International Journal of Molecular Sciences最新文献

Chronic kidney disease (CKD) is associated with chronic inflammation and metabolic dysregulation. While endothelin-1 (ET-1) has been extensively studied, the role of endothelin-2 (ET-2) in CKD remains poorly understood. This cross-sectional study included 76 participants, 12 healthy controls and 64 CKD patients, stratified into three groups based on estimated glomerular filtration rate (eGFR): Group 1 (eGFR ≥ 90 mL/min/1.73 m²), Group 2 (eGFR 45-89 mL/min/1.73 m²), and Group 3 (eGFR 15-44 mL/min/1.73 m²). Serum concentrations of ET-1, ET-2, ET-3, uric acid (UA), and inflammatory markers (hsCRP and IL-6) were measured. ET-2 levels were significantly higher in the advanced CKD group (median 24.49 pg/mL) compared to controls (median 19.32 pg/mL; p = 0.030). No significant differences were observed for ET-1 or ET-3 across groups. ET-2 levels positively correlated with UA (rho = 0.243, p = 0.036), hsCRP (rho = 0.241, p = 0.039), and IL-6 (rho = 0.244, p = 0.038). These findings suggest that ET-2 may represent a potential biomarker reflecting metabolic and inflammatory dysregulation in CKD and highlight its possible relevance in disease severity assessment.

Evidence indicates that seminal plasma (SP) has pregnancy-favorable biological effects, but there is no definitive proof that exposure to SP increases pregnancy rates in assisted reproductive techniques. We previously showed that this discrepancy may be due to male stress altering SP composition. This study investigated the association between male stress biomarkers in saliva, serum and SP and key determinants of female fertility in women exposed to their partner's SP during the intracytoplasmic sperm injection (ICSI) cycle. The prospective pilot study included couples with tubal infertility who had unprotected intercourse during the ICSI cycle, supplemented by intravaginal SP injection on the oocyte retrieval day. Salivary cortisol and seminal noradrenaline were quantified by enzyme-linked immunosorbent assay to assess the activity of the hypothalamic-pituitary-adrenal axis and sympathetic nervous systems. Seminal interleukin-18 was measured using LegendPlex™ technology. Cluster analysis of male stress biomarkers identified two neuroendocrine-immune (NEI) phenotypes, characterized by signs of acute (phenotype-1) and chronic (phenotype-2) stress. Women with NEI phenotype-2 partners had fewer collected, mature, and fertilized oocytes, thinner endometrium, and significantly lower pregnancy rates (18.2%) compared to those with NEI phenotype-1 partners (84.6%). These data may suggest a dual role for SP in female fertility, depending on the type of male stress.

Numerous studies report cognitive impairment in COVID-19 patients from the acute to post-acute phases, linked to blood inflammation affecting blood-brain barrier (BBB) permeability and causing leakage of glial and neuronal proteins. However, a clear classification of these cognitive deficits and molecular blood events over time is still lacking. This narrative review summarizes the neuropsychological consequences of COVID-19 and evidence of altered cytokines and BBB disruption as potential mediators of cognitive impairment across post-infection phases. Post-COVID-19 cognitive dysfunction appears to follow a temporal course, evolving from acute focal deficits in attention, working memory, and executive function to more persistent multidomain impairments. We reviewed key cytokines released into the blood during COVID-19 infection, including antiviral (IFNγ, CXCL1, CXCL10), inflammatory (IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, GM-CSF, TNFα), and monocyte chemoattractants (MCP1/CCL2, MCP3/CCL7, MIP-1α/CCL3, GM-CSF, G-CSF). This analysis shows that several inflammatory and viral cytokines remain elevated beyond the acute phase and are associated with cognitive deficits, including IL-6, IL-13, IL-8, IL-1β, TNFα, and MCP1 in long-term post-COVID-19 patients. In addition, we examined studies analyzing changes over time in neurovascular unit proteins as biomarkers of BBB disruption, including extracellular matrix proteins (PPIA, MMP-9), astrocytes (S100β, GFAP), and neurons (NFL). These proteins are elevated in acute COVID-19 but generally return to control levels within six months, suggesting BBB restoration. However, in patients followed for over a year, BBB disruption persists only in those with cognitive impairment and is associated with systemic inflammation, with TGFβ as a related biomarker. Although cognitive sequelae can persist for over 12 months after SARS-CoV-2 infection, further studies are needed to investigate long-term neurocognitive outcomes and their link to sustained proinflammatory cytokine elevation and brain impact.

Microalgae display remarkable resilience to harsh environments, partly through the biosynthesis of diverse secondary metabolites. Cyanobacteria and red algae are well known to produce mycosporine-like amino acids (MAAs)-low-molecular-weight, water-soluble UV-absorbing compounds with anti-inflammatory, anticancer, and antimicrobial activities. By contrast, green microalgae typically lack detectable MAAs under standard conditions, and their responses under abiotic stress remain poorly characterized. Here, we investigated the freshwater green microalga Jaagichlorella luteoviridis grown under three stressors (salinity, heat, and UV) and assessed MAA induction. High-performance liquid chromatography (HPLC) revealed that stressed cultures accumulated multiple MAAs, whereas untreated controls showed no such accumulation. All stress treatments (UV, salinity, and heat) produced a substantial increase in peak intensity at 323-350 nm, whereas the control samples showed significantly lower absorption in this region. We also optimized an MAA extraction protocol suitable for "green" downstream applications in the pharmaceutical, nutraceutical, and cosmeceutical sectors and formulated an emulsion showing preliminary positive results and exhibiting an increased SPF index from 3.60 (control) to 3.78 when 0.2% MAA extract was added. Transcriptomic profiling against a reference genome revealed stress-specific differential gene expression and overexpression of specific genes of the MAA pathway, like ArioC and AroM/Aro1 SAM methyltransferases, thus identifying candidate targets for engineering enhanced MAA production. Given market demand for environmentally friendly and safe bioactives, microalgae represent a promising source of these valuable molecules.

The cardiac extracellular matrix (ECM) is a dynamic, tissue-specific scaffold essential for cardiovascular development, homeostasis, and disease. Once considered a passive structural framework, the ECM is now recognized as an active regulator of mechanical, electrical, and biochemical signaling in the heart. Its composition evolves from embryogenesis through adulthood, coordinating cardiomyocyte maturation, chamber formation, and postnatal remodeling. In pathological states, diverse stimuli-including ischemia, pressure or volume overload, metabolic dysfunction, and aging-disrupt ECM homeostasis, triggering fibroblast activation, myofibroblast transformation, and maladaptive collagen deposition. These processes underpin myocardial fibrosis, a key driver of impaired contractility, diastolic dysfunction, arrhythmogenesis, and heart failure across ischemic and non-ischemic cardiac diseases. ECM alterations also exhibit age- and sex-specific patterns that influence susceptibility to cardiovascular pathology. Advances in imaging and circulating biomarkers have improved fibrosis assessment, though limitations persist. Therapeutic strategies targeting ECM remodeling, including modulation of profibrotic signaling pathways, non-coding RNAs, cellular therapies, and nano-delivery systems, show promise but remain largely experimental. Collectively, expanding knowledge of ECM biology highlights its central role in cardiovascular physiology and pathology and underscores the need for targeted diagnostic and therapeutic innovations.

The interaction of metals with serum γ-globulins is of particular interest, as it can modulate immune system function and lead to unforeseen consequences following the intake of metal ions or their complexes, which are often considered (pro)drugs. This paper focuses on the interactions between gold(III) species and bovine or human serum γ-globulins in aqueous solutions. Using UV-Vis, fluorescence, and CD (circular dichroism) spectroscopy in diluted or 0.1 M NaCl aqueous solutions, we determined the most probable stoichiometry of the gold(III)-protein associates and their conditional binding constants. On average, 13 to 19 gold atoms bind per protein molecule, depending on the medium and protein origin, with apparent binding constants ranging from 3.6 to 4.6 (log K values; hydroxyl-containing complexes exhibit lower binding affinity). CD spectra revealed no changes in protein secondary structure induced by the increase in electrolyte concentration. However, the addition of gold(III) species resulted in a decrease in β-sheet content and a corresponding increase in turns or disordered fragments.

Melanocytic tumorigenesis is thought to occur through stepwise genomic evolution from normal skin to nevi and, ultimately, melanoma. To investigate this progression, we performed targeted deep sequencing of a 46-gene panel in matched healthy skin, nevus, and melanoma samples from 15 patients, including 14 complete tissue trios. Mutation burden increased progressively across tissues, with median mutation counts rising from benign skin to nevi and showing the highest levels in melanoma, consistent with cumulative somatic alterations. Canonical MAPK pathway mutations were common: BRAF V600E and NRAS Q61 variants were detected in many nevi and melanomas and were shared between lesions in 8 of 15 patients, providing direct evidence of clonal continuity. Variant allele frequencies for driver and nonsynonymous mutations were higher than those of passenger and synonymous mutations, reflecting selective expansion of functionally relevant clones. UV-signature substitutions were abundant, particularly among synonymous variants, suggesting background mutagenesis without clonal advantage. Melanoma-private mutations in genes such as ARID1A, ARID2, PIK3CA, and CDKN2A indicated additional late events contributing to malignant progression. Overall, this study supports a model in which many melanomas evolve from pre-existing nevi through sequential acquisition and clonal amplification of somatic mutations, while also revealing heterogeneous evolutionary trajectories.

Obesity-associated inflammation underlies much of cardiometabolic pathology, reflecting the convergence of chronic, low-grade systemic immune activation with region-specific maladaptation of adipose depots. Among these, epicardial adipose tissue (EAT)-a visceral fat layer contiguous with the myocardium and sharing its microvasculature-functions as a cardio-proximal immunometabolic interface that influences atrial fibrillation, heart failure with preserved ejection fraction, and coronary atherogenesis through paracrine crosstalk. These relationships extend beyond crude measures of adiposity, emphasizing the primacy of local inflammatory signaling, adipokine flux, and fibro-inflammatory remodeling at the EAT-myocardium interface. Of importance, substantial weight reduction only partially reverses obesity-imprinted transcriptional and epigenetic programs across subcutaneous, visceral, and epicardial depots, supporting the concept of an enduring adipose memory that sustains cardiovascular (CV) risk despite metabolic improvement. Accordingly, therapeutic strategies should move beyond weight-centric management toward mechanism-guided interventions. Resolution pharmacology-leveraging specialized pro-resolving mediators and their cognate G-protein-coupled receptors-offers a biologically plausible means to terminate inflammation and reprogram immune-stromal interactions within adipose and CV tissues. Although preclinical studies report favorable effects on vascular remodeling, myocardial injury, and arrhythmic vulnerability, clinical translation is constrained by pharmacokinetic liabilities of native mediators and by incomplete validation of biomarkers for target engagement. This review integrates mechanistic, depot-resolved, and therapeutic evidence to inform the design of next-generation anti-inflammatory strategies for obesity-related CV disease.

Monogenic forms of severe early-onset obesity often involve genetic disruptions in the hypothalamic leptin-melanocortin pathway. Pathogenic variants in the SIM1 gene, a key transcription factor required for the development of the paraventricular nucleus, are a known cause of Prader-Willi-like syndrome, characterized by hyperphagia, severe obesity, and developmental delay. We performed targeted next-generation sequencing of 52 obesity-associated genes on a cohort of pediatric patients with severe early-onset obesity. Identified variants were analyzed for population frequency and predicted pathogenicity using in silico tools. The structural impact of the novel missense variants was assessed using protein domain modeling with AlphaFold3. We identified five rare SIM1 variants in eleven patients. Four were heterozygous nonsynonymous variants: one frameshift in the bHLH domain (p.Ser18Ter), one frameshift in the Per-ARNT-Sim domain (p.His143Ter), and two missense variants, p.Pro30Ala and p.Ser663Leu. Structural modeling suggested that the missense variants are likely to disrupt critical protein-protein interactions. The fifth variant was a synonymous change, c.1173G>A, p.(Ser391Ser), which was detected in five unrelated patients. Bioinformatic analysis predicted that this variant could alter splicing. Structural modeling suggested that the missense variants interfere with SIM1 function. This study expands the mutational spectrum of SIM1-linked monogenic obesity, reporting novel likely pathogenic frameshift variants, a missense variant, and a recurrent synonymous variant with a potential splice-site effect. The majority of the variants are predicted to affect the SIM1 protein. Our findings strengthen the critical role of the SIM1 gene in hypothalamic development and energy homeostasis. The results underscore the importance of including the SIM1 gene in genetic testing panels for children with severe obesity and hyperphagia, enabling precise diagnosis and potential future personalized management. Functional in vitro or in vivo validation of these variants is required to confirm their pathogenicity.

Sarcopenia is highly prevalent among patients with chronic kidney disease (CKD) and chronic heart failure (CHF), yet the underlying immunometabolic mechanisms remain insufficiently understood. Short-chain fatty acids (SCFAs), inflammatory cytokines, and body-composition alterations may jointly contribute to the development of muscle dysfunction in this population. In this cross-sectional study, 80 patients with CKD and CHF underwent comprehensive clinical, biochemical, bioimpedance, inflammatory, and SCFA profiling. Sarcopenia was diagnosed according to EWGSOP2 criteria. Multivariable logistic regression, LASSO feature selection, correlation analysis, PCA, and Random Forest modeling were used to identify key determinants of sarcopenia. Sarcopenia was present in 39 (49%) participants. Patients with sarcopenia exhibited significantly lower body fat percentage, reduced ASM, and slower gait speed. Hexanoic acid (C6) showed an independent positive association with sarcopenia (OR = 2.24, 95% CI: 1.08-5.37), while IL-8 showed an inverse association with sarcopenia (OR = 0.38, 95% CI: 0.13-0.94), indicating that lower IL-8 levels were more frequently observed in individuals with sarcopenia. Correlation heatmaps revealed distinct SCFA-cytokine coupling patterns depending on sarcopenia status, with stronger pro-inflammatory clustering in C6-associated networks. The final multivariable model integrating SCFAs, cytokines, and body-composition metrics achieved excellent discrimination (AUC = 0.911) and good calibration. Sarcopenia in CKD-CHF patients represents a systemic immunometabolic disorder characterized by altered body composition, chronic inflammation, and dysregulated SCFA signaling. Hexanoic acid (C6) and IL-8 may serve as informative biomarkers of muscle decline. These findings support the use of multidimensional assessment and highlight potential targets for personalized nutritional, microbiota-modulating, and rehabilitative interventions.