Search Results (111)

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality, with therapeutic resistance continuing to limit long-term responses. Among emerging resistance mechanisms, dysregulation of nucleocytoplasmic transport has gained attention for its ability to inactivate tumor suppressor pathways. Exportin 1 (XPO1), the primary nuclear export protein, is frequently overexpressed in NSCLC and promotes the cytoplasmic mislocalization of proteins involved in cell cycle control, apoptosis, and DNA repair. This includes key regulators such as p53, FOXO, and RB, whose inactivation supports tumor progression and therapy resistance. Inhibition of XPO1 with selective inhibitors of nuclear export (SINE) compounds, including selinexor, has demonstrated the ability to restore nuclear localization and function of these proteins, thereby enhancing cellular sensitivity to DNA-damaging agents, kinase inhibitors, and immunotherapies. In preclinical NSCLC models, XPO1 inhibition has shown efficacy both as monotherapy and in combination strategies, with particular promise in KRAS- and EGFR-driven tumors. This review explores the role of XPO1 in NSCLC biology and therapy resistance, the rationale for targeting nuclear export, and the current landscape of XPO1-directed clinical development in lung cancer. Full article

Aging results in decreased collagen synthesis and the disruption of extracellular matrix integrity, primarily due to increased oxidative stress. This study evaluated whether atelocollagen can restore collagen synthesis in aged skin by modulating glycine transporter 1 (GlyT1)-mediated glycine uptake, regulating oxidative stress, and influencing extracellular matrix remodeling factors in senescent human cells and the skin of older mice. Human dermal fibroblasts (HDFs) and aged mouse skin were treated with atelocollagen, with analyses of GlyT1 expression, glutathione and intracellular glycine concentrations, oxidative stress markers, nuclear factor-kappa-B (NF-κB) activity, matrix metalloproteinases (MMPs), SMAD proteins (SMADs) signaling, and collagen I/III. Treatment with GlyT1 inhibitors and glycine was tested. Atelocollagen significantly increased GlyT1 expression and intracellular glycine concentration, promoted glutathione synthesis, and reduced oxidative stress. These effects led to decreased NF-κB activity and MMP1/3/9 expression, increased SMAD2/3 phosphorylation, and upregulated type I/III collagen synthesis in senescent HDFs and aged mouse skin. All beneficial effects were blocked by GlyT1 inhibition and were generally superior to glycine alone. Histology showed increased collagen density and improved skin elasticity in atelocollagen-treated mice. In summary, atelocollagen enhances collagen synthesis and reduces oxidative stress in aged skin through GlyT1-dependent glycine transport, providing a potential strategy for skin rejuvenation. Full article

Rotenone, a classical inhibitor of mitochondrial complex I, disrupts electron transport and promotes the generation of reactive oxygen species (ROS), contributing to inflammation and cell death. However, the precise molecular mechanisms linking mitochondrial dysfunction to inflammatory signaling remain incompletely understood. In this study, we investigated the role of the cGAS–STING pathway in rotenone-induced NLRP3 inflammasome activation in PMA-differentiated THP-1 macrophages. Rotenone treatment activated the cGAS–STING axis, as evidenced by increased cGAS expression and the phosphorylation of STING and TBK1. This activation led to the nuclear translocation of NF-κB and the upregulation of NLRP3, promoting inflammasome priming and IL-1β secretion. Inhibition of STING using H-151 markedly suppressed NLRP3 expression, NF-κB activation, and IL-1β release. Similarly, cyclosporin A, an inhibitor of mitochondrial permeability transition pore opening, reduced mitochondrial ROS, cytosolic oxidized mitochondrial DNA, and downstream activation of the cGAS–STING pathway, thereby attenuating inflammasome activation. These findings demonstrate that rotenone activates the NLRP3 inflammasome via mitochondrial ROS-mediated release of mtDNA and subsequent activation of the cGAS–STING–NF-κB signaling axis in THP-1-derived macrophages. Full article

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving the progressive degeneration of upper and lower motor neurons. While oxidative stress, RNA-binding protein (RBP) pathology, mitochondrial dysfunction, and glial–neuronal dysregulation is involved in ALS pathogenesis, current therapies provide limited benefit, underscoring the need for multi-target disease-modifying strategies. Nuclear factor erythroid 2-related factor 2 (Nrf2), classically regarded as a master regulator of redox homeostasis, has recently emerged as a central integrator of cellular stress responses relevant to ALS. Beyond its canonical antioxidant function, Nrf2 regulates critical pathways involved in mitochondrial quality control, proteostasis, nucleocytoplasmic transport, RNA surveillance, and glial reactivity. Experimental models demonstrate that astrocyte-specific Nrf2 activation enhances glutathione metabolism, suppresses neuroinflammation, promotes stress granule disassembly, and reduces RBP aggregation. In C9orf72-linked ALS, Nrf2 activation mitigates dipeptide repeat protein toxicity and restores RNA processing fidelity via modulation of nonsense-mediated decay and R-loop resolution. Recent advances in Nrf2-targeted interventions including Keap1–Nrf2 protein–protein interaction inhibitors, dual Nrf2/HSF1 activators, and cell-type-selective Adeno-associated virus 9 (AAV9) vectors show promise in preclinical ALS models. These multimodal approaches highlight Nrf2’s therapeutic versatility and potential to address the upstream convergence points of ALS pathogenesis. Taken together, positioning Nrf2 as a systems-level regulator offers a novel framework for developing precision-based therapies in ALS. Integrating Nrf2 activation with RNA- and glia-directed strategies may enable comprehensive modulation of disease progression at its molecular roots. Full article

Epigenetic modifications are long-lasting changes to the genome that influence a cell’s transcriptional potential, thereby altering its function. These modifications can trigger adaptive responses that impact protein expression and various cellular processes, including differentiation and growth. The primary epigenetic mechanisms identified to date include DNA and RNA methylation, histone modifications, and microRNA-mediated regulation of gene expression. The intricate crosstalk among these mechanisms makes epigenetics a compelling field for the development of novel control strategies, particularly through the use of epigenetic drugs targeting arthropod vectors such as ticks. In this study, we identified the Rhipicephalus microplus orthologs of canonical histone-modifying enzymes, along with components of the machinery responsible for m⁵C and ⁶mA-DNA, and m⁶A-RNA methylations. We further characterized their transcriptional profiles and enzymatic activities during embryonic development. To explore the functional consequences of epigenetic regulation in R. microplus, we evaluated the effects of various epigenetic inhibitors on the BME26 tick embryonic cell line. Molecular docking simulations were performed to predict the binding modes of these inhibitors to tick enzymes, followed by in vitro assessment of their effects on cell viability and morphology. Tick cells exposed to these inhibitors presented phenotypic and molecular alterations. Notably, we observed high levels of DNA methylation in the nuclear genome. Importantly, inhibition of DNA methylation using 5′-azacytidine (5′-AZA) was associated with increased activity of the mitochondrial electron transport chain and ATP synthesis but reduced cellular proliferation. Our findings highlight the importance of epigenetic regulation during tick embryogenesis and suggest that targeting these pathways may constitute a novel and promising strategy for tick control. Full article

Background: Post-myocardial infarction (MI) heart failure (HF) is characterized by myocardial energy metabolism disorder, with excessive glycolysis playing a key role in its progression. Silybin (SIL), a flavonoid derived from Silybum marianum, has demonstrated hepatoprotective and metabolic regulatory effects. However, the role of this flavonoid in ameliorating post-myocardial infarction heart failure (post-MI HF) by modulating energy metabolism remains unclear. Methods: This study employed an oxygen–glucose deprivation (OGD) model to induce myocardial cell injury in vitro, with YC-1 treatment used to inhibit hypoxia-inducible factor-1α (HIF-1α) for mechanistic validation. A myocardial infarction-induced HF mouse model was used for in vivo experiments. Results: In vitro, SIL enhanced cell viability, increased ATP levels, and decreased lactate production and reactive oxygen species (ROS) accumulation in OGD-treated myocardial cells. SIL downregulated the mRNA and protein expression of HIF-1α, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), glucose transporter 1 (GLUT1), and lactate dehydrogenase A (LDHA) while inhibiting HIF-1α nuclear translocation. Furthermore, SIL suppressed glycolytic proteins (PFKFB3, GLUT1, and LDHA) in a manner comparable to the HIF-1α inhibitor YC-1. This confirms that SIL’s inhibition of glycolysis is HIF-1α-dependent. In vivo, SIL treatment improved cardiac function parameters (LVEF and LVFS) and attenuated left ventricular remodeling (LVID;d and LVID;s) in post-MI HF mice. Additionally, myocardial fibrosis markers were significantly reduced, accompanied by a decrease in the myocardial mRNA and protein expression of glycolytic proteins, including HIF-1α, PFKFB3, GLUT1, and LDHA. Conclusions: Silybin effectively ameliorates post-myocardial infarction heart failure through the HIF-1α-mediated regulation of glycolysis, leading to improved myocardial energy metabolism and enhanced cardiac function. Full article

Chlorophyll, the green pigment essential for photosynthesis, abundantly found in green vegetables and algae, has attracted growing scientific interest for its potential therapeutic effects, particularly in diabetes management. Recent research highlighted that chlorophyll and its derivatives may beneficially influence glucose metabolism and oxidative stress, key factors in diabetes. This review examines current knowledge on how chlorophyll compounds could aid diabetes control. Chlorophyll and its derivatives appear to support glucose regulation primarily through actions in the gastrointestinal tract. They modulate gut microbiota, improve glucose tolerance, reduce inflammation, and alleviate obesity-related markers. While chlorophyll itself does not directly inhibit digestive enzymes like α-glucosidase, its derivatives such as pheophorbide a, pheophytin a, and pyropheophytin a may slow carbohydrate digestion, acting as α-amylase and α-glucosidase inhibitors, reducing postprandial glucose spikes. Additionally, chlorophyll enhances resistant starch content, further controlling glucose absorption. Beyond digestion, chlorophyll derivatives show promise in inhibiting glycation processes, improving insulin sensitivity through nuclear receptor modulation, and lowering oxidative stress. However, some compounds pose risks due to photosensitizing effects and toxicity, warranting careful consideration. Chlorophyllin, a stable semi-synthetic derivative, also shows potential in improving glucose and lipid metabolism. Notably, pheophorbide a demonstrates insulin-mimetic activity by stimulating glucose uptake via glucose transporters, offering a novel therapeutic avenue. Overall, the antioxidant, anti-inflammatory, and insulin-mimicking properties of chlorophyll derivatives suggest a multifaceted approach to diabetes management. While promising, these findings require further clinical validation to establish effective therapeutic applications. Full article

Background and Objectives: Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies worldwide. Although chemotherapy is an effective treatment for colorectal cancer (CRC), its effectiveness is frequently hindered by the emergence of resistant cancer cells. Studies have demonstrated a linkage between drug resistance and the pregnane X receptor (PXR), which influences the metabolism and the transport of chemotherapeutic agents. Likewise, autophagy is also a well-established mechanism that contributes to chemotherapy resistance, and it is closely tied to tumor progression. This pre-clinical study aims to investigate the role of mtKRAS-dependent autophagy with PXR expression after treatment with Irinotecan in colorectal cancer. Methods: CRC lines were treated with specific inhibitors, such as 3-methyladeninee, hydroxychloroquine PI-103, and irinotecan hydrochloride, and subjected to various assays, including MTT for cell viability, Western blot for protein expression, siRNA-mediated PXR knock-out, and confocal microscopy for autophagic vacuole visualization. Protein quantification, gene knockdown, and subcellular localization studies were performed under standardized conditions to investigate treatment effects on autophagy and apoptosis pathways. Conclusions: Our experiments showed that PXR knockdown does not alter autophagy levels following Irinotecan treatment, but it promotes apoptotic cell death despite elevated autophagy. Moreover, late-stage autophagy inhibition reduces PXR expression, whereas induction through PI3K/AKT/mTOR inhibition leads to increased expression of PXR. Our experiments uncover a mechanism by which autophagy facilitates the nuclear translocation of the PXR, thereby promoting resistance to Irinotecan across multiple cell lines. Full article

Hepatitis B virus (HBV) specifically infects hepatocytes and has a complex life cycle owing to the stabilization and pooling of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. We previously reported that the suppression of dedicator of cytokinesis 11 (DOCK11) decreases cccDNA and HBV-DNA levels and identified it as a new HBV therapeutic target. The DOCK11-associated gene, Wnt/β-catenin signaling regulator tankyrase (TNKS), was identified using in vitro methods; however, its function in the HBV life cycle remains unknown. Here, we used various inhibitors, antagonists, and short-hairpin RNA treatments related to TNKS signaling in HBV-infected hepatocytes. The role of TNKS-related Wnt/β-catenin signaling in the HBV life cycle was evaluated using immunoprecipitation assays with DOCK11 and bulk RNA sequencing methods. TNKS and Wnt/β-catenin signaling inhibitors significantly repressed cccDNA and HBV-DNA levels. Conversely, certain Wnt/β-catenin signaling agonists enhanced the HBV life cycle. DOCK11 directly binds to β-catenin to regulate HBV using its nuclear transport system. SKL2001, normally used as a Wnt/β-catenin signaling agonist, strongly reduced cccDNA in HBV-infected hepatocytes and in combination with entecavir predominantly eradicated HBV without cytotoxicity. Therefore, DOCK11 and other Wnt/β-catenin signaling molecules may be therapeutic targets to prevent persistent HBV infection. Full article

As one of the important components of placental structure, the integrity of placental trophoblast cells is crucial for placental function. When oxidative stress continues to act on placental trophoblast cells, it can cause changes in placental structure and function. Research has shown that folic acid (FA) has a certain alleviating effect on the functional damage of trophoblast cells caused by oxidative stress, but the mechanism of action is still unclear. Therefore, this study focuses on bovine placental trophoblast cells (BPTCs) to explore the effects and mechanisms by which FA regulates oxidative stress in cells, with the aim of providing a theoretical foundation for improving the reproductive performance of cows. The results show that, compared with the H₂O₂ group, the FA+ H₂O₂ group showed an increase in the cell proliferation index (PI), superoxide dismutase 2 (SOD2), glutathione peroxidase (GSH-px), and catalase (CAT) mRNA expression and total antioxidant capacity (T-AOC) of cells, while the content of reactive oxygen species (ROS) decreased. In addition, the mRNA expression of tight junction factors, nutrient transporters, placental functional factors, mammalian rapamycin (mTOR) and its downstream factors, and nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream factors in the FA+ H₂O₂ group increased, while the protein abundance of nuclear NRF2 decreased. After treatment with the inhibitor ML385, it was found that the protective effect of FA on H₂O₂-induced cellular oxidative damage was alleviated. These results indicate that FA can regulate the NRF2/mTOR signaling pathway, promote the expression of antioxidant factors, and alleviate the damage to the cell barrier and nutrient transport function in BPTCs caused by oxidative stress. Full article

The nucleocytoplasmic transport of proteins using XPO1 (exportin 1) plays a vital role in cell proliferation and survival. Many viruses also exploit this pathway to promote infection and replication. Thus, inhibiting the XPO1-mediated nuclear export pathway with selective inhibitors has a diverse effect on virus replication by regulating antiviral, proviral, and anti-inflammatory pathways. The XPO1 inhibitor Selinexor is an FDA-approved anticancer drug predicted to have antiviral or proviral functions against viruses. Here, we observed that the pretreatment of cultured cell lines from human or mouse origin with the nuclear export inhibitor Selinexor significantly enhanced the protein expression and replication of mouse hepatitis virus (MHV), a mouse coronavirus. The knockdown of cellular XPO1 protein expression also significantly enhanced the replication of MHV in human cells. However, for SARS-CoV-2, Selinexor treatment had diverse effects on virus replication in different cell lines. These results indicate that XPO1-mediated nuclear export pathway inhibition might affect coronavirus replication depending on cell types and virus origin. Full article

Viruses frequently exploit the host’s nucleocytoplasmic trafficking machinery to facilitate their replication and evade immune defenses. By encoding specialized proteins and other components, they strategically target host nuclear transport receptors (NTRs) and nucleoporins within the spiderweb-like inner channel of the nuclear pore complex (NPC), enabling efficient access to the host nucleus. This review explores the intricate mechanisms governing the nuclear import and export of viral components, with a focus on the interplay between viral factors and host determinants that are essential for these processes. Given the pivotal role of nucleocytoplasmic shuttling in the viral life cycle, we also examine therapeutic strategies aimed at disrupting the host’s nuclear transport pathways. This includes evaluating the efficacy of pharmacological inhibitors in impairing viral replication and assessing their potential as antiviral treatments. Furthermore, we emphasize the need for continued research to develop targeted therapies that leverage vulnerabilities in nucleocytoplasmic trafficking. Emerging high-resolution techniques, such as advanced imaging and computational modeling, are transforming our understanding of the dynamic interactions between viruses and the NPC. These cutting-edge tools are driving progress in identifying novel therapeutic opportunities and uncovering deeper insights into viral pathogenesis. This review highlights the importance of these advancements in paving the way for innovative antiviral strategies. Full article

Signal-dependent transport into and out of the nucleus mediated by members of the importin (IMP) superfamily is crucial for eukaryotic function, with inhibitors targeting IMPα being of key interest as anti-infectious agents, including against the apicomplexan Plasmodium species and Toxoplasma gondii, causative agents of malaria and toxoplasmosis, respectively. We recently showed that the FDA-approved macrocyclic lactone ivermectin, as well as several other different small molecule inhibitors, can specifically bind to and inhibit P. falciparum and T. gondii IMPα functions, as well as limit parasite growth. Here we focus on the FDA-approved antiparasitic moxidectin, a structural analogue of ivermectin, for its IMPα-targeting and anti-apicomplexan properties for the first time. We use circular dichroism and intrinsic tryptophan fluorescence measurements to show that moxidectin can bind directly to apicomplexan IMPαs, thereby inhibiting their key binding functions at low μM concentrations, as well as possessing anti-parasitic activity against P. falciparum in culture. The results imply a class effect in terms of IMPα’s ability to be targeted by macrocyclic lactone compounds. Importantly, in the face of rising global emergence of resistance to approved anti-parasitic agents, the findings highlight the potential of moxidectin and possibly other macrocyclic lactone compounds as antimalarial agents. Full article

Chronic kidney disease (CKD) is a major public health concern around the world. It is a significant risk factor for cardiovascular disease (CVD), and, as it progresses, the risk of cardiovascular events increases. Furthermore, end-stage kidney disease severely affects life expectancy and quality of life. Type 2 diabetes and hypertension are not only primary causes of CKD but also independent risk factors for CVD, which underscores the importance of effective treatment strategies for these conditions. The current therapies, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and sodium–glucose co-transporter 2 inhibitors, are administered to control hypertension, slow the progression of CKD, and reduce cardiovascular risk. However, their efficacy remains suboptimal in certain instances. Mineralocorticoid receptor (MR), a nuclear receptor found in various tissues, such as the kidney and heart, plays a pivotal role in the progression of CKD. Overactivation of MR triggers inflammation and fibrosis, which exacerbates kidney damage and accelerates disease progression. MR antagonists (MRAs) have substantial beneficial effects in patients with cardiac and renal conditions; however, their use has been constrained because of adverse effects, such as hyperkalemia and kidney dysfunction. Recently, novel non-steroidal MRAs are more efficacious and have superior safety profiles to steroidal MRAs, making them promising potential components of future treatment strategies. Here, we discuss recent findings and the roles of MRAs in the management of hypertension and CKD, with a focus on the evidence obtained from fundamental research and major clinical trials. Full article

Background: Cytochromes P450 (CYPs) are heme-containing oxidoreductase enzymes with mono-oxygenase activity. Human CYPs catalyze the oxidation of a great variety of chemicals, including xenobiotics, steroid hormones, vitamins, bile acids, procarcinogens, and drugs. Findings: In our review article, we discuss recent data evidencing that the same CYP isoform can be involved in both bioactivation and detoxification reactions and convert the same substrate to different products. Conversely, different CYP isoforms can convert the same substrate, xenobiotic or procarcinogen, into either a more or less toxic product. These phenomena depend on the type of catalyzed reaction, substrate, tissue type, and biological species. Since the CYPs involved in bioactivation (CYP3A4, CYP1A1, CYP2D6, and CYP2C8) are primarily expressed in the liver, their metabolites can induce hepatotoxicity and hepatocarcinogenesis. Additionally, we discuss the role of drugs as CYP substrates, inducers, and inhibitors as well as the implication of nuclear receptors, efflux transporters, and drug–drug interactions in anticancer drug resistance. We highlight the molecular mechanisms underlying the development of hormone-sensitive cancers, including breast, ovarian, endometrial, and prostate cancers. Key players in these mechanisms are the 2,3- and 3,4-catechols of estrogens, which are formed by CYP1A1, CYP1A2, and CYP1B1. The catechols can also produce quinones, leading to the formation of toxic protein and DNA adducts that contribute to cancer progression. However, 2-hydroxy- and 4-hydroxy-estrogens and their O-methylated derivatives along with conjugated metabolites play cancer-protective roles. CYP17A1 and CYP11A1, which are involved in the biosynthesis of testosterone precursors, contribute to prostate cancer, whereas conversion of testosterone to 5α-dihydrotestosterone as well as sustained activation and mutation of the androgen receptor are implicated in metastatic castration-resistant prostate cancer (CRPC). CYP enzymatic activities are influenced by CYP gene polymorphisms, although a significant portion of them have no effects. However, CYP polymorphisms can determine poor, intermediate, rapid, and ultrarapid metabolizer genotypes, which can affect cancer and drug susceptibility. Despite limited statistically significant data, associations between CYP polymorphisms and cancer risk, tumor size, and metastatic status among various populations have been demonstrated. Conclusions: The metabolic diversity and dual character of biological effects of CYPs underlie their implications in, preliminarily, hormone-sensitive cancers. Variations in CYP activities and CYP gene polymorphisms are implicated in the interindividual variability in cancer and drug susceptibility. The development of CYP inhibitors provides options for personalized anticancer therapy. Full article