Diabetic vascular diseases: molecular mechanisms and therapeutic strategies

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: April 10, 2023

Abstract Vascular complications of diabetes pose a severe threat to human health. Prevention and treatment protocols based on single vascular complication are no longer suitable for the long-term management patients with diabetes. Diabetic panvascular disease (DPD) is clinical syndrome in which vessels various sizes, including macrovessels microvessels cardiac, cerebral, renal, ophthalmic, peripheral systems diabetes, develop atherosclerosis as common pathology. Pathological manifestations DPDs usually manifest macrovascular atherosclerosis, well microvascular endothelial function impairment, basement membrane thickening, microthrombosis. Cardiac, microangiopathy coexist microangiopathy, while renal retinal predominantly microangiopathic. The following associations exist between DPDs: numerous similar molecular mechanisms, risk-predictive relationships diseases. Aggressive glycemic control combined early comprehensive intervention key prevention treatment. In addition widely recommended metformin, glucagon-like peptide-1 agonist, sodium-glucose cotransporter-2 inhibitors, latest aldose reductase peroxisome proliferator-activated receptor-γ agonizts, glucokinases mitochondrial energy modulators, etc. under active development. proposed obtain more systematic care requires center focusing This would leverage advantages cross-disciplinary approach achieve better integration pathogenesis therapeutic evidence. Such strategy confer benefits promote development DPD discipline.

Language: Английский

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Signaling pathways of chronic kidney diseases, implications for therapeutics

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: June 9, 2022

Abstract Chronic kidney disease (CKD) is a chronic renal dysfunction syndrome that characterized by nephron loss, inflammation, myofibroblasts activation, and extracellular matrix (ECM) deposition. Lipotoxicity oxidative stress are the driving force for loss of including tubules, glomerulus, endothelium. NLRP3 inflammasome signaling, MAPK PI3K/Akt RAAS signaling involves in lipotoxicity. The upregulated Nox expression decreased Nrf2 result directly. injured resident cells release proinflammatory cytokines chemokines to recruit immune such as macrophages from bone marrow. NF-κB JAK-STAT Toll-like receptor cGAS-STING major pathways mediate inflammation inflammatory cells. produce secret great number profibrotic TGF-β1, Wnt ligands, angiotensin II. TGF-β Notch evoke activation promote generation ECM. potential therapies targeted these also introduced here. In this review, we update key lipotoxicity, stress, kidneys with injury, drugs based on latest studies. Unifying will be instrumental advance further basic clinical investigation CKD.

Language: Английский

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Lipoproteins and fatty acids in chronic kidney disease: molecular and metabolic alterations

Nature Reviews Nephrology, Journal Year: 2021, Volume and Issue: 17(8), P. 528 - 542

Published: May 10, 2021

Language: Английский

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Endothelial Cell Dysfunction and Increased Cardiovascular Risk in Patients With Chronic Kidney Disease

Circulation Research, Journal Year: 2023, Volume and Issue: 132(8), P. 970 - 992

Published: April 13, 2023

The endothelium is considered to be the gatekeeper of vessel wall, maintaining and regulating vascular integrity. In patients with chronic kidney disease, protective endothelial cell functions are impaired due proinflammatory, prothrombotic uremic environment caused by decline in function, adding increase cardiovascular complications this vulnerable patient population. review, we discuss functioning healthy conditions contribution dysfunction disease. Further, summarize phenotypic changes disease relation risk We also review mechanisms that underlie consider potential pharmacological interventions can ameliorate health.

Language: Английский

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Associations between Per- and Polyfluoroalkyl Substances Exposures and Blood Lipid Levels among Adults—A Meta-Analysis

Environmental Health Perspectives, Journal Year: 2023, Volume and Issue: 131(5)

Published: May 1, 2023

Associations between per- and polyfluoroalkyl substances (PFAS) blood lipid levels in humans were mixed.The objective of this meta-analysis was to summarize associations PFAS lipids adults.A literature search conducted on PubMed Web Science for articles published through 13 May 2022 that examined lipids, including total cholesterol (TC), high-density lipoprotein (HDL-C), low-density (LDL-C), triacylglycerols (TGs). Inclusion criteria included the presence five (PFOA, PFOS, PFHxS, PFDA, PFNA) four measures (TC, HDL-C, LDL-C, TGs) adults. Data study characteristics PFAS-lipid extracted. Assessments individual quality performed. changes corresponding 1 interquartile range (IQR)-unit increase pooled using random effects models. Dose-response relationships examined.Twenty-nine publications present analyses. Every IQR PFOA significantly associated with a 2.1-mg/dL TC (95% CI: 1.2, 3.0), 1.3-mg/dL TGs 0.1, 2.4), 1.4-mg/dL LDL-C 0.6, 2.2). PFOS also levels, values 2.6 1.5, 3.6) 1.9 0.9, respectively. HDL-C largely null. For minor species, PFHxS higher [0.8 0.5, 1.2)]. Inverse observed PFDA [-5.0 -8.1, -1.9)] PFNA [-1.7 -3.5, -0.02)], whereas positive association [1.4 2.7)]. Nonsignificant nonlinear dose-response identified certain lipids.PFOA Whether these findings may translate into an elevated cardiovascular disease risk exposure warrants further investigation. https://doi.org/10.1289/EHP11840.

Language: Английский

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Oxidative Stress and Cardiovascular Complications in Type 2 Diabetes: From Pathophysiology to Lifestyle Modifications

Antioxidants, Journal Year: 2025, Volume and Issue: 14(1), P. 72 - 72

Published: Jan. 9, 2025

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that significantly increases the risk of cardiovascular disease, which leading cause morbidity and mortality among diabetic patients. A central pathophysiological mechanism linking T2DM to complications oxidative stress, defined as an imbalance between reactive oxygen species (ROS) production body’s antioxidant defenses. Hyperglycemia in promotes stress through various pathways, including formation advanced glycation end products, activation protein kinase C, mitochondrial dysfunction, polyol pathway. These processes enhance ROS generation, endothelial vascular inflammation, exacerbation damage. Additionally, disrupts nitric oxide signaling, impairing vasodilation promoting vasoconstriction, contributes complications. This review explores molecular mechanisms by pathogenesis disease T2DM. It also examines potential lifestyle modifications, such dietary changes physical activity, reducing mitigating risks this high-risk population. Understanding these critical for developing targeted therapeutic strategies improve outcomes

Language: Английский

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Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(1), P. 531 - 531

Published: Jan. 4, 2022

Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role endothelium in protecting from thrombosis, as well its cardioprotective regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including underlying molecular mechanisms, into comprehensive overview. Therefore, we conducted systematic review describing uremic serum or toxin-induced dysfunction special focus endothelium. This revealed 39 studies analyzing effects toxins indoxyl sulfate, cyanate, modified LDL, advanced glycation end products N-carboxymethyl-lysine N-carboxyethyl-lysine, p-cresol p-cresyl phosphate, uric acid asymmetric dimethylarginine. Most described an increase oxidative stress, leukocyte migration adhesion, cell death phenotype upon conditions toxin treatment cells. Cellular signaling pathways that were frequently activated included ROS, MAPK/NF-κB, Aryl-Hydrocarbon-Receptor RAGE pathways. Overall, provides detailed insights pathophysiological mechanisms CKD. Targeting these may provide new therapeutic strategies reducing

Language: Английский

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Lipids and lipoproteins in cardiovascular diseases: a classification

Trends in Endocrinology and Metabolism, Journal Year: 2022, Volume and Issue: 33(6), P. 409 - 423

Published: March 31, 2022

A new classification of lipids and lipoproteins based on their mechanistic impact cardiovascular disease (CVD) not only intrinsic function is urgently needed to discover therapeutic opportunities, focusing lipid classes impacting CVDs individual subclasses.Lipids classified under 'lipids enhancing CVDs' lead similar outcomes CVD, synergistic effect should be targeted for CVD treatment.Lipids are emerging as drug delivery systems drugs such urokinase tanshinone II.Lipids ideal imaging probes atherosclerotic plaques in vivo trackers diagnosis CVDs. Lipids lipoproteins, metabolism, transport essential contributing factors they regulate plasma cholesterol concentration, uptake by macrophages, leading foam cell formation ultimately resulting plaque inflammation. However, have cardioprotective functions well, preventing oxidation proatherogenic molecules downregulating inflammatory proteins. This review gives an update about our current knowledge the mechanisms lipoprotein subclasses 'classifies' them this basis or with a conditional no known CVDs'. Low dysfunctional high-density (HDL-C), high low-density (LDL-C), elevated triglycerides (TGs) most common targets reducing risk, therefore, which health emphasised. recently emerged agents because localised within plaques, facilitating application probes. Recent studies show that liposomes HDL-mimicking nanoparticles (HDL-NPs) promising results animal models now being extended human trials. summarises genesis, progression, diagnosis, treatment. causes mortality worldwide [1.World Health Organisation Cardiovascular diseases (CVDs) fact sheet.2017Google Scholar]. major genesis progression means cellular synthesis, transportation, assembly, degradation, oxidation, concentrations [2.Upadhyay R.K. Emerging risk biomarkers disorders.J. Lipids. 2015; 2015971453Crossref PubMed Google Scholar,3.Yu X.H. et al.Cholesterol system: integrated model involved atherosclerosis.Prog. Lipid Res. 2019; 73: 65-91Crossref Scopus (103) Traditionally, 'storage lipids' [e.g., fatty acids (FAs), TGs, sterols] 'structural phospholipids (PLs), glycolipids, ceramides] (Figure 1A ) various physiological processes supporting biological life. third group comprises subclassified into five types density size: chylomicrons, very (VLDL), intermediate-density (IDL), LDL, HDL [4.Nelson D.L. al.Lehninger Principles Biochemistry. 4th edn. W.H. Freeman, 2005Google Scholar] (Table 1).Table 1Types propertiesSizeDensity (g/cm3)ApolipoproteinsSurface composition (protein/phospholipids/free %)Core (triacylglycerols/cholesteryl esters %)FunctionChylomicrons75–100<0.95A-I, A-II, A-IV, B-48, C-I, C-II, C-III, E2/7/385/3Transport dietary exogenous core substances from intestine tissuesVery lipoprotein30–70<1.006B-100, E8/17/855/12Transport endogenous liver tissuesIntermediate-density lipoprotein25–401.006–1.019B-100, E17/22/922/30Transport tissuesLow-density lipoprotein17–251.019–1.063B-10022/17/89/44Transport tissuesHigh-density lipoprotein2–101.063–1.210A-I, D, E50/28/46/12Transport tissues Open table tab Blood level was identified first direct link between circulating Framingham Heart Study (FHS) [5.Kannel W.B. al.Factors development coronary heart – six year follow-up experience. The Study.Ann. Intern. 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Therefore, urgent demand relevance identifying potential biomolecules prevention Classification necessary instead traditional functions. we suggest classifying three categories: (i) CVDs, (ii) (iii) due lack evidence 1B). classification, line Scholar], reflects affecting discussing vital survival pathological altered 1A). [17.Parolini C. al.HDL therapy diseases.Curr. Pharmacol. 2009; 7: 550-556Crossref (16) decrease [18.Stein E.A. Raal F.J. Lipid-lowering prevention: looking future.Curr. Rep. 17: 104Crossref (17) [19.Maki K.C. al.Triglyceride-lowering therapies event hypertriglyceridemia.J. 10: 905-914Abstract (38) interventions therefore been studied extensively subclasses. VLDL, (a) [Lp(a)], trans-fatty (TFAs), phosphatidylcholine, lysophosphatidic acid (LPA) strong thrombosis atherosclerosis. High IDL, Lp(a) enhance promoting thrombus [20.Krauss R.M. Lipoprotein subfractions risk.Curr. 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Sci. 16: 401-419Crossref (31) macrophage phagocytosed modified converted free liposomal lipase further acetyl-coenzyme acetyltransferase, endoplasmic reticulum exported out cells transporters atherogenicity inability degraded thereby aggregates intensify atherosclerosis triggering secretion cytokines growth arterial wall [25.Aviram M. Modified forms atherosclerosis.Atherosclerosis. 1993; 98: 1-9Abstract (324) Furthermore, production asymmetric dimethylarginine activating S-adenosylmethionine-dependent methyltransferases, deteriorate vascular tone decreasing nitric oxide through endothelial synthase inhibition [26.Mudau al.Endothelial dysfunction: early predictor atherosclerosis.Cardiovasc. Afr. 2012; 23: 222-231Crossref (296) promote formation, inflammation, 2A ). VLDL intercellular leukocyte migration interaction fibrin, aiding inflammation [27.Yakovlev S. al.Anti-VLDL receptor monoclonal antibodies inhibit fibrin-VLDL fibrin-dependent transmigration.Thromb. Haemost. 116: 1122-1130Crossref (12) combination deposition calcium phosphate salts, [28.Yu B. induces aortic valve interstitial calcification.JACC Basic Transl. 2: 358-371Crossref (42) accelerates process vitro increasing alkaline phosphatase activity p38 mitogen-activated protein kinase (MAPK), glycogen 3 beta (GSK3β), Wingless-related integration (Wnt) signal pathways Hypertriglyceridaemia leads reduced hepatic and/or glycosylphosphatidylinositol-anchored HDL-binding 1, liver, concentration [29.Talayero Sacks F.M. atherosclerosis.Curr. 13: 544-552Crossref (210) Scholar,30.Zheng al.Apolipoprotein C-III metabolic hypertriglyceridemia phenotype.Circulation. 121: 1722-1734Crossref (176) TG-rich produce proteins derived containing monocyte chemoattractant protein-1, adhesion molecule-1 (ICAM-1), E-selectins, metalloproteases [31.Santamaria de Groot R. ADAMTS proteases physiology disease.Open 10200333Crossref platelet molecule-1, interleukin (IL)-6, released transcription nuclear kappa-light-chain-enhancer activated (NF-κB) cAMP response element-binding [32.Norata G.D. al.Triglyceride-rich hypertriglyceridemic induce pro-inflammatory endothelium: molecular gene expression studies.J. Cell. 2006; 40: 484-494Abstract (51) migrate accumulation remnant cholesterol-aiding whereas remains plagues, [33.Nordestgaard Varbo A. Triglycerides disease.Lancet. 384: 626-635Abstract (721) Elevated activate hydroxylated linoleates 9-hydroxyoctadecadienoic (HODE) [34.Zhu al.The lipidome widely remodeled fast food versus Mediterranean diet 4 days.Metabolomics. 15: 114Crossref 13-HODE (LPL) lipolysis upregulation reactive oxygen species (ROS), ICAM, tumour necrosis factor-α (TNFα), responses, [35.Goldberg I.J. al.Triglycerides disease: still hypothesis?.Arterioscler. 1716-1725Crossref (151) Scholar,36.Wang L. releases neutral oxidized FFAs inflammation.J. 50: 204-213Abstract (190) 9-HODE interact peroxisome proliferator-activated surface FAs, CD36 atherogenic SR [37.Vaughan A.M. Oram J.F. ABCG1 redistributes domains removable lipid-depleted apolipoproteins.J. Chem. 2005; 280: 30150-30157Abstract (219) along release 9-HODE, 13-HODE, ROS, TNFα 2B). TFAs systemic IL-6, TNF densities, causing [38.Mozaffarian D. al.Trans failure.Am. Nutr. 2004; 80: 1521-1525Crossref (149) TFA intake dysfunction soluble ICAM-1, transmigration leukocytes blood vessels [39.Lopez-Garcia E. al.Consumption trans related dysfunction.J. 135: 562-566Crossref (468) (VCAM-1) acting scaffold transduction, stimulating [40.Cook-Mills J.M. al.Vascular signaling during regulation antioxidants.Antioxid. Redox Signal. 1607-1638Crossref (295) Phosphatidylcholine phosphatidylcholine biosynthesis macrophages. maintains cholesterol/phosphatidylcholine cell, prerequisite survival, achieved choline-phosphate cytidylyltransferase enzyme [41.Krahmer N. al.Balancing fat: droplets disease.EMBO 2013; 973-983Crossref (278) metabolised intestinal microbes, metabolites, choline betaine, upregulate SRs. Choline betaine gut microflora trimethylamine before N-oxide (TMAO) flavin monooxygenase. There dose-dependent TMAO burden. contributes end-stage renal [42.Wang Z. al.Gut flora metabolism promotes disease.Nature. 472: 57-63Crossref (3209) LPA accumulates both activation thrombogenesis, cofactor alongside ICAM-1 VCAM-1 collagen I III. triggers cytokines, factors, coagulation inducing factor-1 [43.Cui M.Z. al.Lysophosphatidic smooth muscle cells: CRE SRE mediate transcription.Arterioscler. 26: 1029-1035Crossref (32) mineralisation osteogenic differentiation interacting receptor-1 Ras homolog family member (RhoA)/NF-κB [44.Nsaibia M.J. al.OxLDL-derived stenosis LPAR1-RhoA-NF-kappaB pathway.Cardiovasc. 113: 1351-1363Crossref (57) tissue cells, macrovascular [45.Cui induction cells.Arterioscler. 2003; 224-230Crossref (44) suppresses autophagy, cardiac hypertrophy receptor-3 B/mammalian target rapamycin signalling pathway [46.Yang suppressing autophagy via LPA3/AKT/mTOR pathway.Front. Physiol. 2018; 9: 1315Crossref (18) subclass profound CVDs; cofactors, lipids. section characterises these lipids, conditions negate effects. Remodelling nascent mature esterification lecithin-cholesterol acyltransferase, well transfer additional transporter ATP-binding cassette subfamily G action SR-B1, [47.Rader Hovingh G.K. 618-625Abstract (392) Scholar,48.Zannis V.I. al.Role apoA-I, ABCA1, LCAT, SR-BI biogenesis HDL.J. 84: 276-294Crossref (301) 2C). Lipid-poor pre-β-HDL remove abundant macrophages reverse transport, otherwise transforms having proatherosclerotic [49.Rosenson R.S. al.Dysfunctional disease.Nat. Rev. 48-60Crossref (390) atheroprotective molecule oxide, triggered Src- phosphatidylinositol 3-kinase-mediated signalling, Akt MAPK [50.Mineo Shaul P.W. stimulation synthase: action.Trends Cardiovasc. 226-231Crossref (94) inhibits contains enzymes antioxidant-like activities paraoxonase platelet-activating acetylhydrolase [51.Bandeali Farmer High-density atherosclerosis: antioxidant activity.Curr. Atheroscler. 14: 101-107Crossref prevents inhibiting transdifferentiation osteoblast-like IL-1β, minimally [52.Parhami regulates cells.Circ. 91: 570-576Crossref (161) caused mutation (LIPG) loss-of-function SNP changes composition, differences unsaturated content; percentage esterified lipids; glycation A-I (ApoA-I), myeloperoxidase, paraoxonase; [53.Ertek (HDL) future HDL.Curr. 490-498Crossref (19) Oxidised cargo molecules, glycated ApoA-I, glucose anti-inflammatory [54.Hedrick C.C. al.Glycation impairs function.Diabetologia. 2000; 43: 312-320Crossref (252) comparison risk-predicting HDL-related analytes HDL2 HDL3, (HDL-P) HDL-P better incident [55.Mackey R.H. concentrations, atherosclerosis, events: MESA (Multi-Ethnic Atherosclerosis).J. Am. Coll. 60: 508-516Crossref (279) Scholar,56.Mora cholesterol, size, number, residual after potent statin therapy.Circulation. 128: 1189-1197Crossref (173) Thus, functions, ability efflux Polyunsaturated FAs omega-3 omega-6 counteractive terms nullifying [57.DiNicolantonio J.J. O'Keefe J.H. Importance maintaining omega-6/omega-3 inflammation.Open Heart. 5e000946Crossref (78) Omega-3 fish oils, 'eicosapentaenoic acid' (EPA) 'docosahexaenoic

Language: Английский

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Utilizing Skyline to analyze lipidomics data containing liquid chromatography, ion mobility spectrometry and mass spectrometry dimensions

Nature Protocols, Journal Year: 2022, Volume and Issue: 17(11), P. 2415 - 2430

Published: July 13, 2022

Language: Английский

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Integrated Metabolomic and Lipidomic Analysis in the Placenta of Preeclampsia

Frontiers in Physiology, Journal Year: 2022, Volume and Issue: 13

Published: Feb. 4, 2022

Preeclampsia is one of the most common severe pregnancy complications in obstetrics, which considered a placental source disease. However, mechanisms underlying preeclampsia remain largely unknown. In this study, UPLC-MS/MS-based metabolomic and lipidomic analysis was used to explore characteristic metabolites preeclampsia. The results revealed that there were significant changes between normotensive placentas. Weighted correlation network (WGCNA) identified module highly related clinical traits reflecting disease severity. metabolic perturbations primarily associated with glycerophospholipid glutathione metabolism, might influent membrane structures organisms mitochondria function. Using linear models, three had an area under receiver operating curves (AUROC) ≥ 0.80 lipids AUROC 0.90. Therefore, metabolomics lipidomics may offer novel insight for better understanding provide useful molecular mechanism

Language: Английский

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