搜索结果：Biochimica

This special volume of Biochimica et Biophysica Acta - Molecular Basis of Disease showcases a transformative era in biomedical research, driven by the convergence of multi-omics technologies, artificial intelligence (AI), and systems biology. The volume is focused across eight thematic sections-spanning cancer, inflammatory and infectious diseases, neurodegeneration, cardiovascular health, autophagy, respiratory disease, and heme biology-this volume highlights how integrative methodologies are helping to simplify the complexity of disease mechanisms. These studies discuss not only biomarker discovery and disease mechanisms, but also how redox biology, lipidomics, machine learning, and proteogenomics are redefining pathophysiological frameworks. From spatial omics in colorectal cancer to ferroptosis in asthma and sepsis, these contributions demonstrate the translational power of different network analysis and validations. Key challenges-including standardization, ethical integration of AI, and global infrastructure gaps-are also addressed as future imperatives. Together, the articles in this volume serve not just as a repository of high-impact findings, but as an example of the roadmap toward precision medicine where diagnostics, therapies, and prognoses are tailored to the molecular individuality of each patient. This collection establishes BBA - Molecular Basis of Disease as a leading platform for next-generation disease biology and personalized healthcare innovation.

Claudin-3, Claudin-4, and Claudin-7 are expressed on the surface of epithelial cells. Their absence in neoplastic cells of epithelial origin is an aggressiveness marker in different cancers. The NF-YA gene codes for the Nuclear-Transcription-Factor-Y-Subunit-A, which is overexpressed in various tumors. In tumors, the relative ratio of the two major NF-YA alternative splicing isoforms, NF-YA long and NF-YA short, is associated with a mesenchymal phenotype and a poor prognosis. Based on a high NF-YA long/NF-YA short ratio, we generated a 158-gene signature that is common to Claudinlow Breast Carcinomas (BRCA) and Stomach Adenocarcinomas (STAD). To better classify STAD Claudinlow tumors, we employed a hierarchical clustering approach based on our 158-gene signature to classify STAD into a Claudinlow subgroup. We tested the classification potential of our signature in TCGA as well as in two additional datasets of tumors. We used the deep-learning DeepCC tool and the 158-gene signature to classify the STAD cell lines available in the CCLE platform. Obtained data were validated with qRT-PCR and Western blots. The 158-gene signature resulted in the selection of a STAD subgroup with effective Claudinlow expression and with a high NF-YA long/NF-YA short ratio. This Claudinlow subgroup was separated from the EMT subgroup of STAD and it is characterized by poor clinical outcome. We identified nine Claudinlow STAD cell lines with a high NF-YA long/NF-Y short ratio and validated the expression of selected markers. Our work supports the notion that three overlapping features-low expression of Claudin-3/4/7, high NF-YA long/NF-YA short ratio and a 158-gene signature-mark a specific subset of STAD characterized by mesenchymal features and poor prognosis.

A plethora of studies have demonstrated the pathophysiological roles played by paraxonase 2 (PON2) in oxidative stress control, inhibition of apoptosis, infections, and the progression of various types of malignancies. The continuous interest in PON2 has not gone hand in hand with the development of its inhibitors. Indeed, only one inhibitor for PON2, namely TQ416, is known, although neither its preparation nor a systematic structure-activity relationship analysis has been so far reported. Herein, we outline the first study aimed at the definition of structure-activity relationships of TQ416 by the preparation of a small library of its analogues. Successfully, we identified some [1,2,4]triazolo[4,3-a]quinoline derivatives more potent than TQ416 as PON2 inhibitors, and among them one endowed with an IC50 value in the nanomolar range. We tested the parent TQ416 and its most effective congener 2 in cells showing their effectiveness and complex behaviour.

Cardio-oncology has traditionally focused on treatment-related cardiovascular toxicity and conventional cardiovascular risk factors. However, increasing evidence suggests that environmental exposures may contribute to both cancer development and cardiovascular disease through shared biological mechanisms. Endocrine-disrupting chemicals (EDCs) are ubiquitous environmental contaminants capable of interfering with hormonal signaling, metabolic homeostasis, vascular function, and inflammatory pathways. Despite growing evidence linking EDCs to cardiometabolic disorders and hormone-sensitive malignancies, their potential role within the cardio-oncology continuum remains largely unexplored. This narrative review summarizes and critically discusses current experimental, translational, and epidemiological evidence regarding the potential contribution of environmental endocrine disruptors to cardiovascular risk and cancer biology. Particular attention is given to molecular pathways relevant to cancer therapy-related cardiovascular toxicity, breast cancer biology, adipose tissue dysfunction, and emerging exposomic determinants of long-term cardiovascular outcomes in patients with cancer. Major classes of EDCs, including bisphenols, phthalates, per- and polyfluoroalkyl substances (PFAS), persistent organic pollutants (POPs), parabens, pesticides, and other environmental contaminants, are continuously encountered through food systems, plastics, consumer products, contaminated water, and healthcare materials. These compounds influence multiple biological processes that are central to both oncogenesis and cardiovascular disease, including oxidative stress, mitochondrial dysfunction, endothelial injury, chronic inflammation, metabolic reprogramming, thrombosis, and epigenetic remodeling. In breast cancer, EDCs may modulate subtype-specific signaling pathways involving estrogen receptor activation, HER2 crosstalk, aryl hydrocarbon receptor signaling, and homologous recombination networks. In parallel, growing evidence supports associations between EDC exposure and hypertension, accelerated atherosclerosis, heart failure, metabolic syndrome, and major adverse cardiovascular events. We further discuss the hypothesis that lipophilic EDCs may accumulate within adipose depots and that dysfunctional epicardial adipose tissue could represent a local toxicological niche capable of amplifying cardiovascular vulnerability in cancer survivors, although direct evidence remains unavailable. EDCs should not yet be considered established cardio-oncology risk factors; however, they represent biologically plausible exposomic modifiers operating at the intersection of cancer, metabolism, and cardiovascular disease. Incorporating environmental exposures into cardio-oncology research may improve understanding of interindividual variability in cardiovascular outcomes and open new avenues for risk stratification, prevention, and survivorship care. Future prospective studies integrating exposure biomarkers, adipose tissue biology, and cardiovascular phenotyping are warranted to define the clinical relevance of EDCs in patients with cancer.

暂无摘要（点击查看详情）

Patients with end-stage renal disease (ESRD) undergoing chronic hemodialysis (HD) frequently report the sensation of prostration, tiredness, weakness, exhaustion, weariness, or fatigue after the hemodialysis treatment. This condition is defined as post-dialysis fatigue and significantly impairs patients' ability to perform routine daily activities. The present study aims to investigate whether territorial or environmental factors such as differences in geographic areas are associated with the prevalence and characteristics of post-dialysis fatigue and time to recovery after dialysis among chronic HD patients. A total of 465 patients from six Italian HD units, located in both northern and central Italy, were enrolled between January and December 2024. Exclusion criteria included a dialysis duration of less than 1 year and a diagnosis of dementia, acute infectious disease, or active cancer. For each participant, demographic, clinical, and laboratory data were collected. The results showed that 61.5% of the patients reported suffering from post-dialysis fatigue. The prevalence and characteristics of post-dialysis fatigue, as well as the length of time to recovery after dialysis, varied significantly among the six HD units. Multivariate analyses revealed that the hemodialysis unit itself was the main variable significantly and independently associated with both post-dialysis fatigue and time to recovery after dialysis. Our findings suggest that environmental factors such as differences in geographic areas are associated with the prevalence and characteristics of post-dialysis fatigue and time to recovery after dialysis among chronic HD patients.

Liver transplantation (LT) remains the definitive treatment for end-stage liver disease, yet early detection of graft dysfunction and rejection is still challenging. Conventional blood-based markers provide systemic information but lack hepatic specificity. Bile, directly secreted by hepatocytes and cholangiocytes, represents an organ-specific biofluid with diagnostic potential for assessing graft viability and early complications. This minireview examined the biochemical, immunological, and molecular features of bile as biomarkers in LT, focusing on pH, bicarbonate, glucose, lactate, bile acids, and proteomic/lipidomic profiles in relation to ischemia-reperfusion injury, early allograft dysfunction, and ischemic-type biliary lesions. The integration of bile-based parameters into ex situ perfusion and post-transplant monitoring, supported by omics technologies and predictive modeling, was also discussed. Building on these insights, we designed a single-center prospective study (ClinicalTrials.gov: NCT03882164) evaluating biliary tacrolimus (TACbile) as a predictor of acute rejection after LT. Paired daily TACbile and plasma tacrolimus levels are measured in recipients with Kehr T-tubes to define a blood-bile ratio of tacrolimus. The primary endpoint was the predictive accuracy of blood-bile ratio of tacrolimus for biopsy-proven rejection; secondary outcomes include associations with early allograft dysfunction. Bile-based biomarkers, particularly TACbile, may revolutionize graft monitoring and personalize immunological surveillance after LT.

Physical exercise (PE) exerts beneficial effects in people with multiple sclerosis (pwMS). Preclinical studies in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, indicate that PE may attenuate key pathological features of the disease, including immune dysregulation and inflammation-driven synaptotoxicity, although the underlying mechanisms remain unclear. Clinical evidence, however, is still limited and fragmented, leaving the disease-modifying potential of PE in MS largely unresolved. Here, we investigated the impact of PE on T cell immunometabolic function and its downstream consequences on synaptotoxicity in both EAE mice and progressive MS (PMS) subjects, also assessing the contribution of vagal innervation to PE-mediated effects in the EAE model. Specifically, we found that PE improved EAE clinical course, by mitigating neuronal damage and modulating peripheral T cell proliferation, activation, and metabolic activity. These beneficial effects were partially blunted by preventive cervical vagotomy, suggesting a role for vagal integrity in mediating PE-driven neuroimmune modulation. In PMS subjects, a structured PE program improved clinical functional outcomes and enhanced mitochondrial respiration in peripheral T cells. Moreover, patch-clamp recordings revealed that glutamatergic synaptotoxicity induced by PMS-derived T cells was abolished following PE. Together, these findings highlight the therapeutic potential and disease-modifying value of PE in MS and suggest the vagal pathway as a key modulator of exercise-induced neuroimmune benefits.

Background: Thyrotropin (TSH), even in the normal range, is associated with components of cardiometabolic syndrome. We aimed to assess the relation between TSH and cardiovascular (CV) risk in euthyroid patients with overweight/obesity without previous cardiac events. Methods: A total of 1588 subjects (1132 females, mean age 53 &#xb1; 14 years) were recruited. This was an observational study. TSH, body mass index, waist circumference (WC), creatinine, hepatic enzymes, homocysteine, C reactive protein, glycated hemoglobin, homeostatic model assessment for insulin resistance (HOMA-IR), basal and 2 h glucose and insulin, fibrinogen, uric acid, a complete blood count, a complete lipid profile, and blood pressure were measured in all subjects. The Atherosclerotic Cardiovascular Disease (ASCVD) risk score was calculated. Results: More severe degrees of obesity were associated with higher TSH quartiles; specifically, 33% of subjects with grade III obesity had TSH in the 75th percentile. Multiple regression showed that female gender (t-value 3.6, p < 0.001), HOMA-IR (1.9, &#x2264;0.05) and aspartate transaminase (AST; 2.8, <0.01) represent independent determinant factors affecting TSH levels in the population at higher CV risk (intermediate-high ASCVD risk score > 7.5%; n = 709). Similarly, TSH determinants in subjects with central obesity (n = 1197, WC >102 cm males, >88 cm females) were female gender (2.2, <0.05), HOMA-IR (2.7, <0.01) and smoking habit (-2.3, <0.5). Moreover, there was no significant relationship between TSH and ASCVD risk score. Conclusions: Higher TSH levels in the euthyroid range are related to high degrees of obesity and some CV risk factors, in subjects at higher cardiometabolic risk; however, for the different weight and sign of CV determinants (e.g., smoking habit) on the TSH system, the ASCVD risk score cannot evidence this relationship.

Strong evidence links Epstein-Barr virus (EBV) infection to Multiple Sclerosis (MS). Peginterferon beta-1a (peg-IFN), currently the most used interferon formulation among first-line treatments in MS, displays immunomodulatory, anti-inflammatory, and antiviral properties and remains also an important therapeutic option in conditions such as pregnancy, lactation and aging patients. In this study we evaluated the ability of peg-IFN to restore a homeostatic EBV-host interaction in MS by regulating antiviral and immunometabolic responses. In people with MS (pwMS), peripheral blood mononuclear cells (PBMCs) were analyzed before (T0) and after six months (T6mos) of peg-IFN administration: IFN-stimulated gene (ISG) levels, EBV DNA load, Epstein-Barr nuclear antigen 2 (EBNA2) allele distribution, and T-lymphocyte phenotyping with glycolytic metabolism were assessed. Peg-IFN increased ISG transcription and glycolysis in CD4+ T lymphocytes, and reduced EBV DNA load without altering EBNA2 allele distribution. Notably, ISG expression increase at T6mos in pwMS infected by the non-risk 1.3B EBNA2 allele, correlating with a better long-term response to peg-IFN after 2-years. Lower T-cell glycolytic capacity at T0 predicted higher peg-IFN responsiveness in pwMS carrying the 1.3B allele, suggesting that EBNA2 variants might be predictive of response to peg-IFN. Here, we found that infection with MS-associated EBNA2 variants might be involved in the clinical response to peg-IFN therapy. The predictive model developed, which integrates immunological and viral parameters, may help clinicians in a finer selection of first-line therapies tailored to patient profiles, supporting personalized medicine approaches.

The aim of this study is to assess the discrepancies between potassium values obtained from point-of-care testing and laboratory analyzers, and to propose a straightforward method to indirectly assess the likelihood of hemolysis in whole blood samples. The data were collected from 409 hospitalized patients (199 males, 210 females; median age 78&#xa0;years, interquartile range 55-87) in whom were simultaneously requested the blood gas profile, including electrolytes (Na, K, Cl and Ca2+) on the GEM Premier 5000 blood gas analyzer and K in plasma samples on the Cobas analytical system. The Wilcoxon test showed a significant difference (p<0.0001) for K measurements, with a number of positive differences between Cobas and GEM Premier 5,000 of 110 and negative differences of 293. The median value of the hemolysis index was 7 (95&#x202f;% CI for the median 6 to 8). The differences between the two K measurements obtained from plasma and whole blood samples showed a lowest and highest differences of&#xa0;-1.7 and 4.6&#x202f;mmol/L. The median difference was 0.63 (95&#x202f;% CI for the median: 0.54-0.73) and the interquartile range (IQR) was 0.48-0.9. Overall, 89 samples (21&#x202f;%) displayed a difference larger than the relative change&#xa0;value. The presence of hemolysis in plasma samples should alert laboratory professionals to carefully evaluate the corresponding whole blood results. Concordant values indicate the presence of hemolysis in the whole blood sample, while discordant values suggest that hemolysis only affects one of the two samples.