Search Results (948)

Advances in mass spectrometry-based metabolomics have enabled the detection of numerous small molecules in biological systems, revealing complex metabolic alterations associated with cancer. Among these, dipeptides are consistently detected in plasma, serum, and tumor tissue metabolomic profiles, yet their biological significance is not fully understood. In most studies, circulating dipeptides are interpreted as nonspecific byproducts of protein degradation generated during increased proteolysis. However, accumulating evidence suggests that at least some endogenous dipeptides may have biological activities, including antioxidant effects, metabolic modulation, and potential signaling functions. In this review, we examine the possible origins, transport mechanisms, and biological implications of circulating dipeptides in cancer metabolomics. We discuss multiple sources of dipeptide generation, including intracellular proteolysis, autophagy, extracellular matrix remodeling, tumor cell death, host tissue catabolism, and microbiome metabolism. We also summarize current knowledge regarding peptide transport systems and intracellular dipeptide metabolism that may regulate the fate of these molecules within mammalian systems. In addition, evidence supporting the biological activities of certain endogenous dipeptides is reviewed to evaluate the possibility that some circulating dipeptides may function as bioactive metabolites. Finally, we propose conceptual frameworks for interpreting circulating dipeptides in cancer, including their potential roles as indicators of protein turnover, intermediates in amino acid recycling, stress-buffering molecules, metabolic signals, or components of tumor–host metabolic communication. A better understanding of circulating dipeptides may provide new insights into cancer metabolism and reveal previously overlooked metabolite classes with potential biomarker or functional significance. Full article

Phosphate (Pi) and calcium (Ca²⁺) are essential mineral ions that play coordinated roles in maintaining normal cellular functions. While various steps of calcium signaling are well characterized, emerging evidence suggests the critical role of both intracellular and extra cellular phosphate in regulating intracellular Ca²⁺. In the cytoplasm, phosphate influences ATP production and organelle calcium buffering and influences the activity of calcium pumps, such as sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) and the plasma membrane Ca²⁺-ATPase (PMCA). Extracellular phosphate, taken up via sodium-dependent phosphate transporters, triggers signaling cascades that affect the processes of calcium influx, storage, and release. Additionally, high extracellular phosphate levels can disrupt calcium homeostasis through the systemic interactions of hormones such as fibroblast growth factor 23 (FGF23), vitamin D and parathyroid hormone (PTH), especially under pathological conditions such as chronic kidney disease (CKD). This article briefly summarizes the current understanding of the bidirectional influence of intra- and extracellular phosphate on calcium dynamics at the cellular level, with a focus on the underlying mechanisms. Full article

The effective growth and maturation of porcine oocytes in vitro are critical for advancing reproductive biotechnologies. In this study, we explored low-temperature plasma (LTP) treatment as a redox modulation strategy to enhance the survival and maturation of denuded porcine oocytes during in vitro primary culture in order to improve animal cellular health through innovative interventions. Freshly isolated oocytes were exposed to plasma treatment for different lengths of time and subsequently cultured under established in vitro conditions. Morphological and redox-related analyses showed that LTP treatment was associated with increased oocyte diameter, a higher first polar body extrusion rate, mitochondrial membrane potential changes, and altered intracellular and extracellular redox-related parameters. These beneficial effects exhibited a distinct time-dependent dose–response pattern. Furthermore, Western blot analysis showed altered expression of the EGFR/ERK signaling cascade and proteins such as Nrf2, suggesting that LTP treatment might participate in the regulation of maturation-related responses in porcine oocytes cultured in vitro by inducing redox-associated changes, along with alterations in EGFR/ERK-related signaling, Nrf2 expression, and molecules involved in maturation and apoptosis. Collectively, these findings highlight the positive role of LTP in supporting porcine oocyte maturation during in vitro primary culture and provide a promising approach for optimizing the in vitro primary culture of porcine oocytes. Full article

Preterm labor is a major cause of neonatal morbidity and mortality and is frequently driven by infection-associated inflammation that promotes premature uterine activation. In this study, we investigated the effects of adipose stem cell-derived extracellular vesicles (ASC-EVs) on macrophage-mediated inflammatory signaling in uterine smooth muscle cells (HUtSMCs). An in vitro model was established by treating HUtSMCs with conditioned media derived from LPS-stimulated RAW264.7 macrophages. Activation of signaling pathways was assessed by Western blotting and immunofluorescence, and functional responses were evaluated using calcium flux and collagen gel contraction assays. Conditioned media from LPS-stimulated macrophages induced robust activation of MAPK (ERK1/2 and JNK) and NF-κB signaling, accompanied by IκB degradation and nuclear translocation of phosphorylated p65, whereas ASC-EVs pretreatment significantly attenuated these responses and reduced the expression of pro-inflammatory cytokines, including IL-6, IL-8, and MCP-1. Furthermore, macrophage-conditioned media enhanced intracellular calcium flux and contractile activity in HUtSMCs, both of which were suppressed by ASC-EVs. Inhibition of TLR4 signaling in macrophages reduced the inflammatory potency of conditioned media, indicating a key upstream role of macrophage TLR4 activation. Collectively, these findings demonstrate that ASC-EVs suppress macrophage-mediated inflammatory activation and downstream contractile responses, suggesting their potential as a cell-free therapeutic strategy for preventing inflammation-associated preterm labor. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. Its main pathological features are extracellular plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated tau. The Aβ hypothesis proposes that Aβ accumulation is a key driver of AD, influencing tau pathology, neuroinflammation, and neurodegeneration. However, therapies that reduce Aβ have shown limited clinical benefits. This suggests that the mechanisms underlying peptide-mediated modulation of AD pathology are much more complex. Both Aβ and tau undergo various post-translational modifications (PTMs) that affect their structure, aggregation, and toxicity. In addition, these abnormal proteins are not efficiently cleared in AD, indicating dysfunction of the protein quality control (PQC) system that maintains proteostasis. Such abnormal PTMs and impaired PQC likely work together to drive disease progression, which may explain the limited success of Aβ-reduction therapies. In this review, we describe how major PTMs, including phosphorylation, ubiquitination, acetylation, glycosylation, and oxidation, regulate the pathological behavior of Aβ and tau. We also discuss the role of the PQC systems in the pathology of AD. We propose that dysregulation of PTMs and PQC constitutes a convergent mechanism underlying AD pathogenesis. Therapeutic strategies targeting these processes may provide more effective and sustained disease modification than approaches focused solely on Aβ reduction. Full article

Vasculogenic mimicry (VM) is the ability of cancer stem cells (CSCs) to express an endothelial-like phenotype and participate in tumor neovascularization via the formation of a blood-conducting, matrix-rich network. We previously reported that pancreatic ductal adenocarcinoma (PDAC) CSCs develop their VM phenotype via two interacting and coordinated factors that support the formation of the VM network: (i) the overexpression of genes for endothelial factors and vascular receptors and (ii) the very high secretion of numerous pro-angiogenic/growth factors. While microenvironmental acidosis (low pHe) is an important driver of tumor metastasis, especially in PDAC, and is a component of the CSC niche, its role in VM and the ion transporters involved remains unknown. As normal stem cell differentiation is regulated by Na⁺/H⁺ exchanger 1 (NHE1)-driven pH, we investigated the role of NHE1 and the intracellular signaling involved in the acidosis-induced VM using a platform of 3D organotypic cultures composed of Matrigel with increasing concentrations of Collagen I. VM was highest on 90% Matrigel:10% Collagen I, representative of an early tumor ECM, and it decreased with increasing concentrations of Collagen I, representative of advanced tumors. In all ECM compositions, VM capacity increased stepwise with pHe acidification, and both basal and acid-stimulated VM were dependent on NHE1 activity. Acidification also decreased resting pHi and increased NHE1 proton extrusion activity, NHE1/ß1 integrin co-expression, and intracellular Ca²⁺. The stimulation of VM by extracellular acidosis depended on the transport of extracellular Ca²⁺ into the cell and the consequent increase in intracellular Ca²⁺. Altogether, these data demonstrate that extracellular acidification triggers cellular mechanisms that upregulate VM to overcome the constraints imposed by ECM composition, thereby permitting VM in ECMs where this phenotype is not expressed and extending the VM phenotype towards the tumor center to further drive metastasis. Full article

The complement system is traditionally recognized as a major effector of innate immunity, essential for pathogen clearance, inflammation and the maintenance of tissue homeostasis. In recent years, however, its role in cancer has been substantially redefined. Beyond its canonical extracellular activity, complement has emerged as a multifaceted regulator of tumor biology, acting not only within the tumor microenvironment but also intracellularly through the recently described intracellular complement system (complosome). While extracellular complement primarily shapes immune responses and the tumor microenvironment, the complosome directly regulates fundamental cellular processes, including metabolism, proliferation, autophagy, stress responses and cell survival. In this review, we discuss current evidence on the canonical and non-canonical roles of complement in cancer. Importantly, complement signaling exhibits a strong context-dependent duality, exerting either tumor-promoting or tumor-restraining effects depending on the tumor type, disease stage, cellular source, and localization. Taken together, the available evidence indicates that the complosome is not merely an extension of classical complement biology, but a distinct and biologically significant signaling network that rewrites our understanding of complement in cancer. Its growing relevance in tumor development and therapy resistance positions it as a promising target for future mechanistic studies and innovative therapeutic interventions. Full article

The inflammatory response possesses a central role in human pathophysiology, regulating the tissue microenvironment and cell signaling. Inflammation occurs either as a symptom of homeostasis disturbance or as a driver for determining cell fate. In this context, cells recruit secreted cytokines, chemokines and intracellular mediators, in cooperation with their surrounding cellular components, to integrate inflammatory stimuli. The extracellular matrix (ECM) acts as a scaffold for shaping tissue structure and simultaneously undergoes continuous remodeling to provide a dynamic network for intercellular communication. Serglycin (SRGN) is the only known intracellular and extracellular proteoglycan, implicated in the formation of secretory vesicles and ECM reorganization. The regulatory roles of SRGN in the bioavailability of secreted factors, as well as SRGN pleiotropic interactions within the ECM, as well as with cell surface receptors, have emerged to beessential for inflammatory diseases and tumor progression. Its overexpression and excessive secretion, alongside its contribution to cell signaling, highlight the potential diagnostic and therapeutic aspects of SRGN in human diseases. Full article

Cancer progression is influenced by the dynamic interplay between tumor cells and the surrounding stromal microenvironment. Therapy-induced senescence (TIS) of stromal fibroblasts represents a common outcome of anticancer treatments, contributing to tumor progression through the senescence-associated secretory phenotype (SASP). While SASP cytokines promote cancer malignancy, the contribution of secreted metabolites from senescent cells remains poorly understood. Here, we investigate the role of senescent stromal metabolism in regulating prostate and ovarian cancer cell invasion. Conditioned media (CM) from TIS-induced human prostate (HPFs) and ovarian fibroblasts (HOFs) promote enhanced invasion of cancer cells. Invasion is partially preserved after exposure to boiled CM, suggesting a role for heat-stable metabolic factors. Metabolomic profiling of senescent fibroblasts-derived CM reveals a significant increase in Glutamine (Gln) levels, identifying senescent stromal fibroblasts as a previously unrecognized source of extracellular Gln in the tumor microenvironment (TME). Exposure of cancer cells to senescent CM increases Gln uptake, together with upregulation of the transporter SLC1A5 and increased intracellular Gln. This metabolic adaptation is associated with increased malignant phenotype including epithelial-to-mesenchymal transition (EMT) and stemness features. Extracellular Gln depletion, pharmacological inhibition of glutaminase-1 (GLS1) in cancer cells, or Gln synthetase (GS) silencing in fibroblasts markedly impair senescent fibroblasts CM-induced invasion, EMT markers expression, and stemness features in cancer cells. Stromal-derived Gln is associated with increased cancer cell invasion through activation of a redox-dependent NRF2/ETS1 signaling axis. Analysis of patient-derived transcriptomic datasets further suggests chemotherapy-associated upregulation of Gln metabolism and ETS1 expression. These findings identify senescent stromal-derived Gln as a key metabolic driver of prostate and ovarian cancer aggressiveness and reveal a TIS-associated metabolic vulnerability that could be explored in future preclinical studies. Full article

Protein turnover and extracellular proteolysis continuously generate diverse peptide fragments within biological systems, yet the metabolic and pharmacological implications of these peptides remain incompletely understood. Among these transporters, members of the solute carrier family 15 (SLC15), including peptide transporter 1 (PEPT1/SLC15A1) and peptide transporter 2 (PEPT2/SLC15A2), mediate the proton-coupled uptake of dipeptides, tripeptides, and structurally related compounds across cellular membranes. While these transporters have been extensively studied in the context of intestinal peptide absorption and drug delivery, their potential roles in cancer biology remain incompletely understood. Tumor microenvironments are characterized by extensive proteolysis and dynamic metabolic remodeling, processes that can generate diverse peptide fragments derived from extracellular matrix proteins and intracellular protein turnover. These peptides may accumulate locally and potentially serve as substrates for cellular peptide transport systems. Once internalized through peptide transporters, dipeptides are typically hydrolyzed into free amino acids that can support biosynthetic pathways, energy metabolism, and cellular growth. In addition to their potential metabolic roles, certain endogenous dipeptides have also been reported to influence cellular signaling pathways and redox homeostasis. The broad substrate specificity of peptide transporters has also attracted significant interest in pharmacology because numerous clinically used drugs exploit these transport systems for efficient cellular uptake. This property raises the possibility that peptide transporters may be utilized for transporter-mediated drug delivery strategies, including the development of peptide-modified prodrugs or dipeptide–drug conjugates. In this review, we summarize the molecular characteristics and physiological functions of dipeptide transport systems with a particular focus on the SLC15 transporter family. We then discuss emerging evidence linking peptide transporters to tumor metabolism and the tumor microenvironment. Finally, we highlight current progress and future perspectives in exploiting peptide transport systems for transporter-mediated drug delivery and therapeutic targeting in cancer. Full article

Keloid is a benign skin disease with excessive growth of fibroblasts, characterized by too much abnormal extracellular matrix deposited in the dermis. It is generally believed that transforming growth factor-β (TGF-β) is the core cytokine that causes keloid. Previously, it was thought that its pathogenic effect was mainly attributed to the classical Smad-dependent pathway. It directly shuttles signals to the nucleus to trigger pro-fibrotic gene transcription. However, accumulating evidence now points to the equally vital role of Smad-independent signaling. Unlike the direct nuclear translocation of Smads, these alternative pathways transmit signals through rapid intracellular kinase cascades. They jointly direct the proliferation, migration, anti-apoptosis, fibrogenesis, and chronic inflammation of fibroblasts in keloids. This review attempts to comprehensively clarify the molecular processes regulated by TGF-β through non-Smad pathways (such as MAPK, PI3K/Akt, Rho GTPase, Wnt/β-catenin, JAK/STAT). Translating these non-Smad insights helps to overcome the high recurrence rates of traditional therapies. Targeting these specific molecular hubs through combination and precision therapies serves to reprogram the fibrotic microenvironment. Full article

Beyond their classical role as “cellular powerhouses”, mitochondria are increasingly recognized as dynamic and interconnected networks whose architecture, quality control, and intercellular communication influence cellular and organismal homeostasis. Mitochondrial dynamics—including fusion–fission balance, mitophagy–biogenesis coupling, intracellular organization, and intercellular transfer via tunneling nanotubes, extracellular vesicles, or transient cell fusion—contribute to tissue adaptation and functional decline during aging. Focusing on cardiac muscle, skeletal muscle, and the nervous system, this narrative review synthesizes current evidence describing how aging disrupts mitochondrial network integrity through altered dynamics, impaired organelle positioning and transport, reduced mitophagy, mtDNA instability, and compromised metabolic coupling between cells. These alterations propagate across tissues, limiting energetic flexibility, stress resilience, and regenerative capacity. Building on these mechanisms, we discuss a systems-level perspective in which aging is associated with progressive loss of mitochondrial network coherence rather than solely cumulative molecular damage. Within this framework, mitochondrial connectivity functions as an integrative descriptor of cellular resilience: well-organized networks counteract metabolic perturbations, whereas functionally decoupled networks amplify stress and promote maladaptive aging trajectories. Emerging evidence indicates that physiological and pharmacological interventions, including endurance exercise, caloric restriction or mimetics, fusion-supporting pathways, and mitophagy-enhancing strategies, can partially restore network organization even later in life. Molecular, cellular, and tissue-level insights are integrated to highlight mitochondrial network dynamics as both a mechanistic contributor to aging and a potentially modifiable target for future preventive and therapeutic interventions. Full article

Chlorella Growth Factor (CGF) is a nucleotide-rich, water-soluble intracellular fraction derived from disrupted Chlorella biomass that has historically been described as a “growth-promoting” extract but remains poorly defined at the molecular level. In this review, we propose that CGF should not be interpreted as a classical receptor-binding growth factor, but rather as a heterogeneous, nucleotide-dominant metabolic fraction that may modulate cellular redox balance and biosynthetic capacity. We integrate available evidence on CGF characterization, including A260-based analytical indices, mineral-dependent biosynthesis, and extraction methodologies, with mechanistic observations from in vitro, animal, and applied biological systems. Across these contexts, CGF-associated fractions have been reported to influence redox-sensitive pathways, including NAD(H)/NADP(H)-linked processes, MAPK/AP-1 signaling, extracellular matrix regulation, and humoral immune responses. However, most mechanistic evidence remains indirect, and compositional heterogeneity limits direct comparability across studies. From a nutritional perspective, CGF contributes minimal macronutrient value but may provide conditionally relevant dietary nucleotides, amino acids, and redox-active metabolites that support metabolic processes under stress conditions. Observed biological effects are consistent with a model of metabolic permissiveness, in which CGF-associated fractions may support endogenous cellular functions rather than directly initiating signaling cascades. Key translational challenges include the lack of compositional standardization, limited nucleotide speciation, variability in extraction protocols, and the absence of pharmacokinetic and controlled human studies using well-characterized CGF preparations. Overall, CGF may be conceptualized as a candidate dietary bioactive with redox-centered and metabolically permissive properties. Further work integrating standardized analytical frameworks with mechanistic and clinical validation will be required to establish its role in human nutrition and functional food applications. Full article

Background/Objectives: Chronic metabolic acidosis (CMA) is a mild, persistent acid–base imbalance characterized by low serum bicarbonate and urinary pH and is common in chronic illness, aging, and metabolic disorders such as type 2 diabetes (T2D). This review highlights the critical, yet often overlooked, role of CMA in T2D (CMAD) and its contribution to disease pathophysiology. Methods: We conducted a comprehensive review of the systemic impacts of CMA, from molecular mechanisms to organ-specific dysfunction. The analysis covers physiological pH dynamics in intracellular (IC) and extracellular (EC) fluids and explores their effects on cellular processes, including the cell cycle and apoptosis. Results: At the molecular level, acidosis significantly alters enzyme kinetics, macromolecule metabolism, and ion conductance. Cell-level analysis shows that pH shifts impact proliferation and programmed cell death. Systemically, the manifestations of CMA align closely with T2D features in vital organs, including the pancreas, liver, skeletal muscle, adipose tissue, and the renal, nervous, and immune systems. Our findings indicate that the pathophysiological landscape of T2D largely mirrors the biological effects of chronic acidosis. Conclusions: The alignment between the effects of CMA and the clinical features of T2D suggests that T2D pathophysiology is worth revisiting through the lens of CMAD. This perspective is further supported by therapeutic interventions showing preliminary efficacy signals in limited studies of acid-neutralization in managing T2D symptoms and progression. Full article

Nitrogen metabolism is fundamental to all organisms, with ammonium transporters (Amt) playing a pivotal role in transmembrane ammonium transport. Brachiopods, as “living fossils”, offer unique insights into the evolutionary adaptation of marine invertebrates. This study systematically identified and characterized the Amt gene family in the brachiopod Lingula anatina. Five canonical Amt genes were identified, with nonrandom chromosomal distribution and evidence of lineage-specific duplication events. Phylogenetic analysis revealed that these Amt proteins cluster into three well-supported clades, showing closer affinity to Caenorhabditis elegans, reflecting conserved ancestral features predating protostome radiation. Structural predictions showed that LanAmtA and LanAmtB retain the canonical 11-transmembrane helix (TMH) topology with an extracellular N-terminus, while LanAmtC features a unique 12-TMH architecture with an intracellular N-terminus, resembling certain vertebrate Amt-related proteins. Critical functional residues involved in ammonium selectivity and transport were preserved across all paralogs. Expression profiling revealed non-redundant spatiotemporal patterns: LanAmtA1 and LanAmtB2 dominate early embryogenesis, with LanAmtB2 becoming the major isoform in late developmental stages; LanAmtC exhibits constitutive high expression across adult tissues. Collectively, our findings demonstrate that the L. anatina Amt family expanded via local duplications, evolving structural stability, regulatory diversity, and functional specificity. This study provides a comprehensive molecular framework for understanding the evolutionary adaptation of nitrogen-handling mechanisms in basal lophotrochozoans and sheds light on how intertidal organisms cope with dynamic environmental conditions. Full article