Biomedicines最新文献

The journal retracts the article titled "Nicotinamide Ameliorates Amyloid Beta-Induced Oxidative Stress-Mediated Neuroinflammation and Neurodegeneration in Adult Mouse Brain" [...].

Heart failure (HF) is a global health challenge characterized by the heart's inability to satisfy metabolic demands, driven by renin-angiotensin-aldosterone system (RAAS) overactivation, a neurohormonal imbalance, and emerging mechanisms like the gut-heart axis and mitochondrial dysfunction. Affecting over 6 million adults in the US alone, HF incurs a 5-year mortality rate of 50% and escalating costs projected to double by 2030. This review examines HF's molecular paradigms, integrating established pathways with advances in omics, stem cell therapy, genetic modification, and personalized medicine. The RAAS blockade remains central, yet its efficacy is limited in HF with preserved ejection fraction (HFpEF). Stem cell therapies (mesenchymal and induced pluripotent stem cells) show regenerative potential but face poor retention (<10% survival at 30 days). CRISPR/Cas9 offers precision, though off-target effects persist. The gut microbiome, via trimethylamine N-oxide, exacerbates inflammation, while omics technologies promise biomarkers for tailored treatments. Challenges include translating these innovations into practice, particularly for HFpEF. Future directions involve novel HFpEF therapies, enhanced stem cell delivery, precise genetic tools, and microbiome interventions, supported with artificial intelligence. By 2030, these advances could shift HF management toward regeneration, contingent on overcoming translational barriers through global collaboration.

Introduction. The etiology of cardiac amyloidosis (CA) involves the systemic or localized deposition of misfolded amyloid proteins within the myocardial interstitium and valvular structures. The primary objective of this study was to employ three-dimensional speckle-tracking echocardiography (3DSTE) to perform a detailed analysis of the aortic valve annulus (AVA) and left ventricular (LV) strains in CA patients and to compare these parameters with those of matched healthy controls. Methods. The initial cohort for this study comprised 35 individuals diagnosed with CA. However, 12 patients were subsequently excluded from the final analysis due to suboptimal image quality precluding accurate measurement of AVA dimensions and/or LV strains. The final analytical group, therefore, consisted of 23 CA patients (14 males), with a mean age of 64.6 ± 7.1 years. The results obtained from the CA patient group were compared with those of a healthy control cohort comprising 23 individuals (14 males; mean age: 53.2 ± 5.3 years). Results. In CA patients, AVA area was greater in end-diastole in 11 out of 23 cases (48%), and in end-systole in 8 out of 23 cases (35%), while it proved to be equal in 4 out of 23 cases (17%). The ratio of healthy controls with greater end-diastolic AVA area (12 out of 23, 52%) and greater end-systolic AVA area (11 out of 23, 48%) did not differ from that of CA patients. End-diastolic and end-systolic maximum and minimum AVA diameters, areas and perimeters did not differ between CA patients and matched controls. AVA plane systolic excursion (AAPSE) was found to be significantly impaired in all CA patients irrespective of AVA area size. Basal LV radial (RS), circumferential (CS) and longitudinal (LS) strains were reduced in CA patients compared with those of controls. End-systolic AVA dimensions tended to be reduced in CA patients with greater end-diastolic AVA area compared with those with greater end-systolic AVA area. While basal LV-RS and LV-CS proved to be similar between CA subgroups, basal LV-LS tended to be higher in CA patients with greater end-systolic AVA area. Controls with greater end-diastolic AVA area showed lower basal LV-RS and LV-LS compared with those with greater end-systolic AVA area. CA patients with equal end-diastolic and end-systolic AVA area (n = 4) showed similarly reduced AAPSE, basal LV-RS, basal LV-CS and LV-LS. Conclusions. In the presence of CA, the AVA is not dilated; however, its spatial displacement is reduced, suggesting its functional impairment, as represented by AAPSE, possibly due to the reduction in all concomitant LV strain parameters.

In this Special Issue, we honor the memory of a giant within cardiovascular pharmacology, Professor Akira Endo, whose scientific vision profoundly transformed the prevention and treatment of cardiovascular disease [...].

Background: Invasive non-functional pituitary adenomas (NFPAs) are associated with high recurrence and unfavorable clinical outcomes, yet their underlying molecular mechanisms remain incompletely understood. This study aimed to identify robust biomarkers of invasiveness by integrating transcriptional networks, machine learning, and epigenetic regulation. Methods: RNA sequencing was performed on 32 NFPA samples (15 invasive, 17 non-invasive). Weighted gene co-expression network analysis (WGCNA) was used to identify invasiveness-associated modules, which were validated in public datasets (GSE169498, GSE51618). Candidate genes were prioritized using machine learning, and their epigenetic regulation was studied using DNA methylation datasets (GSE207937, GSE115783). Results: We identified a five-gene signature associated with invasiveness (KIFC3, PNMA3, ARHGAP18, LRRC10B, and KCNC4). All five genes were consistently downregulated in invasive NFPAs (all p < 0.01) and were enriched in oxidative phosphorylation and neuroactive ligand-receptor interaction pathways. A machine learning validation approach (Random Forest followed by forward stepwise logistic regression) showed strong discriminative performance for this signature (mean AUC = 0.919). DNA methylation analyses indicated no robust differences at the genome-wide level or across promoter regions of the core genes; nevertheless, several locus-specific CpG sites (e.g., near KIFC3) showed suggestive methylation changes. Conclusions: Using an integrative multi-omics framework, we identified a novel five-gene signature associated with NFPA invasiveness. The coordinated downregulation of these genes may reflect alterations in cellular energy metabolism and microenvironmental signaling. Although the signature demonstrated promising diagnostic potential, its transcriptional repression is unlikely to be primarily explained by DNA methylation. These findings provide candidate markers and mechanistic hypotheses for understanding invasive NFPA and developing risk-stratification tools.

Background: One of the main causes of cancer-related mortality globally is lung adenocarcinoma (LUAD), necessitating the development of novel therapeutic targets. The parathyroid hormone type 2 receptor (PTH2R) exhibits differential expression across multiple cancers, yet its role in LUAD remains unclear. Methods: Through an integrated analysis of multiple public databases (including SangerBox 3.0, UALCAN, Kaplan-Meier Plotter, and TIMER), we identified PTH2R-a member of the family B1 GPCRs-as a candidate therapeutic target with significant prognostic value in LUAD. Subsequently, the antitumor effects of PTH2R knockdown and melatonin were evaluated through cell proliferation, colony formation, migration, and apoptosis assays. Transcriptome analysis revealed key biological processes and signaling pathways regulated by PTH2R, identified key genes modulated by PTH2R, and validated core gene expression via RT-qPCR. Results: PTH2R is a potential therapeutic target for lung adenocarcinoma. Both PTH2R knockdown and melatonin treatment significantly inhibited LUAD cell proliferation, colony formation, and migration capabilities while promoting apoptosis. Notably, the combination of PTH2R knockdown and melatonin treatment demonstrated synergistically enhanced antitumor effects. Transcriptome analysis revealed two key genes within the PTH2R signaling pathway, and RT-qPCR validated the expression of these two key genes. Conclusions: Our work provides the first evidence confirming the substantial value of PTH2R as a novel therapeutic target for LUAD. It preliminarily demonstrates the mechanism by which melatonin inhibits LUAD by targeting PTH2R, offering crucial experimental evidence and theoretical support for developing precision therapeutic strategies against this cancer.

Human-induced pluripotent stem cells (hiPSCs) have an innate ability to differentiate into the three germ layers: the ectoderm, endoderm, and mesoderm. By using targeted differentiation methods and carefully controlling growth factors, morphogens, and signaling modulators, hiPSCs can be guided to develop into specific lineage cell types. For clinical applications of hiPSCs and their derivatives, it is crucial to use xenogen-free, chemically defined culture media, reagents, recombinant growth factors, morphogens, and extracellular matrix (ECM) scaffolds. One major obstacle is the widespread use of Matrigel as an hiPSC culture matrix. Matrigel, derived from Engelbreth-Holm-Swarm (EHS) mouse sarcoma, is an extract of basement membrane material with a complex, poorly defined, and variable composition. It also exhibits batch-to-batch variability in mechanical and biochemical properties and is difficult to modify, which limits its rational use in the production of therapeutic cells and organoids. Synthetic ECM matrices and scaffolds offer a promising alternative because they can have a fully defined composition, highly tunable physical properties, surface modifications, and functionalization with recombinant signaling peptides and growth factors. This provides a suitable microenvironment for hiPSC culture and the directed differentiation towards lineage-specific cells and organoid development, and can be used in clinical-grade tissue transplantation and regenerative medicine.

Background: Peripheral nerve injury can happen for a variety of causes. Despite major breakthroughs in microsurgery, nerve repair results are not always sufficient. Methods: Thirty-two Wistar albino rats were split into four groups: primary nerve repair (PNR), PNR with vitamin D3 treatment, nerve crush injury (NCI), and NCI with vitamin D3 treatment. In the PNR + D3 and NCI + D3 groups, 1 mcg/kg of vitamin D3 was given intraperitoneally on days 1, 3, 5, and 7 of the 12-week healing period. Electrophysiological measurements were taken prior to the injury. At 12 weeks after damage, a hot plate test was performed to assess acute pain, and the electrophysiological measurements were repeated. Before the rats were sacrificed, biopsy samples from the right sciatic nerve were collected for histopathological evaluation. Results: Post-healing action potential values were not statistically different between the PNR and PNR + D3 groups; however, they were considerably lower in the NCI + D3 group than in the NCI group. The reaction time in the hot plate test was considerably slower in the D3-treated groups compared to the control groups. Histopathology score was substantially higher in the PNR + D3 group as compared to the PNR group, and lower in the NCI + D3 group as compared to the NCI group. Conclusions: Other than improved myelination, vitamin D3 treatment following primary repair of transected nerves produced no statistically significant improvement. Vitamin D3 treatment caused a negative impact on the crush injury, as assessed by the findings of histopathology and electrophysiological measurements. Overall, the results indicate that the efficacy of vitamin D3 treatment may vary depending on the type of injury.

Background: Sepsis remains a leading cause of morbidity and mortality worldwide, where timely and accurate pathogen detection is critical for improved outcomes. Conventional blood cultures are the gold standard but are limited by prolonged turnaround times and suboptimal sensitivity, often delaying targeted therapy. Methods: This single-center retrospective study evaluated the diagnostic performance and clinical utility of the T2Bacteria and T2Resistance Panels compared with conventional blood cultures in 30 adult patients admitted to the cardiovascular intensive care unit with a suspected bloodstream infection. Results: The T2Bacteria Panel demonstrated high diagnostic accuracy for on-panel organisms (100%), detecting all cases of Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, while blood cultures detected 9 of 12 on-panel infections. In contrast, two off-panel organisms were isolated from five patients exclusively by blood cultures, highlighting the complementary roles of both methods. Importantly, antimicrobial therapy was modified in 6 of 10 T2-positive patients (60%) based on T2 results, preceding blood culture reporting by a median of more than 100 h. Conclusions: These findings underscore the value of T2 assays in enabling earlier, evidence-based therapeutic decisions and supporting antimicrobial stewardship. While limited by the sample size and single-center design, these findings-consistent with pathogen distributions reported in European ICU settings-suggest that integrating T2-based diagnostics into cardiovascular ICU workflows may enhance early therapeutic decision-making and antimicrobial stewardship.

Background: Chronic periodontitis is a prevalent inflammatory disease. It goes beyond the oral cavity, exerting systemic immunomodulatory effects through continuous low-grade inflammation, microbial dysbiosis, and cytokine spillover. Accumulating evidence suggests that the immunological consequences of periodontitis may influence systemic immune homeostasis and alter responses to cancer immunotherapies, specifically checkpoint blockade. Objectives: This narrative review describes how periodontal inflammation induces systemic immune reprogramming. It also investigates possible effects on the efficacy of immunotherapy. Methods: The paper synthesizes current findings on molecular and cellular mechanisms linking periodontitis to immune dysfunction. It underscores the mutual signaling pathways NF-κB, STAT3, and PD-1/PD-L1 that connect oral and systemic immunity. Results: Chronic periodontal inflammation reprograms innate and adaptive immune responses. It elevates proinflammatory mediators, such as IL-1β, IL-6, and TNF-α. It alters T-cell polarization and promotes myeloid cell "training". This process may lead to immune exhaustion, impaired antigen presentation, and treatment resistance. Preclinical and new clinical data suggest that controlling periodontal inflammation may partially reduce systemic inflammatory burden, although clinical evidence in immunotherapy-treated cancer cohorts remains limited. Conclusions: Periodontal health should be considered in the management of immunotherapy. This can facilitate new studies that integrate oral and systemic immunology. Understanding the two-way link between periodontal inflammation and systemic immune reprogramming may offer fresh opportunities for personalized immunomodulation and combined interventions.