Journal of Receptors and Signal Transduction最新文献

Endometrial cancer (EC) is one of the most common gynecological carcinomas in both developed and developing countries. Majority of the gynecological malignancies are hormonally driven where estrogen signaling acts as an oncogenic signal. Estrogen's effects are mediated via classical nuclear estrogen receptors; estrogen receptor alpha and beta (ERα and ERβ) and a trans-membrane G protein-coupled estrogen receptor (GPR30 and GPER). ERs and GPER through ligand binding triggers multiple downstream signaling pathways causing cell cycle regulation, cell differentiation, migration, and apoptosis in various tissues including endometrium. Although the molecular aspect of estrogen function in ER-mediated signaling is now partly understood, the same is not true for GPER-mediated signaling in endometrial malignancies. Understanding the physiological roles of ERα and GPER in EC biology therefore leads to the identification of some novel therapeutic targets. Here we review the effect of estrogen signaling through ERα-and GPER in EC, major types, and some affordable treatment approaches for endometrial tumor patients which has interesting implications in understanding uterine cancer progression.

Purpose: Although bone marrow mesenchymal stem cells (BMMSCs) have been reported to exhibit a protective effect on animal models of chronic kidney disease (CKD), the exact mechanisms involved require further investigation. This study aims to investigate the underlying molecular mechanisms of BMMSCs in inhibiting ferroptosis and preventing an Adriamycin (ADR)-induced CKD injury.

Methods: A rat model of long-term CKD induced through the injection of ADR administered twice weekly via the tail vein was used in this study. After BMMSCs were systemically administered through the renal artery, pathological staining, western blotting, ELISA, and transmission electron microscopy were used to analyze ferroptosis.

Results: Analyses of renal function and histopathological findings indicated that ADR-mediated renal dysfunction improved in response to the BMMSC treatment, which was also sufficient to mediate the partial reversal of renal injury and mitochondrial pathological changes. BMMSCs decreased the ferrous iron (Fe²⁺) and reactive oxygen species and elevated glutathione (GSH) and GSH peroxidase 4. Moreover, the BMMSC treatment activated the expression of ferroptosis-related regulator NF-E2-related factor 2 (Nrf2) and inhibited Keap1 and p53 in CKD rat kidney tissues.

Conclusions: BMMSCs alleviate CKD, possibly resulting from the inhibition of kidney ferroptosis by regulating the Nrf2-Keap1/p53 pathway.

The purpose of the article: To identify novel small molecule antagonists of Urotensin II receptor with acceptable pharmacological profile.

Materials and methods: Structure-activity-relationship (SAR) studies on 2-{N-[(2,4,5-trichlorophenoxy) acetyl]-N-methylamino}-3-pyrrolidinepropanamide series were conducted and shortlisted compounds were synthesized and evaluated in in vitro cell-based assays. Human and mouse Urotensin II receptor overexpressing CHO cells were used for calcium release and radioligand binding assays. Initial molecules in this series had solubility and inter-species variability issue in the calcium release assay. We, therefore, conducted SAR to overcome these 2 issues and molecules with accepted in vitro profile were evaluated further in mouse pressor response model to generate the in vivo proof of concept for UII receptor antagonization.

Results and conclusions: We report herewith identification of 2-{N-[(2,4,5-trichlorophenoxy)acetyl]-N-methylamino}-3-pyrrolidinepropanamides series to obtain novel small molecule antagonists of Urotensin II receptor with acceptable pharmacological profile.

Salvia grossheimii is a perennial herb with antidiabetic and cytotoxic constituents. In continuation of our study on S. grosshiemii to identify the bioactive phytochemicals, we have reported the characterization of seven undescribed triterpenoids. The aerial parts of the plant were extracted in dichloromethane and its constituents were isolated using chromatography techniques. The structures of compounds were identified using 1D, 2D NMR, and ESI-MS spectral data. Seven new oleanane- and ursane-type triterpenoids (1-7) were identified in S. grossheimii. The structures of 1-7 were characterized as; 2α-hydroxy-3β-acetoxy-olean-9(11),12-diene (1), 2α-acetoxy-3β-hydroxy-olean-9(11),12-diene (2), 3β-acetoxy-olean-18-ene,2α,11α-diol (3), 2α-hydroxy-3β-acetoxy-urs-9(11),12-diene (4), 2α-acetoxy-3β-hydroxy-urs-9(11),12-diene (5), 2α,3β-diacetoxy-urs-12-ene-11α,20β-diol (6), 2α,3β-diacetoxy-urs-9(11),12-diene-20β-ol (7). Triterpenoids (2, 5, and 7) were intramolecular transesterification or dehydration products of their corresponding isomers or allylic alcohol in the C rings, respectively, produced in-situ during NMR spectroscopy. Virtual screening of 1-7 was performed with molecular docking analysis to identify the potential SARS-CoV-2 and α-glucosidase inhibitors using the smina molecular docking algorithm. The best binding energy values (kcal/mol) against COVID-19 main protease M^pro were calculated for 6 (-8.77) and 7 (-8.68), and the higher binding affinities toward human α-glucosidase were obtained for 2 (-9.39) and 6 (-8.63). This study suggests S. grossheimii as a rich source of bioactive triterpenoids and introduces new natural compounds. Considering the high binding energy values of 2, 6, and 7, these structures could be candidates for anti-COVID-19 and antidiabetic drug development in the future.

Indole and its derivatives are common heterocyclic compounds in nature that have a wider range of medicinal activities such as antifungal, anti-inflammatory, and anti-seizure. Virtually all indole derivatives showed outstanding antifungal activity against Candida albicans. The aim of this study was to QSAR modeling of indole derivatives and the design of new drugs that have antifungal activity. In this study, 52 compounds were selected. All optimized compounds and quantum descriptors were obtained using Gaussian software and DFT/B3LYP computational method with 6-31 G (d) basis set al, so other descriptors were determined using Dragon software. To examine the relationship between these descriptors and the activity of these compounds, the MLR linear correlation method was used, and the QSAR equation with R² = 0.7884 and R = 0.8879 was obtained for it. Likewise, MSE = 0.1897, RMSE = 0.2848, and Q² = 0.68663 approve the acceptability of the obtained model. The obtained equation reveals that the activity of these compounds is related to the negative coefficient of GATS8p, R7e +, and G2e, which means that with increasing the values ​​of these description nodes, the amount of activity declines. On the other hand, the activity of these compounds depended on the positive coefficients of HATS3p, MATS5e, and RDF045, i.e. with increasing these values, the activity of these compounds also increases, and a good correlation was obtained between the experimental and predicted activity values.

The E3 ubiquitin ligase is an important regulator of cell signaling and proteostasis and is tightly controlled in many diseases, including cancer. Our study aimed to investigate the biological role of the E3 ubiquitin ligase CBLC in breast cancer and elucidate the specific mechanistic network underlying CBLC-mediated target substrate degradation, cell proliferation and metastasis. Here, we showed that CBLC expression was higher in breast cancer tissues and cells than that in normal tissues and cells. Higher expression of CBLC predicted a better prognosis for breast cancer patients. CBLC inhibited the proliferation, migration and invasion of breast cancer cells. Co-IP and immunofluorescence co-localization assays demonstrated that CBLC interacted with CTTN in the cytoplasm. CBLC promoted the degradation of CTTN through the ubiquitin-proteasome pathway without affecting its mRNA level. The inhibitory effect of CBLC on breast cancer cell proliferation, migration and invasion could partly be reversed by CTTN. Taken together, our study clarified the biological role of CBLC as a tumor suppressor and discovered its functional substrate, providing a molecular basis for CBLC/CTTN as a potential therapeutic target in breast cancer.

Purpose: Cancer is a significant public health problem and ranks as a leading cause of death globally. Multidrug resistance (MDR) affects the therapeutic potential of conventional chemotherapeutic agents in cancer chemotherapy. Receptor tyrosine kinases (RTKs) are enzymes whose aberrant activation contributes to the tumorigenesis of various types of cancers. The ability of several RTKs, such as c-Met, to reverse ABC transporters mediated MDR was shown before. We aimed to explore the ability of c-Met inhibitors to circumvent MDR in cancer by inhibiting the ABCB1 transporter using in silico studies.

Methods: Docking virtual screening of several potent and structurally diverse c-Met inhibitors were applied to find repurposed candidates to target the ATP binding sites and drug-substrate binding pockets of the ABCB1 transporter. The selected candidate was subjected to molecular dynamics simulations.

Results: Based on docking findings, among 19 clinical c-Met inhibitors, several drugs, particularly golvatinib, exerted the affinity to both ATP binding sites in the nucleotide-binding domains (NBDs) as well as the drug-substrate binding site in the transmembrane domains (TMDs). Moreover, several non-clinical c-Met inhibitors obtained from the ChEMBL database had strong interactions with TMDs and NBDs, among which CHEMBL1950194 and CHEMBL2385194 compounds showed the highest binding affinity, respectively. Additionally, as a potential repositioning drug, MD simulation studies of golvatinib, corroborated the docking results.

Conclusion: We applied docking and molecular dynamics simulations to screen the potential c-Met inhibitors as the MDR reversing agents targeting ATP and drug-substrate binding sites, and the results suggested several repurposed candidate drugs.

Loss-of-function mutations of the arginine vasopressin receptor 2 gene (AVPR2) cause Nephrogenic diabetes insipidus (NDI). AVPR2 is a kind of G protein coupled receptor (GPCR) and mainly couples with Gαs protein leading to cAMP accumulation in the cell as a secondary messenger. Recent studies showed that some AVPR2 mutations could cause biased Gαq/11 protein coupling rather than Gαs. Investigation into the characterization of biased receptors may give insights into the relationship between the conformational change of the receptor because of the mutation and related downstream signaling. In this study, R68W and V162A were analyzed to whether they show a bias to Gαs or Gαq/11 proteins. Their functionality in terms of cAMP production via Gαs protein coupling was decreased compared to the wild-type receptor. On the other hand, they showed the ability to couple with Gαq/11 protein and make Ca²⁺ mobilization at different levels in the cell. R68W showed bias to coupling with Gαq/11 protein rather than V162A and wild-type receptor. Studies about the Gα protein coupling bias of mutant AVPR2s may broaden our understanding of the relationship between the changed conformation of the receptor and consequently activated signaling pathways, and also may shed light on the development of more effective new therapeutics.

PI3K/AKT/mTOR pathway is one of the frequently disrupted signaling pathways in renal cell carcinoma (RCC) that plays a significant role in tumor formation, disease progression and therapeutic resistance. Therefore, novel natural molecules targeting the critical proteins of this pathway will provide the best alternative to existing drugs, which are toxic and develops resistance. Recent studies have recognized the anti-cancer therapeutic potential of mycocompounds. The current study is focused on screening various mycocompounds from Astraeus hygrometricus against key cancer signaling proteins phosphoinositide 3-kinase (PI3K), protein kinase B, PKB (AKT1) and mammalian target of rapamycin (mTOR). We also studied in-silico cancer cells cytotoxicity and ADMET (absorption, distribution, metabolism, excretion and toxicity) profiles to elucidate the molecular mechanism against RCC and also to uncover the pharmacokinetic profile of these compounds. Astrakurkurone and Ergosta-4,6, 8-(14) 22-tetraene-3-one were the two most efficacious compounds with highest interaction scores and bonding. These compounds were both active against RCC4 and VMRC-RCZ cell lines of RCC. The ADME profiles of both were satisfactory based on druglikeness and bioavailability score criteria. Thus, this proposed study identified astrakurkurone and ergosta-4,6, 8-(14) 22-tetraene-3-one as potential anticancer drug candidates, and provides comparative structural insight into their binding to the 3 protein kinases.

Purpose: Myocardial ischemia-reperfusion injury (I/R) is a detrimental process contributing to the pathological progression of coronary artery diseases. Studies indicate that miRNAs are implicated in ischemic heart disease, and ozone therapy could protect the heart from ischemic heart disease. In this study, we investigated the effect of ozone on miR-200c expression and the potential role of miR-200c in an I/R myocardial injury model.

Methods: A myocardial cellular model of I/R was established to detect the expression of miR-200c. Cardiomyocytes with I/R induction were treated with ozone as a cellular model to detect miR-200 expression and investigate its functional roles. The downstream target of miR-200c was predicted with Starbase online tools and validated by dual luciferase reporter assay. The function of miR-200c/FOXO3 axis in I/R was examined by CCK-8 proliferation and apoptotic assays.

Results: miR-200c was upregulated in primary cardiomyocytes of the I/R model. In cardiomyocyte cells, cell proliferation in the I/R group was significantly impaired, which could be partially rescued by miR-200c inhibitor or ozone treatment. Cell death detected by LDH release and apoptosis assay in the I/R model could also be inhibited by miR-200c inhibitor or ozone treatment. FOXO3 was identified as a downstream target of miR-200c, which was induced by ozone treatment and suppressed by miR-200c. Silencing FOXO3 abrogated the protective effect of ozone treatment on the I/R cell model.

Conclusion: Overall, our results suggest that ozone plays a cardio-protective role in I/R through regulating miR-200/FOXO3 axis, and indicate that targeting miR-200/FOXO3 axis could potentially alleviate I/R.