Search Results (3,035)

Background/Objectives: Medulloblastoma is the most common malignant brain tumor in children and comprises four molecular subtypes—WNT, SHH, Group 3, and Group 4—each with distinct genetic, epigenetic, and metabolic features. Increasing evidence highlights the critical role of metabolic reprogramming and epigenetic alterations in driving tumor progression, therapy resistance, and clinical outcomes. This review aims to explore the interplay between metabolic and epigenetic mechanisms in medulloblastoma, with a focus on their functional roles and therapeutic implications. Methods: A comprehensive literature review was conducted using PubMed and relevant databases, focusing on recent studies examining metabolic pathways and epigenetic regulation in medulloblastoma subtypes. Particular attention was given to experimental findings from in vitro and in vivo models, as well as emerging preclinical therapeutic strategies targeting these pathways. Results: Medulloblastoma exhibits metabolic adaptations such as increased glycolysis, lipid biosynthesis, and altered amino acid metabolism. These changes support rapid cell proliferation and interact with the tumor microenvironment. Concurrently, epigenetic mechanisms—including DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation—contribute to tumor aggressiveness and treatment resistance. Notably, metabolic intermediates often serve as cofactors for epigenetic enzymes, creating feedback loops that reinforce oncogenic states. Preclinical studies suggest that targeting metabolic vulnerabilities or epigenetic regulators—and particularly their combination—can suppress tumor growth and overcome resistance mechanisms. Conclusions: The metabolic–epigenetic crosstalk in medulloblastoma represents a promising area for therapeutic innovation. Understanding subtype-specific dependencies and integrating biomarkers for patient stratification could facilitate the development of precision medicine approaches that improve outcomes and reduce long-term treatment-related toxicity in pediatric patients. Full article

Osteoarthritis (OA) is a chronic progressive joint disease characterized by cartilage degradation, subchondral bone remodeling, and synovial inflammation. This complex disorder arises from the interplay between mechanical stress and inflammatory processes, which is mediated by interconnected molecular signaling pathways. This review explores the dual roles of inflammatory and mechanical signaling in OA pathogenesis, focusing on crucial pathways such as NF-kB, JAK/STAT, and MAPK in inflammation, as well as Wnt/β-catenin, Integrin-FAK, and Hippo-YAP/TAZ in mechanotransduction. The interplay between these pathways highlights a vicious cycle wherein mechanical stress exacerbates inflammation, and inflammation weakens cartilage, increasing its vulnerability to mechanical damage. Additionally, we discuss emerging therapeutic strategies targeting these pathways, including inhibitors of cartilage-degrading enzymes, anti-inflammatory biologics, cell-based regenerative approaches, and non-pharmacological mechanical interventions. By dissecting the molecular mechanisms underlying OA, this review aims to provide insights into novel interventions that address both inflammatory and mechanical components of the disease, paving the way for precision medicine in OA management. Full article

Androgenetic alopecia (AGA) is a common progressive hair loss disorder driven by elevated dihydrotestosterone (DHT) levels, leading to follicular miniaturization. This study investigated sulforaphane-rich broccoli sprout extract (BSE) as a potential oral therapy for AGA. BSE exhibited dose-dependent proliferative and migratory effects on keratinocytes, dermal fibroblasts, and dermal papilla cells, showing greater in vitro activity than sulforaphane (SFN) and minoxidil under the tested conditions, while maintaining low cytotoxicity. In a testosterone-induced AGA mouse model, oral BSE significantly accelerated hair regrowth, with 20 mg/kg achieving 99% recovery by day 15, alongside increased follicle length, density, and hair weight. Mechanistically, BSE upregulated hepatic and dermal DHT-metabolizing enzymes (Akr1c21, Dhrs9) and activated Wnt/β-catenin signaling in the skin, suggesting dual actions via androgen metabolism modulation and follicular regeneration. Pharmacokinetic analysis revealed prolonged SFN plasma exposure following BSE administration, and in silico docking showed strong binding affinities of key BSE constituents to Akr1c2 and β-catenin. No systemic toxicity was observed in liver histology. These findings indicate that BSE may serve as a safe, effective, and multitargeted natural therapy for AGA. Further clinical studies are needed to validate its efficacy in human populations. Full article

Bone is the most frequent site of distant metastasis in advanced prostate cancer (PCa), contributing substantially to patient morbidity and mortality. Hypoxia, a defining feature of the solid tumour microenvironment, plays a pivotal role in driving bone-tropic progression by promoting epithelial-to-mesenchymal transition (EMT), cancer stemness, extracellular matrix (ECM) remodelling, and activation of key signalling pathways such as Wingless/Integrated (Wnt) Wnt/β-catenin and PI3K/Akt. Hypoxia also enhances the secretion of extracellular vesicles (EVs), enriched with pro-metastatic cargos, and upregulates bone-homing molecules including CXCR4, integrins, and PIM kinases, fostering pre-metastatic niche formation and skeletal colonisation. In this review, we analysed current evidence on how hypoxia orchestrates PCa dissemination to bone, focusing on the molecular crosstalk between HIF signalling, Wnt activation, EV-mediated communication, and cellular plasticity. We further explore therapeutic strategies targeting hypoxia-related pathways, such as HIF inhibitors, hypoxia-activated prodrugs, and Wnt antagonists, with an emphasis on overcoming therapy resistance in castration-resistant PCa (CRPC). By examining the mechanistic underpinnings of hypoxia-driven bone metastasis, we highlight promising translational avenues for improving patient outcomes in advanced PCa. Full article

Hydrogen-rich water (HRW) has shown neuroprotective effects in acute brain injury, but its role in chronic radiation-induced brain injury (RIBI) remains unclear. This study investigated the long-term efficacy of HRW in mitigating cognitive impairment and neuronal damage caused by chronic RIBI. Fifty male Sprague Dawley rats were randomly divided into five groups: control, irradiation (IR), IR with memantine, IR with HRW, and IR with combined treatment. All but the control group received 20 Gy whole-brain X-ray irradiation, followed by daily interventions for 60 days. Behavioral assessments, histopathological analyses, oxidative stress measurements, ¹⁸F-FDG PET/CT imaging, transcriptomic sequencing, RT-qPCR, Western blot, and serum ELISA were performed. HRW significantly improved anxiety-like behavior, memory, and learning performance compared to the IR group. Histological results revealed that HRW reduced neuronal swelling, degeneration, and loss and enhanced dendritic spine density and neurogenesis. PET/CT imaging showed increased hippocampal glucose uptake in the IR group, which was alleviated by HRW treatment. Transcriptomic and molecular analyses indicated that HRW modulated key genes and proteins, including CD44, CD74, SPP1, and Wnt1, potentially through the MIF, Wnt, and SPP1 signaling pathways. Serum CD44 levels were also lower in treated rats, suggesting its potential as a biomarker for chronic RIBI. These findings demonstrate that HRW can alleviate chronic RIBI by preserving neuronal structure, reducing inflammation, and enhancing neuroplasticity, supporting its potential as a therapeutic strategy for radiation-induced cognitive impairment. Full article

Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack of specific markers (CD271, ABCB5, ALDH, Nanog) and the ability of cells to dynamically change their phenotype. Phenotype-maintaining signaling pathways (Wnt/β-catenin, Notch, Hedgehog, HIF-1) promote self-renewal, treatment resistance, and epithelial–mesenchymal transitions. Tumor plasticity reflects the ability of differentiated cells to acquire stem-like traits and phenotypic flexibility under stress conditions. The interaction of CSCs with the tumor microenvironment accelerates disease progression: they induce the formation of cancer-associated fibroblasts (CAFs) and neo-angiogenesis, extracellular matrix remodeling, and recruitment of immunosuppressive cells, facilitating immune evasion. Emerging therapeutic strategies include immunotherapy (immune checkpoint inhibitors), epigenetic inhibitors, and nanotechnologies (targeted nanoparticles) for delivery of chemotherapeutic agents. Understanding the role of CSCs and tumor plasticity paves the way for more effective innovative therapies against melanoma. Full article

Miller–Dieker Syndrome (MDS) is a rare neurodevelopmental disorder caused by a heterozygous deletion of approximately 26 genes within the MDS locus of human chromosome 17. MDS, which affects 1 in 100,000 babies, can lead to a range of phenotypes, including lissencephaly, severe neurological defects, distinctive facial abnormalities, cognitive impairments, seizures, growth retardation, and congenital heart and liver abnormalities. One hallmark feature of MDS is an unusually smooth brain surface due to abnormal neuronal migration during early brain development. Several genes located within the MDS locus have been implicated in the pathogenesis of MDS, including PAFAH1B1, YWHAE, CRK, and METTL16. These genes play a role in the molecular and cellular pathways that are vital for neuronal migration, the proper development of the cerebral cortex, and protein translation in MDS. Improved model systems, such as MDS patient-derived organoids and multi-omics analyses indicate that WNT/β-catenin signaling, calcium signaling, S-adenosyl methionine (SAM) homeostasis, mammalian target of rapamycin (mTOR) signaling, Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and others are dysfunctional in MDS. This review of MDS integrates details at the clinical level alongside newly emerging details at the molecular and cellular levels, which may inform the development of novel therapeutic strategies for MDS. Full article

Cell proliferation plays a pivotal role in multiple physiological processes, including osteoporosis alleviation, wound healing, and immune enhancement. Numerous novel peptides with cell proliferation-promoting activity have been identified. These peptides exert their functions by modulating key cellular signaling pathways, thereby regulating diverse biological processes related to cell proliferation. This work summarizes peptides derived from animals and plants that stimulate cell proliferation, focusing on their amino acid composition, physicochemical properties, and preparation techniques. Furthermore, we highlight the major signaling pathways—such as the PI3K/Akt, MAPK/ERK, and Wnt/β-catenin pathways—that have been implicated in the mechanistic studies of food-derived peptides. Through the analysis and summary of previous studies, we observe a notable lack of in vivo animal models and clinical trials, indicating that these may represent promising directions for future research on food-derived bioactive peptides. Meanwhile, the potential safety concerns of proliferation-enhancing peptides—such as immunogenicity, appropriate dosage, and gastrointestinal stability—warrant greater attention. In summary, this review provides a comprehensive overview of the sources and mechanisms of cell proliferation-promoting peptides and addresses the challenges in industrializing bioactive peptide-based functional foods; therefore, further research in this area is encouraged. Full article

Developmental exposure to polybrominated diphenyl ethers (PBDEs), which are commonly used as flame retardants, results in irreversible cognitive impairments. Postnatal hippocampal neurogenesis, which occurs in the subgranular zone (SGZ) of the dentate gyrus, is critical for neuronal circuits and plasticity. Wnt7a-Frizzled5 (FZD5) is essential for both neurogenesis and synapse formation; moreover, Wnt signaling participates in PBDE neurotoxicity and also contributes to the neuroprotective effects of melatonin. Therefore, we investigated the impacts of perinatal decabromodiphenyl ether (BDE-209) exposure on hippocampal neurogenesis and synaptogenesis in juvenile rats through BrdU injection and Golgi staining, as well as the alleviation of melatonin pretreatment. Additionally, we identified the structural basis of Wnt7a and two compounds via molecular docking. The hippocampal neural progenitor pool (Sox2+BrdU+ and Sox2+GFAP+cells), immature neurons (DCX+) differentiated from neuroblasts, and the survival of mature neurons (NeuN+) in the dentate gyrus were inhibited. Moreover, in BDE-209-exposed offspring rats, it was observed that dendritic branching and spine density were reduced, alongside the long-lasting suppression of the Wnt7a-FZD5/β-catenin pathway and targeted genes (Prox1, Neurod1, Neurogin2, Dlg4, and Netrin1) expression. Melatonin alleviated BDE-209-disrupted memory, along with hippocampal neurogenesis and dendritogenesis, for which the restoration of Wnt7a-FZD5 signaling may be beneficial. This study suggested that melatonin could represent a potential intervention for the cognitive deficits induced by PBDEs. Full article

The B-cell lymphoma 2 (Bcl-2)-related ovarian killer (BOK), a member of the Bcl-2 protein family, shares a similar domain structure and amino acid sequence homology with the pro-apoptotic family members BAX and BAK. Although BOK is involved in the development of various types of cancer, its mechanism of action in breast cancer remains unclear. This study found that BOK was involved in the process of MG132, inhibiting the migration and epithelial–mesenchymal transition (EMT) of breast cancer cells induced by transforming growth factor-β. Furthermore, interfering BOK reversed the inhibition of breast cancer cell migration and the EMT process by MG132. Additional studies revealed that BOK silencing promoted the expression of EMT-related markers in breast cancer cells, while BOK overexpression inhibited EMT and migration. Using RNA-seq sequencing and Western blotting, we confirmed that the Wnt signaling pathway is involved in BOK regulating the EMT process in breast cancer cells. Therefore, we conclude that low BOK expression promotes breast cancer EMT and migration by activating the Wnt signaling pathway. This study enhances our understanding of breast cancer pathogenesis and suggests that BOK may serve as a potential prognostic marker and therapeutic target for breast cancer. Full article

Mycotoxins represent a group of highly toxic secondary metabolites produced by diverse fungal pathogens. Mycotoxin contaminations frequently occur in foods and feed and pose significant risks to human and animal health due to their carcinogenic, mutagenic, and immunosuppressive properties. Notably, deoxynivalenol, zearalenone, fumonisins (mainly including fumonisins B1, B2, and FB3), aflatoxin B1 (AFB1), and T-2/HT-2 toxins are the major mycotoxin contaminants in foods and feed. Undoubtedly, exposure to these mycotoxins can disrupt gut health, particularly damaging the intestinal epithelium in humans and animals. In this review, we summarized the detrimental effects caused by these mycotoxins on the intestinal health of humans and animals. The fundamental molecular mechanisms, which cover the induction of inflammatory reaction and immune dysfunction, the breakdown of the intestinal barrier, the triggering of oxidative stress, and the intestinal microbiota imbalance, were explored. These signaling pathways, such as MAPK, Akt/mTOR, TNF, TGF-β, Wnt/β-catenin, PKA, NF-kB, NLRP3, AHR, TLR2, TLR4, IRE1/XBP1, Nrf2, and MLCK pathways, are implicated. The abnormal expression of micro-RNA also plays a critical role. Finally, we anticipate that this review can offer new perspectives and theoretical foundations for controlling intestinal health issues caused by mycotoxin contamination and promote the development of prevention and control products. Full article

The biggest challenge in cancer therapy is tumor resistance to the classical approach. Thus, research interest has shifted toward the cancer stem cell population (CSC). CSCs are a small subpopulation of cancer cells within tumors with self-renewal, differentiation, and metastasis/malignant potential. They are involved in tumor initiation and development, metastasis, and recurrence. Method. A narrative review of significant scientific publications related to the topic and its applicability in endometrial cancer (EC) was performed with the aim of identifying current knowledge about the identification of CSC populations in endometrial cancer, their biological significance, prognostic impact, and therapeutic targeting. Results: Therapy against the tumor population alone has no or negligible effect on CSCs. CSCs, due to their stemness and therapeutic resistance, cause tumor relapse. They target CSCs that may lead to noticeable persistent tumoral regression. Also, they can be used as a predictive marker for poor prognosis. Reverse transcription–polymerase chain reaction (RT-PCR) demonstrated that the cultured cells strongly expressed stemness-related genes, such as SOX-2 (sex-determining region Y-box 2), NANOG (Nanog homeobox), and Oct 4 (octamer-binding protein 4). The expression of surface markers CD133+ and CD44+ was found on CSC as stemness markers. Along with surface markers, transcription factors such as NF-kB, HIF-1a, and b-catenin were also considered therapeutic targets. Hypoxia is another vital feature of the tumor environment and aids in the maintenance of the stemness of CSCs. This involves the hypoxic activation of the WNT/b-catenin pathway, which promotes tumor survival and metastasis. Specific antibodies have been investigated against CSC markers; for example, anti-CD44 antibodies have been demonstrated to have potential against different CSCs in preclinical investigations. Anti-CD-133 antibodies have also been developed. Targeting the CSC microenvironment is a possible drug target for CSCs. Focusing on stemness-related genes, such as the transcription pluripotency factors SOX2, NANOG, and OCT4, is another therapeutic option. Conclusions: Stemness surface and gene markers can be potential prognostic biomarkers and management approaches for cases with drug-resistant endometrial cancers. Full article

Drug resistance remains a critical barrier to effective treatment in several cancers, particularly triple-negative breast cancer (TNBC). Estrogen receptor α36 (ERα36), a variant of the estrogen receptor in ER-negative breast cancer cells, plays important roles in cancer cell proliferation. We investigated the role of ERα36 in regulating multidrug resistance protein 1 (MDR1) in MDA-MB-231 human breast cancer cells. The activation of ERα36 by BSA-conjugated estradiol (BSA-E2) increased cell viability under Adriamycin exposure, suggesting its involvement in promoting drug resistance. BSA-E2 treatment significantly reduced the intracellular rhodamine-123 levels by activating the MDR1 efflux function, which was linked to increased MDR1 transcription and protein expression. The mechanical ERα36-mediated BSA-E2-induced activation of EGFR and downstream signaling via c-Src led to an activation of the Akt/ERK pathways and transcription factors, NF-κB and CREB. Additionally, ERα36 is involved in activating Wnt/β-catenin pathways to induce MDR1 expression. The silencing of ERα36 inhibited the BSA-E2-induced phosphorylation of Akt and ERK, thereby reducing MDR1 expression via downregulation of NF-κB and CREB as well as Wnt/β-catenin signaling. These findings demonstrated that ERα36 promotes MDR1 expression through multiple non-genomic signaling cascades, including Akt/ERK-NF-κB/CREB and Wnt/β-catenin pathways, and highlight the role of ERα36 as a promising target to enhance chemotherapeutic efficacy in TNBC. Full article

Topically applied TH1579 alleviated the psoriatic phenotype in the imiquimod-induced psoriasis mouse model by decreasing CD45⁺, Ly6b⁺, and CD3⁺ cell infiltration and downregulating the expression of the proliferation marker PCNA. Moreover, TH1579 strongly suppressed IL-17 expression in mouse skin, accompanied by reduced infiltration of IL-17-producing γδ-T cells. Furthermore, TH1579 decreased keratinocyte viability and proliferation. Mass spectrometry data analysis revealed the enrichment of proteins associated with nucleotide excision repair and cell cycle regulation. The key cell cycle regulatory protein F-box protein S-phase kinase-associated protein 2 (SKP2) was significantly downregulated, along with the psoriasis-associated proliferation marker WNT5a, identified as a SKP2 downstream target. The downregulation of SKP2 and WNT5a was confirmed in MTH1i-treated mouse skin. Our findings support the topical administration of MTH1i TH1579 as a psoriasis treatment. The therapeutic effects depended on the SKP2/WNT5a pathway, which mediates psoriatic hyperproliferation. This study introduces a conceptually innovative topical treatment for psoriasis patients with mild-to-moderate disease who have limited therapeutic options. Full article

The recent identification of early-onset mutational signatures with geographic variations by Diaz-Gay et al. is a significant finding, since early-onset colorectal cancer has emerged as an alarming public health challenge in the past two decades, and the pathomechanism remains unclear. Environmental risk factors, including lifestyle and diet, are highly suspected. The identification of colibactin from Escherichia coli as a potential pathogenic source is a major step forward in addressing this public health challenge. Therefore, the following opinion manuscript aims to outline the likely onset of the pathomechanism and the critical role of acquired Piezo2 channelopathy in early-onset colorectal cancer, which skews proton availability and proton motive force regulation toward E. coli within the microbiota–host symbiotic relationship. In addition, the colibactin produced by the pks island of E. coli induces host DNA damage, which likely interacts at the level of Wnt signaling with Piezo2 channelopathy-induced pathological remodeling. This transcriptional dysregulation eventually leads to tumorigenesis of colorectal cancer. Mechanotransduction converts external physical cues to inner chemical and biological ones. Correspondingly, the proposed quantum mechanical free-energy-stimulated ultrafast proton-coupled tunneling, initiated by Piezo2, seems to be the principal and essential underlying novel oscillatory signaling that could be lost in colorectal cancer onset. Hence, Piezo2 channelopathy not only contributes to cancer initiation and impaired circadian regulation, including the proposed hippocampal ultradian clock, but also to proliferation and metastasis. Full article