The eukaryotic initiation factor 5A2 gene (EIF5A2) is a highly conserved and multifunctional gene that significantly influences various cellular processes, including translation elongation, RNA binding, ribosome binding, protein binding and post-translational modifications. Overexpression of EIF5A2 is frequently observed in multiple cancers, where it functions as an oncoprotein. Additionally, EIF5A2 is implicated in drug resistance through the regulation of various molecular pathways. In the review, we describe the structure and functions of EIF5A2 in normal cells and its role in tumorigenesis. We also elucidate the molecular mechanisms associated with EIF5A2 in the context of tumorigenesis and drug resistance. We propose that the biological roles of EIF5A2 in regulating diverse cellular processes and tumorigenesis are clinically significant and warrant further investigation.

Breast cancer continues to be a major cause of death among women globally, with triple-negative breast cancer (TNBC) presenting a particularly difficult challenge due to its aggressive behaviour and the lack of effective treatment options. Nanotechnology, particularly the use of silver nanoparticles (AgNPs), has emerged as a promising avenue in oncological research. This review explores into the escalating field of green synthesis of nanoparticles, emphasizing sustainable approaches utilizing plant-based resources. Critical factors influencing nanoparticle synthesis, including reaction conditions, precursor types, and plant phytochemicals, are explored alongside advanced characterization techniques essential for evaluating nanoparticle properties. Special focus is given to the phytofabrication of silver nanoparticles and their multifaceted roles in breast cancer treatment, with detailed insights into their mechanisms, such as inducing apoptosis, generating reactive oxygen species (ROS), and disrupting mitochondrial function, particularly in TNBC cells. The review further highlights the advantages of plant-derived AgNPs, such as biocompatibility and reduced toxicity, while addressing challenges like scalability, reproducibility, and regulatory hurdles. Concluding with future prospects, this paper reflects the potential of green-synthesized AgNPs as a keystone in next-generation cancer therapeutics, paving the way for innovative and eco-friendly approaches in oncology.

The phosphoinositide 3-kinase (PI3K) pathway plays a crucial role in cancer, including cell growth, survival, metabolism, and metastasis. Its major role in tumor growth makes it a key target for cancer therapeutics, offering significant potential to slow tumor progression and enhance patient outcomes. Gain-of-function mutations, gene amplifications, and the loss of regulatory proteins like PTEN are frequently observed in malignancies, contributing to tumor development and resistance to conventional treatments such as chemotherapy and hormone therapy. As a result, PI3K inhibitors have received a lot of interest in cancer research. Several kinds of small-molecule PI3K inhibitors have been developed, including pan-PI3K inhibitors, isoform-specific inhibitors, and dual PI3K/mTOR inhibitors, each targeting a distinct component of the pathway. Some PI3K inhibitors such as idelalisib, copanlisib, duvelisib, alpelisib, and umbralisib have received FDA-approval, and are effective in the treatment of breast cancer and hematologic malignancies. Despite promising results in preclinical and clinical trials, the overall clinical success of PI3K inhibitors has been mixed. While some patients may get substantial advantages, a considerable number of them acquire resistance as a result of feedback activation of alternative pathways, adaptive tumor responses, and treatment-emergent mutations. The resistance mechanisms provide barriers to the sustained efficacy of PI3K-targeted treatments. This study reviews recent advancements in PI3K inhibitors, covering their clinical status, mechanism of action, resistance mechanisms, and strategies to overcome resistance.

Breast cancer (BC) is one of the most common human malignancies, but the mechanisms of BC have not been fully elucidated. Recently, tetraspanin 31 (TSPAN31) is reported to be linked to cancer progression. However, the function of TSPAN31 remains unclear in BC. Investigation of the function and potential mechanism of TSPAN31 in BC was the purpose of this study. Immunohistochemistry, western blot, and quantitative real-time polymerase chain reaction were applied to measure TSPAN31 expression. Loss and gain functional experiments were utilized to survey the influences of TSPAN31 on BC biological process, including cell growth, invasion, migration, and fatty acid metabolism. Mechanistically, Kyoto Encyclopedia of Genes and Genomes analysis based on DepMap database and Gene Set Enrichment Analysis based on The Cancer Genome Atlas database were executed to find TSPAN31-related pathway. Western blot was carried out to assess the changes of fatty acid synthase (FASN), sterol regulatory element binding protein 1 (SREBP1), acyl-CoA synthetase long-chain family member 1 (ACSL1), phosphatidylinositol 3-kinase (PI3K), phosphorylated (p)-PI3K, protein kinase B (AKT), and p-AKT. In human non-triple negative breast cancer tissues and cells, TSPAN31 expression was upregulated. TSPAN31 knockdown induced BC cell apoptosis, inhibited cell proliferation, invasion, migration, and fatty acid metabolism, and reduced the protein levels of FASN, SREBP1, ACSL1, p-PI3K/PI3K, and p-AKT/AKT. In contrast, TSPAN31 overexpression led to the opposite results. Additionally, the activator of PI3K (740 Y-P) attenuated the inhibition of TSPAN31 knockdown on fatty acid metabolism, proliferation, and invasion in BC cells. Through activation of fatty acid metabolism and PI3K/AKT pathway, TSPAN31 played a carcinogenic role in BC. For the mechanism of BC tumorigenesis, our study provides an interesting insight.

The phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB or AKT)/mammalian target of rapamycin (mTOR) signaling pathway (PAM pathway) plays a critical role in breast cancer pathogenesis and progression, and is closely linked with resistance to endocrine therapy in advanced breast cancer. Randomized clinical trials have shown that PI3K/AKT/mTOR inhibitors deliver significant clinical benefits, particularly for patients with advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

In 2022, the Breast Cancer Expert Committee of the National Cancer Quality Control Center convened specialists in related fields to draft the "Expert Consensus on the Clinical Application of PI3K/AKT/mTOR Inhibitors in the Treatment of Advanced Breast Cancer." This consensus raised awareness of these inhibitors among oncologists in China and improved the precision of clinical decision-making. In recent years, growing evidence has emphasized the importance of targeting the PAM pathway, reflected in the approval of several innovative agents. This consensus is an updated 2025 edition that retains the foundational structure of the 2022 edition while incorporating notable updates.

Updates to the consensus include the introduction of newly approved PAM pathway inhibitors, updated data from recent clinical trials, and expanded therapeutic applications. The revised guidance also offers updated recommendations for genetic testing to detect alterations in relevant pathways. The section on managing drug-related adverse events has been significantly expanded, providing detailed insights into different types of adverse events and their management. These updates aim to enhance the clinical application of PAM pathway inhibitors, promote precision medicine, and ultimately, improve survival outcomes for patients with breast cancer.

Breast cancer (BC) is a complex disease that affects millions of women worldwide. Its growing impact calls for advanced treatment strategies to improve patient outcomes. The PI3K/AKT/mTOR pathway is a key focus in BC therapy because it plays a major role in important processes like tumor growth, survival, and resistance to treatment. Targeting this pathway could lead to better treatment options and outcomes. The present review explores how the PI3K/AKT/mTOR pathway becomes dysregulated in BC, focusing on the genetic changes like PIK3CA mutations and PTEN loss that leads to its aggravation. Current treatment options include the use of inhibitors targeting PI3K, AKT, and mTOR with combination therapies showing promise in overcoming drug resistance and improving effectiveness. Looking ahead, next-generation inhibitors and personalized treatment plans guided by biomarker analysis may provide more accurate and effective options for patients. Integrating these pathway inhibitors with immunotherapy offers an exciting opportunity to boost anti-tumor responses and improve survival rates. This review offers a comprehensive summary of the current progress in targeting the PI3K/AKT/mTOR pathway in BC. It highlights future research directions and therapeutic strategies aimed at enhancing patient outcomes and quality of life.

Inflammation serves as a critical driver in coronary artery disease pathogenesis. Emerging clinical evidence demonstrates that low-dose colchicine therapy significantly reduces ischemic event incidence in patients with coronary heart disease while attenuating myocardial ischemia-induced inflammatory cascades. Nevertheless, the precise cardioprotective mechanisms underlying colchicine-a plant-derived anti-inflammatory agent-in limiting post-infarction cardiomyocyte injury remain incompletely elucidated. This study systematically investigates colchicine's myocardial preservation mechanisms through an integrated experimental approach.

To establish experimental models of myocardial injury, we performed permanent ligation of the left anterior descending coronary artery (LAD) in mice for in vivo studies, while HL-1 mouse atrial cardiomyocytes were treated with 0.3 mM H₂O₂ to induce oxidative stress in vitro. Following successful model validation, colchicine was administered to both systems. Comprehensive evaluations included echocardiographic assessment of cardiac function, histological examination of inflammatory infiltration and collagen deposition through H&E and Masson's trichrome staining respectively, quantitative analysis of cardiomyocyte apoptosis by flow cytometry, and Western blot detection of key signaling pathway components and pyroptosis-related proteins (including NLRP3, caspase-1, and GSDMD).

Our experimental data revealed that colchicine treatment significantly attenuated myocardial injury and fibrosis while improving cardiac function (P < 0.05). Mechanistically, colchicine administration reduced proinflammatory cytokine release (IL-1β and IL-18), decreased neutrophil infiltration, and suppressed cardiomyocyte pyroptosis. These cardioprotective effects were associated with modulation of the ESR1-PI3K-Akt-NF-κB signaling pathway (P < 0.05), suggesting a potential therapeutic mechanism for colchicine in myocardial protection.

Colchicine inhibits myocardial pyroptosis and reduces myocardial cell injury after myocardial infarction through the ESR1-PI3K-Akt-NF-κB signaling pathway.

Natural products rich in phytoestrogens, particularly those derived from traditional Chinese medicine (TCM) herbs, have garnered increased attention. Plant-derived extracellular vesicles are emerging as a promising strategy in cell communication and disease defense. Here, a comprehensive study on Herba Epimedium-derived extracellular nanovesicles (EELNs) for postmenopausal osteoporosis treatment was conducted. The results showed that EELNs exhibit a typical exosome morphology with an average diameter of 130 nm and are rich in specific small-molecule metabolites and miRNAs. Network pharmacology and KEGG analysis highlighted the therapeutic potential of EELNs in osteoporosis through multiple classical osteogenic pathways. In vitro experiments proved that EELNs potentiated the osteogenic differentiation of BMSCs by targeting the Pi3k/Akt/mTOR pathway. In vivo, EELN-loaded hydroxyapatite nano-whisker (E-GW) composites were used to repair mandibular defects in an OVX-induced osteoporosis rat model. The results indicate that EELNs are promising therapeutic agents for the regeneration and bone mass maintenance of alveolar defects in postmenopausal osteoporosis patients and offer potential perspectives for natural products in postmenopausal osteoporosis treatment.

The airway and lung tissue inflammation and structural changes caused by COPD lead to persistent and irreversible airflow limitation in patients. Several studies have associated IL-17A with COPD airway inflammation and collagen deposition, while autophagy is essential for maintaining normal cell function. Based on these findings, we propose a hypothesis that IL-17 affecting the autophagy of macrophages through the PI3K/AKT/mTOR pathway may contribute to the regulation of the airway remodeling process in COPD. The COPD airway remodelling model was confirmed by pulmonary function tests and HE and Masson staining. IL-17A, IL-6 and CCL20 were detected by ELISA, autophagosomes (APs) were observed by transmission electron microscopy, and western blotting was used to detect PI3K/AKT/mTOR-related proteins, autophagy-related proteins and collagen. Immunofluorescence revealed colocalization of LC3 in mouse bronchial fibroblasts (MBFs). MBFs were isolated and cultured via lentiviral transfection, IL-17RA overexpression or silencing, and quantitative analysis of PI3K/AKT/mTOR pathway-related proteins and autophagy-related proteins via western blotting. The results validated the establishment of the COPD model. Increased IL-17A in the COPD airway and increased IL-6 and CCL20 expression were observed in the COPD mice supplemented with the autophagy inhibitor 3MA. Using TEM, we observed a significant reduction in the number of APs in the airways in both the COPD and 3MA groups. Moreover, the PI3K/AKT/mTOR pathway phospho-p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR ratios were also increased in the COPD group. Moreover, as P62 increased, Beclin-1 and LC3II/I expression decreased correspondingly, while Collagen I and Collagen III also increased. In our study of cultured mouse MBFs, the results showed that overexpression (OE) virus-mediated transfection of MBFs overexpressing IL-17RA increased the p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR ratios, increased the P62 content and reduced the expression of Beclin-1 and LC3II/I. However, compared with the OE group, the silencing (sh)-mediated transfection of MBFs with IL-17RA had almost opposite effects. Increased collagen production and the expression of IL-17A, IL-6 and CCL20 in the airways of COPD mice. Autophagy decreased, and the PI3K/AKT/mTOR pathway was activated in COPD airway tissue. In primary cultured MBFs from COPD mice, IL-17A combined with IL-17RA activates the PI3K/AKT/mTOR pathway, thereby inhibiting autophagy.

Despite decreasing trends in incidence, colorectal cancer (CRC) is still a major contributor to malignancy-related morbidities and mortalities. Groundbreaking advances in immunotherapies and targeted therapies benefit a subset of CRC patients, with sub-optimal outcomes. Hence, there is an unmet need to design and manufacture novel therapies, especially for advanced/metastatic disease. KRAS, the most highly mutated proto-oncogene across human malignancies, particularly in pancreatic adenocarcinoma, non-small cell lung cancer, and CRC, is an on-off switch and governs several fundamental cell signaling cascades. KRAS mutations not only propel the progression and metastasis of CRC but also critically modulate responses to targeted therapies.

We discuss the impacts of KRAS mutations on the CRC's tumor microenvironment and describe novel strategies for targeting KRAS and its associated signaling cascades and mechanisms of drug resistance.

Drug development against KRAS mutations has been challenging, mainly due to structural properties (offering no appropriate binding site for small molecules), critical functions of the wild-type KRAS in non-cancerous cells, and the complex network of its downstream effector pathways (allowing malignant cells to develop resistance). Pre-clinical and early clinical data offer promises for combining KRAS inhibitors with immunotherapies and targeted therapies.

Breast cancer (BC) is a global health concern with significant mortality rates, necessitating a deep understanding of its molecular landscape. Luminal A and B BC, characterized by estrogen receptor (ER) and/or progesterone receptor (PR) positivity, face challenges in endocrine therapy due to acquired resistance, frequently driven by PI3K/AKT/mTOR pathway activation. This study focuses on the frequency of PIK3CA mutations across molecular subtypes BC within the Indonesian population. The study analyzed collected samples from diverse Indonesian regions, representing various islands. Histopathological analysis and immunohistochemistry classified samples into molecular subtypes. Genetic analysis using PIK3CA mutation detection kits revealed a mutation frequency of 32.9%, with 30 (14.5%) samples located in exon 9 and 38 (18.4%) samples in exon 20. Statistical analyses highlighted associations between PIK3CA mutations and molecular subtypes (p = 0.029), with luminal B HER2-negative (40.5%) and luminal A (40.2%) exhibiting the highest mutation rate. A significant association was also observed between the exon location of only mutated PIK3CA samples and age group (p < 0.001), with most of the PIK3CA exon 9 being ≤ 50 years old (72.4%) and PIK3CA exon 20 being > 50 years old. No statistically significant association was observed between the location of PIK3CA mutation (exons 9 and 20) and the breast site, histopathological diagnosis, and molecular subtypes. Comparisons with existing literature and inconsistencies in PIK3CA mutation frequencies across different BC subtypes underline the need for population-specific research. The study emphasizes the importance of assessing PIK3CA mutations in BC management, offering insights for personalized therapies and potential advancements in understanding this complex disease within the Indonesian context.

Breast cancer stem cells (BCSCs) are a unique subpopulation of tumor cells driving tumor resistance, progression, metastasis, and recurrence. Reprogrammed cellular metabolism and key signaling pathways, including Wnt/β-catenin, TGF-β, STAT3, and PI3K/AKT/mTOR pathway play a vital role in maintaining BCSCs. Importantly, PI3K/Akt/mTOR pathway regulates metabolism, survival, growth, and invasion, with PIK3CA, encoding the PI3K catalytic subunit p110α, the most frequently mutated gene in breast cancer. This study investigates the effects of alpha-lipoic acid (LA) on the metabolic profile of BCSCs, focusing on its interaction with PI3K signaling. LA was found to bind PI3K, disrupting cancer-associated metabolic pathways and significantly inhibiting BCSC metabolism. Metabolomic analysis of MCF-7 and MDA-MB-231-derived breast cancer spheroids showed LA-induced metabolic shifts. In MCF-7 spheroids, LA induced upaccumulation of 15 metabolites and downaccumulation of 5, while in MDA-MB-231 spheroids, it induced upaccumulation of 3 and downaccumulation of 16. LA also enhanced the sensitivity of breast cancer spheroids to doxorubicin (Dox), demonstrating a synergistic effect. Mechanistically, LA modulates the PI3K/Akt/mTOR pathway, impairing cell survival and proliferation. These findings highlight the potential of LA as a therapeutic agent for reprogramming cancer metabolism and enhancing chemotherapy efficacy. These results provide a strong rationale for incorporating LA into combination therapy strategies for breast cancer treatment.

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor associated with high fatality rates, poor prognosis, and limited treatment options. In this study, we utilized RNA-Seq gene count data from GBM patients, sourced from the Gene Expression Omnibus (GEO) database, to conduct an in-depth analysis of gene expression patterns.

Our investigation involved stratifying samples into two distinct sets, Group I and Group II, comparing normal, low-grade, and GBM tumor samples, respectively. Subsequently, we performed differential expression analysis and enrichment analysis to uncover significant gene signatures. To elucidate the protein-protein interactions associated with GBM, we used the STRING plugin within Cytoscape for comprehensive network visualization and analysis.

By applying Maximal clique centrality (MCC) scores, we identified a set of 10 hub genes in each group. These hub genes were subjected to survival analysis, highlighting their prognostic relevance. In Group I, comprising BUB1, DLGAP5, BUB1B, CDK1, TOP2A, CDC20, KIF20A, ASPM, BIRC5, and CCNB2, these genes emerged as potential biomarkers associated with the transition to low-grade tumors. In Group II, genes such as LIF, LBP, CSF3, IL6, CCL2, SAA1, CCL20, MMP9, CXCL10, and MMP1 were found to be involved in the transformation to adult glioblastoma. Kaplan-Meier's overall survival analysis of these hub genes revealed that modifications, particularly the upregulation of these candidate genes, were associated with reduced survival in GBM patients.

The findings established the significance of genomic alterations and differential gene expression in GBM, presenting opportunities for prognostic and targeted therapeutic interventions. This study provides valuable insights into potential avenues for enhancing the clinical management of GBM.

Doxorubicin (Dox) is a potent chemotherapeutic agent commonly used in cancer treatment. However, cardiotoxicity severely limited its clinical application. To address this challenge, a novel self-assembled nanomedicine platform, PMDDH, is developed for the co-delivery of Dox and metformin, an antidiabetic drug with cardioprotective and anti-tumor properties. PMDDH integrates metformin into a polyethyleneimine-based bioactive excipient (PMet), with Dox intercalated into double-stranded DNA and a hyaluronic acid (HA) coating to enhance tumor targeting. The PMDDH significantly improves the pharmacokinetics and tumor-targeting capabilities of Dox, while metformin enhances the drug's anti-tumor activity by downregulating programmed cell death ligand 1 (PD-L1) and activating the AMP-activated protein kinase (AMPK) signaling pathway. Additionally, the DNA component stimulates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which synergizes with Dox-induced immunogenic cell death (ICD) to promote a robust anti-tumor immune response. PMDDH markedly reduces Dox-induced cardiotoxicity by preserving mitochondrial function, reducing reactive oxygen species (ROS) production, and inducing protective autophagy in cardiomyocytes. These findings position PMDDH as a promising dual-function nanomedicine that enhances the anti-tumor efficacy of Dox while minimizing its systemic toxicity, offering a safer and more effective alternative for cancer therapy.

This meta-analysis aims to evaluate the efficacy and safety of rapamycin (mTOR) inhibitors with endocrine therapy versus endocrine therapy alone in treating advanced or metastatic estrogen receptor/progesterone receptor (ER/PR) + breast cancer.

We conducted a comprehensive search in PubMed, Web of Science, Embase, and the Cochrane Library for randomized controlled trials (RCTs) comparing mTOR inhibitors plus endocrine therapy with endocrine therapy alone up to September 2024.

This analysis included 10 RCTs comprising 3,337 patients. Relative to endocrine therapy alone, the combination of mTOR inhibitors and endocrine therapy significantly improved the clinical benefit rate (RR = 1.41, p < 0.001), overall response rate (RR = 1.40, p = 0.006), progression-free survival (PFS; HR = 0.67, p < 0.001), and overall survival (OS; HR = 0.86, p = 0.056), although the improvement in OS was not statistically significant. Subgroup analyses indicated a more pronounced PFS advantage in patients under 65 years of age (HR = 0.55, p = 0.013) and those who had previously received chemotherapy (HR = 0.51, p = 0.001). However, the incidence of adverse events was higher in the combination therapy group, notably stomatitis (p < 0.001), elevated aspartate aminotransferase/alanine aminotransferase (p = 0.04), and diarrhea (p = 0.01).

The combination of mTOR inhibitors with endocrine therapy offers superior efficacy with manageable toxicities in patients with advanced or metastatic ER/PR+ breast cancer.

Natural selection leaves detectable patterns of altered spatial diversity within genomes, and identifying affected regions is crucial for understanding species evolution. Recently, machine learning approaches applied to raw population genomic data have been developed to uncover these adaptive signatures. Convolutional neural networks (CNNs) are particularly effective for this task, as they handle large data arrays while maintaining element correlations. However, shallow CNNs may miss complex patterns due to their limited capacity, while deep CNNs can capture these patterns but require extensive data and computational power. Transfer learning addresses these challenges by utilizing a deep CNN pretrained on a large dataset as a feature extraction tool for downstream classification and evolutionary parameter prediction. This approach reduces extensive training data generation requirements and computational needs while maintaining high performance. In this study, we developed TrIdent, a tool that uses transfer learning to enhance detection of adaptive genomic regions from image representations of multilocus variation. We evaluated TrIdent across various genetic, demographic, and adaptive settings, in addition to unphased data and other confounding factors. TrIdent demonstrated improved detection of adaptive regions compared to recent methods using similar data representations. We further explored model interpretability through class activation maps and adapted TrIdent to infer selection parameters for identified adaptive candidates. Using whole-genome haplotype data from European and African populations, TrIdent effectively recapitulated known sweep candidates and identified novel cancer, and other disease-associated genes as potential sweeps.

Anoikis, defined as programmed cell death triggered by the loss of cell-extracellular matrix (ECM) and cell-cell interactions, is crucial for maintaining tissue homeostasis and preventing aberrant cell migration. Cancer cells, however, display anoikis resistance (AR) which in turn enables cancer metastasis. AR results from alterations in apoptotic signaling, metabolic reprogramming, autophagy modulation, and epigenetic changes, allowing cancer cells to survive in detached conditions. In this review we describe the mechanisms underlying both anoikis and AR, focusing on intrinsic and extrinsic pathways, disrupted cell-ECM interactions, and autophagy in cancer. Recent findings (i.e., between 2014 and 2024) on epigenetic regulation of AR and its role in metastasis are discussed. Therapeutic strategies targeting AR, including chemical inhibitors, are highlighted alongside a network analysis of 122 proteins reported to be associated with AR which identifies 53 hub proteins as potential targets. We also evaluate in vitro and in vivo models for studying AR, emphasizing their role in advancing metastasis research. Our overall goal is to guide future studies and therapeutic developments to counter cancer metastasis.

Intervertebral disc degeneration (IDD) is the progressive deterioration of the structure and function of an intervertebral disc (IVD), which manifests as excessive catabolism of the IVD extracellular matrix, which may lead to the gradual loss of IVD proteoglycans and water, thus altering the IVD composition and eventually leading to degeneration. As a traditional Chinese medicine, Er-Xian decoction (EXD) can balance the body's yin and yang, tonify the liver and kidney, invigorate blood circulation, and prevent blood stasis. Pharmacological research has shown that EXD regulates antioxidant and endocrine metabolism, maintains immune balance, and improves microcirculation.

To clarify the efficacy of EXD on treating IDD.

Serum was collected from model IDD rabbits treated with EXD for metabolomics analysis, and its mechanism of action was predicted on the basis of the metabolomics and network pharmacology data. Nucleus pulposus cells (NPCs) were induced with IL-1β to build an in vitro IDD model, and EXD was administered along with an inhibitor. All groups of cells were subjected to CCK-8 assays, ELISA and flow cytometry, immunohistochemistry, Western blot, and immunofluorescence staining analyses to explore how EXD protects NPCs and the underlying mechanism.

EXD reduced inflammatory processes, restored IVD height, and alleviated IDD in rabbits. Integrated metabolomics and network pharmacology analyses revealed that EXD exerts its therapeutic effects on IDD primarily via the mTOR and HIF-1 signalling pathways, and the active components of EXD, including anhydroicaritin, β-sitosterol, kaempferol, quercetin, and stigmasterol, bound strongly to pivotal targets within these pathways. Moreover, EXD reduced the inflammatory factor levels, inhibited NPC apoptosis, and upregulated the key proteins p-mTOR, HIF-1α, and p-AKT. Conversely, the HIF-1 inhibitor BAY872243 increased the inflammatory factor levels and led to NPC deterioration.

EXD regulates disc cell metabolism and inflammatory responses by modulating the mTOR and HIF-1 signalling pathways, thereby slowing or reversing IDD.

Orthosiphon aristatus (Blume) Miq. (O. aristatus), a traditional herbal medicine, exhibits a wide range of biological activities but its anti-breast cancer effect is not fully established. In this study, sinensetin was isolated and purified through a multistep process, beginning with liquid-liquid partitioning using dichloromethane, followed by classic column chromatography using gradient elution. Preparative high-performance liquid chromatography with acetonitrile-water (41:59, v/v) mobile phase successfully isolated sinensetin to 95% purity. In silico screening of O. aristatus-derived bioactive compounds revealed that flavonoids (including sinensetin), polyphenols (i.e. 2,3-O-dicaffeoyltartaric acid, rosmarinic acid), diterpenoid (i.e. trans-ozic acid), triterpenoids and dipeptide (i.e. aurantiamide acetate) have good binding affinities with 17β-HSD1, ErbB2/HER2 and PI3K-PKB/Akt proteins. These findings suggest that O. arsistatus could be a rich natural source of inhibitors targeting molecular pathways involved in breast cancer, offering promising therapeutic benefits.

The management of breast cancer, one of the most common and heterogeneous malignancies, has transformed with the advent of precision medicine. This review explores current developments in genetic profiling, molecular diagnostics, and targeted therapies that have revolutionized breast cancer treatment. Key innovations, such as cyclin-dependent kinases 4/6 (CDK4/6) inhibitors, antibody-drug conjugates (ADCs), and immune checkpoint inhibitors (ICIs), have improved outcomes for hormone receptor-positive (HR+), HER2-positive (HER2+), and triple-negative breast cancer (TNBC) subtypes remarkably. Additionally, emerging treatments, such as PI3K inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, and mRNA-based therapies, offer new avenues for targeting specific genetic mutations and improving treatment response, particularly in difficult-to-treat breast cancer subtypes. The integration of liquid biopsy technologies provides a non-invasive approach for real-time monitoring of tumor evolution and treatment response, thus enabling dynamic adjustments to therapy. Molecular imaging and artificial intelligence (AI) are increasingly crucial in enhancing diagnostic precision, personalizing treatment plans, and predicting therapeutic outcomes. As precision medicine continues to evolve, it has the potential to significantly improve survival rates, decrease recurrence, and enhance quality of life for patients with breast cancer. By combining cutting-edge diagnostics, personalized therapies, and emerging treatments, precision medicine can transform breast cancer care by offering more effective, individualized, and less invasive treatment options.

Breast cancer, which is considered the most common type of cancer among women worldwide, is estimated to reach 4.4 million cases in 2070. Early diagnosis has become very important to prevent this expected increase. Various traditional methods, such as mammography, biopsy, enzyme immunoassay (EI), liquid biopsy, immunohistochemistry (IGH), fluorescence in situ hybridization (FISH) are used to diagnose breast cancer, but the fact that these methods are very expensive, have low sensitivity, and cause mutations in tissues due to X-rays has led researchers to discover faster, more cost-effective, and easily detectable methods. In particular, increased levels of new blood-based biomarkers in the circulation can be detected sensitively and selectively by electrochemical methods to facilitate early disease screening and rapid diagnosis. This comprehensive review focuses on the prevalence and pathology of breast cancer, clinical diagnosis of breast cancer, and electrochemical sensors of molybdenum-based compounds for the detection of various breast cancer biomarkers in recent years. Electrochemical analysis studies carried out in the field in recent years are compiled and are considered as aptamer-based, nucleotide-based, and immunosensors. The chemical properties of molybdenum compounds are discussed, and the modifications of these compounds to the electrode surface are discussed under 4 headings: drop casting, electrodeposition, atomic layer deposition, and electrophoretic deposition.

Thymidine phosphorylase (TYMP), a protein found in both prokaryotic and eukaryotic cells, is encoded by a gene located in the q13 region of chromosome 22. With a relative molecular mass of 55,000, TYMP exists as a homodimer. Recent research has increasingly illuminated the diverse functions of TYMP. It is known to facilitate platelet activation, osteoclast differentiation, and angiogenesis. Mutations in the TYMP gene are linked to mitochondrial neurogastrointestinal encephalomyopathy. Beyond its physiological roles, TYMP contributes significantly to tumor growth and cancer progression, where it promotes angiogenesis, modulates epigenetic genes, inhibits apoptosis, and acts as a critical enzyme in the nucleoside metabolic rescue pathway. Moreover, TYMP holds substantial implications in cancer treatment and prognosis. Given its involvement in cancer progression, TYMP inhibitors may prove valuable in inhibiting tumor growth and metastasis. Interestingly, while TYMP can drive tumor growth, certain concentrations of TYMP also enhance the cytotoxic effects of chemotherapy drugs such as 5-fluorouracil (5-FU). Although challenges exist-such as the potential disruption of normal physiological functions when inhibiting TYMP-the protein remains a promising target for cancer treatment. Ongoing research on TYMP could deepen our understanding of human physiology and the pathogenesis of cancer and open new avenues for therapeutic interventions. This article provides a comprehensive review of TYMP's structure, physiological functions, and its role in tumorigenesis and anti-tumor therapy.

Ajuga decumbens, a traditional Chinese medicine, possesses anti-breast cancer effects. Its main component, 8-O-acetylharpagide, exhibits potential anticancer activity; however, the active metabolites and mechanisms underlying its effects remain unclear.

The metabolism and excretion of 8-O-acetylharpagide in rats were investigated using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry analysis of bile, urine, and feces. Active metabolites were identified and evaluated using network pharmacology, molecular docking, and Western blotting assays.

A total of 21 metabolites were identified, with demethylation, hydrolysis, and glucuronidation being the primary metabolic pathways. M3 and M5 were identified as key metabolites, showing strong binding affinity to cancer-related targets, such as AKT1, MMP9, and STAT3. M5 displayed strong pharmacokinetic properties, including better lipid solubility and reduced polarity. Network pharmacology analysis indicated that these metabolites exert anticancer effects by modulating the PI3K/AKT signaling pathway. In vivo experiments demonstrated that oral administration of 8-O-acetylharpagide significantly inhibited the proliferation of 4T1 tumor tissues by suppressing the expression of the AKT/NF-κB/MMP9 signaling axis. This may be related to inhibition of the expression of the AKT/NF-κB/MMP9 signaling axis in 4T1 tumor tissues after metabolism of 8-O-acetylharpagide to M5 and M3.

As a prodrug, 8-O-acetylharpagide is metabolized to M5, which may subsequently exert an anti-breast cancer effect through downregulation of the AKT/NF-κB/MMP9 signaling axis. This study provides a theoretical basis for the clinical application of Ajuga decumbens in breast cancer therapy.

Long intergenic non-protein coding RNA 1559 (LINC01559), a long non-coding RNA (lncRNA) located on chromosome 12p13.1, plays a critical role in the progression of various cancers. The aberrant expression of LINC01559 significantly impacts multiple biological processes in tumor cells, including cell proliferation, epithelial-mesenchymal transition (EMT), migration, invasion, angiogenesis, and cellular stemness. Notably, the expression levels of LINC01559 correlate with the pathological features and prognosis of several cancers, such as pancreatic, breast, and gastric cancers, and it may serve as a diagnostic marker for non-small cell lung cancer. Moreover, the expression of LINC01559 is regulated by various mechanisms and can influence cancer initiation and progression through a competing endogenous RNA (ceRNA) network, where it interacts with a cohort of eight different microRNAs (miRNAs). Additionally, LINC01559 may directly interact with downstream proteins, thereby promoting their functions or enhancing their stability. LINC01559 is also implicated in key signaling pathways associated with cancer development, including the PI3 K/AKT, RAS, and autophagy signaling pathways. Furthermore, it has been linked to drug resistance in breast cancer and hepatocellular carcinoma. This review provides a comprehensive assessment of the clinical implications of dysregulated LINC01559 expression across various cancer types, highlighting its crucial functions and underlying molecular mechanisms in tumorigenesis. Additionally, we present in-depth discussions and propose hypotheses regarding the functional roles of LINC01559 in cancer pathogenesis, while outlining potential research avenues for future exploration of this molecular target.

Gastric cancer, marked by its high incidence and poor prognosis, demands the urgent development of novel and effective treatment strategies, especially for patients ineligible for surgery or those who have had limited success with chemotherapy, radiotherapy and targeted therapies. Recently, antibody-drug conjugates (ADCs) have become a key area of investigation due to their high specificity and potent antitumor effects. These therapies combine monoclonal antibodies, designed to bind to tumor-specific antigens, with cytotoxic agents that selectively target and destroy malignant cells. ADCs have generated significant interest in clinical trials as a promising approach to improve both treatment efficacy and patient outcomes in gastric cancer. However, their clinical application is not without challenges and limitations that must be addressed. This review discusses the recent progress in the use of ADCs for gastric cancer treatment.

The prevalence of breast cancer among women has led to a growing need for innovative anti-breast cancer medications and an in-depth investigation into their molecular mechanisms of action, both of which are essential tactics in clinical intervention. In the clinical practice of Traditional Chinese Medicine, Radix Bupleuri and its active components have shown promise as potential anti-breast cancer agents due to their ability to target multiple pathways, exhibit synergistic effects and reduce toxicity. These compounds are considered to enhance the prognosis of patients with cancer, prolong survival and combat chemotherapy resistance. The present review aimed to delve into the anti-breast cancer properties of Radix Bupleuri and its active ingredients, highlighting their mechanisms, such as inhibition of cell proliferation, promotion of apoptosis, metastasis prevention, microenvironment improvement and synergy with certain chemotherapeutic agents. These findings may provide a scientific rationale for combining Radix Bupleuri and its active components with traditional chemotherapy agents for the management of breast cancer.

Liver cancer (LC) is a deadly malignancy with limited therapeutic options in recent years. Natural killer cell-derived exosomes (NK-exo), as an important bridge of information transmission between cells, also have a certain killing effect on tumor cells. On this basis, this study investigated the specific regulatory mechanism of NK-exo on LC cells.

NK-exo was collected by differential centrifugation. The diameter and size distribution were characterized by dynamic light scattering (DLS), respectively. Western Blot (WB) assay detected the expression levels of exosome marker protein, PD-L1, and PI3K-AKT-mTOR signal-related proteins. The effect of NK-exo treatment on LC cell viability was measured by the CCK-8. With the use of CFDA·SE, we assessed the proliferation ability of CD8+T cells in direct co-culture with LC cells. The content of cytokines secreted by CD8+T cells in each treatment group was determined by enzyme-linked immunosorbent assay (ELISA) kits. We employed flow cytometry to analyze the expression of PD-L1 protein on the surface of LC cells and CD8 level in mice tumor tissues.

CCK-8 assay demonstrated that NK-exo repressed the cell viability of LC cells. WB uncovered that the protein expressions of PD-L1, p-AKT, and p-mTOR in NK-exo treated LC cells were decreased, which was returned to the control level after the addition of PI3K agonist. When NK-exo-treated LC cells were directly co-cultivated with CD8+T cells, the proliferation ability and cytokine secretion content of T cells were considerably elevated, and the expression of PD-L1 on LC cell surface was considerably reduced. However, these effects were restored to control levels by PI3K agonists.The in vivo experiments also confirmed that NK-exo could effectively inhibit the progression of LC, and the PI3K agonist could restore this effect to the level of the control group.

This study provided the first evidence that exosomes derived from NK cells inhibited the PI3K-AKT-mTOR signaling pathway in LC cells, and reduced PD-L1 expression, thereby promoting tumor immunity. In comparison to traditional immune checkpoint inhibitors, NK-exo possessed unique mechanisms of action and potential advantages. NK-exo holds the promise of becoming an innovative immunotherapy for the treatment of LC.

Acute myeloid leukemia (AML) is a common hematological malignancy with complex etiology; however, current standard chemotherapy regimens for AML show limited efficacy and unsatisfactory tolerability. Herein, a novel class of trisubstituted triazine mTOR inhibitors was designed and synthesized, and the optimal compound, HPT-11, exhibited potent inhibition against mTOR kinase and Molm-13 cell proliferation activities with inhibitory IC50 values of 0.7 and 12 nM, respectively. An antitumor mechanism investigation demonstrated that HPT-11 could potently block the downstream signaling pathway of mTOR and effectively induce apoptosis and autophagy. In addition, in vitro metabolic stability tests further confirmed the stable profiles of HPT-11 in artificial gastrointestinal fluids, rat plasma, and liver microsomes incubating conditions. Overall, our current medicinal chemistry work confirmed that compound HPT-11 is a potent mTOR inhibitor with promising activity in vitro, suggesting its potential as a candidate for further development in the treatment of AML.

Pyridone heterocycles, such as furo[2,3-b]pyridines, have emerged as prominent scaffolds in medicinal chemistry due to their versatile pharmacological properties, including significant anticancer activity. In this study, we successfully synthesized new pyridine-2(H)-one, nicotinonitrile, and furo[2,3-b]pyridine derivatives from chalcones bearing 4-(benzyloxy)phenyl and dichlorothiophenyl subunits to explore their therapeutic potential against breast cancer. By employing a synthetic strategy involving Claisen-Schmidt condensation followed by sequential cyclizations and functional modifications, we synthesized and characterized four compounds (MI-S0, MI-S1, MI-S2, and MI-S3) using various spectroscopic methods, including FT-IR, 1H-NMR, 13C-NMR, DEPT, H,H- and C,H-COSY, and HRMS. The in vitro cytotoxic activity of these compounds was evaluated against two breast cancer cell lines, MCF-7 and MDA-MB-231, and compared with a noncancerous breast cell line, MCF-10A. All compounds exhibited potent cytotoxic activities with minimal selectivity toward normal cells. Molecular docking studies targeting the serine/threonine kinase AKT1, estrogen receptor alpha (ERα), and human epidermal growth factor receptor 2 (HER2) revealed strong binding affinities, suggesting a mechanism involving the disruption of key cellular signaling pathways. These findings underscore the potential of furo[2,3-b]pyridine derivatives as promising candidates for further development into anticancer agents, laying the groundwork for future investigations into their selective therapeutic efficacy and molecular mechanisms of action.

Trogocytosis is the process by which a recipient cell siphons small membrane fragments and proteins from a donor cell and can be utilized by cancer cells to avoid immune detection. We observed lymphocyte specific protein expressed by triple negative breast cancer (TNBC) cells via immunofluorescence imaging of patient samples. Image analysis of Cluster of Differentiation 45RA (CD45RA) expression, a naïve T cell specific protein, revealed that all stages of TNBCs express CD45RA. Flow cytometry revealed TNBC cells trogocytose CD45 protein from T cells. We also showed that the acquisition of these lymphoid markers is contact dependent. Confocal and super-resolution imaging further revealed CD45+ spherical structures containing T cell genomic DNA inside TNBC cells after co-culture. Trogocytosis between T cells and TNBC cells altered tumor cell expression of PTPRC, the gene that encodes for CD45. Our results revealed that CD45 is obtained by TNBC cells from T cells via trogocytosis and that TNBC cells express CD45 intracellularly and on the membrane.

This study examines the critical role of non-coding RNAs (ncRNAs) in regulating epithelial-mesenchymal transition (EMT) in breast cancer, a prevalent malignancy with significant metastatic potential. EMT, wherein cancer cells acquire mesenchymal traits, is fundamental to metastasis. ncRNAs-such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs)-modulate EMT by influencing gene expression and signaling pathways, affecting cancer cell migration and invasion. This review consolidates recent findings on ncRNA-mediated EMT regulation and explores their diagnostic and therapeutic potential. Specifically, miRNAs inhibit EMT-related transcription factors, while lncRNAs and circRNAs regulate gene expression through interactions with miRNAs, impacting EMT progression. Given the influence of ncRNAs on metastasis and therapeutic resistance, advancing ncRNA-based biomarkers and treatments holds promise for improving breast cancer outcomes.

Breast cancer remains one of the most prevalent diseases worldwide, primarily affecting women. Its heterogeneous nature poses a significant challenge in the development of effective and targeted treatments. Molecular characterization has enabled breast cancer to be classified into four main subtypes: luminal A, luminal B, HER2-positive, and triple-negative breast cancer, based on hormone receptor expression and HER2 status. A deeper understanding of these molecular markers and their associated signaling pathways, such as MAPK and PI3K/AKT, is essential for improving prognosis and optimizing treatment strategies. Currently, several therapeutic agents are utilized in neoadjuvant and adjuvant therapies, often in combination with surgical interventions. However, emerging evidence highlights the growing challenge of drug resistance, which significantly limits the efficacy of existing treatments. Addressing this issue may require innovative approaches, including combination therapies and precision medicine strategies, tailored to the molecular profile of each patient. Therefore, a comprehensive understanding of the pathophysiologic mechanisms driving breast cancer progression and resistance is crucial for the development of advanced targeted therapies with greater precision and efficacy. This review aims to explore recent advancements in molecular research related to breast cancer subtypes and provide a critical analysis of current therapeutic approaches within the framework of precision medicine.

Radiotherapy is a cornerstone of breast cancer (BRCA) treatment. Accurately predicting tumor radiosensitivity is critical for optimizing therapeutic outcomes and personalizing treatment strategies. DNA repair pathways are key determinants of radiotherapy response. Thus, we aimed to develop a novel DNA repair-related radiosensitivity model and to identify potential targets for enhancing radiotherapy efficacy.

A retrospective study was conducted using data from 942 BRCA patients from TCGA database. A radiosensitivity model, comprising a radiosensitivity index, was developed using LASSO regression analysis. Patients were stratified into radiosensitive (RS) and radioresistant (RR) groups based on their radiosensitivity index (RSI). Associations between the RSI, clinicopathological parameters, and PD-L1 status were analyzed. The CIBERSORT and ESTIMATE algorithms were employed to characterize the immune landscape of the tumor microenvironment. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and pRRophetic platform were used to predict treatment responses. Key genes identified in the radiosensitivity model were further validated using in vitro qRT-PCR experiments.

We successfully constructed a radiosensitivity index incorporating 10 DNA repair-related genes. Patients in the RS group exhibited significantly better prognosis compared to the RR group, but this benefit was limited to those receiving radiotherapy. This survival benefit associated with the radiosensitivity signature was absent in patients who did not receive radiotherapy. The RS group displayed a distinct molecular profile characterized by enrichment of TGF-β signaling and protein secretion pathways, potentially contributing to enhanced radiosensitivity. Furthermore, the RS group exhibited increased infiltration of immune cells. Notably, the RS-PD-L1-high subgroup demonstrated the most favorable survival outcomes and highest immune cell infiltration, highlighting their potential responsiveness to immunotherapy. In addition, the RR group exhibited a distinct profile characterized by enrichment of DNA repair pathways and a heightened sensitivity to CDK and HER2 inhibitors. Conversely, this group displayed resistance to DNA-damaging drugs. These findings were supported by in vitro experiments using MCF-7 and radioresistant MCF-7/IR cell lines, confirming differential expression of key radiosensitivity index genes.

In conclusion, we established a radiosensitivity model for predicting radiotherapy benefit in breast cancer. Our study reveals a strong association between radiosensitivity, enhanced antitumor immunity, and potential immunotherapy benefit, particularly within the RS-PD-L1-high subgroup.

Natural products and their extracts are increasingly considered valuable sources for small-molecule anti-cancer drugs. This study investigates the biological impacts of isogarcinol (ISO) on breast cancer (BC) cells and delves into the underlying mechanisms. In vitro, treatment of ISO at 13 μM substantially reduced the viability, proliferation, and mobility of BC. In vivo, ISO treatment at 5, 10, and 15 mg/kg reduced the tumorigenic activity of MDA-MB-231 cells and decreased the levels of Ki-67 and CD31. ISO exerted tumor suppressive effects by reducing the protein level of methionyl-tRNA synthetase (MARS), as the MARS restoration reversed the trends induced by ISO. Phosphorylation levels of phosphatidyl inositol 3 (PI3K) and protein kinase B (AKT) in BC cells were reduced by ISO but restored by MARS. In the presence of MARS upregulation, further treatment of Alpelisib, a suppressor of the PI3K/AKT pathway, suppressed the malignant properties of BC cells. Collectively, these results demonstrate that ISO curbs the malignant behavior of BC cells by reducing the MARS protein level and deactivating the PI3K/AKT pathway. ISO may be considered a promising regimen for the management of BC.

We aimed to answer the following question: How effective is the addition of AKT inhibitors to the treatment of advanced or metastatic breast cancer?

We searched PubMed, Embase and Cochrane for randomized controlled trials (RCTs) that investigated AKT inhibitors for advanced or metastatic BC. We computed hazard-ratios (HRs) for binary endpoints.

A total of 5 RCTs were included in the meta-analysis, comprising 1,334 patients with BC. The use of AKT inhibitors demonstrated a significant improvement in OS (HR 0.70; 95% CI, 0.58-0.85; P < .001) and PFS (HR 0.6797; 95% CI, 0.5499-0.8403; P < .001) in the overall population. Within the PIK3CA/AKT1/PTEN-altered subgroup (n = 645), the OS rate also significantly favored AKT inhibitors over the control group (HR 0.62; 95% CI, 0.42-0.92; P = .019), as well as PFS (HR 0.5224; 95% CI, 0.3366-0.8105; P = .004).

Our findings suggest that the incorporation of AKT inhibitors holds promise for treating patients with advanced or metastatic PIK3CA/AKT1/PTEN-altered BC.

Background: Phosphoinositide 3-kinase is a potent target for cancer therapy due to its significant role in the regulation of cellular growth and proliferation. Dysregulation of the PI3k signaling cascade can constitutively activate growth pathways to trigger the progression of cancer, resulting in the development of multiple inhibitors as cancer therapeutics. Objectives: The wide array of cells expressing PI3k also include immune cells, and the inhibition of these receptors has shown promise in combating inflammation and infectious disease, a relationship we sought to examine further. Methods: We infected wild-type and PI3kγ knockout murine macrophages as well as PI3kγ inhibitor-treated THP-1 human macrophage-like cells with Staphylococcus aureus and quantified inflammation through gene expression analysis, protein secretion assays, and immunofluorescence imaging. Results: We observed that knockout of PI3kγ in murine macrophages alongside pharmacological inhibition through IPI549 treatment in THP-1 cells led to an NF-κB-driven suppression in transcription and release of inflammatory cytokines upon infection with methicillin-resistant Staphylococcus aureus. We were also able to confirm that this suppression of NF-κB translocation and subsequent decrease in inflammatory cytokine release did not compromise and even slightly boosted the bacterial killing ability. Conclusion: PI3k is primarily targeted for cancer therapies, but further exploration can also be carried out on its potential roles in treating bacterial infection.

To investigate the therapeutic potential of cirsiliol in hepatocellular carcinoma (HCC), focusing on its impact on glutamine metabolism.

HCC cell lines HCCLM3 and Huh7 were treated with cirsiliol, and cell viability and proliferation were assessed using CCK-8 assay. Intracellular concentrations of glutamine, α-ketoglutaric acid (α-KG), and adenosine triphosphate (ATP) were measured to evaluate glutamine metabolism. A xenograft tumor model was employed to examine the in vivo effects of cirsiliol. Additionally, network pharmacological analysis was used to identify potential targets of cirsiliol in HCC. Western blotting was conducted to analyze the modulation of the PI3K/AKT signaling pathway by cirsiliol.

Cirsiliol significantly inhibited HCC cell growth both in vitro and in vivo while reducing levels of glutamine, α-KG, and ATP, indicating suppression of glutamine metabolism. Activation of the PI3K signaling pathway reversed the inhibitory effects of cirsiliol on HCC cell growth and metabolism.

Cirsiliol suppresses glutamine metabolism and inhibits the growth of HCC cells by modulating the PI3K/AKT signaling pathway.

Breast cancer (BC) is the most common malignant tumor in women and the leading cause of cancer-related deaths in women. As one of the most common subtypes of breast cancer, patients with hormone receptor-positive (HR+) breast cancer usually experience disease progression over an extended period of time, triggering the search for therapeutic strategies other than endocrine therapy. In recent years, continuous research on various targets has led to dramatic changes in the treatment of hormone receptor-positive breast cancer patients, resulting in prolonged clinical survival. With the redefinition of human epidermal growth factor-2 (HER2) expression, more precise and individualized treatment is possible. This review comprehensively reviews targeted therapies and critical clinical trials for HR+ breast cancer and tracks the latest advances. It also provides valuable insights into the future direction of targeted therapies.

Breast cancer management has traditionally relied on tissue biopsies and imaging, which offer limited insights into the disease. However, the discovery of circulating tumor DNA (ctDNA) and minimal residual disease (MRD) detection has revolutionized our approach to breast cancer. ctDNA, which is fragmented tumor DNA found in the bloodstream, provides a minimally invasive way to understand the tumor's genomic landscape, revealing heterogeneity and critical mutations that biopsies may miss. MRD, which indicates cancer cells that remain after treatment, can now be detected using ctDNA and other advanced methods, improving our ability to predict disease recurrence. This allows for personalized adjuvant therapies based on individual MRD levels, avoiding unnecessary treatments for patients with low MRD. This review discusses how ctDNA and MRD represent a paradigm shift towards personalized, genomically guided cancer care, which has the potential to significantly improve patient outcomes in breast cancer.

Natural selection leaves detectable patterns of altered spatial diversity within genomes, and identifying affected regions is crucial for understanding species evolution. Recently, machine learning approaches applied to raw population genomic data have been developed to uncover these adaptive signatures. Convolutional neural networks (CNNs) are particularly effective for this task, as they handle large data arrays while maintaining element correlations. However, shallow CNNs may miss complex patterns due to their limited capacity, while deep CNNs can capture these patterns but require extensive data and computational power. Transfer learning addresses these challenges by utilizing a deep CNN pre-trained on a large dataset as a feature extraction tool for downstream classification and evolutionary parameter prediction. This approach reduces extensive training data generation requirements and computational needs while maintaining high performance. In this study, we developed TrIdent, a tool that uses transfer learning to enhance detection of adaptive genomic regions from image representations of multilocus variation. We evaluated TrIdent across various genetic, demographic, and adaptive settings, in addition to unphased data and other confounding factors. TrIdent demonstrated improved detection of adaptive regions compared to recent methods using similar data representations. We further explored model interpretability through class activation maps and adapted TrIdent to infer selection parameters for identified adaptive candidates. Using whole-genome haplotype data from European and African populations, TrIdent effectively recapitulated known sweep candidates and identified novel cancer, and other disease-associated genes as potential sweeps.

Conditioned media derived from Mesenchymal stem cells (MSC-CM) was suggested as a promising alternative cell-free regenerative therapy. It is hypothesized that the synergistic effect of MSC-CM with anticancer drugs may improve their antiproliferative and antimetastatic effects against cancer cells. Herein, the MSC-CM was impregnated with Wortmannin, a pan-PI3K/Akt/mTOR inhibitor, and their combined effect was investigated against breast cancer cells.

To explore this, the cytotoxic, apoptotic, and autophagic potentials were assessed in luminal-A breast cancer cells (MCF-7).

We found that incubation of MCF-7 to Wort-containing-CM induced apoptosis- and autophagy-mediated cell death, meanwhile prolonged exposure caused massive necrotic cell death. The involvement of MSC-CM effectively reduced Wortmannin IC50 observed in Wort-treated cells. Also, Wort-loaded-CM induced nuclear DNA fragmentation and reduced in vitro cell migration. These findings were associated with a Wort-dependent reduction in cell viability, the formation of the phosphorylated Akt and mTOR proteins, reduced the expression of mRNA, and downregulated the expression of the catalytic domain of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K-Ca).

These findings revealed the promising antiproliferative and antimetastasis effects of combining pan-PI3K/Akt/mTOR inhibitors with MSC-derived-CM in breast cancer via the downregulation of PI3K/AKT/mTOR signaling pathways. Further studies are required to validate this chem-regenerative strategy in cancer treatment.

Triple-negative breast cancer (TNBC) has become one of the most challenging cancers to date due to its great variability in biological features, high growth rate, and rare options for treatment. This review examines several innovative strategies for tailored treatment of TNBC, focusing mainly on the most recent developments and potential directions. The molecular landscape of TNBC is covered in the first section, which keeps the focus on transcriptome and genomic profiling while highlighting key molecular targets like mutations in the BRCA1/2, PIK3CA, androgen receptors (AR), epidermal growth factor receptors (EGFR), and immunological checkpoint molecules. This review also covers novel therapies that aim to block well-defined pathways, including immune checkpoint inhibitors (ICI), EGFR inhibitors, drugs that target AR, poly ADP ribose polymerase (PARP) inhibitors, and drugs that disrupt the PI3K/AKT/mTOR pathway. Additionally, it covers novel strategies focusing on combination therapy, targeting the DNA damage response pathway, and epigenetic modulators. Conclusively, it emphasizes perspectives and directions on topics such as personalized medicine, artificial intelligence (AI), predictive biomarkers, and treatment planning with the inclusion of machine learning (ML).

Tamoxifen (TAM) is vital in breast cancer (BC) treatment, yet its resistance significantly impairs its efficacy. While miR-592 is known for its suppressive role in BC, its effect on chemotherapy resistance remains unclear. In this study, we observed a significant reduction in miR-592 levels in TAM-resistant BC tissues and cell lines. Low miR-592 expression was significantly associated with advanced TNM stage, lymph node metastasis, and poorer patient survival. Dual-luciferase assay confirmed miR-592 binding to the predicted gene PIK3CA. Increasing miR-592 levels decreased the IC50 of TAM, inhibited cell viability, migration, and invasion, and enhanced apoptosis in vitro, which was mimicked by PIK3CA knockdown and reversed by PIK3CA overexpression. Moreover, miR-592 upregulation suppressed tumor growth and improved TAM responsiveness in vivo. Molecularly, both si-PIK3CA and miR-592 mimics decreased the expression ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR, while increasing cleaved caspase-3 and E-cadherin expression in MCF-7/TAM cells. PIK3CA overexpression partially reversed these reductions. In conclusion, our study demonstrates that miR-592 attenuates TAM resistance by inhibiting the PIK3CA-driven PI3K/AKT/mTOR signaling pathway, representing a promising strategy to address chemoresistance in BC.