Search Results (751)

Cancer stem cells (CSCs) drive therapeutic resistance and tumor relapse by exploiting redundant regulatory networks that integrate Wnt/β-catenin, Notch, and Hedgehog signaling with metabolic reprogramming, epigenetic plasticity, and tumor microenvironment crosstalk, a network architecture that renders single-pathway inhibition strategies insufficient. This review systematically examines evidence that natural compounds (curcumin, sulforaphane, resveratrol, EGCG, berberine, and quercetin) act as multitarget modulators of CSC plasticity, analyzing their molecular mechanisms of action in specific cancer models. Each compound engages distinct regulatory nodes: curcumin suppresses β-catenin nuclear translocation and STAT3 phosphorylation in lung cancer CSC models; sulforaphane represses ΔNp63α-driven stemness transcription in colorectal cancer and reduces CSC self-renewal in prostate and head and neck models; resveratrol dissociates the β-catenin–GLI-1 interaction in oral and lung CSC populations and induces Wnt/β-catenin-dependent autophagy in breast CSCs; EGCG inhibits DNMT and HDAC activity in glioblastoma and colorectal models; berberine activates AMPK-mediated suppression of mTORC1 in colorectal cancer; and quercetin suppresses PI3K/AKT/mTOR signaling while downregulating EMT transcription factors in breast and colorectal systems. We critically assess persistent methodological limitations, including bulk cell-line models, supraphysiological concentrations, and the absence of functional tumor-initiating validation, that currently prevent stronger translational conclusions. Natural compounds from Latin American biodiversity are identified as an underexplored source of CSC-active molecules. We conclude by defining the experimental standards required to reposition natural compounds as clinically relevant network-level modulators of CSC plasticity. Full article

Reproductive inefficiency associated with impaired oocyte competence and embryonic loss remains a major limitation in livestock production. Although glycine is classified as a non-essential amino acid, its endogenous synthesis is often insufficient to meet increased metabolic demands during gestation and early embryonic development. This suggests that glycine has a conditionally essential role in reproductive physiology. However, the mechanisms through which glycine integrates metabolic and signaling processes to regulate reproductive outcomes are not fully understood. This review summarizes the recent advances in understanding glycine’s role in animal reproduction, emphasizing its function as a metabolic regulator rather than merely a structural component. Glycine contributes to reproductive processes by maintaining redox homeostasis, supporting mitochondrial function and stabilizing cellular environments as part of its osmolyte function during critical developmental stages. Additionally, glycine participates in one-carbon metabolism, influencing nucleotide synthesis and epigenetic regulation. Furthermore, emerging evidence suggests that glycine may modulate key signaling pathways, including the AMP-activated protein kinase (AMPK)-mechanistic target of rapamycin complex 1 (mTORC1) pathway. Consistent with these mechanistic roles, glycine supplementation has been associated with improvements in oocyte maturation and embryonic development, particularly in vitro. These findings highlight the potential of glycine as a dietary or culture medium supplement to enhance reproductive performance in livestock. However, most current evidence is derived from in vitro systems, and the translation of these findings into livestock production strategies requires validation through well-designed in vivo studies. Full article

Background: The mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase that integrates inputs on nutrient status, energy levels, and growth factor stimulation to accordingly regulate cell growth and metabolism. It does this by activating or repressing target proteins covering a broad array of cellular processes. mTOR nucleates two structurally and functionally distinct protein complexes, mTORC1 and mTORC2. Because of their wide-ranging effects in the cell, both mTOR complexes are presumed to have a large number of targets. However, only a relatively small number have been conclusively identified. Methods: With emphasis on mammalian mTOR, we previously reviewed the extensive mTOR literature (1991–2021) and compiled a list of all reported substrates of mTORC1 and mTORC2. We have updated this list for the period 2022–2025. Results/Conclusions: Many of the targets are involved in autophagy, underscoring the major role of mTOR in the regulation of this process. From the perspective of this Special Issue, targets linked to cancer may be responsible for executing an mTOR-driven pro-oncogenic program and merit future study. Full article

Background: Skeletal muscle hypertrophy has traditionally been attributed to transient spikes in translational efficiency governed by the mTORC1 signaling cascade. However, contemporary molecular evidence reveals that sustained macroscopic growth is strongly associated with the physical expansion of the translational machinery itself. The activation of RNA Polymerase I and the subsequent synthesis of new ribosomes represent a critical biological correlate for long-term protein accretion. Objective: This comprehensive review critically examines ribosome biogenesis as the primary structural bottleneck shaping human skeletal muscle adaptation, differentiating acute signaling efficiency from chronic translational capacity. Synthesis: We dissect the molecular orchestration of nucleolar expansion and critically address the pervasive methodological pitfalls plaguing the current literature. Specifically, we highlight the moving denominator paradox, demonstrating how flawed bulk RNA normalization strategies systematically underestimate true ribosomal accretion in actively growing tissue. By synthesizing in vivo human evidence, we delineate how age, concurrent training, and training volume modulate this structural capacity. We further establish the high-responder phenotype as a function of successful nucleolar adaptation. Finally, we explore advanced molecular frontiers, including epigenetic chromatin remodeling, ribosomal heterogeneity as an emerging frontier, non-coding RNA regulation, and nuclear mechanotransduction via the YAP/TAZ axis. Conclusions: Acute anabolic signaling is merely permissive. Permanent hypertrophic adaptation fundamentally relies on overcoming the translational capacity bottleneck. Shifting the scientific and applied focus toward the architectural expansion of the nucleolus will fundamentally redefine practical hypertrophy programming and clinical interventions for sarcopenia. Full article

Glioblastoma (GBM) is highly invasive, and diffuse tumor cell migration into surrounding brain tissue remains a major obstacle to durable therapeutic control. Pharmacological ascorbate (P-AscH⁻) exhibits anticancer activity through pro-oxidant mechanisms; however, its effects on GBM motility and invasion remain incompletely defined. Transcriptomic analyses revealed a strong association between glioma aggressiveness and gene programs governing migration and invasion. Here, we demonstrate that P-AscH⁻ markedly suppresses migration and invasion of GBM cells. These phenotypic effects are accompanied by coordinated repression of epithelial–mesenchymal transition (EMT) programs, characterized by reduced expression of mesenchymal markers (ZEB1, N-cadherin, Vimentin, Slug, and Twist1) and induction of the epithelial marker Claudin-1 at both transcriptional and protein levels. In parallel, P-AscH⁻ significantly downregulates invasion-associated matrix metalloproteinases MMP2 and MMP9 at the mRNA level. Mechanistically, catalase rescue experiments establish extracellular hydrogen peroxide as an essential mediator of P-AscH⁻-induced inhibition of GBM motility and EMT-associated gene and protein expression. In addition, P-AscH⁻ attenuates mTOR signaling, and combination with a dual mTORC1/2 inhibitor further reinforces suppression of migratory behavior and mesenchymal programs. Importantly, these phenotypic and molecular effects are conserved in a patient-derived glioblastoma model, underscoring translational relevance. Collectively, these findings identify extracellular hydrogen peroxide-driven redox signaling as a key mechanism by which pharmacological ascorbate suppresses EMT and invasive programs in GBM, providing mechanistic support for ongoing clinical evaluation and highlighting its potential utility as an invasion-targeted therapeutic strategy in GBM and other highly plastic malignancies. Full article

The clinical management of nutrition in acute and chronic diseases requires an integrated understanding of the interactions between energy intake, dietary protein, and amino acids (AAs). Many conditions (including sepsis, major trauma, cancer cachexia, chronic heart failure, chronic obstructive pulmonary disease, renal and liver failure, autoimmune diseases, and aging) share a common pathophysiological feature: the hypercatabolic state (HCS). HCS is characterized by systemic inflammation and neuroendocrine activation that increase basal metabolic rate, induce insulin resistance, and accelerate skeletal muscle proteolysis, leading to negative nitrogen balance, sarcopenia, and cachexia. Under these conditions, skeletal muscle acts as a metabolic reservoir of AAs mobilized to support energy production, gluconeogenesis, immune function, and vital organ metabolism, often at the expense of lean body mass and clinical outcomes. This narrative review examines the distinct and non-overlapping roles of calories, proteins, and AAs in metabolic regulation, with a particular focus on HCS. Calories primarily act as a permissive factor for protein utilization, whereas proteins and especially essential amino acids (EAAs) function not only as substrates for protein synthesis but also as signaling molecules (metabokines) regulating anabolic and catabolic pathways, including mTORC1 and AMPK. Energy provision alone is insufficient to prevent muscle loss when EAA availability is inadequate, while high protein intake without sufficient energy fails to sustain anabolism due to anabolic resistance. Evidence indicates that protein quality and the balanced availability of all EAAs are more critical for lean mass preservation than total caloric intake alone. Strategies based solely on calorie provision or protein quantity are therefore limited, whereas targeted EAA supplementation may partially overcome anabolic resistance in selected hypercatabolic conditions. Overall, this review supports a shift from calorie-centered nutrition toward a signal-based, quality-oriented approach, based on personalized needs, that integrates metabolic status, protein quality, and AA signaling to preserve lean body mass and improve clinical outcomes. Full article

Polycystic kidney disease (PKD) is a genetic disorder characterized by renal cyst formation and progressive renal dysfunction, where inflammation, immune responses, and metabolic dysregulation critically drive disease progression, while emerging evidence increasingly links its pathogenesis to mitochondrial dysfunction. Mitochondria, central to cellular energy production, metabolism, and redox homeostasis, exhibit profound abnormalities in PKD, contributing to disease pathogenesis. Current evidence on mitochondrial mechanisms driving PKD progression includes metabolic reprogramming, oxidative stress, disrupted mitochondrial dynamics, and impaired mitophagy. Polycystic kidney disease is caused by mutations in the PKD1 or PKD2 genes, which encode polycystin 1 and polycystin 2. The formation of dysfunctional polycystins (PC1/PC2) is a key event in the pathogenesis of this disease, triggering impaired calcium signaling, increased production of mitochondrial reactive oxygen species (ROS), and reduced oxidative phosphorylation, thereby promoting cyst growth and fibrosis. Key signaling pathways such as mTORC1 hyperactivation, AMPK suppression, and disrupted calcium homeostasis further exacerbate mitochondrial defects. Emerging therapeutic strategies targeting mitochondrial pathways, such as mitochondrial antioxidants, modulators of mitophagy, calcium signaling regulators, and metabolic reprogramming agents, show promise in preclinical models. However, challenges remain in translating these findings to clinical applications, including drug specificity and minimizing off-target effects. This review underscores mitochondria as pivotal players in PKD pathogenesis and highlights their potential as therapeutic targets to mitigate cystogenesis and disease progression. Full article

Gestational diabetes mellitus (GDM) is increasingly recognized as a complex pathology rooted in systemic and organelle-level dysfunction, specifically involving chronic low-grade inflammation (CLGI), mitochondrial impairment, and endoplasmic reticulum (ER) stress. Central to this pathophysiology is mitochondrial dysfunction, characterized by reduced respiration, impaired metabolic flexibility, and dysregulated fission/fusion machinery, which fuels a self-perpetuating cycle of reactive oxygen species (ROS) production. Concurrently, chronic ER stress triggered by hyperglycemia and lipotoxicity activates the unfolded protein response (UPR), further amplifying redox imbalance through the Endoplasmic Reticulum Oxidoreductin 1/Protein Disulfide Isomerase (ERO1/PDI) axis and bridging metabolic toxicity to inflammation via c-Jun N-terminal kinase (JNK) and nuclear factor kappa-light-chain–enhancer of activated B cells (NF-κB) signaling. The Advanced Glycation Endproducts (AGEs) and the Receptor for Advanced Glycation Endproducts (RAGE) axis act as a molecular catalyst that sequester antioxidants and drive pro-inflammatory feedback loops. These converging mechanisms culminate in profound placental maladaptation, including structural abnormalities like chorangiosis and functional defects in nutrient transport mediated by hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling. This review article provides insight into recent evidence to elucidate the meta-inflammatory environment of GDM, where modest but sustained elevations in biomarkers like Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) disrupt redox homeostasis and impair insulin signaling pathways through the activation of stress-sensitive kinases. By integrating these molecular perspectives, the article underscores the necessity of targeting the systemic inflammatory and oxidative continuum spanning pre-conception to the antenatal period through lifestyle interventions and emerging therapeutic strategies to mitigate GDM risk and improve maternal–fetal outcomes. Full article

A common hypoxic scenario in tumors involves unresolved acute hypoxia that eventually leads to sustained (chronic) hypoxia. This shift drives a characteristic “HIF switch”, where the key hypoxia-responsive factors change from HIF-1α to HIF-2α over time, and importantly, this switch is closely linked to stemness regulation. However, the mechanisms underlying this switch and its impact on stemness regulation are not yet fully understood. Here, we developed a mechanistic network model integrating the HIF-1/HIF-2 signaling axis with the stemness regulators OCT4 and SOX2. We found that the duration and intensity of hypoxia jointly shape the dynamics of HIF-1α and HIF-2α, ultimately regulating OCT4-mediated stemness. Under physioxia, HIF-2α–mTORC2 positive feedback supports the gradual accumulation of HIF-2α toward a modest steady level and low OCT4 expression, corresponding to a primed state. Under prolonged mild hypoxia, the concurrent induction of HIF-1α, albeit at low levels, and accelerated accumulation of HIF-2α elevate OCT4 to intermediate levels, promoting stem-like traits. Under moderate hypoxia, PHD-2-mediated negative feedback triggers pulsatile HIF-1α dynamics, driving a shift toward HIF-2α dominance. Ultimately, cooperative HIF-1α/HIF-2α signaling induces REDD1 and suppresses mTORC1-dependent protein synthesis, pushing OCT4 into a high-expression state associated with differentiation. This work presents a unified framework for understanding how the HIF signaling hierarchy coordinates metabolic and transcriptional programs to direct cell fate across varying hypoxic landscapes. Full article

Background/Objectives: Obesity represents a significant global health challenge. Although alternate-day fasting (ADF) has been shown to effectively improve metabolic parameters, long-term adherence to this regimen remains limited. This study aimed to investigate whether highly polymerized persimmon tannin (DP31) could serve as a practical alternative to ADF for the prevention of high-fat diet (HFD)-induced obesity in mice. Methods: Male C57BL/6J mice (n = 10 per group) were subjected to an HFD for 11 weeks, during which they concurrently received either DP31 or ADF. Body weight, fat mass, serum lipid levels, glucose tolerance, fasting glucose, and insulin levels were assessed. Additionally, hepatic transcriptomics, Western blotting, 16S rRNA sequencing, and short-chain fatty acids (SCFAs) analysis were conducted. Results: DP31 demonstrated comparable efficacy to ADF in reducing body weight gain and improving lipid profiles, while exhibiting superior effects on glucose tolerance and fasting glucose levels (p < 0.05). Both interventions effectively reversed HFD-induced hepatic gene dysregulation, leading to the upregulation of genes involved in processes related to steroid metabolism. In addition, both treatments activated the hepatic AMPK-mTORC1-Lpin1 axis, suppressed lipogenesis, upregulated PGC1α, and increased β-hydroxybutyrate levels, indicating enhanced fatty acid oxidation (p < 0.05). Notably, DP31 outperformed ADF in enriching beneficial gut genera, such as Akkermansia, and boosting SCFAs production, which may elucidate its superior glycemic control. Overall, DP31 exhibits comparable effects to ADF in preventing obesity-related metabolic disorders, while demonstrating superior effects on glucose homeostasis. Full article

Background/Objectives: Capivasertib is a selective pan-AKT inhibitor recently approved in combination with fulvestrant for the treatment of hormone receptor-positive (HR+)/HER2- breast cancer with alterations in the PI3K/AKT pathway. The PI3K/AKT/mTOR signaling cascade represents a critical indication of endocrine resistance and tumor progression in this subtype of breast cancer. The present review summarizes current clinical data regarding the efficacy of capivasertib, either as monotherapy or in combination with other therapeutic agents and discusses emerging biomarkers and mechanisms of resistance. Methods: A literature search of the PubMed database was conducted to identify clinical trials evaluating capivasertib in breast cancer. Studies on capivasertib as monotherapy or in combination with fulvestrant, paclitaxel, or olaparib were included. Results: Findings from phase I–III clinical trials indicate that capivasertib in combination with fulvestrant significantly prolongs progression-free survival in patients with HR+/HER2- advanced breast cancer, particularly in tumors containing PIK3CA, AKT1, or PTEN alterations. Drug combination approaches with paclitaxel or olaparib have demonstrated additive or synergistic effects in triple-negative and DNA repair-deficient contexts, respectively. Monotherapy studies confirm effective pathway inhibition with modest clinical benefit, primarily in AKT1-mutant tumors. Translational analyses suggest that persistent mTORC1-mediated protein synthesis and compensatory signaling activation contribute to acquired resistance. Conclusions: Capivasertib constitutes a clinically validated therapeutic approach for the inhibition of AKT signaling in breast cancer. Its efficacy is most evident when combined with endocrine therapy; however, optimization of patient selection and rational combination strategies remains necessary to overcome resistance associated with mTORC1 activation and signaling redundancy. Full article

Inadequate choline intake-induced choline metabolic stress (CMS) has been divergently linked to metabolic dysfunction-associated steatotic liver disease (MASLD), yet underlying mechanisms remain unclear. We hypothesized that CMS modifies plasma-free amino acid (PFAA) signatures to influence MASLD risk. In a nested case–control study of 125 participants, dietary choline intake and blood choline metabolites were assessed together with targeted metabolomics and transcriptomic profiling. MASLD was characterized by low choline intake, reduced plasma betaine/choline ratio (Pbcr), elevated homocysteine, increased branched-chain amino acids (BCAAs), and depleted serine/glycine, achieving strong predictive accuracy (AUC = 0.90). CMS was associated with reduced lymphocytic transcripts involved in BCAA catabolism and altered mTORC1/Akt/IRS1 signaling. Nonlinear Pbcr- and intake-dependent MASLD risk patterns were attenuated after adjustment for genetic–metabolite networks. These findings identify CMS-responsive metabolic mediators supporting precision choline interventions. Full article

Acne vulgaris is a chronic inflammatory disease of the pilosabaceous unit with a multifactorial pathogenesis involving sebaceous gland activity, follicular hyperkeratinization, microbial dysbiosis, and immune dysregulation. Increasing attention has been given to the role of the skin and gut microbiome, as well as the gut–skin axis, although their clinical significance has not yet been fully explained. This review critically evaluates the current evidence regarding the use of probiotics, prebiotics, and synbiotics in the treatment of acne. Available studies suggest that microbiome-targeted interventions may influence inflammatory pathways, microbial composition, and metabolic regulators such as IGF-1 and mTORC1. Some clinical trials indicate improvements in acne severity and skin parameters following oral or local interventions. However, the evidence is heterogeneous and limited by small sample sizes, short study durations, and variability in formulations and outcomes. Therefore, although microbiome-based strategies may have potential as adjunctive therapy, their clinical efficacy remains uncertain. Further, well-designed, large-scale studies are needed to determine their role in dermatological practice. Full article

Mulibrey nanism is a rare autosomal recessive multisystem disorder caused by biallelic loss of function variants in TRIM37 encoding a peroxisomal E3 ubiquitin ligase. Initially described in Finland, where it remains most prevalent due to a founder mutation, the condition is now recognized worldwide and is characterized by severe prenatal-onset growth failure, distinctive craniofacial features, radiological abnormalities, ocular findings, and hepatopathy. Although its clinical spectrum extends far beyond these core manifestations, the major determinant of morbidity and mortality is progressive cardiovascular disease, including constrictive pericarditis and restrictive cardiomyopathy. Additional features include metabolic dysfunction such as insulin resistance and type 2 diabetes, gonadal insufficiency, skeletal abnormalities including fibrous dysplasia, and an increased risk of benign and malignant tumours. The clinical course evolves across the lifespan from early growth and developmental abnormalities to progressive multisystem disease in adolescence and adulthood. Recent advances have expanded understanding of TRIM37 function, linking it to mTORC1 TFEB signalling autophagy, centrosome integrity, extracellular matrix regulation, and immune cell function, providing mechanistic insights into tumour predisposition, skeletal pathology, and immune dysregulation. Management remains supportive and requires multidisciplinary care with emphasis on early recognition and treatment of cardiac disease, metabolic complications, and malignancy risk. Prognosis is variable but improves with early diagnosis and appropriate surveillance. This review summarises the clinical spectrum molecular mechanisms and current management of Mulibrey nanism and highlights priorities for future research. Full article

Background/Objectives: The development of non-alcoholic fatty liver disease (NAFLD) is closely linked to oxidative stress and inflammation. Aerobic exercise has been shown to improve NAFLD, although its underlying mechanisms remain incompletely understood. This study utilized ApoE^-/- mice to investigate the role of Sestrin2 in aerobic exercise-induced amelioration of NAFLD. Methods: Random assignment of C57BL/6J and ApoE^-/- mice yielded four groups: C (control), CE (aerobic exercise), AS (ApoE^-/- control), and AE (ApoE^-/- aerobic exercise). Aerobic exercise lasting 12 weeks was administered to the CE and AE groups. Serum biomarkers were analyzed by ELISA, liver tissue morphology was assessed via HE and ORO staining, and macrophage polarization was evaluated through immunofluorescence. Additionally, mRNA and protein expression levels were measured by qPCR and Western blot. Results: Aerobic exercise reduced liver wet weight, lipid accumulation, and steatosis in ApoE^-/- mice. Aerobic exercise attenuates hepatic oxidative stress, and upregulated the expression of regulation oxidative stress related gene and proteins of Nrf2, HO-1, CAT, and SOD1 in ApoE^-/- mice. Aerobic exercise promoted a shift in macrophage polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype in the liver, and significantly reduced TNF-α and IL-1β levels, accompanied by upregulation of Sestrin2 expression, enhanced AMPK phosphorylation, inhibited mTORC1 in the liver. Conclusions: These findings suggest that aerobic exercise alleviates oxidative stress and inflammation in NAFLD, with Sestrin2 activation playing a central role. Full article