Rational design of agonists for bitter taste receptor TAS2R14: from modeling to bench and back.

Rational design of agonists for bitter taste receptor TAS2R14: from modeling to bench and back. Cell Mol Life Sci. 2019 Jun 24;: Authors: Di Pizio A, Waterloo LAW, Brox R, Löber S, Weikert D, Behrens M, Gmeiner P, Niv MY Abstract Human bitter taste receptors (TAS2Rs) are a subfamily of 25 G protein-coupled receptors that mediate bitter taste perception. TAS2R14 is the most broadly tuned bitter taste receptor, recognizing a range of chemically diverse agonists with micromolar-range potency. The receptor is expressed in several extra-oral tissues and is suggested to have physiological roles related to innate immune responses, male fertility, and cancer. Higher potency ligands are needed to investigate TAS2R14 function and to modulate it for future clinical applications. Here, a structure-based modeling approach is described for the design of TAS2R14 agonists beginning from flufenamic acid, an approved non-steroidal anti-inflammatory analgesic that activates TAS2R14 at sub-micromolar concentrations. Structure-based molecular modeling was integrated with experimental data to design new TAS2R14 agonists. Subsequent chemical synthesis and in vitro profiling resulted in new TAS2R14 agonists with improved potency compared to the lead. The integrated approach provides a validated and refined structural model of ligand-TAS2R14 interactions and a general framework for structure-based discovery in the absence of closely related experimental structures. PMI...
Source: Cellular and Molecular Life Sciences : CMLS - Category: Cytology Authors: Tags: Cell Mol Life Sci Source Type: research

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In conclusion, the developed UHPLC-Q-TOF-MS method with high sensitivity and resolution is suitable for identifying and characterizing the chemical constituents of XAJDD in vitro and characterizing the primary components and their metabolites in vivo; moreover, the results will provide essential data for further studying the relationship between the chemical components and pharmacological activity of XAJDD.
Source: Journal of Pharmaceutical and Biomedical Analysis - Category: Drugs & Pharmacology Source Type: research
Authors: Tribius S, Würdemann N, Laban S, Hoffmann TK, Sharma SJ, Klussmann JP Abstract At this year's Annual Meeting of the American Society for Clinical Oncology (ASCO), the keyword search "HPV-associated head and neck cancer" resulted in 920 hits-74% of the hits on human papillomavirus (HPV). This underlines the relevance of the topic. The spectrum ranged from validation and separation of the prognostic groups of patients with HPV-associated oropharyngeal carcinoma (OPSCC) according to TNM 8, to the characterization of new tumor markers and tumor mutational burden for possible de-escalation s...
Source: HNO - Category: ENT & OMF Tags: HNO Source Type: research
Abstract The combined immunotherapy of nivolumab and ipilimumab causes a variety of autoimmune-related adverse events (irAEs). The current report details a 70-year-old woman with clear cell renal cell carcinoma metastasis in the lung. Two weeks after two courses of treatment, the patient complained of headache, dizziness and nausea. Cerebrospinal fluid (CSF) analysis revealed an elevated protein level of 195 mg/dl and a significantly elevated white blood cell (WBC) count of 830/mm3 (lymphocytes, 825/mm3; neutrophils, 5/mm3). The results excluded malignancy and infection. The patient was diagnosed with aseptic meni...
Source: Clinical Lung Cancer - Category: Cancer & Oncology Authors: Tags: Mol Clin Oncol Source Type: research
Publication date: Available online 9 November 2019Source: Preventive MedicineAuthor(s): Walter J. PsoterAbstractThis is a letter to the Editor of Preventive Medicine responding to Drs. Al-Soneidara, Madathilb, and Nicolaub's “Commentary: Oral cancer examinations and lesion discovery as reported by U.S. general dentists.” (Al-Soneidar WA, Madathil SA, Nicolau B. Commentary: Oral cancer examinations and lesion discovery as reported by U.S. general dentists. Preventive medicine 2019;124:124–5).
Source: Preventive Medicine - Category: International Medicine & Public Health Source Type: research
Publication date: Available online 10 November 2019Source: Journal of Pharmaceutical and Biomedical AnalysisAuthor(s): Ziming Wang, Changmin Shao, Zhiwei Hu, Jian Zheng, Qiang Zhang, Xiaohan Kou, Zijia Wang, Tao Yu, Zhisong Cao, Yang WangAbstract9-Nitrocamptothecin-20-O-propionate (CZ112) and 9-Nitrocamptothecin (9NC) are the bioactive derivatives of camptothecin (CPT), an alkaloid isolated from Camptotheca acuminata, and have been confirmed to possess high anti-cancer properties. In the present study, 9NC was identified as the major metabolite of CZ112 in rat plasma through HPLC/photodiode array detection (PDA) and liquid...
Source: Journal of Pharmaceutical and Biomedical Analysis - Category: Drugs & Pharmacology Source Type: research
Authors: Mirhafez SR, Hariri M Abstract L-arginine is an important factor in several physiological and biochemical processes. Recently, scientists studied L-arginine effect on inflammatory mediators such as C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). We conducted a systematic review on randomized controlled trials assessing L-arginine effect on inflammatory mediators. We searched data bases including Google scholar, ISI web of science, SCOPUS, and PubMed/Medline up to April 2019. Randomized clinical trials assessing the effect of L-arginine on inflammatory mediat...
Source: International Journal for Vitamin and Nutrition Research - Category: Nutrition Tags: Int J Vitam Nutr Res Source Type: research
ConclusionsThere is a need for novel ways to prepare patients for HNC surgery and to support them in recovery, including ways to connect and help patients feel human again.
Source: Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology - Category: ENT & OMF Source Type: research
CONCLUSION: Our study demonstrated no clear association between the levels of serum OC and CTX and bisphosphonate-related osteonecrosis of the jaw (BRONJ). To date, there is no clinically useful biomarker for the prediction of jaw osteonecrosis. More studies are needed using different bone turnover markers in order to identify patients at risk for BRONJ. PMID: 31697256 [PubMed - in process]
Source: Archivos Espanoles de Urologia - Category: Urology & Nephrology Tags: Arch Esp Urol Source Type: research
Lee Fah Yap Ian C. Paterson Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and includes squamous cell carcinomas of the oropharynx and oral cavity. Patient prognosis has remained poor for decades and molecular targeted therapies are not in routine use. Here we showed that the overall expression of collagen subunit genes was higher in cancer-associated fibroblasts (CAFs) than normal fibroblasts. Focusing on collagen8A1 and collagen11A1, we showed that collagen is produced by both CAFs and tumour cells, indicating that HNSCCs are collagen-rich environments. We then focused on ...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
SummaryThe PI3K/AKT/mTOR pathway activation plays a central role in glioblastoma multiforme (GBM) development and progression, and in resistance to anti-cancer therapies. Inhibition of the PI3K pathway has been shown to sensitize cultured glioma cells and tumor xenografts to the effects of temozolomide (TMZ) and radiation. Vistusertib is an oral inhibitor of mTORC1/2 complexes. The primary objective of this Canadian Cancer Trials Group phase I study was to determine the recommended phase II dose (RP2D) of vistusertib in patients with GBM receiving TMZ at first progression following primary treatment. Vistusertib was admini...
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research
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