Search Results (198)

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

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

Cancer represents a significant global health hazard marked by elevated morbidity and mortality rates. Furthermore, the majority of tumor therapies encounter challenges, including metastasis, recurrence, and drug resistance. Consequently, it is essential to identify a specific and efficient tumor treatment approach. In recent years, the ongoing investigation and comprehension of tumors have led to significant attention towards cancer stem cells (CSCs). CSCs can facilitate tumor progression via self-renewal, differentiation capabilities, and multidrug resistance. Their function as a fundamental contributor to tumor heterogeneity, drug resistance, recurrence, and metastasis has emerged as a significant focus in cancer therapy research. In recent years, microRNAs (miRNAs) have been identified as crucial post-transcriptional regulators in biological processes, including chemosensitivity, self-renewal, apoptosis, invasion, and metastasis of cancer stem cells (CSCs). This paper systematically reviews the molecular mechanisms through which miRNAs influence the characteristics of cancer stem cells by targeting essential genes (e.g., SOX2, EGFR, c-Met) and modulating signaling pathways, including Wnt/β-catenin, Notch, Hedgehog, and PI3K/Akt. Furthermore, we investigated the viability of miRNAs as non-invasive biomarkers for cancer diagnosis and prognosis evaluation, examined the similarities and attributes of pivotal miRNAs in modulating cancer stem cell functionality, and deliberated on therapeutic approaches stemming from miRNA regulation of cancer stem cell activity. We anticipate that this research will yield novel insights into targeted cancer therapy. Full article

Oral cancer, the most common form of head and neck cancer, is worldwide a serious public health problem. Most patients present a locally advanced disease, and face poor prognosis, even with multimodality treatment. They may also develop second primary tumors in the entirety of their upper aerodigestive tract. The most altered signaling pathways are the PI3K/AKT/mTOR, TP53, RB, and the WNT/β-catenin pathways. Genomic and molecular cytogenetic analyses have revealed frequent losses at 3p, 8p, 9p, and 18q, along with gains at 3q, 7p, 8q, and 11q, and several genes frequently affected have been identified, such as TP53, CCND1, CTTN, CDKN2A, EGFR, HRAS, PI3K, ADAM9, MGAM, SIRPB1, and FAT1, among others. Various epigenetic alterations were also found, such as the global hypomethylation and hypermethylation of CDKN2A, APC, MGMT, PTEN, CDH1, TFP12, SOX17, GATA4, ECAD, MGMT, and DAPK. Several microRNAs are upregulated in oral cancer, including miR-21, miR-24, miR-31, miR-184, miR-211, miR-221, and miR-222, while others are downregulated, such as miR-203, miR-100, miR-200, miR-133a, miR-133b, miR-138, and miR-375. The knowledge of this molecular pathogenesis has not yet been translated into clinical practice, apart from the use of cetuximab, an EGFR antibody. Oral tumors are also genetically heterogenous and affect several pathways, which means that, due to the continuous evolution of these genetic alterations, a single biopsy is not sufficient to fully evaluate the most adequate molecular targets when more drugs become available. Liquid biopsies, either resorting to circulating tumor cells, extracellular vesicles or cell-free nucleic acids, have the potential to bypass this problem, and have potential prognostic and staging value. We critically review the current knowledge on the molecular, genetic and epigenetic alterations in oral cancer, as well as the applications and challenges of liquid biopsies in its diagnosis, follow-up, and prognostic stratification. Full article

Androgenetic alopecia (AGA), the most prevalent form of hair loss worldwide, faces significant therapeutic challenges due to high costs and limited efficacy of current interventions, necessitating safer and more effective solutions. Periplaneta americana (L.)-derived PA-011, endowed with anti-inflammatory and antioxidant properties, has demonstrated notable hair growth-promoting effects in AGA mouse models. This study employed LC-MS/MS, peptidomics, and network pharmacology to characterize PA-011’s chemical composition and predict its potential targets in AGA pathogenesis. Using Western blot and RT-qPCR, PA-011 intervention significantly inhibited inflammatory responses and oxidative stress levels in mouse skin tissues. Concurrently, PA-011 activated the proliferative potential of hair follicle stem cells, as demonstrated by upregulated expression of the cell proliferation marker Ki67, and activated the Wnt/β-catenin signaling pathway in DHT-induced AGA mice. Transcriptomic and metabolomic analyses revealed multi-target effects of PA-011, including modulation of PI3K-Akt/MAPK pathways, pentose phosphate metabolism, and amino acid biosynthesis. 16S rRNA sequencing and metagenomic analysis showed that AGA disrupts skin microbial homeostasis, while PA-011 intervention normalized the microbiota composition. Topical application of PA-011 promoted robust hair regrowth without detectable toxicity in safety assessments. This preclinical study establishes PA-011 as a promising candidate for AGA therapy, warranting further translational investigation. Full article

Astragalus polysaccharides (APS), bioactive compounds derived from Astragalus membranaceus, have emerged as promising natural agents in the treatment of hepatocellular carcinoma, a leading cause of cancer-related mortality. Preclinical studies indicate that APS exerts significant anti-liver cancer effects through multiple biological actions, including the promotion of apoptosis, inhibition of proliferation, suppression of epithelial–mesenchymal transition, regulation of autophagy, and modulation of immune responses. These therapeutic effects are closely associated with the regulation of critical signalling pathways, such as PI3K/AKT/mTOR, Wnt/β-catenin, JAK/STAT, and TGF-β/Smad. APS also reshapes the tumour microenvironment by enhancing macrophage activity, reducing the regulatory T cell function, and improving host immune response. In addition, APS exhibits synergistic effects when combined with conventional chemotherapeutics and interventional treatments such as transarterial chemoembolisation, improving efficacy and reducing toxicity. Despite the robust experimental evidence, limitations such as low bioavailability and a lack of large-scale clinical trials remain challenges for clinical translation. This review summarises the recent advances in understanding the anti-hepatocellular carcinoma activities of APS, their molecular targets and potential applications, aiming to provide a scientific basis for future studies and the development of APS-based therapeutic strategies. Full article

Colorectal cancer remains a leading malignancy. As the aberrant activation of Wnt/β-catenin signaling causes colorectal cancer, Wnt/β-catenin signaling inhibitors are potential candidates for colorectal cancer treatment. Our drug screening platform identified ursolic acid (UA), a triterpenoid with various biological activities, as a potential anticancer drug because it inhibits the T-cell factor (TCF)/β-catenin-mediated transcriptional activity. Here, we discovered that UA inhibited Wnt signaling by reducing the Wnt reporter activity and Wnt target gene expression, leading to a delay in cell cycle progression and the suppression of cell proliferation. Stepwise epistatic analyses suggested that UA functions on β-catenin protein stability in Wnt signaling. Further studies revealed that UA reduced β-catenin protein levels by Western blotting and immunofluorescent staining and induced autophagy by microtubule-associated protein 1 light chain 3 beta (LC3B) punctate staining. The cotreatment with UA and the autophagy inhibitors chloroquine and wortmannin recovered the β-catenin protein levels. Therefore, UA was confirmed to induce β-catenin degradation by the autophagy–lysosomal degradation system through inhibition in the phosphatidylinositol 3-kinase (PI3K)/Ak strain transforming (protein kinase B; AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Our results not only highlight the potential of UA in Wnt-driven colorectal cancer therapy but also provide a workable Wnt signaling termination approach for the treatment of other Wnt-related diseases. Full article

Despite numerous studies, colon cancer is still one of the leading cancers in the world, both in terms of incidence and mortality. One of the most important methods of monitoring and studying changes in cancer is the use of biomarkers in the form of microRNA. Their remarkable stability and detectability in body fluids make them promising diagnostic and prognostic biomarkers. This review highlights selected deregulated miRNAs in colorectal cancer, including miR-21, miR-29b, miR-148a, miR-149, miR-155, miR-194, and miR-200b and lesser known ones such as miR-6803-5p or miR-4772-3p. Deregulation of their expression in colon cancer is associated with abnormal cell proliferation, migration, changes in the microenvironment or response to treatment, caused by their involvement in such pathways as Wnt/β-catenin, PI3K/Akt or EGFR. Additionally, we explore their therapeutic potential, particularly their ability to enhance tumour sensitivity to chemotherapeutic agents like 5-FU and oxaliplatin. The purpose of this review is to emphasize the growing relevance of miRNAs as both non-invasive diagnostic tools and potential therapeutic targets in colorectal cancer management. Full article

Reciprocal signaling between acute myeloid leukemia (AML) cells and the surrounding bone-marrow microenvironment (BMME) promotes AML progression through several mechanisms. One of the most important mechanisms is the induction of Galectin-3 (Gal-3) expression by AML cells and bone marrow mesenchymal stromal cells (BM-MSCs). Emerging evidence indicates that Gal-3 upregulation in the BMME promotes AML cell adhesion and survival, leading to the development of chemotherapy resistance, relapse, and poor prognosis. Identifying the biological function and critical signaling pathways of Gal-3 may contribute to overcoming acquired drug resistance and preventing post-treatment relapse. Gal-3 is involved in several molecular signaling pathways, including PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, JAK/STAT, JNK, Wnt/β-catenin, PLC/PKC and NF-κB, which are interconnected to promote AML cell survival and resistance to chemotherapy. This review focuses on the biological effects, molecular mechanisms of action and regulation of Gal-3 in the pathogenesis and progression of AML. The therapeutic potential of potent synthetic small-molecule Gal-3 inhibitors in high-risk patients with AML is also discussed based on preclinical and clinical evidence from several human diseases. Currently, the effect of these Gal-3 inhibitors in AML has not been investigated either in vitro or in vivo. The findings provide a rationale for targeting Gal-3 that may be a very promising therapeutic approach, especially for patients with relapsed/refractory AML, and may enhance the efficacy of conventional chemotherapeutic drugs and/or immune checkpoint inhibitors. Full article

Transglutaminase 2 (TG2) is a multifunctional protein and plays a role in cancer progression. We previously identified TG2 as an early-recurrence biomarker in hepatocellular carcinoma (HCC). TG2-knockdown (shTG2) and control (shCtl) HCC cell lines were used for comparative analyses to clarify the molecular mechanisms underlying the contribution of this protein to HCC malignancy. The proliferation of shTG2 cells was slightly but significantly decreased compared with that of shCtl cells. Differential gene expression profiling based on GeneChip arrays revealed the enrichment of the PI3K-Akt signaling pathway and showed that the expression of Dickkopf-1 and -3 (DKK1 and DKK3, respectively), inhibitors and modulators of the Wnt/β-catenin signaling pathway, was increased in shTG2 cells. The expression of epithelial–mesenchymal transition (EMT)-related genes was similar in both shCtl and shTG2 cells before and after TGF-β1 treatment, even though TGF-β1 markedly upregulated TG2. Thus, TG2 may contribute to cancer malignancy via the stimulation of cell proliferation signaling, such as PI3K-Akt and Wnt/β-catenin signaling, but not EMT. This effect might be further enhanced by humoral factors such as TGF-β1 from the tumor microenvironment. Full article

Breast cancer ranks as the fifth-most-prevalent malignancy worldwide, characterized by high heterogeneity and multifactorial etiology across molecular subtypes. Despite advancements in conventional therapies, including surgery and chemotherapy, persistent challenges such as treatment-related adverse effects and acquired drug resistance necessitate alternative therapeutic strategies. Matrine, a naturally occurring alkaloid derived from Sophora flavescens, has demonstrated significant anticancer potential through multiple mechanisms. Experimental evidence indicates that matrine exerts inhibitory effects on tumor cell proliferation, promotes apoptosis, and attenuates metastatic progression via modulation of critical signaling pathways, particularly PI3K/Akt, JAK/STAT, NF-κB, MAPK/ERK, and Wnt/β-catenin. This review systematically examines subtype-specific responses to matrine treatment, highlighting its potential utility in precision oncology for distinct breast cancer classifications. Furthermore, we evaluate matrine’s capacity to synergize with standard chemotherapeutic regimens, potentially overcoming drug resistance while reducing required dosages. By integrating current preclinical and clinical findings, this analysis provides new perspectives on matrine’s therapeutic applications and underscores the imperative for translational studies to establish optimized treatment protocols for clinical implementation. Full article

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality globally, prompting the investigation of novel therapeutic targets. Progranulin (PGRN), a glycoprotein initially associated with neurodegenerative disorders, has emerged as a critical protective agent in cardiovascular health. Recent studies indicate that PGRN exerts its protective effects through various mechanisms, including the modulation of inflammatory pathways, enhancement of mitochondrial function, and promotion of vascular integrity. By engaging with key signaling pathways, such as PI3K/Akt, NF-κB and Wnt/β-catenin, PGRN mitigates oxidative stress and fosters an environment conducive to cardiac repair following ischemic injury. Furthermore, PGRN’s role in lipid metabolism and vascular smooth muscle cell behavior highlights its complexity in influencing atherogenesis and vascular homeostasis. This review synthesizes current knowledge regarding PGRN’s protective mechanisms in CVD, emphasizing its potential as a therapeutic target and paving the way for innovative approaches to prevent and treat cardiovascular diseases, ultimately improving patient outcomes in this critical area of public health. Full article

Background: Endometrial receptivity is crucial for successful embryo implantation in assisted reproductive technologies (ARTs). MicroRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) have emerged as important post-transcriptional regulators of endometrial function, although their diagnostic and molecular functions are poorly understood. Methods: A systematic review was conducted following PRISMA 2020 principles and registered in PROSPERO (CRD420251001811). We looked at 28 peer-reviewed publications published between 2010 and 2025 that used endometrial tissue, blood, uterine fluid, saliva, and embryo culture medium to study miRNAs and other non-coding RNAs in endometrial receptivity, recurrent implantation failure (RIF), and infertility. Results: MiRNAs like miR-145, miR-30d, miR-223-3p, and miR-125b influence implantation-related pathways such as HOXA10, LIF-STAT3, PI3K-Akt, and Wnt/β-catenin. Dysregulated expression profiles were linked to inadequate decidualization, immunological imbalance, and poor angiogenesis. CeRNA networks that include lncRNAs (e.g., H19 and NEAT1) and circRNAs (e.g., circ_0038383) further regulate miRNA activity. Non-invasive biomarkers derived from plasma, uterine fluid, and embryo media showed high prediction accuracy for implantation outcomes. Conclusions: MiRNA signatures offer a functional and diagnostic blueprint for endometrial receptivity. This systematic review provides a timely and thorough synthesis of the existing literature, with the goal of bridging the gap between molecular discoveries and therapeutic applications. By emphasizing both the mechanistic importance and diagnostic value of certain miRNA signatures, it paves the way for future precision-based techniques in embryo transfer and endometrial assessment in ART. Full article

Collagen peptides are recognized for their diverse bioactivities; however, efficiently screening potent peptides from hydrolysates remains challenging. This study employed an integrated strategy that combined in silico antioxidant activity prediction and molecular docking to myeloperoxidase (MPO) to screen active peptides derived from yak bone collagen hydrolysates. Focusing on low molecular weight peptides, containing motifs such as GVM, GLP, GPM, and GPQ, we identified nine antioxidant peptides (KC1–KC9). Their activities were validated through in vitro free radical scavenging assays, with peptide KC7 demonstrating superior performance. Furthermore, peptide KC7 promoted proliferation, differentiation, and mineralization in MC3T3-E1 cells by upregulating osteogenic markers such as Runx2 and osteocalcin, modulating the Wnt/β-catenin and PI3K/Akt pathways, and reducing the Bax/Bcl-2 ratio. These results highlight KC7’s dual capacity to mitigate oxidative stress and potentially reduce apoptotic susceptibility, thereby stimulating osteogenesis. This positions peptide KC7 as a promising candidate for bone regeneration and oxidative stress-related disorders. Moreover, this study underscores the effectiveness of integrating computational and experimental approaches for the discovery of multifunctional natural peptides. Full article