Identification and Validation of PKR as a Direct Target for the Novel Sulfonamide-Substituted Tetrahydroquinoline Nonselective Inhibitor of the NLRP3 Inflammasome.

The NLRP3 inflammasome is a critical component of the innate immune system. The persistent abnormal activation of the NLRP3 inflammasome is implicated in numerous human diseases. Herein, sulfonamide-substituted tetrahydroquinoline derivative S-9 was identified as the most promising NLRP3 inhibitor, without obvious cytotoxicity. In vitro, S-9 inhibited the priming and activation stages of the NLRP3 inflammasome. Incidentally, we also observed that S-9 had inhibitory effects on the NLRC4 and AIM2 inflammasomes. To elucidate the multiple anti-inflammatory activities of S-9, photoaffinity probe P-2, which contained a photoaffinity label and a functional handle, was developed for target identification by chemical proteomics. We identified PKR as a novel target of S-9 in addition to NLRP3 by target fishing. Furthermore, S-9 exhibited a significant anti-neuroinflammatory effect in vivo. In summary, our findings show that S-9 is a promising lead compound targeting both PKR and NLRP3 that could emerge as a molecular tool for treating inflammasome-related diseases.

[Socio-psychological factors related to temporary ejaculation failure in male patients undergoing IVF: Results of logistic regression analyses].

OBJECTIVE: To explore the socio-psychological factors associated with male temporary ejaculation failure (TEF) during in vitro fertilization (IVF) and provide some theoretical evidence for the clinical intervention and treatment of the condition. METHODS: We conducted a questionnaire investigation among 298 males undergoing IVF, 75 with and 223 without TEF. The questionnaires covered general information, Perceived Stress Scale (PSS), Stigma Questionnaire, Perceived Social Support Scale (PSSS), and Positive Psychological Capital Questionnaire (PPQ). We subjected the relevant social psychological factors found in the investigation to logistic regression analysis and compared them between the patients in the TEF and non-TEF groups. RESULTS: Statistically significant differences were found between the two groups in age, education level, perceived stress, stigma, social support and psychological capital (P < 0.05). Univariate logistic regression analysis indicated that age, perceived stress, stigma, family support, friend support, other supports, self-efficacy, resilience, hope and optimism in psychological capital significantly affected the incidence of TEF. Multivariate logistic regression analysis showed age (OR = 1.071, 95% CI: 1.025－1.119) and stigma (OR = 1.132, 95% CI: 1.044－1.227) to be independent risk factors for TEF, capable of positively predicting the condition, and family support (OR = 0.877, 95% CI: 0.791－0.971) to be an independent protective factor against TEF, capable of negatively predicting the disorder. CONCLUSIONS: Age, stigma and family support are associated with the incidence of TEF during IVF. The social psychology-related influencing factors may help provide a new intervention target for effectively reducing the incidence of TEF and improving the success rate of IVF.

Effects of straw amendment on selenium aging in soils: Mechanism and influential factors.

Soil dissolved organic matter (DOM) alters heavy metal availability, but whether straw amendment can manipulate soil selenium (Se) speciation and availability through DOM mineralization remains unclear. In this study, allochthonous maize straw and selenate were incubated together in four different soils for 1 y. The transformation and availability of DOM associated Se (DOM-Se) was investigated during aging. Results indicated that soil solution and soil particle surfaces were dominated by hexavalent hydrophilic acid-bound Se (Hy-Se). The amount of fulvic acid bound Se in soil solution (SOL-FA-Se) was higher than humic acid bound Se in soil solution (SOL-HA-Se), except in krasnozems, and mainly existed as hexavalent Se (Se(VI)). Tetravalent Se (Se(IV)) was the main valence state of FA-Se adsorbed on soil particle surfaces (EX-FA-Se) after 5 w of aging. The proportion of soil-available Se (SOL + EX-Se) decreased with increasing straw rate. However, under an application rate of 7500 kg·hm-2, soluble Se fraction (SOL-Se) reduction was minimal in acidic soils (18.7%-34.7%), and the organic bound Se fraction (OM-Se) was maximally promoted in alkaline soils (18.2%-39.1%). FA and HON could enhance the availability of Se in the soil solution and on particle surfaces of acidic soil with high organic matter content. While Se incorporation with HA could accelerate the fixation of Se into the solid phase of soil. Three mechanisms were involved in DOM-Se aging: (1) Reduction, ligand adsorption, and inner/outer-sphere complexation associated with the functional groups of straw-derived DOM, including hydroxyls, carboxyl, methyl, and aromatic phenolic compounds; (2) interconnection of EX-FA-Se between non-residual and residual Se pools; and (3) promotion by soil electrical conductivity (EC), clay, OM, and straw application. The dual effect of DOM on Se aging was highly reliant on the characteristics of the materials and soil properties. In conclusion, straw amendment could return selenium in soil and reduce soluble Se loss.

Effects of Liuwei Dihuang Granule ([symbols; see text]) on the outcomes of in vitro fertilization pre-embryo transfer in infertility women with Kidney-yin deficiency syndrome and the proteome expressions in the follicular fluid.

OBJECTIVE: To observe the effects of Liuwei Dihuang Granule ([symbols; see text], LDG) for tonifying Kidney (Shen) on the outcomes of in vitro fertilization pre-embryo transfer (IVF-ET) of infertility women with Kidney-yin deficiency syndrome and to explore its mechanism by detecting the proteome expression in the follicular fluid. METHODS: Sixty-six infertility patients of Kidney-yin deficiency syndrome who would undergo IVF-ET, were randomly assigned to a treatment group and a control group according to a random number table, 33 cases in each group. Another 33 cases of non-Kidney-yin deficiency syndrome was taken as a syndrome-control group. Besides Western routine therapy, LDG was given 3 menstrual cycles before IVF to the treatment group, and a placebo granule to the control and syndrome-control groups. The scores of Kidney-yin deficiency symptoms (sore waist and knees, dry vagina, dysphoria with feverish sensation in the chest, palms and soles, etc.) were assessed, the number of retrieved oocytes, rates of high quality oocytes and embryos, fertility rate and clinical pregnancy rate were recorded, and the follicular fluid was collected on the day when the ovum was picked up, the differential protein expression was detected using two-dimensional gel electrophoresis, and then, matrix assisted laser desorption ionization time-of flight mass spectrometry (MALDI-TOF-MS) was applied to identify the proteins. RESULTS: The syndrome score in the treatment group decreased significantly from 16.09±2.58 to 8.67±2.13, while it changed insignificantly in the control group, with a significant difference in the lowering score between the two groups (P<0.05); the high quality rates of oocytes and embryos and clinical pregnancy rate were all superior in the treatment group to the control group (82.29% vs 78.08%, 76.76% vs 68.79%, 63.64% vs 36.36%, all P<0.05). The protein expression map from the follicular fluid showed that compared with the control group, 33 differential protein expressions were found in the syndrome-control group, among which 18 were down-regulated, and 15 up-regulated; in the treatment group 28 differential protein expressions were found, among which 15 were down-regulated, and 13 up-regulated. Through MALDI-TOF-MS, 14 proteins were identified (P<0.05). CONCLUSIONS: For the infertility patients undergoing IVF, LDG could alleviate clinical symptoms, improve rates of high quality oocytes and embryos, so as to raise clinical pregnancy rate. The mechanism may be through regulating proteome expression in the follicular fluid to improve the developmental microenvironment for oocytes which would lead to a successful embryo implantation.