL]与术后第1日胸引液的量[（275.00±145.42）mL vs（347.60±125.80）mL]比较，机器人组均少于胸腔镜组；机器人组与胸腔镜组的淋巴结清扫数量[（22.67±9.67）个 vs（15.51±5.41）个]及淋巴结清扫站数[（6.31±1.43）站 vs （4.91±1.04）站]比较，机器人组均多于胸腔镜组，差异具有统计学意义；两组的其他指标比较，差异均无统计学意义。结论 达芬奇机器人行非小细胞肺癌根治术安全、有效，在近期术后疗效上优于胸腔镜组。.
Previous studies have found that α-momorcharin (α-MMC) can selectively regulate cytokine release from monocytes. In this study, we assessed the inhibitory effect of α-MMC on the inflammatory cytokine storm and explored the associated mechanism in LPS-treated macrophages and an acute pneumonia mouse model. Briefly, Human macrophages were stimulated with LPS, and the expression of inflammatory cytokines was assessed by ELISA. After LPS was injected into the trachea, cytokine levels in mouse lung tissue and plasma were evaluated by ELISA, and inflammatory lesions in lung tissue were observed by hematoxylin and eosin (H&E) staining. TLR4-MAPK/NF-κB signalling pathway-related protein expression were analysed by proteomics and phosphoproteomics analysis and western blotting. The results showed that, Alpha-MMC significantly inhibited the LPS-induced expression of inflammatory cytokines such as TNF-a, IL-1β, IL-6, IL-8, MIP-1α and MCP-1 in a dose-dependent and time-dependent manner,α-MMC also inhibited the inflammatory cytokine storm in LPS-induced acute pneumonia model mice and alleviated inflammation in lung tissue. Moreover, a-MMC inhibited TAK1/p-TAK1 and subsequently inhibited the downstream signalling proteins p-JNK, p-AP-1 and NF-κB/p-P65. The LRP1 receptor blocker RAP blocked this inhibitory effect. It is suggested that, α-MMC can inhibit the LPS-induced inflammatory cytokine storm in vitro and in vivo by first inhibiting TAK1 in the TLR4 pathway through the LRP1 receptor and then blocking the downstream MAPK and NF-κB pathways. The ability of α-MMC to inhibit inflammatory cytokines may make it a very promising drug for the treatment of diseases in which the cytokine storm is the main pathological feature.
The long noncoding (lnc) RNA MIR4435-2HG is known to promote lung cancer; however, its role in prostate carcinoma (PCa) remains unknown. The aim of the current study was therefore to investigate the role of MIR4435-2HG in PCa by detecting differential gene expression using quantitative PCR and ELISA kits. Furthermore, overexpression experiments were performed to analyze gene interactions and Transwell assays were used to analyze cell invasion and migration. The present study demonstrated that plasma levels of MIR4435-2HG and transforming growth factor-β1 (TGF-β1) were significantly higher in patients with PCa compared with healthy controls. Furthermore, MIR4435-2HG and TGF-β1 plasma levels were positively correlated in patients with PCa, but not in healthy controls. The results from the follow-up study suggested that MIR4435-2HG was closely associated with patient survival. MIR4435-2HG overexpression and treatment with TGF-β1 promoted cancer cell invasion and migration. In addition, TGF-β inhibitor attenuated the enhancing effects of MIR4435-2HG overexpression on cell invasion and migration. MIR4435-2HG overexpression led to upregulation of TGF-β1 expression, whereas TGF-β1 treatment had no effect on MIR4435-2HG expression. These results suggested that MIR4435-2HG may promote PCa by upregulating TGF-β1.
Abstract Background: CaMKIV has been identified as a potential regulator of skeletal muscle glucose metabolism and insulin gene expression. However, the mechanism of CaMKIV involved in adipose insulin resistance is not fully understood. Autophagy has to be shown as a potential therapeutic target for endoplasmic reticulum (ER) stress and insulin resistance. The purpose of this study is to investigate the effect of CaMKIV on the ER stress, autophagic function and insulin signaling in tunicamycin induced adipocytes. Methods: In the present study, we first used tunicamycin to establish a cell model of ER stress. Then recombinant CaMKIV and/or targeted-siRNA of CREB and mTOR were added into medium of tunicamycin-induced adipocytes. The ER stress indicators, autophagy activation, mTOR/CREB signaling and insulin sensitivity were analyzed by western blotting or electron microscopy. Results: The results suggested CaMKIV not only reversed tunicamycin-induced ER stress, but also improved impaired insulin sensitivity through regulating abnormal autophagy in adipocytes. Moreover, CaMKIV inhibited activated ER stress and elevated insulin sensitivity in Atg7-/- adipocytes. However, the protective effects of CaMKIV were nullified by suppression of mTOR or CREB in tunicamycin induce adipocytes, suggesting that CaMKIV could inhibit ER stress, suppress autophagy and restore insulin signaling at least partly through mTOR/CREB signaling. Conclusion: We conclude that CaMKIV inhibits ER stress and improves insulin signaling through reduction of autophagy in adipocytes viamTOR/CREB signaling, which could be regarded as novel opportunities for treatment of obesity and type 2 diabetes.
Nickel is a confirmed human lung carcinogen. Nonetheless, the molecular mechanisms driving its carcinogenic impact on lung tissue remain poorly defined. In this study, we assessed SESN2 expression and the signaling pathways responsible for cellular transformation in human bronchial epithelial cells (HBECs) as a result of nickel exposure. We employed the Western blotting to determine the induction of SESN2 by nickel. To clarify the signaling pathways leading to cellular transformation following nickel exposure, we applied techniques such as gene knockdown, methylation-specific PCR, and chromatin immunoprecipitation. Exposure to nickel results in the upregulation of SESN2 and the initiation of autophagy in human bronchial epithelial cells (HBECs). This leads to degradation of HUR protein and consequently downregulation of USP28 mRNA, PP2AC protein, β-catenin protein, and diminished VHL transcription, culminating in the accumulation of hypoxia-inducible factor-1α (HIF-1α) and the malignant transformation of these cells. Mechanistic studies revealed that the increased expression of SESN2 is attributed to the demethylation of the SESN2 promoter induced by nickel, a process facilitated by decreased DNA methyl-transferase 3 A (DNMT3a) expression, while The downregulation of VHL transcription is linked to the suppression of the PP2A-C/GSK3β/β-Catenin/C-Myc pathway. Additionally, we discovered that SESN2-mediated autophagy triggers the degradation of HUR protein, which subsequently reduces the stability of USP28 mRNA and inhibits the PP2A-C/GSK3β/β-Catenin pathway and c-Myc transcription in HBECs post nickel exposure. Our results reveal that nickel exposure leads to the downregulation of DNMT3a, resulting in the hypomethylation of the SESN2 promoter and its protein induction. This triggers autophagy-dependent suppression of the HUR/USP28/PP2A/β-Catenin/c-Myc pathway, subsequently leading to reduced VHL transcription, accumulation of HIF-1α protein, and the malignant transformation of human bronchial epithelial cells (HBECs). Our research offers novel insights into the molecular mechanisms that underlie the lung carcinogenic effects of nickel exposure. Specifically, nickel induces aberrant DNA methylation in the SESN2 promoter region through the decrease of DNMT3a levels, which ultimately leads to HIF-1α protein accumulation and the malignant transformation of HBECs. Specifically, nickel initiates DNA-methylation of the SESN2 promoter region by decreasing DNMT3a, ultimately resulting in HIF-1α protein accumulation and malignant transformation of HBECs. This study highlights DNMT3a as a potential prognostic biomarker or therapeutic target to improve clinical outcomes in lung cancer patients.
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