Search Results (3,987)

Background/Objectives: Neuropsychological changes induced by cancer and its treatments, especially chemotherapy, represent a significant clinical challenge, being responsible for persistent cognitive deficits known as chemobrain. This study aimed to identify microRNAs (miRNAs) associated with these alterations, map their interaction networks, and determine the main biological pathways involved. Methods: An integrative review and in silico analysis were conducted to study the role of microRNAs. Results: Six experimental studies using animal models were selected, which showed that agents such as doxorubicin, cisplatin, and methotrexate induce changes in domains such as memory, attention, and learning. Among the analyzed miRNAs, miR-155-5p, miR-21-5p, and miR-125b-5p stood out, being associated with pathways related to neuroinflammation, oxidative stress, apoptosis, and synaptic dysfunction. Computational analyses revealed that these miRNAs act on pathways such as MAPK, PI3K-Akt, mTOR, neurotrophins, and cytokine receptors. The interaction analysis among target genes also revealed a functionally connected network, with coordinated involvement in inflammation, neuronal apoptosis, and glial differentiation processes, suggesting a role in cellular stress responses and neuroinflammatory pathologies. Conclusions: These findings suggest that miRNAs play a central role in mediating the observed neurocognitive changes and may represent promising biomarkers and therapeutic targets to mitigate the effects of chemobrain. The study also highlights the need for future research integrating molecular and behavioral analyses to achieve more precise clinical applications. Full article

Acute Lymphoblastic Leukemia (ALL) is a heterogeneous hematological malignancy in which disease progression and response to therapy are influenced by a complex network of molecular alterations, interactions with the bone marrow microenvironment, and epigenetic modulation mechanisms. Crosstalk between oncogenic, inflammatory, and immunoregulatory signaling pathways, together with epigenetic modifications, contributes to the maintenance of leukemic survival and the development of therapeutic resistance. This review analyzes the role of cytokines and chemokines such as IL-6, TNF-α, and CXCL12, which act as biological biomarkers and key mediators of leukemia niche remodeling, and the main signaling pathways involved in ALL, such as Wnt/β-catenin, JAK/STAT, PI3K/AKT/mTOR, Notch, and BCR, highlighting their functional interconnection with the tumor microenvironment. The role of epigenetics in modulating the dialogue between leukemia cells and stromal components is also discussed. Epigenetic programs govern leukemia’s dependence on stromal support, inflammatory and niche-derived signals, as well as the microenvironment signaling pathways. Overall, targeting leukemia-niche interactions is a crucial strategy for improving outcomes in ALL and to identify potential molecular vulnerabilities, also for developing new therapeutic approaches for the treatment of the disease. Full article

Cervical small-cell neuroendocrine carcinoma (SCNEC) is a rare cervical cancer with high metastatic potential and is frequently associated with high-risk human papillomavirus (HPV) infection. Because of its low incidence, SCNEC remains understudied and treatment options are limited, posing major therapeutic challenges. This study aimed to characterize SCNEC at the molecular and functional levels to support more informed therapeutic strategies. Organoids and spheroids were generated from a cervical SCNEC biopsy, and a matched organoid-derived xenograft was established in immunodeficient mice. Model fidelity was evaluated by histopathology and immunohistochemistry. HPV status was assessed by p16 immunostaining and HPV18 PCR, and viral–host integration sites were inferred using whole-exome sequencing (WES) junction reads. WES was also used to compare shared somatic variants and copy-number alterations across the patient tumor, organoid, and xenograft. Drug responses were assessed in organoids and spheroids following exposure to a panel of chemotherapeutic agents and a targeted inhibitor. Organoids exhibited robust growth, morphologic maturation, and efficient recovery after cryopreservation. The organoids and matched xenografts faithfully recapitulated SCNEC, with preserved neuroendocrine differentiation (CD56, synaptophysin, and NSE positivity), a high Ki-67 proliferative index (>80%), and strong p16 expression. HPV18 status was conserved across the primary tumor, organoids, and xenografts, with an integration site at chr8 (8q24.21) associated with increased MYC expression. Whole exome sequencing (WES) revealed strong cross-model concordance, including 26 shared somatic variants with a canonical PIK3CA hotspot mutation (p.E542K) and conserved oncogenic copy-number gains of PIK3CA, TERT, and MYC, as well as copy number loss of TP53. Functional assays showed dose-dependent loss of viability following exposure to conventional cytotoxic agents or an mTOR pathway inhibitor. This study presents the first integrated molecular and functional analyses of patient tumors and matched organoid and xenograft models in cervical SCNEC. These models offer robust resources for mechanistic studies and may enable precision therapeutic strategies for this rare malignancy. Full article

Prostate cancer (PCa) is the most general cancer in men and is often linked with distant metastasis in its later stages. The caffeic acid (CA) derivative, N-(4-methoxyphenyl)methylcaffeamide (MPMCA), demonstrates superior liver-protective effects compared to CA. Nevertheless, the functions of MPMCA on prostate cancer metastasis remain unclear. Here, we demonstrate that MPMCA blocks migration and invasion in prostate cancer cells without affecting cell viability. By suppressing the production of mesenchymal markers Vimentin, N-cadherin and β-catenin and upregulating the production of the epithelial marker Zonula Occludens-1 (ZO-1), MPMCA also controls Epithelial–Mesenchymal Transition (EMT). The Phosphoinositide 3-kinase (PI3K), Protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) pathway has been documented to regulate MPMCA-inhibited cell motility. Transfection with Snail and Slug cDNA reverses MPMCA’s suppression of EMT, migration, and invasion in prostate cancer cells. Importantly, our in vivo data indicates that MPMCA reduces Snail and Slug expression and prostate cancer metastasis. Our evidence suggests that MPMCA is a novel therapeutic candidate for treating metastatic prostate cancer. Full article

Pancreatic neuroendocrine tumors (pNETs) are rare, clinically heterogeneous neoplasms with rising incidence linked to improved diagnostics. This review examines pNET management, addressing epidemiology, classification, diagnosis, treatment, and emerging therapies. Epidemiologically, pNETs show higher prevalence in Western populations, with emerging associations to metabolic disorders. The 2022 WHO classification highlights distinct prognoses for well-differentiated NETs versus poorly differentiated NECs, guided by Ki-67 and mitotic indices. Non-functional tumors often present late, while functional variants manifest hormonal syndromes, necessitating tailored approaches. Advanced imaging (contrast-enhanced CT/MRI, ⁶⁸Ga-DOTATATE PET) and endoscopic ultrasound-guided biopsy enable precise localization and grading. Surgical resection remains curative for localized disease, with minimally invasive techniques reducing morbidity. Active surveillance is favored for small (<2 cm), low-grade, non-functional tumors, while larger or aggressive lesions require resection. Systemic therapies, including mTOR inhibitors (everolimus), anti-angiogenics (surufatinib), and peptide receptor radionuclide therapy (PRRT), extend survival in advanced cases, though immunotherapy efficacy remains limited. Future strategies emphasize molecular profiling, biomarker development, and multidisciplinary integration to optimize outcomes. This evolving paradigm prioritizes precision medicine, balancing oncologic control with quality of life and functional preservation. Full article

Tuberous Sclerosis Complex (TSC) is a genetic disorder caused by mutations that inactivate TSC1 or TSC2 genes. TSC1 or TSC2 mutations activate the mammalian target of rapamycin complex 1 (mTORC1) protein kinase pathway. Although many patients inherit a single copy of a mutant TSC gene, somatic mutations that cause loss of heterozygosity in inhibitory neuroprogenitor cells are hypothesized to be one cause of abnormal development. This may lead to cortical malformations or benign growths along the ventricular-subventricular zone (V-SVZ), cortex, olfactory tract, and olfactory bulbs (OB). This idea is supported by focal single-cell knockout experiments that induce CRE-mediated recombination following neonatal electroporation of conditional Tsc2 or Tsc1 mice. Loss of Tsc2 causes mTORC1 pathway activation and the formation of striatal hamartomas composed of ectopic clusters of abnormal cells and cytomegalic neurons, including within the OB. Neural phenotypes in this model can be partially rescued with Rapalink-1, a bisteric mTOR inhibitor, demonstrating the importance of mTOR in pathogenesis. We previously demonstrated that global V-SVZ neural stem cell (NSC) Tsc2 mutation induced by nestin-CRE-ER^T2 causes mTORC1 pathway activation, which is accompanied by transcriptional and translational errors. While we previously described cultured NSCs and OB granule cells from these mice, we did not thoroughly describe changes outside this region. Here, we provide evidence that removal of Tsc2 from neonatal V-SVZ NSCs causes subtle and rare brain malformations. This is exemplified by ectopic clusters of cytomegalic neurons and mTORC1 activation. This data supports that loss of Tsc2 in NSCs during neonatal development leads to heterotopic clusters in the adult brain. This model may be useful to study TSC, but the rarity and stochastic nature of lesions make the use challenging for identifying mechanisms and testing therapies. Full article

Background: Prostate cancer is one of the most prevalent and deadly neoplasias in the male population. Despite the availability of therapies that increase the long-term survival of patients with localized tumors, metastatic prostate cancer is challenging to treat. A previous study revealed that the 2-aminopyridine derivative (named Neq0440) inhibited the PI3K-AKT-mTOR pathway and presented selective cytotoxicity toward the metastatic prostate cancer cell line PC-3. Methods: Here, we further analyzed the mechanism of action of these molecules by using cell-based colorimetric, fluorometric, epifluorescence microscopy, and Western blot assays. Results: Mitochondrial depolarization increased the AMPK level at 24 h inhibition with Neq0440, which led to the PI3K-AKT-mTOR pathway downregulation after 48 h. The phosphorylation was inhibited for AKT and the downstream quinases (S6RP and 4EBP1) from the PI3K-AKT-mTOR pathway, which can work together with the mitochondrial depolarization, lowering the pH of the medium, increasing ROS levels, and translocating the lysosomes toward the nucleus to trigger cell death. Conclusions: Therefore, Neq0440 can be used as a lead compound to obtain derivatives with a novel anticancer mechanism of action. Full article

Ovarian cancer remains a major cause of mortality in women aged 74 years and under. Dysregulation of the PI3K/AKT/mTOR and NFκB signaling pathways has been associated with poor outcomes and treatment resistance. This study evaluated three potential anticancer agents targeting these pathways: buparlisib (a pan-PI3K/mTORC1 inhibitor), SN32976 (a PI3K p110α inhibitor), and pterostilbene (a resveratrol analogue that downregulates PI3K/AKT and NFκB signaling). Their efficacy was tested in 3D collagen models of ovarian cancer, using SKOV3 and OVCAR8 cell lines, activated by tumor necrosis factor-alpha (TNFα) and lysophosphatidic acid (LPA). Using concentrations derived from 2D assays, viability, collagen gel sizes, secretion of interleukin 6/8 (IL-6/8) and signal pathway proteins were analyzed. All compounds were less effective in 3D models than in 2D cultures, with high cell viability maintained. TNFα and LPA did not significantly alter drug sensitivity, and collagen gel contraction was largely unaffected. While the compounds did not consistently change signaling protein levels, they generally reduced secretion of pro-inflammatory cytokines IL-6 and IL-8. Growth in 3D collagen gels conferred drug resistance on OVCAR8 but not SKOV3 models. Overall, these findings provide preclinical support for further investigation of SN32976 and pterostilbene in ovarian cancer models. Full article

Solar ultraviolet B (UVB) irradiation is a primary environmental driver of skin photoaging, characterized by oxidative stress accumulation and mitochondrial dysfunction. In this study, we investigated the protective efficacy and underlying molecular mechanisms of Cardiospermum halicacabum extract (CHE) against UVB-induced senescence in human skin fibroblasts (HSFs). Phytochemical profiling via LC-MS characterized CHE as a rich source of bioactive flavonoids, organic acids, and glycosides. We demonstrated that pretreatment with CHE significantly ameliorated UVB-triggered cellular senescence, as evidenced by the alleviation of cell cycle arrest and the downregulation of senescence-associated markers p53 and p16. Furthermore, CHE effectively inhibited intracellular ROS generation and restored mitochondrial respiratory function. Transcriptomic analysis, validated by molecular assays, revealed that CHE exerts its protective effects primarily by suppressing the UVB-induced hyperactivation of the PI3K/Akt/mTOR signaling cascade. Collectively, these preliminary in vitro findings highlight CHE as a promising natural protective candidate that mitigates skin photoaging by targeting the PI3K/Akt/mTOR axis to attenuate oxidative stress and restore mitochondrial homeostasis. Full article

Neuroblastoma, the predominant extracranial solid malignancy in the pediatric population, remains a major clinical challenge due to pronounced intratumoral heterogeneity and intrinsic therapeutic resistance. 4-Methoxydalbergione (4-MD), a benzoquinone derivative isolated from Dalbergia odorifera, has demonstrated anticancer activity in several tumor models; however, its effects and underlying cell death mechanisms in neuroblastoma remain unclear. Here, we investigated the cytotoxic effects of 4-MD in human neuroblastoma cells using cell viability assays, flow cytometry, immunoblotting, and fluorescence microscopy. 4-MD reduced cell viability in a dose- and time-dependent manner and induced caspase-3 cleavage accompanied by MAPK activation, indicating apoptotic cell death. Concurrently, 4-MD promoted autophagosome accumulation, as evidenced by LC3-II accumulation, acidic vesicular organelle formation, ATG5 upregulation, and p62 degradation, in association with activation of the AMPK/mTOR/ULK1 signaling axis. Pharmacological inhibition of autophagy significantly attenuated 4-MD-induced cytotoxicity without affecting caspase-3 activation, demonstrating a caspase-independent, pro-death role of autophagy. Reactive oxygen species (ROS) acted as a critical upstream mediator, as antioxidant treatment suppressed both apoptotic and autophagic signaling. Moreover, inhibition of Na⁺,K⁺-ATPase with ouabain selectively reduced autophagy-dependent cell death, implicating autosis as an additional mechanism. Notably, 4-MD exhibited minimal toxicity toward primary cortical neurons. Collectively, these findings demonstrate that 4-MD engages multiple, non-redundant cell death pathways through coordinated ROS–MAPK–AMPK/mTOR/ULK1 signaling, highlighting its potential to overcome therapeutic resistance in heterogeneous neuroblastoma cells. Full article

Glioblastoma (GB) is one of the most aggressive brain tumours, with a high mortality rate. Tumour heterogeneity, GB’s invasive nature, the blood–brain barrier (BBB) and resistance development offer significant challenges in devising an effective strategy to manage GB. Clinicians rely on tumour resection, radiotherapy and temozolomide (TMZ) chemotherapy, but their efficacy is hindered due to poor BBB penetration. EGFR (epidermal growth factor receptor), NF-κB, angiogenic pathways, RAS/RAF/MAPK, PI3K/Akt/mTOR, etc., play an important role in GB progression. Development in nanotechnology, pharmaceutical science and genetic engineering enables the design of drug candidates with superior efficacy and safety profiles. This review delves into recent advancements in nanoparticles, hydrogels, extracellular vesicles, microneedles and other drug delivery platforms used in GB treatment. These novel drug delivery systems achieved superior BBB penetration, tumour targeting, and controlled release and better survival outcomes in preclinical setups. This review also discusses the major translational challenges, including those of large-scale production, tumour heterogeneity, off-target effects and M2 macrophage induction. Innovative strategies focusing on drug delivery as a biological decision-making process, integrating tumour stress responses into drug carrier and system-level design principles, are discussed, outlining future prospects. Full article

The Italian peninsula is, as shown by satellite and ground-based measurements, a pollution hotspot. In recent years, ground-based MAX-DOAS commercial systems have been installed in the Po Valley and the area surrounding Rome to monitor NO₂ tropospheric column densities and validate coincident satellite (e.g., TROPOMI) products. Three of the instruments are located in the Po Valley at San Pietro Capofiume (Bologna), Bologna city, and Mount Cimone (Modena), and one is located in Tor Vergata (Rome). The chosen system is the SkySpec-2D from Airyx. All the recorded spectra are saved in the FRM4DOAS format and processed with QDOAS software to obtain slant column densities (SCDs) of NO₂, O₄, and other trace gases. The MAX-DOAS SCD sequences are then analysed with the DEAP code to retrieve tropospheric profiles of NO₂ and aerosol extinction, while zenith-sky SCDs are used to retrieve NO₂ total columns. A dedicated campaign, involving the network instruments, has been conducted in the Po Valley to compare the performance of the individual instruments in the network with respect to the one that participated in the CINDI-3 campaign (Cabauw, The Netherlands). The results of the intercomparison campaign indicated that all instruments showed comparable performance. As an example of obtainable products, one year (from September 2024 to August 2025) of NO₂ tropospheric columns, as well as their comparison with TROPOMI measurements, is presented, highlighting the potential of this network for both air quality studies and satellite validation. Due to Italy’s location in the highly complex Mediterranean hotspot region, these data represent an important contribution to satellite validation efforts, particularly in view of upcoming missions such as Copernicus Sentinel-4, Sentinel-5, and the Copernicus Anthropogenic Carbon Dioxide Monitoring (CO2M) constellation. We found a negative TROPOMI bias relative to SkySpec-2D for NO₂ tropospheric columns ranging from −13% in San Pietro Capofiume, to −25% in Bologna and −44% in Rome Tor Vergata. The comparison between NO₂ total columns from TROPOMI and SkySpec-2D at Mount Cimone shows generally good agreement, with TROPOMI being 15% higher. Full article

Objectives: This research sought to examine the impact of gossypol on cervical cancer tumors that have been transplanted subcutaneously in nude mice, as well as the associated risk of liver damage and its underlying mechanisms. Methods: A subcutaneous cervical cancer tumor model was established in nude mice using the cell suspension inoculation method. Tumor volume and morphological changes in various organs were observed, and the serum concentrations of IL-6, IL-10, and TNF-α were assessed. Protein expression was analyzed using Western blotting. Untargeted metabolomics was employed to identify differential metabolites in mouse liver tissues. Network toxicology was utilized to pinpoint common targets associated with gossypol and hepatotoxicity, followed by KEGG and GO enrichment analyses. Molecular docking was conducted to preliminarily explore the mechanisms underlying gossypol-induced liver injury. Results: Gossypol significantly suppressed the development of subcutaneous cervical cancer tumors in immunodeficient mice. The Western blotting technique results revealed that increasing doses of gossypol led to a reduction in the expression levels of PIK3R2, GRB2, and MAPK1, compared to the model group (p < 0.05). Untargeted metabolomics revealed 1464 metabolites, from which 9 distinct metabolites were selected for further analysis. Network toxicology results indicated that the hepatotoxicity-related targets of gossypol included MTOR, TNF, CASP3, BCL2L1, and BCL2. KEGG analysis suggested that the toxic mechanisms may be linked to pathways involved in malignancy, the HIF-1 signaling pathway, proteoglycans in cancer, apoptosis, and others. Conclusions: Gossypol demonstrates a significant therapeutic effect against cervical cancer; however, its hepatotoxicity risk, mediated through multiple targets and pathways, requires further investigation. Full article

Platelet hyperreactivity is a central driver of thromboinflammatory diseases, including ischemic stroke, cardiovascular disorders, and autoimmune conditions. Current antiplatelet therapies primarily target surface receptors or coagulation pathways and are frequently limited by drug resistance, bleeding risk, and inadequate control of metabolically or inflammation-driven platelet dysfunction. Emerging evidence reveals that platelets possess a fully functional autophagic machinery that critically regulates mitochondrial quality, redox balance, granule secretion, cytoskeletal remodeling, and activation thresholds. This intracellular pathway represents a previously underrecognized but highly druggable regulatory axis in platelet biology. In this review, we examine the molecular framework governing autophagy in platelets, with emphasis on mTOR, AMPK, PI3K/AKT, and mitophagy signaling networks, and discuss how basal and activation-induced autophagy determine thrombotic behavior under physiological and pathological conditions. We then integrate clinical and preclinical evidence demonstrating how dysregulated platelet autophagy contributes to thrombotic risk in ischemic stroke, cardiovascular disease, metabolic disorders, and autoimmune diseases. Importantly, we highlight how pharmacological agents, including mTOR inhibitors, AMPK activators, natural autophagy enhancers, and lysosomal inhibitors, modulate platelet function through autophagy-dependent mechanisms. These findings position platelet autophagy as a promising intracellular therapeutic target that complements conventional antiplatelet strategies. We further discuss the translational challenges of autophagy-targeted therapy, including context dependency, lack of platelet-specific modulators, delivery strategies, and the need for reliable biomarkers to guide personalized intervention. By framing platelet autophagy as a druggable pathway rather than a biological curiosity, this review outlines a precision-targeted therapeutic framework for managing thromboinflammatory diseases through intracellular modulation of platelet behavior. Full article

Sensorineural hearing loss (SNHL), the predominant form of global hearing impairment, stems from the irreversible loss of inner ear sensory cells and neurons. Since mammalian cochlea lacks regenerative capacity, cell death represents a final common pathway for diverse insults. Current therapies are merely compensatory, underscoring an urgent need for mechanistic, targeted interventions. Autophagy, a critical homeostatic process, plays complex and dynamic roles in the cochleae. This review synthesizes current evidence on its regulation, highlighting its stage-specific and dual roles in SNHL. We emphasize mitophagy and its context-dependent effects on cell survival. Critically, we discuss an emerging therapeutic paradigm: a dual-phase autophagy modulation strategy. This approach proposes enhancing cytoprotective autophagy in early stages to maintain homeostasis, while inhibiting excessive autophagic flux later to prevent catastrophic cell death. This precision-targeting framework holds significant promise for guiding novel drug development and future clinical translation, moving beyond symptomatic management towards transformative treatment. Full article