Search Results (2,120)

Background/Objectives: Neuroblastoma (NB) is an aggressive pediatric malignancy that accounts for nearly 15% of all childhood cancer-related deaths, with high-risk cases showing a poor 20% prognosis and limited response to current therapies. Survivin, encoded by the BIRC5 gene, is an anti-apoptotic protein frequently overexpressed in NB and linked to treatment resistance and unfavorable clinical outcomes. Methods and Results: An analysis of 1235 NB patient datasets revealed a significant association between elevated BIRC5 expression and reduced overall and event-free survival, highlighting survivin as an important therapeutic target in NB. To explore this strategy, we evaluated the efficacy of YM-155, a small-molecule survivin inhibitor, across multiple NB cell lines. YM-155 displayed potent cytotoxic activity in six NB cell lines with IC₅₀ values ranging from 8 to 212 nM and significantly inhibited colony formation and 3D spheroid growth in a dose-dependent manner. Mechanistic analyses revealed that YM-155 downregulated survivin at both mRNA and protein levels, induced apoptosis by about 2–7-fold, and caused G0/G1 phase cell cycle arrest. Moreover, YM-155 treatment enhanced p53 expression, suggesting reactivation of tumor suppressor pathways. Notably, combining YM-155 and the chemotherapeutic agent etoposide resulted in synergistic inhibition of NB growth with ED75 values ranging from 0.17 to 1, compared to either agent alone. In the xenograft mouse model, YM-155 inhibited tumor burden in contrast to controls by about 3-fold, and without any notable toxic effects in vivo. Conclusion: Overall, our findings identify YM-155 as a promising therapeutic agent for high-risk NB by directly targeting survivin and enhancing chemosensitivity. These results support continued preclinical development of survivin inhibitors as part of rational combination strategies in pediatric cancer treatment. Full article

Elevated cholesterol levels play important mitogenic roles. Pseurotin A (PsA) is a fermentation product that has recently been reported as a dual inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) secretion and protein-protein interaction (PPI) with the LDLR. PsA showed a high acute safety profile and therapeutic potential against metastatic castration-resistant prostate cancer (mCRPC). The study aims to uncover the chronic safety, distribution, and anti-mCRPC genomic and molecular mechanistic insights of PsA. A 90-day chronic safety assessment of PsA up to 80 mg/kg in Swiss albino mice showed no signs of hematological, biochemical, or major organ toxicity. PsA demonstrated rapid intravenous distribution and elimination in Swiss albino mice. PsA is biodistributed to multiple key organs but was not detected in the brain, indicating its inability to cross the blood-brain barrier. PsA effectively suppressed the recurrence of nude mice xenografted mCRPC, which was subjected to a neoadjuvant docetaxel and enzalutamide regimen, followed by surgical excision. Collected PsA and vehicle control-treated recurrent tumors were subjected to RNA-sequencing and pathway enrichment analysis (PEA) of differentially expressed genes (DEGs). PsA-treated tumors revealed multiple significantly enriched pathways associated with promoting tumor apoptosis and inhibiting both invasion and migration. The PPI network analyses for the downregulated DEGs displayed prominent networks of genes associated with the ubiquitin-proteasome system. Results provide comprehensive mechanistic and preclinical validations for PsA’s potential as a novel PC recurrence suppressive lead entity. Full article

Bulbine species (Asphodelaceae) are routinely used in many African communities to treat various dermatological disorders, including wounds, due to their relative accessibility, affordability, safety records, and reported efficacies. However, these reported biological activities lack robust empirical evidence and well-validated cellular mechanisms for plausible applications. Hence, this review was aimed at investigating the bioactive compounds of Bulbine species linked to their cellular wound healing attributes, their toxicity, and cytotoxicity. A detailed literature search was conducted using Web of Science, Google scholar, and PubMed, followed by Scopus and VOSviewer (version 1.6.20) bibliographic analyses. Bulbine frutescens (L.) Willd. and Bulbine natalensis Baker safely mediate tissue healing and coagulation cascade as adaptogens and cytotoxic agents. The wound healing activities of the Bulbine species were linked to the synergistic wound healing or tissue repair properties of bioactive compounds (such as saponins, terpenoids, luteolin, and apigenin) via the expression of collagen type-I, alpha-2 (COL1A2) gene, collagen III, increase in the wound tensile strength, and anti-cytokine interleukin-10 (IL-10) mRNA. Bulbine species were also reported to contain specialised biomarker compounds (such as naphthoquinones, bulbine-emodin, and aloe-emodin) which mediate the activation of hydroxyproline, Aryl Hydrocarbon Receptor, transforming growth factor beta—β1 (TGFβ1), and the suppressor of mothers against decapentaplegic proteins (SMAD), which ultimately induce tissue granulation, myofibroblast differentiation, re-epithelialization, higher protein complexes, and scar tissue formations. These findings give credence to the wound healing therapeutic potential of Bulbine species. However, additional clinical studies are necessary to further ascertain the reported efficacies of Bulbine species’ bioactive principles, their overall safety, and the underlying cellular mechanisms involved in the wound healing process and carcinogenesis. Full article

Ovarian cancer (OCa) remains the most lethal gynecologic malignancy in the United States, with low-grade serous and mucinous subtypes frequently driven by KRAS mutations. These mutations activate downstream MAPK and PI3K/AKT signaling pathways, contributing to tumor progression and resistance to therapy. Although the MEK inhibitor trametinib is used to target these pathways, its efficacy is limited in KRAS-mutant OCa due to compensatory activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) axis. In this study, we evaluated the therapeutic potential of combining trametinib with EC359, a selective LIFR inhibitor, in Ras/Raf-driven OCa models. EC359 significantly reduced cell viability, clonogenic survival, and induced cell death via ferroptosis in vitro. Mechanistic studies revealed that EC359 suppressed trametinib-induced activation of LIFR downstream signaling. RNA-seq analysis showed that combination therapy downregulated mitochondrial translation and MYC target genes while upregulating apoptosis-related genes. In vivo, EC359 and trametinib co-treatment significantly reduced tumor growth in xenograft and PDX models without inducing toxicity. Our studies identify LIFR signaling as a critical vulnerability in Ras/Raf-mutant and low grade serous OCa. Further, it provides strong preclinical rationale for EC359 and trametinib combination therapy as a new therapeutic strategy for treating Ras/Raf-driven OCa and low-grade serous OCa. Full article

Perfluorooctane sulfonamide (PFOSA), the direct precursor to perfluorooctane sulfonate (PFOS), is widely present in the environment. Research has indicated that PFOSA is cardiotoxic and hepatotoxic, but its impact on neurodevelopment remains unclear. In the current study, we observed that exposure of PFOSA caused neurodevelopmental toxicity in zebrafish embryos in a dose-dependent manner, as evidenced by impaired motor abilities and decreased swimming distance. We then demonstrated that PFOSA exposure downregulated the mRNA expression of neurodevelopment-related genes including a1-tubulin, elavl3, ache and dat. Moreover, PFOSA exposure resulted in dose-dependent oxidative stress, which triggers apoptosis in the brains of zebrafish larvae. We further showed that inhibition of the aryl hydrocarbon receptor (AhR) alleviated the oxidative stress and apoptosis induced by PFOSA, thereby counteracting the neurodevelopmental abnormalities in zebrafish larvae. In conclusion, these findings indicate PFOSA causes neurodevelopmental disorders by inducing oxidative stress and apoptosis through the AhR pathway. Full article

Overcoming immune resistance remains the critical barrier to durable immunotherapy responses. Tumors with non-inflamed, “cold” microenvironments exclude cytotoxic lymphocytes and evade checkpoint blockade. Innate nucleic acid-sensing pathways—including TLRs, RIG-I-like RNA sensors, and the cGAS–STING DNA-sensing axis—can recondition this hostile landscape by licensing dendritic cells, restoring antigen presentation, and recruiting effector T and NK cells. In this review, we synthesize mechanistic insights into how these receptors function across tumor and immune compartments and evaluate recent translational advances spanning small-molecule and nucleic acid agonists, engineered delivery systems, and clinical trials. We highlight challenges that have limited clinical impact, including pathway silencing, systemic toxicity, and lack of predictive biomarkers, while emphasizing emerging solutions such as tumor-intrinsic targeting, CAR-T/NK engineering, and biomarker-guided patient selection. By integrating innate activation into rational combination regimens, innate immune reprogramming offers a blueprint to convert resistant disease into one susceptible to durable immune control. Full article

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor and leads to high human malignancy and mortality. Because PDAC is highly drug-resistant and current treatments have adverse reactions, exploring novel approaches for PDAC prevention and therapy is urgently needed. Methods: Antitumor activities of Salecan were evaluated on multiple human pancreatic adenocarcinoma cells in vitro. Cell viability, colony formation, migration and invasion, flow cytometry, caspase-3 activity, qRT-PCR and Western blotting were monitored. RNA-seq was conducted to clarify the mechanism underlying Salecan’s inhibition of pancreatic cancer cell progression. Results: Here we show that Salecan, a naturally occurring polysaccharide of β-glucan, can significantly inhibit pancreatic cancer cell proliferation and exhibit no toxicity in normal cells. We find that Salecan impedes pancreatic cancer cell migration and invasion via the epithelial-to-mesenchymal transition (EMT) pathway. Mechanistically, through RNA sequencing, we reveal that Salecan induces pancreatic cancer cell necroptosis, instead of apoptosis. Moreover, Salecan’s anti-pancreatic cancer bioactivity is attributed to its promotion of the receptor-interacting protein kinase 1 (RIPK1) and mixed lineage kinase-like (MLKL) signaling pathway. Conclusions: Salecan can inhibit pancreatic cancer cell proliferation, migration and invasion in vitro and accelerate cell death by inducing the necroptosis via the MLKL/RIPK1 pathway. These findings identify that Salecan may become a potential functional food component for preventing and treating PDAC. Full article

Efficient allocation of mineral nutrients and photoassimilates is essential for grain development in rice. However, the transcriptional programs governing nutrient transport at key reproductive stages remain largely unresolved. Here, we performed a comprehensive transcriptome analysis of rice (Oryza sativa L.) across spatial (nodes, roots, and five other tissues) and temporal (seven reproductive stages) dimensions to elucidate the molecular basis of nutrient transport and allocation. RNA-seq profiling of node I identified stage-specific gene expression patterns, with the grain filling stage marked by strong induction of transporters involved in mineral allocation (e.g., OsYSL2, OsZIP3, OsSULTR3;3, SPDT) and carbohydrate distribution (e.g., OsSWEET13, OsSWEET14, OsMST6). Comparative analysis with the neck-panicle node (NPN) and root revealed tissue-specific regulatory networks, including nitrate (OsNRT1.1A, OsNRT2.3) and phosphate (OsPHT1;4, OsPHO1;3) transporters enriched at the grain filling stage. Root expression of Cd/As-related transporters (OsNRAMP5, OsCd1, OsLsi1, OsLsi2, OsLsi3) during grain filling highlights the contribution of belowground uptake to grain metal accumulation. Together, our study establishes a spatiotemporal atlas of nutrient transporter gene activity during rice reproductive development and identifies candidate genes regulating upward and lateral nutrient allocation. These findings provide insights into improving nutrient use efficiency and reducing toxic metal accumulation in rice grains through targeted manipulation of nodal and root transport systems. Full article

Deoxynivalenol (DON), a mycotoxin from Fusarium that contaminates cereals, can also induce intestinal injury. However, the mechanisms underlying DON-induced jejunal barrier injury remain unclear. This study demonstrates that shikimic acid (SA) alleviates DON-induced jejunal barrier damage and dysbiosis via antioxidant pathways. Fifty 5-week-aged male KM mice were divided into control (CON), model (MOD, 2.4 mg/kg bw DON), and SA-treated groups (LDG/MDG/HDG: 25/50/100 mg/kg bw SA + DON). After SA treatment, notably MDG, reversed DON-induced weight loss and jejunal hyperemia; ameliorated villus atrophy, crypt deepening and goblet cell loss, increasing villus/crypt ratio; reduced gut permeability markers (D-LA/DAO) and pro-inflammatory cytokines (TNF-α/IL-6/IL-1β); and dose-dependently upregulated tight junction proteins (ZO-1/Occludin/Claudin1). Mechanistically, SA activated the Nrf2/HO-1/NQO1 pathway, elevating antioxidants (GSH/SOD/AOC) while reducing MDA, with MDG showing optimal efficacy. 16S rRNA sequencing revealed MDG counteracted DON-induced dysbiosis by enriching beneficial bacteria (e.g., Bacteroidota at phylum level; Muribaculaceae at family level) and suppressing pathogens (Staphylococcaceae) (LDA score > 4.0). Thus, SA mitigates DON toxicity via Nrf2-mediated barrier restoration, anti-inflammation, and microbiota modulation. This research provides new insights for the further development of Shikimic Acid and the treatment of DON-induced jejunal barrier injury. Full article

Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease are characterized by progressive neuronal loss, driven mainly by the misfolding, aggregation, and accumulation of each disease’s specific proteins. These pathogenic aggregates, including tau, α-synuclein, TDP-43, and huntingtin, disrupt cellular proteostasis and initiate cascades of neuroinflammation, oxidative stress, mitochondrial dysfunction, and synaptic failure. While protein aggregation has been a long-recognized hallmark of these disorders, growing evidence points towards a more complex interplay of initial molecular pathways with defects in RNA processing, stress granule pathology, and cell-type-specific vulnerability. Notably, such events may manifest differentially with respect to sex and are further modulated by age-related loss of the protein quality control processes like the ubiquitin–proteasome pathway, autophagy–lysosome pathway, and molecular chaperones. This review synthesizes current insights into the structural and functional dynamics of protein aggregation and its significance for neuronal well-being. It highlights the role of post-translational modifications, prion-like transmission, and aggregation kinetics in the regulation of toxicity. The review further discusses promising therapeutic strategies centered on restoring proteostasis, including small molecules that inhibit aggregation, protein clearance pathway enhancers, immunotherapy, antioxidant therapy, and diagnostic prospects such as the identification of reliable molecular signatures in bodily fluids that can reflect pathological changes even before clinical symptoms emerge. Advancements in single-cell transcriptomics and multi-omics platforms, which are changing our understanding of disease onset and progression and opening avenues for precision medicine and personalized treatments, were also discussed. Ultimately, deciphering the molecular logic that distinguishes physiological from pathological protein assemblies and understanding how cellular systems fail to adapt under stress will be key to the development of effective, disease-modifying therapies for these debilitating disorders. Full article

Human papillomavirus (HPV) plays a major role in the development of head and neck cancers (HNCs), particularly oropharyngeal squamous cell carcinoma. This review highlights the key molecular mechanisms of HPV-driven carcinogenesis, focusing on the oncogenic E6 and E7 proteins and their disruption of tumor suppressor pathways and epigenetic regulation. We discuss the rising prevalence of HPV-related HNCs, their distinct clinical features, and diagnostic approaches such as p16 immunohistochemistry and HPV DNA/RNA detection. HPV-positive tumors show better prognosis and response to treatment, prompting interest in therapy de-escalation. Emerging strategies including immune checkpoint inhibitors, therapeutic vaccines, CRISPR-based gene editing, and ctDNA monitoring are advancing precision oncology in this field. We also examine the preventive potential of HPV vaccination and ongoing research into its role across various HNC subtypes. A deeper understanding of HPV’s molecular impact may guide more effective, targeted, and less toxic interventions. Full article

Background/Objectives: This study explores the potential of the inducible G protein-coupled kinin B1 receptor (B1R) as a target for the diagnosis and treatment of prostate cancer (PCa) and aims to develop the first theranostic agent targeting hB1R for both molecular imaging and radionuclide therapy. Methods: B1R expression was analyzed via qPCR and immunohistochemistry in human PCa cells and tissues specimens. A novel ⁶⁴Cu/NOTA-conjugated peptide analog of the potent B1R antagonist R954 was synthetized and evaluated in vitro and in vivo. Results: B1R was confirmed to be expressed (RNA, protein) by varying degrees in all PCa cell lines and tissues investigated, with protein level significantly correlating with tumor grades. This finding was supported by similar analyses from the TCGA and MSKCC databases. In vitro, the ⁶⁴Cu/NOTA-βAla-R954 conjugate showed nanomolar affinity/potency at hB1R, complete plasma stability over 24 h, significant cellular uptake (up to 33% of ID at 24 h), and dose-dependent anti-clonal growth effects. In vivo, the radioconjugate remained stable in circulation for up to 90 min and was primarily excreted intact via the kidneys following IV administration. Intravenous ⁶⁴Cu/NOTA-βAla-R954 (7.5 MBq) effectively detected subcutaneous PCa xenografts via µPET imaging in male athymic nude mice. At a single higher dose (65 MBq; 50 µg/kg), it significantly reduced tumor growth without observable toxicity. This antitumor effect was associated with increased apoptosis (active caspase-3) and reduced proliferation (Ki67), as shown by immunohistochemistry. In contrast, the nonradioactive ^NatCu/NOTA-βAla-R954 had no therapeutic effect at the same dose. Conclusions: Our findings provide proof-of-concept for the potential theranostic use of ⁶⁴Cu/NOTA-R954 in PCa, and potentially other types of B1R-positive solid cancers. Full article

Hepatocellular carcinoma is a primary malignant tumor of the liver, which is a serious health problem due to its aggressive nature, late diagnosis, and metastasis to other organs. We present, for the first time, the mRNA expression patterns of a wide range of genes involved in inflammation, fibrosis, endoplasmic reticulum stress, various forms of cell death, and signaling cascades in the lungs and kidneys of mice with thioacetamide-induced HCC. It is known that HCC often metastasizes to the lungs, and it is also important to understand which pathological processes occur in the kidneys, since the liver and kidneys are key target organs of toxicity. The main goal of this work was to study the pathological processes in the lungs and kidneys in HCC and the effectiveness of selenium nanocomplexes, as well as the well-known drug sorafenib, in mitigating these pathological consequences. These results present a significant contribution to the study of HCC metastasis to the lungs and kidneys and to the development of drugs that are most effective in the late stages of HCC. In addition, a hierarchy of the distribution of the selenium in the liver, kidneys, and lungs was established after the treatment of mice with HCC with selenium nanoparticles and a selenium–sorafenib nanocomplex. These data are important for developing a treatment protocol and determining optimal dosages of the drugs under study, which allows for achieving the desired therapeutic effect and neutralizing the toxic effect of selenium on healthy tissues and organs. Full article

Background: Intermittent fasting (IF) is emerging as a promising non-pharmacological intervention in oncology, with the potential to modulate key biological processes including metabolic reprogramming, inflammation, autophagy, and immune function, particularly through the PI3K/AKT/mTOR pathway. However, translating IF into clinical practice requires robust tools to monitor its biological impact and therapeutic effectiveness. Objective: This narrative review aims to present and critically evaluate current diagnostic and monitoring strategies that can support the safe and effective integration of IF into oncological care. Methods: A comprehensive literature search was conducted across PubMed/Medline, Science Direct, Scopus, Wiley Online Library, and Google Scholar using a combination of free-text and MeSH terms related to intermittent fasting, oncology, biomarkers, immunophenotyping, metabolic pathways, gut microbiome, and diagnostic imaging. Results: Two principal categories of monitoring objectives were identified. The first—mechanistic monitoring—focuses on elucidating IF-induced biological effects, including modulation of insulin/IGF-1 signaling, oxidative stress reduction, autophagy activation, immune reprogramming, and microbiome alterations. Advanced research tools such as single-cell RNA sequencing, proteomics, metabolomics, and circulating tumor DNA (ctDNA) assays offer high-resolution insights but currently remain limited to preclinical or translational settings due to cost and complexity. The second—clinical response monitoring—assesses IF’s impact on treatment outcomes, including chemotherapy and immunotherapy response, toxicity reduction, tumor dynamics, and maintenance of nutritional and functional status. This requires clinically validated, accessible, and interpretable diagnostic tools. Conclusions: A dual-layered monitoring framework that integrates both mechanistic insights and clinical applicability is essential for the personalized implementation of IF in oncology. Although preliminary findings are promising, large-scale randomized trials with standardized protocols are necessary to confirm the efficacy, safety, and feasibility of IF in routine oncological care. The integration of IF with modern diagnostics may ultimately contribute to a more individualized, biologically informed cancer treatment paradigm. Full article

Petroleum pollution can pose a serious threat to soil health and its ecological functions. This study investigated the efficacy of bacterial treatments for bioremediation of diesel-contaminated soil under outdoor conditions for a period of 4 months. Unlike most previous studies conducted under laboratory conditions, this study applied single and multi-bacterial consortia directly into diesel-contaminated soil under outdoor conditions, evaluating both hydrocarbon degradation and soil toxicity changes. Three treatments using a single strain, a 4-strain consortium, and an 8-strain consortium were applied to 2% (v/w) diesel-contaminated soil, and their performance was compared to uncontaminated and untreated controls. Total petroleum hydrocarbon (TPH) degradation was quantified using GC-FID, and the soil toxicity was assessed using Eisenia fetida toxicity test and higher plant germination assays. As the experiment demonstrated, the multi-strain bacterial consortium (BT3) achieved the highest TPH degradation (78.3%) and demonstrated significant reduction in long-chain hydrocarbon fractions (C₁₄-C₂₈). Toxicity measurements showed that all three bioremediation treatments, especially BT3, significantly increased earthworm survival, body weight change and plant germination rate after the bioremediation. Microbial community analysis based on 16S rRNA sequencing revealed significant shifts in the dominant bacterial genera over time, accompanied by a noticeable reduction in alpha diversity. In particular, BT3 showed a significant decrease in Shannon diversity index values from 9.4 at S₁ to 6.9 at S₃ (p < 0.01), whereas BT1 and BT2 remained relatively stable (p > 0.05). Overall, the results demonstrated that all three bacterial treatments significantly enhanced diesel degradation and reduced soil toxicity under outdoor conditions, highlighting their potential for future large-scale applications in sustainable soil remediation. Importantly, this study combines constructed microbial consortia with multi-level toxicity assessments, providing a comprehensive framework to guide future bioremediation strategies. Full article