The causal relationship between depression and obstructive sleep apnea: A bidirectional Mendelian randomization study.

OBJECTIVE: Numerous studies have reported the close association of depression with obstructive sleep apnea (OSA). However, the causal nature and direction remain unclear. This study aimed to identify the genetic causal relationship between depression and OSA using Mendelian randomization (MR). METHODS: Based on publicly available genome-wide association studies data of depression and OSA, we conducted a bidirectional two-sample MR study. The inverse-variance weighted (IVW) was used as the main analysis method. Moreover, multivariable MR was performed to further explore the underlying genetic causality of OSA and depression after adjusting for several potential mediators. RESULTS: The univariable MR analysis revealed a significant causality of depression on the susceptibility of OSA (ORivw = 1.29, 95%CI:1.11,1.50; p < 0.001). This relationship was evidenced by the phenotypes for broad depression (ORivw = 3.30, 95%CI: 1.73, 6.29; p < 0.001), probable major depression (ORivw = 18.79, 95%CI: 5.69, 61.99; p < 0.001), and ICD-10 major depression (ORivw = 23.67, 95%CI: 4.13, 135.74; p < 0.001). In the reverse direction, no significant causal effect of OSA on depression was found. After adjusting for smoking, alcohol use, obesity, type 2 diabetes, insomnia, age, gender, and codeine, most of these results suggested that depression remained significantly and positively associated with OSA. CONCLUSION: These findings may contribute to the understanding of the etiology of depression and OSA and also suggest the clinical significance of controlling depression for the prevention of OSA.

The application of enhanced recovery after surgery in minimally invasive gastrectomy for gastric cancer: a meta-analysis of randomized controlled trials.

OBJECTIVE: We aimed to investigate the efficacy and safety of enhanced recovery after surgery (ERAS) for patients with gastric cancer undergoing minimally invasive surgery (MIS). METHODS: We searched the PubMed, Cochrane Library, Web of Science, Embase, CNKI, VIP, WanFang, and CBM for relevant RCTs from the database inception until December 2021, for studies that compared the ERAS and traditional care (TC) in MIS for gastric cancer. RESULTS: A total of 25 RCTs comprising 2809 patients were included in this study. When compared with the traditional care TC group, the ERAS group had a shorter postoperative hospital stay [MD = -1.88,95%CI (-2.22, -1.55), P < 0.00001] and an earlier time at first postoperative flatus [MD = -18.12,95%CI (-21.45,-14.80), P < 0.00001] along with lower medical costs [SMD = -0.64, 95% CI (-0.85, -0.43), P < 0.00001] and an overall reduction in postoperative complication rates [RR = 0.55, 95% CI (0.44, 0.69), P < 0.00001]. However, the difference in the readmission rates    was not significant. CONCLUSIONS: ERAS can shorten the postoperative hospital stay, hasten the first postoperative flatus and reduce medical costs and overall postoperative complication rate without increasing readmission rates. Therefore, the ERAS protocol is preferable for gastric cancer patients undergoing MIS.

Clinical efficacy and safety of robot assisted surgery for choledochal cysts excisions: a systematic review and meta-analysis.

BACKGROUND: This study aimed to evaluate the safety and therapeutic effect of Robot-assisted surgery (RAS) for choledochal cysts (CCs) excisions. RESEARCH DESIGN AND METHODS: PubMed, EMBASE, Cochrane Library, Web of Science, CNKI, WanFang, VIP, and CBM were searched from database inception to 1 May 2022. The Newcastle-Ottawa scale (NOS) was used to conduct quality assessments, and RevMan (Version 5.4) was used to perform the meta-analysis. RESULTS: In all, 9 studies, involving 623 patients, were analyzed. RAS compared with LAS was associated with less intraoperative blood loss, shorter time to start solid diets, shorter postoperative hospital stay, and lower complications. There was no significant difference in operative time between the two groups, but the total costs were higher in RAS. Our subgroup analysis showed that RAS had significant advantages over LAS in the child group: minor bleeding, shorter length of hospital stay, and fewer postoperative complications. CONCLUSIONS: The available evidence indicates that the RAS system has the advantages of less intraoperative blood loss, minor tissue damage, quick recovery, and sound healing in treating choledochal cyst, which proves that the RAS is safely feasible. Especially in children, RAS tends to be a better choice.

Comparative efficacy and safety of local palliative therapeutics for unresectable malignant biliary obstruction: a Bayesian network meta-analysis.

BACKGROUND: Both radiofrequency ablation (RFA), photodynamic therapy (PDT), and biliary stent alone are common local palliative therapies for unresectable malignant biliary obstruction (MBO), but the best modality is uncertain. RESEARCH DESIGN AND METHODS: Embase, Cochrane Library, PubMed, and Web of Science were systematically searched up to 30 January 2022, for eligible studies that compared either two or all modalities in unresectable MBO. RESULTS: Thirty-three studies with 2974 patients were included in this study. The PDT+Stent and RFA+Stent groups had better overall survival and longer mean survival time than Stent alone (all P < 0.05). Moreover, patients with RFA+Stent demonstrated better mean duration of stent patency (MD: 2.0, 95%CI,1.1 to 2.8, P < 0.05) than Stent alone. The three modalities had similar postoperative mild bleeding, cholangitis, and pancreatitis (all P ≥ 0.05). According to network ranking, PDT+Stent was most likely to provide better survival, RFA+Stent was most likely to maintain stent patency. CONCLUSIONS: RFA or PDT plus biliary stent is effective and safe local palliative therapy for unresectable MBO, but the current studies cannot absolutely determine which modality is the best. We should offer patients the most appropriate treatment according to the advantage of each therapy and the patient's performance status.

Local palliative therapies for unresectable malignant biliary obstruction: radiofrequency ablation combined with stent or biliary stent alone? An updated meta-analysis of nineteen trials.

BACKGROUND: Recently, there has been a burgeoning interest in radiofrequency ablation combined with stent (RFA + Stent) for unresectable malignant biliary obstruction (MBO). This study aimed to perform a meta-analysis to evaluate the efficacy and safety of RFA + Stent compared with biliary stent alone. METHODS: We searched PubMed, Cochrane Library, Embase, and Web of Science databases from their inception dates to June 20, 2021, for studies that compared RFA + Stent and stent alone for unresectable MBO. The main outcomes were survival, patency, and adverse effects. All meta-analyses were calculated using the random-effects model. RESULTS: A total of 19 studies involving 1946 patients were included in this study. Compared with stent alone, RFA + Stent was significantly associated with better overall survival (HR 0.55; 95% CI 0.48, 0.63; P < 0.00001), longer mean survival time (SMD 2.20; 95% CI 1.17, 3.22; P < 0.0001), longer mean stent patency time (SMD 1.37; 95% CI 0.47, 2.26; P = 0.003), higher stent patency at 6 months (OR 2.82; 95% CI 1.54, 5.18; P = 0.0008). The two interventions had similar incidence of postoperative abdominal pain (OR 1.29; 95% CI 0.94, 1.78; P = 0.11), mild bleeding (OR 1.28; 95% CI 0.65, 2.54; P = 0.48), cholangitis (OR 1.09; 95% CI 0.76, 1.55; P = 0.65), pancreatitis (OR 1.39; 95% CI 0.82, 2.38; P = 0.22). Furthermore, the serum bilirubin levels and stricture diameter after operations were significantly alleviated than before operations, but the degree of alleviation between the two groups were not significantly different (all P > 0.05). CONCLUSION: Although the alleviation of serum bilirubin and stricture diameter did not differ between the two interventions, RFA + Stent can significantly improve the survival and stent patency with comparable procedure-related adverse events than stent alone. Thus, RFA + Stent should be recommended as an attractive alternative to biliary stent alone for patients with unresectable MBO.

Early predictive value of circulating biomarkers for sorafenib in advanced hepatocellular carcinoma.

INTRODUCTION: Sorafenib is currently the first-line therapeutic regimen for patients with advanced hepatocellular carcinoma (HCC). However, many patients did not experience any benefit and suffered extreme adverse events and heavy economic burden. Thus, the early identification of patients who are most likely to benefit from sorafenib is needed. AREAS COVERED: This review focused on the clinical application of circulating biomarkers (including conventional biomarkers, immune biomarkers, genetic biomarkers, and some novel biomarkers) in advanced HCC patients treated with sorafenib. An online search on PubMed, Web of Science, Embase, and Cochrane Library was conducted from the inception to 15 August 2021. Studies investigating the predictive or prognostic value of these biomarkers were included. EXPERT OPINION: The distinction of patients who may benefit from sorafenib treatment is of utmost importance. The predictive roles of circulating biomarkers could solve this problem. Many biomarkers can be obtained by liquid biopsy, which is a less or noninvasive approach. The short half-life of sorafenib could reflect the dynamic changes of tumor progression and monitor the treatment response. Circulating biomarkers obtained from liquid biopsy resulted as a promising assessment method in HCC, allowing for better treatment decisions in the near future. ABBREVIATIONS: Alpha-fetoprotein (AFP); American Association for the Study of Liver Diseases (AASLD); Angiopoietin (Ang); Barcelona Clinic Liver Cancer stage (BCLC); Circulating endothelial progenitor (CEP); Circulating free DNA (cfDNA); Complete response (CR); Des-γ-carboxy prothrombin (DCP); Endothelium-derived nitric oxide synthase (eNOS); Hepatocellular carcinoma (HCC); Hepatocyte growth factor (HGF); Hepatoma arterial-embolization prognosis score (HAP); High mobility group box 1 (HMgb1); Interferon-gamma (IFN-γ); Long non-coding RNA (lncRNAs); Micro RNAs (miRNAs); Monocyte-to-lymphocyte ratio (MLR); National Comprehensive Cancer Network (NCCN); Neutrophil-lymphocyte ratio (NLR); Newcastle-Ottawa Scale (NOS); Nitric oxide (NO); Overall survival (OS); Partial response (PR); Platelet-lymphocyte ratio (PLR); Prediction of survival in advanced sorafenib-treated HCC (PROSASH); Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA); Prognostic nutritional index (PNI); Progression-free survival (PFS); Progressive disease (PD); Randomized controlled trials (RCTs); Response Evaluation Criteria in Solid Tumors (RECIST); Single nucleotide polymorphisms (SNPs); Sorafenib advanced HCC prognosis score (SAP); Stable disease (SD); Time to progression (TTP); Transcatheter arterial chemoembolization (TACE); Vascular endothelial growth factor (VEGF).

Clinical efficacy and safety of robotic distal gastrectomy for gastric cancer: a systematic review and meta-analysis.

BACKGROUND: Robotic distal gastrectomy (RDG) is a new technique that is rapidly gaining popularity and may help overcome the limitations of laparoscopic distal gastrectomy (LDG); however, its safety and therapeutic efficacy remain controversial. Therefore, this meta-analysis was performed to evaluate the safety and efficacy of RDG. METHODS: We searched PubMed, EMBASE, the Cochrane Library, and Web of Science for studies that compared RDG and LDG and were published between the time of database inception and May 2021. We assessed the bias risk of the observational studies using ROBIN-I, and a random effect model was always applied. RESULTS: The meta-analysis included 22 studies involving 5386 patients. Compared with LDG, RDG was associated with longer operating time (Mean Difference [MD] = 43.88, 95% CI = 35.17-52.60), less intraoperative blood loss (MD = - 24.84, 95% CI = - 41.26 to - 8.43), a higher number of retrieved lymph nodes (MD = 2.41, 95% CI = 0.77-4.05), shorter time to first flatus (MD = - 0.09, 95% CI = - 0.15 to - 0.03), shorter postoperative hospital stay (MD = - 0.68, 95% CI = - 1.27 to - 0.08), and lower incidence of pancreatic fistula (OR = 0.23, 95% CI = 0.07-0.79). Mean proximal and distal resection margin distances, time to start liquid and soft diets, and other complications were not significantly different between RDG and LDG groups. However, in the propensity-score-matched meta-analysis, the differences in time to first flatus and postoperative hospital stay between the two groups lost significance. CONCLUSIONS: Based on the available evidence, RDG appears feasible and safe, shows better surgical and oncological outcomes than LDG and, comparable postoperative recovery and postoperative complication outcomes.

The efficacy and safety of 5-fluorouracil based adjuvant therapy in resected biliary tract cancer: A systematic review and meta-analysis.

OBJECTIVES: The adjuvant therapy (AT) for biliary tract cancer (BTC) patients after surgery has always been controversial. More therapeutic regimens and high-quality evidence were needed to evaluate AT's survival benefit further. Thus, this study was performed to investigate the efficacy and safety of the 5-fluorouracil (5-FU) regimen in resected BTC patients. METHODS: PubMed, Cochrane Library, Web of Science, and the Embase were systematically searched from inception to Feb.3, 2021, for eligible studies. The pooled analyses were performed using Review Manager, Stata, and SPSS software. RESULTS: A total of 9 trials involving 1339 participants were included in the meta-analysis. Resected BTC patients could significantly benefit from a 5-FU regimen (HR:0.51, 95%CI, 0.38-0.69, P<0.0001), regardless of gallbladder carcinoma (GBC) or cholangiocarcinoma (CCA). Moreover, both adjuvant chemotherapy (HR:0.61, 95%CI, 0.47-0.79, P=0.0003) and chemoradiotherapy (HR:0.35, 95%CI, 0.14-0.83, P=0.02) could significantly improve clinical survival of resected BTC patients than the surgery alone group. In the subgroup analyses, patients with node-positive (P=0.02) or vascular invasion disease (P=0.002) could better benefit from postoperative AT. CONCLUSION: This study provides the latest evidence to support the 5-FU regimen in resected BTC patients regardless of GBC or CCA. Furthermore, high-risk patients are more likely to benefit from it, such as node-positive or vascular invasion disease.

Efficacy and safety of preoperative biliary drainage in patients undergoing pancreaticoduodenectomy: an updated systematic review and meta-analysis.

OBJECTIVES: This study aimed to evaluate the effect of preoperative biliary drainage (PBD) on outcomes of pancreaticoduodenectomy (PD) in patients with biliary obstruction. METHODS: We searched PubMed, EMBASE, Cochrane library, and Web of Science from database inception to 11 March 2021. We used the ROBINS-I tool and Cochrane risk of bias tool 2.0 to assess the risk of bias. The data were statistically analyzed using the RevMan software (Version 5.4). RESULTS: In all, 43 studies, including 23,076 patients, were analyzed, of which 13,922 patients were treated with PBD and 9154 were treated with no preoperative biliary drainage (NPBD). The morbidity     , infection morbidity      , and postoperative pancreatic fistulae (POPF)       in patients undergoing PBD, were significantly higher than those in patients undergoing NPBD. Further, PBD may lead to a significantly worse 2- and 3-year overall survival (OS) rates           . In subgroup meta-analysis, the differences in morbidity, POPF, and OS outcomes lost significance between the PBD and NPBD groups when the mean total serum bilirubin (TSB) concentration was below 15 mg/dl. CONCLUSIONS: Routine PBD still cannot be recommended because it showed no beneficial effect on postoperative outcomes. However, in patients with < 15 mg/dl TSB concentration, PBD tends to be a better choice.

Immune checkpoint blockade in the treatment of malignant tumor: current statue and future strategies.

After being stagnant for decades, there has finally been a paradigm shift in the treatment of cancer with the emergence and application of immune checkpoint inhibitors (ICIs). The most extensively utilized ICIs are targeting the pathways involving programmed death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). PD-1, as an crucial immune inhibitory molecule, by and large reasons the immune checkpoint response of T cells, making tumor cells get away from immune surveillance. Programmed cell death ligand-1 (PD-L1) is exceptionally expressed in most cancers cells and approves non-stop activation of the PD-1 pathway in the tumor microenvironment. PD-1/PD-L1 inhibitors can block the combination of PD-1 and PD-L1, inhibit hostile to regulatory signals, and restore the activity of T cells, thereby bettering immune response. The current researchers assume that the efficacy of these drugs is related to PD-L1 expression in tumor tissue, tumor mutation burden (TMB), and other emerging biomarkers. Although malignant tumors can benefit from the immunotherapy of PD-1/PD-L1 inhibitors, formulating a customized medication model and discovering biomarkers that can predict efficacy are the new trend in the new era of malignant tumor immunotherapy. This review summarizes the mechanism of action of PD-1/PD-L1 inhibitors, their clinical outcomes on various malignant tumors, their efficacy biomarkers, as well as predictive markers of irAEs.

Incisional negative pressure wound therapy for clean-contaminated wounds in abdominal surgery: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The role of incisional negative-pressure wound therapy (iNPWT) in preventing surgical site infections (SSIs) in clean-contaminated abdominal wounds is still controversial. This meta-analysis was performed to evaluate whether the use of iNPWT could reduce SSIs and other complications in clean-contaminated abdominal surgery. METHODS: The authors searched PubMed, EMBASE, Cochrane library, and Web of Science from database inception to 23 January 2021 for randomized controlled trials (RCTs). They assessed the risk of bias using the Cochrane Collaboration risk of bias tool and conducted a meta-analysis using RevMan 5.4. RESULTS: Eleven RCTs, including 4112 patients, were analyzed, of which 2057 were treated with iNPWT and 2055 with standard dressings. The SSI rates (OR = 0.76, 95% CI = 0.61-0.94, P = 0.01), in patients undergoing an iNPWT intervention were significantly lower than those in patients receiving standard dressings. There was no statistically significant difference between the rates of incision dehiscence, seroma, and readmission between groups. CONCLUSIONS: Application of iNPWT for clean-contaminated wounds in abdominal surgery reduced SSI rates but showed similar rates of wound dehiscence, seroma, and readmission compared with standard dressings.

PCAT6 may be a new prognostic biomarker in various cancers: a meta-analysis and bioinformatics analysis.

BACKGROUND: LncRNA prostate cancer-associated transcript 6 (PCAT6) has been reported to be dysregulated in several cancers and is associated with tumor progression. Here, we have performed a meta-analysis to assess the general prognostic role of PCAT6 in malignancies. METHODS: Four public databases (Embase, Pubmed, Web of Science, Cochrane Library) were used to identify eligible studies, then data was extracted and associations between prognostic indicators and clinical characteristics were combined to estimate hazard ratio (HR) or odds ratio (OR) with a 95% confidence interval (CI). Publication bias was measured using the Begg's test, and the stability of the combined results was measured using sensitivity analysis. Subsequently, results were validated using Gene Expression Profiling Interactive Analysis (GEPIA) and the National Genomics Data Center (NGDC). RESULTS: Ten studies were considered eligible for inclusion. In total, 937 patients and eight types of cancer were included. Our results revealed that overexpression of PCAT6 was significantly associated with a shorter OS (HR = 1.82; 95% CI, [1.40, 2.38]; P < 0.0001) and progression-free survival (PFS) (HR = 1.66; 95% CI, [1.22, 2.25]; P < 0.0001) in cancer patients, and that PCAT6 overexpression was significantly associated with individual tumor clinicopathological parameters, including TNM stage (OR = 0.29; 95% CI, [0.09, 0.94]; P = 0.04), gender (OR = 1.84; 95% CI, [1.31, 2.59]; P = 0.0005), and whether the tumor was metastatic (OR = 5.02; 95% CI, [1.36, 18.57]; P = 0.02). However, PCAT6 overexpression was not correlated with patient age and tumor differentiation. PCAT6 expression was significantly up-regulated in four types of cancer, which was validated using the GEPIA cohort. Combining OS and disease-free survival (DFS) of these four types of cancer revealed a shorter OS and DFS in patients with PCAT6 overexpression. PCAT6 expression in various types of cancer was also validated in NGDC. A total of eight cancers were analyzed and PCAT6 was highly expressed in all eight cancers. Further functional predictions suggest that PCAT6 is correlated with tumor prognosis, and that PCAT6 may be useful as a new tumor-specific marker. CONCLUSIONS: LncRNA PCAT6 is highly expressed in multiple cancer types and its upregulation was significantly associated with patient prognosis and poorer clinical features, thereby suggesting that PCAT6 may be a novel prognostic factor in multiple cancer types.

Comparison of intraoperative endoscopic retrograde cholangiopancreatography and laparoscopic common bile duct exploration combined with laparoscopic cholecystectomy for treating gallstones and common bile duct stones: a systematic review and meta-analysis.

BACKGROUND: This study aimed to compare the efficacy and safety of laparoscopic cholecystectomy combined with intraoperative endoscopic retrograde cholangiopancreatography (LC-IntraERCP) and laparoscopic cholecystectomy combined with laparoscopic common bile duct exploration (LC-LCBDE) to determine which one-stage therapeutic strategy provides better outcomes for patients with gallstones and common bile duct stones. METHODS: Cochrane Library, EMBASE, PubMed, and Web of Science databases were searched to identify eligible articles from the database inception to September 2020. The revised Cochrane risk of bias tools for randomized trials (RoB-2) and non-randomized interventions (ROBINS-I) was used to assess the quality of the included studies. The overall quality of evidence was assessed through the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. The primary outcomes consisted of surgical success, retained stones, and overall postoperative complications, while secondary outcomes included postoperative bleeding, postoperative pancreatitis, postoperative bile leakage, conversion to laparotomy, and operative time. RESULTS: Eight studies (four RCTs and four Non-RCTs with high quality) with 2948 patients were included. No significant difference was seen between the two groups regarding surgical success, overall postoperative complications, conversion to laparotomy, and operative time. The meta-analysis demonstrated that in the LC-IntraERCP group, the rate of retained stones (OR 0.51, 95% CI 0.28-0.91) and postoperative bile leakage were lower (OR 0.25, 95% CI 0.09-0.69), while in the LC-LCBDE group, postoperative bleeding (OR 5.24, 95% CI 1.65-16.65) and postoperative pancreatitis (OR 4.80, 95% CI 2.35-9.78) decreased. CONCLUSIONS: LC-IntraERCP and LC-LCBDE exhibited similar efficacies when surgical success rate, overall postoperative complications, conversion to laparotomy, and operative time were compared. However, LC-IntraERCP is probably to be more effective in terms of lowering the rate of retained stones.

T-tube or no T-tube for biliary tract reconstruction in orthotopic liver transplantation: an updated systematic review and meta-analysis.

Objectives: Biliary tract reconstruction with or without T-tube is commonly used in orthotopic liver transplantation (OLT). However, the efficacy and safety of T-tube usage remain controversial. This meta-analysis was conducted to assess the latest evidence of clinical outcomes.Methods: Embase, Cochrane Library, PubMed, and Web of Science were systematically searched from inception to 20 January 2021 for eligible studies. The analyses were performed using Review Manager and Stata.Results: A total of 24 trials involving 3320 participants were included in the meta-analysis. Compared with the no T-tube group, there was a higher incidence of overall biliary complications (OR:1.54; 95%CI, 1.06-2.24; P = 0.02), bile leaks (OR:2.34; 95%CI,1.57-3.48; P < 0.0001), cholangitis (OR:2.78; 95%CI,1.19-6.51; P = 0.002), and longer cold ischemia time (MD:22.27; 95%CI,0.80-43.74; P = 0.04) in the T-tube group. Furthermore, the no T-tube group had significantly higher odds of biliary strictures than the T-tube group (OR:0.60; 95%CI, 0.47-0.78; P = 0.0001).Conclusion: T-tube is still not routinely recommended, but is a good choice for OLT patients at high risk of biliary strictures. Notably, the higher rate of biliary complications in the T-tube group did not translate into an increase in endoscopic or re-operative interventions.

A chemical cross-linking method for the analysis of binding partners of heat shock protein-90 in intact cells.

Members of the heat shock protein-90 (Hsp90) family are key regulators of biological processes through dynamic interaction with a multitude of protein partners. However, the transient nature of these interactions hinders the identification of Hsp90 interactors. Here we show that chemical cross-linking with ethylene glycolbis (succinimidylsuccinate), but not shorter cross-linkers, generated an abundant 240-kDa heteroconjugate of the molecular chaperone Hsp90 in different cell types. The combined use of pharmacological and genetic approaches allowed the characterization of the subunit composition and subcellular compartmentalization of the multimeric protein complex, termed p240. The in situ formation of p240 did not require the N-terminal domain or the ATPase activity of Hsp90. Utilizing subcellular fractionation techniques and a cell-impermeant cross-linker, subpopulations of p240 were found to be present in both the plasma membrane and the mitochondria. The Hsp90-interacting proteins, including Hsp70, p60Hop and the scaffolding protein filamin A, had no role in governing the formation of p240. Therefore, chemical cross-linking combined with proteomic methods has the potential to unravel the protein components of this p240 complex and, more importantly, may provide an approach to expand the range of tools available to the study of the Hsp90 interactome.

Impact of pyrrolidine dithiocarbamate and interleukin-6 on mammalian target of rapamycin complex 1 regulation and global protein translation.

Interleukin-6 (IL-6) is a proinflammatory cytokine that exerts a wide range of cellular, physiological, and pathophysiological responses. Pyrrolidine dithiocarbamate (PDTC) antagonizes the cellular responsiveness to IL-6 through impairment in signal transducer and activator of transcription-3 activation and downstream signaling. To further elucidate the biological properties of PDTC, global gene expression profiling of human HepG2 hepatocellular carcinoma cells was carried out after treatment with PDTC or IL-6 for up to 8 h. Through an unbiased pathway analysis method, gene array analysis showed dramatic and temporal differences in expression changes in response to PDTC versus IL-6. A significant number of genes associated with metabolic pathways, inflammation, translation, and mitochondrial function were changed, with ribosomal protein genes and DNA damage-inducible transcript 4 protein (DDIT4) primarily up-regulated with PDTC but down-regulated with IL-6. Quantitative polymerase chain reaction and Western blot analyses validated the microarray data and showed the reciprocal expression pattern of the mammalian target of rapamycin (mTOR)-negative regulator DDIT4 in response to PDTC versus IL-6. Cell treatment with PDTC resulted in a rapid and sustained activation of Akt and subsequently blocked the IL-6-mediated increase in mTOR complex 1 function through up-regulation in DDIT4 expression. Conversely, down-regulation of DDIT4 with small interfering RNA dampened the capacity of PDTC to block IL-6-dependent mTOR activation. The overall protein biosynthetic capacity of the cells was severely blunted by IL-6 but increased in a rapamycin-independent pathway by PDTC. These results demonstrate a critical effect of PDTC on mTOR complex 1 function and provide evidence that PDTC can reverse IL-6-related signaling via induction of DDIT4.

Negative regulation of STAT3 protein-mediated cellular respiration by SIRT1 protein.

In mammals, the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) is regulated by the deacetylase SIRT1. However, whether the newly described nongenomic actions of STAT3 toward mitochondrial oxidative phosphorylation are dependent on SIRT1 is unclear. In this study, Sirt1 gene knock-out murine embryonic fibroblast (MEF) cells were used to delineate the role of SIRT1 in the regulation of STAT3 mitochondrial function. Here, we show that STAT3 mRNA and protein levels and the accumulation of serine-phosphorylated STAT3 in mitochondria were increased significantly in Sirt1-KO cells as compared with wild-type MEFs. Various mitochondrial bioenergetic parameters, such as the oxygen consumption rate in cell cultures, enzyme activities of the electron transport chain complexes in isolated mitochondria, and production of ATP and lactate, indicated that Sirt1-KO cells exhibited higher mitochondrial respiration as compared with wild-type MEFs. Two independent approaches, including ectopic expression of SIRT1 and siRNA-mediated knockdown of STAT3, led to reduction in intracellular ATP levels and increased lactate production in Sirt1-KO cells that were approaching those of wild-type controls. Comparison of profiles of phospho-antibody array data indicated that the deletion of SirT1 was accompanied by constitutive activation of the pro-inflammatory NF-κB pathway, which is key for STAT3 induction and increased cellular respiration in Sirt1-KO cells. Thus, SIRT1 appears to be a functional regulator of NF-κB-dependent STAT3 expression that induces mitochondrial biogenesis. These results have implications for understanding the interplay between STAT3 and SIRT1 in pro-inflammatory conditions.

Activation of heat shock factor 1 plays a role in pyrrolidine dithiocarbamate-mediated expression of the co-chaperone BAG3.

Adaptive responses to physical and inflammatory stressors are mediated by transcription factors and molecular chaperones. The transcription factor heat shock factor 1 (HSF1) has been implicated in extending lifespan in part by increasing expression of heat shock response genes. Pyrrolidine dithiocarbamate (PDTC) is a small thiol compound that exerts in vivo and in vitro anti-inflammatory properties through mechanisms that remain unclear. Here we report that PDTC induced the release of monomeric HSF1 from the molecular chaperone heat shock protein 90 (Hsp90), with concomitant increase in HSF1 trimer formation, translocation to the nucleus, and binding to promoter of target genes in human HepG2 cells. siRNA-mediated silencing of HSF1 blocked BAG3 gene expression by PDTC. The protein levels of the co-chaperone BAG3 and its interaction partner Hsp72 were stimulated by PDTC in a dose-dependent fashion, peaking at 6h. Inhibition of Hsp90 function by geldanamycin derivatives and novobiocin elicited a pattern of HSF1 activation and BAG3 expression that was similar to PDTC. Chromatin immunoprecipitation studies showed that PDTC and the inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin enhanced the binding of HSF1 to the promoter of several target genes, including BAG3, HSPA1A, HSPA1B, FKBP4, STIP1 and UBB. Cell treatment with PDTC increased significantly the level of Hsp90α thiol oxidation, a posttranslational modification known to inhibit its chaperone function. These results unravel a previously unrecognized mechanism by which PDTC and related compounds could confer cellular protection against inflammation through HSF1-induced expression of heat shock response genes.

The role of increased liver triglyceride content: a culprit of diabetic hyperglycaemia?

The role of fat in the aetiology of insulin resistance and type 2 diabetes has been re-considered in the present review. This is because of the questions raised by recent created mouse models imitating human lipodystrophy diabetes. It appears that hepatic steatosis, which is shared by both lipodystrophy and most if not all obesity patients, may play a key role in the pathogenesis of insulin resistance and type 2 diabetes despite the fact that lipodystrophy is an extreme state and occurs more rarely than obesity. The possible link between lipid and glucose metabolisms via peroxisome activity has been examined and its role in determining hyperglycaemia is suggested. Moreover, new avenues towards a better understanding of insulin resistance at the genomic level have also been proposed. It appears that one of the most fundamental biological phenomena, fuel selection, may underlie the causes of diabetic hyperglycaemia and perplex the role of fat in the aetiology of insulin resistance.