Meta-analysis of the <i>IL10</i> −1082G/A polymorphism and SLE.

<p>OR: odds ratio; CI: confidence interval; SLE: systemic lupus erythematosus.</p>*<p>exclude the studies deviating from Hardy-Weinberg equilibrium.</p>#<p>exclude the study by Shen (2003).</p

Meta-analysis of the IL-10.G and IL-10.R microsatellites with SLE.

<p>OR: odds ratio; CI: confidence interval; SLE: systemic lupus erythematosus.</p

Flow diagram of the study selection process.

<p>Flow diagram of the study selection process.</p

Meta-analysis of the <i>IL10</i> −819C/T polymorphism and SLE.

<p>OR: odds ratio; CI: confidence interval; SLE: systemic lupus erythematosus.</p>*<p>exclude the studies deviating from Hardy-Weinberg equilibrium.</p>#<p>exclude the study by Wang (2007).</p

Characteristics of included studies in this meta-analysis.

<p>ASO: allele-specific oligonucleotid hybridization; RFLP: restriction fragment length polymorphism; PCR-SSP: polymerase chain reaction sequence specific primer; HPLC: high-performance liquid chromatography; MS: mass spectrometry; PLACE-SSCP post-PCR fluorescent labeling and automated capillary electrophoresis under single-strand conformation polymorphism conditions; SNPs: single nucleotide polymorphisms.</p>#<p>no polymorphisms.</p

Discovery of New SIRT2 Inhibitors by Utilizing a Consensus Docking/Scoring Strategy and Structure–Activity Relationship Analysis

SIRT2, which is a NAD+ (nicotinamide adenine dinucleotide) dependent deacetylase, has been demonstrated to play an important role in the occurrence and development of a variety of diseases such as cancer, ischemia-reperfusion, and neurodegenerative diseases. Small molecule inhibitors of SIRT2 are thought to be potential interfering agents for relevant diseases. Discovery of SIRT2 inhibitors has attracted much attention recently. In this investigation, we adopted a consensus docking/scoring strategy to screen for novel SIRT2 inhibitors. Structural optimization and structure–activity relationship (SAR) analysis were then carried out on highly potent compounds with new scaffolds, which led to the discovery of 2-((5-benzyl-5<i>H</i>-[1,2,4]­triazino­[5,6-<i>b</i>]­indol-3-yl)­thio)-<i>N</i>-(naphthalen-1-yl)­acetamide (<b>SR86</b>). This compound showed good activity against SIRT2 with an IC₅₀ value of 1.3 μM. <b>SR86</b> did not exhibit activity against SIRT1 and SIRT3, implying a good selectivity for SIRT2. In in vitro cellular assays, <b>SR86</b> displayed very good antiviability activity against breast cancer cell line MCF-7. In Western blot assays, <b>SR86</b> showed considerable activity in blocking the deacetylation of α-tubulin, which is a typical substrate of SIRT2. Collectively, because of the new scaffold structure and good selectivity of <b>SR86</b>, it could serve as a promising lead compound, hence deserving further studies

Discovery of Small Molecule Agonist of Gonadotropin-Releasing Hormone Receptor (GnRH1R)

The gonadotrophin-releasing hormone (GnRH) is a central regulator of the human reproductive system and exerts physiological effects by binding to GnRH1R. The GnRH–GnRH1R system is a promising therapeutic target for the maintenance of reproductive function. There are several GnRH1R agonists on the market, but like GnRH, they are all peptide compounds and are limited by their way of administration (subcutaneous or intramuscular injection). To date, no published GnRH1R small molecule agonists have been reported. In this paper, the HTRF-based screening method has been used to screen our in-house chemical library, and we found and confirmed CD304 as a hit compound. Subsequently, structure optimization led to the discovery of compound 6d, exhibited with a certain GnRH1R activation activity (EC50: 1.59 ± 0.38 μM). Further molecular dynamics simulation experiments showed that 6d can well bind to the orthosteric site of GnRH1R through forming a hydrogen-bonding interaction with Y2836.51. Binding of 6d further induces conformational changes in TM6 and TM7, promoting the formation of a continuous water channel in GnRH1R, thereby promoting GnRH1R activation. This well-characterized hit compound will facilitate the further development of novel small molecule agonists of GnRH1R

Discovery of Small Molecule Agonist of Gonadotropin-Releasing Hormone Receptor (GnRH1R)

The gonadotrophin-releasing hormone (GnRH) is a central regulator of the human reproductive system and exerts physiological effects by binding to GnRH1R. The GnRH–GnRH1R system is a promising therapeutic target for the maintenance of reproductive function. There are several GnRH1R agonists on the market, but like GnRH, they are all peptide compounds and are limited by their way of administration (subcutaneous or intramuscular injection). To date, no published GnRH1R small molecule agonists have been reported. In this paper, the HTRF-based screening method has been used to screen our in-house chemical library, and we found and confirmed CD304 as a hit compound. Subsequently, structure optimization led to the discovery of compound 6d, exhibited with a certain GnRH1R activation activity (EC50: 1.59 ± 0.38 μM). Further molecular dynamics simulation experiments showed that 6d can well bind to the orthosteric site of GnRH1R through forming a hydrogen-bonding interaction with Y2836.51. Binding of 6d further induces conformational changes in TM6 and TM7, promoting the formation of a continuous water channel in GnRH1R, thereby promoting GnRH1R activation. This well-characterized hit compound will facilitate the further development of novel small molecule agonists of GnRH1R