Search Results (1,848)

In vitro embryo production (IVP) has emerged as a crucial tool in assisted reproduction and animal biotechnology. A key factor in this process is in vitro oocyte maturation (IVM), a critical process preceding fertilization that directly influences embryo quality. FLI supplementation, composed of fibroblast growth factor (FGF2), leukemia inhibitory factor (LIF), and insulin-like growth factor 1 (IGF1), has been shown to facilitate the IVM process to mimic essential aspects of in vivo oocyte development, and therefore, promote higher rates of oocyte maturation, embryonic viability, blastocyst formation, and improve the number of live animals born after embryo transfer. Individually or together, these components participate in signaling pathways that are crucial for improving oocyte competence and early embryo development. This review highlights the individual and combined roles of FGF2, LIF, and IGF1 in maturation and embryo culture medium, their influence on subsequent embryonic development, and their signaling pathways. Additionally, the incorporation of antioxidants and amino acids as supplementary components in combination with FLI is explored as a strategy to mitigate oxidative stress and enhance metabolic support during IVM and embryo culture. Together, these elements can significantly improve IVP outcomes, providing a potential pathway for optimizing the efficiency of embryo production in various species. Full article

Objective: Based on previous findings on the Lingguizhugan (LGZG)-mediated gut–liver axis, this study clarifies the therapeutic mechanisms of LGZG in metabolic dysfunction-associated steatotic liver disease (MASLD), with a focus on the gut microbiota–bile acid–TGR5 (GPBAR1) axis. Methods: C57BL/6J mice were fed a high-fat diet (HFD) for 8 weeks to induce MASLD, followed by 4-week LGZG intervention (21.57 g/kg/day, oral gavage). Metabolic phenotypes, gut microbiota (16S rRNA sequencing), serum/hepatic bile acids (targeted metabolomics), and molecular targets (qPCR/Western blot) were analyzed. Results: LGZG significantly alleviated HFD-induced obesity, insulin resistance, and hepatic steatosis, while enhancing whole-body energy expenditure (increased oxygen consumption (VO₂), and heat production (p < 0.05). It also reduced serum ALT (p < 0.001) and AST levels (p < 0.01). Mechanistically, LGZG remodeled the gut microbiota, specifically increasing Akkermansia, Bifidobacterium and Lachnospiraceae_NK4A236_group while decreasing Lactobacillus. This shift inhibited the intestinal FXR-Fgf15 axis, concurrently activating the hepatic alternative bile acid synthesis pathway (upregulating CYP27A1 and CYP7B1 protein expression; p < 0.001 and p < 0.01, respectively). Consequently, systemic accumulation of non-12α-hydroxylated bile acids (non-12-OH BAs) such as hyocholic acid (HCA) and 7-ketolithocholic acid (7-ketoLCA) occurred—known TGR5 agonists and intestinal FXR antagonists. These changes elevated serum GLP-1 levels (p < 0.05) and activated adipose TGR5-cAMP/PKA/CREB signaling. The metabolic benefits primarily originated from non-12-OH BAs enrichment and TGR5-mediated adipose browning, not hepatic FXR activation. Conclusions: Our findings show that LGZG ameliorates MASLD by remodeling bile acid profiles via intestinal FXR-Fgf15 axis inhibition and hepatic alternative synthesis pathway activation. This study highlights the TGR5-targeting properties of LGZG, providing a mechanistic basis for its therapeutic use in metabolic disorders. Full article

Rare earth elements (REE), such as gadolinium (Gd) and erbium (Er), are increasingly recognised as emerging environmental contaminants due to their widespread use in industrial processes, electronics, and medical imaging applications. Despite their extensive presence in aquatic ecosystems, little is known about their developmental toxicity. In this study, Xenopus laevis embryos were exposed to environmentally relevant concentrations of Gd and Er during critical early developmental stages. The assessed endpoints included survival, malformations, growth (body length), and heart rate. Both Gd and Er caused significant sublethal effects, including increased axial malformations, reduced growth, and altered cardiac activity. To explore potential mechanisms of toxicity, the expression patterns of key developmental genes (fgf8, bmp4, sox9, egr2, rax1, pax6) and pro-inflammatory cytokines (tnfα, il1β, p65) were analysed using Real-Time PCR. The results showed dysregulation of gene expression, indicating disruption to pathways involved in morphogenesis and neurodevelopment. Elevated reactive oxygen species levels suggested that oxidative stress was a contributing factor. Raman spectroscopy confirmed biochemical changes affecting proteins, lipids, and nucleic acids, providing evidence of cellular stress and metabolic imbalance. Overall, our findings demonstrate that even low-level exposure to Gd and Er can impair amphibian embryonic development and disturb molecular homeostasis. These results emphasise the ecological risks of REE pollution and highlight the importance of ongoing environmental monitoring and long-term toxicological research. Full article

Gallbladder diseases spanning cholelithiasis, cholecystitis, and gallbladder cancer represent a clinically heterogeneous continuum in which type 2 diabetes mellitus (T2DM) acts as a key metabolic modifier. Conventional models centered on bile supersaturation alone do not sufficiently account for the persistent inflammation and inter-individual variability frequently observed in practice. Here, we synthesize emerging evidence implicating the gut microbiota–bile acid (BA) axis as an integrative mechanism linking metabolic dysregulation, barrier dysfunction, and biliary pathobiology in the diabetic host. Hyperglycemia and insulin resistance, together with impaired mucosal resilience, are associated with shifts in microbial community structure and BA-transforming functions (e.g., bile salt hydrolase and 7α-dehydroxylation), favoring a more hydrophobic BA pool. These changes may disrupt BA receptor signaling, including FXR–FGF15/19 and TGR5-related pathways, thereby amplifying metabolic inflammation, promoting lithogenic bile formation, and impairing gallbladder motility. In parallel, barrier vulnerability may facilitate microbial translocation and LPS-driven immune activation, reinforcing a feed-forward loop that supports the gallstone–inflammation–carcinogenesis trajectory. Translationally, microbiome- and BA-oriented strategies (dietary patterns, bile acid therapeutics, and targeted microbiome modulation) are promising adjuncts, yet precision management should explicitly consider medication- and weight loss–related confounding—particularly with incretin-based therapies—to optimize biliary outcomes across disease stages. Full article

Diabetic cognitive impairment (DCI) is a serious and growing public health concern. The role of N6-methyladenosine (m⁶A), the predominant mRNA modification in the mammalian brain, in DCI pathogenesis remains not fully elucidated. Here, GEO-derived diabetes datasets were combined with in vivo and in vitro models to reveal aberrant expression of m⁶A-related genes. The results showed that the overall level of m⁶A RNA methylation in both the diabetic group and the high-glucose group was significantly decreased compared to the normal group. In addition, the expression of methyltransferase METTL3, which is involved in the regulation of m⁶A RNA methylation, was downregulated in both diabetic and hyperglycemic groups, and was positively correlated with the downregulation of the overall m⁶A level. Neuronal models with stable METTL3 knockdown were generated using lentiviral transduction. Subsequent ¹H-NMR metabolomic and MeRIP-qPCR analyses demonstrated that METTL3 deficiency disrupts key metabolic pathways, including phosphatidylethanolamine and phosphatidylcholine biosynthesis and glucose–alanine metabolism, and identified Fgf15 (the mouse ortholog of human FGF19) and H6PD as candidate downstream targets. Collectively, these data suggest that METTL3-dependent m⁶A RNA methylation alterations may contribute to DCI through metabolic dysregulation, positioning METTL3 as a promising therapeutic target for DCI. Full article

On university campuses, trees and green spaces shape how students and staff move and use outdoor spaces. To support planning, tree species information is needed at the level of individual trees. Tree species classification from UAV RGB imagery remains difficult in complex campus scenes because roads, buildings, shadows and subtle inter species differences degrade recognition. To address background interference, the loss of subtle fine-grained cues before tokenization, and insufficient local structure modeling in lightweight transformer-based classification, we propose TreeSpecViT for tree species classification. It uses a MobileViT backbone and a Background Suppression Module (BSM) to reduce clutter from non-canopy regions. A Fine-Grained Feature Guidance (FGF) module is inserted before the unfold operation to enhance canopy details and guide tokenization toward key regions. $1\times 1$ convolutional neck layers align channels, and a Global and Local Fusion (GLF) module jointly models overall crown semantics and local textures for species recognition. From the predicted masks and species labels, we build an individual tree digital archive. The archive stores per tree geometric attributes and can be linked with grids of campus activity intensity to analyze how activity patterns relate to vegetation structure. TreeSpecViT achieves an Accuracy of 87.88% (+6.06%) and an F1 score of 76.48% (+5.08%) on the SZUTreeDataset. On our self constructed NJFUDataset, it reaches 76.30% (+5.10%) in Accuracy and 70.10% (+7.20%) in F1. These results surpass mainstream models. Ablation experiments show that the modules jointly reduce background clutter and enhance canopy features. Overall, TreeSpecViT supports campus scale analyses that link human activity intensity to vegetation patterns and provides a practical basis for planning and adjusting campus green spaces. Full article

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disorder characterized by hyperphosphatemia and ectopic calcifications. Mutations in GALNT3, which encodes a key enzyme responsible for O-glycosylation of FGF23, represent a major genetic cause of HFTC. This modification is essential for the stability and secretion of FGF23. We investigated a 4-year and 6-month-old Chinese girl with HFTC to characterize the clinical features, identify the causative variants, and explore the underlying pathogenic mechanism. Whole-exome sequencing followed by Sanger validation identified novel compound heterozygous variants in GALNT3 (c.659T>A, p.Ile220Asn and c.1850C>A, p.Ser617*). The patient exhibited hyperphosphatemia with a biochemical profile consistent with FGF23 deficiency, including extremely low intact FGF23 and elevated C-terminal fragments. Functional studies using Western blotting and wheat germ agglutinin affinity chromatography demonstrated that the mutant GALNT3 caused a severe defect in FGF23 O-glycosylation, leading to impaired secretion of intact FGF23. Glycosylated FGF23 was detected only in the medium of cells expressing wild-type GALNT3. These findings indicate that defective O-glycosylation results in failure of FGF23 secretion and functional inactivation. This study expands the mutational spectrum of GALNT3 and provides mechanistic insight into the role of GALNT3 in phosphate homeostasis. Full article

Background/Objectives: Congenital anomalies of the kidney and urinary tract (CAKUTs) represent the leading cause of pediatric chronic kidney disease, yet the molecular mechanisms underlying these malformations remain incompletely understood. While genetic studies have identified numerous CAKUT-associated genes, conventional knockout approaches often result in embryonic lethality or fail to reveal tissue-specific gene functions. This review aims to synthesize findings from conditional knockout mouse studies that have elucidated the spatiotemporal requirements of key signaling pathways during kidney development. Methods: We conducted a narrative synthesis of studies employing Cre-loxP conditional gene targeting in mouse models, identified through systematic searches of PubMed and cross-referencing of key primary research. Studies were selected based on their use of lineage-specific Cre drivers (Six2-Cre, Hoxb7-Cre, Foxd1-Cre) to investigate nephron progenitor maintenance, ureteric bud branching morphogenesis, and stromal–epithelial interactions. Results: Conditional knockout studies have redefined CAKUT pathogenesis as a disorder of dose-dependent signaling, temporal regulation, and inter-compartmental communication. WNT/β-catenin signaling operates in a biphasic, dose-dependent manner in nephron progenitors, with Six2-Cre-mediated β-catenin deletion causing premature progenitor depletion. BMP and FGF pathways demonstrate dose-dependent and context-specific functions in progenitor maintenance, while GDNF/RET signaling is essential for ureteric bud outgrowth and branching. Importantly, stromal-specific deletions have uncovered non-cell-autonomous mechanisms regulating nephron formation. Haploinsufficiency studies demonstrate that partial pathway disruption can reduce nephron endowment without overt CAKUT, predisposing to adult-onset hypertension and chronic kidney disease. Conclusions: Conditional gene targeting has mechanistically redefined CAKUT from a collection of structural malformations to a spectrum of disorders arising from quantitative perturbations in lineage-specific signaling networks. These findings establish that phenotypic severity is determined by the degree of pathway disruption, the developmental timing of insult, and the compartment affected, providing a framework for interpreting oligogenic interactions and variable penetrance in human CAKUTs. Full article

Background/Objectives: Obstructive sleep apnea (OSA) syndrome is characterized by recurrent upper airway obstruction during sleep and is closely associated with systemic inflammation and cardiometabolic risk. α-Klotho and fibroblast growth factor-23 (FGF-23) are emerging biomarkers with potential roles in vascular homeostasis, inflammation, and metabolic regulation. However, their relevance in OSA remains insufficiently elucidated. The aim of this study was to evaluate serum α-Klotho and FGF-23 levels in patients with OSA and to investigate their associations with disease severity. This represents a novel approach that may provide new insights into the pathophysiological mechanisms linking OSA with cardiometabolic risk. Methods: A total of 133 participants were included in this study and categorized into three groups according to apnea–hypopnea index: 1—simple snoring (n = 44); 2—non-severe OSA (n = 44); and 3—severe OSA (n = 45). Comparisons between two groups were performed using Student’s t-test for normally distributed variables. Comparisons among three or more groups were conducted using one-way ANOVA and the Kruskal–Wallis test. ANCOVA was applied to compare α-Klotho and FGF-23 levels between groups after adjustment for age, BMI, diabetes, hypertension, asthma, COPD, and thyroid disease. The predictive performance of α-Klotho and FGF-23 for severe obstructive sleep apnea was evaluated using ROC curve analysis. Results: Serum α-Klotho levels decreased significantly with increasing OSA severity (p = 0.001). Serum FGF-23 levels increased significantly across AHI groups (p = 0.001). After adjustment for age, BMI, diabetes, hypertension, asthma, thyroid disease, COPD and vitamin D levels, α-Klotho levels were lower in the severe and non-severe OSA group (p = 0.001, both) compared to the simple snoring group, whereas FGF-23 levels were higher in the severe and non-severe OSA group (p = 0.001; both) compared to the simple snoring group. In predicting the risk of severe OSA compared with non-severe OSA, an α-Klotho cut-off value of 280.3 yielded a sensitivity of 84.44% and specificity of 75%, whereas an FGF-23 cut-off value of 75.5 yielded a sensitivity of 62.2% and specificity of 72.7%. Conclusions: Serum α-Klotho levels significantly decrease while FGF-23 levels increase in correlation with OSA severity. α-Klotho exhibited superior predictive performance over FGF-23 in identifying severe OSA, suggesting its potential as a more sensitive biomarker for systemic involvement. These results indicate that the α-Klotho/FGF-23 axis is independently associated with OSA and may play a pivotal role in the pathophysiological mechanisms linking intermittent hypoxia to increased cardiometabolic risk. Full article

This study examines the distinct roles of the neural cell adhesion molecules Ncam1a and Ncam1b in zebrafish neuromasts during both homeostasis and hair cell regeneration. While both molecules contribute to the initial development of the lateral line system, previous work showed that a morpholino knockdown of ncam1b causes more severe developmental defects than ncam1a knockdown. However, in ncam1b mutants, only minor changes in FGF/Wnt signaling and cell proliferation are observed in the migrating primordium, which do not affect overall development of the lateral line development, suggesting compensation by Ncam1a. This work shows that after neomycin-induced hair cell loss, only Ncam1b is strongly re-expressed in regenerating hair and support cells. ncam1b mutants show delayed hair cell regeneration, with an increased number of proliferating support cells but impaired differentiation into hair cells. Notably, Ncam1a is not re-expressed during regeneration in ncam1b mutants. These regeneration defects likely arise from disrupted interactions of signaling pathways. Our data suggest that Ncam1b supports regeneration by sustaining the FGF pathway activity required for atoh1a induction. It also maintains balanced Notch signaling, which regulates support cell fate decisions. Together, these results highlight the crucial, non-redundant role of Ncam1b in coordinating signaling pathways to ensure proper hair cell regeneration in zebrafish neuromasts. Full article

Cashmere goats produce high-value fine fibers derived from secondary hair follicles; however, the molecular mechanisms underlying this trait remain incompletely understood. In this study, comparative transcriptome sequencing was performed on skin tissues from Inner Mongolian cashmere goats and normal goats to characterize gene expression differences associated with cashmere fiber production. High-quality RNA-seq data with strong mapping efficiency and reproducibility were obtained across all samples. Differential expression analysis identified 1543 significantly differentially expressed genes (DEGs) between cashmere and normal goats, including genes involved in hair follicle morphogenesis, epidermal differentiation, cell proliferation, and extracellular matrix organization. Multivariate analyses showed a clear transcriptomic separation between fleece types, indicating that fleece phenotype is the primary driver of variation in global gene expression. Functional enrichment revealed significant involvement of the Wnt, MAPK, and PI3K–Akt signaling pathways, and several biologically relevant regulators of hair follicle development and hair cycle control, including FGF5, SOX9, LHX2, and VDR, were differentially expressed. Gene fusion events were rare and showed no group specific patterns, whereas alternative splicing was widespread, with exon skipping as the predominant splicing event in goat skin. Overall, these results provide quantitative transcriptomic evidence linking signaling regulation, follicle development, and structural differentiation to secondary hair follicle activity and cashmere fiber formation, offering candidate genes and molecular pathways for functional validation and molecular breeding in cashmere goats. Full article

This study investigates the mechanisms underlying drought adaptability in Duolang sheep, a local breed from two distinct habitats in Xinjiang—an arid southern region and a grassland northern region—aiming to identify key factors driving differential environmental adaptation. Integrated multi-omics analyses were performed, including serum biochemical assays, untargeted metabolomics of perirenal and tail fat tissues, and transcriptomic profiling of lung, liver, and kidney samples. Our results revealed notable differences: (1) serum levels of GSH-Px, IL-2, and IgG were significantly higher in the southern group (p < 0.01); (2) metabolomic analysis identified key differential metabolites, including EPA (involved in unsaturated fatty acid biosynthesis), choline (glycerophospholipid metabolism), L-serine and glutathione (cofactor biosynthesis), and taurine (sulfur metabolism); and (3) transcriptomic analysis revealed significant differential expression of genes such as FGF21 (thermogenesis), CD14 and DUSP2 (MAPK signaling pathway), GOT1 (arginine biosynthesis), and AVPR2 (vasopressin-regulated water reabsorption). Integrative correlation analysis further indicated that glutathione, EPA, GOT1, and CD14 are involved in energy and lipid metabolism, while taurine, AVPR2, and DUSP2 contribute to oxidative stress resistance and immune regulation. These molecular and metabolic adjustments collectively enhance drought adaptability in southern Xinjiang Duolang sheep. In conclusion, adaptation to arid environments requires enhanced antioxidant capacity and immune function, with metabolites such as EPA supporting lipid metabolism and genes such as FGF21 regulating fatty acid oxidation to limit triglyceride accumulation. Full article

Mice genetically deficient in α-Klotho (henceforth Klotho) display accelerated aging. The mechanisms are only partially understood. Here, we examine how these relate to the 12 hallmarks of aging consisting of chronic inflammation (inflammaging), as well as damaging changes to the genome (DNA damage), telomeres, epigenetic regulation, proteostasis, nutrient sensing, mitochondria, stem cells, intercellular communication, macroautophagy, microbiome and cell replication (senescence). Inflammation aggravates the other hallmarks. We report that Klotho counters the majority of these hallmarks. It ameliorates mitochondrial function and reduces reactive oxygen species (ROS), telomere attrition and cellular senescence. It protects against inflammation by inhibiting NF-κB and the NLRP3 inflammasome. This applies to inflammaging, several chronic inflammatory diseases, atherosclerosis, diabetes, and Alzheimer’s disease. Klotho also counters some aging factors outside of these hallmarks. Low Klotho (often due to kidney disease) produces hyperphosphatemia, which injures cells (especially endothelial cells) and promotes aging. Another key action of Klotho is the mitigation of fibrosis in major organs (kidneys, heart, lungs and other), mainly through the inhibition of TGF-β and Wnt. Klotho also protects against muscle atrophy (sarcopenia)—a common feature of aging—and exhibits anti-cancer activity. We describe several factors that increase Klotho, and are potentially amenable to clinical therapy. Full article

Background: Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) has been implicated in vascular inflammation beyond its action on LDL-C degradation. We investigated whether PCSK9 may exacerbate proinflammatory signaling of M1 macrophages and if its neutralization with alirocumab could attenuate this effect and plaque progression by LDL-C independent mechanisms. Methods: ApoE⁻/⁻ mice were treated with alirocumab for 13 weeks, and aortic arches were isolated for atherosclerotic plaque characterization based on lesion size and lipid and macrophage infiltration. Plasma and splenic monocytes/macrophages were also assessed by flow cytometry, and PCSK9, the lipid profile, and inflammatory cytokines were measured by qPCR or Western blot. Cultured THP-1-derived M1 macrophages were stimulated with PCSK9 and evaluated for TLR4-NFκB-NLRP3 activation and cytokine production. In addition, soluble PCSK9, LDL-C, and proinflammatory factors were analyzed in 1190 patients with acute coronary syndrome (ACS). Results: Alirocumab reduced plaque lesion (0.42-fold; p < 0.05) and lipid (0.63-fold; p < 0.01) and macrophage (0.61-fold; p < 0.05) infiltration, mainly the M1 subtype (0.37-fold; p < 0.01), as well as TLR4, NLRP3 and caspase-1 expressions (0.49-fold, 0.51-fold and 0.51-fold, respectively; p < 0.05), without altering LDL-C. Also, it decreased proinflammatory cytokines but enhanced anti-inflammatory factors and M2 markers at the descending aorta. Alirocumab enriched circulating Ly6C^low monocytes (1.51-fold; p < 0.05) and splenic M2 macrophages (1.32-fold; p < 0.01), while reducing M1 (0.62-fold; p < 0.05). In cultured M1 macrophages, PCSK9 overexpressed proinflammatory cytokines (i.e., CXCL9, CXCL10, TNF-α, IL-1β, and IL-6), downregulated anti-inflammatory mediators (i.e., CCL17, TGM2, TGF-β1, and IL-10), and promoted NFκB-p65 nuclear translocation and NLRP3 and gasdermin-D activation. However, TLR4 inhibition or silencing blunted these effects. In patients with AC, there was a positive association between PCSK9 and hsCRP and FGF-23 plasma levels, independently of LDL-C. Conclusions: PCSK9 may be released in parallel to proinflammatory factors such as hsCRP and FGF-23 in patients with ACS, independently of LDL-C levels. PCSK9 may directly promote macrophage-driven inflammatory responses through the TLR4-NFκB-NLRP3 signaling, but its neutralization with alirocumab attenuated this inflammatory axis and limited atherosclerotic progression, supporting an anti-inflammatory benefit secondary to PCSK9 inhibition. Full article

Physical exercise is a potent non-pharmacological strategy for the prevention and management of Metabolic dysfunction—associated steatotic liver disease (MASLD), a multifactorial disorder characterized by hepatic lipid accumulation, insulin resistance, oxidative stress, and chronic inflammation. Emerging evidence demonstrates that the benefits of exercise extend beyond caloric expenditure and are largely mediated by coordinated molecular and cellular adaptations within the liver and peripheral tissues. This review synthesizes current knowledge on the mechanisms through which exercise modulates MASLD pathophysiology, emphasizing intracellular signaling pathways, mitochondrial remodeling, antioxidant defenses, and myokine-driven muscle–liver crosstalk. Exercise induces acute and chronic activation of pathways such as AMPK, PGC-1α, Nrf2, and Akt, resulting in enhanced mitochondrial biogenesis, improved fatty acid oxidation, restored insulin signaling, and reduced inflammatory and oxidative stress. Repeated skeletal muscle contraction stimulates the release of myokines—including irisin, IL-6, and FGF21—that act through endocrine and paracrine routes to regulate hepatic lipid metabolism, promote systemic metabolic flexibility, and attenuate disease progression. Epigenetic modifications and exercise-responsive microRNAs further contribute to long-term hepatic metabolic reprogramming. Collectively, these molecular adaptations position exercise as a systemic, disease-modifying stimulus capable of restoring hepatic homeostasis, slowing the transition from steatosis to NASH and fibrosis, and improving long-term metabolic health. Understanding these mechanisms provides a foundation for developing targeted, personalized exercise-based interventions in the clinical management of MASLD. Full article