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Cell migration is a fundamental biological process essential for embryonic development and hematopoiesis. In a shRNA screen, we identified the TRAM-LAG1-CLN8 domain-containing transmembrane protein TMEM56 as a previously uncharacterized regulator of stromal cell-derived factor 1 (SDF-1)-mediated cell migration. This study investigates the molecular mechanisms underlying TMEM56 function. TMEM56 is expressed in both murine embryonic and adult tissues, with enrichment in hematopoietic stem and erythroid progenitor cells. Lipidomic analysis reveals that TMEM56 modulates ceramide metabolism, particularly affecting levels of hexosylated ceramides. Co-immunoprecipitation assays indicate that TMEM56 physically interacts with ceramide synthase 2 (CerS2), suggesting a role in lipid signaling pathways. Our findings identify TMEM56 as a key regulator of cell migration, linking lipid metabolism with hematopoietic and developmental processes. These results provide novel insights into the molecular mechanisms governing migration.

Hypoxia-driven dysregulated lactate metabolism is a feature of intervertebral disc degeneration (IDD). However, biological metabzymes and most biomimetic counterparts are ineffective under hypoxic conditions and often generate harmful metabolites. Here, a single-atom nanozyme is presented that exhibits catalytic activity rivaling a biological metabzyme and pathological context-aware metabolism functions within the male rats' disc microenvironment, termed the "biogenic Fe-N-C artificial metabzyme". The spatially dynamic metabolomics and assessments of IDD tissues demonstrate that biogenic Fe-N-C artificial metabzyme efficiently catalyzes the conversion of excess lactate into pyruvate and reduced glutathione within IDD. Subsequent metabolic convergence of mitochondria and extracellular matrix coordinates the recovery of the internal and external nucleus pulposus cells environment, constituting IDD metabolic therapy. The current work proves that creating artificial metabzymes tailored to the pathological tissue environment can be used to correct metabolic dysfunction.

Transcriptomic and metabolic comparisons reveal putative regulatory and metabolic differences underlying juice sac initiation in citrus fruit. The edible portion of citrus fruits consists of juice sacs-specialized structures unique among fruits-that develop shortly after anthesis from the endocarp, originating from the innermost layers of the albedo. While their physiological and biochemical properties are well studied, the regulatory mechanisms controlling juice sac initiation remain poorly understood. In this study, we compared two cultivars of citron (Citrus medica L.)-the Calabria citron, which develops juice sacs normally, and the Yemenite citron, which does not-across four developmental stages: closed flowers, flowers at anthesis, and fruitlets at one and two weeks post-anthesis. We performed a comparative transcriptomic analysis of endocarp cells, followed by Weighted Gene Co-Expression Network Analysis (WGCNA) and a metabolomic analysis of whole ovaries and fruitlets. As expected, the Calabria endocarp exhibited higher expression of genes associated with cell wall formation, DNA replication, and cell proliferation, particularly two weeks post-anthesis. In contrast, stress-related genes were more abundant in the Yemenite endocarp. Calabria ovaries and fruitlets showed an increase in amino acids, whereas those of the Yemenite citron exhibited induction of TCA cycle and energy metabolism pathways. Integrating transcriptomic and metabolomic data revealed significant enrichment of carbohydrate and energy metabolism pathways in the Yemenite citron. Additionally, we identified a transcription factor regulatory network that may contribute to juice sac initiation. These findings provide new insights into the molecular processes underlying juice sac initiation and establish a foundation for future research aimed at elucidating its regulatory mechanisms.

Protein palmitoylation is a reversible lipid post-translational modification that influences protein stability, membrane association, and signal transduction. Increasing evidence indicates that dysregulated palmitoylation contributes to tumor development by altering the activity of oncogenes, tumor suppressors, transcription factors, and membrane proteins, as well as by reshaping the tumor microenvironment. However, the biological significance of this modification in hepatocellular carcinoma (HCC) has not yet been fully clarified. This review summarizes current knowledge of palmitoylation-mediated regulation in HCC and evaluates its potential as a therapeutic target. Relevant studies were identified through systematic searches of PubMed and Web of Science using keywords including "protein palmitoylation," "post-translational modification," "hepatocellular carcinoma," and "tumor therapy." Published evidence was analyzed to examine the roles of palmitoylation in HCC cell proliferation, apoptosis, migration, invasion, and associated signaling pathways. Accumulating evidence indicates that protein palmitoylation contributes to hepatocellular carcinoma progression by modulating the activity and localization of key signaling proteins, including Ras, AKT, and YAP. Through these regulatory effects, palmitoylation influences multiple oncogenic pathways such as Wnt/β-catenin, PI3K/AKT/mTOR, Hippo/YAP, and STAT3 signaling. In addition, metabolic regulatory circuits, including the FASN-ZDHHC-20 and PHF2-SREBP1c axes, link lipid metabolism with palmitoylation-dependent signaling in HCC. Emerging pharmacological approaches targeting palmitoylation-related enzymes-such as palmitoyltransferases and depalmitoylases-have shown promising antitumor activity in preclinical studies. Protein palmitoylation represents an important regulatory layer in hepatocellular carcinoma biology, integrating lipid metabolism with oncogenic signaling networks. Therapeutic strategies targeting enzymes that control palmitoylation dynamics may therefore offer new opportunities for HCC treatment. Future investigations should focus on defining the substrate specificity and regulatory mechanisms of individual ZDHHC enzymes, PATs, and depalmitoylases to facilitate the development of more selective therapeutic interventions.

CD36 deficiency is associated with abnormal fatty acid metabolism, which may increase the risk of developing atherosclerosis. However, there are few reports on a possible link between CD36 deficiency and cerebral white matter lesions. We present the case of a 44-year-old woman with heart failure due to CD36 deficiency and multiple white matter lesions. Her comprehensive examination for heart failure, including a single-photon emission computed tomography (SPECT) with 201thallium and 123I-β-methyl-p-iodophenyl pentadecanoic acid, revealed a fatty acid metabolism disorder in the myocardium. Flow cytometry confirmed CD36 deficiency, and a subsequent head magnetic resonance imaging (MRI) demonstrated multiple T2-hyperintense lesions in the cerebral white matter. Although the patient had hypertriglyceridemia and a history of smoking, the contribution of CD36 deficiency to the formation of white matter lesions remains unclear. This case suggests a potential association between CD36 deficiency and cerebral small-vessel disease. Further studies in patient cohorts with CD36 deficiency are warranted to clarify the impact of this condition on cerebral microcirculation.

Trichomonas vaginalis is the causative agent of trichomoniasis, the most common and prevalent sexually transmitted infection (STI) globally, with about 156 million cases annually. Trichomoniasis is a critical public health problem, and it is aggravated due to its association with a higher risk of HIV-1 acquisition and transmission and complications such as preterm delivery and pelvic inflammatory disease. This STI is treated mainly through the 5-nitroimidazole class, specifically metronidazole and tinidazole. However, drug resistance, which can represent between 5 and 20% of clinical cases, and hypersensitivity reactions are a general concern. In this context, drug development for trichomoniasis is an ever-growing research field. Therefore, considering how important drug targets and the mechanism of action of compounds can be to drug discovery, there is a growing interest in better understanding how some molecules can be used as targets. This article offers an overview of T. vaginalis drug targets, their significance in metabolism, pathogenesis, or survival, and their contribution to drug development for trichomoniasis.

Chili pepper (Capsicum annuum L.) produces specialized metabolites, notably the pungent capsaicin and the red capsanthin. Although their biosynthetic pathways are well characterized, the cellular architecture that underpins spatial regulation remains unclear. Here we present a spatiotemporal single-nucleus atlas of pepper development, integrating single-nucleus RNA sequencing and spatial transcriptomics, profiling 332,468 high-quality cells from 57 samples spanning seedlings to mature fruits. This resource reveals a multilayered organization and precisely maps metabolic genes to defined cell types and spatial regions. We further identify laminar patterning transcription factors, including WRKY6, ZAT10 and BTF3, whose layer-specific expression correlates with localized capsanthin accumulation. Our work establishes a framework for dissecting laminar control of specialized metabolism and provides a valuable reference for comparative studies across species. The atlas is openly accessible at http://Pepper-Cell-Atlas.com .

Muscle atrophy, which is characterized by the loss and dysfunction of skeletal muscle proteins, is a major degenerative condition that is associated with aging and glucocorticoid therapy. Marine-derived compounds, particularly polyphenols, have recently potential in modulating muscle metabolism and regeneration. This study aimed to investigate the effects of the ethanolic extract from Padina arborescens (PAE) on myogenic differentiation and dexamethasone (DEXA)-induced muscle atrophy using C2C12 myotubes and a zebrafish model. PAE treatment significantly promoted myotube differentiation by modulating the Akt/mTOR signaling pathway and enhancing the expression level of myogenic regulatory factors (MyoD and myogenin). In DEXA-treated myotubes, PAE effectively suppressed the ubiquitin proteasome system, restored myosin heavy chain protein synthesis, and recovered myotube morphology. In vivo, PAE supplementation ameliorated the DEXA-induced locomotor dysfunction in zebrafish without causing developmental or neurotoxic abnormalities, as confirmed by the normal survival rate, body length, and heart rate. Collectively, these findings indicated that polyphenol-rich PAE exerts protective and anabolic effects by promoting myogenesis and preventing glucocorticoid-induced muscle degradation. Therefore, PAE may be used as a promising marine-derived therapeutic agent for maintaining skeletal muscle health and preventing muscle atrophy.

The adoption of biodegradable synthetic polymers in biomedical and tissue engineering becomes a focal point, offering alternative solutions to organ transplantation and conventional permanent restoration. The key principle in developing scaffold-based for physiological implantation is the synchronisation of polymer's degradation kinetics with the regeneration timeline of host tissues. Different implantation lesions exhibit vastly different healing durations, ranging from a few weeks to several months or years. A mismatch timeline can be detrimental where premature degradation will remove the physical framework needed for cell integration, whereas overly slow degradation will restrict spaces for new tissue growth. This review study provides a comprehensive discussion on the degradation mechanisms of biodegradable synthetic polymers in physiological environments. Four widely studied polymers-polylactic acid (PLA), polyvinyl alcohol (PVA), polycaprolactone (PCL), and polyurethane (PU)-were reviewed in depth on the degradation mechanisms and influencing factors. Scientific experimental data from the previous studies were summarised, including degradation percentage, experimental conditions, degradation timeline, and estimated complete degradation period. Specifically, four degradation mechanisms are associated with the degradation of synthetic polymers in physiological environments including chemical hydrolysis, enzymatic-mediated metabolism, oxidative degradation, and pH-dependent degradation. Each of the mechanisms may act independently or synergistically under different biological conditions. The degradation of polymers is accordingly influenced by the chemical structures, fabrication routes, degradation pathways, and physicochemical factors. These data are correlated with their optimal use in biomedical and TE applications for fast regenerating tissues to slow-healing or load-bearing structures. Comprehensively, PVA is aligned well with short-to-intermediate healing tissues such as the skin and the cornea due to its high degradation capability, while PLA, PCL, and PU that degrade from weeks to years are suitable for mediate-healing soft tissues to long-term implantations such as load-bearing bone, cartilage, ligament, neural, and vascular implantations. By aligning polymer degradation profiles with the biological timelines of tissue regeneration, this review provides a translational framework for synthetic polymer selection to enable optimum scaffold's functionalities and clinical outcomes.

Cytosolic DNA, derived from cellular damage or microbial infection, functions as a pivotal trigger for the host innate immune responses by activating intracellular DNA-sensing machinery, including the cGAS-STING pathway. However, whether cytosolic DNA is involved in DNA-sensing pathway-independent biological processes remains largely unknown. Here, we show that cytosolic DNA interacts with UBTF and POLR1A, two essential components of the RNA polymerase I transcription machinery, and sequesters these two proteins in the cytoplasm. This retention decreases nuclear UBTF and POLR1A, inhibits rDNA transcription, suppresses protein synthesis, and curtails cell proliferation. Furthermore, we demonstrate that STING-induced autophagy specifically eliminates cytosolic DNA and restores nuclear UBTF and POLR1A, thereby abolishing the inhibitory effects of cytosolic DNA on rDNA transcription, protein synthesis, and cell proliferation. Thus, our findings uncover a novel role of cytosolic DNA in rDNA transcription, suggesting that cytosolic DNA not only activates immune responses but also interferes with cell metabolism.

BAP1-deficient melanocytic tumors exhibit strong immunosuppressive features and poor prognosis. Currently, no immune-competent preclinical models exist to study their tumor-immune interactions or test new immunotherapies. This limitation hinders progress in understanding how BAP1 loss drives tumor aggressiveness and immune evasion. To address this, we generate a syngeneic BAP1 knockout melanocyte tumor line using CRISPR-Cas9. We then evaluate its functional and immunological impact in immune-competent mice, including its ability to recapitulate metabolic and immunosuppressive features of human BAP1-deficient melanomas. The selected knockout clone exhibits hallmarks of aggressive skin and intraocular melanomas, including epithelioid morphology, in vivo tumorigenic potential, rapid growth, and key immunosuppressive features, mirroring those observed in human BAP1-deficient melanomas. Cross-species single-cell transcriptome analysis demonstrates strong molecular overlap between BAP1 knockout mouse tumors and high-risk (class 2) human uveal melanomas, highlighting shared pathways in lipid metabolism, transmembrane receptor signaling, and immune modulation. Gene Set Enrichment Analysis confirms that lipid metabolic reprogramming, previously described in human tumors, is also a key feature of our model, validating its ability to recapitulate human disease biology. This study introduces a syngeneic preclinical model that mimics the immunosuppressive landscape of BAP1-deficient melanocytic tumors, enabling the development and optimization of new combination immunotherapies.

Haskap berries have great potential as a superfood due to high polyphenolic content which confers both anti-inflammatory and antioxidant activity. These health impacts are mitigated, at least in part, by the gut microbiome as most ingested polyphenols pass to the large intestine for microbial enzymatic action and conversion to secondary phenolic metabolites. These microbial actions mediate both the bioavailability and the bioefficacy of Haskap-derived phenolics. However, clinical intervention trials characterizing the impact of long-term Haskap consumption on human health and the interaction between Haskap-derived phenolics and the gut microbiome are limited. This study aims to determine the impact of Haskap consumption on gut microbiome composition, gut microbial and serum metabolites, and other health outcome metrics in a cohort of adults with both low and high risk of metabolic syndrome. This is a four-armed, randomized, triple-blind, placebo-controlled clinical trial conducted in a cohort of adults with both low and high risk of metabolic syndrome. A total of 120 participants (60 metabolically healthy, 60 metabolically unhealthy) will be randomized in a 1:1 ratio to consume a daily dose of either Haskap or placebo juice for 8 weeks. Outcome measures will be collected before and after the intervention period to determine the health impacts of Haskap in both groups. Primary outcome measures include fasting blood markers of glucose and lipid metabolism and inflammation, fat oxidation rates during submaximal exercise, 16S rRNA fecal microbial composition data, and mass spectrometry-acquired fecal and serum metabolomic data. Secondary outcome measures include anthropometric and sleep quality measures as well as acute and habitual dietary intake data. Investigating how the gut microbiome influences the health benefits of consuming Haskap berries will help elucidate potential mechanisms of Haskap-induced metabolic health benefits and help inform the development of effective strategies to decrease metabolic disease risk through Haskap consumption. ClinicalTrials.gov NCT06546020. Registered on 1 August 2024.

Toxoplasmosis is a widespread parasitic disease affecting roughly one-third of the global population. In immunocompromised individuals or during pregnancy, infection can result in severe complications. Following primary infection, Toxoplasma gondii forms dormant bradyzoite cysts in tissues such as the brain and eyes. These cysts can rupture, particularly in immunocompromised hosts, releasing active parasites and triggering recrudescence. Efforts to experimentally induce and study bradyzoite cyst recrudescence have been hindered by the limited capacity of cell culture adapted strains to form tissue cysts in vivo. T. gondii employs diverse strategies to persist within host cells, including manipulation of host metabolism and immune responses, and these strategies may vary by host cell type. Here, we profiled epigenomic and transcriptomic features associated with differential parasite survival in distinct cell types. Using an ex vivo model of the Type II ME49 strain unadapted to fibroblast culture, we compared parasite survival and epigenetic profiles in neonatal mouse astrocytes (AST) and human foreskin fibroblasts (HFF). Comparative analyses revealed marked divergence in parasite population dynamics, accompanied by reduced H3K4me3 enrichment at promoter regions in parasites grown in HFF. This epigenetic shift correlated with transcriptomic changes in genes linked to cell cycle progression, growth, and development, including a subset of AP2 transcription factors, underscoring the influence of host cell type on parasite biology.

Microplastics (MP) pollution is widespread in livestock farming environments. Exposure to MP can impair the gastrointestinal barrier, alter the structure and metabolism of the microbiota, and subsequently lead to organ damage. MP not only hinder cattle farming but also enter the food chain, posing a potential risk. Polyethylene (PE), a type of MP commonly detected in ruminant feed, has not yet been studied for its specific effects on cattle. Using calves as an animal model, this study investigates how exposure to MP induces toxicity via the rumen microbiota-gut-liver axis. Exposure to MP impaired weight gain and liver development in cattle, altered liver tissue pathology, increased blood lipopolysaccharide (LPS) levels, and triggered a systemic inflammatory response, identifying the liver as the primary target organ. Inflammation was closely associated with the dysbiosis of rumen microbiota and metabolites. MP exposure also damages the barrier integrity of the rumen, jejunum, and colon. The underlying mechanism involves MP altering the rumen microbial composition, which in turn triggers metabolic disorders, activates LPS synthesis pathways, and inhibits tight junction protein expression in the jejunum and colon. Although MP do not cause significant architectural damage to muscle tissue, they disrupt lipid homeostasis and nutrient composition, thereby promoting the deposition of pro-inflammatory LPS within muscle tissue. Rumen fluid metabolomics analysis revealed that differential metabolites were mainly enriched in the ATP-binding cassette transporter (ABC) pathway, with 4-fluoro-3-phenoxybenzoic acid and isovalerylglutamic acid being significantly correlated with levels of LPS, IL-6, TNF-α, and IL-1β. Notably, the concurrent increase in TNF-α and LPS in both the bloodstream and liver, alongside altered blood metabolomics, indicates that MP induce hepatic damage by disrupting the rumen microbiota-gut-liver axis. Transcriptomic analysis revealed that liver inflammatory injury was closely associated with NF-κB activation. Further mechanistic analysis supported the central role of the TLR4/MyD88/NF-κB signaling pathway. MP impair liver function in cattle by disrupting the rumen microbiota-gut-liver axis. This process involves the perturbation of rumen flora and intestinal barriers, triggering LPS translocation into the bloodstream, and ultimately causing liver damage. Video Abstract.

Zinc is an essential trace element, but excessive exposure can disrupt copper metabolism and lead to clinically significant hematologic abnormalities. This systematic review aimed to synthesize published evidence on zinc-induced hematologic toxicities. Literature search was performed in PubMed and Scopus to identify descriptive studies reporting zinc-induced hematologic toxicity in humans. Eligible studies described anemia, neutropenia, leukopenia, thrombocytopenia, pancytopenia, or bone marrow suppression attributed to zinc exposure. Data on patient demographics, zinc source and dose, duration of exposure, laboratory and bone marrow findings, treatment strategies, and outcomes were extracted. Study quality was assessed using Joanna Briggs Institute critical appraisal tools. Thirty-four publications describing 37 individual cases were included, spanning from 1972 to 2025. Zinc exposure most commonly resulted from oral supplements, denture adhesive creams, and coin ingestion, with reported daily elemental zinc doses ranging from approximately 50 mg to more than 1500 mg and exposure durations ranging from weeks to years. Anemia was present in nearly all cases, most often accompanied by neutropenia and leukopenia, with pancytopenia occurring in cases of severe or prolonged exposure. Serum copper levels were reduced in all patients. Bone marrow examination frequently revealed vacuolated hematopoietic precursors and ring sideroblasts, leading to frequent initial misdiagnosis as myelodysplastic syndrome. Discontinuation of zinc exposure with copper supplementation resulted in hematologic recovery in the majority of cases, typically within weeks to months, while neurological manifestations improved more slowly and were sometimes incomplete. Zinc-induced hematologic toxicity is an uncommon but underrecognized and largely reversible condition. Excessive zinc exposure should be considered in patients presenting with unexplained anemia and cytopenias. Routine assessment of zinc exposure and copper status can prevent misdiagnosis, support timely treatment, and decrease the risk of persistent neurological complications.

T-cell metabolism is targeted by cancer cells in an attempt to escape immune surveillance. The mitochondrial branched-chain aminotransferase, BCATm, is overexpressed in cancer, yet its role in T-cell immunity is suggested but understudied. C57BL/6 mice with T-cell specific-single BCATm deficiency were used to determine the impact of BCATm on T-cell function in vitro and in vivo using the murine EL4-OVA lymphoma. The studies were complemented by a transcriptomic correlation analysis of BCATm in human T cells and by using siRNA to knock-down BCATm in Jurkat T cells. The loss of BCATm from CD4+ T cells increased mitochondrial respiration but reduced the coupling between oxygen consumption and ATP synthesis, redirecting the cells to glycolysis. This compensation sustained T-cell functionality as seen by increased release of IFN-γ from CD4+ T cells or granzyme B and perforin from CD8+ T cells. Human studies further suggested that BCATm negatively affected T-cell mitochondria. While EL4-OVA tumours from T-BCATmKO mice were enriched in memory precursor CD4+ and CD8+ T cells, reduced EL4-OVA lymphoma growth was achieved in mice with T cells carrying a combined deletion of BCATm and BCATc. BCATm is an immunosuppressive enzyme that may weaken T-cell performance in the lymphoma microenvironment.

In this study, we analyzed a unique Nicotiana tabacum BY-2 line that was gradually adapted to and subsequently maintained in 190 mM NaCl for over 15 years. Years of continuous high salinity shaped a stable "new homeostasis" in BY-2 suspension cells. Salt-adapted cells were smaller and formed tighter clusters. Metabolomics revealed constitutive enrichment of osmoprotectants and antioxidant-associated metabolites-including proline, GABA, and selected purine derivatives-and a marked increase in β-sitosterol, together pointing to osmoadaptation, membrane stabilization, and ROS buffering without broad induction of classical antioxidant enzymes. Proteomics showed modest changes dominated by information-processing layers: higher abundance of histone deacetylases, RNA-binding and splicing-related factors, and enzymes linked to mRNA polyadenylation/decapping. In contrast, many 60S ribosomal proteins were less abundant, indicating restrained translation. Despite persistent osmotic pressure, enzymes of central metabolism changed little overall, whereas lipid-associated shifts and sterol enrichment suggest ongoing membrane remodeling. Collectively, these multi-omics data indicate that long-term salt adaptation in BY-2 cells prioritizes small-molecule osmolytes and post-transcriptional control over costly protein turnover, supporting sustained function under high osmolarity. This work provides novel insights into the molecular features underlying the reprogramming of the metabolome and proteome, enabling plant cells to survive long-term in high-salinity conditions.