Search Results (38,948)

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by high metabolic activity, chronic endoplasmic reticulum stress, and persistent redox imbalance. Excessive immunoglobulin synthesis and adaptation to the hypoxic bone marrow microenvironment lead to sustained production of reactive oxygen species (ROS). Their excessive accumulation promotes genomic instability, disease progression, osteolytic bone disease, and resistance to therapy. Paradoxically, MM cells adapt to oxidative stress by activating antioxidant and metabolic defense mechanisms, including Nuclear factor erythroid 2-related factor 2 (NRF2)- and Heme Oxygenase 1 (HMOX1)-dependent pathways, metabolic reprogramming, and overexpression of ROS-scavenging enzymes such as peroxiredoxin 6 (PRDX6), allowing survival at the threshold of oxidative toxicity. Evidence indicates that biomarkers of oxidative stress—such as lipid and protein oxidation products, antioxidant enzyme activity, and the Oxidative Stress Score—correlate with disease stage, prognosis, and treatment response. Redox-modulating therapeutic strategies, including pharmacological ROS induction, inhibition of antioxidant defenses, and the use of natural pro-oxidant compounds, are emerging as promising adjuncts to standard MM therapies. Recent studies also highlight the gut microbiota as an indirect regulator of oxidative balance, immune modulation, and metabolic homeostasis in MM. This review summarizes current knowledge on oxidative stress in multiple myeloma, emphasizing its role in pathogenesis, drug resistance, biomarker development, and emerging therapeutic and supportive strategies. Full article

Mitophagy serves as an essential quality control mechanism that maintains mitochondrial homeostasis through selective autophagic clearance of damaged organelles. Vascular dementia (VD) has been increasingly associated with mitophagy dysregulation in recent studies. However, the precise molecular mechanisms underlying mitophagy’s involvement in VD pathogenesis remain poorly characterized. To elucidate the role of mitophagy in VD, we systematically examined the expression of key mitophagy pathways in hippocampal neurons of bilateral common carotid artery occlusion (BCCAO) rats and in oxygen–glucose deprivation (OGD)-treated HT22 cells. Intriguingly, under autophagy-deficient conditions, both BNIP3 and BNIP3L were markedly downregulated, whereas FUNDC1 expression increased; PINK1/Parkin levels remained unaltered. To further dissect the functional contributions of BNIP3 and BNIP3L, we administered the mitochondrial fission inhibitor Mdivi-1 to BCCAO model rats. Histopathological analysis revealed pronounced neuronal damage and apoptosis in the hippocampal region, which was further exacerbated upon Mdivi-1 treatment. In vitro, BNIP3 silencing significantly compromised cell viability, elevated reactive oxygen species (ROS) accumulation, disrupted mitochondrial membrane potential (ΔΨm), suppressed mitophagy, and increased apoptotic rates. Conversely, BNIP3 overexpression reversed these detrimental effects. Notably, treatment with the autophagy inhibitor 3-methyladenine (3-MA) diminished LC3B-Tomm20 colocalization and intensified apoptosis, reinforcing the critical role of BNIP3-mediated mitophagy in neuronal survival. Similarly, BNIP3L overexpression enhanced cell viability, attenuated ROS production, restored ΔΨm, and mitigated apoptosis, while 3-MA treatment again impaired mitophagic flux and worsened cell death. Collectively, these findings underscore the critical and distinct roles of BNIP3 and BNIP3L in maintaining mitochondrial homeostasis and neuronal survival under ischemic conditions. Full article

Background: Multiple myeloma remains an incurable malignancy in which patients ultimately experience relapses and refractory disease despite therapeutic advances. Triple-class exposed relapsed/refractory MM (TCE/RRMM) patients represent both a population with high unmet clinical needs and a substantial economic burden for the Italian National Health Service (NHS). Recently, BCMA-CD3 bispecific antibodies, including elranatamab and teclistamab, have expanded the treatment options for these patients. This study aimed to evaluate the cost-effectiveness of elranatamab versus teclistamab in adults with TCE/RRMM from the Italian NHS perspective. Methods: A partitioned survival model with three health states—progression-free survival, post-progression survival, and death—was developed over a 25-year lifetime horizon, adopting weekly cycles and a 3% annual discount rate. Clinical data for elranatamab were derived from the MagnetisMM-3 trial, while teclistamab outcomes were estimated through matching-adjusted indirect comparisons using MajesTEC-1 data. Direct medical costs included those associated with drug acquisition and administration, disease management, adverse event management, and end-of-life care. Utility values were obtained from EQ-5D-based assessments in MagnetisMM-3. Deterministic and probabilistic sensitivity analyses were performed to test model robustness. Results: Elranatamab yielded 3.31 life-years and 2.33 QALYs per patient, compared with 1.83 life-years and 1.27 QALYs for teclistamab. Total lifetime costs were lower for elranatamab (EUR 153,337) versus teclistamab (EUR 224,610), generating EUR 71,273 in savings. Thus, elranatamab is considered to be dominant, due to its higher efficacy and lower cost. Furthermore, the robustness of these findings was confirmed through sensitivity analyses. Conclusions: From the Italian NHS perspective, elranatamab represents a clinically superior and economically favorable option for patients with TCE/RRMM. The obtained results support its value and sustainability within the national treatment landscape. Full article

Chronic kidney disease (CKD) involves uremic toxin-driven tubular injury and systemic vascular dysfunction, in which mitochondrial impairment and apoptotic cell loss contribute to progressive tissue deterioration. Accordingly, a targeted EV platform is required to enable efficient miRNA delivery to the toxin-stressed tubular–endothelial compartment. Based on our previous study showing that melatonin restores miR-4516 levels under CKD-related stress, we directly loaded miR-4516 into engineered extracellular vesicles (EVs) to evaluate its effects on mitochondrial function and cell survival. Here, we engineered EVs with a G3-C12/RGD surface modification and established a miR-4516 loading strategy to enhance delivery to kidney proximal tubule cells and vascular endothelial cells. miR-4516 loading increased EV-associated miR-4516 levels without major changes in particle size distribution, and EV identity was supported by CD9 and CD81 expression. Confocal microscopy and flow cytometry demonstrated increased cellular uptake of miR-4516-loaded G3-C12/RGD-EVs compared with control EVs in TH1 proximal tubule cells and HUVECs. Under indoxyl sulfate stress, engineered EV treatment restored intracellular miR-4516 and improved mitochondrial function, as indicated by recovery of respiratory Complex I and Complex IV activities and improved Seahorse bioenergetic parameters (OCR/ECAR, basal and maximal respiration, ATP-linked respiration, and spare respiratory capacity). Annexin V staining further indicated reduced toxin-induced apoptosis. In an adenine diet-induced CKD mouse model, intravenous administration of miR-4516-loaded G3-C12/RGD-EVs improved urinary albumin-to-creatinine ratio (UACR), blood urea nitrogen (BUN), and serum creatinine. These findings indicate that miR-4516-loaded, targeting-engineered EVs may mitigate uremic toxin-associated mitochondrial dysfunction and renal impairment in CKD. Full article

Vertical transmission of plant pathogenic viruses is an important component of viral persistence, survival, and spread in agricultural production systems. This type of transmission is of considerable economic significance as it can cause major crop losses by serving as the initial focus of infection for future epidemics. Vertical transmission occurs when a virus is passed on to offspring either by direct invasion of the developing seed embryo from infected mother plants or through infected pollen grains after fertilization. We have recently demonstrated via high-throughput sequencing that mature seeds of the agriculturally important forage crop alfalfa (Medicago sativa L.) are associated with a broad range of viruses, some of which could potentially spread over long distances via seed. With the exception of the alfalfa mosaic virus, little is currently known about viral transmission through alfalfa pollen and its subsequent impact on the disease epidemiology of the crop. The objective of this study was to screen pollen from diverse alfalfa genotypes for pathogenic viruses and assess their risk of transmission. The pollen was collected from alfalfa genotypes selected for fungal disease resistance and agronomic performance in the USDA ARS pre-breeding program in Prosser, WA. Full article

Background/Objectives: Clonal evolution is mainly defined based on the appearance or expansion of clones harboring specific somatic mutations and/or cytogenetic abnormalities, whereas few studies have investigated immunophenotypic heterogeneity assessed by flow cytometry and its relationship with disease progression. In this study, flow cytometry immunophenotyping of acute myeloid leukemia (AML) was carried out to identify phenotypic subclones based on antigen expression and to investigate clonal sweep. Methods: A total of 24 patients diagnosed with AML followed at the Hematology and Transplant Center of Salerno were included. Bone marrow or peripheral blood specimens were subjected to flow cytometry immunophenotyping and leukemic cell characterization. Phenotypic profiles were also compared to molecular alterations detected by next-generation sequencing. Results: We found that flow cytometry-defined clonal heterogeneity was more complex than molecular heterogeneity at diagnosis and disease relapse. Flow cytometry enabled the identification of small phenotypic subclones that were not detected by molecular profiling and that, in several cases, expanded over time, consistent with a phenotypic clonal sweep. The presence of small clones was associated with shorter progression-free survival and overall survival. Conclusions: Flow cytometric clonal heterogeneity, especially the presence of small clones (defined by antigen expression from 2 to 30%), may serve as an additional prognostic factor in AML. Immunophenotyping integrated with molecular data may improve risk stratification, enhance measurable residual disease assessment, and contribute to a more personalized disease monitoring strategy. Full article

Beach sands may harbor human pathogens and antibiotic resistance genes, prompting the proposal of low-dose quicklime (CaO; 1–3% w/w) as a remediation strategy to improve microbiological quality in highly contaminated areas. After application, CaO is converted into calcium carbonate (CaCO₃), yet the ecological effects of this residual compound on benthic fauna remain poorly understood. This study evaluated the short-term impact of CaCO₃-enriched sediment (3% w/w) on the Manila clam, Ruditapes philippinarum, under controlled mesocosm conditions. Adult clams were exposed for one week, and survival, burrowing behavior, feeding- and metabolism-related parameters (clearance, ingestion, absorption efficiency and rate, ammonia excretion), and oxidative stress (malondialdehyde, MDA) were assessed using a hierarchical design, with a tank as the experimental unit. No significant differences were detected between control and CaCO₃-enriched treatments for any measured endpoint. Survival remained high, functional responses showed overlapping ranges, and MDA levels did not differ significantly between groups. Although limited to short-term exposure and a single concentration, these findings suggest that residual CaCO₃ derived from quicklime application did not induce detectable adverse effects in adult R. philippinarum under the tested conditions. Further long-term and multi-species studies are needed to confirm ecological safety. Full article

The management of Culex pipiens (Diptera: Culicidae), key vectors of arboviruses like West Nile virus, necessitates sustainable alternatives to chemical insecticides. This study screened indigenous entomopathogenic fungi (EPF) from forest soils in Achaia, Greece, for their larvicidal efficacy against Cx. pipiens biotype molestus. Fifteen fungal isolates were obtained via insect baiting and identified as Beauveria and Metarhizium species. A comprehensive bioassay at 1 × 10⁸ conidia mL⁻¹ revealed significant variation in pathogenicity after 72 h. Two isolates, Beauveria bassiana (BB) (Hypocreales: Cordycipitaceae) and Metarhizium anisopliae (K3(1)) (Hypocreales: Clavicipitaceae), exhibited the highest virulence among the tested isolates, each causing 60% mortality with a rapid median lethal time (LT₅₀) of ~18.5 h. Survival analysis, Cox modeling, and non-linear kinetic modeling (Gompertz/Richards) classified three distinct virulence clusters: high/rapid, moderate/consistent, and low/delayed. A pathogenicity network analysis and a composite virulence index further validated BB and K3(1) as the most effective candidates. These results demonstrate the high isolate specificity of fungal efficacy and underscore the importance of screening local fungal diversity. The identified high-virulence isolates represent promising, environmentally sound candidates for the development of targeted biopesticides. Future research should focus on formulation for aquatic environments and integration into resistance-resilient integrated vector management programs. Full article

Neurodegeneration and cancer are fundamentally distinct disorders: one signifies gradual neuronal loss while the latter signifies uncontrolled cell growth and survival. However, emerging evidence explores an inverse association between these conditions, suggesting that they do not arise from independent biological processes. Understanding the context-dependent behaviour of major pathways (for example, p53, PI3K/AKT/mTOR, Wnt, and immune–stress signaling) remains pivotal in elucidating the relationship between these two diseases. Pathways promoting early-life fitness, tissue repair, and tumor suppression in dividing cells can become detrimental later in life for post-mitotic neurons. Cross-species genomics studies reveal how evolution has repeatedly adapted these shared networks to balance cancer resistance with survival. Research on species exhibiting exceptional longevity and disease resistance, including naked mole rats and bowhead whales, shows that cancer resistance and longevity are not fixed traits but rather are controlled by precise regulatory mechanisms. In this review, we integrate insights from broad species genomics and multi-omic and single-cell studies to understand how evolutionarily conserved molecular crosstalks diverge at the interface of cancer and neurodegeneration. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by irreversible fibrosis. Aberrant cell differentiation plays a crucial role in the development of IPF. Although recent studies have suggested that mitochondrial dysfunction may play a role in IPF, its direct impact on fibrosis remains unclear. This study aimed to clarify the role of mitochondria in lung cell differentiation and pulmonary fibrosis development by employing mito-mice ND6^M, in which the activity of respiratory chain complex I is decreased due to a mitochondrial DNA mutation (G13997A). Pulmonary fibrosis was induced by administering bleomycin (BLM) to both wild-type and mito-mice ND6^M. Bone marrow-derived macrophages and primary lung fibroblasts, generated from both types of mice, were analyzed to evaluate M1/M2 polarization and myofibroblast differentiation, respectively. Compared to wild-type mice, mito-mice ND6^M exhibited more severe fibrosis and lower survival rates following BLM inoculation. Lactate production in the lungs after BLM administration was significantly higher in mito-mice ND6^M than in wild-type mice. TGF-β1-treated fibroblasts from mito-mice ND6^M exhibited increased α-smooth muscle actin expression. While type I collagen expression was not different between these mice, TGF-β1-induced expression of phosphoserine phosphatase and serine hydroxymethyltransferase2, two of the enzymes involved in the serine–glycine pathway, was significantly higher in mito-mice ND6^M than in wild-type mice. On the other hand, mitochondrial dysfunction had a small effect on pulmonary inflammation and on M1/M2 macrophage polarization. In conclusion, mitochondrial dysfunction promotes TGF-β1-induced myofibroblast differentiation and BLM-induced pulmonary fibrosis. Mitochondria-dependent metabolic reprogramming may therefore represent a promising therapeutic target in IPF. Full article

Background: Persistent endodontic infections involving Enterococcus faecalis and Candida albicans are a major cause of root canal treatment failure. Although conventional irrigants, such as sodium hypochlorite and chlorhexidine (CHX), exhibit strong immediate antimicrobial activity, microbes may survive and recover from the initial antimicrobial effect, hence limiting their effectiveness, especially in complex root canal anatomies and in the apical terminus of the tooth. Antibacterial dressing techniques were not proven satisfactory due to depletion of the antibacterial component or difficulty in spreading it evenly along the entire root canal. This study aimed to develop and evaluate the antimicrobial efficacy and release characteristics of a novel sustained-release device (SRD), delivering CHX via gutta-percha points coated with a sustained-release formulation used as a temporary intracanal medicament. Methods: Gutta-percha points were coated with two sustained-release CHX varnishes (CHX1 and CHX2) or a placebo and assessed in vitro. Antimicrobial activity against E. faecalis and C. albicans was evaluated using agar diffusion assays over time. Release kinetics were analyzed using Rhodamine-labeled SRD in a 3D-printed acrylic molar tooth model via fluorescence microscopy. Additionally, biofilm-infected acrylic molar teeth were treated with a placebo, a single 2% CHX irrigation, or SRD-coated gutta-percha points placed as an intracanal dressing prior to obturation. Microbial viability was quantified by colony-forming unit (CFU/mL) analysis from root canals and gutta-percha points. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post hoc multiple comparison test (p < 0.05). Results: SRD-coated gutta-percha points demonstrated sustained antimicrobial activity for up to 21 days against E. faecalis and 19 days against C. albicans. Fluorescence analysis, in an acrylic tooth model, confirmed continuous release for up to 15 days, with pronounced diffusion in the isthmus and palatal canals. In biofilm-infected acrylic teeth models, SRD treatment resulted in a significant reduction of 2–3 log₁₀ CFU/mL compared to placebo groups (p < 0.001) and prevented microbial rebound over the 14-day observation period. In contrast, a single application of 2% CHX solution showed only transient reduction followed by regrowth. Conclusions: Sustained-release CHX delivery via polymer-coated gutta-percha points provided prolonged antimicrobial activity against bacterial and fungal biofilms compared to conventional single-dose CHX application in this in vitro model. These findings support the potential use of coated gutta-percha points as a removable intracanal drug delivery platform prior to final obturation, although further studies incorporating direct-release quantification and in vivo validation are required before clinical translation. Full article

Soil is essential for human survival, with approximately 95% of global food production originating from land. However, over the past century, overexploitation has led to soil degradation and biodiversity loss, with significant impacts on agroecosystems. Portuguese agriculture faces diverse challenges, particularly in the horticultural sector, which occupies substantial territory and supports key economic chains. Consequently, indicators for assessing soil quality are crucial, with mesofauna serving as sensitive bioindicators due to their ecosystemic roles. Among sustainable practices, cover crops are believed to mitigate soil issues by enhancing the biotic functionalities. This study aimed to evaluate the impact of cover crops on soil biological quality in horticultural systems in Portugal. From 2022 to 2025, six horticultural fields in the Alentejo, Ribatejo, and Oeste regions were assessed, introducing cover-crops before main crops and comparing them to controls. Soil samples were collected during cover and main crop presence; mesofauna was extracted via Berlese-Tullgren funnels and classified under the QBS-ar methodology. Results showed enhanced soil biological quality (p < 0.001) in cover crop plots compared to controls, with no significant differences across regions (p = 0.66) or crop types (p = 0.37), indicating the implementation of cover crops as the primary driver for enhanced soil health. Full article

Background and Objectives: The benefits of prophylactic supraclavicular lymph node dissection for esophageal squamous cell carcinoma (ESCC) remain controversial. This study investigated whether prophylactic supraclavicular (cervical) lymphadenectomy improves the long-term outcomes of patients with upper or middle thoracic esophageal squamous cell carcinoma. Materials and Methods: This retrospective, single-center study included 290 patients who underwent thoracoscopic esophagectomy between January 2010 and December 2017. Patients treated with two-field lymphadenectomy (2FL) were compared with those who underwent prophylactic three-field lymphadenectomy (p3FL) after propensity score matching based on age, tumor location, clinical T and N stage, and preoperative treatment. The primary outcome was overall survival (OS), and secondary outcomes included postoperative complications and recurrence patterns. In a secondary analysis, the long-term outcomes were assessed in patients with solitary postoperative cervical (supraclavicular) lymph node recurrence in the 2FL group. Results: In the overall cohort, statistically significant differences were observed between the groups with respect to age, tumor location (p = 0.0002), cT and cN stages (p < 0.0001 and p < 0.0001), preoperative treatment (p = 0.02). No significant differences were observed between groups regarding age, organ for reconstruction, or postoperative complications. After propensity score matching, no significant differences were observed between the 2FL and p3FL groups in terms of overall survival or postoperative complications. Six patients (4.4%) in the p3FL group had pathologically confirmed supraclavicular lymph node metastasis, whereas four patients (2.6%) in the 2FL group developed solitary postoperative cervical lymph node recurrence. Patients with isolated cervical recurrence achieved favorable long-term survival following additional treatment. Conclusions: Prophylactic cervical lymphadenectomy did not improve the survival of patients with upper or middle thoracic esophageal squamous cell carcinoma. Given the low incidence of isolated cervical lymph node recurrence and the favorable outcomes achievable with additional treatment, routine prophylactic supraclavicular dissection appears unnecessary when two-field lymphadenectomy is feasible. Full article

Background/Objectives: Ovarian cancer is the most lethal gynecologic malignancy, largely due to late diagnosis and the high prevalence of malignant ascites, a hallmark of advanced disease that is difficult to control and contributes to immune suppression and treatment failure. Despite advances in standard care, durable responses are rare. This study investigates a novel immunotherapeutic strategy designed to overcome the suppressed peritoneal microenvironment using an oncolytic vaccinia virus engineered to express a decoy-resistant IL-18 mutein. Methods: We generated a vaccinia virus (vvDD-nsmDR-18) expressing a non-secreted, mature, decoy-resistant IL-18. Viral expression was validated via RT-qPCR and fluorescence microscopy, while cytotoxicity was confirmed using CCK-8 assays. The antitumor efficacy of vvDD-nsmDR-18 was evaluated in the aggressive murine ID8a ovarian cancer model. The underlying mechanisms of action were investigated using flow cytometry and transcriptional profiling. Results: Treatment with vvDD-nsmDR-18 significantly prolonged survival and was associated with reduced abdominal distension consistent with decreased ascites burden. Immune analyses indicated enhanced T cell activation across multiple anatomical compartments, including tumors, peritoneal cavity, and spleens, the latter recently suggested to serve as a reservoir for tumor-reactive T cells. This systemic activation was characterized by increased IFN-γ and perforin expression. In addition, vvDD-nsmDR-18 treatment was associated with expansion of CD39⁺CD103⁺CD8⁺ tumor-reactive T cells and a shift toward a lower PD-1 expression phenotype within this population. Conclusions: These findings demonstrate that nsmDR-18-expressing oncolytic viruses can remodel the immunosuppressive landscape of advanced ovarian cancer, suggesting this approach is a promising candidate for further clinical development. Full article

Background: Cardiovascular complications stemming from diabetes pose a grave threat to patients’ survival. Both type 1 diabetes (T1D) and type 2 diabetes (T2D) significantly increase the risk of heart failure, yet no reports have clarified whether there are differences in the pathway alterations involved in these two conditions. Investigating the heterogeneity of the cardiac remodeling between these two types of diabetes is conducive to reducing the incidence of cardiovascular events in diabetic patients in clinical practice. Methods: T1D and T2D models were established in adult mice, and the hearts were collected for RNA sequencing. Differential expression analysis (DEA) was performed. Integrating functional enrichment analyses, we probed into gene and pathway heterogeneity. Subsequently, we compared single-cell RNA sequencing (scRNA-seq) data of hearts from T1D and T2D mice, focusing on three cell populations (endothelial cells, macrophages, and fibroblasts) to identify gene and pathway differences. Finally, we evaluated shared genes and common signaling pathway changes across these three cell populations in both diabetes types. Results: We have successfully established T1D and T2D models in mice. Compared with shared genes, the two types of diabetes had more consistent pathway changes. Further scRNA-seq analysis identified endothelial cells, macrophages, and fibroblasts as significantly associated with the diabetic phenotype. In shared pathway, endothelial cells were significantly enriched in pathways related to endothelial proliferation and angiogenesis; macrophages were enriched in immune response pathways; and fibroblasts were enriched in pathways involving fibrosis, cell proliferation, and apoptosis. In endothelial cells, inflammatory response and fatty acid metabolism pathways were predominantly enriched in T1D, while energy metabolism pathways were dominant in T2D. In macrophages, antiviral immune pathways were specifically enriched in T1D, whereas macrophages in T2D were additionally implicated in the regulation of cardiomyocyte function. In fibroblasts, immune-related pathways were characteristically enriched in T1D, while cell respiration and energy supply pathways were prominent in T2D. Common functional enrichment pathways across the three cell types in both diabetes types mainly involved innate immune responses and cardiac morphogenesis, with the proportion of shared pathways being significantly higher than that of shared genes. Conclusions: This study, by combining RNA sequencing and scRNA-seq, revealed that cardiac pathologies induced by T1D and T2D exhibit a higher degree of consistent pathway changes compared to shared gene changes. Interventions targeting these common pathways may hold greater value in preventing and treating diabetic cardiomyopathy. Full article