Journal of Receptors and Signal Transduction最新文献

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.

Colorectal cancer (CRC) exhibits high morbidity and mortality worldwide. Targeting protein for Xenopus kinesin-like protein 2 (TPX2) impacts various cancers; however, mechanism of TPX2 in CRC remains unclear. Xenograft nude mouse models were constructed by subcutaneous injection of HCT116 cells with sh-NC, sh-TPX2, OE-NC, and OE-TPX2 transfection. Following the test of tumor growth, immunohistochemistry and TUNEL staining were done. In vitro, HCT116, RKO, and SW480 cells were divided into sh-NC, sh-TPX2, and sh-TPX2 + 3-methyladenine (3-MA, autophagy inhibitor) groups. Further, sh-p53 and rapamycin (RA, autophagy agonist) were added in HCT116 cells. EdU staining, flow cytometry, transparent electron microscopy, and Western blot were performed. Comparing with sh-NC group, sh-TPX2 inhibited tumor growth and Ki67 expression, and increased LC3-II expression and apoptosis, whereas OE-TPX2 group presented an opposite trend. In vitro, HCT116 and RKO cells in sh-TPX2 group enhanced apoptosis and LC3 II/LC3 I expression, and inhibited proliferation and P62 expression, which were reversed after further 3-MA intervention. The above results were not found in SW480 cells. Moreover, compared to sh-TPX2 group, sh-TPX2 + RA group enhanced apoptosis and autophagy, and suppressed the proliferation of HCT116 cells, which were reversed following further sh-p53 intervention. Therefore, sh-TPX2 mediated p53 activation to induce autophagy for anti-CRC effects, providing new ideas for CRC treatment.

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_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.

Objectives: This study explores the relationship between immune recognition diversity and colorectal cancer (CRC) risk using a bidirectional Mendelian randomization approach.

Methods: 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.

Results: 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, p = .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, p = .0095), indicating a protective effect. Sensitivity analyses confirmed no pleiotropic effects.

Conclusions: 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.

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.

Gastric cancer (GC) is one of the major cancers of the digestive system, ranking fifth in both incidence and cancer-related mortality worldwide. However, the molecular mechanisms underlying the occurrence and progression of GC remain elusive. By analyzing differentially expressed genes (DEGs) using datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we identified that MFAP2 mRNA is significantly overexpressed in GC tissues, and higher MFAP2 expression is associated with poorer prognosis in GC patients. Gain- and loss-of-function experiments confirmed that MFAP2 promotes the proliferation of MKN45 using CCK8 assays and colony formation assays. Mechanistically, bioinformatics analysis revealed that MFAP2 could activate the PI3K/AKT signaling pathway, which was further validated by rescue experiments. Finally, we confirmed that MFAP2 also promotes the proliferation of GC cells in vivo by subcutaneous xenograft model in BABL/c mice. Our study provided new insights for the early diagnosis and precision treatment of GC.

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.

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.

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.

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 (p < 0.0001). 40% SASP was successful in inducing oxidative stress and increased mitochondrial density, whilst reducing membrane potential following 48 h of incubation (p < 0.0001) and blocking NF-κβ, restored glucose utilization (p < 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 (p < 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.