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Our study aimed to investigate the impact of environmental exposures, such as ambient air pollutants, on systemic inflammation and cellular senescence in middle-aged and older women. We utilized epidemiological data linked with exposure data of six air pollutants (particulate matters [PM10, PM2.5], sulphur dioxide [SO2], nitrogen dioxide [NO2], carbon monoxide [CO], and ozone [O3]) and blood samples of 380 peri- and postmenopausal women participants of the Korean Genome and Epidemiology Study. We measured blood high-sensitivity C-reactive protein (hsCRP) and age-related 27 circulatory senescence-associated secretory phenotypes (SASP) produced by senescent cells. We employed single exposure models to explore the general pattern of association between air pollution exposure and proteomic markers. Using quantile g-computation models, we assessed the association of six air pollutant mixtures with hsCRP and SASP proteins. In single-exposure, single-period models, nine out of the 27 SASP proteins including IFN-γ (ß = 0.04, 95% CI: 0.01, 0.07 per interquartile range-increase), IL-8 (0.15, 95% CI: 0.09, 0.20), and MIP1α (0.11, 95% CI: 0.04, 0.18) were positively associated with the average level of O3 over one week. Among the age-related SASP proteins, IFN-γ (0.11, 95% CI: 0.03, 0.20) and IL-8 (0.22, 95% CI: 0.05, 0.39) were positively associated with exposure to air pollutant mixture over one week. The MIP1ß was higher with an increasing one-month average concentration of the air pollutant mixture (0.11, 95% CI: 0.00, 0.21). The IL-8 showed consistently positive association with the ambient air pollutant mixture for the exposure periods ranging from one week to one year. O3 predominantly showed positive weights in the associations between air pollutant mixtures and IL-8. These findings underscore the potential of proteomic indicators as markers for biological aging attributed to short-term air pollution exposure.
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The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the "SASP Atlas," a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA). Our findings will facilitate the identification of proteins characteristic of senescence-associated phenotypes and catalog potential senescence biomarkers to assess the burden, originating stimulus, and tissue of origin of senescent cells in vivo.
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Envejecimiento/metabolismo , Biomarcadores/metabolismo , Senescencia Celular/fisiología , Proteoma/análisis , Vías Secretoras/fisiología , Biomarcadores/análisis , Células Cultivadas , Bases de Datos de Proteínas , Exosomas/química , Exosomas/metabolismo , Femenino , Humanos , Fenotipo , Proteoma/metabolismo , ProteómicaRESUMEN
Background and Objectives: The medial collateral ligament (MCL) is one of the major supporting ligaments of the knee joint, and MCL injuries are common where excessive valgus loading is applied to the knee joint. Although most MCL injuries can be treated conservatively, healing of the MCL can take several weeks to months. Furthermore, once injured, the biomechanical properties of the healed MCL differ from those of the native MCL, resulting in an increased risk of re-injury and chronic remnant symptoms. Mesenchymal stem cells (MSCs), owing to their therapeutic potential, have been investigated in various musculoskeletal injuries, and some preclinical studies regarding MSC-based approaches in MCL injuries have shown promising results. Despite satisfactory results in preclinical studies, there is still a lack of clinical studies in the orthopedic literature. This article describes the basic knowledge of the MCL, standard treatments for MCL injuries, and recent studies regarding the application of MSCs for enhanced healing of the MCL. MSC-based approaches are expected to be a potential therapeutic option for enhanced healing of the MCL in the future.
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Lesiones del Ligamento Cruzado Anterior , Ligamentos Colaterales , Células Madre Mesenquimatosas , Humanos , Articulación de la Rodilla/cirugía , Cicatrización de HeridasRESUMEN
BACKGROUND: Recent studies have reported improved diastolic function in patients administered sodium-glucose cotransporter 2 inhibitors (SGLT2i). We aimed to investigate the effect of dapagliflozin on left ventricular (LV) diastolic function in a diabetic animal model and to determine the molecular and cellular mechanisms underlying its function. METHODS: A total of 30 male New Zealand white rabbits were randomized into control, diabetes, or diabetes+dapagliflozin groups (n = 10/per each group). Diabetes was induced by intravenous alloxan. Cardiac function was evaluated using echocardiography. Myocardial samples were obtained for histologic and molecular evaluation. For cellular evaluation, fibrosis-induced cardiomyoblast (H9C2) cells were obtained, and transfection was performed for mechanism analysis (serum and glucocorticoid-regulated kinase 1 (SGK1) signaling analysis). RESULTS: The diabetes+dapagliflozin group showed attenuation of diastolic dysfunction compared with the diabetes group. Dapagliflozin inhibited myocardial fibrosis via inhibition of SGK1 and epithelial sodium channel (ENaC) protein, which was observed both in myocardial tissue and H9C2 cells. In addition, dapagliflozin showed an anti-inflammatory effect and ameliorated mitochondrial disruption. Inhibition of SGK1 expression by siRNA decreased and ENaC and Na+/H+ exchanger isoform 1 (NHE1) expression was confirmed as significantly reduced as siSGK1 in the diabetes+dapagliflozin group. CONCLUSIONS: Dapagliflozin attenuated left ventricular diastolic dysfunction and cardiac fibrosis via regulation of SGK1 signaling. Dapagliflozin also reduced macrophages and inflammatory proteins and ameliorated mitochondrial disruption.
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Diabetes Mellitus , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Masculino , Conejos , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Fibrosis , Glucósidos/farmacología , Glucósidos/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
Despite remarkable advances in the clinical outcomes after anterior cruciate ligament reconstructions (ACLRs), residual rotational instability of the knee joint remains a major concern. Since the anterolateral ligament (ALL) on the knee joint has been "rediscovered", the role of anterolateral structures, including ALL and deep iliotibial band, as secondary stabilizers of anterolateral rotatory instability has gained interest. This interest has led to the resurgence of anterolateral procedures combined with ACLRs to restore rotational stability in patients with anterior cruciate ligament (ACL) deficiencies. However, the difference in concepts between anterolateral ligament reconstructions (ALLRs) as anatomical reconstruction and lateral extra-articular tenodesis (LETs) as non-anatomical reinforcement has been conflicting in present literature. This study aimed to review the anatomy and biomechanics of anterolateral structures, surgical techniques, and the clinical outcomes of anterolateral procedures, including LET and ALLR, in patients with ACL deficiencies.
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Lesiones del Ligamento Cruzado Anterior , Reconstrucción del Ligamento Cruzado Anterior , Inestabilidad de la Articulación , Ligamento Cruzado Anterior , Lesiones del Ligamento Cruzado Anterior/cirugía , Reconstrucción del Ligamento Cruzado Anterior/métodos , Fenómenos Biomecánicos , Cadáver , Humanos , Inestabilidad de la Articulación/cirugía , Articulación de la Rodilla/cirugía , Rango del Movimiento ArticularRESUMEN
The intricate interplay between cellular senescence and alterations in the gut microbiome emerges as a pivotal axis in the aging process, increasingly recognized for its contribution to systemic inflammation, physiological decline, and predisposition to age-associated diseases. Cellular senescence, characterized by a cessation of cell division in response to various stressors, induces morphological and functional changes within tissues. The complexity and heterogeneity of senescent cells, alongside the secretion of senescence-associated secretory phenotype, exacerbate the aging process through pro-inflammatory pathways and influence the microenvironment and immune system. Concurrently, aging-associated changes in gut microbiome diversity and composition contribute to dysbiosis, further exacerbating systemic inflammation and undermining the integrity of various bodily functions. This review encapsulates the burgeoning research on the reciprocal relationship between cellular senescence and gut dysbiosis, highlighting their collective impact on age-related musculoskeletal diseases, including osteoporosis, sarcopenia, and osteoarthritis. It also explores the potential of modulating the gut microbiome and targeting cellular senescence as innovative strategies for healthy aging and mitigating the progression of aging-related conditions. By exploring targeted interventions, including the development of senotherapeutic drugs and probiotic therapies, this review aims to shed light on novel therapeutic avenues. These strategies leverage the connection between cellular senescence and gut microbiome alterations to advance aging research and development of interventions aimed at extending health span and improving the quality of life in the older population.
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A disintegrin and metalloproteinase 15 (ADAM15), the only ADAM protein containing an Arg-Gly-Asp (RGD) motif in its disintegrin-like domain, is a widely expressed membrane protein that is involved in tumor progression and suppression. However, the underlying mechanism of ADAM15-mediated tumor suppression is not clearly understood. This study demonstrates that ADAM15 is released as an exosomal component, and ADAM15 exosomes exert tumor suppressive activities. We found that exosomal ADAM15 release is stimulated by phorbol 12-myristate 13-acetate, a typical protein kinase C activator, in various tumor cell types, and this results in a corresponding decrease in plasma membrane-associated ADAM15. Exosomes rich in ADAM15 display enhanced binding affinity for integrin αvß3 in an RGD-dependent manner and suppress vitronectin- and fibronectin-induced cell adhesion, growth, and migration, as well as in vivo tumor growth. Exosomal ADAM15 is released from human macrophages, and macrophage-derived ADAM15 exosomes have tumor inhibitory effects. This work suggests a primary role of ADAM15 for exosome-mediated tumor suppression, as well as functional significance of exosomal ADAM protein in antitumor immunity.
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Proteínas ADAM/metabolismo , Exosomas/metabolismo , Macrófagos/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas ADAM/genética , Proteínas ADAM/inmunología , Animales , Secuencia de Bases , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , ADN Complementario/genética , Exocitosis , Exosomas/efectos de los fármacos , Femenino , Humanos , Integrina alfaVbeta3/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteína Quinasa C/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Trasplante Heterólogo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/inmunología , Proteínas Supresoras de Tumor/metabolismo , Vitronectina/metabolismoRESUMEN
OBJECTIVE: This study aimed to examine the association of circulating senescence-associated secretory phenotype proteins, secreted by senescent cells, with indicators of women's ovarian reserve. METHODS: This secondary analysis of cross-sectional baseline survey data was undertaken by the Korean Genome and Epidemiology Study Cardiovascular Disease Association Study. A total of 223 women (aged 40-82 y), without any history of oophorectomy, hysterectomy, or other medical conditions that could lower the ovarian reserve, were enrolled in this analysis. Chronological age (years), menopausal status, and serum anti-müllerian hormone (ng/mL) level were used to assess the associations among biological aging, accelerated menopausal aging, and ovarian reserve. RESULTS: Of the 223 women participants (53.4 ± 11.0 y), 147 (46.4 ± 3.9 y) and 76 (67.0 ± 6.9 y) were premenopausal and postmenopausal, respectively. Serum levels of senescence-associated secretory phenotype proteins were generally higher in postmenopausal, than in premenopausal, women. In the analyses adjusted for chronological age and body mass index, 17 senescence-associated secretory phenotype proteins were associated with menopausal status. However, in premenopausal women, no association trends with the level of anti-müllerian hormone were detected for a total of 28 senescence-associated secretory phenotype proteins. CONCLUSIONS: In a cohort of middle-aged/older women, the level of circulating senescence-associated secretory phenotype proteins indicated chronological age and menopausal status. Yet, serum levels of senescence-associated secretory phenotype protein potentially have limited predictive value for ascertaining ovarian reserve in premenopausal women.
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Reserva Ovárica , Persona de Mediana Edad , Femenino , Humanos , Anciano , Estudios Transversales , Hormona Antimülleriana , Fenotipo Secretor Asociado a la Senescencia , MenopausiaRESUMEN
Senolytic drugs are designed to selectively clear senescent cells (SnCs) that accumulate with injury or aging. In a mouse model of osteoarthritis (OA), senolysis yields a pro-regenerative response, but the therapeutic benefit is reduced in aged mice. Increased oxidative stress is a hallmark of advanced age. Therefore, here we investigate whether senolytic treatment differentially affects joint oxidative load in young and aged animals. We find that senolysis by a p53/MDM2 interaction inhibitor, UBX0101, reduces protein oxidative modification in the aged arthritic knee joint. Mass spectrometry coupled with protein interaction network analysis and biophysical stability prediction of extracted joint proteins revealed divergent responses to senolysis between young and aged animals, broadly suggesting that knee regeneration and cellular stress programs are contrarily poised to respond as a function of age. These opposing responses include differing signatures of protein-by-protein oxidative modification and abundance change, disparate quantitative trends in modified protein network centrality, and contrasting patterns of oxidation-induced folding free energy perturbation between young and old. We develop a composite sensitivity score to identify specific key proteins in the proteomes of aged osteoarthritic joints, thereby nominating prospective therapeutic targets to complement senolytics.
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Osteoartritis , Senoterapéuticos , Masculino , Ratones , Animales , Modelos Animales de Enfermedad , Estrés Oxidativo , Envejecimiento/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Senescencia CelularRESUMEN
Despite the introduction of a diagnostic code and acceptance of a diagnostic process for sarcopenia as a new health technology in Korea, many practitioners remain unfamiliar with the evaluation of sarcopenia. Thus, the Korean Working Group on Sarcopenia (KWGS) developed clinical practice guidelines for the diagnosis of sarcopenia in older Korean adults. A two-phase Delphi interview comprising 19 questions was conducted with 40 expert panelists, 22 of whom participated in the first round between June and August 2022. The second round of the Delphi interview included the remaining 11 questions that were not agreed upon in the first round. The screening process for sarcopenia includes various questionnaires and examinations used in different research and clinical settings. The diagnostic process for sarcopenia was simplified by combining the steps of case finding and assessment. The Short Physical Performance Battery test was given particular emphasis owing to its multifaceted nature. Regardless of muscle mass, having low muscle strength with low physical performance is considered clinically relevant and newly defined as "functional sarcopenia." Comprehensive geriatric assessment is important for diagnosing sarcopenia. The KWGS's clinical guideline aims to facilitate the early detection of sarcopenia by allowing various screening tools to be used in a unified process and reducing confusion about which tools to use for diagnosis. This recommendation expands the conceptual definition of sarcopenia as a complex pathophysiological state in line with the concept of frailty and aims to stimulate further research on the diagnosis and management of sarcopenia in clinical settings.
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We aimed to investigate the association of circulatory senescence-associated secretory phenotypes (SASPs) produced by senescent cells with chronological and menopausal age in women aged 45 years or more. The proteomic profiles for 32 SASP factors of plasma samples were measured in 76 healthy postmenopausal women aged 46-82 years from the Korean Genome and Epidemiology Study Cardiovascular Disease Association Study (KoGES-CAVAS). We assessed the association between the SASP factors and aging indicators (chronological age, menopausal age, and years since menopause) using single- and multiprotein models. First, we composed a profile of proteins associated with chronological age, menopausal age, and years since menopause. In a single-protein model, three proteins (growth differentiation factor 15 [GDF15], insulin-like growth factor binding protein-2 [IGFBP-2], and tumor necrosis factor-α [TNF-α]) are positively associated with chronological age. Menopausal age and years since menopause are interrelated with interleukin-8 (IL-8). The direction of association between menopausal age and monocyte chemoattractant protein-1 (MCP-1) was only negative, and IGFBP-2 and TNF-α were significant in all three aging factors. We also constructed parsimonious multiprotein models to confirm the association of the proteomic signature for aging after adjusting for covariates and the combination of proteomic signature of 13 proteins (GDF15, interferon-γ [IFN-γ], IGFBP-2, IGFBP-7, IL-15, IL-1ß, IL-17A, IL-8, MCP-1, tissue inhibitors of metalloproteinase-2 [TIMP-2], TNF-α, vascular endothelial growth factor-A [VEGF-A], and interferon-inducible protein 10 [IP-10]) appear to be associated with chronological age and menopausal state of individuals. Thus, by observing association between the selected SASPs and age-related markers among healthy postmenopausal women, we examine how menopause in women relates to proteomic indicators of aging and highlight the potential use of SASP factors as a marker to reflect the state of biological aging attributed by ovarian senescence.
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Envejecimiento , Senescencia Celular , Proteoma , Anciano , Anciano de 80 o más Años , Envejecimiento/metabolismo , Biomarcadores , Quimiocina CCL2/metabolismo , Femenino , Factor 15 de Diferenciación de Crecimiento/metabolismo , Humanos , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Interleucina-8/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Persona de Mediana Edad , Posmenopausia , Proteómica , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Despite remarkable improvements in clinical outcomes after anterior cruciate ligament reconstruction, the residual rotational instability of knee joints remains a major concern. The anterolateral ligament (ALL) has recently gained attention as a distinct ligamentous structure on the anterolateral aspect of the knee joint. Numerous studies investigated the anatomy, function, and biomechanics of ALL to establish its potential role as a stabilizer for anterolateral rotational instability. However, controversies regarding its existence, prevalence, and femoral and tibial insertions need to be addressed. According to a recent consensus, ALL exists as a distinct ligamentous structure on the anterolateral aspect of the knee joint, with some anatomic variations. The aim of this article was to review the updated anatomy of ALL and present the most accepted findings among the existing controversies. Generally, ALL originates slightly proximal and posterior to the lateral epicondyle of the distal femur and has an anteroinferior course toward the tibial insertion between the tip of the fibular head and Gerdy's tubercle below the lateral tibial plateau.
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Cells secrete extracellular vesicles (EVs) carrying cell-of-origin markers to communicate with surrounding cells. EVs regulate physiological processes ranging from intercellular signaling to waste management. However, when senescent cells (SnCs) secrete EVs, the EVs, which are newly regarded as senescence-associated secretory phenotype (SASP) factors, can evoke inflammation, senescence induction, and metabolic disorders in neighboring cells. Unlike other soluble SASP factors, the biophysical properties of EVs, including small EVs (sEVs), derived from SnCs have not yet been investigated. In this study, sEVs were extracted from a human IMR90 lung fibroblast in vitro senescence model. Their biomechanical properties were mapped using atomic force microscopy-based quantitative nanomechanical techniques, surface potential microscopy, and Raman spectroscopy. The surfaces of sEVs derived from SnCs are slightly stiffer but their cores are softer than those of sEVs secreted from non-senescent cells (non-SnCs). This inversely proportional relationship between deformation and stiffness, attributed to a decrease in the concentration of genetic and protein materials inside the vesicles and the adsorption of positively charged SASP factors onto the vesicle surfaces, respectively, was found to be a peculiar characteristic of SnC-derived sEVs. Our results demonstrate that the biomechanical properties of SnC-derived sEVs differ from those of non-SnC-derived sEVs and provide insight into the mechanisms underlying their formation and composition.
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Vesículas Extracelulares , Espectrometría Raman , Humanos , Microscopía de Fuerza Atómica , Fibroblastos/metabolismo , BiofisicaRESUMEN
Aging is a risk factor for the development of osteoarthritis (OA), a progressive joint disease leading to cartilage damage, pain, and loss of function. In a mouse model of OA, senolytic drugs to selectively clear senescent cells (SnCs) that accumulate with injury or aging yielded a chondroprotective effect; however, this therapeutic benefit was limited in aged mice. Due to inconsistency between cartilage destruction and pain-associated symptoms, we studied the therapeutic effect of senolytics on joint pain in spontaneous OA. We orally treated 21- and 22-month old mice with an ABT263 and Dasatinib and Quercetin (D+Q) drug combination. Selective elimination of the SnCs that accumulated in the articular cartilage and synovium by these two drugs did not alter cartilage degeneration and abnormal bone changes during spontaneous OA progression. Treatment reduced thermal and mechanical hyperalgesia associated with OA and peripheral sensitization through decreased expression of axon guidance proteins (nerve growth factor NGF/TrkA) and nociceptive neuron (calcitonin gene-related peptide, CGRP) projection to the synovium, subchondral bone marrow, and dorsal root ganglion, and knee joint angiogenesis. Selective removal of the SnCs from in vitro cultures of synovial cells from human OA patients also decreased expression of senescent markers, axonal growth-promoting factors, such as NGF, and angiogenesis markers. We suggest that systemic administration of ABT263 and D+Q is an exciting therapeutic approach to age-related OA pain.
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Factor de Crecimiento Nervioso , Osteoartritis , Animales , Humanos , Ratones , Nocicepción , Osteoartritis/metabolismo , Dolor , Preparaciones Farmacéuticas , SenoterapéuticosRESUMEN
ABSTACT: Ageing is the largest risk factor for many chronic diseases. Studies of heterochronic parabiosis, substantiated by blood exchange and old plasma dilution, show that old-age-related factors are systemically propagated and have pro-geronic effects in young mice. However, the underlying mechanisms how bloodborne factors promote ageing remain largely unknown. Here, using heterochronic blood exchange in male mice, we show that aged mouse blood induces cell and tissue senescence in young animals after one single exchange. This induction of senescence is abrogated if old animals are treated with senolytic drugs before blood exchange, therefore attenuating the pro-geronic influence of old blood on young mice. Hence, cellular senescence is neither simply a response to stress and damage that increases with age, nor a chronological cell-intrinsic phenomenon. Instead, senescence quickly and robustly spreads to young mice from old blood. Clearing senescence cells that accumulate with age rejuvenates old circulating blood and improves the health of multiple tissues.
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Senescencia Celular , Parabiosis , Envejecimiento/fisiología , Animales , Senescencia Celular/fisiología , Masculino , RatonesRESUMEN
BACKGROUND: Ferroptosis is an iron-dependent, non-apoptotic programmed cell death. Cellular senescence contributes to aging and various age-related diseases through the expression of a senescence-associated secretory phenotype (SASP). Senescent cells are often resistant to ferroptosis via increased ferritin and impaired ferritinophagy. In this study, we investigated whether treatment with JQ1 could remove senescent cells by inducing ferroptosis. METHODS: Senescence of human dermal fibroblasts was induced in vitro by treating the cells with bleomycin. The senolytic effects of JQ1 were evaluated using a SA-ß gal assay, annexin V analysis, cell counting kit-8 assay, and qRT-PCR. Ferroptosis following JQ1 treatment was evaluated with qRT-PCR and BODIPY staining. RESULTS: At a certain range of JQ1 concentrations, JQ1 treatment reduced the viability of bleomycin-treated cells (senescent cells) but did not reduce that of untreated cells (non-senescent cells), indicating that JQ1 treatment can selectively eliminate senescent cells. JQ1 treatment also decreased SASP expression only in senescent cells. Subsequently, JQ1 treatment reduced the expression of ferroptosis-resistance genes in senescent cells. JQ1 treatment induced lipid peroxidation in senescent cells but not in non-senescent cells. CONCLUSION: The data indicate that JQ1 can eliminate senescent cells via ferroptosis. This study suggests ferroptosis as a new mechanism of senolytic therapy.
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Ferroptosis , Preparaciones Farmacéuticas , Envejecimiento , Senescencia Celular , Fibroblastos , HumanosRESUMEN
The meniscus is a semilunar fibrocartilage structure that plays important roles in maintaining normal knee biomechanics and function. The roles of the meniscus, including load distribution, force transmission, shock absorption, joint stability, lubrication, and proprioception, have been well established. Injury to the meniscus can disrupt overall joint stability and cause various symptoms including pain, swelling, giving-way, and locking. Unless treated properly, it can lead to early degeneration of the knee joint. Because meniscal injuries remain a significant challenge due to its low intrinsic healing potential, most notably in avascular and aneural inner two-thirds of the area, more efficient repair methods are needed. Mesenchymal stem cells (MSCs) have been investigated for their therapeutic potential in vitro and in vivo. Thus far, the application of MSCs, including bone marrow-derived, synovium-derived, and adipose-derived MSCs, has shown promising results in preclinical studies in different animal models. These preclinical studies could be categorized into intra-articular injection and tissue-engineered construct application according to delivery method. Despite promising results in preclinical studies, there is still a lack of clinical evidence. This review describes the basic knowledge, current treatment, and recent studies regarding the application of MSCs in treating meniscal injuries. Future directions for MSC-based approaches to enhance meniscal healing are suggested.
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The clinical use of bioactive molecules in bone regeneration has been known to have side effects, which result from uncontrolled and supraphysiological doses. In this study, we demonstrated the synergistic effect of two bioactive molecules, bone morphogenic protein-2 (BMP-2) and alendronate (ALN), by releasing them in a sequential manner. Collagen-hydroxyapatite composite scaffolds functionalized using BMP-2 are loaded with biodegradable microspheres where ALN is encapsulated. The results indicate an initial release of BMP-2 for a few days, followed by the sequential release of ALN after two weeks. The composite scaffolds significantly increase osteogenic activity owing to the synergistic effect of BMP-2 and ALN. Enhanced bone regeneration was identified at eight weeks post-implantation in the rat 8-mm critical-sized defect. Our findings suggest that the sequential delivery of BMP-2 and ALN from the scaffolds results in a synergistic effect on bone regeneration, which is unprecedented. Therefore, such a system exhibits potential for the application of cell-free tissue engineering.
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Alendronato/administración & dosificación , Proteína Morfogenética Ósea 2/administración & dosificación , Regeneración Ósea , Durapatita/química , Ingeniería de Tejidos/métodos , Andamios del Tejido/química , Alendronato/farmacología , Animales , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/farmacología , Diferenciación Celular , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Our recent study has established that young blood factors are not causal, nor necessary, for the systemic rejuvenation of mammalian tissues. Instead, a procedure referred to as neutral blood exchange (NBE) that resets signaling milieu to a pro-regenerative state through dilution of old plasma, enhanced the health and repair of the muscle and liver, and promoted better hippocampal neurogenesis in 2-year-old mice (Mehdipour et al., Aging 12:8790-8819, 2020). Here we expand the rejuvenative phenotypes of NBE, focusing on the brain. Namely, our results demonstrate that old mice perform much better in novel object and novel texture (whisker discrimination) tests after a single NBE, which is accompanied by reduced neuroinflammation (less-activated CD68+ microglia). Evidence against attenuation/dilution of peripheral senescence-associated secretory phenotype (SASP) as the main mechanism behind NBE was that the senolytic ABT 263 had limited effects on neuroinflammation and did not enhance hippocampal neurogenesis in the old mice. Interestingly, peripherally acting ABT 263 and NBE both diminished SA-ßGal signal in the old brain, demonstrating that peripheral senescence propagates to the brain, but NBE was more robustly rejuvenative than ABT 263, suggesting that rejuvenation was not simply by reducing senescence. Explaining the mechanism of the positive effects of NBE on the brain, our comparative proteomics analysis demonstrated that dilution of old blood plasma yields an increase in the determinants of brain maintenance and repair in mice and in people. These findings confirm the paradigm of rejuvenation through dilution of age-elevated systemic factors and extrapolate it to brain health and function.
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Cognición , Rejuvenecimiento , Envejecimiento , Animales , Ratones , Neurogénesis , PlasmaRESUMEN
Extracellular RNAs (exRNAs) are a type of RNA molecules that present in various biological fluids. exRNAs are heterogenous populations including small (e.g., miRNA) and long non-coding RNAs and coding RNAs (e.g., mRNA). They can exist in a free form or associate with carriers range from lipo- and ribo-proteins to extracellular vesicles such as exosomes in the extracellular fluids. exRNAs participate in cell-to-cell communication to regulate a broad array of physiological and pathological processes. exRNAs have been widely studied as a biomarker for cancer and other diseases. In this review, we will discuss the sorts of exRNAs with potential carriers as well as their roles in cancer.