Macrophage modulation with dipeptidyl peptidase-4 inhibitors:A new frontier for treating diabetic cardiomyopathy?

This editorial introduces the potential of targeting macrophage function for diabetic cardiomyopathy(DCM)treatment by dipeptidyl peptidase-4(DPP-4)inhibitors.Zhang et al studied teneligliptin,a DPP-4 inhibitor used for diabetes management,and its potential cardioprotective effects in a diabetic mouse model.They suggested teneligliptin administration may reverse established markers of DCM,including cardiac hypertrophy and compromised function.It also inhibited the NLRP3 inflammasome and reduced inflammatory cytokine production in diabetic mice.Macrophages play crucial roles in DCM pathogenesis.Chronic hyperglycemia disturbs the balance between pro-inflammatory(M1)and antiinflammatory(M2)macrophages,favoring a pro-inflammatory state contributing to heart damage.Here,we highlight the potential of DPP-4 inhibitors to modulate macrophage function and promote an anti-inflammatory environment.These compounds may achieve this by elevating glucagon-like peptide-1 levels and potentially inhibiting the NLRP3 inflammasome.Further studies on teneligliptin in combination with other therapies targeting different aspects of DCM could be suggested for developing more effective treatment strategies to improve cardiovascular health in diabetic patients.

Dipeptidyl peptidase-4 inhibitor for steroid-induced diabetes

The addition of the dipeptidyl peptidase-4 (DDP-4) inhibitor has been reported to achieve greater improvements in glucose metabolism with fewer adverse events compared to increasing the metformin dose in type 2 diabetic patients. We present a patient with steroid-induced diabetes whose blood glucose levels were ameliorated by the use of the DPP-4 inhibitor, showing that the DPP-4 inhibitors may be an effective and safe oral anti-diabetic drug for steroid-induced diabetes.

Cardiovascular efficacy and safety of dipeptidyl peptidase-4 inhibitors:A meta-analysis of cardiovascular outcome trials

BACKGROUND Dipeptidyl peptidase-4(DPP-4)inhibitors are a generally safe and well tolerated antidiabetic drug class with proven efficacy in type 2 diabetes mellitus(T2DM).Recently,a series of large,randomized controlled trials(RCTs)addressing cardiovascular outcomes with DPP-4 inhibitors have been published.AIM To pool data from the aforementioned trials concerning the impact of DPP-4 inhibitors on surrogate cardiovascular efficacy outcomes and on major cardiac arrhythmias.METHODS We searched PubMed and grey literature sources for all published RCTs assessing cardiovascular outcomes with DPP-4 inhibitors compared to placebo until October 2020.We extracted data concerning the following“hard”efficacy outcomes:fatal and non-fatal myocardial infarction,fatal and non-fatal stroke,hospitalization for heart failure,hospitalization for unstable angina,hospitalization for coronary revascularization and cardiovascular death.We also extracted data regarding the risk for major cardiac arrhythmias,such as atrial fibrillation,atrial flutter,ventricular fibrillation and ventricular tachycardia.RESULTS We pooled data from 6 trials in a total of 52520 patients with T2DM assigned either to DPP-4 inhibitor or placebo.DPP-4 inhibitors compared to placebo led to a non-significant increase in the risk for fatal and non-fatal myocardial infarction[risk ratio(RR)=1.02,95%CI:0.94-1.11,I2=0%],hospitalization for heart failure(RR=1.09,95%CI:0.92-1.29,I2=65%)and cardiovascular death(RR=1.02,95%CI:0.93-1.11,I2=0%).DPP-4 inhibitors resulted in a non-significant decrease in the risk for fatal and non-fatal stroke(RR=0.96,95%CI:0.85-1.08,I2=0%)and coronary revascularization(RR=0.99,95%CI:0.90-1.09,I2=0%),Finally,DPP-4 inhibitors demonstrated a neutral effect on the risk for hospitalization due to unstable angina(RR=1.00,95%CI:0.85-1.18,I2=0%).As far as cardiac arrhythmias are concerned,DPP-4 inhibitors did not significantly affect the risk for atrial fibrillation(RR=0.95,95%CI:0.78-1.17,I2=0%),while they were associated with a significant increase in the risk for atrial flutter,equal to 52%(RR=1.52,95%CI:1.03-2.24,I2=0%).DPP-4 inhibitors did not have a significant impact on the risk for any of the rest assessed cardiac arrhythmias.CONCLUSION DPP-4 inhibitors do not seem to confer any significant cardiovascular benefit for patients with T2DM,while they do not seem to be associated with a significant risk for any major cardiac arrhythmias,except for atrial flutter.Therefore,this drug class should not be the treatment of choice for patients with established cardiovascular disease or multiple risk factors,except for those cases when newer antidiabetics(glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors)are not tolerated,contraindicated or not affordable for the patient.

Review on the Effect of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors for the Treatment of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease（NAFLD） is a common liver disease and it represents the hepatic manifestation of metabolic syndrome, which includes type 2 diabetes mellitus（T2DM）, dyslipidemia, central obesity and hypertension. Glucagon-like peptide-1（GLP-1） analogues and dipeptidyl peptidase-4（DPP-4） inhibitors were widely used to treat T2 DM. These agents improve glycemic control, promote weight loss and improve lipid metabolism. Recent studies have demonstrated that the GLP-1 receptor（GLP-1R） is present and functional in human and rat hepatocytes. In this review, we present data from animal researches and human clinical studies that showed GLP-1 analogues and DPP-4 inhibitors can decrease hepatic triglyceride（TG） content and improve hepatic steatosis, although some effects could be a result of improvements in metabolic parameters. Multiple hepatocyte signal transduction pathways and m RNA from key enzymes in fatty acid metabolism appear to be activated by GLP-1 and its analogues. Thus, the data support the need for more rigorous prospective clinical trials to further investigate the potential of incretin therapies to treat patients with NAFLD.

Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases:Current evidence

Dipeptidyl peptidase-4 inhibitors(DPP-4i)have an important place in the management of type 2 diabetes.The DPP-4 enzyme is ubiquitously distributed throughout the human body and has multiple substrates through which it regulates several important physiological functions.DPP-4 regulates several immune functions,including T-cell activation,macrophage function,and secretion of cytokines.Studies have reported an increase in autoimmune diseases like bullous pemphigoid,inflammatory bowel disease,and arthritis with DPP-4i use.The relationship of DPP-4i and autoimmune diseases is a complex one and warrants further research into the effect of DPP-4 inhibition on the immune system to understand the pathogenesis more clearly.Whether a particular cluster of autoimmune diseases is associated with DPP-4i use remains an important contentious issue.Nevertheless,a heightened awareness from the clinicians is required to identify and treat any such diseases.Through this review,we explore the clinical and pathophysiological characteristics of this association in light of recent evidence.

Risk of pancreatic adverse events associated with the use of glucagon-like peptide-1 receptor agonist and dipeptidyl peptidase-4 inhibitor drugs: A systematic review and metaanalysis of randomized trials

AIM: To systematically assess risk of pancreatic adverse events with glucagon-like peptide-1(GLP-1) receptor agonist and dipeptidyl peptidase-4(DPP-4) inhibitor drugs.METHODS: We searched Pub Med, Embase, CINAHL, Cochrane review of clinical trials, pharmaceutical company clinical trials register, United States Food and Drug Administration website, European Medicines Agency website and Clinical Trials.gov for randomized controlled trials from inception to October 2013. Randomized control trial studies were selected for inclusion if they reported on pancreatic complication events and/or changes in pancreatic enzyme levels(serum amylase and serum lipase) as adverse events or as serious adverse events for patients who were on GLP-1 receptor agonist and DPP-4 inhibitor drugs. Two independent reviewers extracted data directly. We performed Peto odds ratio(OR) fixed effect meta-analysis of pancreatic adverse events a, and assessed heterogeneity with the I^2 statistic.RESULTS: Sixty-eight randomized controlled trials were eligible. A total of 60720 patients were included in our analysis of the association of risk of pancreatic complication events with GLP-1 agents. A total of 89 pancreatic related adverse events occurred among the GLP-1 agents compared to 74 events among the controls. There was a statistically significant increased risk of elevation of pancreatic enzymes associated with GLP-1 agents compared with control(Peto OR = 3.15, 95%CI: 1.56-6.39, P = 0.001, I2 = 0%). There was no statistically significant difference in the risk of pancreatic adverse event associated with GLP-1 agent compared with controls(Peto OR = 1.00, 95%CI: 0.73-1.37, P = 1.00, I2 = 0%). There were a total of 71 pancreatitis events in patients on GLP-1 agents and 56 pancreatitis events occurred in the control patients. There were 36 reports of pancreatic cancer in these studies. Of these cases, 2 used linagliptin, 2 used alogliptin, 1 used vildagliptin, 7 used saxagliptin while 6 used sitagliptin. The remaining 18 cases occurred among controls.CONCLUSION: Although GLP-1 based agents are associated with pancreatic enzyme elevation, we were unable to confirm a significant risk of pancreatitis or pancreatic cancer.

Neuroprotection by dipeptidyl-peptidase-4 inhibitors and glucagonlike peptide-1 analogs via the modulation of AKT-signaling pathway in Alzheimer’s disease

Alzheimer’s disease(AD)is the most common reason for progressive dementia in the elderly.It has been shown that disorders of the mammalian/mechanistic target of rapamycin(mTOR)signaling pathways are related to the AD.On the other hand,diabetes mellitus(DM)is a risk factor for the cognitive dysfunction.The pathogenesis of the neuronal impairment caused by diabetic hyperglycemia is intricate,which contains neuro-inflammation and/or neurodegeneration and dementia.Glucagon-like peptide-1(GLP1)is interesting as a possible link between metabolism and brain impairment.Modulation of GLP1 activity can influence amyloid-beta peptide aggregation via the phosphoinositide-3 kinase/AKT/mTOR signaling pathway in AD.The GLP1 receptor agonists have been shown to have favorable actions on the brain such as the improvement of neurological deficit.They might also exert a beneficial effect with refining learning and memory on the cognitive impairment induced by diabetes.Recent experimental and clinical evidence indicates that dipeptidyl-peptidase-4(DPP4)inhibitors,being currently used for DM therapy,may also be effective for AD treatment.The DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models.Although further studies for mTOR,GLP1,and DPP4 signaling pathways in humans would be intensively required,they seem to be a promising approach for innovative AD-treatments.We would like to review the characteristics of AD pathogenesis,the key roles of mTOR in AD and the preventive and/or therapeutic suggestions of directing the mTOR signaling pathway.

Diabetes therapies in hemodialysis patients: Dipeptidase-4 inhibitors

Although several previous studies have been published on the effects of dipeptidase-4(DPP-4) inhibitors in diabetic hemodialysis(HD) patients, the findings have yet to be reviewed comprehensively. Eyesight failure caused by diabetic retinopathy and aging-related dementia make multiple daily insulin injections difficult for HD patients. Therefore, we reviewed the effects of DPP-4 inhibitors with a focus on oral antidiabetic drugs as a new treatment strategy in HD patients with diabetes. The following 7 DPP-4 inhibitors are available worldwide: sitagliptin, vildagliptin, alogliptin, linagliptin, teneligliptin, anagliptin, and saxagliptin. All of these are administered once daily with dose adjustments in HD patients. Four types of oral antidiabetic drugs can be administered for combination oral therapy with DPP-4 inhibitors, including sulfonylureas, meglitinide, thiazolidinediones, and alpha-glucosidase inhibitor. Nine studies examined the antidiabetic effects in HD patients. Treatments decreased hemoglobin A1 c and glycated albumin levels by 0.3% to 1.3% and 1.7% to 4.9%, respectively. The efficacy of DPP-4 inhibitor treatment is high among HD patients, and no patients exhibited significant severe adverse effects such as hypoglycemia and liver dysfunction. DPP-4 inhibitors are key drugs in new treatment strategies for HD patients with diabetes and with limited choices for diabetes treatment.

Association between plasma dipeptidyl peptidase-4 levels and cognitive function in perinatal pregnant women with gestational diabetes mellitus

BACKGROUND Dipeptidyl peptidase-4(DPP4)is associated with cognitive dysfunction in patients with type 2 diabetes.AIM To assess a possible relationship between serum DPP4 and cognitive function in perinatal pregnant women with gestational diabetes mellitus(GDM).METHODS The study subjects were divided into three groups:GDM group(n=81),healthy pregnant(HP)group(n=85),and control group(n=51).The Montreal Cognitive Assessment(MoCA)was used to assess the cognitive status of each group.Venous blood samples were collected to measure blood lipids,glycated hemoglobin,and glucose levels.For each participant,a 3-mL blood sample was collected and centrifuged,and the serum was collected.Blood samples were stored at-80℃,and DPP4,interleukin-6(IL-6),and 8-iso-prostaglandin F2α(8-iso-PGF2α),and brain-derived neurotrophic factor(BDNF)were detected using ELISA.RESULTS The MoCA scores in the GDM and HP groups were significantly different from those in the control group in terms of visuospatial/executive function and attention(P<0.05);however,the scores were not significantly different between the GDM and HP groups(P>0.05).In terms of language,the GDM group had significantly different scores from those in the other two groups(P<0.05).In terms of memory,a significant difference was found between the HP and control groups(P<0.05),as well as between the GDM and HP groups.The levels of DPP4,IL-6,and 8-iso-PGF2αin the GDM group were significantly higher than those in the HP and control groups(P<0.05);however,the differences between these levels in the HP and control groups were not significant(P>0.05).The level of BDNF in the GDM group was significantly lower than that in the HP and control groups(P<0.05),although the difference in this level between the HP and control groups was not significant(P>0.05).CONCLUSION Cognitive dysfunction in perinatal pregnant women with GDM mainly manifested as memory loss,which might be associated with elevated DPP4 levels.

Efficacy of omarigliptin,once-weekly dipeptidyl peptidase-4 inhibitor,in patients with type 2 diabetes

BACKGROUND Omarigliptin is one of several once-weekly dipeptidyl peptidase-4 inhibitors(DPP-4is).Despite the high frequency of switching from various daily DPP-4is to omarigliptin in actual clinical practice,data regarding its efficacy in patients with type 2 diabetes(T2D)after switching are limited.AIM To analyze the efficacy of omarigliptin in Japanese patients with T2D who had previously received treatment with other glucose-lowering agents.METHODS Forty-nine T2D patients treated for the first time with omarigliptin were recruited retrospectively and divided into four groups defined as either add-on or switched from daily DPP-4is:switched from linagliptin,switched from sitagliptin,and switched from vildagliptin.During a 3-mo follow-up,the clinical parameters among these groups were assessed and compared,with the impact of the switch on glycemic variability as measured by continuous glucose monitoring also being evaluated in the switched groups.RESULTS Hemoglobin A1c levels saw a significant decrease of-0.32%±0.41%in the add-on group(P=0.002).However,the other groups’variables depended on the preswitch daily DPP-4i:switched from linagliptin,-0.05%±0.22%;switched from sitagliptin,-0.17%±0.33%;and switched from vildagliptin,0.45%±0.42%,which saw significant worsening(P=0.0007).Multivariate logistic regression analysis revealed that switching from vildagliptin to omarigliptin was independently associated with worsening glycemic control(P=0.0013).The mean and standard deviation of sensor glucose value,the mean amplitude of glycemic excursions,and the mean of daily difference significantly improved when switching the patient from either linagliptin or sitagliptin to omarigliptin.However,in patients switched from vildagliptin,not only did the glucose variability indices see no improvements,the mean of daily difference even underwent significant worsening.CONCLUSION Administering omarigliptin as add-on therapy or switching to it from sitagliptin and linagliptin,but not vildagliptin,improves glycemic control and thus should help in decision making when selecting DPP-4is for T2D patients.

Peroxisome proliferator-activated receptor-alpha activation and dipeptidyl peptidase-4 inhibition target dysbiosis to treat fatty liver in obese mice

BACKGROUND Obesity and comorbidities onset encompass gut dysbiosis,altered intestinal permeability,and endotoxemia.Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease(NAFLD)management.Peroxisome proliferator-activated receptor(PPAR)-alpha activation and dipeptidyl-peptidase-4(DPP-4)inhibition alleviate NAFLD,but the mechanism may involve gut microbiota modulation and merits further investigation.AIM To address the effects of PPAR-alpha activation and DPP-4 inhibition(isolated or combined)upon the gut-liver axis,emphasizing inflammatory pathways in NAFLD management in high-fat-fed C57BL/6J mice.METHODS Male C57BL/6J mice were fed a control diet(C,10%of energy as lipids)or a highfat diet(HFD,50%of energy as lipids)for 12 wk,when treatments started,forming the groups:C,HF,HFA(HFD+PPAR-alpha agonist WY14643,2.5 mg/kg body mass),HFL(HFD+DPP-4 inhibitor linagliptin,15 mg/kg body mass),and HFC(HFD+the combination of WY14643 and linagliptin).RESULTS The HFD was obesogenic compared to the C diet.All treatments elicited significant body mass loss,and the HFC group showed similar body mass to the C group.All treatments tackled oral glucose intolerance and raised plasma glucagon-like peptide-1 concentrations.These metabolic benefits restored Bacteroidetes/Firmicutes ratio,resulting in increased goblet cells per area of the large intestine and reduced lipopolysaccharides concentrations in treated groups.At the gene level,treated groups showed higher intestinal Mucin 2,Occludin,and Zo-1 expression than the HFD group.The reduced endotoxemia suppressed inflammasome and macrophage gene expression in the liver of treated animals.These observations complied with the mitigation of liver steatosis and reduced hepatic triacylglycerol,reassuring the role of the proposed treatments on NAFLD mitigation.CONCLUSION PPAR alpha activation and DPP-4 inhibition(isolated or combined)tackled NAFLD in dietinduced obese mice by restoration of gut-liver axis.The reestablishment of the intestinal barrier and the rescued phylogenetic gut bacteria distribution mitigated liver steatosis through antiinflammatory signals.These results can cope with NAFLD management by providing pre-clinical evidence that drugs used to treat obesity comorbidities can help to alleviate this silent and harmful liver disease.

Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 agonists as potential neuroprotective agents

Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists is a breakthrough in the field of neural regeneration research increasing glucagon like peptide-1 bioavailability, hence its neuroprotective activities. In this article, the authors suggest not only crossing blood-brain barrier and neurodegenerative disease as off target for dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists, but also for ophthalmic preparations for diabetic retinopathy, which may be the latest breakthrough in the field if prepared and used in an appropriate nano-formulation to target the retinal nerves. The relation of neurodegenerative diseases' different mechanisms to the dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists should be further examined in preclinical and clinical settings. The repositioning of already marketed antidiabetic drugs for neurodegenerative diseases should save the high cost of the time-consuming normal drug development process. Drug repositioning is a hot topic as an alternative to molecular target based drug discovery or therapeutic switching. It is a relatively inexpensive pathway due to availability of previous pharmacological and safety data. The glucagon like peptide-1 produced in brain has been linked to enhanced learning and memory functions as a physiologic regulator in central nervous system by restoring insulin signaling. Intranasal administration of all marketed gliptins(or glucagon like peptide-1 receptor agonists) may show enhanced blood-brain barrier crossing and increased glucagon like peptide-1 levels in the brain after direct crossing of the drug for the olfactory region, targeting the cerebrospinal fluid. Further blood-brain barrier crossing tests may extend dipeptidyl peptidase-4 inhibitors' effects beyond the anti-hyperglycemic control to intranasal spray, intranasal powder, or drops targeting the blood-brain barrier and neurodegenerative diseases with the most suitable formula. Moreover, novel nano-formulation is encouraged either to obtain favorable pharmacokinetic parameters or to achieve promising blood-brain barrier penetration directly through the olfactory region. Many surfactants should be investigated either as a solubilizing agent for hydrophobic drugs or as penetration enhancers. Different formulae based on in vitro and in vivo characterizations, working on sister gliptins(or glucagon like peptide-1 receptor agonists), different routes of administration, pharmacokinetic studies, dose response relationship studies, monitoring of plasma/brain concentration ratio after single and multiple dose, and neurodegenerative disease animal models are required to prove the new method of use(utility) for dipeptidyl peptidase-4 inhibitors as potential neuroprotective agents. Furthermore, investigations of glucagon like peptide-1 receptor agonists' neuroprotective effects on animal models will be considered carefully because they crossed the blood-brain barrier in previous studies, enabling their direct action on the central nervous system. Combination therapy of dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists with already marketed drugs for neurodegenerative disease should be considered, especially regarding the novel intranasal route of administration.

No significant association between dipeptidyl peptidase-4 inhibitors and adverse outcomes of COVID-19

BACKGROUND Dipeptidyl peptidase-4(DPP4)is commonly targeted to achieve glycemic control and has potent anti-inflammatory and immunoregulatory effects.Recent structural analyses indicated a potential tight interaction between DPP4 and severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),raising a promising hypothesis that DPP4 inhibitor(DPP4i)drugs might be an optimal strategy for treating coronavirus disease 2019(COVID-19)among patients with diabetes.However,there has been no direct clinical evidence illuminating the associations between DPP4i use and COVID-19 outcomes.AIM To illuminate the associations between DPP4i usage and the adverse outcomes of COVID-19.METHODS We conducted a multicenter,retrospective analysis including 2563 patients with type 2 diabetes who were hospitalized due to COVID-19 at 16 hospitals in Hubei Province,China.After excluding ineligible individuals,142 patients who received DPP4i drugs and 1115 patients who received non-DPP4i oral anti-diabetic drugs were included in the subsequent analysis.We performed a strict propensity score matching(PSM)analysis where age,sex,comorbidities,number of oral hypoglycemic agents,heart rate,blood pressure,pulse oxygen saturation(SpO2)<95%,CT diagnosed bilateral lung lesions,laboratory indicators,and proportion of insulin usage were matched.Finally,111 participants treated with DPP4i drugs were successfully matched to 333 non-DPP4i users.Then,a linear logistic model and mixed-effect Cox model were applied to analyze the associations between inhospital DPP4i use and adverse outcomes of COVID-19.RESULTS After rigorous matching and further adjustments for imbalanced variables in the linear logistic model and Cox adjusted model,we found that there was no significant association between in-hospital DPP4i use(DPP4i group)and 28-d allcause mortality(adjusted hazard ratio=0.44,95%CI:0.09-2.11,P=0.31).Likewise,the incidences and risks of secondary outcomes,including septic shock,acute respiratory distress syndrome,or acute organ(kidney,liver,and cardiac)injuries,were also comparable between the DPP4i and non-DPP4i groups.The performance of DPP4i agents in achieving glucose control(e.g.,the median level of fasting blood glucose and random blood glucose)and inflammatory regulation was approximately equivalent in the DPP4i and non-DPP4i groups.Furthermore,we did not observe substantial side effects such as uncontrolled glycemia or acidosis due to DPP4i application relative to the use of non-DPP4i agents in the study cohort.CONCLUSION Our findings demonstrated that DPP4i use is not significantly associated with poor outcomes of COVID-19 or other adverse effects of anti-diabetic treatment.The data support the continuation of DPP4i agents for diabetes management in the setting of COVID-19.

Dipeptidyl Peptidase-4 Inhibitors and Inflammation: Dpp-4 Inhibitors Improve Mean Pleatelet Volume and Gamma Glutamyl Transferase Level

AIM: The purpose of this research was to determine the changes of the inflammatory parameters in the long term with the use of dipeptidyl peptidase-4 inhibitors. Material and Methods: In this research we have retrospectively reviewed the records of 80 patients who had added dipeptidyl peptidase-4 inhibitors (40 sitagliptin and 40 vildagliptin) to their ongoing therapies. Patients’ values of inflammation at the beginning of this process were taken as initial values, while values at the end of this process were considered as final values. Results: A total of 80 patients [38.8% (n = 31) of the patients were male, while 61.3% (n = 49) were female] enrolled in the study. When the whole group was evaluated, the mean age was 56.1 ± 9.7 years. The median follow-up time of the patients with DPP-4 inhibitors was 18 (2 - 64) months. The mean MPV value was measured as 8.79 ± 1.71 fL before DPP-4 inhibitors and it was 10.06 ± 1.42 fL after the follow-up period (p < 0.001). The median value serum GGT was 30.5 (13 - 194) U/L before DPP-4 inhibitor and 29.5 (12 - 112) U/L at the end (p = 0.048). The mean uric acid level before the use of di-peptidyl peptidase-4 inhibitors was 4.7 ± 1.6 mg/dL, and this level was 5.0 ± 1.5 mg/dL after the follow-up period (p = 0.048). Conclusion: In this study, it was observed that MPV and GGT levels were improved by dipeptidyl peptidase-4 inhibitors in long-term.

血管生成素样蛋白4通过调节成纤维细胞和内皮细胞功能影响糖尿病足进程

背景:研究表明,血管因素对糖尿病足的发生具有重要影响。目的:探讨血管生成素样蛋白4在糖尿病足形成中的重要作用。方法:①对糖尿病足患者的基因表达谱数据进行生物信息学分析,找到关键基因。收集糖尿病足患者以及无糖尿病健康人的皮肤标本进行苏木精-伊红染色、免疫组化染色以及qRT-PCR实验,检测血管生成素样蛋白4表达情况。②培养人永生化皮肤成纤维细胞系和原代人脐静脉内皮细胞,将2种细胞分别分为对照组和外源性补充血管生成素样蛋白4组,通过划痕实验以及CCK-8实验分别检测成纤维细胞的迁移能力和增殖能力,通过Ki67实验检测内皮细胞的增殖能力。结果与结论:①生信分析发现,血管生成素样蛋白4基因的下调可能是导致糖尿病足形成的关键基因。②苏木精-伊红染色结果显示,与正常皮肤相比,血管生成素样蛋白在糖尿病足皮肤内弱表达,且其mRNA水平相对表达量降低(P<0.01)。③划痕实验结果显示,与对照组相比,血管生成素样蛋白4组成纤维细胞迁移能力明显增强;CCK-8细胞增殖实验显示,血管生成素样蛋白4组成纤维细胞的吸光度值在24,48 h均高于对照组(P<0.01,P<0.001);提示血管生成素样蛋白4可增强高糖处理的成纤维细胞迁移及增殖能力。④Ki67实验结果显示,与对照组相比,血管生成素样蛋白4组内皮细胞Ki67阳性细胞数目明显多于对照组;CCK-8细胞增殖实验显示,血管生成素样蛋白4组内皮细胞的吸光度值在24,48 h均高于对照组(P<0.05,P<0.001)。(5)以上结果均提示血管生成素样蛋白4可增强高糖处理内皮细胞的增殖能力。

六方Al_(4)SiC_(4)弹性性质、电子结构和光学性质的第一性原理计算

采用基于密度泛函理论(DFT)的第一性原理计算方法系统地研究了Al_(4)SiC_(4)的晶体结构、弹性常数、电子结构和光学性质,并对结果进行了理论分析.计算得到的晶格常数和弹性常数均与实验值及其它计算值相符,并说明了六方Al_(4)SiC_(4)的晶体结构是稳定的;计算得到了六方Al_(4)SiC_(4)的体积、剪切、杨氏模量及泊松比与文献值一致,Al_(4)SiC_(4)的禁带宽度为1.076 eV.计算得到了六方Al_(4)SiC_(4)在(100)和(001)方向上的光学响应函数随光子能量的变化关系,包括复介电函数、复折射率、吸收光谱及反射光谱.在(100)和(001)方向上,计算得到其静态介电常数分别为7.74和8.96,折射率分别为2.78和2.99.计算结果可以为相关应用提供理论依据.

单轴应变对本征和N掺杂4H-SiC电子结构的影响

采用基于密度泛函理论的第一性原理方法,研究了单轴应变对本征和N掺杂4H-SiC电子结构的影响.研究表明应变可以有效调控本征和N掺杂4H-SiC的带隙,在拉应变作用下,带隙单调减小;而在压应变作用下,带隙先增大后减小,当压应变为-1%时,带隙达到最大值.对态密度的分析可知本征和N掺杂4H-SiC的价带顶主要来自Si 3p和C 2p态电子,导带底主要来自Si 3p态电子,C 2p态和Si 3p态通过影响价带顶和导带底从而导致应变结构中带隙发生变化.通过Mulliken布局和差分电荷密度分析可知,随着晶格常数的增加Si原子向C原子和N原子转移的电荷减少,同时Si-C原子和Si-N原子之间的共价性减弱.

ACSL4介导铁死亡及在动脉粥样硬化性心血管病中的潜在作用

背景:铁死亡是一种铁依赖性调节细胞死亡形式,其特征是铁依赖性脂质过氧化,长链酰基辅酶A合酶4参与脂质过氧化底物的形成进而导致铁死亡。近几年研究表明,长链酰基辅酶A合酶4介导铁死亡在动脉粥样硬化性心血管疾病中发挥关键作用。目的:总结长链酰基辅酶A合酶4的结构功能和调控机制及其介导铁死亡的潜在分子机制,阐述长链酰基辅酶A合酶4驱动铁死亡在动脉粥样硬化、缺血性脑卒中和心肌梗死中的应用,以期为治疗动脉粥样硬化心血管疾病提供新的治疗策略。方法:在PubMed数据库检索自建库起至2023年8月收录的相关文献,以“atherosclerosis,ferroptosis,long-chain acyl-coenzyme A synthase 4,ACSL4,glutathione peroxidase 4,ischemic stroke,myocardial infarction,endothelial cell,smooth muscle cells,foam cell”为检索词,最终纳入76篇文献进行综述分析。结果与结论:①长链酰基辅酶A合酶4参与形成多不饱和脂肪酸的辅酶衍生物并将其插入磷脂,为铁死亡发生的核心机制脂质过氧化提供底物;②在长链酰基辅酶A合酶4表达的调节因子中,整合素α6β4、细胞内囊泡转运因子p115、锌脂蛋白A20负调控其表达,同时多种miR通过结合3′-UTR下调其表达,相反长链酰基辅酶A合酶4的表达上调大部分通过转录因子转录调控;③长链酰基辅酶A合酶4依赖性生成含有多不饱和脂肪酸的磷脂是脂质过氧化并执行铁死亡必不可少的必要条件,且长链酰基辅酶A合酶4与谷胱甘肽过氧化酶4作为铁死亡的正负调控因子相互制约,其具体机制仍待进一步研究;④长链酰基辅酶A合酶4介导铁死亡参与动脉粥样硬化、心肌梗死、缺血性脑卒中的病理机制,动脉粥样硬化中内皮细胞损伤与长链酰基辅酶A合酶4介导的铁死亡密切相关,但长链酰基辅酶A合酶4参与泡沫细胞形成、平滑肌细胞表型转化、钙化的研究尚未见报道;⑤长链酰基辅酶A合酶4作为铁死亡的生物标志物和潜在靶点成为研究热点,靶向长链酰基辅酶A合酶4抑制铁死亡可能成为治疗动脉粥样硬化性心血管疾病的新方向,而抑制长链酰基辅酶A合酶4的药物研究较少,未来还需进一步研究。

MgN_(4)掺杂石墨烯CO氧化催化活性的密度泛函研究

鉴于镁卟啉所呈现的催化活性,采用密度泛函理论考察了MgN_(4)结构掺杂石墨烯的CO氧化催化活性.研究发现MgN_(4)掺杂石墨烯具有良好的结构稳定性,O_(2)优先吸附在金属活性位点且不易解离.其CO氧化以Eley-Rideal(ER)机理实现,决速步能垒仅为0.67 eV,与FeC_(3)、AlN_(4)掺杂石墨烯具有相当的催化活性.MgN_(4)掺杂石墨烯有望是一种具有潜在CO氧化催化活性的催化剂.

Li掺杂对4H-SiC光电性质影响的理论研究

采用基于密度泛函理论的第一性原理方法,计算了Li掺杂4H-SiC体系的电子结构及光学性质.结果表明,掺杂前后的4H-SiC均为间接带隙半导体,Li原子间隙掺杂后形成n型半导体,Li原子替位式掺杂体系的禁带中出现了杂质能级,降低了电子跃迁时所需的能量;对电荷差分密度图的分析表明,Li原子失去电子,导致Li-C键和Li-Si键的共价性降低,以离子性为主;在可见光区域,相比于4H-SiC体系,掺杂体系的吸收率峰值均有所提高,其中Li间隙掺杂体系吸收带边最小,吸收率峰值最大,掺杂后的4H-SiC体系对红外、可见光、紫外均能够有所吸收,说明Li掺杂能够有效拓宽4H-SiC对光的响应范围.