Search Results (3,482)

The orbital fat of bighead carp (Hypophthalmichthys nobilis) represents a structural fat deposit located posterior to the eyes and constitutes an important edible component of the head region. Nevertheless, molecular mechanisms governing lipid accumulation during ontogenetic development remain insufficiently characterized. Here, we performed RNA-Seq on orbital fat tissues from 6-month-old (juvenile) and 18-month-old (market-size) bighead carp. A total of 1042 DEGs were identified, with 807 up-regulated and 235 down-regulated in the 6-month-old stage. Functional enrichment revealed key pathways including fatty acid metabolism, PPAR signaling, and glycolysis/gluconeogenesis. qRT-PCR validation confirmed RNA-Seq reliability. Notably, the differential expression patterns of genes such as cpt1a, cpt1b, slc27a1, fads2, and scd suggest their association with an elevated capacity for lipid synthesis in the orbital fat of 18-month-old bighead carp. This study presents the first transcriptome analysis of orbital fat development in a freshwater fish, offering insights into the genetic improvement of head meat quality traits and growth in bighead carp head. Full article

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide, arising from complex interactions among metabolic, genetic, and environmental factors. Nicotinamide N-methyltransferase (NNMT) has recently emerged as a key metabolic regulator in CVD pathogenesis. By consuming nicotinamide and methyl groups, NNMT perturbs epigenetic, metabolic, and redox pathways that are critical for cardiovascular health. NNMT-mediated NAD⁺ depletion impairs mitochondrial function, sirtuin (SIRT) activity, redox balance, and energy metabolism, thereby creating a pro-atherogenic environment. NNMT and its product 1-methylnicotinamide (1-MNA) show a complex duality: they modulate SIRT activity—particularly SIRT1 and SIRT3—to influence gluconeogenesis, cholesterol synthesis, lipogenesis, and mitochondrial antioxidant defenses. NNMT upregulation also elevates homocysteine levels, activating pro-inflammatory and pro-oxidative cascades (e.g., TLR4–NF-κB and STAT3–IL-1β). Growing evidence links NNMT to major CVD risk factors, including hyperlipidemia, hypertension, diabetes mellitus, and obesity. Thus, NNMT has a multifaceted role in cardiovascular health: while its enzymatic activity is often pathogenic (via NAD⁺/SAM consumption and homocysteine production), its metabolite 1-MNA can exert protective effects (via NRF2 activation and anti-thrombotic mechanisms). This duality highlights the need to delineate the molecular processes that balance these opposing actions. Experimental studies using small-molecule NNMT inhibitors and RNA interference have shown promising cardiometabolic benefits in preclinical models, including improved insulin sensitivity, reduced atherosclerosis, and attenuated cardiac dysfunction. However, no clinical trials have yet targeted NNMT specifically in CVD. Future research should clarify the tissue-specific functions of NNMT and translate these insights into novel therapeutic strategies. Full article

The in vitro granulosa cell (GC) model presents a valuable tool to explore antral follicle development. A full understanding of the reasons and blocking methods that occur during in vitro luteinization of sheep GCs, stimulated by serum culture, is a complex goal that has not been completely achieved. Herein, the phenomenon and causes of GC differentiation, as well as the methods for inhibiting luteinization in an in vitro culture system, were investigated by immunofluorescence, Western blot, RT-qPCR, and ELISA techniques. The results reveal that, when compared to fresh GCs, FSHR protein levels in primary GCs significantly decreased in serum-containing media, while STAR protein levels significantly increased, implying that sheep GCs can differentiate in serum-containing media. LH concentrations were significantly greater in serum-containing media compared to serum-free media. The LH receptor (LHR) mRNA expression in primary-generation GCs steadily increased with longer culture times, indicating that LH-LHR signaling leads to GC luteinization in vitro. In primary and second-generation GCs, 180 nmol/L BAY-899, an LHR-specific antagonist, significantly increased FSHR protein expression, reduced STAR protein synthesis, and inhibited P4 secretion within 48 h of in vitro culture compared to controls. BAY-899 showed no adverse effects on fifth-generation GCs growth, implying that BAY-899 can inhibit GC luteinization while not affecting cell proliferation. In conclusion, this study found that the LHR antagonist BAY-899 can preserve the features of sheep GCs in vitro by suppressing the spontaneous luteinization process caused by LH-LHR signaling, which has a key methodological implication for studying the mechanics of antral follicle formation in vivo. Full article

Ischemic stroke is one of the leading causes of morbidity and mortality worldwide, with carotid atherosclerosis being its key etiological factor. MicroRNA-21 (miR-21) regulates intracellular signal pathways responsible for vascular changes and ischemic brain injury, and is recognized as a potential diagnostic and prognostic biomarker. It modifies the activity of macrophages (MΦ) and vascular smooth muscle cells, causing inflammation and affecting the stability of atherosclerotic plaques. A deficiency of miR-21 in macrophages stimulates the inflammatory response and plaque growth. It promotes both the synthesis of extracellular matrix, stabilizing the plaque, and the degradation of the fibrin cap, which leads to plaque instability. The effect of miR-21 on endothelial cells differs: it stimulates both NO· synthesis and inflammation. During ischemic stroke, miR-21 demonstrates neuroprotective effects by modulating post-ischemic inflammation and protecting the integrity of the blood–brain barrier. Therapy targeting miR-21 shows potential in experimental models, but it requires cell-specific delivery and precise timing. Further research efforts should focus on the effects of miR-21 on different cell types, as well as the development of new technologies for diagnostic and therapeutic applications. Full article

Nannochloropsis oceanica (Suda & Miyashita) R. E. Lee holds considerable potential for the production of high-value compounds, including pigments, lipids, and polyunsaturated fatty acids. Sodium acetate, a widely used carbon source in microbial cultivation, is both cost-effective and efficient. Although it has been reported to enhance biomass production in various microalgae, its effects on metabolic pathways differ substantially across species. In this study, we investigated the transcriptional responses of N. oceanica to sodium acetate supplementation using high-throughput mRNA sequencing. Sodium acetate significantly promoted growth but elicited a distinct metabolic reprogramming in contrast to patterns commonly observed in other microalgae. We identified 747 differentially expressed genes (399 upregulated and 348 downregulated), reflecting a substantial transcriptomic shift. Pathways related to lipid metabolism, carbon fixation, and photosynthesis were markedly suppressed. Notably, genes associated with photosynthesis were downregulated by 34–43 fold, suggesting a strategic reallocation of resources away from energy-intensive photosynthetic processes in the presence of an external organic carbon source. In sharp contrast to Chlamydomonas reinhardtii P. A. Dangear and Haematococcus pluvialis (Flotow) Wille, lipid metabolism in N. oceanica was not enhanced under sodium acetate supplementation. Instead, expression of lipid metabolism genes decreased by 5–14 fold, with most fatty acid- and lipase-related genes also downregulated (4–30 fold). Together, these findings reveal that N. oceanica adopts a unique adaptive strategy, channeling acetate-derived carbon primarily into rapid biomass accumulation rather than energy storage or high-value metabolite synthesis. This work provides new insights into the species-specific responses of microalgae to organic carbon sources. Full article

Background/Objectives: Obesity and type 2 diabetes mellitus (T2DM) profoundly disrupt lipid metabolism within local microenvironments of skeletal muscle and its associated connective tissues, including adipose tissue, bone, and fascia. However, the role of local communication between skeletal muscle and its proximal connective tissues in propagating metabolic dysfunction is incompletely understood. This narrative review synthesizes current evidence on these local metabolic interactions, highlighting novel insights and existing gaps. Methods: We conducted a comprehensive literature analysis of primary research published in the last decade, sourced from PubMed, Web of Science, and ScienceDirect. Studies were selected for relevance to skeletal muscle, adipose tissue, fascia, and bone lipid metabolism in the context of obesity and T2DM, with emphasis on molecular, cellular, and paracrine mechanisms of local crosstalk. Findings were organized into thematic sections addressing physiological regulation, pathological remodeling, and inter-organ signaling pathways. Results: Our synthesis reveals that local lipid dysregulation in obesity and T2DM involves altered fatty acid transporter dynamics, mitochondrial overload, fibro-adipogenic remodeling, and compartment-specific adipose tissue dysfunction. Crosstalk via myokines, adipokines, osteokines, bioactive lipids, and exosomal miRNAs integrates metabolic responses across these tissues, amplifying insulin resistance and lipotoxic stress. Emerging evidence highlights the underappreciated roles of fascia and marrow adipocytes in regional lipid handling. Conclusions: Collectively, these insights underscore the pivotal role of inter-tissue crosstalk among skeletal muscle, adipose tissue, bone, and fascia in orchestrating lipid-induced insulin resistance, and highlight the need for integrative strategies that target this multicompartmental network to mitigate metabolic dysfunction in obesity and T2DM. Full article

Background: Donor lymphocyte infusion (DLI) is employed to enhance the graft-versus-leukemia (GvL) effect and improve remission rates following allogeneic hematopoietic cell transplantation (alloHCT). However, graft-versus-host disease (GvHD) remains a significant complication of both alloHCT and DLI. Regular exercise has been shown to reduce cancer risk, enhance treatment responses, and mitigate therapy-related toxicities. This study investigated the effects of voluntary wheel running on GvL and GvHD following DLI in a xenogeneic mouse model. Methods: Immunodeficient NSG-IL15 mice were challenged with a luciferase-expressing chronic myelogenous leukemia cell line (K562), and then they received DLI with peripheral blood mononuclear cells (PBMCs) from healthy volunteers (GvL model). Non-tumor bearing mice received DLI to model GvHD. Half of the mice in each group were then given free access to a running wheel. Tumor growth (bioluminescence), GvHD, and body weight were monitored biweekly for ~40 days. Results: In the GvHD model, exercise extended overall survival by 60% and reduced GvHD severity. In the GvL model, exercise significantly lowered tumor burden and extended tumor-free survival in both DLI and vehicle control groups by 44.5% and 37.5%, respectively, suggesting both immune-dependent and immune-independent mechanisms. RNA sequencing of bone marrow from saline-injected mice revealed that genes associated with mitochondrial function, protein synthesis, and metabolic processes were downregulated in tumors from exercised mice. Conclusions: In summary, voluntary wheel running improved DLI outcomes by enhancing GvL and reducing GvHD. These benefits may be mediated, in part, through exercise-induced metabolic reprogramming of leukemia cells. Full article

Thrombospondin-1 potently inhibits T cell activation by engaging its cell surface receptor CD47. This inhibitory signal requires glycosaminoglycan modification of CD47. CD47 also regulates the composition of RNAs in extracellular vesicles released by T cells and their functional activities. Because CD47 is also present in extracellular vesicles, we examined the effect of T cell activation on CD47 glycoforms in T cells and extracellular vesicles released by these cells. Activation increased both heparan and chondroitin sulfate biosynthesis by globally inducing mRNA levels of the respective glycosaminoglycan synthases and sulfotransferases. T cell activation in the presence of thrombospondin-1 inhibited induction of these biosynthetic enzymes, but not in cells lacking CD47. Therefore, CD47 signaling controls its own post-translational modification by glycosaminoglycans that are required for thrombospondin-1 signaling. Activation of Jurkat T lymphoblasts and primary CD4 and CD8 T cells increased the release of proteoglycan isoforms of CD47 and amyloid precursor-like protein-2 associated with extracellular vesicles and smaller macromolecular complexes. However, cell surface levels of CD47 were minimally changed during activation. BJAB and RAJI B cell lines also produced CD47⁺ extracellular vesicles and showed increased release of highly glycosylated CD47 following B cell receptor engagement. Therefore, T and B lymphocyte activation results in a selective increase in the synthesis and release of extracellular vesicles containing proteoglycan isoforms of CD47. Full article

Diaphorina citri is the primary global vector of “Candidatus Liberibacter asiaticus”, the bacterium responsible for Huanglongbing. Syntaxin-1A (Syx1A), a member of the Qa-SNARE family, is essential for vesicle fusion and signal transduction, though its function in hemipteran insects remains poorly understood. This study presents the first comprehensive analysis of Syx1A expression in D. citri. Transcripts were detected across all life stages, with peak expression in the salivary glands. RNAi silencing of Syx1A reduced mRNA levels by 39.0% in nymphs and 58.0% in adults, resulting in 58.3% nmortality in nymphs within 5 days and 73.3% in adults within seven days, along with significant weight loss. Treated females showed marked declines in fecundity, ovarian degeneration, and deficient yolk deposition. RT-qPCR confirmed significant downregulation of Vg1, VgA, and VgR. These findings establish Syx1A as a regulator of growth and reproduction in citrus psyllids via modulation of yolk synthesis. RNAi targeting of Syx1A represents a promising strategy for ecologically sound pest control and may contribute to efforts in halting the transmission of the Huanglongbing pathogen CLas. Full article

Screens for specific phenotypes have long been a cornerstone of biology. Here, we present an updated synthesis of our large-scale visual screens for Arabidopsis (Arabidopsis thaliana) mutants that exhibit leaf morphology defects. In our 2009 review, we used phenotypes to group the leaf mutants that we had isolated and characterized since 1992; here, by contrast, we functionally classified the mutations that we studied over the last 16 years based on the biological programs they disrupt. Since 2009, we have identified and analyzed 38 genes required for proper leaf development; these genes are involved in translation, chloroplast function, cell wall construction, auxin homeostasis, microRNA biogenesis, and epigenetic regulation. Many of the identified mutants have pleiotropic phenotypes, consistent with the central roles of the affected pathways in development. In this review, we systematically link morphological traits to specific molecular dysfunctions, highlighting the enduring utility of forward genetic approaches. We found that the Arabidopsis leaf is a model organ of a model organism, and we have used this model-in-a-model system to dissect whole-plant traits such as cell proliferation and expansion, and to improve our understanding of the genetic control of plant form and size. Full article

Background: Chinese Red Steppe cattle (CRS) combine indigenous environmental resilience with moderate dairy performance, whereas Holstein cattle (HOL), despite their high milk yield, suffer reduced genetic diversity and compromised adaptation. A comparative analysis of their population genetic architecture and selection signatures can reveal valuable targets for CRS dairy improvement. Methods: We genotyped 61 CRS and 392 HOL individuals using the Illumina GGP Bovine 100K SNP array and performed stringent quality control. Population structure was assessed via principal component analysis, neighbor-joining trees, and sparse nonnegative matrix factorization. Historical effective population size (Ne) and divergence time were inferred with SMC++. Genome-wide selection scans combined Fixation Index (FST) and Cross-Population Composite Likelihood Ratio test (XP-CLR); overlapping high-confidence regions were annotated and subjected to GO and KEGG enrichment analyses. Results: CRS and HOL were clearly separated along PC1 (explaining 57.48% of variance), with CRS exhibiting high internal homogeneity and weak substructure, versus greater diversity and complex substructure in HOL. SMC++ indicated a split approximately 3500 years ago (700 generations) and a pronounced recent decline in Ne for both breeds. Joint selection mapping identified 767 candidate genes; notably, the ACSM1/2B/3/4 cluster on chromosome 25—key to butanoate metabolism—showed the strongest signal. Enrichment analyses highlighted roles for proteasome function, endoplasmic reticulum stress response, ion homeostasis, and RNA processing in regulating milk fat synthesis and protein secretion. Conclusion: This study delineates the genetic divergence and demographic history of CRS and HOL, and pinpoints core genes and pathways—particularly those governing butanoate metabolism and protein quality control—underlying dairy traits. These findings furnish molecular markers and theoretical guidance for precision breeding and sustainable utilization of Chinese Red Steppe cattle. Full article

The ribosome in eukaryotic cells is a macromolecular complex composed of four ribonucleic acids and over 80 proteins. This organelle facilitates protein synthesis in cells, and its activity is strongly upregulated in human cancers. Immune cells, a variety of cellular stressors and numerous structurally and mechanistically distinct anti-cancer agents have been shown to induce ribosomal RNA degradation in tumour cells in vitro and in vivo—a phenomenon we termed “RNA disruption”. RNA disruption can be quantified in cultured cell lines and patient samples using the RNA disruption assay (RDA). Unlike well-known high-throughput anti-cancer drug sensitivity assays, RDA can distinguish between dying and arrested tumour cells, making it an attractive assay for anti-cancer drug discovery and development. Low tumour RNA disruption during neoadjuvant chemotherapy (as measured using RDA) is strongly associated with residual disease and reduced disease-free survival, making it a potentially valuable chemo-resistance assessment tool. High RNA disruption may also indicate chemo-responsiveness. RDA holds the prospect of being a useful tool to escalate or de-escalate neoadjuvant chemotherapy in cancer patients. Moreover, the assay’s ability to predict treatment outcomes during neoadjuvant chemotherapy may permit its use in adaptive clinical trials and in drug approval by regulatory agencies. This review provides insight into the cellular processes involved in chemotherapy-induced RNA disruption. It also describes the results of clinical studies on tumour RNA disruption in cancer patients and suggests possible approaches that could be considered for the utilization of RDAs in the clinical management of breast cancer patients undergoing current neoadjuvant chemotherapy regimens. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, synaptic loss, and multifaceted pathology involving amyloid-β (Aβ) aggregation, tau hyperphosphorylation, neuroinflammation, and impaired proteostasis. In recent years, biologic therapies, such as monoclonal antibodies, vaccines, antisense oligonucleotides (ASOs), and gene therapies, have gained prominence as promising disease-modifying strategies. In this review, we provide a comprehensive synthesis of current biologic approaches under clinical evaluation for AD. Drawing on data curated from ClinicalTrials.gov (as of 2025), we systematically summarise the molecular targets, therapeutic modalities, mechanisms of action, trial phases, and sponsors of over 60 biologic agents. These include Aβ-directed antibodies targeting distinct conformers such as protofibrils, pyroglutamate-modified species, and soluble oligomers; tau-targeted immunotherapies and RNA-based interventions; and emerging platforms focused on neuroimmune modulation, peptide hormones, and microbiota-based strategies. Gene and RNA therapeutics, particularly ASOs and small interfering RNAs (siRNAs) delivered intrathecally or via lipid nanoparticles, are also reviewed for their potential to modulate intracellular targets with high specificity. We also analyse the historical landscape of biologic candidates that failed to reach approval, discussing key reasons for trial discontinuation, including lack of clinical efficacy, safety concerns (e.g., amyloid-related imaging abnormalities), or inadequate biomarker responses. These cases offer crucial insights for refining future drug design. Looking ahead, we highlight major challenges and evolving perspectives in AD biologic therapy: expanding therapeutic targets beyond Aβ and tau, overcoming delivery barriers to the brain, designing prevention-oriented and genetically stratified trials, and navigating regulatory and ethical considerations. Together, these efforts signal a paradigm shift in AD drug development, from symptomatic treatment to mechanism-based precision biologics. By integrating real-time clinical trial data with mechanistic insight, this review aims to inform both translational research and therapeutic innovation in AD. Full article

Linezolid (LNZ) is a synthetic oxazolidinone antibiotic that inhibits bacterial protein synthesis through binding to ribosomal RNA, also preventing the assembly of the initiation complex during translation. It is one of the last-line therapeutic options for serious infections caused by problematic Gram-positive pathogens, including vancomycin-resistant and multidrug-resistant Enterococcus species. Data from recent large-scale studies show a 2.5-fold increase in the prevalence of clinical LNZ-resistant enterococci (LRE) over the past decade with a global detection rate of 1.1% for LNZ-resistant E. faecium (LREfm) and 2.2% for LNZ-resistant E. faecalis (LREfs). Most reported cases have originated from China, followed by South Korea and the United States. LREfm typically belongs to the high-risk clonal complex 17, whereas LREfs demonstrates a heterogeneous population structure. Mutations in the 23S rRNA and ribosomal proteins, as well as acquired resistance genes such as cfr, optrA, and poxtA are involved in the development of LNZ resistance among enterococci. Whole-genome sequencing (WGS) has been recognized as a gold standard for identifying the underlying molecular mechanisms. It exposes that numerous LRE isolates possess multiple LNZ resistance determinants and mutations, further complicating the treatment strategies. The present review article summarizes all known mutational and non-mutational LNZ resistance mechanisms and presents a global overview of WGS-based studies with emphasis on resistome analysis of clinical LREfs and LREfm isolates published in the literature during the period 2014–2025. Full article

The tumor microenvironment creates strong stress conditions, including hypoxia and nutrient depletion, which cause the blocking of cap-dependent translation. Under stressful conditions, cancer cells exploit the cap-independent translation mechanism mediated by internal ribosome entry site (IRES), which ensures continued protein synthesis. IRES elements located in the 5′ untranslated regions of specific mRNAs allow selective translation of key anti-apoptotic and adaptive proteins. These proteins promote cellular processes that sustain cell survival, among them metabolic reprogramming, redox balance, and epithelial-to-mesenchymal transition, thus facilitating tumor progression and therapy resistance. IRES activity is dynamically regulated by IRES trans-acting factors, such as YB-1, PTB, and hnRNPA1, which respond to cellular stress by enhancing translation of crucial mRNAs. Emerging therapeutic strategies include pharmacological IRES inhibitors, RNA-based approaches targeting ITAF interactions, and IRES-containing vectors for controlled therapeutic gene expression. A deeper understanding of translational reprogramming, IRES structural diversity, and ITAF function is essential to develop targeted interventions to overcome therapeutic resistance and eliminate persistent tumor cell populations. Full article