The efficacy and safety of yukmijihwang-hwan (Liuweidihuang-wan) for type 2 diabetes mellitus without complications: A protocol for systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis of randomized controlled trials (RCTs) will aim to assess the efficacy and safety of Yukmijihwang-hwan for type 2 diabetes without complications. METHODS: To identify eligible studies, we will perform a systematic search of the following electronic databases: MEDLINE (PubMed), EMBASE, the Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Citation Information by NII, Korean Information Service System, Korean Medical Database, Oriental Medicine Advanced Searching Integrated System, and ScienceON. Search terms will include "Type 2 Diabetes" for participants as well as "Yukmijihwang-tang" or "Liuwei dihuang tang" for interventions. Two independent researchers will perform data extraction and assessment using Cochrane's risk of bias tool, with disagreements being resolved through discussions with a third researcher. RESULTS: This study will evaluate the antidiabetic effects of Yukmijihwang-hwan from 3 perspectives (blood glucose level, insulin resistance, and ß-cell function) as well as its safety by reviewing the reported adverse effects. CONCLUSION: This systematic review will provide evidence regarding the antidiabetic efficacy and safety of Yukmijihwang-tang in type 2 diabetes mellitus.

Efficacy of Geumguesingi-hwan (jinkuishenqi-wan, kinkijinki-gan) in decreasing blood glucose levels in patients with uncomplicated type 2 diabetes: A protocol for systematic review and meta-analysis.

BACKGROUND: The purpose of a systematic review and meta-analysis is to verify the clinical efficacy and safety of Geumguesingihwan for patients with uncomplicated type 2 diabetes. METHODS: The systematic review and meta-analysis will be performed following the guidelines of the National Evidence-based Healthcare Collaborating Agency. We will conduct a systematic search of randomized controlled trials in 8 electronic databases until August 31, 2021. RESULTS: This study will provide evidence regarding the clinical efficacy of Geumguesingi-hwan from the following 3 perspectives: improving blood glucose level, insulin resistance, and ß-cell function. Additionally, we will examine the safety of Geumguesingi-hwan by evaluating the adverse effects. CONCLUSIONS: This study will verify the antidiabetic efficacy and safety of Geumguesingi-hwan in patients with uncomplicated type 2 diabetes.

Discovery of Benzopyridone-Based Transient Receptor Potential Vanilloid 1 Agonists and Antagonists and the Structural Elucidation of Their Activity Shift.

Among a series of benzopyridone-based scaffolds investigated as human transient receptor potential vanilloid 1 (TRPV1) ligands, two isomeric benzopyridone scaffolds demonstrated a consistent and distinctive functional profile in which 2-oxo-1,2-dihydroquinolin-5-yl analogues (e.g., 2) displayed high affinity and potent antagonism, whereas 1-oxo-1,2-dihydroisoquinolin-5-yl analogues (e.g., 3) showed full agonism with high potency. Our computational models provide insight into the agonist-antagonist boundary of the analogues suggesting that the Arg557 residue in the S4-S5 linker might be important for sensing the agonist binding and transmitting signals. These results provide structural insights into the TRPV1 and the protein-ligand interactions at a molecular level.

Discovery of N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea as a potent TRPV1 antagonistic template.

A series of homologous analogues of prototype antagonist 1 and its urea surrogate were investigated as hTRPV1 ligands. Through one-carbon elongation in the respective pharmacophoric regions, N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea was identified as a novel and potent TRPV1 antagonistic template. Its representative compound 27 showed a potency comparable to that of lead compound 1. Docking analysis of compound 27 in our hTRPV1 homology model indicated that its binding mode was similar with that of 1S.

2-Sulfonamidopyridine C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists.

A series of 2-sulfonamidopyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide were investigated as hTRPV1 ligands. Systematic modification on the 2-sulfonamido group provided highly potent TRPV1 antagonists. The N-benzyl phenylsulfonamide derivatives 12 and 23 in particular showed higher affinities than that of lead compound 1. Compound 12 exhibited strong analgesic activity in the formalin pain model. Docking analysis of its chiral S-form 12S in our hTRPV1 homology model indicated that its high affinity might arise from additional hydrophobic interactions not present in lead compound 1S.

Design and synthesis of protein kinase C epsilon selective diacylglycerol lactones (DAG-lactones).

DAG-lactones afford a synthetically accessible, high affinity platform for probing structure activity relationships at the C1 regulatory domain of protein kinase C (PKC). Given the central role of PKC isoforms in cellular signaling, along with their differential biological activities, a critical objective is the design of isoform selective ligands. Here, we report the synthesis of a series of DAG-lactones varying in their side chains, with a particular focus on linoleic acid derivatives. We evaluated their selectivity for PKC epsilon versus PKC alpha both under standard lipid conditions (100% phosphatidylserine, PS) as well as in the presence of a nuclear membrane mimetic lipid mixture (NML). We find that selectivity for PKC epsilon versus PKC alpha tended to be enhanced in the presence of the nuclear membrane mimetic lipid mixture and, for our lead compound, report a selectivity of 32-fold.