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Increased TWEAK and decreased MyoG expression in age-related impairment of muscle regeneration and H2O2-induced senescence-associated changes in C2C12 cells.

Sarcopenia is characterized by the progressive loss of skeletal muscle mass and strength, accompanied by impaired regenerative capacity. This study examined age-related changes in skeletal muscle regeneration and the associated expression of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and myogenin (MyoG). Male C57BL/6 mice aged 3, 13, and 23 months were subjected to barium chloride (BaCl2)-induced tibialis anterior muscle injury. In parallel, C2C12 cells were exposed to repeated low-dose hydrogen peroxide (H2O2) to induce senescence-associated changes under oxidative stress, a

RNF10 attenuates age-related muscle atrophy by promoting p53 degradation and alleviating oxidative stress.

Evidence identifies proteostasis imbalance and oxidative stress serve as fundamental pathological hallmarks of muscular atrophy, yet ring finger protein 10 (RNF10), a novel E3 ubiquitin ligase, in age-related muscular atrophy remains poorly characterized. Employing a natural aging mouse model and D-galactose-induced senescent C2C12 myotubes, we performed loss- and gain-of-function approaches for RNF10 with the aim of elucidating its downstream regulatory mechanisms. Aged mice showed significant declines in skeletal muscle mass and exercise capacity. Histological analysis revealed a significant

A BCL-xL/BCL-2 PROTAC effectively clears senescent cells in the liver and reduces MASH-driven hepatocellular carcinoma in mice.

Accumulation of senescent cells (SnCs) plays a causative role in many age-related diseases and has also been implicated in the pathogenesis and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Senolytics that can selectively kill SnCs have the potential to be developed as therapeutics for these diseases. Here we report the finding that 753b, a dual BCL-xL/BCL-2 proteolysis-targeting chimera (PROTAC), acts as a potent and liver-tropic senolytic. We found that treatment with 753b selectively reduced SnCs in the liver in aged mice and STAM mice in part due to its s

hESC-derived extracellular vesicles enriched with MFGE-8 and the GSH redox system act as senotherapeutics for neural stem cells in ischemic stroke.

Human embryonic stem cells (hESCs) and their extracellular vesicles (EVs) hold significant potential for tissue repair and regeneration. Neural stem cells (NSCs) in the adult brain often acquire senescent phenotypes after ischemic injuries, releasing neurodegenerative senescence-associated secretory phenotype factors. In this study, we investigated the senotherapeutic effects of hESC-EVs on NSCs and confirmed their neuroprotective effects in neurons via rejuvenation of NSC secretions. Proteomic profiling of hESC-EVs identified MFGE-8 as a critical bridging molecule to NSCs. We also found that

Senolytic-sensitive p16Ink4a+ fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity.

Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identify p16Ink4a+ cancer-associated fibroblasts enriched with senescent phenotypes that promote fatty acid uptake and utilization by aggressive lung adenocarcinoma (LUAD) driven by Kras and p53 mutations. Furthermore, rewiring of lung cancer metabolism by p16Ink4a+ cancer-associated fibroblasts also alters tumor cell identity to a highly plastic/dedifferentiated state associated with

Magnesium promoting OVX rats' rotator cuff tear repair with relieving stem cell senescence effect.

The rotator cuff tear (RCT) repairing of tendon-to-bone junction (enthese) after surgery in osteoporotic patients is mainly hindered by poor bone formation at the damaged humeral tuberosity region. We found that long-term oral supplementation of Magnesium ions (Mg2+) can significantly promote humeral tuberosity bone formation and enthese regeneration after RCT surgery in ovariectomized (OVX) rats, attributing to the promotive effect of Mg2+ on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and its inhibition of new bone mineralization. Meanwhile, the in vitro repl

Wen-Shen-Tong-Luo-Zhi-Tong Decoction alleviates bone loss in aged mice by suppressing LONP1-mediated macrophage senescence.

CONTEXT: Aging leads to senile osteoporosis (SOP), marked by bone loss and increased fracture risk. Macrophages, as active immune cells in bone tissue, play an important role in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) during aging. Wen-Shen-Tong-Luo-Zhi-Tong Decoction (WSTLZTD), a traditional Chinese herbal formula, has been clinically validated for its efficacy in treating SOP. However, the specific mechanisms by which WSTLZTD exerts its anti-SOP effects-particularly through modulating macrophage senescence-remain unclear. OBJECTIVE: The study aims to elucida

The Integration of Olink Proteomics with Transcriptomics Elucidates that TNF-α Induces Senescence and Apoptosis in Transplanted Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) are frequently employed in transplantation therapies for chronic inflammatory diseases. However, the impact of the inflammatory microenvironment on the functionality of MSCs remains poorly understood. Tumor necrosis factor-alpha (TNF-α) is a prevalent inflammatory mediator at transplantation sites, and prior research has indicated that the role of TNF-α in MSCs transplantation is ambiguous. The mechanisms by which TNF-α modulates the function of MSCs require further elucidation. To investigate this, we conducted comprehensive OLINK proteomic and transcriptomic ana

Mitochondria-rich extracellular vesicles derived from the culture supernatant of human synovial Fluid-derived mesenchymal stem cells Inhibited senescence of Stressed/inflammatory Licensed chondrocytes and Delayed Osteoarthritis progression.

BACKGROUND: Mitochondrial dysfunction induces chondrocyte senescence, thereby precipitating articular cartilage (AC) degeneration in the pathogenesis of osteoarthritis (OA). Although the transfer of mitochondria from mesenchymal stem cells (MSCs) to host cells and their potential protective role have been demonstrated, whether MSCs can alleviate chondrocyte mitochondrial dysfunction or reverse OA progression remains unclear. METHODS: A mitochondrial tracer was used to investigate the transfer of mitochondria-rich extracellular vesicles (MEV) derived from the culture supernatant of human synov

Сокращение ячеек не улучшает восстановления мышей при искусственном обезвоживании аутоиммунной энцефаломиэлитом (EAE).

Множественный склероз (MS) — хроническое воспалительное заболевание центральной нервной системы (CNS), характеризующееся демиэлированием на основе иммунных клеток и прогрессивным нейродегенерацией. В последнее время в хронических поражениях MS наблюдались чувствительные клетки (КЦ), что указывает на их возможное участие в прогрессии заболеваний. Вместе с тем роль СК и потенциальные терапевтические выгоды их сокращения с помощью сенолитной терапии еще предстоит определить в экспериментальной аутоиммунной энцефаломиелите (EAE), широко используемой доклинической модели MS. Здесь мы показываем, чт

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… Discussion Cellular senescence is a well-established mechanism that prevents tumorigenesis by inducing irreversible cell cycle arrest triggered by telomere shortening. … As a result, this model imposes limitations on our understanding of the potential role of cellular senescence and the therapeutic effects of senolytic therapy in progressive MS. …

Impairment of the trans-Golgi-Lysosomal Pathway Accelerates Dopaminergic Neuronal Senescence in LRRK2R1627P Rats.

Leucine-rich repeat kinase 2 (LRRK2)-R1628P mutation has been shown to be one of the common risk factors for Parkinson's disease (PD) in Asian populations, but the mechanism by which R1628P mutations cause neuronal dysfunction remains unknown. We used LRRK2R1627P knock-in rats (human LRRK2-R1628P corresponds to rat LRRK2-R1627P) to investigate the R1627P mutation on function of dopaminergic neurons (DANs) and their susceptibility to the environmental toxin Lipopolysaccharide (LPS) during aging. LRRK2R1627P rats showed no significant loss of DANs, dopamine and its metabolites, or motor dysfunct

Filbertone Reduces Senescence in C2C12 Myotubes Treated with Doxorubicin or H2O2 through MuRF1 and Myogenin.

It has been demonstrated that filbertone, the principal flavor compound of hazelnuts, exhibits preventive effects against hypothalamic inflammation, obesity, neurodegenerative diseases, and muscle lipid accumulation. However, its influence on muscle aging has yet to be elucidated. The objective of this study was to investigate the effects of filbertone on muscle aging in C2C12 myotubes subjected to senescence induction by either doxorubicin or hydrogen peroxide. To ascertain the mechanisms by which filbertone exerts its effects, we conducted a series of experiments, including Western blot anal

Sex hormone binding globulin (SHBG) modulates mitochondrial dynamics in PPARγ-depleted equine adipose derived stromal cells.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that promotes adipogenesis, lipid uptake and storage, insulin sensitivity, and glucose metabolism. Hence, defects in PPARγ have been associated to the development of metabolic disorders. Sex hormone-binding globulin (SHBG) is a glycoprotein primarily produced in the liver that regulates the bioavailability of sex hormones. Alike PPARγ, low SHBG levels have been correlated with insulin resistance and associated endocrine abnormalities. Therefore, this study aimed to verify whether SHBG may restore depleted PPARγ

IL-17A exacerbates corpus cavernosum fibrosis and neurogenic erectile dysfunction by inducing CSMC senescence via the mTORC2-ACACA pathway.

BACKGROUND: Neurogenic erectile dysfunction, characterized by neurological repair disorders and progressive corpus cavernosum fibrosis (CCF), is an unbearable disease with limited treatment success. IL-17A exhibits a complex role in tissue remodelling. Nevertheless, the precise role and underlying mechanisms of IL-17A in CCF under denervation remain unclear. METHODS: PCR array was employed to identified differentially expressed genes between neurogenic ED and normal rats. IL-17A expression and its main target cells were analyzed using Western blotting, immunofluorescence and immunohistochemis

The transcription factor GATA6 accelerates vascular smooth muscle cell senescence-related arterial calcification by counteracting the role of anti-aging factor SIRT6 and impeding DNA damage repair.

Arterial calcification is a hallmark of vascular pathology in the elderly and in individuals with chronic kidney disease (CKD). Vascular smooth muscle cells (VSMCs), after attaining a senescent phenotype, are implicated in the calcifying process. However, the underlying mechanism remains to be elucidated. Here, we reveal an aberrant upregulation of transcriptional factor GATA6 in the calcified aortas of humans, mice with CKD and mice subjected to vitamin D3 injection. Knockdown of GATA6, via recombinant adeno-associated virus carrying GATA6 shRNA, inhibited the development of arterial calcific

Restoration of hippocampal neural precursor function by ablation of senescent cells in the aging stem cell niche.

Senescent cells are responsible, in part, for tissue decline during aging. Here, we focused on CNS neural precursor cells (NPCs) to ask if this is because senescent cells in stem cell niches impair precursor-mediated tissue maintenance. We demonstrate an aging-dependent accumulation of senescent cells, largely senescent NPCs, within the hippocampal stem cell niche coincident with declining adult neurogenesis. Pharmacological ablation of senescent cells via acute systemic administration of the senolytic drug ABT-263 (Navitoclax) caused a rapid increase in NPC proliferation and neurogenesis. Gen

Type I Interferon Induction in Cutaneous DNA Damage Syndromes.

Type I interferons (IFNs) as part of the innate immune system have an outstanding importance as antiviral defense cytokines that stimulate innate and adaptive immune responses. Upon sensing of pattern recognition particles (PRPs) such as nucleic acids, IFN secretion is activated and induces the expression of interferon stimulated genes (ISGs). Uncontrolled constitutive activation of the type I IFN system can lead to autoinflammation and autoimmunity, which is observed in autoimmune disorders such as systemic lupus erythematodes and in monogenic interferonopathies. They are caused by mutations

Unrestrained Gαi2 Signaling Disrupts Neutrophil Trafficking, Aging, and Clearance.

Neutrophil trafficking, homeostatic and pathogen elicited, depends upon chemoattractant receptors triggering heterotrimeric G-protein Gαiβγ signaling, whose magnitude and kinetics are governed by RGS protein/Gαi interactions. RGS proteins typically limit Gαi signaling by reducing the duration that Gαi subunits remain GTP bound and able to activate downstream effectors. Yet how in totality RGS proteins shape neutrophil chemoattractant receptor activated responses remains unclear. Here, we show that C57Bl/6 mouse neutrophils containing a genomic knock-in of a mutation that disables all RGS prote

Tsc1 Regulates the Proliferation Capacity of Bone-Marrow Derived Mesenchymal Stem Cells.

TSC1 is a tumor suppressor that inhibits cell growth via negative regulation of the mammalian target of rapamycin complex (mTORC1). TSC1 mutations are associated with Tuberous Sclerosis Complex (TSC), characterized by multiple benign tumors of mesenchymal and epithelial origin. TSC1 modulates self-renewal and differentiation in hematopoietic stem cells; however, its effects on mesenchymal stem cells (MSCs) are unknown. We investigated the impact of Tsc1 inactivation in murine bone marrow (BM)-MSCs, using tissue-specific, transgelin (Tagln)-mediated cre-recombination, targeting both BM-MSCs and

Interleukin-11 signaling underlies fibrosis, parenchymal dysfunction, and chronic inflammation of the airway.

Interleukin (IL)-11 evolved as part of the innate immune response. In the human lung, IL-11 upregulation has been associated with viral infections and a range of fibroinflammatory diseases, including idiopathic pulmonary fibrosis. Transforming growth factor-beta (TGFβ) and other disease factors can initiate an autocrine loop of IL-11 signaling in pulmonary fibroblasts, which, in a largely ERK-dependent manner, triggers the translation of profibrotic proteins. Lung epithelial cells also express the IL-11 receptor and transition into a mesenchymal-like state in response to IL-11 exposure. In mic