Current Issues in Molecular Biology最新文献

Although the impact of COVID-19, caused by SARS-CoV-2, may appear to have diminished in recent years, the emergence of new variants still continues to cause significant global health and economic challenges. While numerous metabolomic studies have explored serum-based alterations linked to the infection, investigations utilizing urine as a biological matrix remain notably limited. This gap is especially significant given the potential advantages of urine, a non-invasive and easily obtainable biofluid, in clinical settings. In the context of patients in intensive care units (ICUs), temporal monitoring through such non-invasive samples may offer a practical and effective approach for tracking disease progression and tailoring therapeutic interventions. This study retrospectively explored the longitudinal metabolomic alterations in COVID-19 patients admitted to the ICU, stratified into three prognostic outcome groups: healthy discharged (HD), polyneuropathic syndrome (PS), and Exitus. A total of 32 urine samples, collected at four distinct time points per patient during April 2020 and preserved at -80 °C, were analyzed by proton nuclear magnetic resonance (¹H-NMR) spectroscopy for comprehensive metabolic profiling. Statistical evaluation using two-way ANOVA and ANOVA-Simultaneous Component Analysis (ASCA) identified significant prognostic variations (p < 0.05) in the levels of taurine, 3-hydroxyvaleric acid and formic acid. Complementary supervised classification via random forest modeling yielded moderate predictive performance with out-of-bag error rate of 40.6% based on prognostic categories. Particularly, taurine, 3-hydroxyvaleric acid and formic acid levels were highest in the PS group. However, no significant temporal changes were observed for any metabolite in analyses. Additionally, metabolic pathway analysis conducted using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database highlighted the "taurine and hypotaurine metabolism" pathway as the most significantly affected (p < 0.05) across prognostic classifications. Harnessing urinary metabolomics, as indicated in our preliminary study, could offer valuable insights into the dynamic metabolic responses of ICU patients, thereby facilitating more personalized and responsive critical care strategies in COVID-19 patients.

Ovarian cancer is frequently diagnosed at an advanced stage due to non-specific symptoms, contributing to high mortality. The limited diagnostic performance of current serum assays in early disease underscores the need for complementary circulating biomarkers. Circulating microRNAs and inflammation-related markers are promising candidates. Although miRNAs are implicated in cancer diagnostics, the role of miRNA-29a in ovarian cancer remains underexplored. Given that sST2 is elevated in several malignancies and is a direct target of miRNA-29a, concurrent evaluation may be informative. This pilot study compared serum miRNA-29a and sST2 levels in 23 ovarian cancer patients and 22 healthy female controls. miRNA-29a expression was quantified by real-time PCR (2^-ΔΔCt), and sST2 was measured by ELISA; diagnostic performance was assessed using ROC analysis. miRNA-29a levels were significantly reduced (p < 0.05), whereas sST2 concentrations were significantly increased (p < 0.001) in patients versus controls. ROC analysis showed modest discrimination for miRNA-29a (AUC 0.678) and higher performance for sST2 (AUC 0.825). No significant correlation was observed between the two markers. These findings suggest that circulating miRNA-29a and sST2 may have biomarker potential in ovarian cancer; larger, well-designed studies are required to confirm clinical utility.

Cellular senescence, characterized by permanent cell cycle arrest, significantly influences cancer development, immune regulation, and progression. However, the precise mechanisms by which senescence contributes to colorectal cancer prognosis remain to be fully elucidated. By integrating expression profiles of senescence-related and prognostic genes in colon adenocarcinoma (COAD) patients, we formulated and confirmed a nine-gene cellular senescence-related signature (CSRS) that integrates senescence-associated and prognosis-predictive genes using data from the CellAge, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A cell senescence-related prognostic formula was developed as follows: CSRS = (CASP2 × 0.2098) + (CDKN2A × 0.1196) + (FOXD1 × 0.1472) + (ING5 × 0.3723) + (OXTR × 0.0786) + (PHGDH × 0.1408) + (SERPINE1 × 0.1127) + (SNAI1 × 0.1034) + (LIMK1 × 0.0747). In a multivariate Cox proportional hazards model, the CSRS score, age and TNM stage were all identified as significant independent indicators for overall survival, affirming their prognostic value in colorectal cancer. The CSRS-high group exhibited significantly up-regulated senescence-associated secretory phenotype (SASP) and immune cell infiltration, whereas the CSRS-low group showed an apparent better response to immune-checkpoint inhibitor therapy. Our findings suggest CSRS score and its constituent genes represent potential biomarkers for prognosis and immunotherapeutic benefit in COAD patients. Extending this nine-gene set into a broader senescence-associated panel should be a next step toward delivering truly individualized treatment plans.

Periodontitis is a chronic inflammatory condition characterized by dysregulated immune responses that promote alveolar bone destruction. Targeting inflammatory signaling pathways has therefore become an important area of investigation. This study investigated the anti-inflammatory and bone-protective effects of Magnolia kobus DC. extract (MKE) in a ligature-induced periodontitis rat model. Rats were assigned to five groups (n = 5 per group): non-ligature control, ligature control, doxycycline (20 mg/kg), MKE 100 mg/kg, and MKE 400 mg/kg, and treated orally for eight weeks. Periodontal damage and alveolar bone loss were assessed by micro-computed tomography (micro-CT), gingival index, and tooth mobility. Micro-CT analysis demonstrated a dose-dependent reduction in alveolar bone loss, as evidenced by a significant decrease in the cementoenamel junction-alveolar bone crest (CEJ-ABC) distance and reduced furcation involvement in MKE-treated groups compared with the ligature control group, while tooth mobility scores were significantly improved. Serum levels of receptor activator of nuclear factor kappa-B ligand, interleukin-1β, tumor necrosis factor-α, and cyclooxygenase-2 were significantly decreased, while nuclear factor kappa-B signaling was suppressed in gingival tissue. The extract also significantly reduced matrix metalloproteinases 3, 8, 9, and 13, and increased collagen type I and II expression. In summary, MKE exerted anti-inflammatory and bone-protective properties, effectively reducing alveolar bone loss and maintaining periodontal structure. These findings support MKE's potential application as a natural anti-inflammatory and bone-protective agent and as a functional food ingredient for periodontitis prevention and treatment, meriting further clinical evaluation.

Due to improper nutrition, high-density lipoproteins (HDLs) can be subjected to structural changes, acquiring a dysfunctional phenotype. Therefore, research efforts are currently focused on improving HDL functionality despite its blood level. The aim of this study was to evaluate the effect of phycocyanin concentrate (as part of a food matrix) on the functional properties of HDL. Male Wistar rats were fed a high-fat diet containing 2% cholesterol for 113 days. Experimental animals were treated with 30 and 300 mg/kg b.w. of phycocyanin concentrate mixed with soy protein isolate. Serum and hepatic cholesterol and triglyceride levels, and the content of protein, triglycerides, choline-containing phospholipids, malondialdehyde, sphingosine-1-phosphate, and paraoxonase-1 in HDL fractions were assessed. The decrease in protein in HDL particles is characteristic for dysfunctional phenotype of these particles. Phycocyanin concentrate diet prevented the depletion of protein in HDL particles, regardless of the dosage. The functionality of HDL is associated with paraoxonase-1 activity, which inhibits lipid peroxidation in lipoproteins. Our results have shown a significant increase in the level of paraoxonase-1 in HDL particles in groups treated with phycocyanin. HDL particles become more enriched with triglycerides with the development of hyperlipidemia. Triglycerides in HDL particles and in serum decreased by two times in animals receiving 30 mg/kg b.w. of phycocyanin. The MDA content in HDL particles decreased in all animals receiving a high-fat diet with the addition of 2% cholesterol. The introduction of 300 mg/kg of phycocyanin returned this indicator to the values of the Control group. Thus, biomarkers of dysfunctional changes in HDL in rodent hyperlipidemia models may be a useful tool for assessing lipid metabolism disorders. Also, the results confirm the potential ability to use phycocyanin concentrate as part of lipid-lowering products.

Hydroxyprogesterone (HP) is a synthetic progestogen widely used in obstetric care, and its potential influence on breast cancer biology has become an emerging area of interest. Despite its clinical use, the molecular mechanisms by which HP affects tumor tissue remain insufficiently explored. In this study, transcriptomic profiling was performed to investigate gene expression changes associated with HP in operable breast cancer. Pre-operative 17α-HP caproate (17-OHPC) exposure was associated, in normal adjacent tissue (NAT), with activation of steroid-hormone and lipid/xenobiotic-metabolism programs and crosstalk to phosphoinositide 3-kinase (PI3K)-Akt and nuclear factor kappa B (NF-κB). In NAT, these pathways showed the largest absolute log₂ fold-change (|log₂FC|); significance is reported as false discovery rate (FDR) throughout (e.g., FKBP5↑ with HP). In tumor tissue, the dominant signal reflected tight-junction/apical-junction and extracellular matrix (ECM)-receptor remodeling (e.g., CLDN4↑). We prioritized FKBP5 (HP pharmacodynamics) and CLDN4 (tumor baseline) as the main candidates; TSPO and SGK1 are reported as exploratory. This discovery-level, hypothesis-generating analysis nominates candidate biomarkers and pathway signals for prioritization and evaluation in independent datasets and future studies. These findings provide mechanistic insight into HP's molecular effects in breast cancer and suggest potential applications in biomarker perioperative management.

Apical periodontitis (AP) is a chronic immunoinflammatory disease influenced by complex interactions between microbial factors and host immune response. Although genetic susceptibility has been implicated in AP, evidence is limited, particularly in admixed populations. This exploratory study aimed to assess whether functional polymorphisms in MMP1 (rs1799750), IL10 (rs1800872), and IL17A (rs7747909) are associated with susceptibility to radiographically defined AP in a Colombian population. A case-control design was employed, including individuals with radiographic evidence of AP and controls without periapical lesions. Genotyping was performed using TaqMan^® assay. The association between single-nucleotide polymorphisms and AP was evaluated using a dominant inheritance model. Effect sizes were estimated as odds ratios (ORs) with 95% confidence intervals (CIs), and p-values were adjusted using the Benjamini-Hochberg false discovery rate (FDR) procedure. The MMP1 rs1799750 polymorphism was associated with increased susceptibility to AP (OR = 3.47, 95% CI = 1.40-8.58; FDR = 0.013). Similarly, the IL10 rs1800872 variant was significantly associated with AP risk (OR = 3.00, 95% CI = 1.52-5.91; FDR = 0.007). The strongest association was observed for IL17A rs7747909 (OR = 8.95, 95% CI = 3.61-22.15; FDR < 0.001). This exploratory candidate-gene study provides preliminary evidence suggesting that genetic variations in MMP1, IL10, and IL17A may contribute to susceptibility to AP in the Colombian population. Given the exploratory design, modest sample size, and absence of ancestry adjustment or functional validation, these findings should be interpreted cautiously and confirmed in larger ancestry-informed cohorts integrating host genetic and microbial data.

Regulatory B cells (Bregs) are integral to the tumor microenvironment (TME) and influence immune responses through the secretion of immunosuppressive cytokines such as IL-10, IL-35, and TGF-β. This review highlights recent findings on the phenotype and mechanisms of Bregs, emphasizing their dual role in regulating immune responses within the TME. Importantly, we further explored the latest advances in Breg regulatory mechanisms from the novel perspectives of epigenetics and metabolic remodeling, including the effects of DNA methylation, histone acetylation, glycolysis, and oxidative phosphorylation on Bregs. We also investigate the therapeutic targeting of Bregs, with a focus on STAT3 inhibitors such as lipoxin A4, cucurbitacins, and resveratrol, which show promising potential in mitigating the suppressive function of Bregs. Furthermore, this review provides a detailed analysis of the impact of Bregs on tumorigenesis and metastasis, emphasizing the importance of inhibiting specific immune pathways to prevent tumor escape. Finally, this review offers a prospective outlook on immunotherapy strategies based on Bregs, foreseeing a more nuanced understanding of their TME function and the evolution of targeted treatments with enhanced therapeutic efficacy.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovitis, in which fibroblast-like synoviocytes (FLSs) serve as the primary effector cells that drive the destruction of joints. Baicalin has previously demonstrated efficacy in significantly ameliorating joint symptoms in rats with CIA. As such, this study aims to investigate its underlying molecular mechanisms and impact on the FLSs of rats with CIA through an integrated proteomics and transcriptomics analysis. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted based on two datasets; it revealed that the retrograde endocannabinoid signaling pathway-associated with susceptibility to RA-is the only one involved in both the signaling and metabolic processes modulated by baicalin. Nineteen differentially expressed proteins (DEPs) downregulated by baicalin comprise seventeen subunits of NADH dehydrogenase and two receptors, glutamate receptor 2 (GRIA2) and γ-aminobutyric acid receptor subunit alpha-5 (GABRA5). Three differential metabolites (DMs) were also affected by baicalin: γ-aminobutyric acid (GABA) and phosphatidylcholine (PC) were upregulated and phosphatidylethanolamine (PE) was downregulated. Our findings suggest that the baicalin-mediated alleviation of joint synovitis is closely related to the upregulation of GABA and PC; downregulation of GRIA2, GABRA5, and PE; and preservation of mitochondrial homeostasis within the retrograde endocannabinoid signaling pathway in FLSs.

Buffaloes (Bubalus bubalis) are central to the dairy and agricultural economy, contributing high-quality milk, meat, draft power, and manure. Rich milk composition, the ability to utilize low-quality roughage, and strong disease resistance make buffaloes indispensable across diverse production systems. Among India's major dairy breeds-Murrah, Nili-Ravi, Jaffarabadi, Surti, Bhadawari, Mehsana, and Nagpuri, none exhibit the distinctive trait of intermittent milking, which is uniquely observed in the Pandharpuri buffalo, a registered indigenous breed of Maharashtra. Despite coexisting with dominant dairy breeds such as Murrah, Pandharpuri buffalo is considered to possess primitive riverine ancestry and may represent one of the ancestral lineages from which several Indian breeds evolved. Its evolutionary relevance and unique intermittent milking capacity underscore the need to understand its genomic architecture. To address this, we applied whole-genome resequencing and the De-Correlated Composite of Multiple Signals (DCMS) approach to identify within-breed selection signatures. Our analyses identified 1337 candidate genes, including several linked to milk production, particularly those relevant to the physiological capacity for intermittent milking. Notable genes included ERBB4, ESR1, SYK, INSR, PTPN11, VAV3, MAPK3, and PRKG1. These signatures provide insights into genomic regions and biological pathways that may be involved in lactation-related processes relevant to intermittent milking. The identified genomic regions offer promising targets for functional validation and future genome-informed breeding strategies aimed at conserving this unique indigenous germplasm while improving lactation efficiency and resilience.