Endothelial dysfunction: molecular mechanisms and clinical implications

MedComm, Год журнала: 2024, Номер 5(8)

Опубликована: Июль 22, 2024

Abstract Cardiovascular disease (CVD) and its complications are a leading cause of death worldwide. Endothelial dysfunction plays crucial role in the initiation progression CVD, serving as pivotal factor pathogenesis cardiovascular, metabolic, other related diseases. The regulation endothelial is influenced by various risk factors intricate signaling pathways, which vary depending on specific context. Despite numerous research efforts aimed at elucidating mechanisms underlying dysfunction, precise molecular pathways involved remain incompletely understood. This review elucidates recent findings pathophysiological including nitric oxide availability, oxidative stress, inflammation‐mediated pathways. We also discuss impact pathological conditions, atherosclerosis, heart failure, diabetes, hypertension, chronic kidney disease, neurodegenerative Furthermore, we summarize traditional novel potential biomarkers well pharmacological nonpharmacological therapeutic strategies for protection treatment CVD complications. Consequently, this to improve understanding emerging approaches reducing developing associated complications, mitigating dysfunction.

Язык: Английский

---

Klotho attenuates epithelial‑mesenchymal transition of retinal pigment epithelial cells in subretinal fibrosis by suppressing the ERK1/2 and Wnt/β‑catenin signaling pathways

International Journal of Molecular Medicine, Год журнала: 2025, Номер 55(3)

Опубликована: Янв. 10, 2025

Retinal pigment epithelial (RPE) cells undergoing epithelial‑mesenchymal transition (EMT) are a key factor in promoting the progression of subretinal fibrosis. The klotho protein and gene exert anti‑fibrotic effects multiple fibrotic diseases. However, mechanisms involved role unclear aim present study was to explore on fibrosis induced by laser photocoagulation mice EMT TGF‑β1 RPE underlying molecular mechanisms. In vitro, overexpression or knockdown performed ARPE‑19 (adult retinal Pigment Epithelial‑19), then treatment applied. Using western blotting, expression markers (zonula occludens‑1), mesenchymal signs (α‑smooth muscle actin, α‑SMA, N‑cadherin, N‑cad collagen I), ERK1/2 Wnt/β‑catenin signaling pathways were assessed. proliferative ability examined CCK‑8 EdU test, migratory wound healing Transwell assays. Furthermore, pathway overexpression, RNA‑sequencing (seq) performed. vivo, used induce mice, which occurs as result choroidal neovascularization (CNV), recombinant mouse administered intravitreally. Upregulation downregulation demonstrated that prevented TGF‑β1‑induced EMT; resulted opposite effects. Additionally, suppressed cell proliferation migration attenuated activated TGF‑β1. RNA‑seq results several pathways, including cellular senescence TNF pathway, associated with overexpression. areas following laser‑induced CNV lesions, illustrated immunofluorescence Masson staining eyes. Western blotting levels significantly downregulated those upregulated. In summary, suggested may have therapeutic value management vitreoretinal disorders such

Язык: Английский

---

Longevity Humans Have Youthful Erythrocyte Function and Metabolic Signatures

Aging Cell, Год журнала: 2025, Номер unknown

Опубликована: Фев. 9, 2025

ABSTRACT Longevity individuals have lower susceptibility to chronic hypoxia, inflammation, oxidative stress, and aging‐related diseases. It has long been speculated that “rejuvenation molecules” exist in their blood promote extended lifespan. We unexpectedly discovered longevity exhibit erythrocyte oxygen release function similar young individuals, whereas most elderly show reduced capacity. Untargeted metabolomics profiling revealed are characterized by youth‐like metabolic reprogramming these metabolites effectively differentiate the from elderly. Quantification analyses led us identify multiple novel longevity‐related within erythrocytes including adenosine, sphingosine‐1‐phosphate (S1P), glutathione (GSH) related amino acids. Mechanistically, we increased bisphosphoglycerate mutase (BPGM) MFSD2B protein levels of collaboratively work together induce elevation intracellular S1P, glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) membrane cytosol, thereby orchestrate glucose toward Rapoport–Luebering Shunt 2,3‐BPG production trigger delivery. Furthermore, glutamine glutamate transporter expression coupled with enhanced metabolism underlie elevated GSH higher anti‐oxidative stress capacity individuals. As such, displayed less systemic hypoxia‐related more antioxidative anti‐inflammatory plasma, healthier clinical outcomes inflammation parameters as well better glucose–lipid metabolism, liver kidney function. Overall, identified youthful enable counteract peripheral tissue thus maintaining healthspan.

Язык: Английский

---

Dietary inflammatory potential and biological aging among US adults: a population-based study

Aging Clinical and Experimental Research, Год журнала: 2023, Номер 35(6), С. 1273 - 1281

Опубликована: Апрель 25, 2023

Язык: Английский

---

Maintaining ideal cardiovascular health is associated with higher serum anti-aging protein klotho in the middle-aged and older populations

The journal of nutrition health & aging, Год журнала: 2024, Номер 28(6), С. 100224 - 100224

Опубликована: Апрель 5, 2024

Maintaining ideal cardiovascular health (CVH) is believed to have potential anti-aging benefits. The American Heart Association (AHA) recently updated the "Life's Essential 8 (LE8)" metrics measure CVH, but its connection with protein klotho still unclear. We aimed explore relationship between and serum in a nationally representative US middle-aged older population. A cross-sectional study. National Health Nutrition Examination Survey (2007−2016). total of 9457 participants. Ideal CVH scores their components were defined according guidelines set by AHA. Serum detected enzyme-linked immunosorbent assay. Weighted multivariable linear regression restricted cubic spline employed examine association score klotho. Subgroup analyses conducted, stratified age (40−59 60−79), sex (Male Female), race (Mexican American, non-Hispanic White, Black, Others) chronic kidney disease (Yes No) fully adjusted models. participants included this study, mean 55.27 ± 0.17 years. level population was 849.33 5.39 pg/mL. After controlling for confounders, LE8 showed positive correlation levels (β: 1.32; 95% CI 0.73, 1.91), non-linear dose-response observed. Furthermore, we also discovered behaviors factors 0.48; 0.07, 0.88 β: 1.05; 0.54, 1.56, respectively), particularly stronger In subgroup analysis, observed significant interaction race. (P <0.05). subscale positively associated populations. Promoting maintenance can contribute delaying aging process.

Язык: Английский

---

Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging

Cells, Год журнала: 2024, Номер 13(17), С. 1413 - 1413

Опубликована: Авг. 24, 2024

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia anomalies. Importantly, it associated with chronic pathologies (often age-related) that have inflammatory component. This includes atherosclerosis, diabetes Alzheimer's disease. Its mode of action these diseases not well understood, but inhibits or regulates multiple major pathways. has a membrane form soluble (s-Klotho). Cytosolic postulated characterized. s-Klotho endocrine properties are incompletely elucidated. binds to FGF receptor 1c (FGFR1c) widely expressed (including endothelial cells). also attaches FGF23, FGF23/Klotho FGFRs. Thus, might be roaming FGF23 coreceptor, functions. Notably, (cell-bound soluble) counteracts inflammation appears mitigate related aging (inflammaging). NF-κB NLRP3 inflammasome. inflammasome requires priming by produces active IL-1β, pores cell death (pyroptosis). In accord, countered injury induced toxins, damage-associated molecular patterns (DAMPs), cytokines, reactive oxygen species (ROS). blocks TGF-β Wnt ligands, which lessens fibrotic Low loss muscle mass (sarcopenia), as occurs diseases. counters inhibitory effects myostatin on muscle, reduces inflammation, improves repair following injury. inhibition factors may protective diabetic retinopathy age-related macular degeneration (AMD). review examines functions especially potential applications.

Язык: Английский

---

Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases

Molecular Biomedicine, Год журнала: 2025, Номер 6(1)

Опубликована: Март 22, 2025

Abstract Klotho, initially introduced as an anti-aging protein, is expressed in the brain, pancreas, and most prominently kidney. The two forms of Klotho (membrane-bound soluble form) have diverse pharmacological functions such anti-inflammatory, anti-oxidative, anti-fibrotic, tumour-suppressive etc. membrane-bound form plays a pivotal role maintaining kidney homeostasis by regulating fibroblast growth factor 23 (FGF 23) signalling, vitamin D metabolism phosphate balance. deficiency has been linked with significantly reduced protection against various pathological phenotypes, including diabetic disease (DKD), which major cause chronic leading to end-stage disease. Owing pleiotropic actions klotho, it shown beneficial effects DKD tackling complex pathophysiology reducing inflammation, oxidative stress, well fibrosis. Moreover, protective effect klotho extends beyond other conditions, cardiovascular diseases, alzheimer's disease, cancer, inflammatory bowel liver Therefore, this review summarizes relationship between expression diseases special emphasis on DKD, distinct mechanisms potential exogenous supplementation therapeutic strategy. Future research into could unravel novel treatment avenues for diseases.

Язык: Английский

---

Emerging role of α-Klotho in energy metabolism and cardiometabolic diseases

Diabetes & Metabolic Syndrome Clinical Research & Reviews, Год журнала: 2023, Номер 17(10), С. 102854 - 102854

Опубликована: Сен. 15, 2023

Язык: Английский

---

Epilepsy: Mitochondrial connections to the ‘Sacred’ disease

Mitochondrion, Год журнала: 2023, Номер 72, С. 84 - 101

Опубликована: Авг. 13, 2023

Over 65 million people suffer from recurrent, unprovoked seizures. The lack of validated biomarkers specific for myriad forms epilepsy makes diagnosis challenging. Diagnosis and monitoring childhood add to the need non-invasive biomarkers, especially when evaluating antiseizure medications. Although underlying mechanisms epileptogenesis are not fully understood, evidence mitochondrial involvement is substantial. Seizures affect 35%-60% patients diagnosed with diseases. Mitochondrial dysfunction pathophysiological in various epilepsies, including those non-mitochondrial origin. Decreased ATP production caused by malfunctioning brain cell mitochondria leads altered neuronal bioenergetics, metabolism neurological complications, Iron-dependent lipid peroxidation initiates ferroptosis, a death pathway that aligns morphology found neurodegenerative diseases (NDDs). Studies mouse genetic models seizure phenotypes where function an essential selenoprotein (GPX4) targeted suggest roles ferroptosis epilepsy. GPX4 pivotal NDDs, selenium protects interneurons ferroptosis. Selenium central nervous system micronutrient trace element. Low serum concentrations other elements minerals, iron, noted diagnosing supplements alleviate intractable seizures children reduced GPX activity. Copper cuproptosis, like iron link NDDs. Connecting these mechanistic pathways selenoproteins provides new insights into treating seizures, pointing using medicines prodrugs lipoic acid treat potential alternative therapeutic approaches transcranial magnetic stimulation (transcranial), photobiomodulation vagus nerve stimulation.

Язык: Английский

---

Knockout of the longevity gene Klotho perturbs aging and Alzheimer’s disease-linked brain microRNAs and tRNA fragments

Communications Biology, Год журнала: 2024, Номер 7(1)

Опубликована: Июнь 11, 2024

Abstract Overexpression of the longevity gene Klotho prolongs lifespan, while its knockout shortens lifespan and impairs cognition via perturbation myelination synapse formation. However, comprehensive analysis effects on mammalian brain transcriptomics is lacking. Here, we report that alters levels aging- related mRNAs, long non-coding RNAs, microRNAs tRNA fragments. These include altered neuronal glial regulators in murine models aging Alzheimer’s disease human post-mortem brains. We further demonstrate interaction knockout-elevated fragments with spliceosome, possibly affecting RNA processing. Last, present cell type-specific short RNA-seq datasets from FACS-sorted neurons microglia live tissue demonstrating in-depth cell-type association knockout-perturbed microRNAs. Together, our findings reveal multiple transcripts both glia are perturbed deficiency neurodegeneration-related.

Язык: Английский

---