Postoperative Recurrent Gout Flares: A Cross-sectional Study From China.

OBJECTIVES: To investigate the morbidity, clinical characteristics, and risk factors for postoperative recurrent gout flares (PRGFs). METHODS: This cross-sectional study included all surgical patients at 2 academic institutions between 2010 and 2018. Data including demographics, prior history of gout, clinical variables, medications, and the occurrence of PRGFs were abstracted from medical records. Forward stepwise multivariable logistic regression analysis was used in the statistical analyses. RESULTS: Among the 518 (0.5% [518/114,760]) surgical patients with a prior diagnosis of gout, 474 had sufficient documentation for analysis. Of these, 191 (40.3%) had experienced a PRGF. Most PRGFs (54.4%) were polyarticular gout; 79.6% had a pretreatment pain score of PRGFs ≥7, and 59.2% required combination pharmacologic therapy. The mean (SD) serum urate (SU) level decreased postoperatively (500.33 [122.77] vs. 380.15 [118.35] µmol/L; p = 0.000), with an average decrease of 125.86 µmol/L. The decrease in the postsurgical SU level was greater in patients who received postoperative total parenteral nutrition (PTPN) than in those who did not (p = 0.009), and it was correlated with the duration of PTPN (r = 0.156, p = 0.031). Factors independently associated with PRGFs were decrease in the postsurgical SU level by ≥126 µmol/L, previous flares involving the ankle, failure to take prophylactic colchicine therapy, and abdominal surgery. CONCLUSIONS: Recurrent gout flares often occur postoperatively and are severe. For high-risk patients, especially those undergoing abdominal surgeries, timely monitoring of postsurgical SU level, colchicine prophylaxis, and avoiding the overuse of PTPN may help prevent PRGFs.

Actinomadura deserti sp. nov., isolated from desert soil.

A Gram-positive, strictly aerobic actinobacterium, designated BMP B8004T, was isolated from desert soil collected in Xinjiang Province, Northwest China. It produced an extensively branched non-fragmenting substrate mycelium, and very scanty aerial mycelium that formed a short hooked chain of arthrospores with a smooth surface. Optimum growth occurred at 28 °C, pH 7.0 and 0 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain BMP B8004T formed a distinct phyletic lineage within the genus Actinomadura. It shared the highest 16S rRNA gene sequence similarity to Actinomadura apis IM17-1T (99.2 %) and Actinomadura rifamycini NBRC 14183T (98.6 %). However, it could be distinguished from the two closest strains based on the low levels of DNA-DNA relatedness (52.7±0.7 and 45±1.8 %, respectively). Chemotaxonomic characteristics, including the main phospholipids, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannosides, the major menaquinones MK-9(H6) and MK-9(H8), the predominant fatty acids iso-C16 : 0, C16 : 0, C18 : 0 10-methyl and C18 : 1ω9c, were also consistent with the properties of the genus Actinomadura. The DNA G+C content of strain BMP B8004T was 71.9 mol%. Based on phenotypic and genotypic features, strain BMP B8004T is considered to represent a novel species of the genus Actinomadura, for which the name Actinomadura deserti sp. nov. is proposed. The type strain is BMP B8004T (=CGMCC 4.7432T=KCTC 39998T).

Design, synthesis and molecular docking of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazole derivatives that act as iNOS/COX-2 inhibitors with potent anti-inflammatory activity against LPS-induced RAW264.7 macrophage cells.

Inflammation, an important biological protective response to tissue damage or microbial invasion, is considered to be an alarming signal for the progress of varied biological complications. Based on the previous reports in the literature that proved the noticeable efficacy of pyrazole and thiazole scaffold as well as nitrogen heterocyclic based compounds against acute and chronic inflammatory disease, a new set of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazole derivatives were synthesized and evaluated their anti-inflammatory activities in vitro. Preliminary structure-activity relationship (SAR) analysis was conducted by their inhibitory activities against nitric oxide (NO) release in lipopolysaccharide (LPS)-induced RAW 264.7 cells, and the optimal compound 12b [3ß-hydroxy-pregn-5-en-17ß-yl-5'- (o- chlorophenyl)- 1'-(4''- phenyl -[1'', 3'']- thiazol-2''- yl) - 4',5'-dihydro - 1'H-pyrazol - 3'- yl] exhibited more potent anti-inflammatory activity than the positive control treatment methylprednisolone (MPS), with an IC50 value of 2.59 µM on NO production and low cytotoxicity against RAW 264.7 cells. In further mechanism study, our results showed that compound 12b significantly suppressed the production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and inhibited the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) through blocking NF-κB p65 nuclear translocation and phosphorylation of IκBα. Compound 12b also attenuated LPS-induced activation of c-Jun amino-terminal kinase (JNK) and p38 phosphorylation in RAW 264.7 cells. Molecular docking study revealed the strong binding affinity of compound 12b to the active site of the COX-2 proteins, which confirmed that compound 12b acted as an anti-inflammatory mediator. These results indicate that steroidal derivatives bearing 4,5-dihydropyrazole thiazole structure might be considered for further research and scaffold optimization in designing anti-inflammatory drugs and compound 12b might be a promising therapeutic anti-inflammatory drug candidate.

Design, synthesis and molecular modeling of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazolinone derivatives as anti-inflammatory agents by inhibition of COX-2/iNOS production and down-regulation of NF-κB/MAPKs in LPS-induced RAW264.7 macrophage cells.

It has been reported that 4,5-dihydropyrazole and thiazole derivatives have many biological functions, especially in the aspect of anti-inflammation. According to the strategy of pharmacophore combination, we introduced thiazolinone and dihydropyrazole moiety into steroid skeleton to design and synthesize a novel series of D-ring substituted steroidal 4,5-dihydropyrazole thiazolinone derivatives, and assessed their in vitro anti-inflammatory profiles against Lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophage cells. The anti-inflammatory activities assay demonstrated that compound 12e was considered as the most effective anti-inflammatory drug, which suppressed the expression of pro-inflammatory mediators including nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), it also dose-dependently inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-induced RAW 264.7 macrophage cells. Furthermore, the results of the Western blot analysis showed a correlation between the inhibition of the Nuclear factor-kappa B (NF-κB) and Mitogen-activated protein kinases (MAPKs) signaling pathways and the suppressive effects of compound 12e on pro-inflammatory cytokines. Molecular docking studies of compound 12e into the COX-2 protein receptor (PDB ID: 5IKQ) active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of dexamethasone (DXM), explaining their remarkable COX-2 inhibitory activity. The findings revealed that these candidates could be identified as potent anti-inflammatory agents, compound 12e could be a promising drug for the treatment of inflammatory diseases.

Synthesis and anti-inflammatory activity of novel steroidal chalcones with 3ß-pregnenolone ester derivatives in RAW 264.7 cells in vitro.

To identify new potential anti-inflammatory agents, we herein report the synthesis of novel steroidal chalcones with 3ß-pregnenolone esters of cinnamic acid derivatives using pregnenolone as the starting material. The structures of the newly synthesised compounds were confirmed by 1H NMR, 13C NMR, HRMS and infrared imaging. All the derivatives were examined to determine their in vitro anti-inflammatory profiles against LPS-induced inflammation in RAW 264.7 cells; the derivates were evaluated by the quantification of the pro-inflammatory mediator nitric oxide (NO) in the cell culture supernatant based on the Griess reaction, which measures nitrite levels, followed by an in vitro cytotoxicity study. Among these novel derivatives, compound 11e [3ß-3-phenyl acrylate-pregn-5-en-17ß-yl-3' -(p-fluoro)-phenylprop-2'-en-1'-one] was identified as the most potent anti-inflammatory agent, which showed significant anti-inflammatory activity by inhibiting the LPS-induced pro-inflammatory mediator NO in a dose-dependent manner without any cytotoxicity. Moreover, compound 11e markedly inhibited the expression of pro-inflammatory cytokines, including inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2), in LPS-induced RAW 264.7 cells. Further studies confirmed that compound 11e significantly suppressed the transcriptional activity of NF-κB in activated RAW 264.7 cells. Molecular docking study revealed the strong binding affinity of compound 11e to the active site of the pro-inflammatory proteins, which confirmed that compound 11e acted as an anti-inflammatory mediator. These results indicated that steroidal chalcones with 3ß-pregnenolone esters of cinnamic acid derivatives might be considered for further research in the design of anti-inflammatory drugs, and compound 11e might be a promising therapeutic anti-inflammatory drug candidate.

Synthesis and evaluation of novel D-ring substituted steroidal pyrazolines as potential anti-inflammatory agents.

To identify new potential anti-inflammatory agents, a number of novel steroidal derivatives with nitrogen heterocyclic side chains 4a-4l were synthesized and evaluated for their anti-inflammatory effects in activated RAW 264.7 macrophage cells. The synthesis scheme involves two steps, Claisen-Schmidt condensation with the corresponding pregnenolone and aromatic aldehydes as the first step followed by nucleophilic addition of thiosemicarbazide across an α, ß-unsaturated carbonyl as a later step. Compound structures were confirmed by 1H NMR, 13C NMR, HRMS, and IR. The compounds were assayed to test their anti-inflammatory effects in activated RAW 264.7 cells. Compound 4g, 3ß-hydroxy-pregn-5-en-17ß-yl-5'-(m-fluorophenyl)-4', 5'-dihydro-1'-carbothioic acid amido pyrazole, was identified as the most potent anti-inflammatory agent of the analysed compounds, with an IC50 value of 0.86 µM on nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 cells for 24 h compared to dexamethasone (IC50 = 0.62 µM) and low cytotoxicity against RAW 264.7 cells. Compound 4g significantly inhibited NO produced by LPS-induced RAW 264.7 cells. Further studies showed that compound 4g markedly inhibited the expression of pro-inflammatory factors, including inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) in LPS-induced RAW 264.7 cells. These results indicate that derivatives bearing pyrazoline structure might be considered for further research and scaffold optimization in designing anti-inflammatory drugs and compound 4g might be a promising therapeutic anti-inflammatory drug candidate.