Journal of Receptors and Signal Transduction最新文献

{"title":"Regulation of elevated expression of Mcl-1 in hepatocellular carcinoma - a review.","authors":"Li Chen, Yuwei He, Xudong Jiang, Audrey Siew Foong Kow, Yu Zhao Lee, Chau Ling Tham, Rohana Yusof, Ming Tatt Lee","doi":"10.1080/10799893.2025.2503393","DOIUrl":"https://doi.org/10.1080/10799893.2025.2503393","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide. Mcl-1 (myeloid cell leukemia-1) is highly expressed in HCC cells and plays a critical role in chemotherapy resistance and is a major contributor to chemotherapy failure in HCC. The purpose of this study is to review the recent research progress that explores the key factors in regulating Mcl-1 overexpression in HCC cells, contributing to chemotherapy resistance. The related studies from the past decade on agents targeting Mcl-1 to inhibit HCC were also reviewed to provide insights into overcoming chemotherapy resistance in HCC. Mcl-1 overexpression in HCC is mainly regulated by transcription factors (such as STAT3, p53), non-coding RNAs (such as miRNA, lncRNA), cell cycle proteins, mitochondrial dynamics, and the hypoxic microenvironment. Targeting Mcl-1, alongside multi-target combination therapies, may overcome HCC chemotherapy resistance and improve outcomes. Future research should focus on strategies addressing multiple pathways to minimize monotherapy resistance risks and offer enhanced treatment options for the betterment of human health.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"1-11"},"PeriodicalIF":2.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and molecular mechanism investigation of ALK inhibitors based on virtual screening and structural descriptor modeling.","authors":"Ya-Kun Zhang, Jian-Bo Tong, Yue Sun, Jia-Le Li, Qi Hou","doi":"10.1080/10799893.2025.2503386","DOIUrl":"https://doi.org/10.1080/10799893.2025.2503386","url":null,"abstract":"<p><p>To address the challenges of target specificity and drug resistance in Anaplastic lymphoma kinase (ALK) inhibition, this study conducted a virtual screening of the BindingDB database, yielding 711 potential ALK inhibitors. Four QSAR models were established using structural clustering and machine learning to elucidate structure-activity relationships. Through substituent fragment optimization, 72 highly active compounds were designed, among which four promising candidates were identified based on ADMET predictions, retrosynthetic analyses and molecular docking analyses. Molecular dynamics simulations and binding free energy calculations further characterized their binding mechanisms. These findings provide a theoretical framework for the rational design of next-generation ALK inhibitors.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"1-14"},"PeriodicalIF":2.6,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the association of cell-surface proteins (ACE2 and GRP78) facilitating pathogen recognition: a computational approach.","authors":"Wael M Elshemey, Ibrahim M Ibrahim, Abdo A Elfiky","doi":"10.1080/10799893.2025.2502383","DOIUrl":"https://doi.org/10.1080/10799893.2025.2502383","url":null,"abstract":"<p><p>Angiotensin-converting enzyme 2 (ACE2) has been reported to be the primary host cell receptor for recognizing SARS-CoV and SARS-CoV-2 spike proteins. This host-cell element, despite having a crucial role in normal cells, may be hijacked by viruses to invade human cells. It has been reported that ACE2 trafficking to the cell membrane is mediated by other cellular factors, such as the endoplasmic reticulum resident chaperone, named glucose-regulated protein 78 (GRP78). GRP78 is the master of the unfolded protein response during cellular stress. This study uses sequence alignment, protein-protein docking, and molecular dynamics simulation (MDS) to predict the potential binding sites between the two proteins for the first time aiming to understand its role in viral recognition and infection. Results revealed three critical regions in ACE2 (C133-C141, C344-C361, and C530-C542), that could be the recognition site for GRP78 from which, the second region (C344-C361) is the suggested best region based on protein-protein docking, MDS, and MM-GBSA calculations. These cyclic regions show similarity (<38% identity) with the cyclic peptide Pep42, which is previously reported to target GRP78 over cancer cells. This approach paves the way toward suggesting potential inhibitors based on the prevention of the association between ACE2 and GRP78.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"1-7"},"PeriodicalIF":2.6,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying potent Janus kinase 3 inhibitors using structure-guided virtual screening for inflammatory and neoplastic disease therapy.","authors":"Mohammad Y Alshahrani, Ali G Alkhathami, Mohammad Asiri, Saad Ali Alshehri, Nazim Nasir, Shadma Wahab","doi":"10.1080/10799893.2025.2497546","DOIUrl":"https://doi.org/10.1080/10799893.2025.2497546","url":null,"abstract":"<p><p>Janus kinases (JAKs) are potential therapeutic targets for anti-inflammatory and anti-cancer agents due to their involvement in cytokine signaling and cell proliferation. One of the major issues in the development of JAK inhibitors is the problem of selectivity for certain isoforms; since the isoforms are highly homologous, selective targeting is difficult. Of the JAKs, Janus kinase 3 (JAK3) which is mainly found in immune cells, is the most suitable isoform to target selectively to enhance the efficacy of treatment. In this study, we used a structure-based virtual screening method to screen PubChem for high-affinity JAK3 inhibitors using known JAK3-inhibitor complex structures. Through stringent filtering criteria, including structural similarity, physicochemical properties, and molecular interactions, we identified two promising compounds, CID:68715657 and CID:68585456, which showed potential JAK3 inhibition activity. These compounds showed better binding affinity than the parent molecules, and the structural modifications also improved the interaction with JAK3, indicating better potency and selectivity. Molecular dynamics (MD) simulations and MM-PBSA confirmed the stability of JAK3 complexes with CID:68715657 and CID:68585456, which further support their prospect as therapeutic targets of JAK3-related diseases. However, this study is limited by its reliance on computational predictions without experimental validation and the constraints of the PubChem database in capturing novel chemical scaffolds. Taken together, the results offer a sound basis for the further optimization of these compounds as highly effective and selective JAK3 inhibitors.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"1-12"},"PeriodicalIF":2.6,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the causal relationship between immune cells and colorectal cancer risk using bidirectional and multivariable Mendelian randomization analysis.","authors":"Jiajie Zhou, Yeliu Liu","doi":"10.1080/10799893.2025.2491068","DOIUrl":"https://doi.org/10.1080/10799893.2025.2491068","url":null,"abstract":"<p><strong>Objectives: </strong>This study explores the relationship between immune recognition diversity and colorectal cancer (CRC) risk using a bidirectional Mendelian randomization approach.</p><p><strong>Methods: </strong>Genetic data from 731 immune cell types were analyzed, with data sourced from the IEU and FinnGen databases and CRC data from genome-wide association studies on the Finnish population. Forward and reverse Mendelian randomization analyses were conducted, with sensitivity analyses to assess pleiotropic effects.</p><p><strong>Results: </strong>Analyses revealed a significant association between increased Effector Memory CD4 and CD8 T cells and higher CRC risk (odds ratio [OR] = 1.11, 95% confidence interval [CI] = 1.04-1.18, <i>p</i> = .0008). Conversely, elevated CD45 on natural killer T cells was associated with a lower CRC risk (OR = 0.93, 95% CI = 0.88-0.98, <i>p</i> = .0095), indicating a protective effect. Sensitivity analyses confirmed no pleiotropic effects.</p><p><strong>Conclusions: </strong>These findings highlight specific immune cells' roles in CRC pathogenesis, suggesting potential avenues for immune-targeted therapies and CRC prevention. Given the rising global incidence of CRC, understanding immune cell roles is crucial for advancing effective treatments.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"1-10"},"PeriodicalIF":2.6,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term spontaneous membrane currents in DRG neurons.","authors":"Sodikdjon A Kodirov, Vera B Plakhova, Owen P Hamill, Boris V Krylov","doi":"10.1080/10799893.2025.2477925","DOIUrl":"https://doi.org/10.1080/10799893.2025.2477925","url":null,"abstract":"<p><p>We have experimented with freshly isolated single DRG neurons from neonatal (P0-5) rats to study currents mediated by voltage dependent Na⁺ (Nav) channels. All experiments were performed using the whole-cell mode of patch-clamp electrophysiology and following the standard steps of this technique. However, in a subgroup of neurons, spontaneous events resembling neurotransmitter release were observed under conditions optimized for whole-cell patch-clamp recordings of <i>I</i>_Na. All events have a fast rise phase (similar to responses of receptor channels), but decay in a heterogeneous manner. The waveform of the event closely matches that of the response of the purinergic receptor P2X type to ATP. This new activity in neurons was observed at -60 mV and was facilitated during relatively strong hyperpolarization. Although spontaneous fluctuations, termed membrane potential instabilities, are described in DRG neurons, the observed inward currents at more hyperpolarized states are distinct and novel. The spontaneous heterogeneous activities could be relevant to the elucidation of pain mechanisms by distinct pharmacological tools.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"1-8"},"PeriodicalIF":2.6,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Focusing on Keap1, IKKβ, and Bcl2 proteins: predicted targets of stigmasterol in neurodegeneration.","authors":"Manoj Soni, Awadhesh Kumar, Rakesh Kumar, Mehak Dangi, Ajit Kumar, Vijay Kumar","doi":"10.1080/10799893.2025.2465243","DOIUrl":"10.1080/10799893.2025.2465243","url":null,"abstract":"<p><p>Oxidative stress, driven by excess ROS, damages lipids, proteins, and DNA, leading to neuronal apoptosis and inflammation, a key factor in neurodegenerative diseases. This study explored stigmasterol, a bioactive phytosterol, with neuroprotective potential, revealing strong docking interactions, especially with Keap1 (binding energy of -11.62 Kcal/mol). Stigmasterol formed two hydrogen bonds with Ile258 and Val305 in Keap1, suggesting it could disrupt Keap1-Nrf2 interactions, potentially activating antioxidant responses by promoting Nrf2 translocation to the nucleus. In the Bcl2-stigmasterol complex, which exhibited a binding energy of -8.41 Kcal/mol, hydrophobic interactions with residues Ser50, Gln52, and Leu185 stabilized the complex, indicating stigmasterol's role in inhibiting apoptosis by strengthening of Bcl2 mediated inhibition of pro-apoptotic factors like Bax. Furthermore, the IKKβ-stigmasterol complex displayed a hydrogen bond between Asp385 residue and stigmasterol (2.83 Å), with a binding energy of -8.33 Kcal/mol, suggested that stigmasterol may regulate inflammation by stabilizing IKKβ, thereby preventing NF-κB translocation and reducing inflammation. Molecular dynamics simulations confirmed the stability of stigmasterol's interactions, especially with Keap1, which showed low RMSD values and consistent hydrogen bonding. RMSF and Rg analyses indicated that stigmasterol had stabilizing effects on Bcl2 and IKKβ. These results underscore stigmasterol's potential for neuroprotection through antioxidant and anti-inflammatory actions.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"83-94"},"PeriodicalIF":2.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The influence of senescent associated secretory phenotype on glucose homeostasis in C2C12 muscle cells: insights into potential p38 inhibitor interventions.","authors":"Karan S Rana, Mandeep K Marwah, Farah N S Raja, Irundika Dias, Yukta Sameer Hindalekar, Mohamad Anas Al Tahan, James E Brown, Srikanth Bellary","doi":"10.1080/10799893.2025.2475441","DOIUrl":"10.1080/10799893.2025.2475441","url":null,"abstract":"<p><p>Increased accumulation of senescent cells with aging is associated with reduced ability of insulin-target tissues to utilize glucose, resulting in increased insulin resistance and glucotoxicity. We investigated the role of the senescent-associated secretory phenotype (SASP) within C2C12, skeletal muscle cells on glucose homeostasis and if such effects could be reduced by blocking pro-inflammatory pathways. C2C12 myotubes were treated with 40% conditioned media from senescent fibroblasts. Indirect glucose uptake and glycogen content were measured. The effect of SASP on the generation of reactive oxygen species [1] and mitochondrial function was also measured. The experiments above were repeated with a p38 inhibitor. 40% SASP treatment significantly decreased glucose utilization and glycogen storage within myotubes (<i>p</i> < 0.0001). 40% SASP was successful in inducing oxidative stress and increased mitochondrial density, whilst reducing membrane potential following 48 h of incubation (<i>p</i> < 0.0001) and blocking NF-κβ, restored glucose utilization (<i>p</i> < 0.01) despite the presence of SASP. Co-incubation of 40% SASP with an NF-κβ inhibitor eliminates excessive ROS production and restores mitochondrial activity to levels comparable to control treatment (<i>p</i> < 0.0001). This study shows changes in glucose homeostasis in senescent cells is mediated through SASP, and interventions aimed at mitigating pro-inflammatory pathways can potentially improve insulin resistance.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"118-127"},"PeriodicalIF":2.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FBXL14 inhibits foam cell formation and atherosclerosis plaque progression by activating the NRF2 signal axis through ubiquitination of DUSP6.","authors":"Wenjie Luo, Yubin Chen, Cheng Fang, Hui Shi, Fanyan Luo","doi":"10.1080/10799893.2025.2466689","DOIUrl":"10.1080/10799893.2025.2466689","url":null,"abstract":"<p><strong>Objectives: </strong>Atherosclerosis is characterized by persistent inflammatory condition, leading to various cardiovascular complications. Foam cell formation, resulting from macrophage uptake of oxidized low-density lipoprotein (ox-LDL), contributes significantly to atherosclerosis progression. This study was designed to investigate the involvement of bispecific phosphatase-6 (DUSP6) and its potential regulatory mechanisms in foam cell formation and atherosclerosis.</p><p><strong>Methods: </strong>We employed THP-1 cells to induce foam cell formation. The lipid droplet accumulation, cholesterol content, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels were evaluated using Oil Red O staining, cholesterol assay, ELISA, and qRT-PCR techniques. We investigated DUSP6 ubiquitination via immunoprecipitation and western blot (WB) analysis. A bioinformatics approach identified FBXL14 as a potential E3 ligase involved in DUSP6 ubiquitination, further confirmed by siRNA and overexpression experiments. The impact of FBXL14 on the NRF2 signaling pathway was assessed using WB analysis.</p><p><strong>Results: </strong>DUSP6 interference suppressed foam cell formation and inflammatory factor secretion. Upon ox-LDL treatment, DUSP6 underwent deubiquitylation, with FBXL14 emerging as the candidate E3 ligase. FBXL14 overexpression induced DUSP6 ubiquitination, leading to the NRF2 signaling pathway activation. It counteracted with DUSP6 overexpression on foam cell formation and inflammation. In ApoE-/- mice, sh-DUSP6 adenovirus injection mitigated atherosclerotic lesion progression and improved the lipid profile, with increased the proteins expression of NQO1, HO-1, and NRF2 in aortic tissue.</p><p><strong>Conclusion: </strong>DUSP6 and FBXL14 play vital roles in modulating foam cell formation and inflammatory responses in atherosclerosis. Targeting these molecules could offer therapeutic potential in attenuating atherosclerosis-related complications.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"107-117"},"PeriodicalIF":2.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influencing hair regrowth with EGCG by targeting glycogen synthase kinase-3β activity: a molecular dynamics study.","authors":"Hamid Raza Moqaddasi, Anshul Singh, Shoma Mukherjee, Fatima Rezai, Arti Gupta, Saurabh Srivastava, Sathvik Belagodu Sridhar, Irfan Ahmad, Vivek Dhar Dwivedi, Sandeep Kumar","doi":"10.1080/10799893.2025.2465240","DOIUrl":"10.1080/10799893.2025.2465240","url":null,"abstract":"<p><p>Hair follicle growth process through several well-organized stages with specific input by several signaling pathways including Wnt/β-catenin and Sonic Hedgehog with GSK3β in this process. As such, this research focus on investigating the efficacy of molecules that are able to inhibit GSK3β action in inducing hair regrowth. Applying computational techniques, three compounds NMN, Resveratrol and EGCG were analyzed for their GSK3β inhibition. It was established that EGCG has the highest values of molecular docking scores and, in the case of the stability criteria such as RMSD and RMSF, presented the most stable dynamic simulation. EGCG has shown considerable TEMPORAL STABILITY with GSK3β in the complex, because over a period of 200 nanoseconds the molecules remained bound through hydrogen bonds and hydrophobic contacts. As confirmed by PCA, the largest conformational changes in GSK3β suggest significant inhibitory interaction. Out of all the studied compounds, EGCG turns out to be the most potent GSK3β inhibitor for hair regrowth purposes. The result obtained from the molecular dynamics simulation indicates that EGCG might exert a favorable impact to extract signaling pathways related with hair follicle cycling which is a significant objective. These outcome sets the phase for further experimental testing to discover the potential of EGCG in the treatment of alopecia.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"95-106"},"PeriodicalIF":2.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}