Search Results (2,221)

Acute myeloid leukemia (AML) represents a heterogeneous group of hematological malignancies characterized by uncontrolled proliferation of myeloid progenitors and accumulation of immature blasts in the bone marrow. Metabolic reprogramming is now recognized as a core hallmark of AML, generating dependencies that distinguish leukemic cells from normal hematopoietic stem and progenitor cells and that can be exploited therapeutically. In this review we follow a single connected line of argument: we first place metabolic rewiring within the broader hallmarks of cancer, then describe the principal metabolic programs altered in AML and the specific features that distinguish AML from other malignancies. We next examine the inhibitors and drugs that target each of these pathways, linking every drug class to its mechanism of synergy with chemotherapy, the preclinical and clinical evidence available, and its association with outcome in AML. We then consider multi-target (combination) therapy as a distinct opportunity, and finally the principal challenges that remainsafety and tolerability, the metabolic heterogeneity and plasticity of AML, and the design of biomarker-guided trials. Multiple classes of metabolic drugs are discussed, including glycolysis inhibitors, oxidative phosphorylation inhibitors, glutamine metabolism antagonists, fatty acid oxidation modulators, and redox-active compounds. Despite significant challenges, targeting cellular metabolism represents a promising strategy to enhance therapeutic outcomes in patients with AML. Full article

Efficient cutaneous wound healing relies on the phenotypic transition of macrophages toward an anti-inflammatory, pro-reparative M2-like state. Non-healing chronic wounds are pathologically characterized by the breakdown of this polarization balance. In this review, we synthesize recent research on biomaterials fabricated from naturally occurring polysaccharides with intrinsic immunomodulatory activity, mainly represented by hydrogels that modulate macrophage phenotypic transitions. We first dissect the immune microenvironment of wound healing and elaborate on the core regulatory networks governing M1/M2 polarization, with a particular focus on signaling pathways and metabolic reprogramming. On this basis, we classify pro-M2 natural polysaccharides into mannose-containing and mannose-free categories according to their core structural motifs that mediate immunomodulatory activity, and detail their molecular mechanisms, including pattern recognition receptor engagement (MR, Dectin-1, CD44, etc.) and downstream signaling cascades (STAT6, PI3K/Akt, NF-κB, etc.). Representative polysaccharides such as konjac glucomannan (KGM), Ganoderma lucidum polysaccharide (GLP), chitosan (CS) and hyaluronic acid (HA) are discussed with a clarified structure–activity relationship (SAR). Finally, we highlight emerging design strategies for multi-functional immunomodulatory hydrogels, including mechano-biochemical coupling platforms and spatiotemporally controlled delivery systems, and analyze ongoing controversies and translational bottlenecks in this field. The relationship between material structure and function enables the rational design of purpose-built polysaccharide dressings that regulate immunity. This review highlights these materials as promising preclinical platforms for chronic wound management, although their clinical translation requires further validation. Full article

Highland Tibetan cattle have evolved unique hypoxic adaptation capabilities from their lowland ancestors; however, the mechanisms that distinguish short-term acclimatization from long-term genetic adaptation remain poorly understood. In this study, we integrated hematological assays and multi-organ transcriptomic analyses across three groups: highland Tibetan cattle (long-term adaptation), highland-acclimatized Holsteins (short-term acclimatization), and lowland Holsteins (controls). Hematologically, highland-acclimatized Holsteins displayed elevated red blood cell count, hemoglobin level, and blood viscosity, consistent with compensatory responses to hypoxia. In contrast, Tibetan cattle maintained lower and more stable hematological parameters, reflecting a blunted adaptive strategy shaped by long-term natural selection. Transcriptomic analysis revealed tissue-specific response to hypoxia: the heart underwent metabolic reprogramming, the liver shifted from metabolic compensation toward immune homeostasis, and the lung exhibited limited transcriptional changes associated with enhanced oxygen exchange efficiency. Pathway analysis and immunohistochemistry implicated GNB1 in PI3K–AKT-associated angiogenic responses to hypoxia. Furthermore, hepatic SLAMF7 upregulation and recombinant SLAMF7 activity against S. aureus and E. coli suggested a potential role in long-term immune resilience. Collectively, our findings clarify the dynamic transition from short-term physiological stress responses to long-term genetic adaptation in cattle under high-altitude hypoxic conditions, providing novel insights into the hypoxic adaptation mechanisms of ruminants. Full article

The stem-boring herbivore Aeolesthes induta severely threatens tea (Camellia sinensis) production, yet the systemic defense mechanisms of tea plants remain largely elusive. The unique age-dependent infestation pattern of A. induta—with minimal damage to young tea plants but infestation rates reaching 20% in 30-year-old trees and nearly 100% in ancient tea trees—necessitated field sampling from naturally infested old tea plantations rather than controlled laboratory conditions. By integrating rhizosphere microbiomics, transcriptomics, and multi-omics modeling, this study characterized the defensive regulatory networks of 30-year-old Shuixian tea cultivars under A. induta infestation. Rhizosphere microbiome analysis revealed that herbivore attack significantly reshaped the microbial community structure, reducing bacterial diversity and simplifying co-occurrence network complexity. Transcriptomic and metabolomic profiling demonstrated a precise source–sink defense allocation between host tissues. In leaves acting as the photosynthetic source, metabolic reprogramming was dominated by the systematic accumulation of soluble sugars and sugar acids for systemic energy reallocation. Concurrently, the roots acting as the metabolic sink vigorously activated the jasmonic acid (JA) signaling cascade and upregulated genes enriched in phenylpropanoid biosynthesis and alpha-linolenic acid metabolism. This molecular activation drove the substantial de novo synthesis of defensive phenolic acids, while downregulating growth-related flavonoids. Integrated network modeling further highlighted the phenylpropanoid pathway as the central regulatory node coupling transcript–metabolite fluctuations. This study constructs an integrated soil microbiome–root–leaf defense network, providing novel mechanistic insights into plant–borer interactions and a valuable foundation for future insect-resistant breeding programs in the tea industry. Full article

The rising incidence of chronic autoimmune and autoinflammatory diseases has been increasingly associated with environmental and lifestyle factors, including Western dietary patterns, intestinal dysbiosis, and reduced production of short-chain fatty acids (SCFAs). Reduced production of acetate, propionate, and butyrate has been associated with impaired epithelial barrier function, altered peripheral immune tolerance, and low-grade systemic inflammation. This article integrates and systematizes current knowledge in the field of immunometabolism, focusing on the role of the microbiota–metabolism–immunity axis. The molecular mechanisms by which these bacterial metabolites modulate immune function—both through the activation of specific surface receptors and direct epigenetic regulation—are analyzed in detail. SCFAs have been shown to actively reprogram the metabolic and transcriptional profiles of effector cells, stimulating anti-inflammatory macrophage polarization, suppressing cellular inflammatory cascades, and inducing the differentiation of protective regulatory T cells. To address the pharmacokinetic limitations of natural fatty acids, this study critically evaluates modern translational strategies. The clinical potential of synthetic receptor agonists, selective epigenetic modulators, and advanced next-generation bacterial consortia is analyzed. The presented data synthesis not only organizes the pathophysiological foundations but, above all, points to promising new directions for personalized non-pharmacological immunomodulation in the treatment of inflammatory diseases. Full article

Ovum pick-up (OPU) enables high-frequency oocyte retrieval from selected dairy cow donors, facilitating favorable genetic progression. However, oocytes obtained via OPU and subjected to in vitro maturation frequently suffer from severe oxidative stress, mitochondrial dysfunction, and DNA damage, resulting in lower pregnancy rates compared to those of in vivo-derived embryos. Melatonin (MT), as a potent antioxidant, may exert beneficial effects on these OPU-retrieved oocytes. In the current study, by combining in vitro and in vivo experiments, the protective effects and potential molecular mechanisms of MT on disrupted oocyte quality and development caused by OPU were systemically investigated. By integrating oocyte quality assessment, follicular fluid metabolomics, and blastocyst transcriptomics, the results showed that subcutaneous administration of MT to cows prior to OPU significantly increased the number of high-quality Grade A oocytes and reduced the number of low-quality Grade D oocytes compared to the control. These improvements were accompanied by reduced local and systemic oxidative stress, enhanced glutathione metabolism, and lower serum progesterone concentrations at the measured time points, coinciding with a more favorable endocrine environment for follicular development. The results from untargeted metabolomics of the follicular fluid revealed that MT supplementation was associated with an altered follicular fluid microenvironment characterized by the upregulation of estrogen derivatives and glutathione-related pathways. Transcriptomic analysis of blastocysts showed significant upregulation of the rate-limiting genes steroidogenic acute regulatory protein (STAR) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), suggesting a potential role in promoting the synthesis of reproductive hormones and maintaining the progress of embryo development. The in vitro study showed that MT supplementation at a concentration of 10⁻⁷ mol/L in oocyte maturation media significantly improved cleavage rates, blastocyst rates, and total blastocyst cell numbers compared to the control. In vitro evaluations demonstrated that MT scavenged intracellular reactive oxygen species (ROS), while transcriptomic analysis indicated a reprogramming of the embryonic transcriptome. These transcriptomic changes were associated with the AMPK, FoxO, and autophagy pathways, as well as the modulation of endoplasmic reticulum stress and cellular senescence. The results from both the in vivo and in vitro studies suggested that MT supplementation was associated with a follicular microenvironment favorable for oocyte growth and protected embryos from oxidative damage. Therefore, MT supplementation effectively reduced the disrupted oocyte development caused by OPU and improved oocyte recovery and quality in general. These findings provide promising experimental evidence for the potential application of MT in dairy breeding and offer insights into the associated molecular pathways. However, further functional validation is required to fully elucidate the underlying mechanisms and establish its large-scale applicability. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a disorder of hepatic lipid metabolic reprogramming rather than a consequence of passive triglyceride accumulation. Chronic nutrient excess, insulin resistance, adipose tissue dysfunction, and altered nutrient-sensing pathways disrupt the balance among hepatic fatty acid uptake, de novo lipogenesis, β-oxidation, lipid storage, and lipoprotein export. These changes promote the accumulation of bioactive lipid species, including saturated fatty acids, ceramides, diacylglycerols, oxidized phospholipids, and free cholesterol. Unlike triglycerides, which may serve an adaptive buffering role under conditions of preserved lipid-storage capacity, these bioactive lipids function as metabolic stress signals that impair insulin signaling, disrupt mitochondrial and endoplasmic reticulum homeostasis, activate PKC, JNK, MAPK, NF-κB, and NLRP3 pathways, and promote hepatocyte death, immune activation, and fibrogenesis. Emerging lipidomic and multi-omic approaches further demonstrate that the molecular composition and subcellular distribution of hepatic lipids may be more closely associated with disease progression than total lipid content. This review critically integrates current evidence on hepatic lipid metabolic reprogramming, lipid-mediated signaling, organelle dysfunction, fibrosis, and molecular heterogeneity in MASLD. It also evaluates the translational potential and limitations of lipidomic biomarkers and mechanism-based therapies targeting lipogenesis, nuclear receptors, ceramide metabolism, inflammatory signaling, and fibrosis. A deeper understanding of disease-specific lipid signatures and signaling networks may support molecular endotyping, mechanism-based therapeutic strategies, and precision hepatology in patients with metabolic dysfunction-associated steatohepatitis (MASH) and progressive fibrosis. Full article

Light critically limits rattan seedling establishment. To elucidate adaptive mechanisms of Calamus viminalis under varied light, we conducted a 360-day pot experiment with four shading levels (0%, 20%, 50%, 75%), integrating morphological, physiological, antioxidant, and RNA-seq analyses. Moderate shading (20%) maximized seedling height (46.97 cm) and ground diameter (12.46 mm), increased net photosynthetic rate by 57.92% versus full light, and raised soluble protein/sugar while minimizing MDA and proline—indicating the lowest oxidative damage. Severe shading (75%) suppressed carbon fixation, reduced antioxidant enzymes, aggravated lipid peroxidation, and drastically lowered survival. Transcriptomics revealed intensity-dependent reprogramming: moderate shading activated phenylpropanoid/flavonoid defense pathways; severe shading upregulated photosynthesis/ribosomal genes but constrained overall carbon flux. Four core pathways (photosynthesis, hormone signaling, phenylpropanoid metabolism, carbon metabolism) coordinated shade responses—BR signaling upregulated (shade avoidance) while ABA downregulated under low light; light deprivation globally downregulated LHCB1 and rbcL, impairing capture/assimilation. We identify 20% shading as optimal for C. viminalis cultivation and reveal multi-level phenotype–physiology–molecule mechanisms, providing a theoretical basis for Calamus viminalis seedling nursery management under controlled nursery conditions. Full article

Renal cell carcinoma (RCC) comprises molecularly diverse tumor subtypes. This diversity is reflected in distinct and adaptable gene-expression programs that enable tumor cells to reprogram metabolism and survive therapeutic pressure. By regulating RNA processing, export, stability, decay, and translation, messenger RNA (mRNA) modifications may help shape these programs. Examining mRNA modifications is therefore important for understanding metabolic adaptation and treatment resistance in RCC. This narrative review focuses on RCC studies of N6-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), N7-methylguanosine (m⁷G), and N4-acetylcytidine (ac⁴C). We focus on protein-coding transcripts and mRNA-centered mechanisms. Transcript-level studies are most extensive for m⁶A, while selected m⁵C and ac⁴C studies have identified defined regulator–mRNA axes. By comparison, RCC data for specific internal m⁷G sites in mRNA remain largely indirect. Many reported links with immune features or treatment response are based on retrospective analyses rather than treatment-specific clinical validation. Different modification pathways converge on PI3K/AKT, Hippo/YAP, metabolism, and treatment resistance, although direct molecular crosstalk has not been shown in RCC. No RNA-modification biomarker or targeted agent is used in routine RCC care. Further progress will require orthogonal site validation, broader coverage of RCC subtypes, and prospective studies conducted within contemporary treatment settings. Full article

Rising atmospheric CO₂ is altering carbon–nitrogen interactions in C₃ crops, with tomato (Solanum lycopersicum L.) showing enhanced carbon assimilation but frequently reduced nitrogen acquisition and assimilation. Nitrate reductase (NR), the rate-limiting enzyme in nitrate reduction, plays a central role by integrating nitrate assimilation with carbon metabolism and nitric oxide (NO) signaling. This review summarizes current knowledge of NR regulation in tomato under elevated CO₂ (eCO₂), focusing on post-translational mechanisms and their contribution to photosynthetic acclimation. Elevated CO₂ modulates NR activity through interconnected changes in photorespiration, carbohydrate-mediated feedback, redox regulation, source–sink dynamics, and nitrogen availability. While eCO₂ generally suppresses leaf nitrate assimilation by reducing photorespiratory support, root-zone CO₂ enrichment can transiently stimulate root NR activity, highlighting tissue-specific regulation. Multi-omics studies further demonstrate extensive metabolic and molecular reprogramming affecting carbon skeleton supply, amino acid biosynthesis, and nitrogen assimilation. In addition, NR-dependent NO production links nitrogen metabolism with stomatal regulation through ABA-independent H₂O₂–NO signaling. Despite these advances, the roles of NR phosphorylation, 14-3-3 protein interactions, and redox-mediated regulation under eCO₂ remain poorly understood. Overall, NR functions as a key metabolic and signaling hub coordinating carbon and nitrogen metabolism under future climate conditions. Understanding these regulatory mechanisms will facilitate strategies to improve nitrogen-use efficiency, sustain photosynthesis, and enhance tomato productivity under elevated atmospheric CO₂ while identifying priorities for future physiological, molecular, and multi-omics research. Full article

Heavy metal contamination is a significant environmental risk factor for ocular dysfunction and retinal degeneration in both aquatic organisms and humans. Zebrafish (Danio rerio) have become an important vertebrate model for retinal toxicology research due to their conserved retinal architecture, cone-rich visual system, optical transparency during development, and remarkable capacity for retinal regeneration. This narrative review synthesizes current evidence on the effects of heavy metals on the development, structure, function, and regenerative responses of the zebrafish visual system, with particular focus on retinal alterations, molecular mechanisms, and visual impairment. Studies indicate that exposure to cadmium, lead, arsenic, chromium, copper, mercury, and metal mixtures results in retinal disorganization, photoreceptor degeneration, vacuolization, retinal pigment epithelium damage, impaired retinogenesis, and alterations in visually mediated behaviors. Mechanistic investigations reveal that heavy metal-induced retinal toxicity involves oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, apoptosis, neuroinflammation, DNA damage, and dysregulation of genes critical for retinal development and photoreceptor maintenance. Functional assays, such as the optomotor response and optokinetic reflex, provide sensitive endpoints for detecting visual dysfunction that may precede overt structural degeneration. Furthermore, the unique regenerative capacity of the zebrafish retina, primarily mediated by Müller glia reprogramming, provides valuable opportunities to study endogenous retinal repair following toxic injury. Overall, current evidence establishes zebrafish as a versatile and translationally relevant model for investigating heavy metal-induced retinal injury, visual dysfunction, and regenerative responses. Future research that incorporates environmentally relevant exposure paradigms, mixture toxicology, multi-omics approaches, and regenerative signaling pathways is likely to enhance understanding of metal-associated retinal disease and support the development of novel therapeutic strategies for retinal degeneration and vision loss. Full article

Background: Immunometabolic reprogramming is increasingly recognized as a fundamental driver of macrophage inflammatory activation. Although pomegranate polyphenols have been widely investigated for their anti-inflammatory activity, the underlying metabolic mechanisms remain poorly understood. Here, we investigated whether a pomegranate waste extract (PWE), obtained through a sustainable dimethyl carbonate (DMC)-based extraction process, modulates macrophage activation by targeting immunometabolic pathways. Methods: Human PBMC-derived macrophages stimulated with LPS and IFN-γ were treated with PWE. Inflammatory mediators, NF-κB transcription factor, histone H3 acetylation, and markers of inflammatory resolution were evaluated. Furthermore, the enzymatic activity of ATP citrate lyase (ACLY) and malic enzyme 1 (ME1) was determined. Rescue experiments with acetate, malate, and NADPH were performed to investigate the functional contribution of the ACLY–ME1 metabolic axis. Results: PWE significantly reduced NF-κB activation and the production of IL-1β, IL-6, TNF-α, ROS, NO•, and PGE₂ without affecting cell viability. Mechanistically, PWE functionally suppressed ACLY and ME1, two central enzymes linking citrate metabolism to cytosolic acetyl-CoA and NADPH generation. Indeed, acetate supplementation restored PGE₂ production and inflammatory cytokine secretion, whereas malate and NADPH rescued oxidative mediator production. PWE also lowered histone H3 acetylation, indicating that metabolic remodeling affected epigenetic regulation of inflammatory gene expression. Finally, PWE increased the expression of CPT1A, SLC25A20, Annexin A1, and FPR2, while enhancing IL-10 and 15-HETE secretion, consistent with activation of pro-resolving macrophage programs. Conclusions: These findings demonstrate that DMC-extracted PWE suppresses inflammatory macrophage activation primarily through immunometabolic modulation. By targeting the ACLY–ME1 metabolic axis, PWE limits acetyl-CoA- and NADPH-dependent inflammatory processes and fosters a shift toward a pro-resolving macrophage phenotype. Our work identifies this sustainable pomegranate waste extract as a promising modulator of macrophage immunometabolism. Full article

Sepsis-induced acute lung injury (SI-ALI) is a severe complication of sepsis characterized by dysregulated inflammatory responses and impaired immune homeostasis. Growing evidence indicates that extracellular vesicles (EVs), particularly exosomes, are important mediators of intercellular communication. Despite the heterogeneity of infectious sources underlying sepsis, EVs can regulate macrophage polarization and functional reprogramming by transferring diverse bioactive cargo. Consequently, EVs are involved in the pathophysiological progression of SI-ALI arising from sepsis of different etiologies. However, the mechanisms through which distinct EV cargos regulate macrophage function and contribute to SI-ALI pathogenesis remain incompletely understood. To address these issues, this review summarizes how different EV subtypes and their cargos, including RNAs, proteins, lipids, and DNA, modulate macrophage functional states through multiple signaling pathways. The effect of such processes further contributes to inflammatory reaction, immune balance, and tissue regeneration in acute lung injury caused by damage to the SI-ALI. Particularly, the EV-mediated modulation of macrophage function goes beyond the rigid M1/M2 dichotomy, being rather based on the dynamic functional repertoire involving both pro-inflammatory response and immune regulation as well as tissue regeneration. The article finally concludes with EV-based treatment approaches aimed at cargo delivery or blocking and the main problems related to translational medicine. Overall, the review article identifies the macrophage regulatory network controlled by EVs, thus helping to understand immunopathogenesis of SI-ALI as well as laying the theoretical foundation for developing EV-based precision medicine. Full article

Schwann cell (SC)-based therapy is currently being debated as an approach to promote functional recovery in patients with multiple sclerosis (MS) and other inflammatory demyelinating diseases of the central nervous system (CNS). The main limitation of SC transplantation in MS patients is the short-term functional activity of SCs in the CNS environment. The goal of this study was to determine phenotypic, functional, and signaling changes in human SCs treated with CSF samples from MS patients in vitro, and to characterize the molecular mechanisms underlying SC injury response in the model MS microenvironment. We demonstrated that SC proliferation and motility were suppressed, while the expression of both pro-myelinating genes and negative regulators of myelination was up-regulated in cells incubated with CSF from MS patients. This was associated with active phosphorylation of ERK and c-Jun, and inhibition of these signaling pathways prevented SC changes. The overall analysis of detected abnormalities and SC markers indicates that SCs do not exhibit either a ‘classic’ dedifferentiation-repair-like phenotype or a myelin-forming maturation phenotype when placed in MS-like conditions. They demonstrate an uncommon pattern of cellular signaling reprogramming, associated with decreased motility and potentially decreased myelination. We thus suggest that ERK- and JNK-modulated SCs should be further investigated as a potential cell source for CNS repair in MS. Full article

Background/Objectives: Hepatocyte proliferation during liver regeneration requires precise transcriptional coordination of metabolic reprogramming, but the key regulators governing this process remain largely unknown. Methods: Hepatocyte-specific retinoic acid receptor-related orphan receptor α (RORα) knockout (RORα-LKO) mice were generated and subjected to two-thirds partial hepatectomy (PHx). Liver regeneration was assessed by liver-to-body weight ratio, histology, and proliferation markers (PCNA, Ki67, cyclin D1). Metabolic changes were evaluated by untargeted metabolomics, Seahorse extracellular flux analysis, and glycolytic enzyme activity assays. The molecular mechanism was investigated through RNA-seq analysis, qPCR, Western blotting, dual-luciferase reporter assays, CUT&Tag-qPCR, and pharmacological inhibition. Results: RORα expression was transiently upregulated during the early phase and declined at the peak of hepatocyte proliferation. RORα-LKO mice exhibited accelerated liver recovery and increased hepatocyte proliferation following a partial hepatectomy, without enhanced inflammation or fatty acid oxidation. Mechanistically, RORα directly binds to the promoter of Me1 to repress its transcription. Loss of RORα upregulates ME1, enhances glycolysis, and increases ATP production. Pharmacological inhibition of ME1 reversed these effects. Conclusions: The RORα–ME1 axis links transcriptional repression to metabolic reprogramming and may represent a therapeutic target for liver regeneration. Full article