Biomolecules & Therapeutics最新文献

{"title":"Quercetin-3-Methyl Ether Induces Early Apoptosis to Overcome HRV1B Immune Evasion, Suppress Viral Replication, and Mitigate Inflammatory Pathogenesis.","authors":"Jae-Hyoung Song, Seo-Hyeon Mun, Sunil Mishra, Seong-Ryeol Kim, Heejung Yang, Sun Shim Choi, Min-Jung Kim, Dong-Yeop Kim, Sungchan Cho, Youngwook Ham, Hwa-Jung Choi, Won-Jin Baek, Yong Soo Kwon, Jae-Hoon Chang, Hyun-Jeong Ko","doi":"10.4062/biomolther.2024.204","DOIUrl":"10.4062/biomolther.2024.204","url":null,"abstract":"<p><p>Human rhinovirus (HRV) causes the common cold and exacerbates chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease. Despite its significant impact on public health, there are currently no approved vaccines or antiviral treatments for HRV infection. Apoptosis is the process through which cells eliminate themselves through the systematic activation of intrinsic death pathways in response to various stimuli. It plays an important role in viral infections and serves as a key immune defense mechanism in the interactions between viruses and the host. In the present study, we investigated the antiviral effects of quercetin-3-methyl ether, a flavonoid isolated from <i>Serratula coronata</i>, on human rhinovirus 1B (HRV1B). Quercetin-3-methyl ether significantly inhibited HRV1B replication in HeLa cells in a concentration-dependent manner, thereby reducing cytopathic effects and viral RNA levels. Time-course and time-of-addition analyses confirmed that quercetin-3-methyl ether exhibited antiviral activity during the early stages of viral infection, potentially targeting the replication and translation phases. Gene expression analysis using microarrays revealed that pro-apoptotic genes were upregulated in quercetin-3-methyl ether-treated cells, suggesting that quercetin-3-methyl ether enhances early apoptosis to counteract HRV1B-induced immune evasion. <i>In vivo</i> administration of quercetin-3-methyl ether to HRV1B-infected mice significantly reduced viral RNA levels and inflammatory cytokine production in the lung tissues. Our findings demonstrated the potential of quercetin-3-methyl ether as a novel antiviral agent against HRV1B, thereby providing a promising therapeutic strategy for the management of HRV1B infections and related complications.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"388-398"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Primed Mesenchymal Stem Cells by IFN-γ and IL-1β Ameliorate Acute Respiratory Distress Syndrome through Enhancing Homing Effect and Immunomodulation.","authors":"Taeho Kong, Su Kyoung Seo, Yong-Seok Han, Woo Min Seo, Bokyong Kim, Jieun Kim, Young-Jae Cho, Seunghee Lee, Kyung-Sun Kang","doi":"10.4062/biomolther.2025.004","DOIUrl":"10.4062/biomolther.2025.004","url":null,"abstract":"<p><p>Acute Respiratory Distress Syndrome (ARDS) is a severe condition characterized by extensive lung inflammation and increased alveolar-capillary permeability, often triggered by infections or systemic inflammatory responses. Mesenchymal stem cells (MSCs)-based therapy holds promise for treating ARDS, as MSCs manifest immunomodulatory and regenerative properties that mitigate inflammation and enhance tissue repair. Primed MSCs, modified to augment specific functionalities, demonstrate superior therapeutic efficacy in targeted therapies compared to naive MSCs. This study explored the immunomodulatory potential of MSCs using mixed lymphocyte reaction (MLR) assays and co-culture experiments with M1/M2 macrophages. Additionally, RNA sequencing was employed to identify alterations in immune and inflammation-related factors in primed MSCs. The therapeutic effects of primed MSCs were assessed in an LPS-induced ARDS mouse model, and the underlying mechanisms were investigated through spatial transcriptomics analysis. The study revealed that MSCs primed with IFN-γ and IL-1β significantly enhanced the suppression of T cell activity compared to naive MSCs, concurrently inhibiting TNF-α while increasing IL-10 production in macrophages. Notably, combined treatment with these two cytokines resulted in a significant upregulation of immune and inflammation-regulating factors. Furthermore, our analyses elucidated the mechanisms behind the therapeutic effects of primed MSCs, including the inhibition of inflammatory cell infiltration in lung tissue, modulation of immune and inflammatory responses, and enhancement of elastin fiber formation. Signaling pathway analysis confirmed that efficacy could be enhanced by modulating NFκB and TNF-α signaling. In conclusion, in early-phase ARDS, primed MSCs displayed enhanced homing capabilities, improved lung function, and reduced inflammation.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"311-324"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective Effect of β-Lapachone against Glutamate-Induced Injury in HT22 Cells.","authors":"Hae Rim Lee, Hye Jin Jee, Yi-Sook Jung","doi":"10.4062/biomolther.2024.241","DOIUrl":"10.4062/biomolther.2024.241","url":null,"abstract":"<p><p>While glutamate, a key neurotransmitter in the central nervous system, is fundamental to neuronal viability and normal brain function, its excessive accumulation leads to oxidative stress, contributing to neuronal damage and neurodegenerative diseases. In this study, we investigated the effect of β-lapachone (β-Lap), a naturally occurring naphthoquinone, on glutamate-induced injury in HT22 cells and explored the underlying mechanism involved. Our results show that β-Lap significantly improved cell viability in a dose-dependent manner. Additionally, β-Lap exhibited a significant antioxidant activity, reducing intracellular reactive oxygen species levels and restoring glutathione levels. The antioxidant capacity of β-Lap was further demonstrated through 2,2-Diphenyl- 1-picrylhydrazyl (DPPH) and 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radical scavenging assays. Western blot analysis revealed that β-Lap upregulated brain-derived neurotrophic factor (BDNF) and promoted the phosphorylation of tropomyosin receptor kinase B (TrkB), extracellular signal-regulated kinase (ERK), and cAMP response elementbinding protein (CREB), which were downregulated by glutamate. Furthermore, β-Lap enhanced the cellular antioxidant molecules, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). In conclusion, β-Lap can protect HT22 cells against glutamate-induced injury by activating the BDNF/TrkB/ERK/CREB and ERK/Nrf2/HO-1 signaling pathways, suggesting its therapeutic potential for neurodegenerative diseases.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"286-296"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-Activity Relationship of NMDA Receptor Ligands and Their Activities on the ERK Activation through Metabotropic Signaling Pathway.","authors":"Dooti Kundu, Mengling Wang, Suresh Paudel, Shujie Wang, Choon-Gon Jang, Kyeong-Man Kim","doi":"10.4062/biomolther.2024.216","DOIUrl":"10.4062/biomolther.2024.216","url":null,"abstract":"<p><p>The N-methyl-D-aspartate receptor (NMDA-R) subunit GluN2B is abundantly expressed in brain regions critical for synaptic plasticity and cognitive processes. This study investigated the structure-activity relationships (SAR) of NMDA-R ligands using GluN2B as a molecular target. Thirty potential NMDA-R antagonists were categorized into two structural classes: 1-(1-phenylcyclohexyl) amines (series A) and α-amino-2-phenylcyclohexanone derivatives (series B). In series A compounds, the phenyl ring and R1 substituents were positioned at the carbon center of the cyclohexyl ring, with R2 substituents at the para- or meta-positions of the phenyl ring. SAR analysis revealed optimal binding affinity when R1 was carbonyl (C=O) and R2 was 4-methoxy (4-OMe). Series B compounds featured a cyclohexanone scaffold with NH-R1 at the α-position and a phenyl ring bearing R2 substituents at ortho-, meta-, or para-positions. Maximum binding affinity was achieved with R1 as hydrogen (H) and R2 as hydroxyl (OH). Compounds were assessed for GluN2B-mediated ERK activation to evaluate potential metabotropic signaling properties. Approximately 50% of the compounds demonstrated ERK activation through a non-ionotropic signaling cascade involving Src, phosphatidylinositol 3-kinase, and protein kinase C. This study elucidated key structural determinants for NMDA-R binding and characterized a novel metabotropic signaling pathway. Notably, our findings suggest that compounds acting as antagonists at the ionotropic site may simultaneously function as agonists through non-ionotropic mechanisms.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"278-285"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pro-Oxidative and Inflammatory Actions of Extracellular Hemoglobin and Heme: Molecular Events and Implications for Alzheimer's and Parkinson Disease.","authors":"Nicole Bon Campomayor, Hee Jin Kim, Mikyung Kim","doi":"10.4062/biomolther.2024.224","DOIUrl":"10.4062/biomolther.2024.224","url":null,"abstract":"<p><p>Hemoglobin (Hb) and heme, which are typically confined within red blood cells (RBCs), are essential for intravascular transport of gases and nutrients. However, these molecules acquire secondary functions upon exposure to the extracellular environment. Hb and heme generate reactive oxygen species (ROS), which are potent pro-inflammatory agents that contribute to oxidative stress and cellular damage. These events are relevant to neurodegenerative processes, where oxidative stress, irregular deposition of protein aggregates, and chronic inflammation are key pathological features. Extracellular Hb, heme, and oxidative stress derived from hemorrhagic events or RBC lysis may contribute to increased blood-brain barrier (BBB) permeability. These events allow Hb and heme to interact with neuroimmune cells and pathological protein aggregates, further amplifying pro-inflammatory signaling and the progression of Alzheimer's disease (AD) and Parkinson disease (PD). Chronic neuroinflammation, oxidative stress, and mitochondrial dysfunction lead to neuronal degeneration. Here, we sought to elucidate the pro-oxidative and inflammatory actions of extracellular Hb and heme, emphasizing their potential impact on AD and PD development.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"235-248"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Histone Deacetylase 6 Inhibitor, 4-FHA, Improves Scopolamine-Induced Cognitive and Memory Impairment in Mice.","authors":"Jee-Yeon Seo, Jisoo Kim, Yong-Hyun Ko, Bo-Ram Lee, Kwang-Hyun Hur, Young Hoon Jung, Hyun-Ju Park, Seok-Yong Lee, Choon-Gon Jang","doi":"10.4062/biomolther.2024.110","DOIUrl":"10.4062/biomolther.2024.110","url":null,"abstract":"<p><p>Although histone deacetylase 6 (HDAC6) is considered a therapeutic target for Alzheimer's disease (AD), its role in cholinergic dysfunction in AD patients remains unclear. This study investigated the effects of (<i>E</i>)-3-(2-(4-fluorostyryl)thiazol-4-yl)-<i>N</i>-hydroxypropanamide (4-FHA), a new synthetic HDAC6 inhibitor, on cognitive and memory impairments in a scopolamine-induced-AD mouse model. Behaviorally, 4-FHA improved scopolamine-induced memory impairments in the Y-maze, passive avoidance, and Morris water maze tests. In addition, 4-FHA ameliorated scopolamine-induced cognitive impairments in the novel object recognition and place recognition tests. Furthermore, 4-FHA increased acetylation of α-tubulin (a major HDAC6 substrate); the expression of BDNF; and the phosphorylation of ERK 1/2, CREB, and ChAT in the hippocampus of scopolamine-treated mice. In summary, according to our data 4-FHA, an HDAC6 inhibitor, improved the cognitive and memory deficits of the AD mouse model by normalizing BDNF signaling and synaptic transmission, suggesting that 4-FHA might be a potential therapeutic candidate for AD.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"268-277"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Licochalcone D Exerts Antitumor Activity in Human Colorectal Cancer Cells by Inducing ROS Generation and Phosphorylating JNK and p38 MAPK.","authors":"Seung-On Lee, Sang Hoon Joo, Seung-Sik Cho, Goo Yoon, Yung Hyun Choi, Jin Woo Park, Kwon-Yeon Weon, Jung-Hyun Shim","doi":"10.4062/biomolther.2024.123","DOIUrl":"10.4062/biomolther.2024.123","url":null,"abstract":"<p><p>Anticancer activities of Licochalcone D (LCD) in human colorectal cancer (CRC) cells HCT116 and oxaliplatin-resistant HCT116 (HCT116-OxR) were determined. Cell viability assay and soft agar assay were used to analyze antiproliferative activity of LCD. Flow cytometry was performed to determine effects of LCD on apoptosis, cell cycle distribution, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) dysfunction, and multi-caspase activity in CRC cells. Western blot analysis was used to monitor levels of proteins involved in cell cycle and apoptosis signaling pathways. LCD suppressed the growth and anchorageindependent colony formation of both HCT116 and HCT116-OxR cells. Cell cycle analysis by flow cytometry indicated that LCD induced cell cycle arrest and increased cells in sub-G1 phase. In parallel with the antiproliferative effect of LCD, LCD up-regulated levels of p21 and p27 while downregulating cyclin B1 and cdc2. In addition, phosphorylation levels of JNK and p38 mitogen-activated protein kinase (MAPK) were increased by LCD. Inhibition of these kinases somehow prevented the antiproliferative effect of LCD. Moreover, LCD increased ROS and deregulated mitochondrial membrane potential, leading to the activation of multiple caspases. An ROS scavenger N-acetyl-cysteine (NAC) or pan-caspase inhibitor Z-VAD-FMK prevented the antiproliferative effect of LCD, supporting that ROS generation and caspase activation mediated LCD-induced apoptosis in CRC cells. In conclusion, LCD exerted antitumor activity in CRC cells by inducing ROS generation and phosphorylation of JNK and p38 MAPK. These results support that LCD could be further developed as a chemotherapeutic agent for treating CRC.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"344-354"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Amphibians-Derived Protein Provides Novel Biotherapeutics for Various Wounds Treatment.","authors":"Hao-Ran Chen, Nan Zhou, Yu-Da Liu, Li-Hua Peng","doi":"10.4062/biomolther.2024.096","DOIUrl":"10.4062/biomolther.2024.096","url":null,"abstract":"<p><p>Acute burns and chronic wounds frequently fail to heal owing to various reasons. Most drugs currently used for wound therapy in clinical practice have notable drawbacks, making their application a substantial concern. For instance, anti-inflammatory drugs can exert multisystem toxicity, and cellular therapies are costly and difficult to retain. In recent years, natural functional proteins derived from animals and plants have gained increasing attention owing to their unique biological activities, low cost, and broad application prospects in wound therapy. Herein, we isolated a new protein (JH015Y) from amphibians and demonstrated its excellent wound repair and regeneration properties compared with those of epidermal growth factor, both <i>in vitro</i> and <i>in vivo</i>. JH015 protein increased the proliferative ability of human keratinocytes and skin fibroblasts by 47.73 and 41.40%, respectively. <i>In vivo</i>, the medium-dose (0.5 mg/dose) groups of JH015Y protein demonstrated accelerated wound healing from day 4, with wound healing rates 1.26, 1.27, and 1.14 times that of the blank group in acute wounds, burn wounds, and diabetic ulcer, respectively. Histological analysis of Masson-stained sections indicated that the JH015Y protein contributed to collagen deposition on the wound surface, markedly reduced inflammatory cell infiltration, and exhibited low biological toxicity. Accordingly, the JH015Y protein is a promising biotherapeutic agent for accelerated wound repair and regeneration.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"399-407"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Galangin Regulates Mucin 5AC Gene Expression via the Nuclear Factor-κB Inhibitor α/Nuclear Factor-κB p65 Pathway in Human Airway Epithelial Cells.","authors":"Rajib Hossain, Hyun Jae Lee, Choong Jae Lee","doi":"10.4062/biomolther.2024.140","DOIUrl":"10.4062/biomolther.2024.140","url":null,"abstract":"<p><p>In this study, we investigated the effects of the flavonoid galangin on the expression of the mucin 5AC (<i>MUC5AC</i>) gene in airway cells. Human pulmonary epithelial NCI-H292 cells were pretreated with galangin for 30 min and then stimulated with phorbol 12-myristate 13-acetate (PMA) for 24 h. We also examined the effects of galangin on the PMA-induced nuclear factor-κB (NF-κB) signaling pathway. Galangin inhibited the production of glycoproteins and the expression of <i>MUC5AC</i> mRNA induced by PMA via prevention of NF-κB inhibitor α degradation and NF-κB p65 nuclear translocation. These findings indicated that galangin suppressed mucin gene expression by modulating the NF-κB signaling pathway in human pulmonary epithelial cells.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"325-330"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isoliquiritigenin Induces Apoptosis via ROS-Mediated Inhibition of p38/mTOR/STAT3 Pathway in Human Melanoma Cells.","authors":"Mi Jeong Kwon, Pawan Kumar Raut, Jeong-Hoon Jang, Kyung-Soo Chun","doi":"10.4062/biomolther.2024.118","DOIUrl":"10.4062/biomolther.2024.118","url":null,"abstract":"<p><p>Isoliquiritigenin (ISL), a phenolic compound derived from licorice, exhibits various biological activities, including anti-inflammatory, anti-viral, anti-tumor, and antioxidant effects. However, the molecular mechanisms underlying its anti-cancer effects are not well understood in SK-MEL-28 melanoma cells. Melanoma, a highly aggressive and treatment-resistant cancer, remains a significant health challenge. This study investigates the anti-cancer effects of ISL, focusing on identifying reactive oxygen species (ROS)-mediated apoptosis mechanisms on SK-MEL-28 melanoma cells. Our results show that ISL treatment induces apoptosis in SK-MEL-28 cells, as evidenced by the cleavage of caspase-9, -7, -3, and PARP. ISL increased Bax expression, decreased Bcl-2 expression, and promoted cytochrome C release into the cytosol. ISL also reduced the expression of cell cycle markers, including cyclin D1, D3, and survivin. Notably, ISL treatment markedly increased intracellular ROS levels and pretreatment with N-acetyl cysteine, a ROS scavenger, abrogated the ISL-induced inhibition of the p38/mTOR/STAT3 pathway and prevented apoptosis. Moreover, ISL significantly diminished the constitutive phosphorylation of mTOR and STAT3 in SK-MEL-28 cells by blocking the phosphorylation of p38 MAPK, an upstream kinase of mTOR. Pharmacological inhibition of mTOR attenuated the STAT3 signaling, indicating that mTOR acts as an upstream kinase of STAT3 in these cells. Collectively, these findings demonstrate that ISL inhibits SK-MEL-28 cell growth by downregulating cell survival proteins and inducing apoptosis through ROS generation.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"378-387"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}