Perivascular cells function as key mediators of mechanical and structural changes in vascular capillaries

Science Advances, Journal Year: 2025, Volume and Issue: 11(2)

Published: Jan. 10, 2025

A hallmark of chronic and inflammatory diseases is the formation a fibrotic stiff extracellular matrix (ECM), typically associated with abnormal, leaky microvascular capillaries. Mechanisms explaining how microvasculature responds to ECM alterations remain unknown. Here, we used microphysiological model capillaries on chip mimicking characteristics healthy or collagen test hypothesis that perivascular cells mediate response vascular mechanical structural changes in human ECM. Capillaries engineered altered had abnormal migration cells, reduced pericyte differentiation, increased leakage, higher regulation inflammatory/remodeling genes, all regulated via NOTCH3 , known mediator endothelial-perivascular cell communication. either endothelial alone silenced for expression showed minimal alterations. These findings reveal previously unknown mechanism health disease.

Language: Английский

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The nuclear factor kappa B signaling pathway is a master regulator of renal fibrosis

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 16, 2024

Renal fibrosis is increasingly recognized as a global public health problem. Acute kidney injury (AKI) and chronic disease (CKD) both result in renal fibrosis. Oxidative stress inflammation play central roles progressive are closely linked form vicious cycle which oxidative induces through various molecular mechanisms. Ample evidence has indicated that hyperactive nuclear factor kappa B (NF-ƙB) signaling pathway plays pivotal role Hyperactive NF-ƙB causes the activation recruitment of immune cells. Inflammation, turn, triggers production reactive oxygen species nitrogen by activating leukocytes resident These events mediate organ apoptosis, necrosis, Therefore, developing strategy to target important for effective treatment This Review summarizes effect on context AKI CKD (immunoglobulin A nephropathy, membranous diabetic hypertensive transplantation). Therapies targeting pathway, including natural products, also discussed. In addition, NF-ƙB-dependent non-coding RNAs involved crucial targets development treatments disease. provides clear pathophysiological rationale specific concept-driven therapeutic pathway.

Language: Английский

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

Cells, Journal Year: 2024, Volume and Issue: 13(17), P. 1413 - 1413

Published: Aug. 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.

Language: Английский

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Cooperation between inhibitory immune checkpoints of senescent cells with immunosuppressive network to promote immunosenescence and the aging process

Ageing Research Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 102694 - 102694

Published: Feb. 1, 2025

Language: Английский

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Reproductive Ageing: Inflammation, immune cells, and cellular senescence in the aging ovary

Reproduction, Journal Year: 2024, Volume and Issue: 168(2)

Published: May 13, 2024

In brief Recent reports suggest a relationship between ovarian inflammation and functional declines, although it remains unresolved if is the cause or consequence of aging. this review, we compile available literature in area point to several current knowledge gaps that should be addressed through future studies. Abstract Ovarian aging results reduced fertility, disrupted endocrine signaling, an increased burden chronic diseases. The factors contributing natural decline follicles throughout reproductive life are not fully understood. Nevertheless, local may play important role driving Inflammation progressively rises aged ovaries during window, potentially affecting fertility. addition inflammatory markers, recent studies show accumulation specific immune cell populations ovaries, particularly lymphocytes. Other hallmarks ovary include formation multinucleated giant cells, collagen deposition, markers cellular senescence. Collectively, these changes significantly impact quantity quality oocytes. This review explores on alterations associated with inflammation, fibrosis, senescence, cells ovary.

Language: Английский

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High glucose dialysate-induced peritoneal fibrosis: Pathophysiology, underlying mechanisms and potential therapeutic strategies

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 165, P. 115246 - 115246

Published: July 29, 2023

Peritoneal dialysis is an efficient renal replacement therapy for patients with end-stage kidney disease. However, continuous exposure of the peritoneal membrane to dialysate frequently leads fibrosis, which alters function and results in withdrawal from patients. Among others, high glucose considered as a predisposing factor fibrosis on dialysis. Glucose-induced inflammation, metabolism disturbance, activation renin-angiotensin-aldosterone system, angiogenesis noninflammation-induced reactive oxygen species are implicated pathogenesis dialysate-induced fibrosis. Specifically, causes chronic inflammation recurrent peritonitis, could cause migration polarization inflammatory cells, well release cytokines High also interferes lipid glycolysis by activating sterol-regulatory element-binding protein-2/cleavage-activating protein pathway increasing hypoxia inducible factor-1α expression, leading Activation system Ras-mitogen activated kinase signaling another contributing Ultimately, transforming growth factor-β1/Smad involved mesothelial-mesenchymal transition or epithelial-mesenchymal transition, development Although possible intervention strategies targeting have occasionally been proposed, lack laboratory evidence renders clinical decision-making difficult. We therefore aim revisit upstream pathways factor-beta1/Smad propose potential therapeutic targets glucose-induced

Language: Английский

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Autologous Fat Grafting—A Panacea for Scar Tissue Therapy?

Cells, Journal Year: 2024, Volume and Issue: 13(16), P. 1384 - 1384

Published: Aug. 20, 2024

Scars may represent more than a cosmetic concern for patients; they impose functional limitations and are frequently associated with the sensation of itching or pain, thus impacting both psychological physical well-being. From an aesthetic perspective, scars display variances in color, thickness, texture, contour, their homogeneity, while aspect encompasses considerations functionality, pliability, sensory perception. located critical anatomic areas have potential to induce profound impairments, including contracture-related mobility restrictions, thereby significantly daily functioning quality life. Conventional approaches scar management suffice certain extent, yet there cases where tailored interventions warranted. Autologous fat grafting emerges as promising therapeutic avenue such instances. Fundamental mechanisms underlying formation include chronic inflammation, fibrogenesis dysregulated wound healing, among other contributing factors. These can potentially be alleviated through application adipose-derived stem cells, which principal cellular component utilized process lipofilling. Adipose-derived cells possess capacity secrete proangiogenic factors fibroblast growth factor, vascular endothelial factor hepatocyte well neurotrophic factors, brain-derived Moreover, exhibit multipotency, remodel extracellular matrix, act paracrine manner, exert immunomodulatory effects cytokine secretion. molecular processes contribute neoangiogenesis, alleviation promotion conducive milieu healing. Beyond obvious benefit restoring volume, regenerative capacities facilitate reduction pruritus, fibrosis. This review elucidates autologous its beneficial on outcomes when applied tissue.

Language: Английский

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Human umbilical cord mesenchymal stem cells inhibit liver fibrosis via the microRNA-148a-5p/SLIT3 axis

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 125, P. 111134 - 111134

Published: Oct. 31, 2023

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have garnered considerable attention as prospective modalities of treatment for liver fibrosis (LF). The inhibition hepatic stellate cell (HSC) activation underlies the anti-fibrotic effects hUC-MSCs. However, precise mechanism by which hUC-MSCs impede HSC remains unclarified. We aimed to elucidate intrinsic mechanisms underlying therapeutic in LF patients.Mice with cirrhosis induced carbon tetrachloride (CCl4) were used experimental models and administered via tail-vein injection. alterations inflammation evaluated through histopathological examinations. RNA sequencing (RNA-seq) bioinformatics analysis then conducted investigate Finally, an in-vitro experiment involving co-cultivation or hUC-MSC-derived exosomes (MSC-Exos) LX2 was performed validate potential hepatoprotective patients.hUC-MSC therapy significantly improved function alleviated CCl4-induced mice. High-throughput RNA-Seq identified 1142 differentially expressed genes that potentially involved mediating These play important role regulating extracellular matrix. miRNA expression data (GSE151098) indicated miR-148a-5p level downregulated samples, but restored following hUC-MSC treatment. delivered exosome pathway, upregulated suppressed activated phenotype cells. SLIT3 within pool target regulated miR-148a-5p. Furthermore, administration miR-148a-5p, played a crucial suppressing SLIT3, thereby palliating fibrosis.hUC-MSCs inhibit HSCs miR-148a-5p/SLIT3 pathway are thus capable alleviating LF.

Language: Английский

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Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti–PD-1 Immune Checkpoint Inhibitor Cancer Therapy

The Journal of Immunology, Journal Year: 2024, Volume and Issue: 212(8), P. 1287 - 1306

Published: March 1, 2024

Myocarditis has emerged as an immune-related adverse event of immune checkpoint inhibitor (ICI) cancer therapy associated with significant mortality. To ensure patients continue to safely benefit from life-saving therapy, understanding fundamental immunological phenomena underlying ICI myocarditis is essential. We recently developed the NOD-cMHCI/II-/-.DQ8 mouse model that spontaneously develops lower mortality than observed in previous HLA-DQ8 NOD strains. Our strain was rendered murine MHC class I and II deficient using CRISPR/Cas9 technology, making it a genetically clean platform for dissecting CD4+ T cell-mediated absence classically selected CD8+ cells. These mice are highly susceptible acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, administration accelerates skeletal muscle myositis. Using histology, flow cytometry, adoptive transfers, RNA sequencing analyses, we performed thorough characterization cardiac cells, identifying shared unique characteristics both populations. Taken together, this report details features rare, but lethal clinical presentation overlapping myositis therapy. This study sheds light on mechanisms provides basis further detailed analyses diagnostic therapeutic strategies.

Language: Английский

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Crosstalk between adipogenesis and aging: role of polyphenols in combating adipogenic-associated aging

Immunity & Ageing, Journal Year: 2024, Volume and Issue: 21(1)

Published: Nov. 7, 2024

In the last forty years, number of people over 60 years age has increased significantly owing to better nutrition and lower rates infectious diseases in developing countries. Aging impacts adipose tissue, which plays crucial role hormone regulation energy storage. This can lead imbalances glucose, overall homeostasis within body. is irreversible phenomena potentially causing lipid infiltration other organs, leading systemic inflammation, metabolic disorders. review investigates various pathways contributing aging-related defects adipogenesis, such as changes tissue function distribution. Polyphenols, a diverse group natural compounds, mitigate aging effects via free radicals, oxidative stress, senescence, age-related diseases. Polyphenols like resveratrol, quercetin EGCG exhibit distinct mechanisms regulate pathways, TGF-β, AMPK, Wnt, PPAR-γ, C/EBP transcription factors, influence epigenetic modifications, DNA methylation histone modification. highlights critical importance understanding intricate relationship between adipogenesis for optimizing well-being with increasing age. These findings highlight therapeutic potential polyphenols resveratrol enhancing promoting healthy aging.

Language: Английский

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