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Non-alcoholic fatty liver disease (NAFLD) is a major metabolic disorder characterized by hepatic lipid accumulation, oxidative stress, and disturbance of lysosomal degradation. Central to these processes is glutathione (GSH), a key antioxidant regulating redox balance and cellular homeostasis. This study aimed to evaluate the therapeutic potential of two dietary antioxidants-astaxanthin and Show less

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Among the genetic risk factors linked to AD, the Apolipoprotein E4 (ApoE4) remains the strongest. It is well known that carrying the ApoE4 isoform is associated with advanced AD pathology, blood-brain barrier (BBB) disruption, and changes in lipid metabolism. In this review, we provide an overview of the role of centrally and peripherally produced ApoE in AD. After this introduction, we focus on new findings regarding ApoE4's effects on AD pathology and BBB function. We then discuss ApoE's role in lipid metabolism in AD, highlighting examples of lipid changes caused by carrying the ApoE4 isoform. Next, the review explores the implications of ApoE4 isoforms for current treatments-whether they involve anti-amyloid therapy or other pharmacological agents used for AD-emphasizing the importance of personalized medicine approaches for patients with this high-risk allele. This review aims to provide an updated overview of ApoE4's effects on AD pathology and treatment. By integrating recent discoveries, it underscores the critical need to consider ApoE4 status in both research and clinical settings to enhance therapeutic strategies and outcomes for individuals with AD. Show less

Training adaptation involves muscular-metabolic remodeling and personality-linked traits such as motivation, self-regulation, and resilience. This narrative review examines how training load oscillation (TLO)-the deliberate variation in exercise intensity, volume, and substrate availability-may function as a systemic epigenetic stimulus capable of shaping both physiological and psychological adaptation. Fluctuating energetic states reconfigure key energy-sensing pathways (AMPK, mTOR, CaMKII, and SIRT1), thereby potentially influencing DNA methylation, histone acetylation, and microRNA programs linked to PGC-1α and BDNF. This review synthesizes converging evidence suggesting links between these molecular responses and behavioral consistency, cognitive control, and stress tolerance. Building on this literature, a systems model of molecular-behavioral coupling is proposed, in which TLO is hypothesized to entrain phase-shifted AMPK/SIRT1 and mTOR windows, alongside CaMKII intensity pulses and a delayed BDNF crest. The model generates testable predictions-such as amplitude-dependent PGC-1α demethylation, BDNF promoter acetylation, and NR3C1 recalibration under recovery-weighted cycles-and highlights practical implications for timing nutritional, cognitive, and recovery inputs to molecular windows. Understanding TLO as an entrainment signal may help integrate physiology and psychology within a coherent, durable performance strategy. This framework is conceptual in scope and intended to generate testable hypotheses rather than assert definitive mechanisms, providing a structured basis for future empirical investigations integrating molecular, physiological, and behavioral outcomes. Show less

Brain-derived growth factor, BDNF, has critical roles in a wide variety of neuronal aspects, including cell survival, differentiation, and synaptic function after their maturation. TrkB, a high-affinity receptor for BDNF, is a major contributor in these neuronal aspects, and its functions are exerted via stimulating intracellular signaling pathways including the mitogen-activated protein kinase (MAPK) pathways. As a family of MAPKs, the functions of ERK1/2, p38MAPK, and JNKs have been extensively studied using in vivo and in vitro neuronal systems. ERK 1/2, a major serine-threonine kinase and belonging to the MAPK family, also works as a downstream molecule after activation of the BDNF/TrkB system. Interestingly, growing evidence has demonstrated that ERK1/2 signaling exerts a positive or negative influence on neurons in both healthy and pathological conditions in the central nervous system (CNS). Indeed, activation of ERK 1/2 stimulated by the BDNF/TrkB system is involved in the regulation of synaptic plasticity. On the other hand, overactivation of ERK1/2 signaling under pathological conditions is closely related to neurodegeneration. Furthermore, cell stress activates p38MAPKs and JNK signaling, contributing to the progression of neurodegeneration. In this review, we show how MAPK pathway signaling affects neuronal fate, including cell survival or cell death, in the CNS. Moreover, we discuss the involvement of overactivation of MAPK signaling in the neurodegeneration observed in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Show less

Pancreatic cancer (PC) is a common gastrointestinal malignancy whose initiation and progression may be closely linked to the gut microbiota. Previous research indicates that Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang (SB-SD) exhibit diverse biological activities, such as anti-inflammatory, antioxidant, and antitumor effects, though their precise regulatory mechanisms are not fully elucidated. Here, we treated PC cells with SB-SD to assess its impact on cell viability, apoptosis, migration, and cell cycle progression, while Western blotting analyzed the expression of HSP90AA1, MAPK3, p53, CDK1, and p21. We also established a pancreatic cancer xenograft model in nude mice to evaluate the in vivo inhibitory effect of SB-SD on tumor growth. Furthermore, we employed metagenomic sequencing, untargeted metabolomics, and quantitative proteomics to comprehensively profile changes in the gut microbiota, serum metabolites, and differentially expressed proteins, with Western blotting subsequently validating BCKDK, GATM and p53 expression. The results show that SB-SD significantly inhibited PC cell proliferation, promoted apoptosis, and induced S/G2 phase cell cycle arrest, potentially via modulation of the HSP90AA1/MAPK3 signaling pathway. Measurements of tumor volume and weight, complemented by histopathological analysis, confirmed that SB-SD effectively suppressed the growth of PANC-1 xenograft tumors. Integrated multi-omics analyses suggest that the antitumor effects of SB-SD may involve the modulation of key gut microbes like Bacteroides caccae and Lactobacillus, the promotion of choline metabolism, and the regulation of BCKDK and GATM. Together, these findings not only corroborate the direct antitumor activity of SB-SD against pancreatic cancer but also offer novel mechanistic insights by constructing a microbiota-metabolite-protein interaction network. Show less

Cardiovascular disease (CVD) is influenced by disturbances in lipoprotein composition and metabolism, including triglyceride-rich lipoproteins (TRLs) and elevated lipoprotein (a) (Lp(a)). While interactions between Lp(a) and very-low-density lipoproteins (VLDL) have been studied in hypertriglyceridemic and CVD populations, data in normotriglyceridemic individuals without CV events are limited. Seventy normotriglyceridemic adults with triglycerides < 150 mg/dL and no CV events were enrolled and divided into two groups based on Lp(a) concentration: <30 mg/dL and ≥30 mg/dL. VLDL was isolated by ultracentrifugation, and concentrations of Lp(a), lipids (triglycerides, cholesterol), and apolipoproteins (apo B, apo C-II, apo C-III, apo E) were measured in serum and VLDL. Serum lipid and apolipoprotein concentrations did not differ between the groups. Individuals with Lp(a) ≥ 30 mg/dL had significantly higher VLDL concentrations of triglycerides (+71%), cholesterol (+54%), apo B (+28%), apo C-II (+36%), and apo C-III (+33%). Ratios of lipids and apolipoproteins to apo B indicated unchanged VLDL particle composition, suggesting that differences reflected increased particle number rather than altered composition. In normotriglyceridemic subjects with Lp(a) ≥ 30 mg/dL, VLDL particles are more abundant but compositionally unchanged. Redistribution of lipids and apolipoproteins toward VLDL may contribute to VLDL residual cardiovascular risk, underscoring the need for further studies on VLDL-Lp(a) interactions. Show less

Olive pomace (OP), a by-product of olive oil production, is a sustainable resource rich in bioactive compounds with potential applications in cosmetics and pharmaceuticals. This study investigates the protective effects of olive pomace juice (OPJ) against H Show less

The integration of omics technologies, including genomics, proteomics, metabolomics, and microbiomics, has transformed sports science, particularly soccer, by providing new opportunities to optimize player performance, reduce injury risk, and enhance recovery. This systematic literature review was conducted in accordance with PRISMA 2020 guidelines and structured using the PICOS/PECOS framework. Comprehensive searches were performed in PubMed, Scopus, and Web of Science up to August 2025. Eligible studies were peer-reviewed original research involving professional or elite soccer players that applied at least one omics approach to outcomes related to performance, health, recovery, or injury prevention. Reviews, conference abstracts, editorials, and studies not involving soccer or omics technologies were excluded. A total of 139 studies met the inclusion criteria. Across the included studies, a total of 19,449 participants were analyzed. Genomic investigations identified numerous single-nucleotide polymorphisms (SNPs) spanning key biological pathways. Cardiovascular and vascular genes (e.g., Show less

Previous studies have shown that plasma amyloid-beta oligomers (AβOs), the toxic form of amyloid-beta (Aβ), are a critical issue in the development or worsening of Alzheimer's disease (AD) and can be regarded as a blood marker for screening in dementia. We examined plasma AβOs with their related biomarkers in a case-control study to clarify these issues. A total of 16 patients diagnosed with Alzheimer's dementia (AD) and 16 cognitively normal controls (NCs) were recruited to compare their plasma biomarkers, AβO, Aβ Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by decreased amyloid-beta (Aβ) clearance, enhanced Aβ aggregation, an increased risk of amyloid-related imaging abnormalities (ARIA), and blood-brain barrier (BBB) dysfunction. The Show less

The primary renal complication of diabetes mellitus is diabetic kidney disease (DKD). The precise pathogenic mechanisms of DKD remain poorly elucidated. The aim of this study was to identify potential energy metabolism-related genes associated with DKD. The GSE30529 and GSE30528 datasets were retrieved from the Gene Expression Omnibus, and energy metabolism-related genes were obtained from the GeneCards database. Differentially expressed genes (DEGs) between DKD and control groups were analyzed. The biological functions and signaling pathways of these DEGs were evaluated using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). The diagnostic performance of hub genes for DKD was assessed using receiver operating characteristic (ROC) curve analysis. Expression levels of five significant energy metabolism-related genes were validated through immunohistochemistry. The Nephroseq V5 tool was used to evaluate gene expression in DKD and to determine correlations between gene expression and renal function in patients with DKD. A total of 17 energy metabolism-related DEGs were identified. Five hub genes-ALB, IGF1, CD36, LPL, and UCP2-were identified. Among these, CD36 and LPL demonstrated relatively high diagnostic accuracy for DKD. The findings suggest that CD36, IGF1, LPL, and UCP2 may serve as potential biomarkers for DKD. The genes CD36, IGF1, LPL, and UCP2 represent potential energy metabolism-related biomarkers with possible applications in the diagnosis and treatment of DKD. Show less

The global aging population has led to a rising prevalence of cognitive impairment, posing a significant public health challenge. Resistance training (RT) is a non-pharmacological intervention that has been increasingly investigated for its potential to support cognitive function in older adults. Clinical evidence suggests that RT may be associated with benefits in certain cognitive domains, including memory, executive function, processing speed, and visuospatial ability. However, findings across studies remain heterogeneous, with several trials reporting neutral outcomes. Most intervention studies involve structured RT programs conducted at moderate to high intensity and performed multiple times per week. However, optimal training parameters have not yet been clearly established due to variability in study design and the absence of formal dose-response analyses. Emerging evidence suggests that the cognitive effects of RT may be mediated, at least in part, through muscle-brain axis signaling involving exercise-induced myokines. Factors such as irisin, brain-derived neurotrophic factor, interleukin-6, interleukin-15, and insulin-like growth factor-1 have been implicated in processes related to neuroplasticity, neuroinflammatory regulation, and neurovascular function, primarily based on preclinical and translational research. This review synthesizes current evidence on RT-related molecular mechanisms and clinical findings to provide an integrative perspective on the potential role of resistance training in mitigating age-related cognitive decline. Show less

Testosterone production by testicular Leydig cells (steroidogenesis) is vital to male fertility and overall male health. Information about how nutrition influences Leydig cell steroidogenesis is lacking. Branched chain amino acids (BCAAs - leucine, isoleucine, and valine) are essential amino acids and important regulators of protein synthesis and energy production. Circulating and tissue BCAA levels are tightly regulated by the enzyme branched chain a-keto acid dehydrogenase kinase (BCKDK), which inhibits their catabolism. This work explored how BCAAs, and especially leucine, modulate male fertility and testosterone production. In a mutant mouse model of Bckdk, breeding analysis showed reduced male fertility and circulating testosterone. Further, morphological evaluation demonstrated testicular and epididymal abnormalities consistent with abnormal testicular androgen signaling. Fertility was partially rescued by feeding a high protein diet while circulating testosterone was not. In wild type testes, Leydig cells were the primary cell type to express BCKDK. Leveraging a primary interstitial cell culture, cell survival and apoptosis analyses demonstrated Leydig cells are highly sensitive to leucine deprivation and this sensitivity is enhanced under steroidogenesis stimulating conditions. Lastly, using the same primary cell culture system, testosterone production was shown to be lost under leucine deprivation. In total, this work demonstrates Leydig cells are uniquely sensitive to BCAA status under steroidogenesis stimulation and that regulated BCAA catabolism may be important for optimal male fertility. Show less

The cardiac lymphatic system plays a crucial role in maintaining myocardial homeostasis by regulating fluid equilibrium, immune surveillance, and metabolite clearance. This review highlights recent advances in understanding its development, molecular regulation, dual roles in pathophysiology, and translational potential. Cardiac lymphatic endothelial cells (LECs) develop from diverse progenitors, including venous endothelium and Isl1⁺ precursors from the second heart field (SHF) under sex-specific molecular guidance. Functionally, the Vascular endothelial growth factor C (VEGFC)/Vascular endothelial growth factor receptor 3 (VEGFR3) signaling is paramount, modulated contextually by factors like adrenomedullin and branched-chain ketoacid dehydrogenase kinase (BCKDK). Lymphatic dysfunction impacts cardiovascular disease paradoxically. While protective in the acute phase of myocardial infarction by limiting inflammatory edema, it becomes detrimental in chronic hypertension and calcific aortic valve disease (CAVD). Single-cell transcriptomics (scRNA-seq) resolve this contradiction by revealing distinct functional LEC subpopulations: Transforming growth factor-beta 1 (TGF-β1)⁺/Interleukin 10 (IL-10)⁺ LECs promote post-infarction repair, while Reelin⁺/C-C motif chemokine ligand 21 (CCL21)⁺ LECs promote osteogenesis and valve calcification in CAVD. Emerging strategies focus on cardiac-targeted nanotherapeutics, epigenetic and metabolic LEC modulation, and sex-specific dosing. Critical unresolved questions involve autonomic nerve-lymphatic integration and lineage-specific epigenetic memory. Advancing precision lymphatic imaging, genotype-informed clinical trials, and spatiotemporal control of LEC phenotypes is critical for therapeutic translation. Deeper understanding promises novel treatments for heart failure, inflammatory cardiomyopathies, and fibrosis. Show less

Alzheimer's disease (AD) is the most widespread neurodegenerative disease, strongly linked to amyloid depositions in the brain consisting of amyloid β (Aβ) peptides. The likelihood of developing late-onset Alzheimer's disease (LOAD) is influenced by the specific isoforms of apolipoprotein E (ApoE), with ApoE4 being the strongest known genetic risk factor for LOAD. Strong evidence suggests that ApoE impacts AD by modulating Aβ aggregation and clearance, although the precise molecular mechanisms remain incompletely understood. Microscale thermophoresis (MST) is a powerful technique for characterizing molecular interactions in solution, which has been used to determine various binding constants, although not the binding of ApoE to Aβ peptides. MST results show that ApoE isoforms bind Aβ1-40 and Aβ1-42 with low micromolar affinity. For Aβ1-42, ApoE3 shows the strongest binding ( Show less

Among ground-based paradigms used to reproduce altered gravity exposure, the hindlimb unloading (HU) model is widely employed to simulate microgravity conditions by removing gravitational loading from the hindlimbs. Despite its extensive use, behavioral adjustments during suspension remain poorly characterized, although they may provide valuable indicators of animal welfare and individual susceptibility. Here, we comprehensively characterized the behavioral profile of mice during and after HU using a dedicated ethogram, with the aim of identifying behavioral markers associated with individual coping strategies. Several exploratory and postural behaviors showed marked time-dependent modulation, with baseline exploratory activity predicting a more adaptive behavioral trajectory during suspension, possibly indicative of greater resilience. In parallel, brain levels of the neurotrophins NGF and BDNF were measured to explore their relationship with behavioral outcomes. Although no significant group differences were detected, suspended mice displayed a progressive reduction in both neurotrophins over time, which paralleled behavioral adaptation. Together, these findings indicate that specific exploratory behaviors represent reliable predictors of resilience to HU, while NGF and BDNF may reflect ongoing neuroplastic processes associated with prolonged suspension. Show less

Tail fat deposition constitutes a distinctive adaptive phenotype in sheep. The Large-tailed Han (LTH) and Small-tailed Han (STH) breeds display pronounced divergence in tail fat storage, offering an ideal model for elucidating lipid metabolism regulation. Integrated sRNA-Seq and RNA-Seq analysis identified 521 differentially expressed genes and 144 miRNAs, which were significantly enriched in lipid metabolism pathways, including fatty acid metabolism and PPAR signaling. Key candidate genes ( Show less

Neuroblastoma (NB) represents a paradigmatic developmental malignancy in which lineage specification, oncogenic signalling, and epigenetic regulation converge to define tumour behaviour. Among the molecular axes shaping NB heterogeneity, neurotrophin receptors of the tropomyosin receptor kinase (Trk) family (TrkA, TrkB, and TrkC) and the p75NTR occupy a central position at the intersection between neuronal differentiation programs and malignant plasticity. While high TrkA and TrkC expression is associated with adrenergic identity, differentiation competence, and favourable clinical outcome, TrkB, frequently sustained by BDNF-driven autocrine loops, characterises mesenchymal-like, therapy-resistant states enriched in metabolic and inflammatory adaptations. Importantly, in NB, the dysregulation of neurotrophin signalling rarely arises from recurrent genetic alterations of neurotrophic tyrosine receptor kinase ( Show less

Fetal growth restriction (FGR) remains a significant problem in obstetrics and is a key risk factor for perinatal brain injury. The fetal neuronal vesicles (FNVs) isolated from maternal blood represent an innovative approach-a "fetal brain liquid biopsy"-enabling early diagnostics of neuronal dysfunction in FGR. Western blotting was used to evaluate the protein pattern expression of FNVs isolated from the blood of pregnant women with FGR and uncomplicated pregnancy. Significant changes in the neurotrophic proteins levels (pro-BDNF, pro-NGF) and presynaptic neurotransmission proteins (SYN1, SYP, SYNPO) were identified. New data were obtained on changes in the expression of proteins of sumoylation (SUMO2/3/4) and neddylation (NAE1, UBC12), which differs in early-onset and late-onset FGR. Moreover, increased SUMO2/3/4 levels can be considered as an endogenous neuroprotective response to cerebral hemodynamic reaction in fetuses with late-onset growth restriction. An association has been established between changes in the expression of the studied proteins and intraventricular hemorrhage (IVH) in newborns with late-onset growth restriction. Show less

Neuroprotection represents a promising approach for mitigating retinal degeneration. Cord blood serum (CBS), rich in trophic factors such as the brain-derived neurotrophic factor (BDNF), has shown therapeutic potential for ocular surface diseases; however, its role in retinal neuroprotection remains underexplored. This study evaluates the protective effects of CBS on retinal pigment epithelium (ARPE-19) and photoreceptor-like (661W) cells exposed to oxidative stress. Cells were cultured in media supplemented with fetal bovine serum (FBS) or CBS with either high (CBS-H) or low (CBS-L) BDNF content. Oxidative stress was induced using hydrogen peroxide (H Show less

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are debilitating disorders with overlapping symptoms such as chronic pain and fatigue. Dysregulation of the endogenous opioid system, particularly µ-opioid receptor function, may contribute to their pathophysiology. This study examined whether epigenetic modifications, specifically µ-opioid receptor 1 gene ( Show less

Chronic ethanol exposure and genetic factors interact to drive neuroadaptations in alcohol use disorders (AUD). However, the system-level coordination of molecular responses across brain regions remains unclear. The 5-HT system and BDNF are key regulators of neuroplasticity in alcoholism. The 5-HT Show less