Search Results (4,881)

Magnolia raw materials have long been used in Chinese folk medicine. The biologically active chemical compounds in Magnolia, mainly lignans, e.g., honokiol, exert health-enhancing effects in certain diseases, including skin conditions. Since the scientific literature does not provide a comparative analysis of the therapeutic properties of honokiol on the skin in various biological models, an attempt was made to supplement the knowledge in this field. This review presents the antimicrobial, anti-inflammatory, and photoprotective properties of honokiol used in dermatological problems and its anticancer activity in melanoma and non-melanoma skin cancers. Honokiol reduces the expression of HSV-1 genes, inhibits DNA replication, lowers the level of proteins, regulates the colonisation of viral glycoproteins with high membrane selectivity, and inhibits the endocytosis process. It has antibacterial activity, as it destroys bacterial cell walls and membranes. It disrupts vacuolar functioning and intracellular calcium homeostasis in dermatophyte cells and inhibits fungal growth by delaying germination, altering membrane permeability, and reducing hyphal growth. It reduces inflammatory cytokines and stimulates anti-inflammatory cytokine IL-10. Honokiol prevents UV-B induced skin cancer through targeting cell cycle regulators, inflammatory mediators, and cell survival signals. It induces apoptosis via extrinsic and intrinsic pathways, activating proapoptotic proteins. It acts as an inhibitor of the oncogenic protein KRT18 in melanoma and prevents the progression of highly metastatic melanoma. Future research should explore the signalling pathways and molecular mechanisms of honokiol action and its synergistic effects at the cellular level and help to develop methods for delivering honokiol to the organism by nanocarriers to improve selective therapies in some diseases. Full article

Background/Objectives: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with a poor prognosis and limited therapeutic options. This study aimed to repurpose methylstat, a selective histone demethylase inhibitor, as a novel anti-glioma agent. We characterized its anti-proliferative efficacy, elucidated mechanisms of cell cycle regulation, and evaluated its blood–brain barrier (BBB) permeability potential. Methods: Compounds with transcriptional profiles enriched for cell cycle arrest and tumor-suppressive pathways were identified via Connectivity Map (CMAP) analysis. Methylstat was selected based on its high connectivity score and favorable physicochemical properties. In vitro assays were performed to evaluate its effects on cell viability, proliferation, cell cycle progression, and expression of related molecular markers in U251 and HOG glioma cell lines. Molecular docking and 200 ns molecular dynamics (MD) simulations were performed to evaluate the binding mode and stability of the Methylstat–JMJD2A complex. An in vitro BBB model was established to assess the ability of Methylstat to cross the BBB. Results: Methylstat significantly inhibited glioma cell proliferation in a dose-dependent manner without inducing apoptosis. It caused G1-phase arrest in U251 cells and G2-phase arrest in HOG cells. Mechanistically, methylstat downregulated cyclins and cyclin-dependent kinases via the p53/p21 pathway. Additionally, methylstat reduced the expression of JMJD2A and its downstream targets, including PDK1, AKT, and mTOR. Molecular docking studies and 200 ns MD simulations confirmed the stable binding of methylstat to the catalytic pocket of JMJD2A, effectively inhibiting its enzymatic activity. HPLC analysis confirmed that methylstat could penetrate the in vitro BBB model to varying extents. Conclusions: Methylstat is a promising small-molecule agent that effectively suppresses glioma cell growth by modulating key cell cycle regulators. Its ability to cross the BBB highlights its potential as a novel therapeutic strategy for GBM and other brain tumors. Full article

Background/Objectives: The effects of PD-L1 are mediated via its binding to the PD-1 receptor, which mediates the signals intracellularly to suppress T-cell responses. The expression levels of PD-L1 on cancer cells are an important indicator of immunosuppression and cause poor prognosis in several types of cancers. Therefore, the identification and characterization of mechanisms that regulate the expression of PD-L1 in cancer patients is very critical. Method: Our experiment was designed to determine the impact of histone deacetylase (HDAC) inhibitor on PD-L1 expression to reverse tumor-induced immunosuppression using H460 and HCC827 lung cancer cell lines. These cells were treated with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). PD-L1 expression levels were assessed along with key regulatory proteins, including p53, p21, acetyl-histones, DNMT3B, MGMT, and trimethyl histones. Results: In our experiments, suberoylanilide hydroxamic acid (SAHA) was able to reduce the expression of PD-L1 by 60% in a dose-dependent manner. While the level of PD-L1 was significantly reduced, a concurrent increase in levels of p53, p21, and acetyl histone levels were observed in H460 and HCC827 cells following SAHA treatment. Furthermore, SAHA treatment was able to decrease the levels of DNMT3B, MGMT, and tri-methyl histones. It appears that the decrease in PD-L1 expression observed is solely because of p53 or p21WAF1/CIP1-mediated negative control on the transcription process. Conclusion: Our results suggest that SAHA can be used along with immune checkpoint inhibitors to potentiate the therapeutic outcomes in patients with excessive immunosuppression due to PD-L1 expression. Full article

Background: The circadian rhythm regulates important functions in the body, such as metabolism, the cell cycle, DNA repair, and immune balance. Disruption of this rhythm can contribute to the development of cancer. Circadian rhythm genes (CRGs) are attracting attention for their connection to various cancers. However, their roles in LUAD are not yet well understood. Additionally, our knowledge of how they function at both the bulk tissue and single-cell levels is limited. This gap hinders a complete understanding of how CRGs impact the development and outcomes of LUAD. Methods: We selected 554 CRGs from public databases. We then obtained transcriptome data from TCGA and GEO. A total of 101 machine learning algorithm combinations were tested using 10 algorithms and 10-fold cross-validation. The best-performing model was based on Stepwise Cox regression and SuperPC. This model was validated with additional datasets. We also examined the relationships between CRGs, immune features, tumor mutation burden (TMB), and the response to immunotherapy. Drug sensitivity was also assessed. Single-cell data identified the cell types with active CRGs. Next, we performed qRT-PCR and other basic experiments to validate the expression of ARNTL2 in LUAD tissues and cell lines. The results indicated that ARNTL2 may play a key role in lung adenocarcinoma. Results: The CRG-based model clearly distinguished LUAD patients based on their risk. High-risk patients exhibited low immune activity, high TMB, and poor predicted responses to immunotherapy. Single-cell data revealed strong CRG signals in epithelial and fibroblast cells. These cell groups also displayed different communication patterns. Laboratory experiments showed that ARNTL2 was highly expressed in LUAD. It promoted cell growth, movement, and invasion. This suggests that ARNTL2 may play a role in promoting cancer. Conclusions: This study developed a machine learning model based on CRGs. It can predict survival and immune status in LUAD patients. The research also identified ARNTL2 as a key gene that may contribute to cancer progression. These findings highlight the significance of the circadian rhythm in LUAD and provide new perspectives for diagnosis and treatment. Full article

Renal cancer is among the deadliest human malignancies. MCM7, a cell cycle-regulating protein, is frequently overexpressed in cancers and is associated with hyperproliferation and cancer progression. miR-25-3p, miR-93-5p, and miR-106b-5p form the miR-106b-25 cluster, located within the MCM7 gene, and have previously been reported as upregulated in RCC. This study investigates whether miRNAs from the miR-106b-25 cluster regulate common target genes, enhance one another’s effect, and act synergistically with MCM7 to promote tumor progression. Tissue samples from clear cell RCC (ccRCC) and paired controls were analysed to assess MCM7 expression and genes targeted by the miR-106b-25 cluster. Findings were further validated using the TCGA-KIRC dataset. Functional studies in RCC-derived cell lines were conducted to evaluate the effects of miRNAs on target gene expression, as well as MCM7, and the combined contributions of MCM7 and the miR-106b-25 cluster to renal cancer progression. We demonstrate that MCM7 is upregulated at both transcript and protein levels in RCC, contributing to cancer progression by regulating cell proliferation and caspase-3/7 activity. Furthermore, we identified cancer-related genes aberrantly expressed in ccRCC (BRMS1L, CPEB3, DNAJB9, KIF3B, NFIB, PTPRJ, RBL2) and targeted by members of the miR-106b-25 cluster, suggesting that their dysregulation may be driven by these miRNAs. Inhibition of the miR-106b-25 cluster increases caspase-3/7 activity. These findings demonstrate that both MCM7 and the miR-106b-25 cluster contribute to renal cancer progression. Full article

Skin cancer remains a significant global health challenge, with rising incidence and associated mortality in late-stage and drug-resistant cases. This underscores a continuing need for more effective novel therapeutic options that can be utilized for efficient management of skin cancers. A promising approach involves exploiting novel targets, which are dysregulated in skin cancer, either alone or in combination with existing therapeutics. Among these, polo-like kinases (PLKs), a family of serine/threonine kinases, has emerged as promising candidates due to their essential role in cell cycle and maintaining genomic stability, key hallmarks of cancer. Within this family, polo-like kinase 4 (PLK4) stands out as a structurally distinct member and the master regulator of centriole duplication, ensuring this process occurs only once per cell division. Dysregulation of PLK4 can disrupt genomic integrity, contributing to tumorigenesis, thus making it a promising target for cancer management. Notably, PLK4 is frequently overexpressed in several cancers, including skin cancer, and its precise role in skin cancer is an area of current investigation. Further, several small-molecule PLK4 inhibitors such as centrinone, YLZ-F5, CFI-400945, and RP-1664 have demonstrated efficacy in targeting PLK4. Among these, CFI-400945 has advanced to clinical trials, where it has shown modest anti-cancer activity. In this review, we provide a comprehensive overview of the known functions of PLK4 in skin cancer. Additionally, we discuss potential mechanistic insights into PLK4′s involvement in skin cancer progression by extrapolating evidence from studies in other cancer types including colorectal cancer, thyroid cancer, lymphomas, leukemia, etc., while identifying gaps for future research. Full article

Background/Objectives: Estrogen deficiency-related menopause is associated with various physical and psychological symptoms. Although hormone replacement therapy (HRT) effectively alleviates these symptoms, its long-term use is associated with several side effects such as an increased risk of breast cancer and cardiovascular disease. Consequently, there is a growing interest in some plant-derived phytoestrogens that are considered safer alternatives to estrogen. Recent studies on Scrophularia buergeriana confirmed their anti-inflammatory and antioxidant properties; however, their effects on menopausal health remain unclear. Therefore, the aim of this study was to investigate the estrogen-like effects of S. buergeriana root (SB-R) extract, a potential phytoestrogen. Methods: Briefly, the MCF-7 cell line, a widely used in vitro model for assessing estrogen-like activity, was treated with SB-R extract and 17β-estradiol (E2; positive control) in the presence or absence of ICI 182,780 (Fulvestrant), an estrogen receptor antagonist. An E-screen assay and flow cytometry were performed to assess the effects of the treatments on cell proliferation and the cell cycle, respectively. Additionally, Western blotting and immunofluorescence assays were performed to elucidate the potential mechanisms underlying the estrogen-like effects of SB-R. Result: Treatment with SB-R extract promoted MCF-7 cell proliferation in a manner similar to E2. However, ICI 182,780 co-treatment inhibited the SB-R extract-induced increase in MCF-7 cell proliferation. Additionally, SB-R extract promoted cell cycle progression by increasing the proportion of cells in the S and G2/M phases. Moreover, Western blotting and immunofluorescence assays showed that SB-R extract increased the expression of estrogen receptor alpha (ERα). Furthermore, SB-R treatment activated downstream signaling pathways by enhancing AKT and ERK phosphorylation and upregulated the expression of cell cycle regulators, including cyclin D1, cyclin dependent kinase 4 (CDK4), cyclin E1, and cyclin dependent kinase 2 (CDK2). Conclusions: SB-R exhibits estrogen-like activity by activating ERα-mediated AKT and ERK pathways and thereby increasing the expression of proteins involved in cell cycle regulation. This makes it a promising phytoestrogen candidate and a safer alternative to conventional hormonal therapy for alleviating menopausal symptoms. Full article

Effective intracellular delivery for ovarian cancer therapy remains a significant challenge. We present chrysin-loaded p(MMA-co-DMAEMA)-b-(OEGMA-co-DMA), PMOD-Chr, a nanoparticle platform precisely engineered via RAFT polymerization for advanced therapeutic delivery. This multi-functional platform features a hydrophobic p(MMA) core encapsulating chrysin (Chr), a pH-responsive p(DMAEMA) segment for endosomal escape, and a hydrophilic OEGMA (Oligo(ethylene glycol) methyl ether methacrylate) shell functionalized for enhanced cellular affinity and systemic stability. The combination of OEGMA and DMA (Dopamine methacrylamide) block facilitates passive targeting of ovarian cancer cells, enhancing internalization. Nanoparticles prepared via the nanoprecipitation method exhibited ~220 nm, demonstrating effective size modulation along with high homogeneity and spherical morphology. In A2780 and OVCAR3 ovarian cancer cells, PMOD-Chr demonstrated significantly enhanced cytotoxicity, substantially lowering the effective IC₅₀ dose of Chr. Mechanistically, PMOD-Chr induced a potent G2/M cell cycle arrest, driven by the upregulation of the CDK1/Cyclin B1 complex. Furthermore, the formulation potently triggered programmed cell death by concurrently activating both the intrinsic apoptotic pathway, evidenced by the modulation of Bax, Bcl2, and caspase 9, and the extrinsic pathway involving caspase 8. These findings emphasize that precision engineering via RAFT polymerization enables the creation of sophisticated, multi-stage nanomedicines that effectively overcome key delivery barriers, offering a highly promising targeted strategy for ovarian cancer. Full article

In this century, cancer is one of the most important causes of death worldwide, and the need for the development of new treatment options is imperative. The use of metal-based compounds in cancer treatment has increased significantly due to certain properties of these elements, and vanadium has been one of the most studied transition metals in recent decades. Vanadium compounds are being explored as an option for cancer treatment because of their wide range of action mechanisms such as the induction of oxidative stress, DNA damage, cell cycle arrest, induction of apoptosis and regulation of the autophagy process, among the most important mechanisms. Their compounds have been demonstrated to be effective against the cancer types with the highest incidence and mortality rates worldwide, such as lung and breast cancer, with promising results. This review discusses a variety of new vanadium compounds, indicating their mechanisms of action and the neoplasms in which they have shown effectiveness. Full article

The liver orchestrates metabolic homeostasis through dynamic post-translational modifications. β-hydroxybutyrylation (Kbhb), a ketone body-driven modification, regulates epigenetics and metabolism in humans and mice but remains unexplored in livestock. Here, we characterize the porcine hepatic β-hydroxybutyrylome using high-resolution mass spectrometry, identifying 4982 Kbhb sites on 2122 proteins—the largest dataset to date. β-hydroxybutyrylation predominantly targets non-histone proteins (99.68%), with enrichment in fatty acid β-oxidation, TCA cycle, and oxidative phosphorylation pathways. Subcellular localization revealed cytoplasmic (38.1%), mitochondrial (18.1%), and nuclear (15.3%) dominance, reflecting BHB-CoA synthesis sites. Motif analysis identified conserved leucine, phenylalanine, and valine residues at modified lysines, suggesting enzyme-substrate specificity. β-hydroxybutyrate treatment elevated global Kbhb levels, increasing TCA intermediates (e.g., α-ketoglutarate, +9.56-fold) while reducing acetyl-CoA, indicating enhanced mitochondrial flux. Cross-species comparisons showed tissue-specific Kbhb distribution (nuclear in human cells vs. mitochondrial in mice), highlighting metabolic adaptations. This study establishes pigs as a model for Kbhb research, linking it to energy regulation and providing insights into metabolic reprogramming. Full article

High hydrostatic pressure (HHP) significantly modulates microbial metabolism, while chemical epigenetic modifiers are known to reactivate silent biosynthetic gene clusters and induce novel natural products. However, the mechanisms by which these epigenetic modifiers regulate fungal responses under differential pressure conditions, and how such regulation affects natural product biosynthesis, remain completely unexplored. Here, we investigated the hadal fungus Alternaria alternata CIEL23 isolated from 7332 m sediments in the Mariana Trench under epigenetic modifier treatment with contrasting pressures (0.1 MPa vs. 40 MPa). Our results revealed that epigenetic perturbations and high pressure significantly altered fungal phenotypes, gene expression, and secondary metabolite composition. Transcriptome-level analysis of epigenetic regulatory mechanisms under epigenetic modifiers in both pressure conditions (0.1 MPa and 40 MPa) demonstrated that the addition of epigenetic modifiers regulated MAPK pathway-related gene expression in response to the environment stimuli. Under dual stress conditions, the IG, CWI, and HOG branches of the MAPK pathway showed significantly altered activity patterns. These changes were associated with differential the regulation of genes related to hyphal growth, cell wall remodeling, cell cycle progression, and osmolyte synthesis, suggesting the coordinated modulation of multiple cellular processes. These findings provide the mechanistic link between epigenetic modification induced HHP-response changes and regulation in hadal fungi. Our study not only advances understanding of hadal fungal response to dual stressors but also unlocks new possibilities for harnessing their stress-driven metabolic versatility for biotechnological applications. Full article

Background/Objectives: Camellia sinensis (L.) Kuntze or tea contains bioactive compounds such as catechin and caffeine, known for their antimicrobial and health-promoting properties. Colibactin-producing Escherichia coli are linked to genotoxicity in colon epithelial cells, potentially contributing to colorectal disease. This study aimed to evaluate the inhibitory effects of tea extracts (green, oolong, and black) and the phytochemicals catechin and caffeine on E. coli pathogenesis mediated by colibactin toxins, including transient infections, DNA damage, and cell cycle alterations in Caco-2 colon cells. Methods: Tea extracts were analyzed by HPLC for phytochemical content. Their antimicrobial activity against colibactin-producing E. coli (ATCC 25922) was assessed. Caco-2 cells were infected with the bacteria and treated with tea extracts or compounds. Cell viability was measured by MTT assay, DNA damage was measured by alkaline comet assay, and the expression of CDK-1, CDK-2, and Ki-67 genes was measurd by qRT-PCR. Results: Tea extracts and catechin inhibited colibactin-producing E. coli and significantly protected Caco-2 cells. Oolong tea showed the highest protection (90.78 ± 2.76%), with others maintaining viability above 80%. DNA damage was markedly reduced, and cell cycle regulation improved. All extracts upregulated CDK-1 and downregulated CDK-2, aiding in cell cycle restoration. Ki-67 expression indicated enhanced cell proliferation during infection. Conclusions: This study highlights new findings showing that tea extracts, including green, oolong, and black tea, as well as the tea compounds catechin and caffeine, can protect against DNA damage and help maintain the normal cell cycle of colon cells infected with E. coli-producing colibactin toxin. These results support their potential role in preventing and mitigating infections caused by such E. coli strains while promoting colon cell health. Full article

Transparent Exopolymer Particles (TEP) play a key role in the marine carbon cycle, facilitating the aggregation and exportation of organic matter. TEP production is particularly relevant during Harmful Algal Blooms (HABs), where dinoflagellates like Lingulaulax polyedra can release significant amounts of exudates. Temperature is a crucial environmental factor that influences HAB dynamics and physiological processes of bloom-forming species, affecting exudate composition and abundance. This study investigates the influence of temperature and nutrient availability on the production of organic exudates in L. polyedra cultures. TEP, Particulate Organic Carbon (POC), and Particulate Organic Nitrogen (PON) concentrations were analyzed under controlled laboratory conditions. Batch cultures were maintained at temperatures of 17, 20, and 25 °C, with two nutrient regimes (low and high nitrate and phosphate concentrations). Exudates were quantified using colorimetric and spectrophotometric methods. We found that temperature and nutrient availability significantly influence exudate production. The highest TEP concentration was recorded at 25 °C in cells cultivated under low-nutrient conditions, whereas POC exhibited a notable increase at 20 °C. ANOVA revealed that TEP and POC were the primary drivers of variability among treatments. These findings reveal that temperature is important in the regulation of L. polyedra exudate production. The role of this variable on organic matter cycling and bloom dynamics in marine ecosystems is discussed. Full article

Breast cancer is a common and chronic condition, and despite improvements in diagnosis, treatment, and prevention, the number of cases of breast cancer is rising annually. New therapeutic drugs that target specific checkpoints should be created to fight breast cancer. Mandragora autumnalis possesses substantial cultural value as a herb and is regarded as one of the most significant medicinal plants; however, little is known about its anticancerous biological activity and chemopreventive molecular pathways against the triple-negative breast cancer (MDA-MB-231) cell line. In this study, the antioxidant, anticancer, and underlying molecular mechanisms of the Mandragora autumnalis ethanolic leaves extract (MAE) were evaluated, and its phytochemical composition was determined. Results indicated that MAE diminished the viability of MDA-MB-231 cells in a concentration- and time-dependent manner. Although MAE exhibited 55% radical scavenging activity at higher concentrations in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, the attenuation of its cytotoxic effects in MDA-MB-231 cells with N-acetylcysteine (NAC) co-treatment suggests a potential role of oxidative stress. Additionally, MAE caused an increase in the tumor suppressor p53. Moreover, this extract caused a significant decrease in the expression of Ki-67 (a cellular proliferation marker), MMP-9 (matrix metalloproteinase-9, an enzyme involved in extracellular matrix degradation and metastasis), and STAT-3 (a transcription factor regulating cell growth and survival). Also, MAE altered cell cycle, cell migration, angiogenesis, invasion, aggregation, and adhesion to suppress cellular processes linked to metastasis. All of our research points to MAE’s potential to function as an anticancer agent and opens up new possibilities for the development of innovative triple-negative breast cancer treatments. Full article

Rosa roxburghii Tratt., a fruit crop known for its high Vitamin C content and other nutritional compounds, has not yet been studied for its auxin response factor (ARF) family members. ARFs are important proteins in auxin-mediated pathways, playing a vital role in plant physiological and biochemical processes such as plant development, and flower and fruit maturation. In the present study, we identified 14 ARF genes (designated as RrARFs) in R. roxburghii, which are distributed across seven chromosomes and grouped into four subfamilies. An analysis of cis-acting elements revealed that these genes might be involved in various biological processes, including plant development, flower development, light responses, cell cycle regulation, phytohormone responses, and responses to abiotic and biotic stresses. A gene expression analysis demonstrated differential expression of RrARF genes across different tissues and stages of fruit development, with four members showing higher expression during the fruit ripening stages. Furthermore, a coexpression analysis identified that RrARF5 was highly coexpressed with RrMDHAR1, a key enzyme involved in Vitamin C biosynthesis. Moreover, transactivation assays and transient overexpression experiments confirmed that RrARF5 activates the transcription of RrMDHAR1. The findings of this study suggest a potential role of the ARF gene family in Vitamin C accumulation in R. roxburghii and enhance our understanding of the diverse regulatory function of the ARF gene family in plants. Full article