Search Results (2,308)

Sarcopenia is an age-related pathological syndrome characterized by progressive and generalized loss of skeletal muscle mass and function, with muscle atrophy representing its cardinal pathological hallmark. Ferroptosis, an iron-dependent regulated cell death, has been implicated in the pathogenesis of muscle atrophy; however, the precise role of iron dysregulation in sarcopenia remains incompletely understood. In the present study, we identified ferroptosis in D-galactose (D-gal)-induced senescent myoblasts, as evidenced by elevated intracellular iron levels and lipid peroxidation, increased malondialdehyde (MDA) content, and upregulated expression of prostaglandin endoperoxide synthase 2 (PTGS2), 4-hydroxynonenal (4-HNE), and long-chain acyl-CoA synthetase 4 (ACSL4), accompanied by diminished glutathione peroxidase 4 (GPX4), SLC7A11 (xCT), and glutathione (GSH) levels, as well as pronounced mitochondrial damage. Notably, treatment with the iron chelator deferoxamine (DFO) significantly attenuated senescence-associated ferroptosis. Moreover, D-gal-induced senescence in myoblasts was accompanied by reduced ferritin expression and elevated nuclear receptor coactivator 4 (NCOA4) levels, both of which were reversed by autophagy inhibition with 3-methyladenine (3-MA) or NCOA4 knockdown, suggesting that NCOA4-mediated ferritinophagy is involved in senescence-induced iron overload and ferroptosis. Furthermore, senescent myoblasts exhibited increased reactive oxygen species (ROS) generation and mitochondrial impairment, which were attributed to cytosolic iron overload-mediated upregulation of mitoferrin 2 (Mfrn2), thereby promoting mitochondria iron import. Finally, pharmacological inhibition of iron overload or ferroptosis by DFO or ferrostatin-1 (Ferr-1) effectively ameliorated skeletal muscle atrophy and functional decline in aged sarcopenia mice. Collectively, these findings elucidate the mechanistic basis of sarcopenia and highlight potential therapeutic avenues targeting iron dysregulation and ferroptosis. Full article

Food scarcity is a major ecological challenge for cavefish; however, their coordinated physiological and molecular responses to prolonged starvation remain poorly understood. Here, we characterized the responses of Triplophysa rosa to 30, 60, and 90 days of food deprivation under controlled laboratory conditions by integrating growth measurements, histology, transcriptomics, quantitative reverse transcription PCR, and transmission electron microscopy. Starvation inhibited growth, reduced the condition factor and hepatosomatic index, and induced hepatocyte shrinkage, consistent with mobilization of hepatic energy reserves. Liver genes with declining temporal expression were enriched mainly in lipid biosynthesis, cholesterol metabolism, ribosomal function, and cell-cycle pathways, consistent with reduced biosynthetic activity. In the spleen, immune-related transcription increased during early starvation and declined at later stages, while the greater prominence of melano-macrophage centers was consistent with greater involvement of cellular clearance and tissue maintenance during prolonged starvation. Prolonged starvation also increased the expression of autophagy-related genes in the liver and spleen, and autophagy-related structures became more prominent in representative transmission electron microscopy images, consistent with increased involvement of intracellular recycling. Together, these findings reveal a coordinated temporal response involving metabolic adjustment, stage-dependent reorganization of splenic immune-related processes, and autophagy-associated cellular maintenance in T. rosa. This integrated approach improves our understanding of physiological maintenance during sustained nutrient limitation in cave-restricted fish. Full article

Naturally derived bioactive compounds that modulate aging-associated mechanisms have attracted growing research interest, yet few reviews examine how such compounds might act together. This narrative review examines four mechanistically distinct compounds, namely spermidine, fisetin, berberine, and urolithin A, as emerging functional food ingredients with scientifically supported effects on key hallmarks of human aging. Spermidine, a dietary polyamine from wheat germ and fermented foods, induces autophagy through EP300 inhibition and is associated with reduced all-cause mortality in prospective studies. Fisetin, a flavonoid from strawberries and apples, exerts senolytic activity by selectively eliminating senescent cells via PI3K/AKT and Bcl-2/Bcl-xL inhibition, with emerging clinical evidence. Berberine, an isoquinoline alkaloid from Berberis species, modulates metabolic dysfunction via AMP-activated protein kinase (AMPK) activation and reshapes gut microbiota composition through direct high intraluminal exposure, with the most extensive clinical dataset of the four compounds. Urolithin A, a gut microbiome-derived postbiotic from ellagitannins in pomegranates and nuts, induces mitophagy via PINK1/Parkin and has been evaluated in a growing number of registered human clinical trials. Together, the four compounds primarily target distinct but complementary aging-associated pathways (autophagy, senolysis, metabolic regulation, mitophagy), suggesting rational potential for combined functional food formulations. Limited direct evidence for their combined use and the need for dedicated co-administration studies are discussed, alongside bioavailability, safety, and regulatory considerations. Full article

Vascular smooth muscle cells (VSMCs), the contractile cells in the tunica media of blood vessels, maintain vascular tone. The proliferation of VSMCs is an important feature of vascular remodeling that contributes to the regulation of blood pressure. Autophagy, an intracellular self-degrading process that delivers cytoplasmic constituents to lysosomes, plays a vital role in VSMC proliferation. This is regulated by the dopaminergic and renin–angiotensin systems but their interplay in their regulation of autophagy in VSMCs is not well-understood. In rat VSMCs, fenoldopam (Fen), a dopamine D1-like receptor agonist, increased autophagy, as determined by the increase in the protein expressions of microtubule-associated protein 1 light chain (LC)3-II and beclin-1 (BECN1), in a time- and concentration-dependent manner. Conversely, angiotensin II (Ang II), the endogenous Ang II type 1 receptor (AT₁R) agonist, decreased the protein expression of LC3-II and BECN1, also in a time- and concentration-dependent manner. The production of cyclic adenosine monophosphate (cAMP) and autophagic LC3-II puncta in VSMCs were increased by Fen and decreased by Ang II. Pre-treatment of VSMCs with Rp-cAMPS, a protein kinase A inhibitor, prevented the Fen-mediated increase and the Ang II-mediated decrease in LC3-II protein expression. Fen decreased, whereas Ang II increased the phosphorylation of P70S6K, a direct downstream mammalian target of rapamycin (mTOR). The inhibitory effect of Fen and stimulatory effect of Ang II on P70S6K phosphorylation were prevented by Rp-cAMPS. Ang II also decreased the Fen-mediated increase in cAMP production, while Fen attenuated the Ang II-mediated increase in cell proliferation, a response that occurs downstream of autophagy. Moreover, Ang II prevented the Fen-mediated inhibition of cell proliferation, an effect that was blocked by losartan, an AT₁R antagonist. These results demonstrate that Fen and Ang II counter-regulate autophagy and proliferation of VSMCs via the mTOR pathway, which is cAMP-dependent. Full article

The high-pathogenicity island (HPI) is a major virulence determinant in pathogenic Escherichia coli (E. coli), contributing to severe inflammation and tissue damage. Autophagy plays a critical role in clearing intracellular pathogens and modulating inflammation, but whether HPI manipulates this process remains unknown. Here, using a swine-pathogenic E. coli strain and its HPI-deficient mutant (Δirp2) generated by CRISPR/Cas9, we investigated the interplay between HPI and autophagy in RAW264.7 macrophages and a mouse intestinal infection model. We found that HPI⁺ infection induced autophagic activation, as evidenced by increased LC3 puncta (immunofluorescence), upregulated Beclin-1 and autophagy-related gene mRNA levels (qPCR), and downregulated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) expression at both mRNA (qPCR) and protein (immunohistochemistry) levels. In a mouse model, HPI⁺ infection upregulated intestinal Microfold (M) cell markers and secretory Immunoglobulin A (IgA), triggered robust production of pro-inflammatory cytokines, and induced more severe tissue pathology than the HPI-deficient mutant. Pharmacological activation of autophagy with rapamycin alleviated HPI-induced inflammation and injury, whereas inhibition of autophagy by 3-methyladenine (3-MA) or Beclin-1 silencing exacerbated damage. These findings suggest that HPI induces autophagy, but the endogenous autophagic response is insufficient to counteract HPI-induced pathology; pharmacological enhancement of autophagy partially alleviated this insufficiency and reduced tissue damage. Notably, Beclin-1 knockdown blunted HPI-induced upregulation of PI3K and autophagy-related genes, suggesting a role for Beclin-1 in the transcriptional regulation of these responses. In conclusion, HPI simultaneously exerts direct pro-inflammatory effects and induces Beclin-1-dependent autophagy. Enhancing this autophagic response pharmacologically, rather than relying on the endogenous level triggered by HPI alone, limits excessive tissue damage. Thus, boosting autophagy may represent a promising therapeutic strategy against HPI-bearing pathogenic E. coli infections. Full article

Cyclin-dependent kinase 4/6 inhibitors have fundamentally changed the management of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. However, these drugs are not interchangeable and the field is moving away from the notion of a uniform “class effect.” In early breast cancer, adjuvant abemaciclib and ribociclib improve invasive disease-free survival in patients at a high risk of recurrence, whereas palbociclib does not. This difference likely stems from agent-specific pharmacological profiles, differences in trial design, and patient selection, rather than simply dosing nuances. In metastatic breast cancer, all three agents prolong progression-free survival when combined with endocrine therapy, but only ribociclib and potentially abemaciclib have shown an overall survival advantage. In addition, resistance remains a major obstacle in clinical practice. We propose that resistance mechanisms can be meaningfully grouped into two categories: target-driven (e.g., RB1 loss, CDK6 amplification) and bypass-driven (e.g., ESR1 mutations, PI3K/AKT pathway activation, APOBEC3-mediated mutagenesis). Distinguishing between these classes helps in the design of rational sequencing algorithms and combinatorial regimens. Emerging strategies, such as next-generation protein degraders, oral selective estrogen receptor degraders, antibody–drug conjugates, and inhibition of autophagy, are promising methods for overcoming resistance. Moving forward, the greatest need in breast cancer treatment will be not simply developing additional agents but using current therapies more intelligently by refining biomarker-guided patient selection, tailoring treatment duration, and ensuring broad global access. Full article

Cancer continues to be a primary cause of death globally, necessitating the constant development of effective and less toxic therapeutics. Cucurbitacins belong to the tetracyclic triterpenoids found mainly in the Cucurbitaceae family. Cucurbitaceae plants exert various biological activities such as anti-diabetic, anti-cancer and anti-inflammatory properties, which make them beneficial in addressing metabolic disorders. This review focuses on cucurbitacins namely A, B, C, D, E, I, IIa, which have been explored in cancer research. Cucurbitacins suppress tumor progression by activating cell death pathways, including apoptosis, autophagy, pyroptosis and ferroptosis. They are known to target multiple crucial biomolecular key players, such as STAT3, AKT, mTOR, ERK, EGFR and TLR4. Additionally, they disrupt cytoskeletal proteins and inhibit cell proliferation, invasion, migration, angiogenesis, and cell-cycle arrest. Cucurbitacins have been demonstrated to modulate tumor microenvironment, leading to enhanced host immune surveillance that reverses traditional therapy resistance from cisplatin, doxorubicin, and paclitaxel. In this review, we highlight the strong potential of cucurbitacins as anti-cancer agents, either as monotherapy or in combination, for the development of safer, cost-effective drugs with improved patient treatment outcomes. Full article

Hedgehog (Hh) signaling regulates cell survival and microenvironmental responses in various cancers, but its role in metabolic adaptation to the hypoxic bone marrow microenvironment in myeloid malignancies remains insufficiently defined. K562, KU812, and U937 cells were cultured under normoxic or hypoxic conditions and treated with the Smoothened (Smo) antagonist Cyclopamine or the agonist SAG (Smoothened Agonist). Cell proliferation, apoptosis- and autophagy-related markers, glycolysis-associated proteins, and metabolic parameters were assessed by viability assays, Western blotting, immunofluorescence, and biochemical assays. Selected findings were further evaluated in CRISPR/Cas9-mediated Smo knockout cells. Smo inhibition reduced cell proliferation, increased PARP cleavage, and decreased BNIP3 expression under both oxygen conditions. It also downregulated glucose transporter 1 (GLUT1), hexokinase 2 (HK2), lactate dehydrogenase (LDH), monocarboxylate transporter 1 (MCT1), carbonic anhydrases IX and XII (CAIX and CAXII), and was associated with reduced glucose consumption, lactate production, and ATP levels. These changes were associated with modulation of the AMPK–mTOR axis and with reduced phosphorylation of mTOR downstream effectors. These findings support a role for Hh signaling in hypoxia-driven metabolic adaptation in myeloid malignancy cell models and suggest a functional link between Smo activity, glycolytic remodeling, and AMPK-mTOR-related signaling. Full article

Goose astrovirus (GoAstV) is a newly identified virus affecting geese, leading to goose gout, which is marked by urate deposits in organs and joints. This research investigates the role of autophagy in renal damage caused by GoAstV in goslings. The findings indicated that GoAstV infection in goslings resulted in characteristic clinical manifestations, with renal tissues displaying tubular swelling, inflammatory infiltration, and autophagosome formation. In vivo experiments demonstrated a significant upregulation of mRNA levels for autophagy-related factors, including AMPK, LC3A, ATG5, ATG7, P62, Beclin1, AMBRA1 and GABARAPL1, while mTOR and LC3B levels were notably decreased. At 3 dpi, the protein expression levels of ATG5, Beclin1, and LC3B II/I increased, while P62 levels decreased, suggesting autophagy activation. In vitro analyses revealed that GoAstV infection led to enhanced autophagy; however, the concurrent upregulation of LC3B II/I and P62 proteins suggested an obstruction in the autophagic flux. Upon the inhibition of autophagy with 3-methyladenine (3-MA, autophagy inhibitor), there was a significant reduction in the expression of autophagy-related factors, accompanied by a marked decrease in viral replication rates. In conclusion, GoAstV infection in gosling kidney cells initially triggers enhanced autophagy and subsequently causes a blockage in the autophagic flux. The virus exploits autophagosomes for replication, ultimately resulting in kidney damage. The application of 3-MA effectively inhibits this autophagic process and diminishes viral replication. Full article

Hypertension-induced vascular remodeling is a major contributor to cardiovascular morbidity and is characterized by endothelial dysfunction, vascular smooth muscle cell phenotypic switching, fibrosis, and inflammation. Sirtuin 3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase, plays an important role in maintaining mitochondrial homeostasis, regulating redox balance, and modulating cellular energy metabolism. Emerging evidence suggests that SIRT3 deficiency accelerates hypertensive vascular remodeling through multiple mechanisms. In vascular smooth muscle cells (VSMCs), reduced SIRT3 activity enhances mitochondrial reactive oxygen species generation, promotes glycolytic reprogramming, and contributes to phenotypic switching and proliferation. In endothelial cells, SIRT3 mitigates oxidative stress (OS) by regulating the activity of superoxide dismutase 2, thereby preserving nitric oxide (NO) bioavailability and improving vascular function. SIRT3 also suppresses fibroblast-to-myofibroblast transformation by inhibiting the transforming growth factor-β/Smad3 pathway, thereby reducing vascular fibrosis. Furthermore, SIRT3 regulates macrophage metabolic reprogramming and autophagy, inhibits NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome activation, and attenuates vascular inflammation. In perivascular adipose tissue, SIRT3 deficiency exacerbates angiotensin II-induced fibrosis and cytokine secretion, thereby aggravating vascular dysfunction. Collectively, SIRT3 acts as a mitochondrial regulator against hypertension-induced oxidative and inflammatory injury. Targeting SIRT3-dependent pathways may represent a promising therapeutic approach to restore vascular homeostasis and prevent hypertensive vascular remodeling. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe, progressive liver disease lacking effective therapies. Disulfiram (DSF), an FDA-approved medication for alcohol dependence, exhibits diverse biological activities beyond its primary indication. This study aimed to evaluate whether DSF holds intervention promise for MASH and to unravel the underlying molecular mechanism. The efficacy of DSF was assessed in a mouse model of MASH induced by a choline-deficient, L-amino acid-defined diet, as well as in hepatocytes exposed to free fatty acids (FFAs) to trigger lipotoxicity. RNA-seq analysis combined with bioinformatic approaches was performed to identify key pathways and hub genes. Mechanistic validation was carried out using Western blotting and qPCR. Computational predictions suggested that DSF may influence insulin resistance, inflammation, autophagy-related markers, and lipid metabolism. In FFAs-treated hepatocytes, DSF administration dose-dependently reduced lipid accumulation and lipotoxicity. Consistently, in MASH mice, DSF administration significantly lowered elevated serum ALT (35%) and AST (40%) levels and the absolute hepatic triglyceride content (reduced from 1 to 0.5 μg/mg protein), and markedly attenuated hepatic steatosis, inflammation, fibrosis, and oxidative stress. Of note, RNA-seq analysis revealed that DSF modulated autophagy-related pathways and identified Aurora kinase A (AURKA) as a central downregulated hub gene. Mechanistically, DSF suppressed AURKA expression, which in turn led to changes in autophagy-related markers. These changes in autophagy-related markers were functionally coupled to a reduction in lipotoxicity. Collectively, DSF alleviates MASH by inhibiting AURKA, thereby relieving AURKA-mediated suppression of autophagy-related markers, which was associated with diminishing lipotoxicity, and ultimately achieving broad suppression of disease progression. Thus, DSF represents a promising hepatoprotective candidate for the intervention of MASH. Full article

Glioblastoma (GBM) remains a lethal brain tumor with poor prognosis and limited therapeutic efficacy from temozolomide (TMZ) treatment. Prodigiosin (PG), a bioactive secondary metabolite, has demonstrated anti-tumor activity across a broad spectrum of tumors. This study aims to investigate the therapeutic potential and mechanism of PG combined with TMZ in treating GBM. The results demonstrated that the combination of PG and TMZ synergistically inhibited GBM cell proliferation, triggered apoptosis, and suppressed migration and invasion. Transcriptomic analysis revealed downregulation of focal adhesion and related signaling pathways. Functionally, the combination therapy reduced focal adhesion numbers and AKT phosphorylation. Co-treatment with PG and TMZ impaired autophagic flux, evidenced by LC3-II and p62 accumulation. Furthermore, the anti-proliferative effect and the accumulation of LC3-II and P62 by the combination therapy were enhanced by the autophagy inhibitor chloroquine (CQ) but not reversed by the autophagy activator rapamycin (Rapa), confirming autophagy inhibition as a key mechanism. In conclusion, PG sensitized GBM cells to TMZ by impairing autophagy and focal adhesion signaling, providing a preclinical rationale for the combinatorial strategy. Full article

Liver fibrosis is a critical determinant of the progression of chronic liver disease (CLD). Total flavonoids from Carthamus tinctorius L. (TFCTLs) exhibit diverse pharmacological activities while their effect on liver fibrosis remains incompletely understood. This study aimed to elucidate the effects and mechanisms of TFCTLs on liver fibrosis. To this end, we first established a carbon tetrachloride (CCl₄)-induced liver fibrosis model in mice. Histological analysis demonstrated that TFCTL treatment significantly alleviated CCl₄-induced liver collagen deposition (p < 0.001). Meanwhile, TFCTLs could also downregulate the expression levels of fibrosis markers α-SMA and collagen I in a dose-dependent manner (p < 0.05). In vitro, a cellular model of fibrosis was generated by treating HSC-T6 cells with TGF-β1. EdU incorporation assays revealed that TFCTLs significantly suppressed HSC proliferation (p < 0.05). Furthermore, immunofluorescence staining for α-SMA demonstrated a marked reduction in HSC activation upon TFCTL treatment. The inhibitory effect of TFCTLs on cell migration was confirmed by wound healing and transwell assays, which revealed a substantial decrease in the number of migrated cells (p < 0.001). Additionally, flow cytometric analysis indicated that TFCTL treatment promoted HSC apoptosis (p < 0.05). Further mechanistic investigations revealed that TFCTLs exert their antifibrotic effects by inhibiting Hedgehog pathway and activating autophagy process. The antifibrotic effect of TFCTLs was partially reversed by the autophagy inhibitor 3-MA. Furthermore, the Hedgehog agonist PUR not only counteracted the anti-fibrotic actions of TFCTLs but also suppressed TFCTL-induced autophagy activation. In conclusion, our study demonstrated that TFCTLs attenuate liver fibrosis by inhibiting Hedgehog signaling and subsequently promoting autophagy, highlighting their potential as a therapeutic agent for liver fibrosis. Full article

Forkhead box O (FoxO) transcription factors act downstream of insulin signaling and play conserved roles in development and metabolic homeostasis in insects. However, whether FoxO participates in 20-hydroxyecdysone (20E)-mediated pupation and fat body remodeling in honeybee larvae remains unclear. Here, we show that FoxO is highly expressed during the prepupal and pupal stages of honeybee development. RNA interference (RNAi)-mediated silencing of FoxO delayed pupation, inhibited ecdysteroid biosynthesis and 20E signaling, and ultimately led to pupal lethality. Knockdown of FoxO also suppressed the expression of lipolytic genes, reduced lipase activity, and increased triglyceride (TG) accumulation in the fat body. Furthermore, FoxO deficiency impaired autophagy, as evidenced by reduced LysoTracker staining, decreased autophagosome formation, and downregulation of Atg genes. These findings demonstrate that FoxO participates in 20E-induced pupation of honeybee by regulating the expression of key genes involved in 20E biosynthesis and the 20E signaling pathway. FoxO coordinates autophagy and lipid mobilization in the fat body to provide energy for pupal development. Collectively, our results establish FoxO as a central regulator linking endocrine signaling, energy metabolism, and tissue remodeling during honeybee metamorphosis. Full article

Potato dry rot, induced by pathogenic Fusarium species, is a prevalent postharvest fungal disease that leads to significant economic losses. This research illustrates the biocontrol efficacy of Bacillus velezensis strain 2-1-9-CJK-2 against potato dry rot. The strain successfully inhibited disease progression, diminished oxidative damage in potato tubers, and augmented the activity of essential defense-related enzymes. It effectively colonized potato tubers and sustained consistent inhibitory activity under diverse environmental challenges. And its cell-free supernatant (CFS) retained consistent inhibitory activity. The crude lipopeptides (CLs) produced by this strain induced hyphal deformation, fragmentation, and cytoplasmic leakage in Fusarium solani. Transmission electron microscopy (TEM) further revealed that CL treatments triggered organelle degradation in the pathogen, with mitochondrial disintegration being particularly prominent. Transcriptomic analysis indicated that CLs upregulated genes linked to mitochondrial autophagy in the pathogen and stimulated plant defense mechanisms, notably the MAPK signaling cascade, in potatoes. The findings were additionally corroborated by qRT-PCR. B. velezensis strain 2-1-9-CJK-2 is a promising biocontrol agent and a great resource for the development of antifungal formulations to enhance sustainable potato production. Full article