Search Results (624)

Deep-sea mussels of the genus Bathymodiolus exhibit adaptability to nutrient-poor deep-sea environments by establishing nutritional intracellular symbiosis with chemosynthetic bacteria harbored within the gill epithelial cells. However, this poses a conflict for the innate immune system of the host, which must balance the tolerance of beneficial symbiotic bacteria with the need to eliminate exogenous microbes. This review synthesizes existing knowledge and recent findings on Bathymodiolus japonicus to outline the cellular and molecular mechanisms governing this symbiotic relationship. In the host immune system, hemocytes are responsible for systemic defense, whereas gill cells are involved in local symbiotic acceptance. Central to the establishment of symbiosis is the host’s phagocytic system, which non-selectively engulfs bacteria but selectively retains symbionts. We highlight a series of cellular events in gill cells involving the engulfment, selection, retention and/or digestion of symbionts, and the regulatory mechanism of phagocytosis through mechanistic target of rapamycin complex 1, which connects bacterial nutrient supply with host immune and metabolic responses. This integrated model of symbiosis regulation, which links immunity, metabolism, and symbiosis, provides a fundamental framework for understanding how hosts establish and maintain a stable coexistence with microbes, offering a new perspective on symbiotic strategies in diverse organisms. Full article

Sarcopenia, characterized by progressive skeletal muscle mass, strength, and functional loss, imposes a substantial global health burden. Irisin, a myokine derived from fibronectin type III domain-containing protein 5 (FNDC5), is critical for muscle health. Here, we investigate its role in mitigating glucocorticoid-induced sarcopenia using a mouse and C2C12 myotubes model. We quantified FNDC5/irisin levels in skeletal muscle and plasma and assessed muscle function (body weight, grip strength, wire-hanging, and locomotor activity), histology, and mitochondrial features following irisin administration to dexamethasone-treated mice. Western blot analyzed synthesis/hydrolysis regulators, apoptosis markers, and mitochondrial regulators in mouse muscle tissues and C2C12 myotubes. The results show that FNDC5/irisin was significantly downregulated in sarcopenic mice and atrophic C2C12 myotubes; exogenous irisin rescued muscle mass loss and functional impairment, improving body weight, muscle mass, grip strength, and mobility. Mechanistically, irisin bound SIRT1 with −12.7 kcal/mol affinity, activating a deacetylation cascade that suppressed FoxO3a transcriptional activity (attenuating proteasomal degradation) and enhanced mTORC1-mediated protein synthesis in C2C12 myotubes. Additionally, irisin potentiated PGC-1α signaling in mouse myocytes, promoting mitochondrial biogenesis and restoring contractile function in dystrophic fibers. Collectively, these findings demonstrate irisin alleviates glucocorticoid-induced muscle atrophy via SIRT1-dependent pathways, rebalancing muscle physiology and systemic energy homeostasis. This highlights irisin-based therapeutics as a promising exercise surrogate for sarcopenia management, offering novel clinical avenues. Full article

Background/Objectives: The mTOR serine/threonine kinase coordinates protein translation, cell growth, and metabolism, and its dysregulation promotes tumorigenesis. We present a reproducible, pan-cancer, network-aware framework that integrates curated resources with genomics to move beyond pathway curation, yielding falsifiable hypotheses and prioritized candidates for mTOR axis biomarker validation. Materials and Methods: We assembled MTOR-related genes and interactions from GeneCards, KEGG, STRING, UniProt, and PathCards and harmonized identifiers. We formulated a concise working model linking genotype → pathway architecture (mTORC1/2) → expression-level rewiring → phenotype. Three analyses operationalized this model: (i) pan-cancer alteration mapping to separate widely shared drivers from tumor-specific nodes; (ii) expression-based activity scoring to quantify translational/nutrient-sensing modules; and (iii) topology-aware network propagation (personalized PageRank/Random Walk with Restart on a high-confidence STRING graph) to nominate functionally proximal neighbors. Reproducibility was supported by degree-normalized diffusion, predefined statistical thresholds, and sensitivity analyses. Results: Gene ontology analysis demonstrated significant enrichment for mTOR-related processes (TOR/TORC1 signaling and cellular responses to amino acids). Database synthesis corroborated disease associations involving MTOR and its partners (e.g., TSC2, RICTOR, RPTOR, MLST8, AKT1 across selected carcinomas). Across cohorts, our framework distinguishes broadly shared upstream drivers (PTEN, PIK3CA) from lineage-enriched nodes (e.g., RICTOR-linked components) and prioritizes non-mutated, network-proximal candidates that align with mTOR activity signatures. Conclusions: This study delivers a transparent, pan-cancer framework that unifies curated biology, genomics, and network topology to produce testable predictions about the mTOR axis. By distinguishing shared drivers from tumor-specific nodes and elevating non-mutated, topology-inferred candidates, the approach refines biomarker discovery and suggests architecture-aware therapeutic strategies. The analysis is reproducible and extensible, supporting prospective validation of prioritized candidates and the design of correlative studies that align pathway activity with clinical response. Full article

Background/Objectives: Cardiovascular disease (CVD) is the leading cause of mortality in patients with rheumatoid arthritis (RA), not fully explained by traditional risk factors and disease activity alone. This study explored the relationship between circulating monocyte subsets, inflammatory cytokine profiles, and Mammalian Target of Rapamycin Complex (mTORC) signaling in RA patients with and without a history of CVD. Methods: Peripheral blood mononuclear cells from 9 RA patients with prior CVD, 9 carefully matched RA controls without CVD, and 6 healthy controls were analyzed by flow cytometry. Matching was rigorously conducted across clinically relevant variables, including age, sex, blood pressure, lipid profile, smoking status, RA duration, disease activity, Disease-Modifying Anti-Rheumatic Drug (DMARD) failures, and steroid use. Monocyte subsets were classified as inflammatory (CD14⁺HLA-DR⁺CCR2⁺) and non-inflammatory (CD14⁺CD163⁺CCR2⁻). Results: RA-CVD⁺ patients exhibited higher frequencies of inflammatory monocytes and elevated intracellular levels of Interleukin 1 β (IL-1β) and Interleukin 6 (IL-6) compared to RA-CVD⁻ patients and healthy controls. mTORC activation, assessed by phosphorylation of S6 Ribosomal Protein (S6Rp), was significantly increased in inflammatory monocytes from RA-CVD⁺ patients. Conclusions: S6Rp correlated with IL-1β and IL-6 levels only in the RA-CVD⁺ group, suggesting a link between mTORC activity and inflammatory monocyte function. Notably, these inflammatory features did not correlate with disease activity scores or disease duration. We observed increased mTORC1 signaling in inflammatory monocytes in RA-CVD⁺ patients, suggesting a potential association with cardiovascular comorbidity. Full article

Background: Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its efficacy is often limited by cancer cell resistance. Although multiple DOX resistance mechanisms have been characterized, the global transcriptomic alterations underlying this phenomenon remain poorly understood. The aim of this work was to determine whether a common transcriptional response associated with DOX desensitization exists across tumor cells of different origins and to identify the core elements of this response. Methods: We performed an integrated bioinformatics analysis, including: analysis of independent transcriptomic datasets (comparing DOX-resistant neuroblastoma, breast, and cervical carcinoma cells to their DOX-sensitive counterparts), functional annotation of differentially expressed genes, reconstruction and topology analysis of gene networks, text mining, and survival analysis. The findings were validated through in vitro functional tests, RT-PCR, and analysis of the Cancer Therapeutics Response Portal and The Cancer Genome Atlas. Results: We showed that DOX resistance in cancer cells is associated with cytoskeletal reorganization, modulation of cell adhesion, cholesterol biosynthesis, and dysregulation of mTORC1, Wnt, and Gβγ signaling pathways. Network analysis identified a conserved regulome of 37 resistance-linked genes, with GJA1, SEH1L, TCF3, TUBA4A, and ZYX emerging as central hubs (mean degree: 8.7–19.7; mean fold change: 2.4–21.3). Experimental validation in DOX-resistant KB-8-5 cervical carcinoma cells and their sensitive counterparts (KB-3-1) confirmed enhanced cellular adhesion and reduced intracellular cholesterol levels associated with chemoresistance, supporting our in silico findings. A detailed follow-up analysis verified the upregulation of these hub genes in chemoresistant cells and their correlation with poor clinical outcomes across multiple cancer types. Conclusions: This integrative analysis identifies conserved transcriptomic signatures of DOX resistance and highlights hub genes GJA1, SEH1L, TCF3, TUBA4A, and ZYX with potential as predictive biomarkers and therapeutic targets. Targeting these pathways may help overcome chemoresistance and improve treatment outcomes in cancer patients. Full article

27-Hydroxycholesterol (27OHChol), a cholesterol metabolite, induces inflammatory responses in monocytic cells and promotes their differentiation into mature dendritic cells. Here, we examined whether inhibition of heat shock protein 90 (HSP90) modulates these responses. Treatment with ganetespib, a selective HSP90 inhibitor, significantly reduced chemokine CCL2 expression, lowering monocytic cell migration. It also suppressed matrix metalloproteinase-9 (MMP-9) expression and attenuated the lipopolysaccharide (LPS) response otherwise amplified by 27OHChol. Furthermore, ganetespib decreased mature dendritic cell markers (CD80, CD83, CD88) and restored endocytic activity, indicating a less activated state. These changes suggest that HSP90 regulates 27OHChol-induced pro-inflammatory activation via its client proteins. To explore this mechanism, we examined the phosphorylation status of signaling proteins. 27OHChol enhanced phosphorylation of Akt and its downstream targets, S6 and 4E-BP1 within the Akt/mTORC1 pathway. Ganetespib reduced total and phosphorylated Akt and 4E-BP1, and selectively inhibited S6 phosphorylation without altering total protein level. Collectively, these findings demonstrate that HSP90 inhibition by ganetespib mitigates 27OHChol-driven monocytic cell activation through suppression of the HSP90-Akt/mTORC1 axis. Targeting this pathway may provide a promising therapeutic strategy for metabolic inflammation associated with oxysterols. Full article

Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options and a poor prognosis. Natural phytochemicals from Dendrobium species, particularly bibenzyl derivatives, possess diverse pharmacological activities, yet their potential against GBM remains largely unexplored. Here, we investigated the anticancer activity of 4,5,4′-trihydroxy-3,3′-dimethoxybibenzyl (TDB), a potent antioxidant bibenzyl derivative isolated from Dendrobium pachyglossum. In U87MG cells, TDB reduced viability in a dose- and time-dependent manner, suppressed clonogenic growth, induced apoptosis via Bax upregulation and Bcl-xL/Mcl-1 downregulation, and inhibited both mTORC1 and mTORC2 signaling. TDB also impaired cell migration and downregulated epithelial–mesenchymal transition (EMT)-associated proteins. Notably, TDB enhanced the cytotoxicity of temozolomide (TMZ), the current standard of care for GBM. These TMZ-sensitizing properties were further confirmed in patient-derived xenograft (PDX) Jx22 cells. To assess its potential for central nervous system delivery, blood–brain barrier (BBB) permeability was predicted using four independent in silico platforms—ADMETlab 3.0, LogBB_Pred, LightBBB, and BBB Predictor (Tree2C)—all of which consistently classified TDB as BBB-permeable. This predicted CNS accessibility, together with its potent anticancer profile, underscores TDB’s translational promise. Collectively, our findings identify TDB as a plant-derived antioxidant with multifaceted anti-GBM activity and favorable BBB penetration potential, warranting further in vivo validation and preclinical development as a novel therapeutic candidate for GBM. Full article

Background: Monocytes can commit to different phenotypes associated with specific features required in inflammation and homeostasis. Classical and alternative activation are two extremes of monocyte polarization and are both influenced by glucocorticoids (GCs). Methods: Human monocytes were sorted from the blood of healthy individuals and activated with LPS or IL-4 and IL-13, either in the absence or presence of dexamethasone (Dex). Metabolic adjustments were analyzed using Seahorse stress tests, SCENITH, and RT-qPCR. Results: LPS enhanced glycolysis and also, to a lesser extent, oxidative phosphorylation (OXPHOS), whereas addition of Dex induced a metabolic switch in favor of the latter. In contrast, activation of monocytes with IL-4 and IL-13 exclusively stimulated OXPHOS, which was suppressed by concomitant Dex treatment. The glycolytic function of monocytes matched alterations in gene expression of glucose transporters and metabolic enzymes, which were upregulated by LPS and inhibited by Dex via interference with the mTORC1 pathway but remained unaltered in response to IL-4 and IL-13. Although the dependency of classically and alternatively activated monocytes on OXPHOS and glucose usage markedly differed, modulation by GCs was limited to the latter polarization state. Conclusions: Our findings unravel a highly selective regulation of human monocyte energy metabolism by different activating stimuli as well as by GCs. Full article

Extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors show therapeutic potential in triple-negative breast cancer (TNBC), but resistance through compensatory signaling limits their efficacy. We previously identified the secretory carrier membrane protein 3 (SCAMP3) as a regulator of TNBC progression and ERK1/2 activation. Here, we investigated the role of SCAMP3 in ERK1/2 signaling and therapeutic response using TMT-based LC-MS/MS phosphoproteomics of wild-type (WT) and SCAMP3 knockout (SC3KO) SUM-149 cells under basal conditions, after epidermal growth factor (EGF) stimulation, and during ERK1/2 inhibition with MK-8353. A total of 4408 phosphosites were quantified, with 1093 significantly changed. SC3KO abolished residual ERK activity under MK-8353 and affected the compensatory activation of oncogenic pathways observed in WT cells. SC3KO reduced the phosphorylation of ERK feedback regulators RAF proto-oncogene serine/threonine-protein kinase Raf-1 (S43) and the dual-specificity mitogen-activated protein kinase kinase 2 (MEK2) (T394), affected other ERK targets, including nucleoporins, transcription factors, and metabolic enzymes triosephosphate isomerase (TPI1) (S21) and ATP-citrate lyase (ACLY) (S455). SCAMP3 loss also impaired the mammalian target of rapamycin complex I (mTORC1) signaling and disrupted autophagic flux, evidenced by elevated sequestosome-1 (SQSTM1/p62) and microtubule-associated protein light chain 3 (LC3B-II) with reduced levels of the autophagosome lysosome maturation marker, Rab7A. Beyond ERK substrates, SC3KO affected phosphorylation events mediated by other kinases. These findings position SCAMP3 as a central coordinator of ERK signaling and autophagy. Our results support SCAMP3 as a potential therapeutic target to enhance ERK1/2 inhibitor clinical efficacy and overcome adaptive resistance mechanisms in TNBC. Full article

Cellular redox pathways are critical regulators of various biological processes, including the intricate modulation of intracellular signaling pathways. This review explores how major redox enzymes—such as catalase, superoxide dismutases, glutathione peroxidases, thioredoxins, and peroxiredoxins—interact with key cellular signaling pathways, including receptor tyrosine kinase, mTORC1/AMPK, Wnt/β-catenin, TGF-β/SMAD, NF-κB, Hedgehog, Notch, and GPCR signaling. By investigating mechanisms such as ROS-mediated activation, cysteine oxidation, spatial enzyme localization, and phosphatase regulation, we demonstrate the extensive influence of redox balance on cellular signaling dynamics. Understanding these redox-dependent interactions provides insights into pathophysiological conditions ranging from cancer to fibrosis, offering novel therapeutic opportunities. Full article

The aim of this study was to investigate the clinical and prognostic significance of the NOTCH1 pathway in oral squamous cell carcinoma (OSCC). To this end, the expression of NOTCH1 and two downstream targets, HES1 and p21, was evaluated by immunohistochemistry in 165 OSCC patient specimens. Clinicopathological associations and impact on survival were assessed. Possible mechanistic crosstalk with epithelial–mesenchymal transition (EMT) induction through combined E-cadherin and Vimentin markers, or mTORC1 activation by means of phospho-S6 expression were also investigated. NOTCH1 staining was detected in 56 (35%) tumors, nuclear HES1 in 131 (81%) and nuclear p21 in 116 (70%) tumors. p21 was strongly correlated with mTORC1 activation and HES1 expression was inversely associated with EMT status. NOTCH1 expression was positively associated with an advanced T stage, neck lymph node metastasis, advanced TNM stage, second primary cancer, and was significantly associated with shorter disease-specific survival (DSS). By contrast, HES1 and p21 expression showed significant associations with early clinical stages, and combined p21 and pS6 expression (p21+/p-S6+) distinguished good-prognosis patients. Multivariate Cox analysis further revealed NOTCH1 expression as a significant independent predictor of poor DSS. Mechanistically, we found a strong link between p21 and pS6 proteins, which could potentially serve as a good-prognosis classifier for OSCC patients. Full article

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver tumor. Due to its aggressive nature and resistance to conventional treatments, there is a pressing need to develop novel and more effective therapies for this deadly malignancy. Here, we explored the therapeutic potential of the DNA minor groove binders trabectedin (TRB) and lurbinectedin (LUR) for the treatment of iCCA using cell lines, spheroids, cancer-associated fibroblasts (CAFs), patient-derived tumor organoids (PDOs), and the chicken chorioallantoic membrane (CAM) in vivo model. TRB and, more substantially, LUR, significantly inhibited cell growth in iCCA cell lines, spheroids, CAFs, and PDOs at very low nanomolar concentrations. Specifically, the two drugs significantly reduced proliferation, triggered apoptosis, and caused DNA damage in iCCA cells. At the metabolic level, TRB and LUR decreased mitochondrial respiration and glycolysis. At the molecular level, the two compounds effectively downregulated the mammalian target of rapamycin complex 1 (mTORC1) and Hippo/YAP pathways and suppressed the expression of yes-associated protein 1 (YAP1), cellular myelocytomatosis oncogene (c-Myc), E2F transcription factor 1 (E2F1), Bromodomain-containing protein 4 (BRD4), TEA domain transcription factor 4 (TEAD4), and cluster of differentiation 7 (CD7) proto-oncogenes. Furthermore, LUR significantly restrained the in vivo growth of iCCA cells in the CAM model. Our data indicate that TRB and LUR possess strong anti-proliferative and pro-apoptotic activities and could represent promising therapeutic agents for the treatment of iCCA. Full article

Background: Arginine (Arg) is thought to potentially stimulate protein synthesis. Although the detailed mechanism by which Arg regulates protein synthesis is not fully known, it is believed to occur primarily through the mechanistic target of rapamycin complex 1 (mTORC1)-dependent activation of translation initiation. The aim of this study was to evaluate the ability of Arg to stimulate translation initiation to upregulate protein synthesis and identify the possible signaling pathways involved in the stimulatory effect of Arg on mRNA translation in skeletal muscle. Methods: Overnight-fasted mice were intraperitoneally injected with Arg, sacrificed 1 h later, and then the gastrocnemius muscles were excised. In addition, to determine the mechanism by which Arg stimulates translation initiation in skeletal muscle, we used mouse-derived C2C12 myotubes. Cells were preincubated with several inhibitors of intracellular signaling or the G protein–coupled receptor, Class C, group 6, subtype A (GPRC6A) antagonist, and then added to the culture with Arg. Phosphorylation of 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase (S6K1) as markers of mTORC1-dependent protein synthesis activity was measured. Results: Intraperitoneal injection of Arg increased 4E-BP1 and S6K1 phosphorylation. In C2C12 myotubes, Arg addition significantly increased the phosphorylation of 4E-BP1 and S6K1, and this upregulation was attenuated by pretreatment with the mTORC1 inhibitor rapamycin. In addition, pretreatment with the PI3K inhibitor LY294002, the AKT inhibitor MK-2206, and the GPRC6A antagonist calindol completely inhibited Arg-upregulated 4E-BP1 and S6K1 phosphorylation. Conclusions: The findings of this study suggest that Arg stimulates the initiation of mRNA translation via the GPRC6A/PI3K/AKT/mTORC1 signaling pathway, thereby stimulating protein synthesis in skeletal muscle. Full article

The mammalian target of rapamycin pathway, mTOR, is a crucial signaling pathway that regulates cell growth, proliferation, metabolism, and survival. Due to its dysregulation it is involved in several ailments such as cancer or age-related diseases. The discovery of mTOR and the understanding of its biological functions were greatly facilitated by the use of rapamycin, an antibiotic of natural origin, which allosterically inhibits mTORC1, effectively blocking its function. In this entirely computational study, we investigated mTOR’s interaction with seven ligands: two clinically established inhibitors (everolimus and rapamycin) and five lignin-derived oligomers, a renewable natural polyphenol recently used for the drug delivery of everolimus. The seven complexes were analyzed through all-atom molecular dynamics simulations in explicit solvent using a high-performance computing platform. Trajectory analyses revealed stable interactions between mTOR and all ligands, with lignin-derived compounds showing comparable or enhanced binding stability relative to reference drugs. To evaluate the stability of the molecular complex and the behavior of the ligand over time, we analyzed key parameters including root mean square deviation, root mean square fluctuation, number of hydrogen bonds, binding free energy, and conformational dynamics assessed through principal component analysis. Our results suggest that lignin fragments are a promising, sustainable scaffold for developing novel mTOR inhibitors. Full article

MYCN amplification without concurrent RB1 mutations characterizes a rare yet highly aggressive subtype of retinoblastoma; however, its precise developmental origins and therapeutic vulnerabilities remain incompletely understood. Here, we modeled this subtype by lentiviral-mediated MYCN overexpression in human pluripotent stem cell-derived retinal organoids, revealing a discrete developmental window (days 70–120) during which retinal progenitors showed heightened susceptibility to transformation. Tumors arising in this period exhibited robust proliferation, expressed SOX2, and lacked CRX, consistent with origin from primitive retinal progenitors. MYCN-overexpressing organoids generated stable cell lines that reproducibly gave rise to MYCN-driven tumors when xenografted into immunodeficient mice. Transcriptomic profiling demonstrated that MYCN-overexpressing organoids closely recapitulated molecular features of patient-derived MYCN-amplified retinoblastomas, particularly through activation of MYC/E2F and mTORC1 signaling pathways. Pharmacological screening further identified distinct therapeutic vulnerabilities, demonstrating distinct subtype-specific sensitivity of MYCN-driven cells to transcriptional inhibitors (THZ1, Flavopiridol) and the cell-cycle inhibitor Volasertib, indicative of a unique oncogene-addicted state compared to RB1-deficient retinoblastoma cells. Collectively, our study elucidates the developmental and molecular mechanisms underpinning MYCN-driven retinoblastoma, establishes a robust and clinically relevant human retinal organoid platform, and highlights targeted transcriptional inhibition as a promising therapeutic approach for this aggressive pediatric cancer subtype. Full article