Journal of Receptors and Signal Transduction最新文献

Objectives: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Clinical trial number: Not applicable.

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.

Heart failure (HF) is one of the leading causes of death from cardiovascular disease among adults worldwide. The role of sex hormone receptors in the pathogenesis of HF and their regulatory mechanisms remain unclear. This study focused on investigating the localization and expression of sex hormone receptors (ERα, ERβ, AR and PR) and calcium handling proteins (SERCA2a and Cav1.2) in the left ventricle (LV) tissues of patients with HF, and to investigate their interactions. The LV tissues of HF patients were collected, and the localization of sex hormone receptors and calcium handling proteins was detected by immunofluorescence and immunohistochemistry. Western blotting was performed to study the expression levels of sex hormone receptors and calcium handling proteins. The interactions between these proteins were identified by immunofluorescence co-location and immunoprecipitation respectively. Compared with the control group, the expression levels of sex hormone receptors and calcium handling proteins in HF patients were significantly decreased. There was co-localization and interaction between protein ERα and Cav1.2, protein AR and SERCA2a, respectively. In summary, sex hormone receptors may be involved in regulating the progression of HF by interacting with calcium handling proteins.

Regulating insulin production by pancreatic beta cells is crucial for maintaining metabolic balance. Previous studies observed elevated neurotransmitter levels, like norepinephrine (NE), in metabolic syndrome mice with impaired insulin secretion. Given the therapeutic potential of β-adrenergic receptors (β-ARs) for diabetes and obesity, and the lack of structural data on murine β-ARs, we aimed to construct and validate 3D models to investigate their roles in insulin secretion regulation. We constructed high-quality 3D models for murine β1-AR, β2-AR, and β3-AR using Phyre2 and Ramachandran plot analysis. Molecular docking revealed NE's strong binding affinity for all three β-AR subtypes through favorable docking scores and hydrogen bond formations. We evaluated the physiological impact of NE on glucose-induced insulin secretion via β-ARs under physiological and elevated glucose conditions using pancreatic islets from C57BL/6J mice. At physiological glucose levels, NE did not significantly increase insulin secretion. However, higher NE concentrations suppressed insulin release at elevated glucose. The β3-AR agonist CL316243 significantly increased (p < 0.01), insulin secretion under normal and hyperglycemic conditions, while the β3-AR antagonist L748337 substantially decreased (p < 0.01)insulin release under normal glucose, confirming their interactions through docking studies. The nonselective β-AR antagonist propranolol significantly decreased (p < 0.01)insulin secretion, suggesting alternative interactions with β1-AR and β2-AR despite lacking hydrogen bonds. Our study enhances the understanding of NE's role in modulating insulin secretion and underscores the significance of β-ARs, especially β3-AR, in its regulation, providing valuable insights for potential therapeutic interventions targeting these receptors in metabolic disorders.

Lysyl oxidase (LOX), a copper-containing secretory oxidase, plays a key role in the regulation of extracellular stiffness through cross-linking with collagen and elastin. Among the LOX family of enzymes, LOX-like 4 (LOXL4) exhibits pro-tumor and anti-tumor properties; therefore, the functional role of LOXL4 in tumor progression is still under investigation. Here, we first determined that transforming growth factor-β1 (TGF-β1) significantly decreased LOXL4 expression in human breast cancer MDA-MB-231 cells, which suggested that decreased LOXL4 may participate in tumor progression. In this study, we also investigated how TGF-β1 decreases LOXL4 expression. TGF-β1-induced intracellular reactive oxygen species (ROS) played a role in LOXL4 protein expression but had no effect on LOXL4 mRNA levels. The proteasomal inhibitor, bortezomib, significantly suppressed TGF-β1-mediated LOXL4 reduction, which indicated that TGF-β1 facilitates LOXL4 proteasomal degradation. Furthermore, bortezomib inhibited TGF-β1-induced MEK/ERK pathways which are involved in LOXL4 reduction and TGF-β1-mediated cell migration. Finally, we also determined the potential role of N-glycosylation in LOXL4 secretion. We found that the dysregulation of N-glycosylation may be involved in the reduction in LOXL4 secretion. Overall, bortezomib is expected to inhibit TNBC progression by inhibiting both the MEK/ERK and proteasomal degradation pathways, which regulate LOXL4 expression.

Serotonin (5-HT) is a neurotransmitter found throughout the human body that regulates many physiological events arising from the brain and central nervous system (CNS), such as sleep and appetite. However, it has many other functions in systems outside. In addition to the routine expression of 5-HT7 receptors in CNS regions, such as the pituitary gland, spinal cord, and hippocampus, many studies have reported the expression of these receptors in pathological conditions outside. The role of 5-HT7 receptors outside the CNS has been attracting increased attention in recent years. This review highlights the fact that 5-HT7 receptors are associated with diseases and systems beyond the CNS increasing or decreasing in response to cellular changes. Clinical, basic, in vivo and in vitro studies to date are described, but more research is needed to better understand the role of 5-HT7 receptors outside the CNS.

USP5 is widely distributed in various malignant tumors and can regulate the stability and promoting tumor progression of many tumor-related proteins. However, there is still a lack of highly active USP5 inhibitors. Therefore, effective inhibitors were screened in the TCMIO database in this study. Three hit compounds, CHEMBL3645368, CHEMBL3689818, and CHEMBL2070208, were finally obtained by molecular docking, molecular fingerprint, quantum chemistry, and molecular dynamics simulation. Molecular docking results showed hit compounds had similar binding mode comparing with positive compound. Quantum chemistry and molecular dynamics results showed hit compounds had better binding energy and higher affinity than the positive compound. ADMET predicted hit compounds had low toxicity. These results all suggest CHEMBL3645368, CHEMBL3689818, and CHEMBL2070208 may inhibit USP5 and could be candidates for further exploration.

CDK12 is essential for cellular processes like RNA processing, transcription, and cell cycle regulation, inhibiting cancer cell growth and facilitating macrophage invasion. CDK12 is a significant oncogenic factor in various cancers, including HER2-positive breast cancer, Anaplastic thyroid carcinoma, Hepatocellular carcinoma, prostate cancer, and Ewing sarcoma. It is also regarded as a potential biomarker, emphasizing its broader significance in oncology. Targeting CDK12 offers a promising strategy to develop therapy. Various monoclonal antibodies have drawn wide attention, but they are expensive compared to small-molecule inhibitors, limiting their accessibility and affordability for patients. Consequently, this research aims to identify effective CDK12 inhibitors using comprehensive high-throughput virtual screening. RASPD protocol has been employed to screen three different databases against the target followed by drug-likeness, molecular docking, ADME, toxicity, Consensus molecular docking, MD Simulation, and in-vitro studies MTT assay. The research conducted yielded one compound ZINC11784547 has demonstrated robust binding affinity, favorable ADME features, less toxicity, remarkable stability, and cytotoxic effect. The identified compound holds promise for promoting cancer cell death through CDK12 inhibition.

The proliferative effects of angiotensin (Ang) II in vascular smooth muscle cells (VSMCs) through its ability to stimulate extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway have been established. The main goal of this study was to explore whether Ang III induces ERK1/2 MAPK and VSMC proliferation in cultured Wistar VSMCs. Further, the Ang III actions were compared to those observed in VSMCs derived from the spontaneously hypertensive rat (SHR). We hypothesized that in VSMCs Ang III will have similar actions as Ang II to induce ERK1/2 MAPK and cellular proliferation and this ability may be different in VSMCs isolated from Wistar versus SHR rats. Time and/or concentration-dependent effects of Ang III and Ang II were determined in VSMCs using western blot analysis and DNA incorporation assay. The results showed that ERK1/2 MAPK phosphorylation mediated by Ang II or Ang III were concentration- and time-dependent in Wistar VSMCs. Moreover, Ang III was less effective in mediating ERK1/2 phosphorylation in SHR VSMCs as compared to effects seen in Wistar rat VSMCs. Ang III induced ERK1/2 phosphorylation through the AT1 receptors activation. Ang II and Ang III induced VSMC DNA synthesis via the AT1 receptor in a concentration-dependent manner in Wistar VSMCs. Moreover, Ang III induced VSMC proliferation and significant differences existed in the peptide's proliferation effects in Wistar versus SHR VSMCs. These results indicate that Ang III stimulates ERK1/2 MAPK and DNA synthesis in VSMCs via AT1 receptors. However, its ability to stimulate these pathways is reduced in SHR VSMCs.

OMVs derived from Helicobacter pylori can lead to cell transformation in gastric epithelium and cancer. Additionally, exosomes (Exos) released by host cells infected with H. pylori can significantly contribute to the development of diseases such as cancer. In this study, the effects of both Exos from AGS cells treated with H. pylori-derived OMVs on the expression of genes related to the TGF-β/SMAD signaling pathway in hepatocellular carcinoma (HCC) cells were investigated. The TGF-β/SMAD pathway is one of the most important pathways that regulate the development and progression of HCC. For this purpose, after treating HepG2 cells with H. pylori-derived OMVs (directly) and Exos from AGS cells treated with H. pylori-derived OMVs (indirectly), the expression levels of TGF-β, SMAD2, SMAD3, SMAD4, and ERK genes were analyzed using Real-time PCR. The findings showed that OMVs derived from H. pylori can significantly increase the expression of genes involved in the TGF-β signaling pathway, which can affect the aggressive behavior of HepG2 cells. Additionally, exosomes secreted from AGS cells or AGS cells treated with OMVs had no effect on changing the expression of the studied genes. Therefore, only the OMVs released from H. pylori can affect the TGF-β/SMAD signaling pathway in HCC cells.