Search Results (358)

Background/Objectives: This study is the first to investigate the potential mechanism of star anise extract (SAE) in protecting against cold stress-aggravated acute lung injury (CSALI) in rats. Methods: A rat CSALI model was induced via combined lipopolysaccharide challenge and cold stress exposure. The preventive effects of SAE were evaluated using cytotoxicity assays, quantification of biochemical indices and inflammatory factors, and histopathological examination. Ultra-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC–HRMS)-based serum metabolomics was employed to systematically profile CSALI-associated metabolic alterations and decipher the potential mechanism underlying the preventive effects of SAE. Results: SAE alleviated pathological progression of CSALI, suppressed inflammatory cell migration, markedly reduced pulmonary inflammatory cell infiltration, and ameliorated lung tissue injury in CSALI rats. SAE also improved abnormal liver function indicators and lowered the levels of pro-inflammatory factors in both serum and bronchoalveolar lavage fluid (BALF). Serum metabolomics analysis identified and annotated 24 disease-altered differential metabolites and evaluated the protective effects of SAE on them. These metabolites were significantly enriched in two key metabolic pathways related to the pathogenesis of CSALI, including arachidonic acid metabolism and glycerophospholipid metabolism. Furthermore, based on metabolite changes, phospholipase A2 was hypothesized as a potential key regulatory factor that may cooperate with arachidonic metabolism to suppress the inflammatory cascade. Conclusions: These findings demonstrated that SAE exerted prominent anti-inflammatory activity and effectively protected against lung injury in CSALI rats. Full article

Reactive aldehydes are potent electrophiles that damage DNA and can ultimately promote cancer. While many aldehydes are ubiquitous in the environment, mammalian metabolism also generates high levels of endogenous aldehydes sufficient to threaten genome integrity. To protect against these aldehyde genotoxins, mammalian cells rely on diverse families of aldehyde detoxification enzymes as well as DNA repair pathways. Here, we review how aldehyde detoxification safeguards genome integrity, focusing on the aldehyde dehydrogenase (ALDH) family, alcohol dehydrogenase 5 (ADH5), and the glyoxalases. We discuss how these enzymes operate in a 2-tier model (in which tier 1 detoxification enzymes cooperate with tier 2 DNA repair pathways in a tissue-specific manner), the consequences for cancer initiation and progression when aldehyde detoxification is compromised, and the opportunities for targeting aldehydes in cancer therapy. Full article

The European perch (Perca fluviatilis) is highly susceptible to heat stress, limiting its sustainable aquaculture. While single-organ thermal responses are partially understood, the systemic, multi-organ cooperative survival mechanisms under acute heat stress remain poorly characterized. To elucidate the underlying tolerance mechanisms and provide genetic markers for breeding, this study investigated the multi-organ responses of European perch (n = 90; body length: 13.15 ± 1.75 cm; body weight: 30.54 ± 7.17 g) transferred from 24 °C to an acute heat stress challenge (31 °C) at an increasing rate of 2 °C/h, and the histopathological changes (liver and gill), hepatic biochemical biomarkers (CAT, SOD, GSH-Px, GST, LDH, and MDA), and transcriptomic changes (liver and kidney) were evaluated over a 24 h period. Heat stress induced progressive structural damage, including gill lamellar edema and hepatocyte necrosis, accompanied by significant hepatic oxidative stress and lipid peroxidation. RNA-seq transcriptome profiling uncovered distinct sets of genes with significant expression changes, comprising 1343 DEGs in liver tissue and 722 DEGs in kidney samples. Both organs shared a systemic endoplasmic reticulum stress response but exhibited highly divergent survival strategies. The liver underwent severe metabolic reprogramming towards anaerobic glycolysis and gluconeogenesis, coupled with vesicle-mediated membrane repair attempts and apoptosis. Conversely, the kidney adopted a strict “energy triage” strategy, suppressing highly energy-consuming immune and osmoregulatory functions while actively silencing pro-apoptotic signals. These findings highlight organ-specific adaptations and identify potential metabolic markers for the future breeding of new heat-tolerant varieties. Full article

Background/Objectives: Metastatic prostate cancer is increasing in the Gulf Cooperation Council countries. This study presents a multimodal treatment protocol incorporating radiotherapy to primary and metastatic sites, guided by PSMA PET/CT, combined with systemic therapy for non-metastatic pelvic node-positive and de novo low-volume metastatic prostate cancer. Methods: We conducted a retrospective cohort study of patients treated with radical radiotherapy doses (68 Gy/25 Fr or 78 Gy/39 Fr) to the prostate gland and gross pelvic disease, and SBRT (35–40 Gy/5 Fr) to distant bone metastases. All patients received LHRH agonists ± abiraterone/prednisone or enzalutamide. Results: Twenty-four consecutive patients were analyzed. The median age was 70.1 years (IQR, 65.7–77.7), the median baseline PSA was 27.9 ng/mL (IQR = 19.7–53.8), and median follow up was 24 months (IQR = 20.4–31.2). Clinical staging was cT3b in (46%), cT2 in (25%), cT4 in (17%), cT3a in (13%) of patients. Pelvic nodal involvement (cN1) was present in 91.7% of patients, while 54.1% had metastatic disease. Treatment was well tolerated. Acute toxicity was predominantly grade 1 genitourinary (GU) toxicity, occurring in 87.5% of patients, with grade 2 GU toxicity observed in 8.2% and no acute gastrointestinal (GI) toxicity. Late toxicity remained minimal, with grade 1 and grade 2 GU toxicity reported in 45.8% and 4.2% of patients, respectively, and no late GI toxicity. Mild systemic treatment-related toxicities were reported in 25% of patients, including sexual dysfunction, hypokalemia, muscle weakness, osteoporosis and depression/anxiety. At the six-month follow-up PSMA PET/CT assessment, 85.7% achieved a complete metabolic response, and 14.2% achieved a partial response. Biochemically, 75% of patients achieved undetectable PSA levels (<0.01 ng/mL), with all patients achieving a PSA nadir < 0.2 ng/mL. Conclusions: This first, hypothesis-generating real-world experience from the GCC, suggests that an integrated approach combining systemic therapy with metastasis-directed therapy is feasible. Prospective randomized studies are required to validate these results. Full article

Background/Objectives: Germ cell tumors (GCTs) are thought to arise from primordial germ cells that fail to appropriately differentiate and instead retain pluripotency programs. PRDM14 is a key regulator of pluripotency and primordial germ cell specification and is aberrantly expressed in multiple GCT subtypes. However, the role of PRDM14 in GCT malignancy remains unclear. In this study, we investigated whether PRDM14 functions in GCTs through CBFA2T2, a transcriptional corepressor previously identified as a PRDM14-interacting partner in pluripotent stem cells and developmental models. Methods: To determine the presence and level of PRDM14 and CBFA2T2 in GCT, a panel of GCT lines were assessed for RNA and protein expression and interaction. Then, to better understand the biological effects of PRDM14 and CBFA2T2 within GCTs, PRDM14 and CBFA2T2 knockdowns were employed. Results: We show that PRDM14 and CBFA2T2 are expressed across GCT cell lines, colocalize predominantly in the nucleus, and cooperate as a complex in GCT cell lines. Knockdown of either PRDM14 or CBFA2T2 resulted in reduced expression of key pluripotency genes and a significant impairment of cell proliferation, indicating a shared role in maintaining an undifferentiated, proliferative state. Transcriptomic analysis following PRDM14 or CBFA2T2 depletion revealed extensive overlap in differentially expressed genes and convergent alterations in developmental and metabolic signaling pathways. Conclusions: Together, these findings suggest that PRDM14 and CBFA2T2 form a functional complex that sustains pluripotency and proliferation in GCT cells. This supports a model in which persistence of germline regulatory mechanisms contributes to GCT malignancy, highlighting this interaction as a novel component of GCT biology. Full article

Ring finger protein 126 (RNF126) is a RING-type E3 ubiquitin ligase that has recently emerged as a multifaceted regulator of cellular homeostasis, stress adaptation, and disease progression. Through its structurally distinct zinc-finger and catalytic RING domains, RNF126 orchestrates substrate recognition and ubiquitin transfer, generating diverse ubiquitin linkages with both proteolytic and nonproteolytic functions. Initially characterized as a component of the protein quality control (PQC) machinery, RNF126 cooperates with chaperones such as BAG6 and UBQLN1 to eliminate mislocalized and misfolded proteins, thereby maintaining proteostasis. Beyond PQC, RNF126 plays pivotal roles in DNA damage response pathways by regulating homologous recombination, non-homologous end joining, checkpoint signaling, and genome stability through substrates, including MRE11, Ku80, RNF168, and 14-3-3σ. Genetic studies have further demonstrated its importance in embryogenesis and male fertility, and accumulating evidence has identified RNF126 as a critical driver of malignancy in multiple cancers. RNF126 promotes tumor progression by degrading or modulating key regulators, such as p21, PTEN, p53, PDKs, and LKB1, thereby enhancing proliferation, metabolic reprogramming, anoikis resistance, metastasis, and chemo/radioresistance. Intriguingly, RNF126 exhibits context-dependent functions, acting as an oncogene or tumor suppressor depending on the tissue type and substrate selection. In addition to cancer, RNF126 has been implicated in neurodegeneration, cardiac pathology, antiviral immunity and adaptive immune regulation. This review summarizes the current knowledge of RNF126 structure, ubiquitin signaling mechanisms, physiological functions, and pathological roles, while discussing emerging therapeutic strategies and future challenges for targeting RNF126 in precision medicine. Full article

Antibiotic-resistant bacteria are widely distributed and threaten public health. Photocatalytic antimicrobial technology can effectively inactivate multidrug-resistant bacteria without readily inducing resistance. We previously showed that oxygen-rich vacancy Bi₂MoO₆ (OBM) exhibits excellent activity against methicillin-resistant Staphylococcus aureus (MRSA), but the underlying molecular mechanisms remain poorly understood. Here, we employed integrated transcriptomics and metabolomics, with qRT-PCR validation, to systematically elucidate the antibacterial mechanism of OBM against MRSA. OBM treatment induced profound transcriptional and metabolic alterations: 231 differentially expressed genes and 206 differentially abundant metabolites were identified. Functional enrichment analysis revealed cooperative involvement in multiple critical pathways, including inhibition of amino acid biosynthesis and protein translation, disruption of cell wall and membrane integrity, induction of oxidative stress, collapse of energy metabolism (suppression of oxidative phosphorylation and impaired ATP synthesis), and imbalance in nucleotide metabolism (down-regulation of DNA helicase and mismatch repair genes, dysregulation of purine/pyrimidine metabolism). These findings demonstrate that OBM photocatalytically inactivates MRSA through a multi-target systemic attack at both the transcriptional and metabolic levels, providing a novel theoretical foundation for the development of photocatalytic materials aimed at controlling MRSA and other drug-resistant bacteria. Full article

The most persistent biomedical challenges of the 21st century are neurodegenerative disorders (NDs), where molecular alterations lead to devastating clinical consequences and progressive neuronal loss. The prevalence of neurodegeneration is continuously rising and becoming the main contributor to chronic disability and mortality. Despite their clinical differences, many conditions share pathogenic processes, including oxidative stress, protein misfolding and aggregation, mitochondrial dysfunction, and neuroinflammation. Instead of functioning independently, these processes cooperate to form a self-reinforcing network that gradually weakens synapses and ultimately leads to neuronal death. This study redefines neurodegeneration as a disorder of system-level failure by emphasizing poor cellular stress integration. In addition to demonstrating how gut microbiome gene networks impact inflammation and amyloid production, new research highlights the relationships between mitochondrial–lysosomal interactions, endoplasmic reticulum stress responses, and transcriptionally driven synaptic vulnerability. A key molecular topic is the interaction and pathogenic convergence of the JAK/STAT, HIF-1α, and Notch signaling pathways. Under ongoing metabolic stress, prolonged stimulation of this triad increases inflammation, hinders the regenerative processes, and maintains pseudo-hypoxic conditions, explaining why single-target treatments have mostly been unsuccessful. This review also explores progress in fluid, digital, and imaging biomarkers that facilitate early diagnosis and patient stratification, and assesses new disease-modifying approaches such as antisense oligonucleotides, immunomodulators, gene therapies, and small-molecular agents. Artificial intelligence is emphasized as an essential tool for integrating multimodal data, drug discovery and predictive modeling. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains among the most therapeutically intractable malignancies, with a 5-year survival rate of approximately 10% and near-universal resistance to immune checkpoint inhibitor (ICI) therapy. This refractoriness arises from the convergence of pronounced intratumoral heterogeneity (ITH) and a profoundly immunosuppressive tumor microenvironment (TME), which together configure PDAC as a prototypical immune-excluded tumor. Beyond low tumor mutational burden, PDAC exhibits layered genetic, epigenetic, transcriptional, and metabolic heterogeneity that enables rapid adaptation and immune evasion under selective pressure, while dense desmoplastic stroma, cancer-associated fibroblasts (CAFs), and immunosuppressive immune populations collectively impose formidable physical and immunologic barriers to antitumor immunity. In this review, we synthesize multi-omics, spatial transcriptomic, and immunologic evidence to elucidate how ITH and the TME dynamically interact to reinforce immune resistance. We examine reciprocal crosstalk mechanisms—including immune-driven clonal selection, interclonal cooperation, metabolic niche specialization, and metabolic–epigenetic coupling—and discuss emerging platforms such as single-cell spatial omics, patient-derived organoid immune co-culture systems, and longitudinal circulating tumor DNA monitoring that enable high-resolution mapping of ITH–TME dynamics. Finally, we evaluate ITH–TME-guided combination therapeutic strategies targeting oncogenic drivers, stromal architecture, myeloid suppression, and metabolic checkpoints, and propose a prioritized framework for near-term and speculative clinical translation in PDAC. Full article

Background: Polyendocrine metabolic ovarian syndrome (PMOS/PCOS) is the most common hormonal disorder in women of reproductive age and is linked to infertility as well as long-term metabolic and psychological problems. In the Gulf Cooperation Council (GCC) region, rising obesity, dietary changes, and sedentary lifestyles may be increasing its burden. However, prevalence estimates remain highly inconsistent due to differences in diagnostic criteria and measurement methods rather than true variation in disease rates. Objective: This study aimed to describe the situation by systematically pooling available evidence on the prevalence of PMOS among women in GCC countries and by summarizing the range of clinical features reported across included studies. Methods: We conducted a systematic review and meta-analysis following PRISMA 2020 guidelines. We searched five major bibliographic databases (PubMed, Scopus, Web of Science, Cochrane Library, and Embase) and the Google Scholar search engine for observational studies published up to 1 June 2026. Studies were eligible if they reported PMOS prevalence and related clinical features among women of reproductive age residing in GCC countries. After removing duplicates and screening 570 initially identified records, 25 studies met our inclusion criteria; 24 were included in the quantitative meta-analysis after excluding one high-risk study. Risk of bias was appraised using the Joanna Briggs Institute Checklist for Prevalence Studies. A random-effects meta-analysis using the DerSimonian-Laird method, combined with the Freeman-Tukey double arcsine transformation, was used to estimate the pooled prevalence. Heterogeneity was quantified using the I² statistic and Cochran’s Q test. Subgroup analyses explored differences by country, diagnostic method, study setting, and publication period. Meta-regression was used to identify study-level factors that explained between-study variability. Results: Across 24 studies involving 77,890 women, the pooled prevalence of PMOS was 17.59% (95% CI: 12.98–23.40%). Country-level estimates ranged from 6.56% in Oman to 23.0% in Saudi Arabia. Heterogeneity across all analyses was extremely high (I² = 99.6%), and meta-regression identified the diagnostic tool as the single most important source of variation, explaining 42.7% of between-study variance. Studies using structured clinical criteria (Rotterdam or NIH) yielded prevalence estimates around 13–14%, while those relying on self-report or physician diagnosis without standardized criteria reported considerably higher figures (20–37%). Common clinical features included menstrual irregularity (up to 100% of PMOS cases in clinical cohorts), hirsutism (5–100%), acne and oily skin (17–74%), and obesity (17–73%). Awareness of PMOS among women in the region was highly variable, ranging from under 3% to nearly 100%. Conclusions: PMOS is a significant public health concern across the GCC region. The markedly higher pooled prevalence combined with high rates of obesity and metabolic risk in this population calls for urgent, coordinated action. Standardizing diagnostic practices, investing in population-level screening, and developing culturally tailored awareness programs are essential steps toward reducing the clinical and social burden of PMOS. Full article

Hepatocellular carcinoma (HCC) is sustained by coordinated interactions among malignant hepatocytes, immune cells, and stromal populations that collectively drive tumor growth, immune evasion, and vascular remodeling. Using integrative single-cell transcriptomics on 93,032 cells from tumor and healthy human liver, we characterized cell-type-specific transcriptional programs underlying immunometabolic reprogramming and reconstructed the intercellular communication circuits that maintain the tumor microenvironment. Malignant hepatocytes displayed upregulation of genes encoding both glycolytic and oxidative phosphorylation (OXPHOS) metabolic enzymes, consistent with metabolic plasticity, while concurrently suppressing genes involved in antigen presentation—a transcriptional pattern indicative of coordinated metabolic and immune-evasive reprogramming. Tumor-associated macrophages acquired TREM2-enriched, lipid-handling phenotypes consistent with immunosuppressive polarization, and tumor endothelial cells upregulated angiocrine and extracellular matrix programs while silencing innate immune outputs. Ligand–receptor inference revealed a qualitative rewiring of intercellular communication: the antigen-presentation-centered network of the healthy liver was replaced by a tumor-driven architecture dominated by pro-angiogenic, ECM–integrin, inflammatory chemokine, and lipid-associated signaling circuits, with malignant hepatocytes, TAMs, and TECs collectively assuming the dominant signaling burden. These findings establish that HCC progression is an emergent property of a stabilized multicellular network, rather than the autonomous behavior of malignant cells, and define cooperative immunometabolic modules that constitute tractable targets for combinatorial therapeutic intervention. Full article

Tumor metastasis constitutes a frequent contributor to high mortality rates, with EMT intimately implicated in this disseminative process. Accumulating evidence in recent years indicates that neoplastic cells undergoing EMT frequently exhibit concurrent metabolic reprogramming. Multiple modalities—including glycolysis, mitochondrial oxidative phosphorylation, lipid metabolism, as well as amino acid metabolism—cooperatively supply energy, facilitate membrane remodeling, and sustain redox homeostasis. Specifically, glycolytic flux, oxidative phosphorylation, lipid turnover, and amino acid catabolism/anabolism function in a concerted manner to meet the bioenergetic demands, support biogenesis of cellular membranes, and preserve the intracellular redox equilibrium during phenotypic conversion. Notably, intermediate metabolites can in turn modulate the trajectory of EMT through signal transduction cascades or epigenetic modifications. This review systematically delineates the bidirectional regulatory circuitry interconnecting EMT and metabolic reprogramming; furthermore, it examines the implications of this crosstalk for neoplastic disease progression. Finally, therapeutic strategies targeting the nexus of metabolic reprogramming and EMT are summarized. Full article

This investigation evaluated temporal variations in metabolic fingerprints, sensory properties, and functional traits of Aronia melanocarpa syrup throughout the fermentation stage followed by an additional 90-day preservation interval. Findings indicated that microbial transformation notably increased the cumulative polyphenolic levels, overall flavonoid concentrations, and DPPH free radical quenching efficiencies of the preparation, which stayed consistent over this duration. Non-targeted metabolomics screening recognized a combined 1918 chemical signatures, whereby phenylpropanoids, fatty acids, and terpenes represented critical components. A total of 1591 distinct metabolites were identified, demonstrating substantial accumulation inside the flavonoid synthesis and pyruvate catabolic pathways. Furthermore, 355 volatile substances were characterized, with aldehydes and esters acting as vital elements providing honey-scented and fragrant tastes. The cooperative impacts of brewing and aging improved the nutritive and gustatory merits of Aronia melanocarpa syrup, providing a theoretical framework for developing superior fermented commodities. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) is now recognized as a leading form of chronic liver disease globally and is strongly associated with metabolic abnormalities. Traditionally, the pathogenesis of MAFLD has mainly been attributed to genetic susceptibility and unhealthy lifestyles (such as high-calorie diets and sedentary behavior). However, in recent years, environmental factors, especially air pollution, have been confirmed as independent risk factors and important promoting factors for MAFLD development and further disease progression. This review summarizes current epidemiological findings on the link between air pollution exposure and MAFLD, while exploring its potential biological mechanisms involving systemic inflammation, oxidative stress, immune alteration, genetic risk, and epigenetic regulation underlying the relationship between air pollution and hepatic steatosis. It also reviews the additive interaction between air pollution and lifestyle or socioeconomic factors in MAFLD. Finally, we also discuss multilevel strategies spanning individual-, community-, national-, and global-level cooperation to address the increasing public health burden caused by air pollution. Therefore, incorporating the assessment and control of air pollution into the comprehensive strategies for MAFLD prevention and treatment has important scientific value and public health significance. Full article

The human gut microbiome comprises a diverse community of bacteria whose interactions with the host range from beneficial mutualism to opportunistic pathogenicity. These interactions are shaped by genomic plasticity and ecological pressures that influence whether microbes support host health, remain conditionally harmless, or contribute to disease. Understanding the mechanisms underlying these shifts is essential for clarifying the balance between cooperation and pathogenicity within the gut ecosystem. This review explores the genomic and evolutionary mechanisms that shape microbial adaptation across the mutualism–pathogenicity spectrum in the human gut. Key processes, including horizontal gene transfer (HGT), host-mediated selection, and niche specialization, enable microbes to acquire, regulate, or retain traits that influence colonization, metabolic function, and virulence. These adaptive mechanisms allow gut bacteria to respond dynamically to ecological pressures such as inflammation, antibiotic exposure, and dietary change, resulting in context-dependent microbial behaviors. The review also considers how concepts from insect endosymbiosis may provide insight into gut microbial adaptation. While both systems exhibit host specialization, major differences in transmission mode, ecological flexibility, and genome evolution limit direct comparisons. Rather than following a fixed progression toward parasitism, gut microbes exhibit flexible adaptive strategies shaped by host and environmental conditions. By integrating ecological and evolutionary perspectives, this review presents a balanced framework for understanding how genomic adaptation influences microbial behavior in the gut. This perspective improves our understanding of dysbiosis and microbial pathogenesis and may support the development of microbiome-informed therapeutic strategies for maintaining host health. Full article