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Ganoderma lucidum (Lingzhi or Reishi) is among the most extensively studied medicinal mushrooms globally, owing to its diverse bioactive compounds and broad pharmacological properties. A scientometric analysis using the Scopus database was conducted to investigate global research trends on the bioactivity of G. lucidum. Bibliometric indicators, collaboration networks, keyword co-occurrence, thematic evolution, conceptual structure mapping, and life cycle modeling were assessed using Bibliometrix/Biblioshiny and VOSviewer version 1.6.20. A total of 2877 publications were included in the analysis. Scientific output increased markedly after 2010, peaking in 2025, indicating sustained growth in the field. China was identified as the leading contributor in terms of publication volume, influential authors, and prominent institutions, while international collaboration networks showed expanding global participation. Keyword and thematic analyses demonstrated a shift from early research focused on bioactivity screening, polysaccharides, and cultivation to mechanistic and translational investigations involving apoptosis, oxidative stress, immunomodulation, metabolomics, gut microbiota, network pharmacology, and disease-specific applications. Life cycle analysis suggested that the field is still in a rapid growth phase and has not yet reached saturation. Research on G. lucidum has evolved into a mature and highly interdisciplinary field, characterized by increasing scientific productivity, expanding international collaboration, and a growing emphasis on mechanistic and translational studies. Full article

More than 20 years after the discovery of lunasin, a clear shift in lunasin research is observable—from an initial focus on its direct in vitro anticancer effects toward strategies aimed at improving its bioavailability and repositioning it as a potential adjunct in cancer therapy. Lunasin, a soy-derived bioactive peptide, has been extensively studied for its antineoplastic properties. However, its limited oral bioavailability restrains its efficacy in clinical trials. Therefore, recent research on lunasin points towards the possibility of using it as an adjunct in cancer treatment, rather than as a stand-alone nutraceutical in humans. In preclinical models, in vitro and in vivo, lunasin can enhance the effects of standard anticancer drugs in breast and colon cancers. Research suggests that lunasin can potentiate the effects of drugs, such as tamoxifen, aspirin, cisplatin, and oxaliplatin, by sensitizing cancer cells to apoptosis, modulating cell cycle progression, reducing metastatic potential, and attenuating drug-resistance pathways, including PI3K/Akt, FAK/MAPK1/NF-κB, and integrin-mediated signaling. In combination with those drugs, lunasin exerts significant anticancer effects at concentrations substantially lower than those proven as effective in monotherapy, suggesting a potential role in dose reduction in conventional agents and, subsequently, mitigation of their adverse effects. Although the enhanced effect of those combinations has been shown in preclinical models, there is a distinct lack of human clinical trials in this matter. Available evidence supports a promising concept of lunasin as a molecular “priming” agent that might complement cytotoxic therapies rather than replace them. This combination-oriented paradigm may represent a shift in lunasin research and offer a novel direction for the use of bioactive peptides in precision oncology; however, further studies exploring this possibility, including human clinical trials, are needed to elucidate lunasin’s role in nutraceutical-assisted cancer therapy. Full article

Background: CDK4/6 inhibitors induce G1/S cell-cycle arrest in bladder cancer; however, adaptive resistance limits their therapeutic efficacy. The role of the m⁶A reader IGF2BP3 in regulating sensitivity to CDK4/6 inhibition remains largely unknown. Methods: Transcriptomic profiling was performed in palbociclib-treated bladder cancer cell lines (T24, RT112, and UMUC-3) to identify m⁶A regulators associated with drug response. The expression and clinical significance of IGF2BP3 were evaluated using The Cancer Genome Atlas (TCGA) data and an independent clinical cohort. Gain- and loss-of-function assays were conducted to investigate the effects of IGF2BP3 on cell proliferation and cell-cycle progression. Mechanistic studies, including RNA-binding, mRNA stability, ubiquitination, and in vivo tumorigenesis assays, were performed to elucidate the underlying regulatory network. Results: IGF2BP3 was identified as the only m⁶A regulator differentially expressed following palbociclib treatment. IGF2BP3 expression was significantly elevated in bladder cancer tissues compared with normal tissues and was associated with poor prognosis and Ki67 positivity. Functionally, IGF2BP3 overexpression (OE) promoted G1/S transition, increased MYC and downstream cell-cycle regulators, and partially rescued palbociclib-induced cell-cycle arrest, whereas IGF2BP3 knockdown (KD) suppressed cell proliferation in an MYC-dependent manner. Mechanistically, IGF2BP3 bound to MYC mRNA in an m⁶A-dependent manner and enhanced its stability. Furthermore, MKRN2 was identified as an E3 ubiquitin ligase that directly interacted with IGF2BP3, promoted its ubiquitination, and facilitated its proteasomal degradation. In vivo, MKRN2 co-overexpression attenuated IGF2BP3-driven tumor growth and synergized with palbociclib to maximally suppress tumor volume, reduce MYC and Ki67 expression, and induce apoptosis. Conclusions: These findings establish the MKRN2–IGF2BP3–MYC axis as a critical regulator of CDK4/6 inhibitor sensitivity in bladder cancer. Targeting IGF2BP3 or enhancing MKRN2 activity may represent a promising strategy to overcome adaptive resistance and improve the therapeutic efficacy of CDK4/6 inhibitors. Full article

Melanoma incidence is steadily on the rise but widespread prevention awareness and novel treatment approaches have substantially ameliorated the prognosis of the disease. Microphthalmia-associated transcription factor (MITF) is an essential transcription factor that plays a central role in the transcriptional circuitry of both normal melanocytes and malignant melanoma. Since over 30 years have elapsed since its discovery in mice, a large number of its target genes have been identified in pigment cells. Many upstream regulators of MITF have also been identified. Despite these substantial discoveries, MITF function, especially in melanomas, still remains elusive in several aspects. MITF is absolutely required for melanin formation because it transcribes virtually all genes required for the synthesis, storage, and transport of the pigment. Importantly, MITF is necessary for prevention of apoptosis in melanomas, at least at the early stages. However, in some metastases, MITF may be absent in most cells and its antiapoptotic function is evidently replaced by other proteins that not yet been fully identified. Furthermore, MITF is a specific nevus and melanoma marker, which is routinely used in immunohistochemistry, along with other markers, to distinguish pigmented and other skin lesions. In melanomas, high-MITF melanoma cell subpopulations are considered differentiated, i.e., pigmented and rapidly proliferating. In contrast, low-MITF cells proliferate slowly but are invasive with cancer stem cell-like properties. Although MITF activates mostly antiapoptotic and pro-proliferative genes, it also activates typical cell cycle inhibitors such as the p16 and p21 proteins. Here we discuss the issues of MITF multifunctionality in melanoma and associated research prospects. Full article

Background: Polycystic ovary syndrome (PCOS) is a frequently encountered endocrine disturbance with a still poorly defined etiology that arises in women during their reproductive years. Increased apoptosis of granulosa cells has been identified as one of the key factors contributing to abnormal follicular development. This study aimed to elucidate the role of six-transmembrane epithelial antigen of prostate 4 (STEAP4) in granulosa cell function using in vitro and in vivo models relevant to PCOS. Methods: We treated KGN cells (a human granulosa-like cell line) and C57BL/6 mice with dehydroepiandrosterone (DHEA) to establish experimental models mimicking PCOS features. STEAP4 expression was assessed by qRT–PCR, Western blot, and immunohistochemistry. Proliferative capacity and apoptotic rates were gauged with CCK-8 assays, EdU labeling, and flow cytometry. The regulatory mechanisms were investigated through immunofluorescence staining for nuclear factor erythroid–2–related factor 2 (Nrf2) nuclear translocation and immunoprecipitation assays for HIF-1α ubiquitination. Results: Exposure to androgen markedly raised both STEAP4 transcript and protein abundance in KGN cells as well as in PCOS model mice. STEAP4 knockdown resulted in increased proliferation and reduced apoptosis in DHEA–treated KGN cells. Mechanistically, STEAP4 enhanced reactive oxygen species levels, promoted Nrf2 nuclear translocation, and stabilized HIF–1α protein by reducing its ubiquitination, leading to increased TERT expression and subsequent TP53 pathway activation. In vivo, STEAP4 silencing significantly alleviated hormonal imbalances, estrous cycle disorders, and reduced oxidative stress levels in ovarian tissue of DHEA-induced PCOS–like mice. Conclusions: Taken together, evidence from these experimental models indicates that STEAP4 shapes oxidative stress and granulosa cell apoptosis by operating through the ROS–TERT–TP53 axis. The data point to a possible contribution of STEAP4 to PCOS pathogenesis and mark it as a candidate therapeutic target that merits additional clinical study. Full article

Trematodes are a class of parasitic flatworms with complex life cycles involving multiple hosts. They can influence the physiology and behavior of their intermediate hosts to improve the efficiency of transmission to definitive hosts, including by increasing host mortality. However, the mechanisms of their effect on the crustacean nervous system leading to neuronal dysregulation and its consequences have not been sufficiently elucidated. This study investigated the effects of infection by metacercariae of the trematode Cercaria fluviocinguli on the serotonin (5-HT) immunoreactivity, inflammation, and pathological processes in the nervous system of the shore crab Hemigrapsus sanguineus. The regions in the brain, the ventral nerve cords (VNC), and the nerves targeted by this parasite were examined by immunohistochemistry and confocal laser scanning microscopy methods. The cysts and the enclosed flukes caused compaction, compression, and distortion of many nerve fibers of the VNC and also impaired conduction in the mixed nerves of the thoracic ganglia controlling locomotion. The infection by C. fluviocinguli induced a decrease in 5-HT-like immunoreactivity in neurons and neuropils of the VNC, damage to nerve fibers and neurons of the VNC, inflammatory reactions, and apoptosis. In heavily infected crabs, the increased content of TUNEL-positive cells in the VNC was correlated with granuloma accumulation. Further investigations into host–parasite interaction mechanisms under controlled experimental conditions are needed to clarify the actual effects of encapsulated and non-encapsulated metacercariae on host behavior and their role in transmission to the next host. Full article

Hepatocellular carcinoma is one of the most aggressive malignancies worldwide, with limited therapeutic options. Boswellia serrata Roxb., an Indian medicinal tree, produces a resin rich in essential oil and boswellic acids, particularly acetyl-11-keto-β-boswellic acid (AKBA), with demonstrated antiproliferative and pro-apoptotic activities. This study investigated the cytotoxic effects of B. serrata essential oil and AKBA on hepatocarcinoma Huh-7 cells in both monolayer and three-dimensional spheroid cultures and characterized the underlying molecular targets. Essential oil was extracted and analyzed by gas chromatography-mass spectrometry (GC-MS). Cytotoxicity was assessed using the cell counting kit-8 (CCK-8). Three-dimensional spheroid cultures were also established to evaluate anti-tumoral potential. Expression of cyclin D1, cyclin-dependent of kinase 4 (CDK4) (cyclin-dependent kinase inhibitor 1A (p21), E-cadherin, (alpha fetoprotein) AFP, epithelial cell adhesion molecule (EpCAM), Myeloid cell leukemia-1 (Mcl-1), and caspase-3 was analyzed by western blot. In addition, an in silico analysis was performed on the main constituents of B. serrata essential oil targeting 5-lipoxygenase (5LO). The results showed cytotoxic effects, with AKBA exhibiting greater potency than the essential oil. Cytotoxicity was associated with caspase-3-mediated apoptosis, with minimal effects on cell cycle and epithelial–mesenchymal transition markers. The in silico analysis predicted that some compounds may act as competitive inhibitors of the 5LO at the catalytic site and partially activate pro-apoptotic pathways. These data support the potential of B. serrata-derived compounds as novel anti-hepatocarcinoma agents, with AKBA and longifolene as leads for further preclinical and clinical research. Full article

Background/Objectives: Glioblastoma remains the most aggressive and lethal form of brain cancer, with no effective cure to date. The molecular mechanisms sustaining its development and relentless proliferation are still not fully understood. SETMAR, a protein lysine methyltransferase involved in various DNA repair and chromatin processes, has been reported as dysregulated in several cancers, including glioblastoma. Interestingly, S-SETMAR, a shorter isoform of SETMAR, has been suggested to antagonize the oncogenic properties of the full-length protein. Here, we explored the cellular and molecular consequences of S-SETMAR overexpression in glioblastoma cells. Methods: We compared native glioblastoma cells (8MGBA) with a recombinant 8MGBA line stably over-expressing αS-SETMAR, a stable form of S-SETMAR, using complementary cellular and molecular approaches. Results: Overexpression of αS-SETMAR markedly prolonged the cell cycle duration (from 27 to 37 h), leading to a significant decrease in cell proliferation. Unexpectedly, αS-SETMAR triggered genomic alterations characterized by an increased DNA content and extensive chromosomal instability, including aneuploidy, chromoanasynthesis-like rearrangements, and tripolar mitoses. Moreover, αS-SETMAR-expressing cells displayed heightened sensitivity to stress conditions mimicking chemotherapy and radiotherapy, resulting in increased apoptosis. Conclusions: Our findings identify αS-SETMAR as a dual modulator of glioblastoma cell fate—simultaneously slowing proliferation and promoting chromosomal instability while enhancing vulnerability to genotoxic stress. These results suggest that αS-SETMAR could serve as both a prognostic marker and a potential therapeutic tool in glioblastoma management. Full article

Momordica charantia L. is a medicinal plant rich in bioactive compounds, including steroidal glycosides, flavonoids, phenolics, triterpenoids, saponins, and polysaccharides, which exhibit antidiabetic, antioxidant, anti-inflammatory, hepatoprotective, and anticancer activities. This review summarizes its nutritional and phytochemical composition, green extraction technologies, molecular mechanisms, and industrial applications based on literature from Google Scholar, PubMed, Scopus, Web of Science, ScienceDirect, and other scientific databases. Ultrasound-assisted extraction is an efficient and eco-friendly method that provides higher recovery of bioactive compounds from M. charantia and improved bioavailability compared with enzyme-assisted, microwave-assisted, and conventional methods. The phytochemicals of M. charantia regulate oxidative stress, inflammation, lipid peroxidation, and glucose homeostasis. Studies show that its antidiabetic effects involve improved insulin sensitivity, enhanced glucose uptake, and inhibition of carbohydrate-digesting enzymes. These compounds also exhibit antioxidant activity through free radical scavenging and anti-inflammatory effects via inhibition of the NF-κB and MAPK pathways. M. charantia further demonstrates anticancer activity by inducing apoptosis, causing cell-cycle arrest, and downregulating proliferation pathways in several cancer cell lines, including MCF-7, HCT-116, HepG2, A549, and PANC-1. Beyond medicinal uses, it is applied in the food industry as a functional ingredient in products such as yogurt, cookies, pickles, bread, juice, oil, and beverages. Overall, M. charantia shows strong potential for therapeutic applications, including functional foods and pharmaceutical formulations targeting diabetes, inflammation, liver diseases, and cancer; however, further studies are needed to confirm its clinical efficacy. Full article

Bats are important reservoirs of zoonotic pathogens and valuable models for studying antiviral tolerance and neuroinflammation within a One Health framework. However, chiropteran neural 2D-in vitro models remain limited. Here, we established and characterized the first chiropteran primary (CpBCs) and immortalized (CiBCs) cell lines from Hypsugo savii species. To overcome the limited lifespan of CpBCs, immortalization strategies based on human telomerase reverse transcriptase (hTERT) and Simian virus 40 large T antigen (SV40) were evaluated. Electroporation-mediated transfection with SV40 successfully generated CiBCs, whereas liposome-mediated and hTERT-based approaches were unsuccessful. RNA sequencing revealed marked transcriptional changes comparing CiBCs with CpCBs, such as the upregulation of pathways related to cell cycle progression, DNA replication, and proliferation in CiBCs, together with the downregulation of apoptosis, inflammatory signaling, and immune-related pathways. Immortalized cells also exhibited enrichment of neural stem cell-like and cancer-associated signatures, suggesting partial dedifferentiation induced by SV40-mediated immortalization. Overall, this study provides a novel chiropteran brain-derived 2D-in vitro platform for investigating bat neurobiology, host–pathogen interactions, viral tolerance, and neurotropic infectious diseases relevant to emerging zoonoses. Full article

Global aquaculture faces increasing threats from declining oxygen levels, with several key aquaculture regions now classified as hypoxic. The gills, responsible for oxygen uptake, pathogen-sensing, and immune responses, are the primary interface for this stress. However, the comparative effects of different hypoxic regimes on the gill resilience of Atlantic salmon (Salmo salar) remain poorly understood. In this study, Atlantic salmon were exposed during a 7-day trial to two different moderate hypoxic stress models, chronic hypoxia and cyclic hypoxia. A whole-genome oligo-microarray revealed that both hypoxic stress regimes cause transcriptomic shifts, driven in the chronic hypoxia group by upregulation of PRRs and other immune components and downregulation of DNA repair and cell cycle maintenance. On the other hand, the cyclic hypoxic group focused on physiological plasticity and rapid cellular adjustments. Additionally, RT-qPCR was used to evaluate key gene expression of hypoxia and immune response. The chronic hypoxia group was characterized by downregulation of hif2a, gshpx, and gr-anx1 signaling, with a continuous upregulation state of tnfa2, suggesting an unresolved inflammatory state, often associated with apoptosis and gill damage. In contrast, the cyclic hypoxia group displayed an increased epo expression and recovery of antioxidant enzymes (e.g., gsphx), accompanied by normalized levels of tnfa2 at the end of the 7-day trial. Therefore, chronic hypoxic stress imposes a significantly higher burden on the gills of Atlantic salmon than cyclic hypoxic stress, compromising their ability to respond to secondary stressors and impairing immune homeostasis. Full article

Enhancer of zeste homolog 2 (EZH2), the catalytic component of the polycomb repressive complex 2, is frequently overexpressed in lung adenocarcinoma and contributes to transcriptional programs that support tumor proliferation and cellular plasticity. However, its role in regulating senescence-associated signaling and tumor–stromal interactions in lung cancer remains incompletely understood. In this study, we combined transcriptomic analysis of The Cancer Genome Atlas lung adenocarcinoma cohort with functional characterization of EZH2 targeting in A549 cells using the catalytic inhibitor EPZ6438 and the EZH2 degrader MS1943. Elevated EZH2 expression was associated with enrichment of cell cycle-related transcriptional pathways. Pharmacological targeting of EZH2 reduced proliferation, migration, stemness-associated features, and sphere-forming capacity, with more pronounced effects observed following EZH2 degradation. Both compounds promoted features consistent with senescence-associated phenotypic remodeling characterized by increased expression of p16 and p21, enhanced β-galactosidase activity, G0/G1 cell cycle arrest, and increased expression of cytokines commonly associated with senescence-related secretory signaling, including IL-6, CCL2, and CXCL8. Conditioned medium from treated tumor cells promoted activation of primary lung fibroblasts, indicating functional paracrine microenvironmental remodeling. Importantly, EZH2 targeting elicited cytostatic responses without induction of apoptosis. Collectively, these findings suggest that EZH2 contributes to regulation of proliferation-associated and senescence-associated phenotypic programs together with stromal signaling in lung adenocarcinoma. Full article

The present study aimed to evaluate the role of ascorbic acid in alleviating ammonia-induced muscle quality deterioration and to clarify its regulatory effects on apoptosis, texture, and flavor-related metabolites in rainbow trout (Oncorhynchus mykiss). The results demonstrated that ascorbic acid alleviated ammonia stress-induced inflammatory and apoptotic damage by regulating toll like receptor 5 (TLR5), myeloid differentiation primary response 88 (MyD88), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression, thereby contributing to the restoration of myofibrillar integrity, reduced extracellular gaps, and increased shear force from 14.18 N to 18.26 N (p < 0.05). Ascorbic acid modulated ammonia handling and ion-exchange responses by upregulating glutamine synthetase (GS) expression from approximately 2.3-fold to 6.7-fold and increasing ornithine and citrulline accumulation. Alterations in tricarboxylic acid cycle-related metabolites further suggested that energy metabolism may be involved in the physiological adaptation to ammonia stress. Meanwhile, the ascorbic acid reduced the accumulation of key off-flavor compounds (1-octene-3-alcohol and (E)-2-nonenal), attenuating the earthy–moldy and fishy flavor. This research proposes a potential strategy to improve muscle quality in live transportation. Full article

Cisplatin (cis-diamminedichloroplatinum(II) [DDP]) is a key chemotherapeutic agent for advanced endometrial cancer; however, chemoresistance substantially limits its clinical benefit. Extracellular vesicles (EVs) mediate intercellular communication and influence tumour cell behaviour and therapeutic response. We investigated whether mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) and natural killer cell-derived extracellular vesicles (NK-EVs) modulate cisplatin responsiveness in endometrial cancer cells (RL95-2 and HEC-1A). MSC-EVs and NK-EVs were isolated and characterised using nanoparticle tracking analysis, scanning electron microscopy, and EV marker profiling. MSC-EVs and NK-EVs reduced RL95-2 and HEC-1A cell viability in a dose-dependent manner, with MSC-EVs exhibiting substantial effects at lower particle concentrations. In a cisplatin-resistant HEC-1A (HEC-1A DDP-R) model, MSC-EVs were associated with greater reductions in cell viability under cisplatin treatment conditions, whereas NK-EVs showed comparatively modest effects. Mechanistic analyses demonstrated altered expression of apoptosis- and cell cycle–related proteins, including increased cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 levels and reduced cyclin A and cyclin D1 expression following MSC-EV treatment. Annexin V-fluorescein isothiocyanate/propidium iodide flow cytometry demonstrated increased apoptotic cell populations after MSC-EV treatment, with MSC-EV + DDP co-treatment resulting in the highest apoptotic fraction in chemoresistant HEC-1A cells. Collectively, these findings indicate that MSC-EVs are associated with altered cellular responses to cisplatin in chemoresistant endometrial cancer cells, accompanied by changes in apoptosis-related protein expression, apoptotic cell populations, and cell-cycle regulators. Further investigation is required to determine their mechanistic role and therapeutic potential in overcoming chemoresistance. Full article

Yaks (Bos grunniens) are large mammals endemic to the Qinghai–Tibet Plateau. Efficient lung development is crucial for their adaptation to high-altitude hypoxia. As progenitor cells of the alveoli, type II alveolar epithelial (AT2) cells warrant further investigation into their physiological functions; however, relevant studies remain limited. In this study, primary AT2 cells were isolated from the lungs of yaks. Concurrently, lung tissues were collected from yaks at distinct developmental stages to investigate the role of the EGF/EGFR axis in regulating AT2 cell proliferation and apoptosis, as well as its essential contribution to yak lung development. Here, we demonstrate that the EGF/EGFR axis plays a beneficial role in yak alveolar development. Exogenous EGF supplementation or EGFR activation upregulated the downstream factors AKT and STAT3, enhanced AT2 cell proliferation, and reduced apoptosis. In contrast, EGFR inhibition promoted AT2 cell apoptosis and suppressed proliferation. Cell cycle analysis revealed that both exogenous EGF and EGFR activation increased the proportion of AT2 cells in the S and G2 phases, whereas EGFR inhibition caused cell cycle arrest at the G0/G1 phase. Moreover, the expression of cell cycle regulators cyclin D1, CDK4, and CDK6 was upregulated, while p16 and p21 expression was downregulated. Further comparative analyses indicated that the EGF/EGFR axis positively contributes to alveolar development in juvenile yaks. Collectively, these findings confirm that in plateau environments, activation of the EGF/EGFR axis promotes AT2 cell proliferation and inhibits apoptosis, thereby facilitating alveolar development in juvenile yaks. A key limitation is the lack of parallel comparisons with low-altitude cattle and other plateau-endemic species (e.g., Tibetan sheep), which precludes definitive assessment of the specificity of the EGFR/EGF axis in yak AT2 cell proliferation and lung development. Full article