Search Results (8,393)

Evidence from clinical trials indicates that dietary protein plays an important and often underappreciated role in lipoprotein lipid metabolism. For this narrative review, literature searches were conducted in the PubMed and Cochrane Central Register of Controlled Trials databases for articles describing randomized controlled trials (RCTs) and systematic reviews and meta-analyses of RCTs, as well as dietary guidelines and dyslipidemia management recommendations, using search terms for protein quantity, source (e.g., animal- and plant-based), and type (e.g., dairy, meat, soy, and nuts) and effects on lipids and lipoproteins in humans. Findings indicated that dietary intakes of both animal-based and plant-based proteins, when replacing refined carbohydrates or saturated fatty acids, lower circulating concentrations of atherogenic lipoproteins. Protein from plant sources appears to produce a somewhat larger effect on lipoprotein lipid concentrations than protein from animal sources. Individual amino acids (e.g., branched-chain amino acids), protein food fractions (e.g., whey), and food-derived peptides may independently impact lipoprotein lipid metabolism. Beyond the effect of replacing one macronutrient for another, the biochemical pathways responsible for the effects of dietary protein on lipoprotein lipid metabolism in humans have not been fully defined. The importance of dietary protein in a healthy diet is emphasized in recent dietary recommendations for the general population and for individuals with dyslipidemias. Additional research is warranted to determine the amount of dietary protein and the best balance of food source(s) to optimize its benefits on lipoprotein lipid concentrations, as well as the mechanisms for these effects. Full article

Calcium (Ca²⁺) and magnesium (Mg²⁺) are essential divalent cations whose homeostasis is essential for cardiovascular, muscular and metabolic function. Absolute or relative imbalances between Ca and Mg can lead to cardiovascular, metabolic and neurological pathologies. Ionized calcium (Ca²⁺) is a biologically active fraction of plasma calcium that is tightly regulated by protein binding, phosphate complexation, magnesium modulation and acid–base status. Ionized calcium plays a central role in multiple physiological processes and is strongly influenced by plasma pH, phosphate concentration and magnesium levels. However, the combined effects of these parameters are difficult to evaluate intuitively because of their nonlinear interactions. In this study, a numerical simulation framework was used to explore how simultaneous variations in pH, phosphate and magnesium may influence ionized calcium under typical physiological plasma conditions as a phenomenological framework linking ionic equilibrium with viscosity-dependent flow parameters under well-mixed plasma conditions. The simulations reveal phenomenological changes in which concurrent increases in pH and phosphate or reductions in magnesium produce disproportionately large decreases in ionized calcium. Within the physiological ranges examined, the results also indicate a region of relative stability for ionized calcium corresponding to Ca/Mg ratios close to 3, while this value should be interpreted as an emergent feature of the modeled parameter space rather than a universal physiological constant. These findings illustrate the importance of considering multiple electrolyte interactions simultaneously when evaluating calcium homeostasis and may provide a conceptual framework for further experimental investigation. Full article

Grass carp (Ctenopharyngodon idella) is a major freshwater aquaculture species in China, but its growth is limited under intensive high-density farming. This study aimed to investigate the characteristics of plasma exosomes associated with distinct growth performance by isolating and characterizing exosomes from fast- and slow-growing grass carp after nine months of culture. Exosomes showed typical morphology and expressed characteristic markers (CD63, CD81, TSG101). Small RNA sequencing identified 3325 miRNAs, with 177 highly abundant miRNAs differentially expressed: immune-related miRNAs were upregulated, while development-inhibitory miRNAs were downregulated in fast-growing fish. Target gene enrichment highlighted pathways in neural and skeletal development and amino acid metabolism. Integrative analysis across tissues revealed 26 miRNAs with coordinated expression patterns between plasma exosomes and brain, liver, or muscle, validated by qPCR. DIA proteomics quantified 4203 proteins, identifying 843 differentially enriched proteins linked to immune response, energy metabolism, and endoplasmic reticulum stress. Notably, TYMP was upregulated in muscle and exosomes, while several proteins (e.g., GYG2, BHMT) showed coordinated downregulation across tissues and exosomes in large fish. These results provide comprehensive evidence of exosome-mediated cross-tissue communication in teleosts and suggest a potential role for plasma exosomal miRNAs and proteins as non-invasive biomarkers correlated with growth status in aquaculture. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) is now the leading cause of hepatocellular carcinoma (HCC) globally. HCC surveillance is currently restricted to patients with cirrhosis, leaving those without cirrhosis, who present with more advanced disease and poorer outcomes without adequate risk stratification tools. This study compared lipid profiles across MAFLD and MAFLD-related HCC (MAFLD-HCC) patients, with and without cirrhosis, to characterise metabolic dysregulation underlying non-cirrhotic MAFLD-HCC (ncMAFLD-HCC). Plasma and liver lipidomic profiles were obtained from 221 patients (140 MAFLD, 66 cirrhotic MAFLD-HCC (cMAFLD-HCC), and 15 ncMAFLD-HCC) using untargeted liquid chromatography mass spectrometry. Univariate, multivariable and enrichment analyses were performed for statistically determining the lipid profile difference between the groups. Seventy percent of lipid classes were more abundant in MAFLD than in ncMAFLD-HCC and cMAFLD-HCC. Multivariate analysis revealed distinct lipid profiles across the three groups in both plasma and liver. Over 100 lipid species including diglyceride (DAG), sphingomyelin (SM), triglyceride (TG), dihydroceramide (DHCer), and linoleic acid derivatives were differentially expressed in ncMAFLD-HCC versus MAFLD, with enrichment in pathways such as glycerolipid metabolism, G-protein signalling, MAPK signalling, EGFR-TKI resistance pathway, implicated in HCC development. ncMAFLD-HCC exhibits a distinct lipid signature, offering preliminary mechanistic insight and a foundation for non-invasive biomarker development. Full article

The influence of natural and synthetic blue food colorants on the human body, including the cardiovascular system, is a complex and not fully understood topic. Considering that various papers have demonstrated that oxidative stress is a crucial step in the development of cardiovascular diseases (CVDs), our experiments on the pro- or antioxidant action of three blue food colorants (one natural colorant—genipin—and two synthetic colorants—brilliant blue FCF and patent blue V) focused on two aspects that are important for the development of CVDs: the level of biomarkers of oxidative stress induced by H₂O₂/Fe²⁺ (the donor of hydroxyl radicals—one of the most aggressive reactive oxygen species produced in humans) in human blood platelets and human plasma, as well as the arachidonic acid cascade in blood platelets stimulated by thrombin (in vitro). Our results demonstrated that two tested blue colorants—genipin and brilliant blue FCF (at four used concentrations: 2, 10, 20, and 200 µM)—reduced plasma lipid peroxidation induced by H₂O₂/Fe²⁺. Moreover, all tested blue colorants (genipin, brilliant blue FCF, and patent blue V; at the concentrations 2, 10, 20, and 200 µM) inhibited lipid peroxidation in blood platelets treated with H₂O₂/Fe²⁺. In contrast, only genipin (at the highest used concentration—200 µM) statistically significantly reduced plasma protein carbonylation induced by H₂O₂/Fe²⁺ (inhibition of this process: about 25%). However, all tested food colorants decreased blood platelet protein carbonylation stimulated by H₂O₂/Fe²⁺, but their action was not always statistically significant. In addition, we noted that all used blue food colorants (1–200 µM) have protector effects on the change in the level of thiol groups in plasma proteins stimulated by H₂O₂/Fe²⁺, but these tested colorants change the level of thiol groups in blood platelets treated with H₂O₂/Fe²⁺ only at the highest used concentration—200 µM. In conclusion, the present study provides the first data on the antioxidant potential of genipin, brilliant blue FCF, and patent blue V in selected elements of blood treated with H₂O₂/Fe²⁺. Earlier and current studies have indicated the promising potential of these blue food colorants, especially genipin (without cytotoxicity toward human blood platelets), which can modify the oxidative stress of platelets and plasma in vitro at concentrations (1–200 µM) which can be obtained in blood during its administration. However, the presented results have limitations, especially concerning the mechanistic clarity surrounding the antioxidant properties of the tested blue food colorants. Therefore, further in vivo experiments are needed to provide a better understanding of their antioxidant potential. Full article

Human endogenous retroviruses (HERVs) originate from ancient retroviral integration into the primate germline. Although most are defective proviruses, the most recently endogenized groups, like the HERV-K family, retain intact ORFs encoding retroviral proteins. HERVs usually remain transcriptionally silent, yet this status is reversible. Multiple HIV-HERV interactions, mainly mediated by the HIV Tat protein, lead to HERV transcription and protein production. The present study investigates HERV-K transcription in particular of Human MMTV-like (HML) group-2 and 6 in peripheral blood of people with HIV (PWH). Using different experimental approaches—such as single-cell and plasma transcriptomics-, we found that HERV-K transcripts may be detected during both acute and chronic phases of the infection, with HML-6 showing higher expression compared to HML-2, predominantly within myeloid cells. Effective combined antiretroviral therapy (cART) was able to significantly reduce HML-6 transcription, regardless of whether the treatment was initiated in the acute or late chronic phases of HIV infection. Notably, chronic infections showed higher HML-6 transcript levels compared to acute infections in both naïve and successfully cART-treated subjects, potentially associated with persistent immune dysregulation observed in chronic HIV infection, although a direct causal role of HML-6 expression remains to be established. Full article

The formation of extracellular traps (ETs) through ETosis has emerged as a key mechanism in immunothrombosis. However, the temporal dynamics and clinical significance of ETosis in coronary thrombi of ST-elevation myocardial infarction (STEMI) patients remain incompletely understood. We investigated whether ETosis burden increases with thrombus age and is associated with DNASE1 and TREX1 genetic variants as well as impaired myocardial reperfusion. Thrombus aspirates from 81 STEMI patients undergoing primary percutaneous coronary intervention were histologically classified as fresh (n = 41) or lytic (n = 40). ETosis was quantified by citrullinated histone H3 (CitH3) immunohistochemistry and digital image analysis, complemented by multiplex staining for myeloperoxidase (MPO), CD68, caspase 3, and CD61. Plasma ET-related markers and genotyping of DNASE1 (rs1053874) and TREX1 (rs11797) were also performed. CitH3-positive cells were present in all thrombi but were more abundant in lytic (older) thrombi compared with fresh thrombi (1348 vs. 591 cells/mm², p < 0.001). Increased ETosis was associated with neutrophil and macrophage infiltration, apoptosis, prolonged ischemia time, elevated systemic inflammation (neutrophil–lymphocyte ratio and C-reactive protein), and impaired myocardial reperfusion (lower TIMI flow grades). Moreover, the DNASE1 GG genotype was associated with higher densities of MPO- and CD68-positive cells, whereas the TREX1 CC genotype was associated with increased densities of CitH3-, MPO-, and CD68-positive cells. This study demonstrates that ETosis increases with coronary thrombus maturation and is associated with local inflammation and impaired reperfusion in STEMI. Genetic variants in DNASE1 and TREX1 may modulate inflammatory cell accumulation within thrombi. These findings suggest ETosis as a potential therapeutic target, particularly in patients with delayed presentation. Full article

Background/Objective: An obesogenic diet triggers intestinal inflammation and oxidative stress, leading to epithelial barrier dysfunction and increased risk of metabolic disorders. This study investigated the mechanisms by which quercetin protects intestinal integrity in high-fat diet (HFD)–fed mice. Methods: Mice were fed an HFD or a low-fat diet (LFD) with or without 1% quercetin, intestinal gene and protein expression, microRNA levels, permeability, and circulating intestinal biomarkers were assessed. Results: Mice fed an HFD with quercetin (HFDQ) showed a 17% improvement in intestinal barrier integrity with increased expression of tight junction and mucin genes and proteins. The nuclear translocation of the nuclear factor-κB (NF-κB) p65 subunit in the ileum decreased by 34%, whereas its acetylation was reduced by 50–57% throughout the intestine, with downregulation of NF-κB-regulated pro-inflammatory genes and proteins. Quercetin increased the nuclear factor erythroid 2-related factor 2 (NRF2) by ~ 25% across intestinal segments and upregulated antioxidant enzyme genes. It suppressed toll-like receptor 4 (TLR4) by 50% and restored AMP-activated protein kinase (AMPK) and sirtuin 1 to levels comparable to those in LFD mice. Altered microRNAs (miRNA-16, 200b, 122, 34a, and 21) supported these molecular changes. Quercetin also restored short-chain fatty acid receptors and serotonin transporters that were affected by HFD. Plasma lipopolysaccharide (LPS), cluster of differentiation 14, LPS-binding protein, and myeloperoxidase activity decreased by 36, 31, 42, and 37%, while glucagon-like peptide-1 increased by 23%. Conclusions: Quercetin protects epithelial barrier integrity against HFD-induced intestinal inflammation and oxidative stress via the AMPK-mediated NF-κB and NRF2 signaling pathways. Full article

Background: A high-fat diet (HFD) contributes to cardiometabolic disease. Gut microbiota-derived metabolites may participate in this process, but their contribution to lipid regulation is not well defined. Indoxyl sulfate (IS), a microbiota-derived metabolite, has been linked to vascular and metabolic dysfunction. Its role in lipid metabolism remains unclear. Methods: In Part A, plasma and urinary concentrations of IS were measured in plasma and urine from HFD-fed rats in which dyslipidemia had developed, together with controls. In Part B, HepG2 cells were exposed to IS, and cell viability and selected cholesterol metabolism-related transcripts and proteins were assessed. In Part C, 10-week-old, male Sprague–Dawley rats maintained on a standard diet received vehicle or IS at two doses for 8 weeks. Hepatic expression of LDLR, SREBP-2, HMG-CoA reductase, and related cholesterol metabolism markers were measured by quantitative real-time PCR and Western blotting. Results: In Part A, higher plasma IS concentrations and higher daily urinary IS excretion were found in samples collected from HFD-fed rats compared to controls. In HepG2 cells, IS reduced cell viability at higher concentrations and increased LDLR mRNA and protein expression. In IS-treated rats, total cholesterol, LDL-cholesterol, and triglycerides increased in a dose-dependent manner. Hepatic SREBP-2 and HMG-CoA reductase protein levels were increased at both IS doses, whereas LDLR protein abundance was increased at the higher dose. Moreover, serum PCSK9 levels were reduced in IS-treated rats. Conclusion: IS increased in HFD-fed rats. IS altered cholesterol metabolism-related pathways in HepG2 cells and in rats. In vivo IS administration increased circulating lipids and hepatic proteins involved in cholesterol synthesis and uptake. These findings indicate that IS may contribute to disturbed lipid homeostasis, although its role in HFD-induced dyslipidemia requires further mechanistic confirmation. Full article

Daratumumab, a human IgG1 monoclonal antibody targeting CD38, is widely used in multiple myeloma and AL amyloidosis. Despite its clinical success, many patients fail to achieve durable responses or relapse, underscoring the importance of understanding resistance mechanisms. Drawing on experience from other better-studied monoclonal antibodies, resistance to daratumumab can be categorized into four main mechanisms: (1) reduced CD38 expression on plasma cells; (2) increased expression of complement inhibitory proteins (CD55/CD59), impairing complement-mediated cytotoxicity; (3) reduced drug bioavailability due to urinary loss in non-selective nephrotic syndrome; and (4) the development of neutralizing anti-daratumumab antibodies. Anti-drug antibodies (ADAs) may represent a potential mechanism of treatment failure through effects on pharmacokinetics, efficacy, and safety, even in patients on daratumumab therapy. Seven different trials have tested anti-daratumumab antibodies. Among them, anti-daratumumab antibodies were identified in only 0–2.4% of patients, and only in a small portion of these has it been proven to be neutralizing. Overall, ADAs appear rare, but these findings are likely underestimated due to short follow-up and suboptimal timing of assessment. In conclusion, standardized ADA monitoring, particularly months after treatment interruption or in cases of inadequate response or infusion-related reactions, may improve patient management and therapeutic outcomes. Full article

The vascular endothelial glycocalyx (EGX) is a gel-like, negatively charged mesh of membrane-bound proteoglycans, glycosaminoglycans, glycoproteins and adsorbed plasma proteins that covers the luminal surface of the endothelium and orchestrates vascular homeostasis through regulation of permeability, leukocyte trafficking, mechanotransduction and anti-thrombotic signalling. Progressive thinning, heterogeneous remodelling and accelerated shedding of the EGX are now recognised as hallmarks of vascular ageing and early drivers of age-related cardiovascular disease. Here, we synthesise current evidence linking EGX integrity to biological ageing, with emphasis on age-dependent remodelling of heparan-sulfate proteoglycans, endothelial progenitor-cell dysfunction, and the heightened susceptibility of the aged EGX to oxidative, inflammatory and infectious insults. We discuss signalling pathways driving EGX shedding—including the IQGAP1/PAR1-2/PI3K/Akt axis—and clinical correlates such as vulnerable coronary plaque in older patients with coronary artery disease and microvascular endotheliopathy in severe COVID-19. Finally, we review emerging anti-ageing strategies targeting the EGX, including direct oral anticoagulants, glycocalyx-mimetic and nitric-oxide-releasing biomaterials, bioinspired antithrombogenic surfaces and microbiome-based modulation, and consider their translational potential for extending cardiovascular healthspan. Full article

Non-obstructive azoospermia (NOA) is characterized by focal and quantitatively limited spermatogenesis, making preoperative prediction of sperm retrieval difficult. Seminal plasma is a biologically plausible liquid-biopsy compartment because it contains testicular, epididymal and accessory-gland secretions enriched with extracellular vesicles, cell-free nucleic acids, proteins and metabolites. This narrative molecular review examines the mechanisms by which germ-cell-derived molecular cargo reaches the ejaculate and organizes seminal-plasma biomarkers by cargo class and spermatogenic stage. Particular attention is given to extracellular-vesicle non-coding RNAs, cell-free seminal mRNAs, germ-cell-enriched proteins including TEX101 and ECM1, and metabolomic and lipidomic signatures. Although several markers show promising discrimination, most remain discovery-stage, single-center and insufficiently validated. The central argument is that the field should move from isolated biomarker nomination toward locked, stage-mapped multi-analyte panels integrated with clinical and genetic predictors under modern prediction-model standards. Seminal plasma is best viewed not as a ready clinical test, but as a biologically coherent platform for future calibrated, externally validated and artificial-intelligence (AI)-ready sperm-retrieval decision support. Full article

Follistatin (FST) binds to and neutralizes members of the transforming growth factor-beta (TGF-β) superfamily, thereby regulating diverse physiological processes, including regulation of skeletal muscle, adipose, and bone homeostasis. FST also promotes adipose browning and enhances energy metabolism, leading to improved plasma lipid profiles and metabolic health in mice. Given the emerging association between brown adipose tissue (BAT) activation and reduced atherosclerosis, we investigated the anti-atherogenic potential of FST. Transcriptomic and metabolomic analyses of the Hybrid Mouse Diversity Panel (HMDP) revealed that Fst expression was negatively correlated with aortic lesion area and positively correlated with the expression of multiple adipose browning-associated genes. Adeno-associated viral delivery of Fst (AAV1-FST344) in Ldlr^−/− mice significantly reduced aortic lesion area, improved plasma lipid profiles, and decreased expression of adhesion (VCAM1) and inflammatory (iNOS, TNF-α) markers in white adipose tissue (WAT), liver, and heart. Fst gene delivery also markedly increased uncoupling protein 1 (UCP1) expression in WAT, consistent with WAT browning. Integrated correlation analyses of Fst expression with tissue metabolites, together with plasma metabolite–lesion associations identified in the HMDP, implicated the arginase 1 (Arg1)-mediated metabolic pathway as a key regulator of atherogenesis. Consistent with these findings, Arg1 expression was significantly elevated in WAT, liver, and heart of AAV1-FST344-treated mice and in wild-type versus Fst-knockout mouse embryonic fibroblasts (MEFs). Immunostaining localized Arg1 predominantly to CD68⁺ macrophages in heart and liver. Given recent evidence identifying Arg1 as a novel mediator of efferocytosis, these findings suggest that Arg1 may promote macrophage metabolic reprogramming and resolution of inflammation by enhancing the clearance of apoptotic cells. Furthermore, Fst gene delivery increased the expression of fibroblast growth factor 21 (Fgf21) and adiponectin (AdipoQ) in WAT. Collectively, these findings identify Fst as a novel anti-atherogenic regulator that protects against vascular disease by promoting adipose browning, improving lipid metabolism, and activating Arg1-mediated metabolic pathways. Full article

Preeclampsia (PE) is a major pregnancy complication characterized by placental dysfunction and metabolic disturbances. Although mitochondrial abnormalities are frequently observed in PE, the upstream regulatory mechanisms remain incompletely understood. Here, we investigated the potential involvement of BACH1 in trophoblast dysfunction in PE and explored its association with mitochondrial metabolic alterations and protein succinylation. BACH1 expression was assessed in placental tissues and plasma samples from patients with PE, its functional effects were examined in trophoblast cell lines and BACH1 overexpression mouse models, and metabolic, bioenergetic, and succinylation-related alterations were evaluated using multi-omics and functional analyses. BACH1 expression was elevated in PE placentas and correlated with disease severity. In trophoblasts, BACH1 overexpression impaired proliferation, invasion, and trophoblast-mediated angiogenesis and was accompanied by mitochondrial and metabolic abnormalities, while quantitative succinylproteomic analysis revealed widespread alterations in mitochondrial protein succinylation. In vivo, BACH1 overexpression induced key PE-like features, including hypertension, fetal growth restriction, and placental abnormalities, and glycine supplementation partially rescued the trophoblast dysfunction associated with BACH1 overexpression. Together, evidence from clinical samples and experimental models suggests that BACH1 is associated with mitochondrial succinylation remodeling and trophoblast dysfunction in PE, supporting the hypothesis that BACH1-associated metabolic dysregulation and mitochondrial succinylation remodeling may contribute to PE pathogenesis. Further studies are required to establish the causal relevance and clinical significance of these mechanisms in human PE. Full article

Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases—caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation—and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes—including volume reduction and cristae loss—represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber’s hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers—such as lipid peroxidation products, decreased GPX4, and iron deposition—rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition—using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers—together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis–ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases. Full article