Biomolecules & Therapeutics最新文献

YAP is a transcription cofactor in the Hippo pathway that interacts with the TEAD family of transcription factors in the nucleus to promote CTGF expression and stimulate cell growth. YAP hyperactivation is frequently observed in fibrotic diseases. The main kinases in the Hippo pathway, MST1/2, a member of the STE20 family, promote Lats phosphorylation, leading to YAP phosphorylation, which prevents its nuclear entry and thus inhibits cell growth. High cell density induces Lats phosphorylation, causing YAP phosphorylation and its exclusion from the nucleus. Additionally, energy stress, such as glucose deprivation, induces AMPK phosphorylation, which also prevents YAP from entering the nucleus. MST3, another member of the STE20 family, has been shown to regulate cell apoptosis, migration, polarization, and ion homeostasis in previous studies. We hypothesized that MST3 is involved in Hippo pathway-mediated fibrosis. To test this, we overexpressed HA-tagged MST3 (HA-MST3) and a kinase-dead mutant (HA-MST3-KD) in MDCK cells. When cells reached a high density, HA-MST3 was activated to phosphorylate YAP, promoting its nuclear exit and inhibiting cell growth. In contrast, HA-MST3-KD cells showed reduced phosphorylated YAP, resulting in YAP retention in the nucleus, continuous cell growth, and NIH/3T3 cell fibrosis. Interestingly, YAP did not exit the nucleus in HA-MST3-KD cells treated with the YAP inhibitor verteporfin, but it did exit under metformin treatment due to energy stress, accompanied by increased AMPK and YAP phosphorylation, which inhibited MST3-KD-mediated fibrosis. These findings suggest that metformin-induced AMPK activation could provide a therapeutic approach for MST3-KD-mediated fibrosis.

Dimethyl sulfoxide (DMSO) is extensively used as a solvent in bioactive compound screening due to its capacity to solubilize a wide range of chemical compounds. This study demonstrates that DMSO significantly influences lineage commitment in human bone marrow-derived mesenchymal stem cells (hBM-MSCs) by enhancing adipogenesis and inhibiting osteogenesis. At concentrations above 25 mM (0.32% in culture media), DMSO significantly promoted adipogenic differentiation in hBM-MSCs. Under osteogenic conditions, however, DMSO suppressed mineralization and downregulated the expression of osteoblast markers, thereby reducing osteoblast differentiation. Notably, DMSO also increased the adipocyte population within a predominantly osteogenic environment, suggesting it may shift the balance of hBM-MSC lineage commitment toward adipogenesis over osteogenesis. These findings emphasize the importance of careful consideration when utilizing DMSO as a solvent in studies involving hBMMSCs differentiation and the biological evaluation of test compounds.

Depressive amnesia, involving memory impairment and mood dysregulation, frequently co-occurs with depression and neurodegenerative diseases. Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to depressive-like behaviors and cognitive deficits. This study evaluated the therapeutic potential of 2',4',6'-trimethoxyacetophenone (TMA), a bioactive compound from Lycoris sanguinea var. koreana, in a mouse model of MGO-induced depressive amnesia. Mice received MGO (60 mg/kg) followed by TMA (5 or 20 mg/kg), and behavioral tests were conducted to assess mood, cognition, and locomotor activity. TMA significantly reduced immobility in tail suspension and forced swim tests, improved locomotion and exploration in the open field, and restored memory in novel object recognition and Y-maze tests. Histological analysis showed that TMA preserved hippocampal integrity, modulated glucocorticoid receptor expression, and reduced cortisol levels, indicating involvement in stress regulation. TMA also attenuated neuroinflammation by lowering IL-1β and microglial activation while increasing IL-10. Additionally, it reduced amyloidogenic markers, including oligomeric Aβ and amyloid precursor protein. These findings highlight the neuroprotective and antidepressant potential of TMA and support its use as a natural therapeutic candidate for treating depression-related cognitive impairment.

Albiflorin, a key active compound in the roots of Paeonia lactiflora Pall, is known to have multiple health benefits. Although albiflorin has been shown to exert its major pharmacological effects via its antioxidant activity, its efficacy in the muscles has not been evaluated. In this study, we examined the protective activity of albiflorin against oxidative injury in C2C12 murine myoblasts. C2C12 cells were pretreated with nontoxic concentrations of albiflorin and exposed to hydrogen peroxide (H₂O₂) to mimic oxidative stress. Albiflorin pretreatment inhibited H₂O₂-mediated decrease in cell viability and extracellular release of lactate dehydrogenase, and reduced comet tail formation, 8-hydroxy-2'-deoxyguanosine production, and phosphorylated form of histone 2AX expression, which are representative biomarkers of DNA damage. Albiflorin also blocked H₂O₂-induced apoptosis by inhibiting the activation of caspase-3, which is associated with the maintenance of mitochondrial membrane stability by decreasing the Bax/Bcl-2 expression ratio. Additionally, albiflorin markedly suppressed H₂O₂-induced accumulation of reactive oxygen species (ROS) and decreased glutathione levels, while increasing the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2) and activating heme oxygenase-1 (HO-1) in the presence of H₂O₂. However, artificial inhibition of HO-1 activity using zinc protoporphyrin (ZnPP) markedly abrogated the protective effects of albiflorin against ROS production and mitochondrial damage in H₂O₂-treated cells. ZnPP significantly reversed the protective effects of albiflorin against H₂O₂-induced apoptosis and decreased cell viability. Taken together, these findings suggest that albiflorin protects myoblasts from oxidative stress-induced DNA damage and apoptosis by activating Nrf2/HO-1 signaling, thus highlighting its potential in the management of myofunctional homeostasis.

Niclosamide is an oral anthelmintic agent and was reported to also have anti-inflammatory effects by suppressing STAT3 signaling pathways. In this study, we investigated the effect of niclosamide on skin inflammatory diseases to determine its potential as a therapeutic drug. We investigated the effects of niclosamide on two models of skin inflammatory diseases: imiquimod -induced psoriasis-like skin inflammation and LL-37-induced rosacea mouse models. Our experimental results showed that niclosamide ameliorated the psoriasis-like skin inflammation and reduced proinflammatory cytokine production in the psoriasis mouse model. Moreover, niclosamide restored the imbalance between IL-17-expressing γδT cells and Tregs in the psoriasis model. Topical application of niclosamide significantly decreased the abundance of IL-17A⁺ γδT cells, which was increased by imiquimod. Moreover, niclosamide significantly increased the abundance of CD4⁺Foxp3⁺ Tregs. In the LL-37-induced rosacea mouse model, niclosamide significantly reduced the number of inflammatory cells including neutrophils and mast cells that play major roles in initiating inflammation and inducing uncontrolled dermal vessel function in rosacea. Lastly, niclosamide significantly reduced the number of p-STAT3-positive cells in mouse skin, which was increased by treatment with imiquimod or LL-37. We found an anti-inflammatory effect of niclosamide in psoriasis and rosacea mouse models and demonstrated the ability of niclosamide in controlling skin inflammation by recalibrating T cell differentiation and restoring T cell regulatory function. Niclosamide, as a STAT3 inhibitor, is a promising therapeutic for skin inflammation, particularly for preventing the relapse of disease by restoring regulatory cell functions.

Liver regeneration is a complex process involving hepatocyte proliferation and differentiation, which is essential for restoring liver function after liver injury. Hepatocyte repopulation plays a central role in this regenerative process, and extensive research has aimed to elucidate the triggering mechanisms of hepatocyte proliferation as well as the origins of new hepatocytes. Partial hepatectomy, drug-induced liver injuries, and other genetic mouse models have been widely employed to investigate the regenerative machinery of the liver. However, the exact sources of regenerating hepatocytes remain controversial. While substantial evidence supports the model in which pre-existing hepatocytes self-duplicate to replenish the liver, alternative hypotheses suggest that biliary epithelial cells and hepatic progenitor cells also contribute under certain injury conditions. Recently, advanced techniques, including lineage tracing and spatial transcriptomics, have been utilized to track cell lineages and analyze changes in cell composition during liver regeneration, greatly advancing the field. Given that hepatocytes perform the majority of liver functions, understanding the contributing signaling pathways of hepatocyte repopulation is the most critical among the whole process of liver regeneration. Therefore, this review specifically focuses on summarizing current findings in the cellular and molecular mechanisms underlying hepatocyte repopulation during liver regeneration.

Curcumenol, a sesquiterpene isolated from Curcuma zedoaria, has a variety of therapeutic effects, such as neuroprotective, antitumor and hepatoprotective effects. This study elucidates whether curcumenol can inhibit ovalbumin (OVA)-induced allergic reactions in a mouse and monoclonal anti-2,4,6-dinitrophenyl (DNP)-immunoglobulin (IgE)/bovine serum albumin (BSA)-mediated allergic reactions in mouse bone marrow-derived mast cells (BMMCs) and rat basophilic leukemia cells (RBL-2H3). IgE-mediated passive cutaneous anaphylaxis and ovalbumin (OVA)-induced anaphylaxis mouse models were performed. β-hexosaminidase release and mast cell degranulation were analyzed in vitro. Western blot analyses were performed to validate the effect of curcumenol on FcεRI signaling pathway. Molecular docking analysis were performed to evaluate curcumenol and tyrosine kinase interaction. Curcumenol alleviated OVA-induced anaphylactic allergic symptoms by increasing rectal temperature in a dosedependent manner. In addition, it reduced the levels of plasma histamine, IgE, and interleukin-4 in mouse model. Curcumenol inhibited IgE-BSA-stimulated β-hexosaminidase release and mast cell degranulation in a dose-dependent manner in BMMCs and RBL-2H3. Curcumenol also inhibited the activation of Src family tyrosine kinases (Fyn and Lyn) and the downstream spleen tyrosine kinase (Syk) in the FcεRI signaling pathway in BMMCs. Furthermore, curcumenol suppressed the activation of Akt, PLCγ1, and mitogen-activated protein kinase signaling. Molecular docking analysis revealed that curcumenol could bind to Fyn and Lyn kinases, thereby suppressing Src family tyrosine kinase signaling. This study suggests that curcumenol inhibits IgE-mediated allergic reactions by suppressing the activation Lyn and Fyn Src family kinases in OVA-challenged model animals. Therefore, curcumenol could be used as an effective alternative therapeutic for allergic diseases.

Glioblastoma is an aggressive brain tumor with poor prognosis and survival. Autophagy is induced in tumor cells under stress conditions such as treatment with chemotherapeutic agents and radiotherapy (RT), causing resistance to therapy. Thus, we analyzed autophagy-related genes using public databases to investigate a novel prognostic autophagy signature for glioblastoma patients who received temozolomide (TMZ) and RT. The TCGA and CGGA RNA sequencing datasets were classified for TMZ/RT-treated patient groups, and autophagy-related genes were obtained from Human Autophagy Database (HADb). Through sequential analyses of the datasets using univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) Cox regression analysis, and log-rank test, four genes (ATG9B, HSPA5, ITGA3, and RAC1) were selected to construct a prognostic risk score model. Multivariate Cox regression analysis of the risk score of these genes in the TCGA dataset demonstrated that TMZ/RT-treated patients with high-risk scores had significantly poorer overall survival and progression-free survival. Most patients designated as a high-risk group were also identified as IDH wild-type and mesenchymal subtypes. The autophagy signature was also validated in the CGGA RNA sequencing dataset and TCGA microarray dataset. Functional analysis of the autophagy signature through gene set enrichment and gene ontology analyses revealed enrichment of cellular responses to stress and the unfolded protein response. We also validated the higher expression of these genes and autophagy flux in TMZ-resistant glioblastoma cells than in TMZ-sensitive cells. Therefore, the autophagy-related gene set could serve as an independent prognostic biomarker for predicting the response to standard therapy in glioblastoma patients.

Triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC) are aggressive malignancies characterized by uncontrolled tumor growth, high recurrence rates, and resistance to chemotherapy. OZ-001 is a small molecule with a dual mechanism of action targeting T-type Ca2+ channels and inhibiting activation of the signal transducer and activator of transcription 3 (STAT3) protein. These properties suggest a potential use as a therapeutic agent for TNBC and PDAC, addressing the urgent need for effective treatments. This study evaluates the anticancer efficacy and underlying mechanism of action of OZ-001. The anticancer activities of OZ-001 were assessed in MDA-MB-231 cells (against TNBC) and MIA PaCa-2 cells (against PDAC) through analyses of cell viability, apoptosis, protein characterization, and cell cycles. Protein affinity and intracellular calcium measurements were conducted to investigate its effects on STAT3 and T-type calcium channels. Xenograft animal models were developed using MDA-MB-231 and MIA PaCa-2 cells to evaluate the in vivo anticancer effects of OZ-001. We found that OZ-001 induced caspase-dependent MDA-MB-231 and MIA PaCa-2 cells by modulating Bcl-2 family proteins. It suppressed STAT3 phosphorylation, reducing the expression of survivin, Bcl-2, and cyclin D1. Specifically, OZ-001 blocked T-type calcium channels, which reduced intracellular calcium levels and activated apoptotic pathways. In vivo, oral administration of OZ-001 significantly reduced tumor growth in both xenograft models, likely due to diminished STAT3 phosphorylation and associated tumorigenic processes. These findings demonstrate the potential of OZ-001 to serve as an effective therapeutic agent for treating TNBC and PDAC.

This comprehensive review explores the relationship between prenatal exposure to particulate matter (PM) air pollution and the development of various neuropsychiatric disorders in offspring. Air pollution, specifically by PM, is a global health concern, with PM_2.5 and PM₁₀ being the most detrimental to health. This review delves into the impact of prenatal PM exposure on neurodevelopment and the onset of disorders such as cognitive impairment, Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD), anxiety, depression, and schizophrenia. Utilizing data from international databases and focusing on full-text research papers from 2013 to 2023, we identified 18 relevant studies that explore the association between prenatal PM exposure and subsequent neuropsychiatric outcomes. The review discusses the potential mechanisms underlying these associations, including systemic inflammation, oxidative stress, and disruptions in the gut-brain axis. Key findings include the detrimental effects of PM exposure on fetal brain development, leading to cognitive deficits, heightened risk of ASD, ADHD, and altered mental health outcomes. Moreover, the review highlights the need for further research to unravel the complex interplay of genetic, environmental, and individual factors in the development of these disorders. The implications of these findings underscore the importance of reducing air pollution exposure, particularly during pregnancy, to safeguard fetal brain development and prevent neuropsychiatric disorders in offspring.