Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies

Pharmacological Reviews, Год журнала: 2021, Номер 73(3), С. 924 - 967

Опубликована: Июнь 4, 2021

The endothelium, a cellular monolayer lining the blood vessel wall, plays critical role in maintaining multiorgan health and homeostasis. Endothelial functions include dynamic maintenance of vascular tone, angiogenesis, hemostasis, provision an antioxidant, anti-inflammatory, antithrombotic interface. Dysfunction endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion hyperpermeability, endothelial cell senescence. Recent studies have implicated altered metabolism endothelial-to-mesenchymal transition as new features dysfunction. dysfunction is regarded hallmark many diverse human panvascular diseases, including atherosclerosis, hypertension, diabetes. has also been severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors interleukin 1β monoclonal antibodies, counter part their clinical benefits. regulation by noncoding RNAs provided novel insights into these newly described regulators dysfunction, thus yielding potential therapeutic approaches. Altogether, better understanding versatile (dys)functions cells will not only deepen our comprehension diseases but accelerate effective drug discovery. In this review, we provide timely overview multiple layers function, describe consequences mechanisms identify pathways targeted therapies.

Significance Statement

was initially considered be semipermeable biomechanical barrier gatekeeper health. recent decades, deepened biological led its recognition ubiquitous tissue regulating behavior, innate immunity, cell-cell interactions, wall. cardiovascular, metabolic, emerging infectious diseases. Pharmacotherapies targeting for treatment cardiovascular other

Язык: Английский

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The sirtuin family in health and disease

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Дек. 29, 2022

Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, involved numerous biological processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles members SIRT family health disease conditions. Notably, this protein plays a variety important cellular biology such as inflammation, metabolism, oxidative stress, apoptosis, etc., thus, it is considered potential therapeutic target for different kinds pathologies including cancer, cardiovascular disease, respiratory other Moreover, identification modulators exploring functions these prompted increased efforts discover new small molecules, which can modify activity. Furthermore, several randomized controlled trials indicated that interventions might affect expression human samples, supplementation diverse impact on physiological function participants. In review, we introduce history structure family, discuss molecular mechanisms elaborate regulatory SIRTs summarize inhibitors activators, review related clinical studies.

Язык: Английский

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Sitagliptin activates the p62–Keap1–Nrf2 signalling pathway to alleviate oxidative stress and excessive autophagy in severe acute pancreatitis-related acute lung injury

Cell Death and Disease, Год журнала: 2021, Номер 12(10)

Опубликована: Окт. 11, 2021

Abstract Acute lung injury (ALI) is a complication of severe acute pancreatitis (SAP). Sitagliptin (SIT) DPP4 inhibitor that exerts anti-inflammatory and antioxidant effects; however, its mechanism action in SAP-ALI remains unclear. In this study, we investigated the effects SIT on specific pathways involved SAP-induced inflammation, including oxidative stress, autophagy, p62–Kelch-like ECH-associated protein 1 (Keap1)–NF-E2-related factor 2 (Nrf2) signalling pathways. Nrf2 knockout (Nrf2 −/− ) wild-type (WT) mice were pre-treated with (100 mg/kg), followed by caerulein lipopolysaccharide (LPS) administration to induce pancreatic injury. BEAS-2B cells transfected siRNA-Nrf2 treated LPS, changes reactive oxygen species (ROS) levels, autophagy measured. reduced histological damage, oedema, myeloperoxidase activity lung, decreased expression pro-inflammatory cytokines, inhibited excessive ROS production via activation p62–Keap1–Nrf2 pathway promotion nuclear translocation Nrf2. Nrf2-knockout mice, effect was reduced, resulting accumulation autophagy. cells, LPS induced activated further enhanced knockdown. This study demonstrates reduces SAP-ALI-associated stress through Nrf2, suggesting therapeutic potential SAP-ALI.

Язык: Английский

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Cellular senescence of renal tubular epithelial cells in acute kidney injury

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Фев. 5, 2024

Abstract Cellular senescence represents an irreversible state of cell-cycle arrest during which cells secrete senescence-associated secretory phenotypes, including inflammatory factors and chemokines. Additionally, these exhibit apoptotic resistance phenotype. serves a pivotal role not only in embryonic development, tissue regeneration, tumor suppression but also the pathogenesis age-related degenerative diseases, malignancies, metabolic kidney diseases. The renal tubular epithelial (RTEC) constitutes critical cellular event progression acute injury (AKI). RTEC inhibits regeneration repair processes and, concurrently, promotes transition AKI to chronic disease via mechanisms underlying are multifaceted include telomere shortening or damage, DNA mitochondrial autophagy deficiency, disorders, endoplasmic reticulum stress, epigenetic regulation. Strategies aimed at inhibiting senescence, targeting clearance senescent RTEC, promoting apoptosis hold promise for enhancing prognosis AKI. This review primarily focuses on characteristics impact intervening AKI, aiming provide foundation understanding providing potentially effective approaches treatment.

Язык: Английский

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Hesperetin modulates the Sirt1/Nrf2 signaling pathway in counteracting myocardial ischemia through suppression of oxidative stress, inflammation, and apoptosis

Biomedicine & Pharmacotherapy, Год журнала: 2021, Номер 139, С. 111552 - 111552

Опубликована: Апрель 9, 2021

Hesperetin (HSP) is a natural flavonoid that offers useful curative effects for cardiovascular diseases, but its effect on myocardial ischemia and precise mechanism remains unclear. The aim of this study to explore the potential cardioprotective HSP caused by isoproterenol (ISO). Adult male Kunming mice were randomly divided into five groups: control, ISO, low-dose (L-HSP, 25 mg/kg/d), high-dose (H-HSP, 50 verapamil (VER) group. Treatment groups received or VER seven days, other than control group injected with ISO (100 mg/kg/d) subcutaneously two consecutive days establish model ischemia. Electrocardiogram heart-histology changes used assess in architecture. activities content oxidative stress markers inflammatory cytokines determined assayed using kits respectively. expressions proteins associated apoptosis Sirt1/Nrf2 pathway evaluated Western blotting. results demonstrate VER, L-HSP H-HSP significantly reduced J-point displacement, heart rate, cardiac pathomorphological changes, levels creatine kinase, lactated dehydrogenase, malonaldehyde, interleukin-6, tumor necrosis factor-α serum while promoting activation superoxide dismutase, catalase, glutathione ISO-treated animals. Furthermore, also reversed ISO-induced signaling pathway, as evident from Bax, Bcl-2, caspase-3, Sirt1, Nrf2, NQO-1, HO-1. In conclusion, plays protective role modulating stress, inflammation, via activation.

Язык: Английский

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Role of Dipeptidyl Peptidase 4 Inhibitors in Antidiabetic Treatment

Molecules, Год журнала: 2022, Номер 27(10), С. 3055 - 3055

Опубликована: Май 10, 2022

In recent years, important changes have occurred in the field of diabetes treatment. The focus treatment diabetic patients has shifted from control blood glucose itself to overall management risk factors, while adjusting goals according individualization. addition, regulators need approve new antidiabetic drugs which been tested for cardiovascular safety. Thus, newest class shown reduce major adverse events, including sodium-glucose transporter 2 (SGLT2) and some glucagon like peptide 1 receptor (GLP1) analog. As such, they a prominent place hyperglycemia algorithms. role DPP4 inhibitors (DPP4i) modified. DPP4i favorable safety profile anti-inflammatory profile, do not cause hypoglycemia or weight gain, require dose escalation. it can also be applied types chronic kidney disease elderly with diabetes. Overall, DPP4i, as safe oral hypoglycemic agents, patients, there is extensive experience their use.

Язык: Английский

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CB2R Attenuates Intervertebral Disc Degeneration by Delaying Nucleus Pulposus Cell Senescence through AMPK/GSK3β Pathway

Aging and Disease, Год журнала: 2022, Номер 13(2), С. 552 - 552

Опубликована: Янв. 1, 2022

Nucleus pulposus (NP) cell (NPC) senescence is one of the main causes intervertebral disc degeneration (IVDD). However, underlying mechanism NPC still unclear. The cannabinoid type 2 receptor (CB2R) a member system and plays an important role in antioxidative stress, anti-inflammatory antisenescence activities. In this study, we used hydrogen peroxide (H₂O₂)-induced model rat acupuncture IVDD to explore CB2R vitro vivo. First, confirmed that expression p16INK4a NP tissues patients models obviously increased accompanied by decrease expression. Subsequently, found activation significantly reduced number SA-β-gal positive cells suppressed senescence-related secretory phenotypes [SASP, including matrix metalloproteinase 9 13 (MMP9, MMP13) high mobility group protein b1 (HMGB1)]. addition, promoted collagen II (Col-2) SRY-Box transcription factor (SOX9), inhibit X (Col-X), restore balance extracellular (ECM) metabolism. AMPK/GSK3β pathway was shown play regulation senescence. Inhibition AMPK reversed effect JWH015 (a agonist). Finally, further demonstrated model, involved on conclusion, our experimental results prove Activation can delay senescence, ECM metabolism, attenuate IVDD.

Язык: Английский

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Contribution of proteases to the hallmarks of aging and to age‐related neurodegeneration

Aging Cell, Год журнала: 2022, Номер 21(5)

Опубликована: Март 29, 2022

Protein quality control ensures the degradation of damaged and misfolded proteins. Derangement proteostasis is a primary cause aging age-associated diseases. The ubiquitin-proteasome autophagy-lysosome play key roles in but, addition to these systems, human genome encodes for ~600 proteases, also known as peptidases. Here, we examine role proteases age-related neurodegeneration. Proteases are present across cell compartments, including extracellular space, their substrates encompass cellular constituents, proteins with signaling functions, Proteolytic processing by can lead changes activity localization or degradation. cooperate systems but have independent proteolytic that impact all hallmarks aging. Specifically, regulate mitochondrial function, DNA damage repair, senescence, nutrient sensing, stem properties regeneration, protein stress responses, intercellular signaling. capacity functions translates into important preserving tissue homeostasis during Consequently, influence onset progression pathologies determinants health span. how certain promote Alzheimer's, Huntington's, and/or Parkinson's disease whereas other protect from Mechanistically, cleavage pathogenic hence impede pathogenesis. Alternatively, generate substrate byproducts increased toxicity, which progression. Altogether, studies indicate importance

Язык: Английский

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New Dawn for Atherosclerosis: Vascular Endothelial Cell Senescence and Death

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(20), С. 15160 - 15160

Опубликована: Окт. 13, 2023

Endothelial cells (ECs) form the inner linings of blood vessels, and are directly exposed to endogenous hazard signals metabolites in circulatory system. The senescence death ECs not only adverse outcomes, but also causal contributors endothelial dysfunction, an early risk marker atherosclerosis. pathophysiological process EC involves both structural functional changes has been linked various factors, including oxidative stress, dysregulated cell cycle, hyperuricemia, vascular inflammation, aberrant metabolite sensing signaling. Multiple forms have documented atherosclerosis, autophagic death, apoptosis, pyroptosis, NETosis, necroptosis, ferroptosis. Despite this, molecular mechanisms underlying or atherogenesis fully understood. To provide a comprehensive update on subject, this review examines historic latest findings alterations associated with different stages

Язык: Английский

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Sirtuin family in autoimmune diseases

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Июль 6, 2023

In recent years, epigenetic modifications have been widely researched. As humans age, environmental and genetic factors may drive inflammation immune responses by influencing the epigenome, which can lead to abnormal autoimmune in body. Currently, an increasing number of studies emphasized important role modification progression diseases. Sirtuins (SIRTs) are class III nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases SIRT-mediated deacetylation is alteration. The SIRT family comprises seven protein members (namely, SIRT1–7). While catalytic core domain contains amino acid residues that remained stable throughout entire evolutionary process, N- C-terminal regions structurally divergent contribute differences subcellular localization, enzymatic activity substrate specificity. SIRT1 SIRT2 localized nucleus cytoplasm. SIRT3, SIRT4, SIRT5 mitochondrial, SIRT6 SIRT7 predominantly found nucleus. SIRTs key regulators various physiological processes such as cellular differentiation, apoptosis, metabolism, ageing, response, oxidative stress, mitochondrial function. We discuss association between common diseases facilitate development more effective therapeutic strategies.

Язык: Английский

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