Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E_2 and cytokines

AIM： To investigate the effect of short-chain fatty acids （SCFAs） on production of prostaglandin E2 （PGE2）, cytokines and chemokines in human monocytes. METHODS： Human neutrophils and monocytes were isolated from human whole blood by using 1-Step Polymorph and RosetteSep Human Monocyte Enrichment Cocktail, respectively. Human GPR41 and GPR43 mRNA expression was examined by quantitative realtime polymerase chain reaction, The calcium flux assay was used to examine the biological activities of SCFAs in human neutrophils and monocytes. The effect of SCFAs on human monocytes and peripheral blood mononuclear cells （PBMC） was studied by measuring PGE2, cytokines and chemokines in the supernatant. The effect of SCFAs in vivo was examined by intraplantar injection into rat paws. RESULTS： Human GPR43 is highly expressed in human neutrophils and monocytes. SCFAs induce robust calcium flux in human neutrophils, but not in human monocytes. In this study, we show that SCFAs can induce human monocyte release of PGE2 and that this effect can be enhanced in the presence of lipopolysaccharide （LPS）. In addition, we demonstrate that PGE2 production induced by SCFA was inhibited by pertussis toxin, suggesting the involvement of a receptor-mediated mechanism. Furthermore, SCFAs can specifically inhibit constitutive monocyte chemotactic protein-1 （MCP-1） production and LPS-induced interleukin-10 （IL-10） production in human monocytes without affecting the secretion of other cytokines and chemokines examined. Similar activities were observed in human PBMC for the release of PGE2, MCP-1 and IL-10 after 5CFA treatment. In addition, SCFAs inhibit LPS-induced production of tumor necrosis factor-α and interferon-7 in human PBIVlC. Finally, we show that SCFAs and LPS can induce PGE2 production in vivo by intraplantar injection into rat paws （P 〈 0.01）. CONCLUSION： SCFAs can have distinct antiinflammatory activities due to their regulation of PGE2, cytokine and chemokine release from human immune cells.

LDL,LDL receptors,and PCSK9 as modulators of the risk for type 2 diabetes:a focus on white adipose tissue

Type 2 diabetes(T2D) and cardiovascular disease(CVD) share many risk factors such as obesity,unhealthy lifestyle,and metabolic syndrome,whose accumulation over years leads to disease onset.However,while lowering plasma low-density lipoprotein cholesterol(LDLC) is cardio-protective,novel evidence have recognised a role for common LDLC-lowering variants(e.g.in HMGCR,PCSK9,and LDLR) and widely used hypocholesterolemic drugs that mimic the effects of some of these variants(statins) in higher risk for T2D.As these conditions decrease plasma LDLC by increasing tissue-uptake of LDL,a role for LDL receptor(LDLR)pathway was proposed.While underlying mechanisms remain to be fully elucidated,work from our lab reported that native LDL directly provoke the dysfunction of human white adipose tissue(WAT) and the activation of WAT NLRP3(Nucleotide-binding domain and Leucine-rich repeat Receptor,containing a Pyrin domain 3)inflammasome,which play a major role in the etiology of T2D.However,while elevated plasma numbers of apolipoprotein B(apoB)-containing lipoproteins(measured as apoB,mostly as LDL) is associated with WAT dysfunction and related risk factors for T2D in our cohort,this relation was strengthened in regression analysis by lower plasma proprotein convertase subtilisin/kexin type 9(PCSK9).This supports a central role for upregulated pathway of LDLR and/or other receptors regulated by PCSK9 such as cluster of differentiation 36(CD36) in LDL-induced anomalies.Targeting receptor-mediated uptake of LDL into WAT may reduce WAT inflammation,WAT dysfunction,and related risk for T2D without increasing the risk for CVD.

Pharmacological inhibition of diacylglycerol acyltransferase-1 and insights into postprandial gut peptide secretion

AIM To examine the role that enzyme Acyl-CoA:diacylglycerol acyltransferase-1(DGAT1) plays in postprandial gut peptide secretion and signaling.METHODS The standard experimental paradigm utilized to evaluate the incretin response was a lipid challenge.Following a lipid challenge,plasma was collected via cardiac puncture at each time point from a cohort of 5-8 mice per group from baseline at time zero to 10 h.Incretin hormones [glucagon like peptide-1(GLP-1),peptide tyrosine-tyrosine(PYY) and glucose dependent insulinotropic polypeptide(GIP)] were then quantitated.The impact of pharmacological inhibition of DGAT1 on the incretin effect was evaluated in WT mice.Additionally,a comparison of loss of DGAT1 function either by genetic ablation or pharmacological inhibition.To further elucidate the pathways and mechanisms involved in the incretin response to DGAT1 inhibition,other interventions [inhibitors of dipeptidyl peptidase-IV(sitagliptin),pancreatic lipase(Orlistat),GPR119 knockout mice] were evaluated.RESULTS DGAT1 deficient mice and wildtype C57/BL6J mice werelipid challenged and levels of both active and total GLP-1 in the plasma were increased.This response was further augmented with DGAT1 inhibitor PF-04620110 treated wildtype mice.Furthermore,PF-04620110 was able to dose responsively increase GLP-1 and PYY,but blunt GIP at all doses of PF-04620110 during lipid challenge.Combination treatment of PF-04620110 and Sitagliptin in wildtype mice during a lipid challenge synergistically enhanced postprandial levels of active GLP-1.In contrast,in a combination study with Orlistat,the ability of PF-04620110 to elicit an enhanced incretin response was abrogated.To further explore this observation,GPR119 knockout mice were evaluated.In response to a lipid challenge,GPR119 knockout mice exhibited no increase in active or total GLP-1 and PYY.However,PF-04620110 was able to increase total GLP-1 and PYY in GPR119 knockout mice as compared to vehicle treated wildtype mice.CONCLUSION Collectively,these data provide some insight into the mechanism by which inhibition of DGAT1 enhances intestinal hormone release.

Prevalence and Associated Factors of Diabetes Mellitus in a Very Elderly Chinese Population: A Cross-sectional Study

Objectives This paper aimed to investigate the prevalence of diabetes mellitus(DM)and explore the associated risk factors in a very elderly southwest Chinese population.Methods From September 2015 to June 2016,a cross-sectional survey was conducted to obtain a representative sample of 1,326 participants over 80 years old living in Chengdu.The presence of DM was based on fasting plasma glucose(FPG)and 2-h plasma glucose(2-h PG)levels during an oral glucose tolerance test(OGTT).A logistic regression model was used to calculate the odds ratios(ORs)and 95%confidence intervals(CIs)of the potential associated factors.Results The participants’mean age was 83.5±3.1 years.The overall prevalence of DM was 27.4%.The prevalence was higher in males(30.2%)than females(24.7%)(P=0.02).The prevalence of DM increased with body mass index(BMI)and decreased with aging.The multivariate analysis suggested that male sex(OR=1.433;95%CI,1.116–1.843),hypertension(OR=1.439;95%CI,1.079–1.936),overweight or obesity(OR=1.371;95%CI,1.023–1.834),high heart rate(≥75 beats/min;OR=1.362;95%CI,1.063–1.746),and abdominal obesity(OR=1.615;95%CI,1.216–2.149)were all significantly positively correlated with DM.However,age was negatively correlated with DM(OR=0.952;95%CI,0.916–0.989).Conclusions The prevalence of DM and newly diagnosed DM in a very elderly southwest Chinese population was high.OGTT screening should be performed regularly in people aged≥80 years to ensure timely diagnosis of DM.

Prevalence and Rates of New Diagnosis and Missed Diagnosis of Diabetes Mellitus among 35-74-year-old Residents in Urban Communities in Southwest China

The high prevalence of diabetes has become a major public health issue worldwide[1], particularly in middle-and low-income countries[2]. The prevalence of diabetes in China, the largest developing country,has more than quadrupled in recent decades, and many cases of diabetes are undiagnosed[3]. The problem with missed diabetes diagnoses is a challenge faced both by China and the rest of the world[4].

Associations between the Serum Zinc Levels and Digestive Tract Tumors:A Meta-Analysis

Background The incidence and mortality rates of digestive tract tumors are among the top ten worldwide.Notably,studies have shown that zinc may be significantly related to digestive tract tumors.This meta analysis was conducted to explore whether the serum zinc level of patients is associated with gastrointestinal cancer.Methods We systematically searched PUBMED,the Cochrane Library,the Web of Science and EMBASE from their start dates up to October 2022 for studies on the association between the serum zinc concentration and digestive tract tumors.The I^(2)statistic was used to assess the heterogeneity.A sensitivity analysis,subgroup analysis and meta-regression analysis were also used to analyze heterogeneity.Moreover,Begg’s and Egger’s tests were adopted to assess potential publication bias.Results In total,we identified 24 eligible studies with 1,499 total participants with digestive tract tumors and 6,039 participants without tumors.The average serum zinc concentration in patients with digestive tract tumors was lower than that in the control group(SMD=-0.98,95%CI:-1.29~-0.66,I^(2):94.1%,P<0.001).Specifically,the serum zinc concentration of patients with esophageal cancer(SMD=-2.08,95%CI:-2.89~-1.26,I^(2):92.9%,P<0.001),gastric cancer(SMD=-0.74,95%CI:-1.16~-0.33,I^(2):92.1%,P<0.001),and colorectal cancer(SMD=-0.85,95%CI:-1.51~-0.19,I^(2):95.9%P<0.05)were significantly different from the controls.Conclusion Our review showed that the serum zinc concentration in patients with digestive tract tumors was lower than that in patients without tumors,and further studies are needed to explore how zinc affects the occurrence and development of digestive tract tumors.

Allele-Specific Effects on Extracellular Superoxide Dismutase Synthesis and Secretion

Plasma extracellular superoxide dismutase (ecSOD) concentrations are significantly (2 - 3-fold) higher in 129 mice than in the C57 strain. We reported earlier that the 129 strain carries a different allele of this enzyme, characterized by two amino acid substitutions and a 10 bp deletion in the 3’UTR of the mRNA. One of the substitutions is at the signal peptide cleavage site (position 21) while the other is within the catalytic site. Since the differences in plasma enzyme concentrations persist in congenic mice expressing the different alleles, the differences in plasma concentrations appear to be largely allele-driven and independent of the remainder of the genome. As expected, in vitro translation using rabbit reticulocyte lysate showed no differences in translational efficiency of transcripts and processing of the newly synthesized enzymes. Determinations of the rates of synthesis and secretion of the two isoforms of this enzyme in stably transfected CHO cells clearly demonstrate that the mature 129 variant is synthesized at rates nearly twice those of the wild-type isoform and has an intracellular pool size twice as large. However, both isoforms are secreted at the same fractional rate and have identical intracellular T1/2 as well as similar extent of degradation. These data explain, at least partially, the higher levels of ecSOD in congenic mice expressing the 129 variant, as well as enzyme levels in the 129 strain of mice. In silico calculations support this conclusion and indicate that the aa change at the signal peptide cleavage site (N21D) results in a substantial increase in cleavage probability at this site for the 129 variant. Our results also highlight the importance of signal peptide cleavage in determining steady-state levels of secretory proteins.

Harnessing interventions during the immediate perioperative period to improve the long-term survival of patients following radical gastrectomy

Although the incidence and mortality of gastric cancer(GC)have been decreasing steadily worldwide,especially in East Asia,the disease burden of this malignancy is still very heavy.Except for tremendous progress in the management of GC by multidisciplinary treatment,surgical excision of the primary tumor is still the cornerstone intervention in the curative-intent treatment of GC.During the relatively short perioperative period,patients undergoing radical gastrectomy will suffer from at least part of the following perioperative events:Surgery,anesthesia,pain,intraoperative blood loss,allogeneic blood transfusion,postoperative complications,and their related anxiety,depression and stress response,which have been shown to affect long-term outcomes.Therefore,in recent years,studies have been carried out to find and test interventions during the perioperative period to improve the long-term survival of patients following radical gastrectomy,which will be the aim of this review.

Nonalcoholic steatohepatitis severity is defined by a failure in compensatory antioxidant capacity in the setting of mitochondrial dysfunction

AIM To comprehensively evaluate mitochondrial(dys) function in preclinical models of nonalcoholic steatohepatitis(NASH).METHODS We utilized two readily available mouse models of nonalcoholic fatty liver disease(NAFLD) with or without progressive fibrosis: Lep^(ob)/Lep^(ob)(ob/ob) and FATZO mice on high trans-fat, high fructose and high cholesterol(AMLN) diet. Presence of NASH was assessed using immunohistochemical and pathological techniques, and gene expression profiling. Morphological features of mitochondria were assessed via transmission electron microscopy and immunofluorescence, and function was assessed by measuring oxidative capacity in primary hepatocytes, and respiratory control and proton leak in isolated mitochondria. Oxidative stress was measured by assessing activity and/or expression levels of Nrf1, Sod1, Sod2, catalase and 8-OHdG. RESULTS When challenged with AMLN diet for 12 wk, ob/ob and FATZO mice developed steatohepatitis in the presence of obesity and hyperinsulinemia. NASH development was associated with hepatic mitochondrial abnormalities, similar to those previously observed in humans, including mitochondrial accumulation and increased proton leak. AMLN diet also resulted in increased numbers of fragmented mitochondria in both strains of mice. Despite similar mitochondrial phenotypes, we found that ob/ob mice developed more advanced hepatic fibrosis. Activity of superoxide dismutase(SOD) was increased in ob/ob AMLN mice, whereas FATZO mice displayed increased catalase activity, irrespective of diet. Furthermore, 8-OHd G, a marker of oxidative DNA damage, was significantly increased in ob/ob AMLN mice compared to FATZO AMLN mice. Therefore, antioxidant capacity reflected as the ratio of catalase:SOD activity was similar between FATZO and C57 BL6 J control mice, but significantly perturbed in ob/ob mice. CONCLUSION Oxidative stress, and/or the capacity to compensate for increased oxidative stress, in the setting of mitochondrial dysfunction, is a key factor for development of hepatic injury and fibrosis in these mouse models.

Mitochondria as therapeutic targets for cancer stem cells

Cancer stem cells(CSCs) are maintained by theirsomatic stem cells and are responsible for tumor initiation, chemoresistance, and metastasis. Evidence for the CSCs existence has been reported for a number of human cancers. The CSC mitochondria have been shown recently to be an important target for cancer treatment, but clinical significance of CSCs and their mitochondria properties remain unclear. Mitochondriatargeted agents are considerably more effective compared to other agents in triggering apoptosis of CSCs, as well as general cancer cells, via mitochondrial dysfunction. Mitochondrial metabolism is altered in cancer cells because of their reliance on glycolytic intermediates, which are normally destined for oxidative phosphorylation. Therefore, inhibiting cancer-specific modifications in mitochondrial metabolism, increasing reactive oxygen species production, or stimulating mitochondrial permeabilization transition could be promising new therapeutic strategies to activate cell death in CSCs as well, as in general cancer cells. This review analyzed mitochondrial function and its potential as a therapeutic target to induce cell death in CSCs. Furthermore, combined treatment with mitochondriatargeted drugs will be a promising strategy for the treatment of relapsed and refractory cancer.

Micro RNAs in the development of non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease or nonalcoholic fatty liver disease(NAFLD) refers to a group of disorders that arise from the accrual of fat in hepatocytes. Although various factors have been associated with the development of NAFLD, including genetic predisposition and environmental exposures, little is known aboutthe underlying pathogenesis of the disease. Research efforts are ongoing to identify biological targets and signaling pathways that mediate NAFLD. Emerging evidence has implicated a role for micro RNAs(mi RNAs), short single-stranded molecules that regulate gene expression either transcriptionally, through targeting of promoter regions, or post-transcriptionally, by blocking translation or promoting cleavage of specific target m RNAs. Several mi RNAs have been associated with NAFLD, although our understanding of the biology underlying their role is still emerging. The goal of this review is to present an overview of the current state of knowledge of mi RNAs involved in the development of NAFLD across a range of in vitro and in vivo models, including mi RNAs that contribute to pathological mechanisms related to fatty liver in humans. Much less is known about the specific targets of mi RNAs in cells, nor the molecular mechanisms involved in the development and progression NAFLD and related outcomes. More recently, the identification and validation of mi RNA signatures in serum may facilitate the development of improved methods for diagnosis and clinical monitoring of disease progression.

Regenerative potential of mouse embryonic stem cell-derived PDGFRα+ cardiac lineage committed cells in infarcted myocardium

BACKGROUND Pluripotent stem cell-derived cardiomyocytes(CMs) have become one of the most attractive cellular resources for cell-based therapy to rescue damaged cardiac tissue.AIM We investigated the regenerative potential of mouse embryonic stem cell(ESC)-derived platelet-derived growth factor receptor-α(PDGFRα)+ cardiac lineagecommitted cells(CLCs), which have a proliferative capacity but are in a morphologically and functionally immature state compared with differentiated CMs.METHODSWe induced mouse ESCs into PDGFRα+ CLCs and αMHC+ CMs using a combination of the small molecule cyclosporin A, the rho-associated coiled-coil kinase inhibitor Y27632, the antioxidant Trolox, and the ALK5 inhibitor EW7197.We implanted PDGFRα+ CLCs and differentiated αMHC+ CMs into a myocardial infarction(MI) murine model and performed functional analysis using transthoracic echocardiography(TTE) and histologic analysis.RESULTS Compared with the untreated MI hearts, the anterior and septal regional wall motion and systolic functional parameters were notably and similarly improved in the MI hearts implanted with PDGFRα+ CLCs and αMHC+ CMs based on TTE.In histologic analysis, the untreated MI hearts contained a thinner ventricular wall than did the controls, while the ventricular walls of MI hearts implanted with PDGFRα+ CLCs and αMHC+ CMs were similarly thicker compared with that of the untreated MI hearts. Furthermore, implanted PDGFRα+ CLCs aligned and integrated with host CMs and were mostly differentiated into α-actinin+ CMs,and they did not convert into CD31+ endothelial cells or αSMA+ mural cells.CONCLUSION PDGFRα+ CLCs from mouse ESCs exhibiting proliferative capacity showed a regenerative effect in infarcted myocardium. Therefore, mouse ESC-derived PDGFRα+ CLCs may represent a potential cellular resource for cardiac regeneration.

Low Shear Stress Induces Inflammatory Response via CX3CR1/NF-κB Signal Pathway in Human Umbilical Vein Endothelial Cells

Background Cardiovascular disease has become a major cause of death worldwide.Atherosclerosis is the pathological basis of many cardiovascular diseases.It is well established that hemodynamics also play an important role in endothelial cell mediated atherosclerotic development.In the process of inflammatory reaction,the damage of vascular endothelial cells is the initial link,and various factors can cause damage of endothelial cells.The change of shear stress is considered to be one of the important factors.In the body,vascular endothelial cells are constantly exposed to blood flow.Flow conditions critically regulate endothelial cell functions in the vasculature.Shear stress not only influences the endothelial cell morphology,migration,differentiation and proliferation,but also regulates the expression of proteins in the endothelial cells.Reduced shear stress resulting from disturbed blood flow can drive the development of vascular inflammatory lesions and promote the formation of atherosclerosis.In the present study,the objective of our study is the comprehensive identification of CX3CR1/NF-κB signaling pathway involved in low shear stress(LSS)-induced inflammation in HUVECs through protein profiling and cell function experiment.Methods Human umbilical vein endothelial cell was cultured onglass slides and placed in a parallel plate flow chamber.M199 culture medium was used for low laminar shear stress at 4.14 dyn/cm2,2 h for the testing group,CX3CR1 sh-RNA and NF-κB inhibitor PDTC are used to block the effects of CX3CR1 and P65.The expression levels of the protein were determined by western blot analysis.Mononuclear cell adhesion assays and scratch assays are used to detect cell adhesion and migration.Results Western blotting analyses revealed that compared with the controls,there is a significant increase in the expression of CX3CR1,nucleusP65,intercellular adhesion molecule-1(ICAM-1),vascular cell adhesion molecule-1(VCAM-1)and Interleukin-6(IL-6),while the expression of cytosolic P65 and IκB was significantly reduced in human umbilical vein endothelial cells(HUVECs)treated with LSS.CX3CR1 Sh-RNA was use to reveal its effect on LSS-induced inflammation.Further,specific NF-κB P65 inhibitors(PDTC)were used to reveal the downstream NF-κB P65 exclusively involved in LSS-induced inflammation in HUVECs,this effect can be abrogated by CX3CR1 sh-RNA and NF-κB inhibitors.Monocyte adhesion assay and scratch test revealed LSS promotes adhesion of monocytes and migration of cells,this effect can be abrogated by CX3CR1 sh-RNA and NF-κB inhibitors.LSS is involved in the expression of adhesion moleculesand chemokines,which are important for the initiation of endothelial inflammation-related atherosclerosis.Conclusions The activation of CX3CR1/NF-κB signaling pathway induced by low shear stress in endothelial cells may lead to the future therapeutic targets of atherosclerotic inflammation.

真实世界中SGLT2抑制剂与肾脏结局临床实践的观察性数据提示相比于DPP4抑制剂,SGLT2抑制剂更受青睐

慢性肾脏疾病在全世界范围内正影响着7亿人,每年因慢性肾脏疾病造成的死亡占到死亡总数的二十分之一。在全球范围内,由慢性肾脏疾病导致的年龄标准化病死率在过去10年中几乎没有变化,相比之下,其他大多数非传染性慢性疾病的病死率均有所下降2。这个看似棘手的问题很大程度上是由糖尿病引起的幕因此,当公布的临床试验结果提示钠-葡萄糖共同转运蛋白2(SGLT2)抑制剂类降糖药物对主要肾脏不良结局有一致性的获益之后.其受到广泛关注也就不足为奇了。