In Silico, In Vitro and In Vivo Pharmacodynamic Characterization of Novel Analgesic Drug Candidate Somatostatin SST4 Receptor Agonists

Kántás, Boglárka; Szöke, Éva; Börzsei, Rita; Bánhegyi, Péter; Asghar, Junaid; Hudhud, Lina; Steib, Anita; Hunyady, Ágnes; Horváth, Ádám; Kecskés, Angela; Borbély, Éva; Hetényi, Csaba; Pethő, Gábor; Pintér, Erika; Helyes, Zsuzsanna

doi:10.3389/fphar.2020.601887

Cited by 9 publications

(8 citation statements)

References 46 publications

(62 reference statements)

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“…MUC1 is anomalously expressed in numerous cancers. The coding production of MUC1 gene was a tumor marker for the diagnosis of thyroid cancer [ 14 , 15 ]. MUC1 expression is reported to be an important molecular marker of cervical squamous cell carcinoma [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Genes in Nasopharyngeal Carcinoma Based on Bioinformatics Analysis

Song

Feng

Cao

et al. 2022

Computational Intelligence and Neuroscience

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Objective. This study aimed to identify key genes associated with the pathogenesis of nasopharyngeal carcinoma (NPC) by bioinformatics analysis. Methods. Datasets (GSE13597 and GSE34573) were screened and downloaded from the comprehensive gene expression database (GEO). GEO2R online tool was adopted to analyze microarray data GSE13597 and GSE34573 related to NPC. Volcano plot was generated using Bioconductor in R software. “Pheatmap” was used to draw heatmaps based on the top 10 regulated genes of GSE13597 and GSE34573. GO and KEGG analyses were conducted via online tool DAVID. We uploaded the DEGs of NPC to STRING software and then used Cytoscape software to draw PPI network of DEGs. Results. 216 DEGs were obtained in GSE13597 between patient and control group (111 up-regulated DEGs and 105 down-regulated DEGs). 1101 DEGs were obtained in GSE34573 (470 up-regulated DEGs and 641 down-regulated DEGs). 63 common differential genes were screened named co-DEGs in the two datasets. These DEGs were mainly associated with defense response to bacterium, cell-matrix adhesion, chemokine-mediated signaling pathway, tissue homeostasis, humoral immune response, cilium movement, cilium organization, cilium assembly, and epithelial cilium movement. KEGG pathway enrichment analysis showed that DEGs were mainly involved in viral protein interaction with cytokine and cytokine receptor, salivary secretion, p53 signaling pathway, IL-17 signaling pathway, cell cycle, PI3K-Akt signaling pathway, and ECM-receptor interaction. We identified seven hub genes, including FN1, MMP-10, MUC1, KIF23, CDK1, MUC5B, and MUC5AC. Conclusions. Seven hub genes, including FN1, MMP-10, MUC1, KIF23, CDK1, MUC5B, and MUC5AC, might be therapeutic potential biomarkers of NPC.

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Section: Discussionmentioning

confidence: 99%

Identification of Key Genes in Nasopharyngeal Carcinoma Based on Bioinformatics Analysis

Song

Feng

Cao

et al. 2022

Computational Intelligence and Neuroscience

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“…Somatostatin was released from nerve endings of isolated murine skin upon application of sodium polysulfide due to the activation of TRPA1 ion channels [6]. Somatostatin enters the systemic circulation and exerts analgesic and anti-inflammatory effects via sst4 receptors [32]. Our earlier data indicated that a reduction in vascular inflammation by DMTS was mediated by sst4 activation, but not by TRPA1 activation [25].…”

Section: Discussionmentioning

confidence: 98%

Investigation of the Role of the TRPA1 Ion Channel in Conveying the Effect of Dimethyl Trisulfide on Vascular and Histological Changes in Serum-Transfer Arthritis

et al. 2022

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Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases. Its therapy is often challenging, even in the era of biologicals. Previously, we observed the anti-inflammatory effects of garlic-derived organic polysulfide dimethyl trisulfide (DMTS). Some of these effects were mediated by activation of the TRPA1 ion channel. TRPA1 was mostly expressed in a subset of nociceptor neurons. We decided to investigate the action of DMTS in K/BxN serum-transfer arthritis, which is a relevant model of RA. TRPA1 gene knockout (KO) and wild-type (WT) mice were used. The interaction of DMTS and TRPA1 was examined using a patch clamp in CHO cells. Arthritis was characterized by mechanical hyperalgesia, paw swelling, movement range of the ankle joint, hanging performance, plasma extravasation rate, myeloperoxidase activity, and histological changes in the tibiotarsal joint. DMTS activated TRPA1 channels dose-dependently. DMTS treatment reduced paw swelling and plasma extravasation in both TRPA1 WT and KO animals. DMTS-treated TRPA1 KO animals developed milder collagen deposition in the inflamed joints than WT ones. TRPA1 WT mice did not exhibit significant cartilage damage compared to ones administered a vehicle. We concluded that DMTS and related substances might evolve into novel complementary therapeutic aids for RA patients.

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“…The experimental determination of the atomic resolution structure of SSTR4 has not been accomplished yet (Introduction). Homology modelling is an alternative method of choice [40,41,48,[51][52][53]61,62] for producing SSTR structures. Building a good SSTR model necessitates the selection of a template protein of good sequential agreement with the receptor.…”

Section: The Structure Of Sstr4mentioning

confidence: 99%

Exploration of Somatostatin Binding Mechanism to Somatostatin Receptor Subtype 4

Börzsei

Zsidó

Bálint

et al. 2022

IJMS

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Somatostatin (also named as growth hormone-inhibiting hormone or somatotropin release-inhibiting factor) is a regulatory peptide important for the proper functioning of the endocrine system, local inflammatory reactions, mood and motor coordination, and behavioral responses to stress. Somatostatin exerts its effects via binding to G-protein-coupled somatostatin receptors of which the fourth subtype (SSTR4) is a particularly important receptor mediating analgesic, anti-inflammatory, and anti-depressant effects without endocrine actions. Thus, SSTR4 agonists are promising drug candidates. Although the knowledge of the atomic resolution-binding modes of SST would be essential for drug development, experimental elucidation of the structures of SSTR4 and its complexes is still awaiting. In the present study, structures of the somatostatin–SSTR4 complex were produced using an unbiased, blind docking approach. Beyond the static structures, the binding mechanism of SST was also elucidated in the explicit water molecular dynamics (MD) calculations, and key binding modes (external, intermediate, and internal) were distinguished. The most important residues on both receptor and SST sides were identified. An energetic comparison of SST binding to SSTR4 and 2 offered a residue-level explanation of receptor subtype selectivity. The calculated structures show good agreement with available experimental results and indicate that somatostatin binding is realized via prerequisite binding modes and an induced fit mechanism. The identified binding modes and the corresponding key residues provide useful information for future drug design targeting SSTR4.

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In Silico, In Vitro and In Vivo Pharmacodynamic Characterization of Novel Analgesic Drug Candidate Somatostatin SST4 Receptor Agonists

Cited by 9 publications

References 46 publications

Identification of Key Genes in Nasopharyngeal Carcinoma Based on Bioinformatics Analysis

Identification of Key Genes in Nasopharyngeal Carcinoma Based on Bioinformatics Analysis

Investigation of the Role of the TRPA1 Ion Channel in Conveying the Effect of Dimethyl Trisulfide on Vascular and Histological Changes in Serum-Transfer Arthritis

Exploration of Somatostatin Binding Mechanism to Somatostatin Receptor Subtype 4

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