Endothelin-1 induces cellular senescence and fibrosis in cultured myoblasts. A potential mechanism of aging-related sarcopenia

Alcalde-Estévez, Elena; Asenjo-Bueno, Ana; Sosa, Patricia; Olmos, Gemma; Plaza, Patricia; Mora, María Ángeles Caballero; Rodríguez‐Puyol, Diego; Ruíz-Torres, María Piedad; López‐Ongil, Susana

doi:10.18632/aging.103450

Cited by 23 publications

(14 citation statements)

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“… 66 α-SMA and Fn are universally known and characterized protein used for assessment of fibrosis in several tissues and organs including the kidney and the relative incorporation of the fibrotic markers α-SMA and Fn into the matrix increases in response to TGF-β. 67 , 68 Considering that inflammation-related cytokines and fibrosis-related factors play an important role in the pathological process of MesPGN, we investigated the expression levels of inflammatory chemokine CCL2, TNF-α, IL-6, IL-β1, TGF-β, α-SMA and Fn. We found that the expression levels of the above factors were significantly increased after HSV modeling, indicating that HSV can effectively promote the expression of inflammation and fibrosis factors in nephritis mice, and the MesPGN model was successfully induced by injected HSV twice through tail vein for evaluating the therapeutic effects of DXMS/CAP@PLGA-ILs in MesPGN.…”

Section: Discussionmentioning

confidence: 99%

Co-Delivery of Dexamethasone and Captopril by α8 Integrin Antibodies Modified Liposome-PLGA Nanoparticle Hybrids for Targeted Anti-Inflammatory/Anti-Fibrosis Therapy of Glomerulonephritis

Zhou

Zhang³

et al. 2022

IJN

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Purpose Mesangial cells-mediated glomerulonephritis refers to a category of immunologically mediated glomerular injuries characterized by infiltration of circulating inflammatory cells, proliferation of mesangial cells, and the common pathological manifestation to the later stage is renal fibrosis, accompanied by excessive accumulation of extracellular matrix (ECM). Treatment regimens include glucocorticoids and immunosuppressive agents, but their off-target distribution causes severe systemic toxicity. Hence, specific co-delivery of “anti-inflammatory/anti-fibrosis” drugs to the glomerular mesangial cell (MC) region is expected to produce better therapeutic effects. Methods A novel kidney-targeted nanocarrier drug delivery system targeting MCs was constructed using passive targeting resulting from the difference in pore size between the glomerular endothelial layer and the basement membrane, and active targeting based on the specific binding of antibodies and antigens. Specifically, a liposome-nanoparticle hybrid (PLGA-LNHy) was formed by coating the surface of PLGA nanoparticles (NPs) with a phospholipid bilayer, and then PLGA-LNHy was co-modified with PEG and α8 integrin antibodies to obtain PLGA immunoliposomes (PLGA-ILs). Results The results showed that the obtained NPs had a core-shell structure, uniform and suitable particle size (119.1 ± 2.31 nm), low cytotoxicity, and good mesangial cell-entry ability, which can successfully accumulate in the glomerular MC region. Both dexamethasone (DXMS) and captopril (CAP) were loaded onto PLGA-ILs with a drug loading of 10.22 ± 1.00% for DXMS and 6.37 ± 0.25% for CAP (DXMS/CAP@PLGA-ILs). In vivo pharmacodynamics showed that DXMS/CAP@PLGA-ILs can effectively improve the pathological changes in the mesangial area and positive expression of proliferating cell nuclear antigen (PCNA) in glomeruli as well as reduce the expression of inflammatory factors, fibrotic factors and reactive oxygen species (ROS). Thus, renal inflammation and fibrosis were relieved. Conclusion We have provided a strategy to increase nanoparticle accumulation in MCs with the potential to implement regulatory effects of anti-inflammatory and anti-fibrosis in glomerulonephritis (GN).

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Section: Discussionmentioning

confidence: 99%

Co-Delivery of Dexamethasone and Captopril by α8 Integrin Antibodies Modified Liposome-PLGA Nanoparticle Hybrids for Targeted Anti-Inflammatory/Anti-Fibrosis Therapy of Glomerulonephritis

Zhou

Zhang³

et al. 2022

IJN

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“…Total RNA from endothelial cells or aorta tissue from mice were isolated using Trizol reagent according to the manufacturer’s protocol. cDNA was synthesized using a High Capacity cDNA reverse transcription kit [ 28 , 51 ]. The expressions of IL-1 beta, IL-6, TNF-alfa and MCP-1 in endothelial cells and the expression of endothelial nitric oxide synthase (Nos3), inducible nitric oxide synthase (Nos2), Nrf-2 factor (Nfe2l2), glutathione peroxidase-1 (Gpx1) and superoxide dismutase-2 Mn (Sod2-Mn) in aortas from mice were determined by quantitative PCR (ABI Prism 7500 Fast Real-Time PCR System) and analyzed with 7500 Fast sequence detection software v1.3.1 (Applied Biosystems Inc., Foster City, CA, USA), using specific TaqMan assays and Double delta Ct method.…”

Section: Methodsmentioning

confidence: 99%

Hyperphosphatemia-Induced Oxidant/Antioxidant Imbalance Impairs Vascular Relaxation and Induces Inflammation and Fibrosis in Old Mice

et al. 2021

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Aging impairs vascular function, but the mechanisms involved are unknown. The aim of this study was to analyze whether aging-related hyperphosphatemia is implied in this effect by elucidating the role of oxidative stress. C57BL6 mice that were aged 5 months (young) and 24 months (old), receiving a standard (0.6%) or low-phosphate (0.2%) diet, were used. Isolated mesenteric arteries from old mice showed diminished endothelium-dependent vascular relaxation by the down-regulation of NOS3 expression, increased inflammation and increased fibrosis in isolated aortas, compared to those isolated from young mice. In parallel, increased Nox4 expression and reduced Nrf2, Sod2-Mn and Gpx1 were found in the aortas from old mice, resulting in oxidant/antioxidant imbalance. The low-phosphate diet improved vascular function and oxidant/antioxidant balance in old mice. Mechanisms were analyzed in endothelial (EC) and vascular smooth muscle cells (SMCs) treated with the phosphate donor ß-glycerophosphate (BGP). In EC, BGP increased Nox4 expression and ROS production, which reduced NOS3 expression via NFκB. BGP also increased inflammation in EC. In SMC, BGP increased Collagen I and fibronectin expression by priming ROS production and NFκB activity. In conclusion, hyperphosphatemia reduced endothelium-dependent vascular relaxation and increased inflammation and vascular fibrosis through an impairment of oxidant/antioxidant balance in old mice. A low-phosphate diet achieved improvements in the vascular function in old mice.

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“…Recent research has implicated cellular senescence-associated alterations in MuSCs as one of the causative mechanism of age-associated sarcopenia, which may result from loss of muscle regenerative potential. Skeletal muscle has plasticity of regeneration and remodeling due to MuSCs function, and the age-related decline of skeletal muscle mass and function (known as sarcopenia) is associated with loss of MuSCs regenerative capacity with aging ( Sousa-Victor and Munoz-Canoves, 2016 ).Researches about some factors such as endothelin-1, TRIM32, and GSK-3α inducing MuSCs senescence, in which knockout of each of these factors results in muscle degeneration and sarcopenia development, have been carried out in this field ( Kudryashova et al, 2012 ; Zhou et al, 2013 ; Alcalde-Estévez et al, 2020 ). Extrinsic changes and intrinsic changes negatively impact MuSC numbers and functionality, which is particularly pronounced in the sarcopenic muscle of both humans and mice ( Sousa-Victor et al, 2014 ; Wan et al, 2021 ).…”

Section: Mechanisms Of Cellular Senescence In Sarcopeniamentioning

confidence: 99%

Cellular Senescence in Sarcopenia: Possible Mechanisms and Therapeutic Potential

Yang

Xie

et al. 2022

Front. Cell Dev. Biol.

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Aging promotes most degenerative pathologies in mammals, which are characterized by progressive decline of function at molecular, cellular, tissue, and organismal levels and account for a host of health care expenditures in both developing and developed nations. Sarcopenia is a prominent age-related disorder in musculoskeletal system. Defined as gradual and generalized chronic skeletal muscle disorder, sarcopenia involves accelerated loss of muscle mass, strength and function, which is associated with increased adverse functional outcomes and evolutionally refers to muscle wasting accompanied by other geriatric syndromes. More efforts have been made to clarify mechanisms underlying sarcopenia and new findings suggest that it may be feasible to delay age-related sarcopenia by modulating fundamental mechanisms such as cellular senescence. Cellular senescence refers to the essentially irreversible growth arrest mainly regulated by p53/p21CIP1 and p16INK4a/pRB pathways as organism ages, possibly detrimentally contributing to sarcopenia via muscle stem cells (MuSCs) dysfunction and the senescence-associated secretory phenotype (SASP) while cellular senescence may have beneficial functions in counteracting cancer progression, tissue regeneration and wound healing. By now diverse studies in mice and humans have established that targeting cellular senescence is a powerful strategy to alleviating sarcopenia. However, the mechanisms through which senescent cells contribute to sarcopenia progression need to be further researched. We review the possible mechanisms involved in muscle stem cells (MuSCs) dysfunction and the SASP resulting from cellular senescence, their associations with sarcopenia, current emerging therapeutic opportunities based on targeting cellular senescence relevant to sarcopenia, and potential paths to developing clinical interventions genetically or pharmacologically.

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Endothelin-1 induces cellular senescence and fibrosis in cultured myoblasts. A potential mechanism of aging-related sarcopenia

Cited by 23 publications

References 58 publications

Co-Delivery of Dexamethasone and Captopril by α8 Integrin Antibodies Modified Liposome-PLGA Nanoparticle Hybrids for Targeted Anti-Inflammatory/Anti-Fibrosis Therapy of Glomerulonephritis

Co-Delivery of Dexamethasone and Captopril by α8 Integrin Antibodies Modified Liposome-PLGA Nanoparticle Hybrids for Targeted Anti-Inflammatory/Anti-Fibrosis Therapy of Glomerulonephritis

Hyperphosphatemia-Induced Oxidant/Antioxidant Imbalance Impairs Vascular Relaxation and Induces Inflammation and Fibrosis in Old Mice

Cellular Senescence in Sarcopenia: Possible Mechanisms and Therapeutic Potential

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