Journal of Receptors and Signal Transduction最新文献

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.

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.

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.

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.

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.

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.