Search Results (26,843)

Unc-51-like kinase 3 (ULK3) is a key member of the ULK serine/threonine kinase family. Aberrant ULK3 expression has been increasingly linked to tumorigenesis and malignant progression in multiple cancer types. However, the precise role of ULK3 in tumor initiation and progression remains incompletely understood. Leveraging integrated multi-omics data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we systematically characterized the expression of ULK3 at both the transcript and protein levels across 33 cancer types. We also evaluated genomic alterations, prognostic significance, alternative splicing, pathway enrichment, tumor stemness, immune infiltration, and immunotherapy-related biomarkers. In parallel, we investigated the function of ULK3 in prostate cancer PC-3 cells using cellular localization analysis, wound-healing assays, and MTT assays. We further applied Connectivity Map (CMap) screening and molecular docking to identify candidate ULK3 activators. ULK3 was significantly upregulated in 13 cancer types, including Bladder Urothelial Carcinoma, Breast Invasive Carcinoma, and Lung Adenocarcinoma. In contrast, ULK3 was downregulated in Cholangiocarcinoma and Head and Neck Squamous Cell Carcinoma. High ULK3 expression was associated with poor overall survival in Adrenocortical Carcinoma, Kidney Renal Clear Cell Carcinoma, and Skin Cutaneous Melanoma. Copy number amplification contributed to ULK3 overexpression. A recurrent A206V missense mutation was detected in the protein kinase (Pkinase) domain. Genes co-expressed with ULK3 were enriched in RNA splicing, methylation, oxidative phosphorylation, and energy metabolism. ULK3 expression showed positive correlations with tumor stemness indices and m1A/m5C/m6A RNA modification regulators. From an immunological perspective, high ULK3 expression was associated with lower Immune Score, increased M2 macrophage infiltration, and co-expression of PD-L1, CTLA4, and LAG3 in most cancers. ULK3 expression was also correlated with Tumor Mutational Burden in Kidney Renal Clear Cell Carcinoma and Rectum Adenocarcinoma. In addition, ULK3 expression was associated with Microsatellite Instability in Brain Lower Grade Glioma, Lung Adenocarcinoma, and Uterine Corpus Endometrial Carcinoma. ULK3 overexpression promoted proliferation and migration in PC-3 cells. Cephaeline was screened as a putative ULK3 activator. Overall, ULK3 expression and amplification were associated with poor clinical outcomes, tumor stemness, immunosuppression, and RNA dysregulation. These findings highlight the potential value of ULK3 as a pan-cancer diagnostic and prognostic biomarker and as a predictor of immunotherapy response, particularly in prostate cancer. Full article

Background/Objectives: Ceratonia siliqua L. (carob) is a rich source of bioactive compounds with potential health-promoting properties. This study investigated the kinetics of serum metabolites following the consumption of a carob beverage and evaluated associated changes in circulating antioxidant status. Methods: Fifteen apparently healthy adult men completed an acute postprandial intervention; only male participants were included to minimize the biological variability related to sex-dependent differences in phytochemical kinetics and antioxidant responses. Participants consumed a beverage from carob pod powder (30 g) dispersed in water (200 mL). Blood samples were collected at baseline and every 30 min for 6 h following intake. Serum metabolic profiling was performed using a non-targeted liquid chromatography–time-of-flight mass spectrometry (LC-TOF-MS) approach. Antioxidant responses were assessed by measuring ferric-reducing antioxidant power (FRAP) and serum resistance to copper sulphate-induced oxidation. Results: Twenty-four putative metabolites were detected, including phenolic compounds, fatty acids, amino acids, dipeptides, monosaccharides, pyridoxine, and gut microbiota-derived metabolites. Urolithin B appeared at 30 min (28.0 ± 4.0 × 10² a.u.), while p-cresol sulfate increased from 53.3 ± 6.5 × 10² a.u. at baseline to 130.0 ± 7.0 × 10² a.u. at 30 min. FRAP values did not change significantly over time (p = 0.332), whereas oxidation lag time showed a significant time effect (p = 0.001), reaching its highest mean at 180 min (9093.5 ± 1885.1 s). Conclusions: Carob beverage consumption resulted in a diverse postprandial serum metabolite profile. Antioxidant responses appeared to be only partly explained by circulating phenolics, suggesting that additional pathways and bioactive constituents may contribute. Full article

Low temperatures limit the yield and stability of autumn-sown oats; thus, investigating cold resistance physiological responses is essential. In this study, we compared a cold-resistant variety (‘Aiwo’) and a cold-sensitive variety (‘Hewang’). ‘Aiwo’ exhibited a significantly higher overwintering survival rate (96.9%) and superior physiological traits, including elevated levels of soluble proteins, proline, putrescine, unsaturated fatty acids, and glutathione, alongside greater ATPase activity and reduced ROS levels. Exogenous putrescine application suggested a potential role of Put in alleviating lipid peroxidation. Metabolomic analysis showed that the arginine–proline and cysteine–methionine pathways were enriched among DAMs associated with ‘Aiwo’, accompanied by the accumulation of stress-protective metabolites. These metabolic changes may contribute to improved energy balance and membrane stability under low-temperature conditions. Our findings suggest that proline, putrescine, and glutathione are candidate physiological indicators associated with the cold-resistant phenotype, which may facilitate future screening of cold-resistant oat germplasm. Full article

Chronic heat stress poses a major challenge to marine aquaculture, yet its sex-associated molecular basis remains poorly understood in Chinese tongue sole (Cynoglossus semilaevis). Juveniles were exposed to a control temperature (24 °C) or elevated temperature (30 °C) for two months, and liver samples from low-temperature females (LF), high-temperature females (HF), low-temperature males (LM), and high-temperature males (HM) were analyzed by RNA sequencing (RNA-seq) and whole-genome bisulfite sequencing (WGBS). Principal component analysis indicated a strong temperature-associated separation, while sex-related separation under heat stress was smaller and was mainly observed along the second principal component. In high-temperature relative to low-temperature comparisons, females showed a broader set of differentially expressed genes (DEGs; LF vs. HF, 1968) than males (LM vs. HM, 506). Differential methylation analyses indicated that cytosine-guanine (CG) methylation was the predominant heat-associated epigenetic signal. Integrative analysis identified 624 overlapping genes between DEGs and CG-associated differentially methylated genes (CG-DMGs) in females and 177 in males, suggesting broader methylation-associated transcriptional remodeling in females. Functional enrichment associated the female overlap genes with immune response, inflammatory signaling, lipid metabolism, and detoxification, whereas male overlap genes were more closely associated with proteostasis, autophagy, and DNA replication/repair. Correlation analyses suggested modest methylation–expression coupling and highlighted candidate W-linked genes, including H2AZ2 and ANKRD13A. Overall, these results should be regarded as a preliminary baseline for understanding sex-associated molecular responses to chronic heat stress in tongue sole and as a source of candidate genes and pathways for future validation and heat-resilience breeding. Full article

Gibberellic acids (GAs) are a class of tetracyclic diterpene carboxylic acid compounds produced by green plants, fungi, and bacteria, which have a wide range of applications in agricultural production and food ingredients processing. Owing to the continuously growing market demand, enhancing GA yield has become imperative. The biosynthesis of GAs is a multi-enzymatic synergistic process that can be enhanced through genetic and metabolic engineering strategies. In this review, we first summarize recent advances in GA production by Fusarium fujikuroi. We then highlight key metabolic engineering strategies, including biosynthetic pathway engineering, cluster-specific channeling of geranylgeranyl diphosphate biosynthesis, cofactor engineering, as well as regulatory mechanisms involving nitrogen modulation and histone modification. Finally, we discuss promising approaches for constructing high-efficiency microbial cell factories, such as implementation of the CRISPR/Cas9 system, the application of strong promoters, the development of target-specific technologies for small molecules, and the employment of genome-scale metabolic models. Recent metabolic engineering efforts have achieved GA3 titers of up to 3.16 g/L through multi-target nitrogen regulation strategies, highlighting the potential for further yield improvement. Full article

Urban pigeons (Columba livia) are widely distributed synanthropic birds closely associated with environments of intense human activity, raising interest in their role in urban microbial dynamics. Here, we characterized the fecal bacterial microbiota of urban pigeons from northern Mexico using 16S rRNA gene amplicon sequencing (V3–V4). A total of 1479 amplicon sequence variants (ASVs) were identified across five pooled samples. Alpha diversity varied among pools, with observed richness ranging from 228 to 514 ASVs. The bacterial community was dominated by Proteobacteria and Firmicutes, particularly Escherichia–Shigella and Enterococcus. PICRUSt2-based functional predictions suggested a predominance of predicted metabolic pathways related to carbohydrate degradation and energy acquisition. Conservative taxonomic screening identified 58 gut-associated taxa, including 15 bacteria previously reported in association with humans; however, only three (Clostridium perfringens, Enterococcus faecalis, and Proteus mirabilis) showed reported zoonotic associations, all at very low relative abundances (<0.07%). These findings indicate that the fecal bacterial communities characterized in this study were dominated by taxa commonly associated with the avian gastrointestinal tract, whereas taxa that could be conservatively linked to documented zoonotic reports represented only a minor fraction of the detected microbiota. Overall, the results contribute to a more ecologically informed understanding of urban pigeon-associated microbiota within a One Health framework. Full article

Metabolic dysfunction-associated steatohepatitis (MASH; formerly non-alcoholic steatohepatitis, NASH) is characterized by oxidative stress, inflammatory activation, hepatocellular injury, and progressive liver dysfunction. However, the global transcriptomic landscape underlying stress-induced hepatic injury remains incompletely understood. In this study, we employed a methionine–choline-deficient (MCD) diet-induced murine model to characterize the phenotypic and transcriptomic alterations associated with liver injury. Male C57BL/6J mice were fed either a control or MCD diet, and hepatotoxicity was assessed by survival analysis, body and liver weight measurements, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, histopathological examination, RNA sequencing, quantitative real-time PCR (qRT-PCR), and tumor necrosis factor-alpha (TNF-α) enzyme-linked immunosorbent assay (ELISA). MCD feeding markedly reduced survival and body weight while inducing hepatomegaly and significant elevations in serum ALT and AST, indicating severe hepatocellular injury. Histopathological analysis demonstrated hepatic steatosis, hepatocellular ballooning, and lobular inflammation without histological evidence of fibrosis. Transcriptomic profiling revealed extensive gene expression remodeling, characterized by activation of inflammatory pathways, enrichment of MAPK-related signaling, dysregulation of lipid metabolism, suppression of antioxidant defense systems, impairment of cytochrome P450-mediated detoxification, and upregulation of apoptosis-associated genes. qRT-PCR further validated the differential expression of representative genes involved in inflammatory signaling (Tlr4, Nfkb1, Nlrp3, and Casp1), MAPK signaling (Fos), xenobiotic metabolism (Cyp4f18), lipid metabolism (Apoa4 and Lpl), extracellular matrix remodeling (Mmp12), and oxidative stress responses (Sod1 and Gstp1). In addition, elevated serum TNF-α levels provided protein-level evidence supporting activation of the TLR4/NF-κB/TNF-α/NLRP3 inflammatory axis. Although fibrosis-associated transcriptional responses were detected, the absence of histological fibrosis suggests transcriptional priming of fibrogenic pathways rather than established fibrogenesis. Collectively, these findings provide a transcriptomic framework linking oxidative stress, impaired detoxification, inflammatory activation, and stress-responsive signaling to MCD-induced hepatic injury. The MCD model provides a valuable experimental platform for characterizing hepatic stress-response transcriptomes and for generating hypotheses that can subsequently be evaluated in environmentally relevant toxicological models. Nevertheless, caution should be exercised when extrapolating these findings to obesity-associated human MASLD, as the MCD model lacks key metabolic features of the human disease, including obesity and insulin resistance. Therefore, the present findings should be interpreted primarily as transcriptomic signatures of stress-induced hepatic injury rather than as a direct representation of the pathophysiological processes underlying human obesity-associated MASLD. Full article

Background: Chronic atrophic gastritis (CAG) is a prevalent precancerous gastric disorder characterized by persistent inflammation, glandular atrophy, and progressive mucosal damage, for which effective multi-target therapeutic strategies remain insufficient. The Lian-Huo-Hua-Zhuo formula (LHHZ), a traditional Chinese herbal prescription, has demonstrated potential anti-inflammatory and gastrointestinal protective effects in clinical practice; however, its active constituents and mechanisms of action against CAG remain undefined. This study aimed to clarify the absorbed bioactive components of LHHZ and explore its therapeutic mechanism for CAG. Methods: Ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap high-resolution mass spectrometry was employed to identify the absorbed components of LHHZ in the gastric and intestinal tissues of mice. The therapeutic effects of LHHZ on CAG were assessed through histopathological staining, ultrastructural observation, and evaluation of serum and gastric functional indicators. Network pharmacology, molecular docking, and molecular dynamics simulations were integrated to predict the core targets and key signaling pathways, while the regulatory effects on the interleukin-17 (IL-17) signaling pathway were further validated by immunofluorescence staining, real-time quantitative polymerase chain reaction, and Western blotting. Additionally, 16S ribosomal RNA gene sequencing and targeted metabolomics were applied to investigate the effects of LHHZ on gut microbiota composition and short-chain fatty acid (SCFA) metabolism. Results: The results revealed that 55 and 48 absorbed components were identified in the gastric and intestinal tissues, respectively, predominantly derived from Coptis chinensis Franch. and Pogostemon cablin (Blanco) Benth. LHHZ significantly alleviated gastric mucosal lesions, reduced intestinal metaplasia, restored the ultrastructure of gastric mucosal cells, improved gastric functional indicators including pepsinogen I (PG I), pepsinogen II (PG II), and gastrin-17 (GAS-17), and decreased the levels of pro-inflammatory cytokines. Network pharmacology combined with in vitro and in vivo experiments demonstrated that the core bioactive components of LHHZ can target and regulate interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), attenuate activation of the IL-17 signaling pathway, and suppress the secretion of downstream pro-inflammatory factors. Furthermore, LHHZ enhanced the alpha diversity of gut microbiota, reduced the Firmicutes to Bacteroidetes (F/B) ratio, restored the abundance of SCFA-producing bacteria such as Bacteroidales and Oscillospirales, and normalized the aberrant levels of eight SCFAs. Significant correlations were also observed between gut microbiota composition and SCFA metabolism. Conclusions: These findings suggest that LHHZ alleviates CAG by inhibiting inflammation via the IL-17 signaling pathway and by modulating the gut microbiota–SCFA axis, thereby providing preclinical evidence supporting its further investigation and development for multi-target therapeutic strategies against CAG. Full article

Saline–alkaline aquaculture is a promising strategy to alleviate freshwater shortages; however, such environments severely impair fish growth and physiological homeostasis. Nutritional regulation has been proposed to improve stress tolerance, yet the benefits of single additives are often limited under the multifactorial challenges imposed by saline–alkaline conditions. Therefore, a compound feed additive (CFA) consisting of glutamate, cholesterol, β-glucan, myo-inositol, zinc methionine, and curcumin was developed and evaluated in Nile tilapia (Oreochromis niloticus). To assess the robustness and practical applicability of this nutritional strategy, three independent feeding trials were conducted using different commercial basal diets as validation systems. Within each dietary system, fish were reared under freshwater (FW), saline–alkaline water (SAW), or saline–alkaline water supplemented with CFA (SAW+CFA). Saline–alkaline stress significantly reduced WG and SR, increased FCR, and elevated VSI and HSI, indicating impaired growth performance and metabolic burden. These changes were accompanied by increased serum glucose and ion concentrations (Na⁺, K⁺, Cl⁻), elevated ammonia levels, and reduced crude protein content. Dietary CFA improved growth and feed utilization under saline–alkaline conditions. It enhanced hepatic glycogen content and reduced serum glucose levels. Meanwhile, it downregulated glycolysis-related genes (hk, pfk1, pk) and upregulated genes involved in gluconeogenesis and the pentose phosphate pathway (g6pase, pc, g6pdh), indicating altered glucose metabolism and improved energy homeostasis. Saline–alkaline stress induced oxidative stress, apoptosis, and histological damage in the liver, whereas CFA alleviated these alterations by reducing MDA levels, enhancing antioxidant enzyme activities (CAT, GSH-Px, T-SOD) and suppressing apoptosis-related genes (caspases, p53, c-myc). In addition, CFA alleviated saline–alkaline stress-induced gill structural damage and reduced serum ion concentrations while modulating ion transport-related gene expression, suggesting improved osmoregulatory capacity. It also enhanced ammonia metabolism and transport, as reflected by reduced serum ammonia levels and altered expression of related genes. Furthermore, Saline–alkaline stress impaired intestinal structure and function, whereas CFA improved intestinal villus structure, increased digestive enzyme activities (amylase, trypsin, lipase), and suppressed pro-inflammatory genes (il-1β, il-8). Importantly, similar beneficial response patterns were observed across the three independently analyzed dietary systems. Overall, CFA improved saline–alkaline adaptability of Nile tilapia and was associated with improvements in energy metabolism, oxidative homeostasis, osmoregulation, ammonia detoxification, and intestinal function, providing a practical nutritional strategy for saline–alkaline aquaculture. Full article

This narrative review examines perimenopause as a critical transitional phase in women’s lives, often accompanied by elevated vulnerability to anxiety and depression. Dysfunction of the gut–brain axis is one of the key factors contributing to perimenopausal mood disorders and is currently receiving extensive attention. GBA dysfunction can trigger neurotransmitter metabolic imbalance, intestinal barrier impairment, and neuroinflammatory responses. Tryptophan (Trp) and γ-aminobutyric acid (GABA) serve as essential precursors and direct modulators of key neurotransmitters, and the dysregulation of their metabolic pathways has been implicated in perimenopausal anxiety and depression in animal models and limited clinical observations. Trp influences 5-hydroxytryptamine (5-HT) by affecting emotional states. GABA is the primary inhibitory neurotransmitter in the central nervous system and is closely associated with anxiety and depression. Fluctuations in estrogen levels during perimenopause significantly alter the composition and metabolic activity of the gut microbiota, which in turn affects Trp metabolism and GABA synthesis through increased intestinal permeability, activation of immune-inflammatory responses, and disruption of hypothalamic–pituitary–adrenal (HPA) axis function. Although traditional hormone replacement therapy and pharmacological treatments are effective, they are associated with some side effects. Preliminary evidence from in vitro and animal studies suggests that nutritional interventions targeting Trp and GABA metabolism within the gut–brain axis may offer a novel research direction, though their efficacy in perimenopausal women remains to be established. Potential nutritional strategies, including supplementation with Trp and its precursors, inhibition of the kynurenine pathway (KP), and supplementation with probiotics and prebiotics, can modulate Trp and GABA metabolism. This review focuses on Trp and GABA metabolic regulation via the gut–brain axis to explore pathogenesis of perimenopausal anxiety and depression and summarize potential nutritional intervention targets, thereby providing a scientific basis for emotional management in perimenopausal women. Full article

In this study, an exploratory transcriptomic investigation was conducted to evaluate the feasibility of using feather transcriptomics to detect sex differences and gene responses to physiological changes in chickens. Feathers represent a promising non-invasive biological source of RNA, as the feather pulp of growing feathers contains living cells capable of active transcription. Growing feathers were collected from 150-day-old male and female chickens (Bionda Piemontese, a slow-growing breed) raised under a free-range system and fed two finisher diets differing in lipid content: low-lipid (LL, ether extract 3.6%) and high-lipid (HL, ether extract 9.3%) diets. RNA was extracted from feather pulp, and 12 pools were subjected to whole RNA-Seq analysis. The study was designed as 2 × 2 factorial experiments investigating the effects of diet and sex on gene expression. A total of 17,360 transcripts were detected and used for downstream analyses. Differential gene expression and functional enrichment analyses were performed. The main effects of diet and sex were estimated with an additive design using the DEseq2 package, while for the sex-specific diet analyses, subgroup comparisons were conducted on the RaNA-Seq platform. The analysis of the main effect of diet reveals that three genes associated with ether lipid metabolism (PLA2G10, PLA2G4F, and ENPP6) were upregulated in chickens fed the HL diet. In roosters, HL feeding significantly altered the expression of APOA1 and SLC27A4, suggesting an effect on lipid transport and metabolic regulation within the PPAR signaling pathway. In contrast, hens showed differential expression primarily in pathways related to apelin signaling, extracellular matrix remodeling, and cardiovascular function, rather than classical lipid metabolism pathways; additionally, gene set enrichment analysis indicated a limited enrichment of linoleic acid metabolism, suggesting secondary involvement of lipid metabolic processes. These findings are consistent with those in the literature reporting sex-related differences between males and females. The results further suggest that transcriptomic responses to dietary lipid supplementation can be investigated through the expression of selected candidate genes in feather pulp. Among the genes identified, PLA2G10, PLA2G4F, ENPP6, APOA1, and SLC27A4 emerged as potential molecular markers associated with dietary treatment, and the importance of sex-dependent transcriptional responses was highlighted. In conclusion, this study demonstrates the potential of feather pulp as a viable source of RNA for transcriptomic analyses in live chickens, providing a minimally invasive alternative to conventional tissue sampling. These preliminary results also support the hypothesis that feathers represent a practical and ethically favorable tissue for future nutrigenomic and genetic improvement studies, ultimately supporting more sustainable poultry production. Full article

Background/Objectives: Fluoride (F) is widely used in public water fluoridation to prevent dental caries, and an optimal level of F has been linked to improved glucose metabolism in animal models. Per- and polyfluoroalkyl substances (PFAS), including fluorotelomer alcohols (FTOHs), are persistent environmental contaminants with potential effects on pancreatic function. Methods: This in vitro and in vivo study investigated the effects of 8:2 FTOH and F (NaF) on pancreatic β-cells, focusing on Ca²⁺ homeostasis, insulin secretion, and the GPR40 pathway. Results: Results showed that 8:2 FTOH alters Ca²⁺ influx in a dose-dependent, biphasic manner, enhancing it at low doses and inhibiting it at high doses, while F increased Ca²⁺ signaling at high doses. High-dose 8:2 FTOH also downregulated GPR40 protein in βTC-6 pancreatic cells and modulated pathways related to lipid metabolism, endoplasmic reticulum stress, and insulin regulation in the mouse pancreas by proteomic analyses (in vivo). Conclusions: These findings exploratory indicate that both PFAS and F can impact β-cell function through complex mechanisms, potentially affecting Ca²⁺ homeostasis. This work highlights the hormesis effect of F and provides novel insights into the pancreatic effects of environmentally relevant PFAS exposures, emphasizing the need for further mechanistic studies at low, human-relevant doses. Full article

Excessive tail fat deposition in sheep limits feed conversion efficiency and carcass quality, making the genetic improvement of this trait a priority. This study aimed to elucidate the molecular mechanisms regulating ovine fat metabolism. We analyzed the tissue specific expression of two candidate microRNAs, miR-320d and miR-151b, alongside their target genes SCD and ACACA, across tissues from fat-tailed and thin-tailed sheep using quantitative real-time PCR. The regulatory function of the tail fat specific miR-320d was further validated in vitro using isolated ovine tail preadipocytes. Results indicated that miR-320d and miR-151b are specifically highly expressed in tail and subcutaneous adipose tissues, respectively, and correlate negatively with their target genes. Dual-luciferase reporter assays confirmed that miR-320d directly targets the 3′UTR of SCD and suppresses its transcription. Overexpression of miR-320d significantly inhibited the proliferation of tail preadipocytes and downregulated downstream genes in the fatty acid metabolism pathway, including ACACA, ELOVL6, ELOVL5, and FASN. In conclusion, miR-320d exerts a negative regulatory effect on sheep tail fat deposition by suppressing preadipocyte proliferation and fatty acid synthesis, while miR-151b emerges as a potential candidate for subcutaneous fat regulation. Full article

Solid tumors frequently experience hypoxia during tumor progression, resulting in profound metabolic alterations. This phenomenon is particularly pronounced in clear-cell renal cell carcinoma (ccRCC) because of loss of the von Hippel–Lindau (VHL) tumor suppressor gene and constitutive activation of hypoxia-inducible factor (HIF) signaling. ccRCC is the most common subtype of kidney cancer, and durable therapeutic responses remain limited despite advances in immune checkpoint inhibition. Owing to its strong pseudohypoxic phenotype and extensive metabolic rewiring, ccRCC is widely regarded as a metabolic disease. These alterations generate a unique immune landscape characterized by abundant immune-cell infiltration together with profound T-cell dysfunction and exhaustion. This paradoxical “immune-hot yet immunosuppressed” phenotype is largely driven by hypoxia-associated immunometabolic reprogramming within tumor cells and the tumor microenvironment (TME). Several metabolic pathways are critically involved in this process, including lactate acidosis, arginine (Arg) depletion, tryptophan (Trp) depletion, kynurenine (Kyn)-mediated T-cell exhaustion, and adenosine-driven immune suppression. This review summarizes the current understanding of hypoxia-driven immunometabolic interactions in ccRCC and discusses how targeting these pathways may improve future therapeutic strategies against this aggressive malignancy. Full article

Amphibian malformation syndromes significantly impact both conservation efforts and aquaculture, yet their underlying systemic pathophysiological mechanisms remain poorly characterized. This study comprehensively examines the multi-level pathological processes associated with the “short-leg” malformation syndrome in the black-spotted frog (Pelophylax nigromaculatus) using an integrated methodology, encompassing morphological, histopathological, gut microbiome, and hepatic transcriptomic analyses. Affected frogs demonstrated shortened limbs, impaired motor function, and a distinctive metabolic phenotype, including increased body weight despite a shorter body length, accumulation of visceral fat, and shortened intestines. Gut microbiota analysis identified significant compositional shifts, characterized by a decreased Firmicutes-to-Bacteroidota ratio, expansion of pro-inflammatory Proteobacteria, and reduction in beneficial Actinobacteriota, suggesting microbial niche restructuring that likely promotes metabolic and inflammatory disorders. Hepatic transcriptome profiling revealed 2617 differentially expressed genes, demonstrating a clear molecular dichotomy with concurrent up-regulation of immune-related pathways (e.g., neutrophil extracellular trap formation, complement cascades, and inflammatory signaling) and broad suppression of metabolic pathways (e.g., lipid oxidation, nutrient absorption, and PPAR and renin–angiotensin systems). This integrated analysis illustrates that the malformation syndrome represents a systemic pathophysiological state involving dysfunction of the gut–liver axis, characterized by the coexistence of gut microbiota alterations, hepatic metabolic suppression, and immune activation. These findings provide a framework for understanding amphibian malformations and suggest potential strategies to improve health outcomes in aquaculture. Full article