Gut microbiota and therapy for obesity and type 2 diabetes.

There has been a major increase in Type 2 diabetes and obesity in many countries, and this will lead to a global public health crisis, which not only impacts on the quality of life of individuals well but also places a substantial burden on healthcare systems and economies. Obesity is linked to not only to type 2 diabetes but also cardiovascular diseases, musculoskeletal disorders, and certain cancers, also resulting in increased medical costs and diminished quality of life. A number of studies have linked changes in gut in obesity development. Dysbiosis, a deleterious change in gut microbiota composition, leads to altered intestinal permeability, associated with obesity and Type 2 diabetes. Many factors affect the homeostasis of gut microbiota, including diet, genetics, circadian rhythms, medication, probiotics, and antibiotics. In addition, bariatric surgery induces changes in gut microbiota that contributes to the metabolic benefits observed post-surgery. Current obesity management strategies encompass dietary interventions, exercise, pharmacotherapy, and bariatric surgery, with emerging treatments including microbiota-altering approaches showing promising efficacy. While pharmacotherapy has demonstrated significant advancements in recent years, bariatric surgery remains one of the most effective treatments for sustainable weight loss. However, access to this is generally limited to those living with severe obesity. This underscores the need for non-surgical interventions, particularly for adolescents and mildly obese patients. In this comprehensive review, we assess longitudinal alterations in gut microbiota composition and functionality resulting from the two currently most effective anti-obesity treatments: pharmacotherapy and bariatric surgery. Additionally, we highlight the functions of gut microbiota, focusing on specific bacteria, their metabolites, and strategies for modulating gut microbiota to prevent and treat obesity. This review aims to provide insights into the evolving landscape of obesity management and the potential of microbiota-based approaches in addressing this pressing global health challenge.

DEK modulates both expression and alternative splicing of cancer­related genes.

DEK is known to be a potential proto­oncogene and is highly expressed in gastric cancer (GC); thus, DEK is considered to contribute to the malignant progression of GC. DEK is an RNA­binding protein involved in transcription, DNA repair, and selection of splicing sites during mRNA processing; however, its precise function remains elusive due to the lack of clarification of the overall profiles of gene transcription and post­transcriptional splicing that are regulated by DEK. We performed our original whole­genomic RNA­Seq data to analyze the global transcription and alternative splicing profiles in a human GC cell line by comparing DEK siRNA­treated and control conditions, dissecting both differential gene expression and potential alternative splicing events regulated by DEK. The siRNA­mediated knockdown of DEK in a GC cell line led to significant changes in gene expression of multiple cancer­related genes including both oncogenes and tumor suppressors. Moreover, it was revealed that DEK regulated a number of alternative splicing in genes which were significantly enriched in various cancer­related pathways including apoptosis and cell cycle processes. This study clarified for the first time that DEK has a regulatory effect on the alternative splicing, as well as on the expression, of numerous cancer­related genes, which is consistent with the role of DEK as a possible oncogene. Our results further expand the importance and feasibility of DEK as a clinical therapeutic target for human malignancies including GC.

IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice.

Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing ß cells. BDC2.5 T cells in BDC2.5 CD4+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice (BDC2.5+ NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progresses rapidly but rarely leads to spontaneous diabetes. This prevention of diabetes is mediated by T regulatory (Treg) cells in these mice. In this study, we investigated the role of interleukin 10 (IL-10) in the inhibition of diabetes in BDC2.5+ NOD mice by generating Il-10-deficient BDC2.5+ NOD mice (BDC2.5+Il-10-/- NOD mice). Our results showed that BDC2.5+Il-10-/- NOD mice displayed robust and accelerated diabetes development. Il-10 deficiency in BDC2.5+ NOD mice promoted the generation of neutrophils in the bone marrow and increased the proportions of neutrophils in the periphery (blood, spleen, and islets), accompanied by altered intestinal immunity and gut microbiota composition. In vitro studies showed that the gut microbiota from BDC2.5+Il-10-/- NOD mice can expand neutrophil populations. Moreover, in vivo studies demonstrated that the depletion of endogenous gut microbiota by antibiotic treatment decreased the proportion of neutrophils. Although Il-10 deficiency in BDC2.5+ NOD mice had no obvious effects on the proportion and function of Treg cells, it affected the immune response and activation of CD4+ T cells. Moreover, the pathogenicity of CD4+ T cells was much increased, and this significantly accelerated the development of diabetes when these CD4+ T cells were transferred into immune-deficient NOD mice. Our study provides novel insights into the role of IL-10 in the modulation of neutrophils and CD4+ T cells in BDC2.5+ NOD mice, and suggests important crosstalk between gut microbiota and neutrophils in type 1 diabetes development.

Toll-like receptor 7 deficiency suppresses type 1 diabetes development by modulating B-cell differentiation and function.

Innate immunity mediated by Toll-like receptors (TLRs), which can recognize pathogen molecular patterns, plays a critical role in type 1 diabetes development. TLR7 is a pattern recognition receptor that senses single-stranded RNAs from viruses and host tissue cells; however, its role in type 1 diabetes development remains unclear. In our study, we discovered that Tlr7-deficient (Tlr7-/-) nonobese diabetic (NOD) mice, a model of human type 1 diabetes, exhibited a significantly delayed onset and reduced incidence of type 1 diabetes compared with Tlr7-sufficient (Tlr7+/+) NOD mice. Mechanistic investigations showed that Tlr7 deficiency significantly altered B-cell differentiation and immunoglobulin production. Moreover, Tlr7-/- NOD B cells were found to suppress diabetogenic CD4+ T-cell responses and protect immunodeficient NOD mice from developing diabetes induced by diabetogenic T cells. In addition, we found that Tlr7 deficiency suppressed the antigen-presenting functions of B cells and inhibited cytotoxic CD8+ T-cell activation by downregulating the expression of both nonclassical and classical MHC class I (MHC-I) molecules on B cells. Our data suggest that TLR7 contributes to type 1 diabetes development by regulating B-cell functions and subsequent interactions with T cells. Therefore, therapeutically targeting TLR7 may prove beneficial for disease protection.

Multi-Omics Prognostic Signatures Based on Lipid Metabolism for Colorectal Cancer.

Background: The potential biological processes and laws of the biological components in malignant tumors can be understood more systematically and comprehensively through multi-omics analysis. This study elaborately explored the role of lipid metabolism in the prognosis of colorectal cancer (CRC) from the metabonomics and transcriptomics. Methods: We performed K-means unsupervised clustering algorithm and t test to identify the differential lipid metabolites determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) in the serum of 236 CRC patients of the First Hospital of Jilin University (JLUFH). Cox regression analysis was used to identify prognosis-associated lipid metabolites and to construct multi-lipid-metabolite prognostic signature. The composite nomogram composed of independent prognostic factors was utilized to individually predict the outcome of CRC patients. Glycerophospholipid metabolism was the most significant enrichment pathway for lipid metabolites in CRC, whose related hub genes (GMRHGs) were distinguished by gene set variation analysis (GSVA) and weighted gene co-expression network analysis (WGCNA). Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis were utilized to develop the prognostic signature. Results: Six-lipid-metabolite and five-GMRHG prognostic signatures were developed, indicating favorable survival stratification effects on CRC patients. Using the independent prognostic factors as variables, we established a composite nomogram to individually evaluate the prognosis of CRC patients. The AUCs of one-, three-, and five-year ROC curves were 0.815, 0.815, and 0.805, respectively, showing auspicious prognostic accuracy. Furthermore, we explored the potential relationship between tumor microenvironment (TME) and immune infiltration. Moreover, the mutational frequency of TP53 in the high-risk group was significantly higher than that in the low-risk group (p < 0.001), while in the coordinate mutational status of TP53, the overall survival of CRC patients in the high-risk group was significantly lower than that in low-risk group with statistical differences. Conclusion: We identified the significance of lipid metabolism for the prognosis of CRC from the aspects of metabonomics and transcriptomics, which can provide a novel perspective for promoting individualized treatment and revealing the potential molecular biological characteristics of CRC. The composite nomogram including a six-lipid-metabolite prognostic signature is a promising predictor of the prognosis of CRC patients.

TLR9 Deficiency in B Cells Promotes Immune Tolerance via Interleukin-10 in a Type 1 Diabetes Mouse Model.

Toll-like receptor 9 (TLR9) is highly expressed in B cells, and B cells are important in the pathogenesis of type 1 diabetes (T1D) development. However, the intrinsic effect of TLR9 in B cells on ß-cell autoimmunity is not known. To fill this knowledge gap, we generated NOD mice with a B-cell-specific deficiency of TLR9 (TLR9fl/fl/CD19-Cre+ NOD). The B-cell-specific deletion of TLR9 resulted in near-complete protection from T1D development. Diabetes protection was accompanied by an increased proportion of interleukin-10 (IL-10)-producing B cells. We also found that TLR9-deficient B cells were hyporesponsive to both innate and adaptive immune stimuli. This suggested that TLR9 in B cells modulates T1D susceptibility in NOD mice by changing the frequency and function of IL-10-producing B cells. Molecular analysis revealed a network of TLR9 with matrix metalloproteinases, tissue inhibitor of metalloproteinase-1, and CD40, all of which are interconnected with IL-10. Our study has highlighted an important connection of an innate immune molecule in B cells to the immunopathogenesis of T1D. Thus, targeting the TLR9 pathway, specifically in B cells, may provide a novel therapeutic strategy for T1D treatment.

Gut microbial metabolites alter IgA immunity in type 1 diabetes.

The incidence of type 1 diabetes (T1D) has been increasing among children and adolescents, in which environmental factors, including gut microbiota, play an important role. However, the underlying mechanisms are yet to be determined. Here, we show that patients with newly diagnosed T1D displayed not only a distinct profile of gut microbiota associated with decreased short-chain fatty acids (SCFAs) production, but also an altered IgA-mediated immunity compared with healthy control subjects. Using germ-free NOD mice, we demonstrate that gut microbiota from patients with T1D promoted different IgA-mediated immune responses compared with healthy control gut microbiota. Treatment with the SCFA, acetate, reduced gut bacteria-induced IgA response accompanied by decreased severity of insulitis in NOD mice. We believe our study provides new insights into the functional effects of gut microbiota on inducing IgA immune response in T1D, suggesting that SCFAs might be potential therapeutic agents in T1D prevention and/or treatment.

The safety and efficacy of anti-PD-1/anti-PD-L1 antibody therapy in the treatment of previously treated, advanced gastric or gastro-oesophageal junction cancer: A meta-analysis of prospective clinical trials.

INTRODUCTION: So far, anti-PD-1/anti-PD-L1 antibody therapy is reportedly in treating gastric cancer or gastro-oesophageal junction cancer (GC/GEJC) in a number of clinical trials. Based on this, we conducted current meta-analysis to assess the safety and efficacy of anti-PD-1/anti-PD-L1 antibody for previously treated advanced GC/GEJC patients. METHODS: We searched five electronic databases for eligible records. Outcomes were presented and analyzed by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse effects (AEs). RESULTS: Nine records involving 1388 participants were selected in our study. The pooled ORR, DCR, OS rate (6 month), PFS rate (6 month), OS rate (12 month) and PFS rate (12 month) were 10% (95% confidence interval [CI]: 6%-14%), 32% (95%CI: 25%-38%), 52% (95%CI: 44%-61%), 18% (95%CI: 13%-24%), 40% (95%CI: 31%-48%) and 8% (95%CI: 5%-10%), respectively. Meanwhile, grade≥3 AEs rate was 12% (95% CI: 10%-15%). Programmed death ligand 1 (PD-L1) positive cases had higher rate of ORR (odds ratio [OR]: 3.75, 95%CI: 2.09-6.74, P=0.58) compared with negative cases. CONCLUSION: The results indicated that anti-PD-1/anti-PD-L1 antibody therapy has an effectual anti-tumor activity and controllable AEs in advanced GC/GEJC patients. Furthermore, overexpression of PD-L1 in advanced GC/GEJC patients had better ORR from anti-PD-1/anti-PD-L1 antibody therapy (PROSPERO registration number: CRD42018116480).

MicroRNA-141-3p affected proliferation, chemosensitivity, migration and invasion of colorectal cancer cells by targeting EGFR.

Colorectal cancer (CRC) is one of the most often diagnosed cancers globally. MicroRNAs are small RNA molecules that play essential roles in tumorigenesis and progression of CRC. Here we evaluated the effects of miR-141-3p on growth, cetuximab sensitivity, migration and invasion of CRC cells. We found that miR-141-3p negatively regulated the proliferation, migration and invasion in CRC cells. In addition, miR-141-3p enhanced the cetuximab sensitivity of CRC cells by EGFR suppression. Moreover, miR-141-3p improved cetuximab-induced apoptosis in CRC cells. Furthermore, miR-141-3p altered the expression of E-cadherin, N-cadherin, snail and Vimentin, indicating miR-141-3p might play a role on epithelial to mesenchymal transition (EMT). Luciferase reporter assay showed that EGFR was the direct binding site of miR-141-3p and the expression levels of p-EGFR, Raf-1, pAKT and p-ERK1/2 were regulated by miR-141-3p. After down-regulation of EGFR by siRNA in CRC cells, the effects of miR-141-3p on proliferation, migration and invasion were reversed. miR-141-3p played important roles in CRC growth and response to cetuximab treatment, and might function as a potential biomarker to predict cetuximab response.

Antiestrogens in combination with immune checkpoint inhibitors in breast cancer immunotherapy.

Breast cancers (BCs) with expression of estrogen receptor-alpha (ERα) occur in more than 70% of newly-diagnosed patients in the U.S. Endocrine therapy with antiestrogens or aromatase inhibitors is an important intervention for BCs that express ERα, and it remains one of the most effective targeted treatment strategies. However, a substantial proportion of patients with localized disease, and essentially all patients with metastatic BC, become resistant to current endocrine therapies. ERα is present in most resistant BCs, and in many of these its activity continues to regulate BC growth. Fulvestrant represents one class of ERα antagonists termed selective ER downregulators (SERDs). Treatment with fulvestrant causes ERα down-regulation, an event that helps overcome several resistance mechanisms. Unfortunately, full antitumor efficacy of fulvestrant is limited by its poor bioavailability in clinic. We have designed and tested a new generation of steroid-like SERDs. Using ERα-positive BC cells in vitro, we find that these compounds suppress ERα protein levels with efficacy similar to fulvestrant. Moreover, these new SERDs markedly inhibit ERα-positive BC cell transcription and proliferation in vitro even in the presence of estradiol-17ß. In vivo, the SERD termed JD128 significantly inhibited tumor growth in MCF-7 xenograft models in a dose-dependent manner (P < 0.001). Further, our findings indicate that these SERDs also interact with ER-positive immune cells in the tumor microenvironment such as myeloid-derived suppressor cells (MDSC), tumor infiltrating lymphocytes and other selected immune cell subpopulations. SERD-induced inhibition of MDSCs and concurrent actions on CD8+ and CD4 + T-cells promotes interaction of immune checkpoint inhibitors with BC cells in preclinical models, thereby leading to enhanced tumor killing even among highly aggressive BCs such as triple-negative BC that lack ERα expression. Since monotherapy with immune checkpoint inhibitors has not been effective for most BCs, combination therapies with SERDs that enhance immune recognition may increase immunotherapy responses in BC and improve patient survival. Hence, ERα antagonists that also promote ER downregulation may potentially benefit patients who are unresponsive to current endocrine therapies.

Synthesis and Structure-Activity Relationship (SAR) Studies of Novel Pyrazolopyridine Derivatives as Inhibitors of Enterovirus Replication.

A series of novel pyrazolopyridine compounds have been designed and prepared by a general synthetic route. Their activities against the replication of poliovirus-1, EV-A71, and CV-B3 enteroviruses were evaluated. The comprehensive understanding of the structure-activity relationship was obtained by utilizing the variation of four positions, namely, N1, C6, C4, and linker unit. From the screened analogues, the inhibitors with the highest selectivity indices at 50% inhibition of viral replication (SI50) were those with isopropyl at the N1 position and thiophenyl-2-yl unit at C6 position. Furthermore, the C4 position offered the greatest potential for improvement because many different N-aryl groups had better antiviral activities and compatibilities than the lead compound JX001. For example, JX040 with a 2-pyridyl group was the analogue with the most potent activity against non-polio enteroviruses, and JX025, possessing a 3-sulfamoylphenyl moiety, had the best activity against polioviruses. In addition, analogue JX037, possessing a novel pyrazolopyridine heterocycle, was also shown to have good antienteroviral activity, which further enlarges the compound space for antienteroviral drug design.

Impaired Glucose Metabolisms of Patients with Obstructive Sleep Apnea and Type 2 Diabetes.

AIMS: Obstructive sleep apnea (OSA) is a very common disorder which is associated with metabolic comorbidities. The aims of this study were to analyze clinical data of patients with OSA and evaluate influence of sleep-disordered breathing on glycometabolism and its underlying mechanisms. METHODS: We designed a cross-sectional study involving 53 OSA patients in The First Hospital of Jilin University from March 2015 to March 2016. They underwent a full-night polysomnography, measurement of fasting blood glucose and blood lipid profiles. Besides, we chose 20 individuals with type 2 diabetes mellitus (T2DM) as a subgroup for an in-depth study. This group additionally underwent a steamed bread meal test and measurement of HbA1c, C-reactive protein, tumor necrosis factor-α, interleukin 6, morning plasma cortisol, and growth hormone. RESULTS: The two groups which with or without T2DM showed no significant differences in baseline characteristics. As for OSA patients with T2DM, the severe OSA group had higher homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.013) than the mild-to-moderate OSA group, whereas had lower morning plasma cortisol levels (P = 0.005) than the mild-to-moderate OSA group. AHI was positive correlated with HOMA-IR (r = 0.523, P = 0.018), yet negative correlated with morning plasma cortisol (r = -0.694, P = 0.001). However, nadir SpO2 was positive correlated with morning plasma cortisol (r s = 0.646, P = 0.002), while negative correlated with HOMA-IR (r s = -0.489, P = 0.029). CONCLUSIONS: Our study showed that sleep-disordered breathing exerted negative influence on glucose metabolisms. The impairment of hypothalamic-pituitary-adrenal axis activity may be one of the underlying mechanisms of the glycometabolic dysfunctions in OSA with T2DM patients.

Synthesis of 2,3-Disubstituted Quinolines via Ketenimine or Carbodiimide Intermediates.

Cyclopenta[b]quinolines and cyclohexa[b]quinolines were prepared via the reactions of α-diazo ketones with N-(2-cyclopropylidenemethylphenyl)phosphanimines and N-(2-cyclobutylidenemethylphenyl) phosphanimine, respectively. The reaction proceeds in a cascade involving ketenimine formation, 6 π-electron ring closure, and 1,3-alkyl shift. A similar approach was developed for the synthesis of dihydropyrrolo-[2,3-b]quinolines from N-(2-cyclopropylidenemethylphenyl)phosphanimines and isocyanates.

[Study of introperitoneal hyperthermic perfusion chemotherapy combined with systemic neoadjuvent chemotherapy in treatment of gastric cancer patients with peritoneal carcinomatosis].

OBJECTIVE: The aim of this study is to discuss the curative effect of introperitoneal hyperthermic perfusion chemotherapy(IHPC) combined with systemic neoadjuvant chemotherapy on the gastric cancer patients with peritoneal carcinomatosis. METHODS: Sixty-four patients with gastric cancer and peritoneal carcinomatosis who were hospitalized in the Department of Gastrointestinal Surgery of First Hospital of Jilin University from December 2006 to December 2013. After peritoneal carcinomatosis was confirmed during laparoscopic exploration, FOLFOX6 (oxaliplatin and calcium folinate and 5-Fu) was performed for systemic chemotherapy. One course was 14 days and a complete treatment includes four courses. At the same time, patients underwent peritoneal catheter insertion and received IHPC(5-Fu 1 500 mg/m(2) and Cisplatin 35 mg/m(2) were added into 0.9% NaCl solution 2 000 ml, the infusion velocity was 35-45 ml/min, infusion time was 45-60 minutes, the temperature was controlled to 41°C). A comprehensive evaluation was taken after the fourth course of treatment before operation. Further surgical therapy was performed according to the assessment result. RESULTS: Sixty-four patients received IHPC combined with systemic chemotherapy. Thirty-two patients(50.0%) had partial response, 18(28.1%) stable disease, and 14(21.9%) progressive disease after chemotherapy. No severe complications or death occurred during the neoadjuvant chemotherapy. Thirty-two patients(50.0%) received radical resection, 10(15.6%) palliative operation, and another 22 patients(37.4%) didn't comply with inclusion criteria of operation. Patients receiving operation had a median survival time of 678 days, which was significantly longer than patients without operation, with a median survival time of 251(χ(2)=23.34, P=0.02). CONCLUSIONS: IHPC combined with systemic chemotherapy is an effective therapeutic method for gastric cancer patients with peritoneal carcinomatosis in terms of reducing preoperative tumor load and achieving radical resection.

Protein profiling of alpha-fetoprotein producing gastric adenocarcinoma.

Alpha-fetoprotein (AFP) producing gastric adenocarcinoma is considered as a rare subtype of gastric adenocarcinoma. Compared with AFP non-producing gastric adenocarcinoma, our study and other previous studies showed that AFP producing gastric adenocarcinoma is more aggressive and prone to liver metastasis. Using the Protein Pathway Array, 11 of out of 286 proteins tested were found to be differentially expressed between AFP producing (n=32) and AFP non-producing (n=45) gastric adenocarcinoma tissues. In addition, the high level expression of XIAP and IGF-Irß in gastric adenocarcinoma tissues was independent factors for poor prognosis in AFP producing gastric adenocarcinoma patients. A risk model based on the XIAP and IGF-Irß expression levels can separate AFP producing gastric adenocarcinoma patients into 2 subgroups and each subgroup had a distinct set of signaling pathways involved. In conclusion, AFP producing gastric adenocarcinoma is a heterogeneous cancer with different clinical outcomes, biological behaviors and underlying molecular alterations.

Clinicopathological characteristics and prognosis of alpha-fetoprotein positive gastric cancer in Chinese patients.

PURPOSE: This study aimed to review the clinicopathological, histochemical, and prognostic features of Alpha-Fetoprotein (AFP) positive gastric cancer. PATIENTS AND METHODS: Six hundred and fifty one patients with gastric cancer who underwent gastrectomy between January 2009 and December 2012 at The First Hospital of Jilin University were enrolled in the study. Among them, 45 patients were identified as AFP positive gastric cancer. The clinicopathologic characteristics and prognosis of the AFP positive gastric cancer patients were analyzed. RESULTS: Among the 45 AFP positive patients, serum levels of AFP were < 100 µg/L in nine patients. The histological classification of 45 patients was as follows: hepatoid type, 25 (55.6%) cases; fetal gastrointestinal type, 12 (26.7%) cases; yolk sac tumor type, 2 (4.4%) cases; and mixed type, 6 (13.3%) cases. Twenty nine (64.4%) cases were AFP positive by immunohistochemical analysis; we found no significant difference in AFP positivity and histologic type. However, the differences in the number of metastasis lymph nodes, the maximum tumor diameter, pathological stage, vascular invasion and liver metastasis between the AFP positive group and the negative group were significant. At the same T stage, the liver metastasis status of the AFP positive group was higher than that of the negative group. The AFP positive group had a much poorer prognosis than the negative group. CONCLUSION: AFP positive gastric cancer is associated with aggressive behavior and poorer prognosis compared to that of AFP negative gastric cancer.

[Effects of omega-3 polyunsaturated fatty acids on postoperative inflammatory reaction and clinical efficacy].

OBJECTIVE: To investigate the effect of omega-3 polyunsaturated fatty acids (PUFA) on postoperative inflammatory response and clinical efficacy in gastric cancer patients with nutritional risk. METHODS: All patients with gastric cancer in our department from June 2013 to January 2014 undergoing radical gastrectomy were prospectively enrolled in the study. Patients who matched the selection criteria were randomly divided into two groups: trial group (with omega-3 PUFA in parenteral nutrition) and control group (without omega-3 PUFA in parenteral nutrition). Levels of inflammatory factors (serum CRP, TNF-α, IL-1, IL-6, IL-10) and nutrition-related proteins (prealbumin, retinol conjugated protein and transferrin) were compared between the two groups before operation and 2, 4 and 6 days after operation. Incidence of postoperative systemic inflammatory response syndrome (SIRS) and other indicators associated with efficacy were compared between the two groups as well. RESULTS: Forty-seven patients were finally included in this study with 21 patients in the trial group and other 26 in the control group. There were no significant differences of inflammatory factors and nutrition-related proteins between the two groups before operation (all P>0.05). In the 6th days after operation, the levels of proinflammatory cytokines, including CRP, IL-1 and IL-6 were significantly lower in the trial group as compared to the control group, while the level of IL-10 (inhibiting inflammatory cytokine) was higher in the trial group, as well as levels of nutrition proteins(all P<0.05). The trial group had significantly lower rate of SIRS than the control group [57.1%(12/21) vs. 84.6% (22/26), P=0.036]. Compared with the control group, patients in the trial group had shorter bowel sound recovery time [(12.3±1.1) d vs. (3.1±1.3) d, P=0.025], earlier passage of flatus [(3.1±1.0) d vs. (3.9±1.2) d, P=0.025] and shorter hospital stay [(9.4±2.1) d vs. (10.9±2.5) d, P=0.038], but there was no difference in postoperative complication rate between the two groups (P=0.678). CONCLUSIONS: Omega-3 PUFA can reduce the release of inflammatory promoters, promote the release of inhibiting inflammatory cytokine IL-10, decrease the incidence of SIRS, improve patients' nutritional state, expedite the recovery of gastrointestinal function and shorten patients' recovery time.

2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling.

We discovered recently that the central metabolite α-ketoglutarate (α-KG) extends the lifespan of C. elegans through inhibition of ATP synthase and TOR signaling. Here we find, unexpectedly, that (R)-2-hydroxyglutarate ((R)-2HG), an oncometabolite that interferes with various α-KG-mediated processes, similarly extends worm lifespan. (R)-2HG accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. We show that, like α-KG, both (R)-2HG and (S)-2HG bind and inhibit ATP synthase and inhibit mTOR signaling. These effects are mirrored in IDH1 mutant cells, suggesting a growth-suppressive function of (R)-2HG. Consistently, inhibition of ATP synthase by 2-HG or α-KG in glioblastoma cells is sufficient for growth arrest and tumor cell killing under conditions of glucose limitation, e.g., when ketone bodies (instead of glucose) are supplied for energy. These findings inform therapeutic strategies and open avenues for investigating the roles of 2-HG and metabolites in biology and disease.

Copper-catalyzed cascade double C3-indolations of 3-diazoindolin-2-imines with indoles: convenient access to 3,3-diaryl-2-iminoindoles.

Symmetrical 3,3-diaryl-2-iminoindoles were prepared from 3-diazoindolin-2-imines and indoles via a copper-catalyzed cascade arylation/dehydrogenative cross-coupling process. By controlling the molar ratio of reactants and the operation procedure, 3-aryl-2-aminoindoles and asymmetrical 3,3-diaryl-2-iminoindoles could be approached.

Preparation of 3-diazoindolin-2-imines via cascade reaction between indoles and sulfonylazides and their extensions to 2,3-diaminoindoles and imidazo[4,5-b]indoles.

3-Diazoindolin-2-imines were constructed from indoles and sulfonylazides via an electronically matched 1,3-dipolar cycloaddition and a subsequent dehydroaromatization/ring-opening cascade. The reaction between 3-substituted indoles and sulfonyl azides provided 2-aminoindoles, while 2-substituted indoles furnished 3-aminoindoles. Moreover, 2,3-diaminoindoles could be prepared from the resulting 3-diazoindolin-2-imines and secondary amines via a rhodium-catalyzed amination. Further extension of 2,3-diaminoindoles led to the formation of imidazo[4,5-b]indoles.