Diabetes Coronary Artery Disease Research Articles

FRI590 Predictors Of Metabolically (Un)Healthy Obesity In Children

Abstract Disclosure: L. Van der Veken: None. X. Chestermann: None. K. Casteels: None. J. Helsen: None. A.M. Rochtus: None. Childhood obesity is a growing problem worldwide and can lead to type 2 diabetes, hypertension, dyslipidemia, and carotid-artery atherosclerosis. This is known as “metabolically unhealthy obesity” (MUO). However, a subgroup of children who are obese have been described as “metabolically healthy” (MHO) due to the absence of these cardiometabolic risk factors. The current definition of MHO only includes cardiometabolic criteria (MHO-CR) such as systolic blood pressure, diastolic blood pressure, triglycerides, HDL-cholesterol and a measure of fasting plasma glucose. The aim of this review is to compare the current definition based on cardiometabolic risk factors with a definition that includes insulin resistance (MHO-IR). We investigated the differences between these definitions in terms of prevalence, characteristics, predictors, and the recommended way of measuring insulin and its respective cut-off value. We searched Pubmed, Embase, Web of Science and Cochrane Library for studies on prevalence and predictors of insulin resistance in pediatric MHO. The prevalence of MHO-CR, MHO-IR, MUO-CR, MUO-IR and MHO, based on combined criteria from both MHO-CR and MHO-IR, were compared and the mean-values for each group were calculated. A meta-analysis study was designed to investigate the characteristics of MHO-CR and MHO-IR. Summary effects were calculated using random effects models. The standardized mean differences (SMD) are presented together with their confidence intervals (5% significance level). The recommended way of measuring insulin resistance was investigated by a frequency-based representation of used units and cut-off values in the included studies. Eight full text articles met the eligibility criteria for inclusion. Out of 4036 participants, the mean prevalence of different groups was MHO-CR (35%), MHO-IR (44%), MUO-CR (61%) and MUO-IR (56%). After combining the cardiometabolic criteria with the factor insulin resistance, prevalence of MHO and MUO were respectively 11% and 54%. The characteristics found to be significantly different between MHO-CR and MHO-IR were fasting insulin [SMD 1.7406; CI (0.0198-3.4614); P=0.0481] and HOMA-IR [SMD 0.7202; CI (0.4414-0.9989); P=0.0007]. HOMA-IR was also significantly higher in MUO-IR than MUO-CR [SMD -0.3940; CI (-0.7471- -0.0409); P=0.0342]. Several predictors for MHO-CR and MHO-IR were defined. The most frequently used unit and cut-off value of MHO was HOMA-IR<3.16.The implementation of insulin resistance in the definition of pediatric MHO could provide a stricter way of categorizing patients as MHO and MUO, and allow earlier treatment interventions. Presentation: Friday, June 16, 2023

Steady solution and its stability of a mathematical model of diabetic atherosclerosis

Atherosclerosis is a leading cause of death worldwide. Making matters worse, nearly 463 million people have diabetes, which increases atherosclerosis-related inflammation. Diabetic patients are twice as likely to have a heart attack or stroke. In this paper, we consider a simplified mathematical model for diabetic atherosclerosis involving LDL, HDL, glucose, insulin, free radicals (ROS), β cells, macrophages and foam cells, which satisfy a system of partial differential equations with a free boundary, the interface between the blood flow and the plaque. We establish the existence of small radially symmetric stationary solutions to the model and study their stability. Our analysis shows that the plague will persist due to hyperglycemia even when LDL and HDL are in normal range, hence confirms that diabetes increase the risk of atherosclerosis.

Inflammation and oxidative stress markers in type 2 diabetes patients with Advanced Carotid atherosclerosis

BackgroundType 2 diabetes mellitus (T2DM) is a major global health issue and a significant risk factor for atherosclerosis. Atherosclerosis in T2DM patients has been associated with inflammation, insulin resistance, hyperglycemia, dyslipidemia, and oxidative stress. Identifying molecular features of atherosclerotic plaques in T2DM patients could provide valuable insights into the pathogenesis of the disease.MethodsThe MASCADI (Arachidonic Acid Metabolism in Carotid Stenosis Plaque in Diabetic Patients) study aimed to investigate the increase of 2-arachidonoyl-lysophatidylcholine (2-AA-LPC) in carotid plaques from T2DM and control patients and to explore its association with plaque vulnerability as well as with blood and intra-plaque biomarkers altered during diabetes.ResultsIn a population of elderly, polymedicated patients with advanced stage of atherosclerosis, we found that T2DM patients had higher systemic inflammation markers, such as high-sensitivity C-reactive protein (hsCRP) and IL-1β, higher levels of oxysterols, increased triglyceride levels, and decreased HDL levels as compared to control patients. Furthermore, 2-AA-LPC was significantly enriched in plaques from diabetic patients, suggesting its potential role in diabetic atherosclerosis. Interestingly, 2-AA-LPC was not associated with systemic markers related to diabetes, such as hsCRP, triglycerides, or HDL cholesterol. However, it was significantly correlated with the levels of inflammatory markers within the plaques such as lysophospholipids and 25-hydroxycholesterol, strengthening the link between local inflammation, arachidonic acid metabolism and diabetes.ConclusionOur study is in line with a key role for inflammation in the pathogenesis of diabetic atherosclerosis and highlights the involvement of 2-AA-LPC. Further research is needed to better understand the local processes involved in the alteration of plaque composition in T2DM and to identify potential therapeutic targets.Trial registrationThe MASCADI was registered on ClinicalTrials.gov (clinical registration number: NCT03202823).

Mechanism of Simiao Decoction in the treatment of atherosclerosis based on network pharmacology prediction and molecular docking.

To explore the molecular mechanism of Simiao Decoction (SMD) intervening atherosclerosis (AS). The main components and potential mechanisms of SMD remain unknown. This study aims to initially clarify the potential mechanism of SMD in the treatment of AS based on network pharmacology and molecular docking techniques. The principal components and corresponding protein targets of SMD were searched on Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and the compound-target network was constructed by Cytoscape3.9.1. AS targets were searched on DrugBank, OMIM, and TTD databases. The intersection of compound target and disease target was obtained and the coincidence target was imported into STRING database to construct a protein-protein interaction network. We further performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis on the targets. The molecular docking method was used to verify the interaction between core components of SMD and targets. We created the active compounds-targets network and the active compounds-AS-targets network based on the network database containing Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, DrugBank, OMIM, and TTD. We discovered that the therapy of AS with SMD involves 3 key substances-quercetin, kaempferol, and luteolin-as well as 5 crucial targets-ALB, AKT1, TNF, IL6, and TP53. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that the shared targets involved a number of signaling pathways, including the advanced glycosylation end product-receptor of AGE signaling pathway in diabetic complications, Hepatitis B, Lipid and atherosclerosis, Chemical Carcinogenesis-Receptor Activation, and Pathways in Cancer. The molecular docking demonstrated that the binding energies of quercetin, kaempferol, and luteolin with 5 important targets were favorable. This study reveals the active ingredients and potential molecular mechanism of SMD in the treatment of AS, and provides a reference for subsequent basic research.

Cardiometabolic Risk: Characteristics of the Intestinal Microbiome and the Role of Polyphenols.

Cardiometabolic diseases like hypertension, type 2 diabetes mellitus, atherosclerosis, and obesity have been associated with changes in the gut microbiota structure, or dysbiosis. The beneficial effect of polyphenols on reducing the incidence of this chronic disease has been confirmed by numerous studies. Polyphenols are primarily known for their anti-inflammatory and antioxidant properties, but they can also modify the gut microbiota. According to recent research, polyphenols positively influence the gut microbiota, which regulates metabolic responses and reduces systemic inflammation. This review emphasizes the prebiotic role of polyphenols and their impact on specific gut microbiota components in patients at cardiometabolic risk. It also analyzes the most recent research on the positive effects of polyphenols on cardiometabolic health. While numerous in vitro and in vivo studies have shown the interaction involving polyphenols and gut microbiota, additional clinical investigations are required to assess this effect in people.

Long-term efficacy and safety of early alogliptin initiation in subjects with type 2 diabetes: an extension of the SPEAD-A study

We previously reported in the study of preventive effects of alogliptin on diabetic atherosclerosis (SPEAD-A) that alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuated the progression of carotid atherosclerosis in subjects with type 2 diabetes and no history of cardiovascular disease. This extension study of the SPEAD-A trial investigated whether early alogliptin initiation improved long-term cardiovascular outcomes. The SPEAD-A trial randomized 341 subjects with type 2 diabetes to either alogliptin or conventional treatment to investigate the effects of alogliptin on atherosclerosis. All subjects who completed that trial were eligible for this prospective, observational cohort study. The primary endpoint was the first occurrence of a major cardiovascular event, defined as death due to any cause, acute myocardial infarction, or stroke. During the 520-week follow-up period, composite primary outcome events occurred in only a few subjects in each group [8 (5.4%) in the alogliptin group and 9 in the conventional treatment group (5.9%)]. There were no significant differences in the incidence rate of the primary outcome between the two groups. Post hoc Poisson regression analysis showed no significant difference between the two groups in the incidence rate of composite recurrence events for the same outcomes as the primary endpoint. On the other hand, this incidence rate was significantly lower in subjects who received DPP-4 inhibitors before an initial cardiovascular event than in those who did not (5.8 vs. 13.3 per 1000 person-years, respectively, p = 0.04). Early initiation of alogliptin was not associated with a reduced risk of composite cardiovascular disease, which could be attributed to fewer events and/or the addition of DPP-4 inhibitors during the follow-up period.

Nonalcoholic fatty liver disease. New nomenclature. Review

At the international hepatological congress of the European Association for the Study of the Liver (EASL), which took place in Vienna on June 21 — 24, 2023, a new classification and nomenclature of fatty liver disease was adopted. Leading scientists‑hepatologists proposed to replace the term «non‑alcoholic fatty liver disease» to the term «metabolic dysfunction‑associated steatotic liver disease» (MASLD). This diagnosis is established in patients with confirmed hepatic steatosis and one of the five cardiometabolic risk factors. MetALD is a new category of steatosis defined in patients with MASLD who consume excessive amounts of alcohol per week (140 and 210 g/ week for women and men, respectively). Cryptogenic steatohepatitis is present in patients with an undetermined disease etiology of the disease or without any metabolic risk factors. The concept of «non‑alcoholic steatohepatitis» (NASH) has been changed to the concept of «metabolic dysfunction‑associated steatohepatitis» (MASH). In the 21st century the problem of diagnosis and treatment of non‑alcoholic fatty liver disease has become especially urgent since it occurs in almost 35% of the population of the planet Earth. In industrialized countries, the percentage of the population affected with this disease is 20 to 40%. Approximately 10 — 20% of patients have associated symptoms of NASH. In Western European countries, the prevalence of NASH is 2 — 6%, and in the USA it is as much as 5 — 6% of the total population. MASH is the most common chronic liver disease that does not depend on age or race. This pathology is directly related to obesity, type 2 diabetes mellitus, insulin resistance, hyperlipidemia, and atherosclerosis. NAFLD is diagnosed 3 — 5 times more often in men than in women. Gender differences are related to the fact that body mass index of men is slightly higher than that in women. The fact that men with this disease often consume more alcohol than women, plays a certain role, too.

Multivessel Coronary Artery Disease Complicated by Diabetes Mellitus Has a Relatively Small Effect on Endothelial and Lipoprotein Lipases Expression in the Human Atrial Myocardium and Coronary Perivascular Adipose Tissue.

Endothelial (EL) and lipoprotein (LPL) lipases are enzymes involved in lipoproteins metabolism and formation of atherosclerosis, a pathological feature of coronary artery disease (CAD). This paper examines the role of the lipases in the right atrial appendage (RAA) and coronary perivascular adipose tissue (PVAT) of patients with CAD alone or with accompanying diabetes. Additionally, correlation analysis for plasma concentration of the lipases, apolipoproteins (ApoA-ApoJ) and blood lipids (Chol, HDL-C, LDL-C, TAG) was performed. We observed that CAD had little effect on the lipases gene/protein levels in the RAA, while their transcript content was elevated in the PVAT of diabetic CAD patients. Interestingly, the RAA was characterized by higher expression of EL/LPL (EL: +1-fold for mRNA, +5-fold for protein; LPL: +2.8-fold for mRNA, +12-fold for protein) compared to PVAT. Furthermore, ApoA1 plasma concentration was decreased, whereas ApoC1 and ApoH were increased in the patients with CAD and/or diabetes. The concentrations of ApoC3 and ApoD were strongly positively correlated with TAG content in the blood, and the same was true for ApoB with respect to LDL-C and total cholesterol. Although plasma concentrations of EL/LPL were elevated in the patients with diabetes, CAD alone had little effect on blood, myocardial and perivascular fat expression of the lipases.

Unraveling Acute and Post-COVID Cytokine Patterns to Anticipate Future Challenges.

The aims of this study were to analyze cytokine profiles in patients with COVID-19, gain insights into the immune response during acute infection, identify cytokines associated with disease severity and post-COVID complications, and explore potential biomarkers for prognosis and therapeutic targets. Using a multiplex analysis, we studied the cytokine pattern in 294 acute COVID-19 and post-COVID patients with varying severities of infection. Our findings revealed that disease severity was associated with elevated levels of IL-15, IL-8, and fractalkine. Severe/extremely severe forms in comparison with mild/moderate disease were associated with MCP-1, IFNa2, IL-7, IL-15, EGF, IP-10, IL-8, Eotaxin, FGF-2, GROa, sCD40L, and IL-10. The key cytokines of post-COVID are FGF-2, VEGF-A, EGF, IL-12(p70), IL-13, and IL-6. By the sixth month after recovering from a coronavirus infection, regardless of disease severity, some patients may develop complications such as arterial hypertension, type 2 diabetes mellitus, glucose intolerance, thyrotoxicosis, atherosclerosis, and rapid progression of previously diagnosed conditions. Each complication is characterized by distinct cytokine profiles. Importantly, these complications can also be predicted during the acute phase of the coronavirus infection. Understanding cytokine patterns can aid in predicting disease progression, identifying high-risk patients, and developing targeted interventions to improve the outcomes of COVID-19.

Exploring the therapeutic mechanism of Banxia Xiexin Decoction in mild cognitive impairment and diabetes mellitus: a network pharmacology approach.

The incidence of mild cognitive impairment (MCI) and diabetes mellitus (DM) is increasing year by year. Clinical findings show that Banxia Xiexin Decoction (BXD) can be combined to treat MCI and DM. However, the principle and mechanism of BXD in treating MCI and DM remain unclear. In this study, to explore the common mechanism of BXD in treating MCI and DM by using the method of network pharmacology.Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) was used to screen the main active components of BXD, as well as to predict and screen its potential targets. Using Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), DisGeNET, GeneCards to select the target proteins of two diseases, and intersecting the drug target and the disease target to obtain the common target of drug diseases, which is imported into cytoscape software to draw the network diagram of "drug components-target diseases" and the interaction network diagram between the common target proteins. According to the Database for Annotation, Visualization and Integrated Discovery (DAVID) database, we analyzed the common targets using two methods, gene ontology Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway enrichment analysis and Gene Ontology (GO) function enrichment analysis, as well as studied the interaction mechanism of the two diseases, with the results validated using molecular docking.A total of 267 main active components of BXD were screened, together with the two diseases shared 233 common targets. The top five key targets identified by the topological analysis were TP53, AKT1, STAT3, TNF, and MAPK3. Go enrichment results indicated that it was primarily related to response to drug, extracellular space, enzyme binding, RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding. t KEGG enrichment pathway analysis identified 20 significant pathways, the majority of which are AGE-RAGE signaling pathways in diabetic complications, lipid and atherosclerosis, fluid shear stress and atherosclerosis, IL-17 signaling pathway, TNF signaling pathway, and so on. The results of molecular docking revealed that the key components of BXD, baicalein, licochalcone a, quercetin, and naringenin, had strong binding ability with core targets TP53, AKT1, STAT3, TNF, MAPK3.BXD can treat MCI and DM by multi-targets and multi-channels,and plays a role of "homotherapy for heteropathy" mainly through response to drug, positive regulation of gene expression, extracellular space and enzyme binding and other ways.

Research Progress of Takeda G Protein-Coupled Receptor 5 in Metabolic Syndrome.

Bile acids are acknowledged as signaling molecules involved in metabolic syndrome. The Takeda G protein-coupled receptor 5 (TGR5) functions as a significant bile acid receptor. The accumulated evidence suggests that TGR5 involves lipid homeostasis, glucose metabolism, and inflammation regulation. In line with this, recent preclinical studies also demonstrate that TGR5 plays a significant role in the generation and progression of metabolic syndrome, encompassing type 2 diabetes mellitus, obesity, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). In this review, we discuss the role of TGR5 in metabolic syndrome, illustrating the underlying mechanisms and therapeutic targets.

Anatomical study of the distal course of the posterior tibial artery: A cadaver study.

This study aimed to describe the course, branches, and variances of the posterior tibial artery, which provides the arterial supply of the plantar surface of the foot, starting from the tarsal tunnel level to provide descriptive information for all surgical interventions, diagnostic radiological procedures, and promising endovascular therapies in the tarsal region. In this study, a dissection of 48 feet was performed on 25 formalin-fixed cadavers (19 males and 6 females). Surgical instruments and a digital caliper were used for dissection and measurements, and the critical structures were recorded by a Canon 250D camera to be illustrated later. All parameters were significantly longer in male cadavers compared to females. According to the correlation analysis, while there was a significant and robust correlation between the axial line and pternion-deep plantar arch (R=.830, P .05), a moderate correlation was found between the axial line and sphyrion-bifurcation (R=.575; P < .05), axial line and deep plantar arch-2nd interdigital commissure (R=.457; P < .05), and sphyrion-bifurcation and pternion-deep plantar arch (R=.480; P < .05). Variation in any branch of the posterior tibial artery was observed in 27 of the 48 studied sides. In our study, the branching and variability of posterior tibial artery on the plantar surface of the foot were described in detail with the determined parameters. In conditions that cause tissue and function loss and require reconstruction, such as diabetes mellitus and atherosclerosis, the most critical factor in increasing treatment success is a better understanding of the region's anatomy.

Hydroxysafflor yellow A inhibits endothelial cell ferroptosis in diabetic atherosclerosis mice by regulating miR-429/SLC7A11

Context Ferroptosis may play an essential role in lipid peroxidation and endothelial dysfunction of aortic endothelial cells (ECs) in type 2 diabetes mellitus (T2DM) with atherosclerosis (AS). Hydroxysafflor yellow A (HSYA) has shown substantial antioxidant stress and anti-ferroptosis. Objective This study confirms whether HSYA improves symptoms in a mouse model of T2DM/AS and elucidates the underlying mechanisms. Materials and methods ApoE-/- mice were fed with high fat combined with 30 mg/kg streptozotocin to establish a T2DM/AS model. Then mice were treated with intraperitoneal injections of 2.25 mg/kg HSYA for 12 weeks. Human Umbilical Vein Endothelial cells (HUVEC) induced by 33.3 mM d-glucose +100 μg/mL ox-LDL were used to construct a high lipid and high glucose cell model treated with 25 μM HSYA. The changes in oxidative stress- and ferroptosis-related markers were detected, and the regulatory effect of HSYA on the miR-429/SLC7A11 was also verified. Normal ApoE-/- mice or HUVEC cells were used as the control group. Results HSYA effectively reduced atherosclerotic plaque formation in the T2DM/AS mouse model and inhibited HUVEC ferroptosis, such as upregulating GSH-Px, SLC7A11 and GPX4, but inhibited ACSL4. Furthermore, HSYA also downregulated the expression of miR-429, which further regulated SLC7A11 expression. After miR-429 mimic or SLC7A11 siRNA transfection in the HUVEC, the antioxidative stress and anti-ferroptosis effects of HSYA were significantly abolished. Conclusions HSYA is expected to become an important health drug to prevent the occurrence and development of T2DM/AS.

Platelet Glycoprotein-Ib (GPIb) May Serve as a Bridge between Type 2 Diabetes Mellitus (T2DM) and Atherosclerosis, Making It a Potential Target for Antiplatelet Agents in T2DM Patients.

Type 2 diabetes mellitus (T2DM) is a persistent metabolic condition that contributes to the development of cardiovascular diseases. Numerous studies have provided evidence that individuals with T2DM are at a greater risk of developing cardiovascular diseases, typically two to four times more likely than those without T2DM, mainly due to an increased risk of atherosclerosis. The rupture of an atherosclerotic plaque leading to pathological thrombosis is commonly recognized as a significant factor in advancing cardiovascular diseases caused by TD2M, with platelets inducing the impact of plaque rupture in established atherosclerosis and predisposing to the primary expansion of atherosclerosis. Studies suggest that individuals with T2DM have platelets that display higher baseline activation and reactivity than those without the condition. The expression enhancement of several platelet receptors is known to regulate platelet activation signaling, including platelet glycoprotein-Ib (GPIb). Furthermore, the high expression of platelet GP1b has been reported to increase the risk of platelet adhesion, platelet-leucocyte interaction, and thrombo-inflammatory pathology. However, the study exploring the role of GP1b in promoting platelet activation-induced cardiovascular diseases in T2DM patients is still limited. Therefore, we summarize the important findings regarding pathophysiological continuity between T2DM, platelet GPIb, and atherosclerosis and highlight the potential therapy targeting GPIb as a novel antiplatelet agent for preventing further cardiovascular incidents in TD2M patients.

153-OR: Genetically Supported Therapeutic Targets for Coronary Artery Disease in Diabetes—Evidence from Proteome-Wide Mendelian Randomization

Coronary artery disease (CAD) remains a major burden in people with diabetes. Genome-wide association studies (GWASs) have identified multiple genetic loci, yet most have yet to translate to clinical applications. The aim of this study was to leverage on genetic data to identify novel drug targets for CAD in diabetes. We applied Mendelian randomization (MR) to investigate the causal association of 1677 plasma proteins from 6 large GWASs, and a recently published GWAS of 15,666 individuals with diabetes (including 3968 CAD cases and 11698 controls). 5 of the 6 proteomic studies were selected as discovery MR analysis, and the remaining one as replication MR to validate the top findings. We employed sensitivity analyses, Bayesian colocalization and transcriptome-wide association study (TWAS) to test the validity of MR assumptions and meanwhile prioritized candidates of drug targets using multi-omics layers. We further integrated phenome-wide MR using the summary data from UK Biobank (N≤408 961) studies and clinical evidence based on DrugBank database to detect potential side effects associated with hypothetical therapeutic agents for CAD in diabetes and prioritize them. Our primary discovery MR analysis identified 4 prioritized proteins (F5, LPA, NPPB and TNFRSF11B) with both MR and colocalization evidence. NPPB and TNFRSF11B could be verified by replication MR analysis. Multi-tissue TWAS analysis revealed all 4 targets whose imputed expression was associated with the outcome. No adverse side effects were found for LPA via phenome-wide MR. By combining the putative causal MR signals with clinical evidence, we suggested these 4 drug repurposing opportunities for the treatment of CAD with diabetes that warranted further investigation. In summary, we prioritized 4 potential drug targets for CAD in diabetes. In particular, LPA might represent a promising target for the treatment of CAD in diabetes, with no predicted adverse side effects. Disclosure C.Huang: None. M.Shi: None. G.Yu: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer Inc., Celltrion, Boehringer Ingelheim and Eli Lilly Alliance, Sanofi, Research Support; AstraZeneca, Servier Laboratories, Viatris Inc., Hua Medicine, Merck KGaA, Applied Therapeutics Inc., Lee Powder, Pfizer Inc., Speaker's Bureau; Novartis, Stock/Shareholder; GemVCare Ltd. R.C.Ma: Advisory Panel; AstraZeneca, Merck &amp; Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk. Funding Research Grants Council of the Hong Kong Special Administrative Region (CU R4012-18); Croucher Foundation

Fufang Zhenzhu Tiaozhi (FTZ) capsule ameliorates diabetes-accelerated atherosclerosis via suppressing YTHDF2-mediated m6A modification of SIRT3 mRNA

Ethnopharmacological relevanceFufang Zhenzhu TiaoZhi (FTZ), a Chinese medicinal decoction, has continuously been used to treat metabolic syndrome. Atherosclerosis is the main pathological basis of cardiovascular disease. The N6 methyladenosine (m6A) modification is a highly dynamic and reversible process involving a variety of important biological processes. Aim of the studyHere, we investigated the therapeutic effects and mechanism of FTZ in diabetes-accelerated atherosclerosis. Materials and methodsDoppler ultrasonography was used to examine the carotid intima-media thickness and plaque area in diabetic atherosclerosis patients. HFD mice were injected with streptozotocin to induce diabetes. HE and Oil red O staining were used to assess the effect of FTZ on lipid deposition. HUVECs were induced with HG/ox-LDL as a model of diabetic atherosclerosis. Furthermore, application of m6A methylation level kit, qRT-PCR, Western blot, tunel staining, reactive oxygen species staining and mPTP staining were performed to analyze the detailed mechanism. ResultsClinical trials of FTZ have shown obvious effect of lowering blood glucose and blood lipids. These effects were reversed after FTZ intervention. Compared with the control, lipid deposition decreased significantly after FTZ administration. FTZ reduced endothelial cell apoptosis. At the same time, we found that FTZ reversed the increase of methylation reader YTHDF2 caused by ox-LDL treatment. Subsequently, we discovered that YTHDF2 degraded SIRT3 mRNA, leading to endothelial cell apoptosis and oxidative stress. ConclusionFTZ attenuated diabetes-accelerated atherosclerosis by decreasing blood glucose and serum lipids levels, and increased endothelial cell antioxidant capacity, inhibited endothelial cell apoptosis via inhibiting YTHDF2-mediated m6A modification of SIRT3 mRNA, which reduced mRNA degradation.

Lactiplantibacillus plantarum and Saussurea costus as Therapeutic Agents against a Diabetic Rat Model-Approaches to Investigate Pharmacophore Modeling of Human IkB Kinase and Molecular Interaction with Dehydrocostus Lactone of Saussurea costus.

Lactic acid bacteria is well-known as a vital strategy to alleviate or prevent diabetes. Similarly, the plant Saussurea costus (Falc) Lipsch is a preventive power against diabetes. Here, we aimed to determine whether lactic acid bacteria or Saussurea costus is more effective in treating a diabetic rat model in a comparative study manner. An in vivo experiment was conducted to test the therapeutic activity of Lactiplantibacillus plantarum (MW719476.1) and S. costus plants against an alloxan-induced diabetic rat model. Molecular, biochemical, and histological analyses were investigated to evaluate the therapeutic characteristics of different treatments. The high dose of S. costus revealed the best downregulated expression for the IKBKB, IKBKG, NfkB1, IL-17A, IL-6, IL-17F, IL-1β, TNF-α, TRAF6, and MAPK genes compared to Lactiplantibacillus plantarum and the control groups. The downregulation of IKBKB by S. costus could be attributed to dehydrocostus lactone as an active compound with proposed antidiabetic activity. So, we performed another pharmacophore modeling analysis to test the possible interaction between human IkB kinase beta protein and dehydrocostus lactone as an antidiabetic drug. Molecular docking and MD simulation data confirmed the interaction between human IkB kinase beta protein and dehydrocostus lactone as a possible drug. The target genes are important in regulating type 2 diabetes mellitus signaling, lipid and atherosclerosis signaling, NF-κB signaling, and IL-17 signaling pathways. In conclusion, the S. costus plant could be a promising source of novel therapeutic agents for treating diabetes and its complications. Dehydrocostus lactone caused the ameliorative effect of S. costus by its interaction with human IkB kinase beta protein. Further, future studies could be conducted to find the clinical efficacy of dehydrocostus lactone.

The role of lncRNA-mediated pyroptosis in cardiovascular diseases.

Cardiovascular disease (CVD) is the leading cause of death worldwide. Pyroptosis is a unique kind of programmed cell death that varies from apoptosis and necrosis morphologically, mechanistically, and pathophysiologically. Long non-coding RNAs (LncRNAs) are thought to be promising biomarkers and therapeutic targets for the diagnosis and treatment of a variety of diseases, including cardiovascular disease. Recent research has demonstrated that lncRNA-mediated pyroptosis has significance in CVD and that pyroptosis-related lncRNAs may be potential targets for the prevention and treatment of specific CVDs such as diabetic cardiomyopathy (DCM), atherosclerosis (AS), and myocardial infarction (MI). In this paper, we collected previous research on lncRNA-mediated pyroptosis and investigated its pathophysiological significance in several cardiovascular illnesses. Interestingly, certain cardiovascular disease models and therapeutic medications are also under the control of lncRNa-mediated pyroptosis regulation, which may aid in the identification of new diagnostic and therapy targets. The discovery of pyroptosis-related lncRNAs is critical for understanding the etiology of CVD and may lead to novel targets and strategies for prevention and therapy.

Insights into the Role of Plasmatic and Exosomal microRNAs in Oxidative Stress-Related Metabolic Diseases.

A common denominator of metabolic diseases, including type 2 diabetes Mellitus, dyslipidemia, and atherosclerosis, are elevated oxidative stress and chronic inflammation. These complex, multi-factorial diseases are caused by the detrimental interaction between the individual genetic background and multiple environmental stimuli. The cells, including the endothelial ones, acquire a preactivated phenotype and metabolic memory, exhibiting increased oxidative stress, inflammatory gene expression, endothelial vascular activation, and prothrombotic events, leading to vascular complications. There are different pathways involved in the pathogenesis of metabolic diseases, and increased knowledge suggests a role of the activation of the NF-kB pathway and NLRP3 inflammasome as key mediators of metabolic inflammation. Epigenetic-wide associated studies provide new insight into the role of microRNAs in the phenomenon of metabolic memory and the development consequences of vessel damage. In this review, we will focus on the microRNAs related to the control of anti-oxidative enzymes, as well as microRNAs related to the control of mitochondrial functions and inflammation. The objective is the search for new therapeutic targets to improve the functioning of mitochondria and reduce oxidative stress and inflammation, despite the acquired metabolic memory.

Sorghum flour's effect on improving plasma lipid profile and atherogenic index in diabetic rats

Dyslipidemia increases the risk of coronary heart disease in people with diabetes. Increased consumption of foods substantial in fiber and antioxidants, such as sorghum, can help people with diabetes manage their lipid profiles and improve insulin sensitivity. The study aimed to evaluate how sorghum flour affected diabetic rats' plasma atherosclerosis index (IAP) score and blood lipid profile. A randomized control design was used for the research's experimental methodology. In 2019, the study was carried out at P3G Laboratory UGM. 18 male Wistar rats served as the subjects and were separated into three groups: treatment (P) (5 g/mouse/day for 28 days), positive control (K+), and negative control of sorghum flour (K-). By administering nicotinamide and streptozotocin (STZ), the DM rat model was created (NA). The GPO-PAP method was used to measure TG levels. Total cholesterol, low-density lipoprotein, and high-density lipoprotein were all measured using CHOD-PAP. The log (TG/HDL) ratio (IAP) calculated the plasma atherosclerosis index. Paired T-tests, Wilcoxon, Anova, and Kruskal-Wallis, were used to evaluate the data. According to the findings, there were significant changes in the groups' baseline and post-intervention levels of total cholesterol (p=0,003), triglycerides (p=0,002), low-density lipoprotein (p=0,003), high-density lipoprotein (p=0,002), and IAP (p=0,001). In conclusion, feeding DM rats sorghum flour altered their blood lipid levels and plasma atherosclerosis index (IAP). Their LDL, triglycerides, and total cholesterol can all be reduced with a daily intake of 5 g per person.