Search Results (10,255)

Leaf-color mutants are crucial for elucidating chlorophyll metabolism mechanisms. Here, we identified yel, a stably inherited rice mutant with a dwarf and yellow-green leaf phenotype controlled by a single recessive nuclear gene. Using BSA-seq, we mapped the candidate causal gene to OsMPEC, encoding a magnesium protoporphyrin IX monomethyl ester cyclase with a G→T substitution. Multi-omics analysis revealed that the functional deficiency of OsMPEC protein—despite unchanged transcript levels—triggers global transcriptional repression of the chlorophyll metabolic network. This defect caused distinct metabolic consequences: impaired synthesis at the early stage (yel1) and toxic metabolite accumulation at the later stage (yel2). Furthermore, metabolic collapse induced systemic reprogramming of hormone signaling, shifting from pro-growth to stress and senescence modes. We propose that the yel phenotype is associated with a self-reinforcing inhibitory loop of “passive synthesis inhibition” and “active degradation acceleration.” This study clarifies OsMPEC’s role in chlorophyll homeostasis and demonstrates how a single genetic defect drives phenotype- through to network-level cascading effects. Full article

Prebiotics are predominantly indigestible carbohydrate-based substrates selectively-utilized by beneficial gut-microbes to support host-health. We previously developed protein-containing prebiotics that co-deliver carbohydrate and protein substrates to the colon, where gut-microbes compete for the limited nitrogen availability, thereby enhancing microbial growth, metabolic activity, and host health compared with conventional carbohydrate prebiotics. Resveratrol is a grape-derived polyphenol with antioxidant, anti-inflammatory, and emerging prebiotic activity. Here, we developed a multifunctional protein-containing prebiotic system based on Maillard conjugates of 2′-fucosyllactose–potato protein hydrolysate (2′-FL-PPH) micelles encapsulating resveratrol, followed by genipin crosslinking. This crosslinked 2′-FL-PPH-resveratrol system is designed to limit premature protein and resveratrol absorption, enhancing their colonic co-delivery. We characterized the encapsulation efficacy, physicochemical properties, digestibility and colonic delivery. The conjugates (10 mg/mL 2′-FL-PPH) effectively entrapped resveratrol (600 µM), exhibiting an average particle size of ~28 nm and an encapsulation efficiency of 79.5 ± 4.9%. Binding studies demonstrated predominantly hydrophobic interactions between resveratrol and 2′-FL-PPH. The conjugates prevented resveratrol crystallization in aqueous media, while genipin crosslinking enhanced resistance to simulated gastrointestinal digestion and inhibited premature resveratrol release, increasing the fraction expected to reach the colon. Collectively, this system enables colonic co-delivery of carbohydrate, peptides, and resveratrol, providing a novel strategy for promoting beneficial-microbiota and gut-health. Full article

Background: Berberine, an isoquinoline alkaloid present in Berberis spp., Coptis chinensis and Hydrastis canadensis, is among the most widely consumed metabolic-health supplements, popularized as “nature’s Ozempic”. Concurrent, often undisclosed use with prescription drugs is common in older adults, yet berberine is far from inert. Objective: To synthesize the evidence on berberine as a perpetrator of supplement–drug interactions, propose a four-axis mechanistic taxonomy, with product quality treated separately as a modifier of exposure rather than as a mechanism, and derive a clinically actionable risk-stratification framework. Methods: Structured narrative review, prepared per the SANRA quality criteria; PubMed/MEDLINE, Scopus, Web of Science and Embase were searched up to May 2026. Results: Despite very low systemic exposure (oral bioavailability 0.68% in rats; low ng/mL plasma concentrations in humans), high luminal, enterocytic and hepatic concentrations generate interaction liability, documented in humans for a few pairs and mechanistic for most, along four mechanistic axes: inhibition, and transcriptional induction, of CYP3A4, with CYP2D6/CYP2C9 inhibition that is quasi-irreversible through a metabolite-intermediate complex; transporter modulation (P-glycoprotein, OCT1/OCT2, and MATE1); pharmacodynamic additivity (hypoglycemia, hypotension, and QT prolongation); and microbiome- and gut-barrier-mediated effects, the last of these being a candidate axis rather than a demonstrated one. Product-quality variability is treated separately, as a modifier of exposure. The clinical anchor is increased cyclosporine exposure in renal-transplant recipients (AUC +34.5%; trough 29.3% above control). These elements are integrated into a three-tier risk-stratification framework that combines perpetrator potency, victim-drug vulnerability, and patient vulnerability, with each tier being linked to a defined pharmacy action. Conclusions: In patients on multiple medications, and particularly when berberine is co-administered with drugs of narrow therapeutic index, it should be managed as an active pharmacological perpetrator rather than as an inert supplement. Unstandardized product quality and an unsettled European regulatory framework, under which national limits differ by more than an order of magnitude, further widen the uncertainty around the dose actually delivered. Berberine use should therefore be elicited routinely at medication reconciliation and stratified by mechanism, by victim-drug vulnerability, and by patient risk, with particular attention to metabolic self-medication in the GLP-1 era. Full article

Streptococcus cristatus (S. cristatus) belongs to the viridans group of streptococci and is a commensal of the human upper respiratory tract. With the non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase, GapN, and the oxidative part of the pentose phosphate pathway (oxPPP), S. cristatus can use two different metabolic pathways to provide reduced nicotinamide adenine dinucleotide phosphate (NADPH), an essential cofactor of anabolic reactions such as fatty acid and amino acid biosynthesis. Regarding their NADP-reducing capacity, streptococci can be categorized into three groups: those that have only GapN, those that use only the oxPPP, and those that use both pathways. Here, we report on the experimental and computational characterization of the catalytic properties of the three NADP-reducing enzymes: GapN, glucose-6-phosphate dehydrogenase (G6PDH), and 6-phosphogluconate dehydrogenase (6PGDH) of S. cristatus. Kinetic analyses showed moderate substrate and cofactor affinities, with GapN displaying the tightest substrate binding, followed by 6PGDH and G6PDH, in agreement with structural and computational predictions. All three enzymes preferentially utilized NADP⁺, with only G6PDH exhibiting limited NAD⁺ promiscuity. Growth-phase-dependent activity patterns suggest dynamic adjustment of NADPH-generating pathways, with reduced GapN contribution and sustained oxPPP activity in the stationary phase. Regulatory screening indicated limited allosteric control, though feedback inhibition by NADPH and the ATP sensitivity of G6PDH point to conserved redox regulatory mechanisms. Comparative analysis across streptococci supports the concept that the coexistence of GapN and the oxidative pentose phosphate pathway in S. cristatus may provide metabolic flexibility by offering alternative routes for NADPH generation. Full article

Differentiated thyroid carcinoma is a morphologic diagnosis, not a direct measure of preserved thyroid function. Although most papillary, follicular, and oncocytic thyroid carcinomas retain architectural or cytologic features of follicular-cell derivation, a clinically important subset loses the molecular machinery required for effective iodine transport, organification, and radioiodine therapy. This functional divergence is central to the biology of radioiodine-indifferent and radioiodine-refractory thyroid cancer. This review examines the role of oncogenic MAPK/ERK signaling as a principal regulator of thyroid lineage suppression and therapeutic failure. Aberrant activation of the RAF–MEK–ERK axis, most prominently through BRAF^V600E, RAS alterations, and receptor tyrosine kinase fusions, does more than promote proliferation. It reshapes follicular-cell identity by repressing thyroid-lineage transcriptional programs and silencing iodine-handling genes, including SLC5A5/NIS, TPO, TG, TSHR, SLC26A4, and related components of the iodine metabolic transcriptome. This repression is mediated through coordinated transcriptional, epigenetic, and post-transcriptional mechanisms involving lineage transcription factors such as PAX8, NKX2-1, and FOXE1; chromatin-modifying programs including histone deacetylation and PRC2/EZH2-associated repression; DNA methylation; and non-coding RNA networks. Importantly, ERK-driven functional dedifferentiation is not always a fixed terminal state. Preclinical models and early clinical trials demonstrate that pharmacologic inhibition of the MAPK pathway can restore iodine avidity in selected radioiodine-refractory tumors, creating the theranostic basis for redifferentiation therapy. Iodine-124 PET/CT and lesion-level dosimetry have shown that restored iodine uptake can be measured diagnostically and then exploited therapeutically with iodine-131. However, clinical translation remains limited by inter- and intratumoral heterogeneity, incomplete durability of response, adaptive pathway reactivation, persistent epigenetic repression, tumor microenvironmental influences, and the absence of standardized dosimetric thresholds. We propose that advanced follicular-cell-derived thyroid cancers should be understood along a functional differentiation continuum rather than through morphology alone. Within this framework, radioiodine refractoriness reflects not merely treatment failure, but a therapeutically interrogable state of lineage suppression. Refinement of redifferentiation therapy will require genotype-informed patient selection, functional imaging, standardized dosimetry, rational combination strategies, and prospective trials capable of distinguishing true restoration of radioiodine therapeutic efficacy from the antiproliferative effects of kinase inhibition alone. Full article

Itaconic acid has been reported to possess anti-inflammatory and antibacterial properties. However, its specific mechanisms of action against pathogenic bacteria, especially in the context of purine metabolism, remain poorly understood. Here, we investigate the impact of itaconic acid on the purine metabolism of PCN033, a highly pathogenic porcine extraintestinal pathogenic Escherichia coli (ExPEC) strain. Our in vitro and in vivo experiments demonstrated that itaconic acid significantly inhibited the proliferation of PCN033. Multi-omics analyses, including transcriptome and metabolome sequencing, revealed that itaconic acid severely disrupted the purine metabolism pathway of PCN033. Further mechanistic studies identified PRPP amidotransferase (PurF), a key enzyme in de novo purine synthesis, as a direct target of itaconic acid. Molecular docking and click chemistry experiments provided compelling evidence that itaconic acid specifically binds to the second cysteine residue (2C) of PurF, leading to the inhibition of its enzymatic activity. These data reveal a novel and critical mechanism by which itaconic acid exerts its antibacterial effects in response to bacterial infection. Importantly, our in vivo data show that supplementation with itaconic acid alleviated weight loss, organ damage, and inflammatory responses induced by PCN033 infection in mice and nursery pigs. These novel findings enhance our understanding of the antibacterial mechanisms of itaconic acid. Supplementation with itaconic acid could serve as a therapeutic strategy for treating pathogenic bacterial infections in humans and other animals. Full article

The liver is an immunologically distinctive organ. Portal blood continuously delivers gut-derived antigens and microbial products, requiring hepatic immunity to balance surveillance with restraint. In hepatocellular carcinoma (HCC), this physiology is commonly overlaid by chronic injury, inflammation, and fibrosis, so the background liver forms part of the disease context in which the tumor microenvironment (TME) develops. This review synthesizes how cellular architecture, tumor-intrinsic programs, and structural, metabolic, and microbial conditions interact to shape immune evasion and heterogeneity. HCC provides the principal evidence base, with intrahepatic cholangiocarcinoma (iCCA) used as a structured, biologically distinct comparator. We organize therapies by the microenvironmental barriers they are intended to modify and distinguish established clinical efficacy from evidence that the proposed mechanisms mediate treatment benefit. Single-cell and spatial studies have resolved cellular states and spatial arrangements, including onco-fetal endothelial–myeloid neighborhoods and a macrophage–fibroblast boundary band separating lymphocyte-rich stroma from malignant tissue. These patterns operate within fibrotic and metabolically altered tissue and vary by etiology, spatial context, and tumor type. Vascular endothelial growth factor blockade with immune checkpoint inhibition and dual checkpoint blockade are established first-line options in advanced HCC. Chemo-immunotherapy is established in biliary tract cancer, and IDH1 inhibition has established efficacy in IDH1-mutant cholangiocarcinoma. Myeloid- and stroma-directed strategies, natural-product approaches, and engineered-cell therapies remain preclinical or early clinical. None of the pivotal trials tested whether the proposed microenvironmental mechanism mediated treatment benefit. The liver TME informs treatment selection without yet determining it. Full article

For many types of cancer, pre-clinical studies have shown that dietary interventions and supplements can be effective in reducing the toxicity and increasing the efficacy of chemotherapeutics. In this context, the polyphenol curcumin is an attractive molecule. We have previously demonstrated that curcumin inhibits adrenocortical carcinoma (ACC) cell growth, has an impact on ACC cell metabolism, decreasing cholesterol availability and promoting glucose and glutamine metabolism. In this study, we evidenced that curcumin downregulates the transcription factors SF-1 and SREBPs and their targets, while inducing a ROS-dependent, HIF1α- and NRF2-mediated metabolic rewiring. NRF2 sustained an adaptive antioxidant mechanism dependent on glutamine, cysteine, and glycine uptake to support glutathione synthesis and avoid lipid peroxidation. Furthermore, the combination of curcumin with mitotane demonstrated synergistic effects in inhibiting ACC cell viability and reducing steroidogenic gene expression. These synergistic effects were observed with sub-therapeutic doses of mitotane, which are reached by patients who fail to attain the therapeutic plasma concentrations of the drug. Crucially, in vivo, curcumin administration to tumor-free mice significantly upregulated NRF2 expression and preserved liver tissue integrity. These results warrant further preclinical evaluation of the proposed combination therapy, particularly for those patients who fail to achieve or maintain mitotane plasma concentrations in the therapeutic range. Full article

Punica granatum L. (pomegranate) is one of the oldest medicinal plants known to humankind, valued across ancient civilisations for treating parasitic, microbial, and metabolic diseases. Its exceptionally rich phytochemical composition, dominated by punicalagins, ellagic acid, anthocyanins, flavonoids, piperidine alkaloids, and the unique conjugated fatty acid punicic acid, confers a remarkably broad spectrum of biological activities of direct relevance to contemporary veterinary medicine. While human-health applications have been extensively reviewed, a comprehensive synthesis of veterinary evidence across multiple species remains lacking. This review consolidates current preclinical and field knowledge on the pharmacological effects of pomegranate preparations in poultry, ruminants, swine, fish, companion animals, and laboratory models. In poultry—the most extensively studied taxon—dietary inclusion of pomegranate peel powder or extract consistently enhances growth performance, antioxidant status, and humoral immunity while exerting meaningful anticoccidial activity. The antiparasitic properties are compellingly supported by evidence against gastrointestinal nematodes of ruminants, tapeworms, schistosomes, and protozoa including Giardia, Cryptosporidium, and Leishmania spp., as well as monogenean fish parasites. Broad-spectrum antimicrobial activity extends to major veterinary pathogens such as Salmonella, Escherichia coli, Staphylococcus aureus (including MRSA), and Clostridium perfringens. Rodent models have validated antidiabetic, hepatoprotective, nephroprotective, and reproductive benefits, including improved post-thaw sperm quality and enhanced litter size. The safety profile is generally favourable at conventional doses, although high dietary inclusion elicits anti-nutritional effects from condensed tannins, and potential drug interactions via cytochrome P450 inhibition warrant clinical caution. Despite this substantial evidence, significant translational barriers persist, including extract heterogeneity, absence of pharmacokinetic data in target species, and scarcity of controlled clinical trials. By providing a species- and pathology-driven synthesis, this review identifies critical research priorities and highlights the immense potential of this ancient, accessible, and economically viable phytobiotic as a natural alternative to antibiotic growth promoters and synthetic antiparasitics in veterinary practice. Full article

Kaempferol, a naturally occurring dietary flavonoid abundantly found in various fruits and vegetables, has garnered significant attention due to its diverse pharmacological properties, most notably its potent anticancer activity. In the orchestration of cancer pathogenesis, the PTEN/PI3K/AKT/mTOR signaling cascade plays a pivotal role, where aberrant activation or dysregulation of this pathway drastically accelerates tumor cell proliferation, survival, and metabolic reprogramming, thereby driving tumorigenesis. Moreover, non-coding microRNAs (miRNAs) have emerged as key modulators involved in regulating this pathway, functioning as either oncogenes or tumor suppressors to determine cancer cell fate. Previous studies have demonstrated that kaempferol and its derivatives, owing to their molecular structures, suppress the PI3K/AKT/mTOR signaling pathway either directly or indirectly, thereby playing a critical role in inhibiting cancer cell proliferation. Hence, this comprehensive review elucidates the therapeutic potential of kaempferol and its derivatives, focusing specifically on their molecular mechanisms in modulating the PTEN/PI3K/AKT/mTOR pathway. Furthermore, this review highlights the crosstalk between kaempferol and the specific miRNAs targeting these signaling components in various cancer types. Full article

Oil palm (Elaeis guineensis Jacq.) is a quintessential tropical oilseed crop, whose distribution and yield are significantly constrained by low-temperature stress. This study conducted physiological and proteomic analyses to investigate the early response mechanisms of one-year-old thin-shelled oil palm seedlings exposed to low temperatures of 8 °C for durations of 0, 0.5, 1, 2, 4, and 8 h. The results indicated that low-temperature treatment inhibited chlorophyll accumulation, reduced photosynthetic efficiency, and increased the levels of malondialdehyde (MDA) and soluble sugars. Concurrently, the activities of antioxidant enzymes exhibited a transient increase, suggesting an imbalance in the antioxidant defense system during the later stages of stress. Proteomics results indicate that the core pathways involved are fatty acid degradation and the regulatory pathways for starch and sucrose metabolism. Within these pathways, key proteins such as ACSL (long-chain fatty acid-CoA ligase), paaF (enoyl-CoA hydratase), HADH (3-hydroxyacyl-CoA dehydrogenase), and HADHA (enoyl-CoA hydratase/long-chain 3-hydroxyacyl-CoA dehydrogenase) are identified among 13 differential accumulation protein (DAPs). It is hypothesized that these key proteins work in concert to regulate osmosis, scavenge reactive oxygen species (ROS), stabilize membranes, and supply energy. Through physiological and proteomic analyses, this study identified physiological indicators, key proteins, and regulatory pathways associated with cold tolerance in oil palm, thus providing a theoretical basis for breeding low-temperature-tolerant oil palm varieties. The findings contribute to the development of low-temperature-tolerant oil palm cultivars. Full article

Ovotransferrin (OvoTf) is an iron-binding glycoprotein of avian innate immunity with antimicrobial activity, but its antifungal mechanism remains incompletely understood. We examined the candidacidal activity of OvoTf and two derived γ-core-containing peptides, kaliocin-3 (Kal-3) and kaliocin-4 (Kal-4), against Candida albicans. All three agents reduced fungal viability in a concentration-dependent manner, with minimal propidium iodide uptake, indicating a predominantly non-permeabilizing mechanism. Their activity was attenuated by extracellular Na⁺ and K⁺, whereas isoosmotic sorbitol did not confer protection. OvoTf induced partial K⁺ release, and tetraethylammonium increased cell survival. Inhibition of mitochondrial complex I or ATP synthase also reduced susceptibility, although none of the agents detectably suppressed oxygen consumption under the conditions tested. OvoTf, Kal-3, and Kal-4 caused plasma membrane depolarization, ATP accumulation, and impaired glucose-induced proton extrusion. This phenotype is consistent with disruption of Pma1-dependent proton and ion homeostasis, with mitochondrial bioenergetic activity contributing as a downstream requirement rather than constituting the primary target. Neither peptide caused detectable hemolysis; Kal-4 had minimal effects on mammalian cell metabolic viability, whereas Kal-3 reduced MCF-7 metabolic viability at higher concentrations. The activity of γ-core regions in both OvoTf lobes supports their further study as templates for mechanism-guided antifungal design. Full article

India contributes 26% of global banana production, yet cultivation is severely threatened by Fusarium wilt (Fusarium oxysporum f. sp. cubense, Foc), necessitating sustainable, eco-friendly management strategies. This study evaluated the biocontrol potential of endophytic bacteria isolated from Foc-resistant and -susceptible banana cultivars. Isolates from the pseudostem, corm, and root of the resistant cultivar showed significantly greater inhibitory activity than those from the susceptible cultivar, underscoring the role of host genotype in shaping functionally competent endophytic communities. Among all isolates, Bacillus sp. from the corm of cv. Rose (AB) showed the highest mycelial inhibition of Foc (70.37–76.54%) in vitro. GC-MS-based metabolite profiling revealed a chemically diverse array of secondary metabolites, fatty acid esters, steroids, terpenoids, siloxanes, and nitrogenous compounds. Corm-associated endophytes exhibited membrane-disruptive and cytotoxic activity, while root-associated endophytes contributed protective, defense-modulatory effects. Halomonas sp. RoRo2 and B. subtilis RoC1 showed the highest inhibition in both agar-well and in planta assays, with unsaturated fatty acids and organic acid derivatives implicated as key antifungal effectors acting through multiple biochemical pathways. These findings identify metabolically versatile endophytes as promising candidates for developing efficient, environmentally compatible bioinoculants as sustainable alternatives to chemical control of Fusarium wilt in banana. Full article

Cesium (Cs) contamination has become an increasing environmental concern because of its high mobility, persistence, and ecological risks. Mosses have attracted considerable attention as bioindicators owing to their high environmental sensitivity; however, their responses to Cs remain poorly understood. In this study, the moss Hypnum plumaeforme was exposed to Cs⁺ (5, 50 and 500 mg L⁻¹) stress, and its morphological characteristics, antioxidant responses, photosynthetic performance and metabolomic alterations were comprehensively investigated. Low Cs⁺ exposure induced early oxidative signaling by increased H₂O₂ accumulation and slight stimulation of photosynthesis, whereas moderate stress triggered pronounced superoxide production and activation of antioxidant defenses. High Cs⁺ exposure caused severe cellular deformation, disruption of photosystem II, excessive hydroxyl radical accumulation, and collapse of the coordinated antioxidant–osmotic regulatory network. Untargeted LC–MS metabolomics further revealed substantial metabolic reprogramming under severe stress, including inhibition of carbon metabolism, significant enrichment of tryptophan metabolism, and accumulation of defensive secondary metabolites, indicating a shift in metabolic resources from growth toward stress defense. Collectively, these findings demonstrate the physiological responses of H. plumaeforme to Cs⁺ in a concentration-dependent manner. The high sensitivity of oxidative biomarkers, chlorophyll fluorescence parameters and metabolic signatures highlights the potential of H. plumaeforme as a bioindicator for assessment of cesium contamination. Full article

Background: Physical activity is widely recommended for preserving musculoskeletal health and managing osteoarthritis-related pain, although its benefits are commonly framed in terms of muscle strengthening, weight control, and physical performance. This narrative review aimed to examine movement more broadly as a physiological regulator of synovial joint homeostasis, sensory calibration, and functional adaptation. Methods: A structured literature search was performed in PubMed/MEDLINE, Scopus, and Web of Science from database inception to 1 February 2026. Experimental studies, observational studies, clinical trials, systematic reviews, meta-analyses, and selected narrative reviews addressing movement-responsive joint biology or pain regulation were considered. Evidence was synthesized across four interrelated domains: mechanical, fluidic, immune-metabolic, and sensory regulation. Results: The narrative synthesis indicates that the concept of the synovial joint as a dynamic mechano-fluidic organ in which cartilage, synovium, synovial fluid, capsule, subchondral bone, periarticular tissues, and sensory pathways interact continuously. Repeated physiological movement may promote synovial fluid exchange, lubrication, cartilage nutrition, hyaluronic acid and lubricin function, matrix turnover, anti-inflammatory signaling, proprioceptive control, and exercise-induced hypoalgesia. In contrast, inactivity and unloading may impair fluid dynamics, promote muscle inhibition, stiffness, inflammatory persistence, sensory deconditioning, and loss of function. Excessive or poorly distributed loading may also disrupt homeostasis through matrix injury, inflammation, fatigue, and nociceptive sensitization. These findings informed the proposed adaptive loading window, a hypothesis-generating conceptual framework rather than a clinically validated threshold, describing the dynamic range of movement within which joint function and pain regulation may be supported without sustained tissue or symptom aggravation. Conclusions: Movement should be viewed not only as a therapeutic intervention, but also as a continuous regulator of joint biology and perception. Its clinical value may depend on identifying an individualized loading range that supports adaptation, function, and confidence in movement while avoiding both underloading and overload. Full article