Search Results (533)

Spodoptera frugiperda (J. E. Smith, 1797), an omnivorous crop pest worldwide, reproduces prolifically. Validamycin, a competitive natural inhibitor of trehalase, is regarded as an effective and safe insecticide. Pupae were injected with a validamycin gradient (0.5–10 µg/µL) to block trehalase; enzyme activity and the Vitellogenin gene (Vg)/its receptor gene (VgR) expression (rpL10 reference) were subsequently quantified to determine the compound’s impact on S. frugiperda ontogeny and fecundity. Validamycin directly inhibited pupal membrane-bound trehalase, sharply lowering glycogen. Both pupal and adult mortality rose with dose, yielding marked abnormalities versus the Control Check (CK) group. At 0.5 μg/μL validamycin, eggs blackened and clumped in the lateral oviduct, blocking release; treated females produced far fewer eggs by day 4, exhibited ovarian atrophy, shorter lifespan, and low hatchability. The expression levels of Vg and VgR in the ovaries of the fall armyworm were consistent with the changes in the ovarian developmental phenotype. Validamycin significantly inhibited the activity of trehalase in S. frugiperda, severely hindering their normal eclosion and lowering the potential reproductive capacity of S. frugiperda. Simultaneously, it directly affects ovarian development and the lifespan of female moths. The results provide data to support the development of new methods for controlling S. frugiperda. Full article

Myelodysplastic syndromes/neoplasms (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, and a variable risk of progression to secondary acute myeloid leukemia (sAML). Despite major advances in the molecular and clinical characterization of MDS, mechanistic and translational research remains constrained by the limited availability of well-validated in vitro models. Many historically used cell lines are difficult to maintain, exhibit restricted proliferative capacity, or represent advanced disease stages rather than bona fide MDS, while others have been affected by misidentification or cross-contamination. This review provides a comprehensive and critical overview of currently available MDS and MDS-related cell lines, including MDS92, MDS-L and its sublines, M-TAT, TER-3, SKK-1, SKM-1, and MOLM-17/18. We summarize their clinical origin, cytogenetic and molecular features, growth factor dependence, differentiation capacity, and experimental applications, with particular emphasis on their relevance to disease stage, clonal evolution, and leukemic transformation. In addition, we discuss the controversy surrounding misidentified models such as PC-MDS and highlight the importance of rigorous cell line authentication. Full article

Aged skeletal muscle satellite cells (MuSCs) exhibit impaired autophagy-related activity, reduced proliferative capacity, and compromised myogenic differentiation, which collectively contribute to defective muscle regeneration during aging. However, whether hypoxia-driven modulation of autophagy-related activity can improve aged MuSC function and the underlying molecular mechanisms remain incompletely understood. In this study, aged MuSCs were divided into three groups: normoxia, hypoxia, and hypoxia combined with an autophagy inhibitor. Aged MuSCs exhibited a decreased LC3B-II/LC3B-I ratio and Beclin-1 expression, together with elevated p62 levels, indicating altered autophagy-related activity. Hypoxic culture was associated with enhanced autophagy-related activity in aged MuSCs, accompanied by HIF-1α stabilization, BNIP3 upregulation, and reduced p62 accumulation. Functionally, hypoxia significantly promoted the proliferation and myogenic differentiation of aged MuSCs. Pharmacological inhibition of autophagy using 3-methyladenine, as well as BNIP3 suppression, markedly attenuated these hypoxia-induced functional improvements. Collectively, these findings suggest that hypoxia is associated with improved proliferative and myogenic capacities of aged MuSCs, potentially involving autophagy-related activity regulated by the HIF-1α/BNIP3 pathway. This study provides insight into the relationship between hypoxic signaling and autophagy in aged MuSCs and may inform future strategies aimed at improving muscle regeneration during aging. Full article

Pulmonary arterial hypertension (PAH) is a severe, progressive vasculopathy characterized by endothelial dysfunction, medial hypertrophy, and maladaptive vascular and cardiac remodelling that ultimately leads to right-heart failure and premature death. Despite advances in vasodilator therapies targeting endothelin, nitric oxide, and prostacyclin pathways, a substantial proportion of patients fail to achieve or maintain a low-risk profile, highlighting the need for disease-modifying strategies. Dysregulation of transforming growth factor-β (TGF-β) superfamily signalling, with excessive activin and growth differentiation factor activity and impaired bone morphogenetic protein signalling, plays a central role in PAH pathobiology. Sotatercept, a first-in-class activin signalling inhibitor, restores this imbalance by selectively trapping pro-proliferative ligands, thereby addressing a key molecular driver of pulmonary vascular remodelling. Evidence from pivotal phase II and III trials—PULSAR, STELLAR, ZENITH, and HYPERION—demonstrates that sotatercept significantly improves exercise capacity, haemodynamics, and risk status when added to background therapy. This review summarises the molecular mechanisms underlying sotatercept’s therapeutic effects, synthesises the current clinical evidence, and discusses its emerging role as a disease-modifying agent capable of promoting reverse pulmonary vascular remodelling within contemporary PAH management. Full article

The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) has been linked to cancer stem cells (CSCs) and telomerase activity; however, the mechanism underlying this association remains unclear. In this study, we engineered dual transcriptional reporters (SORE6-GFP and TERT-BFP) to isolate SOX2⁺OCT4⁺TERT^high subpopulations from AsPC-1 and BxPC-3 cells. We combined Fluorescence-Activated Cell Sorting with functional assays, RNA-seq, and network analysis. Clinically, tumors co-expressing high SOX2/OCT4/TERT levels were associated with reduced overall survival, whereas single-gene elevations were not prognostic. We identified a minority SOX2⁺OCT4⁺TERT^high fraction (~9%) enriched for pluripotency transcripts (SOX2, OCT4, NANOG, and ALDH1A1), which exhibited the highest proliferative, migratory, and invasive capacities. Transcriptomic profiling of SOX2⁺OCT4⁺TERT^high cells showed enrichment of KRAS, telomere maintenance, epithelial–mesenchymal transition, and developmental pathways (WNT and Hedgehog). Connectivity profiling highlighted actionable vulnerabilities, including NF-κB, WNT, and telomerase inhibition pathways. Together, these data define an aggressive telomerase-engaged, pluripotency-driven CSC-like state in PDAC and suggest testable therapeutic strategies that target TERT^high dependencies. Full article

Microorganisms have emerged as prolific and versatile producers of steroidal natural products, displaying a remarkable capacity for structural diversification that extends far beyond classical sterol frameworks. This review critically examines steroidal metabolites isolated from microbial sources, with a particular emphasis on marine-derived and endophytic fungi belonging to the genera Aspergillus and Penicillium, alongside selected bacterial and lesser-studied fungal taxa. Comparative analysis reveals that these organisms repeatedly generate distinctive steroid scaffolds, including highly oxygenated ergostanes, secosteroids, rearranged polycyclic systems, and hybrid architectures arising from oxidative cleavage, cyclization, and Diels–Alder-type transformations. While many reported compounds exhibit cytotoxic, anti-inflammatory, antimicrobial, or enzyme-inhibitory activities, the biological relevance of these metabolites varies considerably, highlighting the need to distinguish broadly recurring bioactivities from isolated or strain-specific observations. By integrating structural classification with biosynthetic considerations and bioactivity trends, this review identifies key steroidal frameworks that recur across taxa and appear particularly promising for further pharmacological investigation. In addition, current gaps in mechanistic understanding and compound prioritization are discussed. Finally, emerging strategies such as genome mining, biosynthetic gene cluster analysis, co-culture approaches, and synthetic biology are highlighted as powerful tools to unlock the largely untapped potential of microbial genomes for the discovery of novel steroidal scaffolds. Together, this synthesis underscores the importance of microorganisms as a dynamic and expandable source of structurally unique and biologically relevant steroids, and provides a framework to guide future discovery-driven and mechanism-oriented research in the field. Full article

Cell senescence is increasingly recognized as a key driver of atherosclerosis progression. Senescent smooth muscle cells (SMCs) lose their proliferative capacity and adopt a pro-inflammatory profile, contributing to impaired vessel repair and weakening of the fibrous cap. Moreover, senescence promotes SMC dedifferentiation and phenotypic modulation into unfavorable phenotypes associated with plaque destabilization. In this review, we will discuss how cell senescence is induced in atherosclerotic plaques, how this influences SMC plasticity, and how this impacts plaque stability. We will also evaluate the potential of current and experimental anti-atherosclerotic drugs to target SMC senescence and/or SMC phenotypic modulation. Full article

The development of functionality in wound dressings has progressed since the discovery by Winter that moist wounds heal more rapidly. Approaches to incorporate functionality on several fronts of wound healing have been targeted. Here, we consider three functional features that have received increased attention for their role in promoting healing in hard-to-heal wounds: control of protease levels, hydrogen peroxide generation, and antibacterial efficacy against multidrug resistance bacteria, the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. We review some clinically employed dressings used to treat chronic and burn wounds that have been characterized by their functional protease-modulating activity and contrast one well-studied analog with a cotton-based technology. Similarly, hydrogen peroxide generation profiles were obtained for dressings in different moist wound healing categories and contrasted with a modified form of a known hemostatic cotton-based technology. We examined ascorbic acid-modified forms of a cotton-based technology used for bleeding control in an ESKAPE antibacterial assessment using the AATCC 100 TM. The results for the cotton-based technology were significant protease uptake, hydrogen peroxide generation capacities at proliferative and antimicrobial levels, and >99.99% efficacy against ESKAPE pathogens. These results reflect the importance of considering new forms of cotton fiber technology for incorporation in advanced wound dressing approaches. Full article

Human adult cardiomyocytes (CMs) have limited regenerative capacity, posing a significant challenge in restoring cardiac function following substantial CM loss due to an acute ischemic event or chronic hemodynamic overload. Nearly half of patients show no improvement in left ventricular ejection fraction during recovery from acute myocardial infarction. At baseline, both humans and mice exhibit low but continuous cell turnover originating from the existing CMs. Moreover, myocardial infarction can induce endogenous CM cell cycling. Consequently, research has focused on identifying drivers of CM rejuvenation and proliferation from pre-existing CMs. High-throughput screening has facilitated the discovery of novel pro-proliferative targets through small molecules, microRNAs, and pathway-specific interventions. More recently, omics-based approaches such as single-nucleus RNA sequencing and spatial transcriptomics have expanded our understanding of cardiac cellular heterogeneity. The big-data strategies provide critical insights into why only a subset of CMs re-enter the cell cycle while most remain quiescent. In this review, we compare several high-throughput screening strategies used to identify novel targets for CM proliferation. We also summarize the benefits and limitations of various screening models—including zebrafish embryos, rodent CMs, human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), and cardiac organoids—underscoring the importance of integrating multiple systems to uncover new regenerative mechanisms. Further work is needed to identify translatable and safe targets capable of inducing functional CM expansion in clinical settings. By integrating high-throughput screening findings with insights into CM heterogeneity, this review provides a comprehensive framework for advancing cardiac regeneration research and guiding future therapeutic development. Full article

Bioactive natural products (NPs) may play a critical role in cancer progression by targeting nucleic acids and a wide array of proteins, including enzymes. Furthermore, a large number of derivatives (NPDs), including semi-synthetic products and pharmacophores from NPs, have been developed to enhance the solubility and stability of NPs. Acute myeloid leukemia (AML) is a poor-prognosis hematologic malignancy characterized by the clonal accumulation in the blood and bone marrow of myeloid progenitors with high proliferative capacity, survival and propagation abilities. A number of potential pathways and targets have been identified for development in AML, and include, but are not limited to, Fms-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenases resulting from genetic mutations, BCL2 family members, various signaling kinases and histone deacetylases, as well as tumor-associated antigens (such as CD13, CD33, P-gp). By targeting nucleic acids, FLT3 or CD33, several FDA-approved NPs and NPDs (i.e., cytarabine, anthracyclines, midostaurin, melphalan and calicheamicin linked to anti-CD33) are the major agents of upfront treatment of AML. However, the effective treatment of the disease remains challenging, in part due to the heterogeneity of the disease but also to the involvement of the bone marrow microenvironment and the immune system in favoring leukemic stem cell persistence. This review summarizes the current state of the art, and provides a summary of selected NPs/NPDs which are either entering or have been investigated in preclinical and clinical trials, alone or in combination with current chemotherapy. With multifaceted actions, these biomolecules may target all hallmarks of AML, including multidrug resistance and deregulated metabolism. Full article

Oxidative stress caused by excessive reactive oxygen species (ROS) disrupts skin and oral epithelial homeostasis and contributes to skin aging, inflammation, periodontitis, and mucosal injury. As the principal defenders in both skin and oral mucosal tissues, keratinocytes are important responders to oxidative stress. However, most existing studies have examined skin or oral keratinocytes in isolation, with few comparative investigations of their tolerance, repair capacity, and antioxidant mechanisms under oxidative stress. In this study, we systematically compared immortalized oral keratinocytes (TIGK) and skin keratinocytes (HaCaT) under hydrogen peroxide (H₂O₂)-induced oxidative stress. Functional analyses, including cell survival, ROS accumulation, stress granule formation, in vitro wound healing, and proliferation recovery assays, were combined with transcriptomic profiling to evaluate differences in antioxidant and pro-oxidant systems. TIGK exhibited significantly higher survival rates, lower ROS accumulation, and superior migratory and proliferative recovery compared with HaCaT after oxidative insult. Transcriptomic analysis further revealed that TIGK consistently expressed higher levels of antioxidant genes and enzymes. In contrast, HaCaT showed greater ROS accumulation and relatively limited antioxidant defenses. The results show that oral and skin keratinocytes adopt distinct adaptive mechanisms under oxidative stress. The intrinsic redox advantage of oral keratinocytes provides new insights into their rapid wound-healing capacity and may inform strategies to enhance epithelial resilience. Full article

Aflatoxin M₁ (AFM₁), a hydroxylated metabolite of aflatoxin B₁ (AFB₁), is a potent hepatotoxic and carcinogenic compound frequently detected in milk and dairy products. Its thermal stability and resistance to processing make it a persistent public health concern, especially in regions prone to fungal contamination of animal feed. This review integrates bibliometric mapping (2015–2025) with toxicological and mitigation perspectives to provide a comprehensive understanding of AFM₁. The bibliometric analysis reveals a sharp global rise in research output over the last decade, with Iran, China, and Brazil emerging as leading contributors and Food Control identified as the most prolific journal. Five research clusters were distinguished: feed contamination pathways, analytical detection, toxicological risk, regulatory frameworks, and mitigation strategies. Toxicological evidence highlights AFM₁’s mutagenic and hepatocarcinogenic effects, intensified by co-exposure to other mycotoxins or hepatitis B infection. Although regulatory limits range from 0.025 µg/kg in infant formula (EU) to 0.5 µg/kg in milk (FDA), non-compliance remains prevalent in developing regions. Current mitigation approaches—adsorbents (bentonite, zeolite), oxidation (ozone, hydrogen peroxide), and biological detoxification via lactic acid bacteria and yeasts—show promise but require optimization for industrial application. Persistent challenges include climatic variability, inadequate feed monitoring, and heterogeneous regulations. This review emphasizes the need for harmonized surveillance, improved analytical capacity, and sustainable intervention strategies to ensure dairy safety and protect consumer health. Full article

Background/Objectives: Mature adipocytes were previously regarded as terminally differentiated cells that are restricted to lipid storage. Recent studies have shown that they can dedifferentiate into fibroblast-like progenitor cells, termed dedifferentiated fat (DFAT) cells. These cells exhibit stem cell-like properties and multilineage potential, highlighting their promising role in regenerative medicine and disease pathology. This systematic review aims to explore and consolidate the evidence regarding mechanisms, culture methods, pathophysiological roles, and therapeutic potential of adipocyte dedifferentiation. Methods: A systematic review was conducted in PubMed using the terms “dedifferentiation”, “de-differentiation”, “transdifferentiation”, and related variants in combination with “adipocyte”. Studies were screened and selected according to the PRISMA 2020 guidelines. Non-English articles, non-full texts, and non-review papers were excluded. After duplicate removal and eligibility assessment, 53 studies were included. Further, these were classified into categories according to their abstracts. Results: The evidence from the included articles indicates that mature adipocytes can dedifferentiate both in vitro, via ceiling culture, and in vivo, yielding DFAT cells with proliferative and multilineage differentiation capacity. Dedifferentiation involves lipid droplet secretion (liposecretion) and is characterized by downregulation of adipogenic genes such as PPARG and C/EBPα, alongside upregulation of proliferation, stemness, and lineage-associated markers. Functionally, DFAT cells contribute positively to tissue regeneration and wound repair, but they can drive adverse outcomes such as fibrosis, insulin resistance, and tumor progression through signaling pathways, including Wnt/β-catenin and TGF-β. Conclusions: Mature adipocyte dedifferentiation marks a dynamic reprogramming mechanism with dual roles—beneficial in regenerative medicine and wound healing, yet detrimental in cancer and metabolic disease. Further research is required to identify in vivo regulators, establish definitive markers, and translate adipocyte plasticity into regenerative medicine applications. Full article

Background/Objectives: Tumor-induced immune reprogramming is increasingly recognized as a key mechanism by which cancers evade surveillance and promote disease progression. The interaction between cancer and immune cells within the tumor microenvironment (TME) can drive phenotypic and functional changes in immune populations, facilitating metastasis and immune evasion. Methods: In this study, we used co-culture models to expose THP1 monocytes to triple-negative breast cancer (TNBC) cells, MDA-MB-231 and BT-549, either directly or indirectly via tumor-conditioned media, to mimic tumor–immune cell communication. Transcriptomic and pathway analyses revealed that cancer-exposed monocytes adopt a reprogrammed phenotype marked by activation of pro-tumorigenic signaling pathways, enhanced proliferative capacity, and elevated expression of pro-inflammatory cytokines such as IL6. Results: Functional assays confirmed a significant increase in monocyte proliferation under both direct and indirect tumor exposure. Importantly, we demonstrated that this tumor-driven proliferation of THP1 cells could be suppressed by the STAT3 inhibitor STAT3-IN-12. This highlights the critical role of STAT3 signaling in mediating immune cell transformation and supporting a novel immunomodulatory approach for therapeutic intervention. Conclusions: These findings support the potential for targeting tumor-educated transcriptional programs as a novel immunomodulatory strategy in cancer treatment. Restoring immune cell homeostasis and suppressing pro-tumor phenotypes through pharmacological inhibition of the key signaling nodes such as STAT3 may complement existing cancer therapies. This study provides new insights into immune cell plasticity in cancer and identifies actionable strategies to counteract tumor-driven immune dysregulation. Full article

Ovarian interstitial tissue (IT) is a prominent but poorly characterised component of the koala ovary. This study analysed the morphology and immunohistochemical profile of IT in the koala ovary across different reproductive phases. Ovaries from ten sexually mature females were examined histologically and immunolabelled for aromatase, HSD3B2, HSD17B1, the follicle stimulating hormone receptor (FSHR), and the luteinizing hormone receptor (LHR). IT occurred as multifocal cortical aggregates composed of two distinct cell types. Large interstitial cells were polygonal with highly vacuolated and weakly eosinophilic cytoplasm and were morphologically consistent with a steroidogenic phenotype. Small interstitial cells were densely eosinophilic, non-vacuolated, and morphologically uniform across reproductive phases. Immunohistochemical analysis revealed that small interstitial cells exhibited the broadest expression of steroidogenic markers in the ovary, with coexpression of HSD3B2, HSD17B1, aromatase, FSHR, and LHR. In contrast, large interstitial cells exhibited comparatively limited enzyme and receptor expression. Staining intensity across all markers was strongest during the interoestrous phase, moderate in the proliferative phase, reduced in the luteal phase, and minimal or absent when the koalas were lactating, suggesting potential cyclical variation in IT function. Granulosa, theca and germinal epithelial cells showed variable expression of steroidogenic enzymes and gonadotropin receptors, indicating that ovarian steroidogenesis in the koala may be more heterogeneous than predicted by the classical two-cell, two-gonadotropin model. Together, these findings provide preliminary evidence for the steroidogenic capacity of ovarian IT in the koala, indicating that its activity varies across reproductive phases, and appear to suggest a unique cellular organisation compared to other mammals. As these results are based on morphology and immunohistochemistry alone, further functional studies are required to confirm the steroidogenic output and clarify the physiological significance of IT in this species. Full article