Inhibition of RIPK1 by ZJU-37 promotes oligodendrocyte progenitor proliferation and remyelination via NF-κB pathway.

Receptor interacting serine/threonine protein kinase 1 (RIPK1) activation and necroptosis have been genetically and mechanistically linked with human multiple sclerosis and neurodegenerative diseases for which demyelination is a common key pathology. Demyelination can be healed through remyelination which is mediated by new oligodendrocytes derived from the adult oligodendrocyte progenitor cells (OPCs). Unfortunately, the efficiency of remyelination declines with progressive aging partially due to the depletion of OPCs following chronic or repeated demyelination. However, to our knowledge, so far there is no drug which enhances proliferation of OPCs, and it is unknown whether inhibiting RIPK1 activity directly affect OPCs, the central player of remyelination. Using TNFα induced RIPK1-dependent necroptosis in Jurkat FADD-/- cells as a cell death assay, we screened from 2112 FDA-approved drugs and the drug candidates of new RIPK1 inhibitors selected by ourselves, and identified ZJU-37, a small molecule modified by introducing an amide bond to Nec-1s, is a new RIPK1 kinase inhibitor with higher potency than Nec-1s which has the best reported potency. We unveil in addition to protecting myelin from demyelination and axons from degeneration, ZJU-37 exhibits a new role on promoting proliferation of OPCs and enhancing remyelination by inhibiting RIPK1 kinase activity with higher potency than Nec-1s. Mechanistically, ZJU-37 promotes proliferation of OPCs by enhancing the transcription of platelet derived growth factor receptor alpha via NF-κB pathway. This work identifies ZJU-37 as a new drug candidate which enhances remyelination by promoting proliferation of OPCs, paving the way for a potential drug to enhance myelin repair.

Stent insertion with high-intensity focused ultrasound ablation for distal biliary obstruction secondary to pancreatic carcinoma.

We determined the clinical effectiveness and long-term outcomes in patients with distal biliary obstruction (DBO) secondary to pancreatic carcinoma (PC) who were treated by self-expanded metallic stent (SEMS) insertion with or without high-intensity focused ultrasound (HIFU) ablation.From January 2014 to December 2018, consecutive patients with DBO secondary to PC underwent SEMS insertion with or without HIFU ablation in our center. The long-term outcomes were compared between the 2 groups.During the included period, 75 patients underwent SEMS insertion with (n = 34) or without (n = 41) HIFU ablation in our center. SEMS insertion was successfully performed in all patients. Liver function was significantly improved after SEMS insertion in both groups. An average of 2.9 HIFU treatment sessions per patient were performed. Twenty patients (stent + HIFU group: 7; stent-only group: 13) experienced stent dysfunction (P = .278). The clinical response rate to HIFU ablation was 79.4%. The median stent patency was significantly longer in the stent with HIFU group than in the stent-only group (175 vs 118 days, P = .005). The median survival was significantly longer in the stent with HIFU group compared with the stent-only group (211 versus 136 days, P = .004). An Eastern Cooperative Oncology Group (ECOG) Performance Status of 3 (hazard ratio: 0.300; P = .002) and subsequent HIFU ablation (hazard ratio: 0.508; P = .005) were associated with prolonged survival.HIFU ablation following stent insertion can prolong the stent patency and survival for patients with DBO secondary to PC.

[Photosynthetic mechanism of tea yield and quality affected by different habitats]. / ç”Ÿå¢ƒå¯¹èŒ¶å¶å“è´¨å’Œäº§é‡å½±å“çš„å ‰åˆç”Ÿç†æœºåˆ¶.

To understand photosynthetic mechanism of tea yield and quality, an experiment was conducted with four different typical habitats, including three intercropping patterns (S1:Osmanthus-Tea, S2:Michelia-Tea, S3:Osmanthus-Michelia-Tea) and a control (CK) at Changsha Agricutural Observation Station of Chinese Academy of Sciences. The photosynthetic physiological and ecological characteristics of tea yield and quality were examined. The results showed that the habitats S1, S2, S3 reduced the leaf temperature (TL), photosynthesis active radiation flux (PAR), net photosynthetic rate (Pn), transpiration rate (Tr), and stomatal conductance (gs), as well as the tea polyphenol content. Habitats S1, S2, S3 significantly increased leaf relative humidity (RHS), total amino-acid content of tea, and the yield and quality of tea, with a pattern of S3>S1>S2>CK. The leaves in habitats S1 and S3 could be made into high-grade green tea and famous green tea respectively. Comprehensive indicators showed that habitat S3 is an ideal intercropping pattern for high quality and high yield of tea garden.

[Application of animal models in gingival retraction experimental curriculum].

PURPOSE: To introduce a teaching method for gingival retraction, and evaluate its efficacy for implementation into experimental curricula. METHODS: First, two kinds of animal models using pigs and cows (below 6 months of age) were established. Twenty-two experienced prosthodontists were then asked to apply gingival retraction on each animal model and evaluate the biofidelity of the 2 models' dento-gingival environment. The data was analyzed with SPSS19.0 software package for paired t test.Then, eighty pre-internship students were randomly divided into 2 groups. Besides the traditional teaching (lecture-based teaching), the experimental group (group A) also had access to skill training (using animal models to practice gingival retraction), while the control group (group B) only used the traditional teaching modality. All students' performance in gingival retraction and impression taking were evaluated in their internship. The data was analyzed with SPSS19.0 software package for Chi-square test. RESULTS: Both pig and cow's dento-gingival environment were similar to that of human being, and there was no significant difference between the two models'biofidelities (P>0.05). In addition, both the effect of gingival retraction and the quality of impression in group A were significantly better than those in group B (P<0.05). CONCLUSIONS: Compared with the traditional strategy,practising gingival retraction on animal models can offer greater opportunities for skill development,and be implemented for a wider range of applications.

Association of DENND1A Gene Polymorphisms with Polycystic Ovary Syndrome: A Meta-Analysis.

OBJECTIVE: The rs2479106 and rs10818854 polymorphisms in the DENND1A gene have been reported to be extensively associated with risk of polycystic ovary syndrome (PCOS). However, the results from these studies remained inconclusive and conflicting. To detect a true association of rs2479106 and rs10818854 polymorphisms with PCOS risk, a single study may be underpowered, particularly for those studies with inadequate sample size. Therefore, we performed a meta-analysis of all available studies to explore this association. METHODS: All studies published up to March 2015 on the association were identified by searching electronic databases PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure. Studies containing available genotype frequencies of those 2 polymorphisms were chosen, and the odds ratios and associated 95% confidence intervals were calculated using fixed- or random- effects models. RESULTS: A total of 8 studies about s2479106 polymorphism (8185 cases and 28675 controls) and 5 studies about rs10818854 polymorphism (6638 cases and 27443 controls) met the inclusion criteria for the meta-analysis. Overall, significant increase of PCOS risk was found between DENND1A-rs10818854 and PCOS susceptibility. In addition, we also found an increased risk of PCOS in rs2479106 allele model, heterozygote variant genetic model, and dominant genetic model. CONCLUSION: This meta-analysis suggested that rs2479106 and rs10818854 polymorphisms in the DENND1A gene were associated with increased risk of PCOS. To validate the association between these polymorphisms and PCOS susceptibility, further large and well-designed studies are needed.

Risk factors of polycystic ovarian syndrome among Li People.

OBJECTIVE: To study the relevant risk factors of polycystic ovarian syndrome (PCOS) of Li People so as to provide basis for early diagnosis and treatment of PCOS. METHODS: With case-control study method, 285 cases of PCOS of Li People were as recruited case group, and 580 cases of non-PCOS of female Li People as control group. Questionnaire was adopted to collect data regarding risk factors of PCOS, then the risk factors of PCOS was searched by univariate and multivariate analysis. RESULTS: Multivariate analysis showed that the risk factors of PCOS included in menstrual cycle disorder (OR = 5.824), bad mood (OR = 2.852), family history of diabetes (OR = 7.008), family history of infertility (OR = 11.953), menstrual irregularity of mother (OR = 2.557) and lack of physical exercise (OR = 1.866). CONCLUSIONS: To target the high risk factors of menstrual cycle disorder, family history of diabetes, family history of infertility, family history of diabetes, bad mood and lack of physical exercise of female population, we should implement early screen, diagnose and treatment of POCS in order to reduce the incidence rate of PCOS and improve prognosis of PCOS.

[Effect of SDS on the adsorption of Cd2+ onto amphoteric modified bentonites].

Under different modified ratios, temperatures, pH and ionic strengths, the effect of sodium dodecyl sulfonate (SDS) on the adsorption of Cd2+ onto bentonites which modified with amphoteric modifier dodecyl dimethyl betaine (BS-12) was studied by batch experiments, and the adsorption mechanism was also discussed. Results showed that the adsorption of Cd2+ on amphoteric bentonites can be enhanced significantly by SDS combined modification, Cd2+ adsorption decreases in the order: BS + 150SDS (BS-12 + 150% SDS) > BS + 100SDS (BS-12 + 100% SDS) > BS +50SDS(BS-12 + 50% SDS) > BS + 25SDS (BS-12 + 25% SDS) > BS (BS-12) > CK (unmodified soil). The adsorption isotherm can be described by the Langmuir equation. The change of temperature effect from positive on CK and amphoteric bentonites to negative on BS + 150SDS bentonites is observed with an increase of SDS modified ratio. The pH has little influence on Cd2+ adsorption on bentonites. The adsorption of Cd2+ on bentonites decreases with ionic strength rise, but the effect of ionic strength can be reduced with an increase of SDS modified ratio also. The adsorption thermodynamic parameters demonstrated that the adsorption of Cd2+ on modified bentonites was spontaneously controlled by entropy increment. When the SDS modified ratio is lower than 100% CEC, the adsorption of Cd2+ on modified bentonites is a process with characteristics of both enthalpy increment and entropy increment, while the SDS modified ratio is equal to or higher than 100% CEC, the adsorption of Cd2+ on modified bentonites becomes a process of enthalpy decrement and entropy increment.

Comparison on serum biomarkers for anovulatory and ovulatory dysfunctional uterine bleeding in Lizu females.

OBJECTIVE: To screen, identify, and compare the serum biomarkers between anovulatory dysfunctional uterine bleeding (ADUB) and ovulatory dysfunctional uterine bleeding (ODUB) in Lizu females. METHODS: The subjects included 128 ADUB patients, 63 ODUB patients, and 93 controls. The serum and supernate of the subjects' mense were collected and stored at -80 °C until use. Differential proteins in the sera of three groups were screened using surface-enhanced laser desorption ionization time-of-flight mass spectrometry. The screened proteins were then identified by tricine-SDS-PAGE gel and spectrometry. Protein expression levels in the menses of ADUB, ODUB, and control subjects were determined using ELISA, RT-PCR, and Western blotting. SPSS 14.1 was used for statistical analysis and chart drawing (α = 0.05). RESULTS: Three differential protein peaks with peak values of 11.80, 13.59, and 14.68 km/z were screened and identified as serum amyploid protein A (SAA), vascular endothelial growth factor, and vitamin K epoxide reductase, respectively. The SAA was highly expressed in the menses of ADUB and ODUB patients but poorly expressed in the controls. The vascular endothelial growth factor was highly expressed in the menses of ODUB and controls but poorly expressed in ADUB patients. Meanwhile, the vitamin K epoxide reductase was highly expressed in the menses of ADUB and control subjects but poorly expressed in ODUB patients. CONCLUSIONS: The SAA is the common serum biomarker of ADUB and ODUB. ADUB may be related to angiogenesis impairment, whereas ODUB may be associated with blood coagulation disruption.

Estrogen up-regulates MMP2/9 expression in endometrial epithelial cell via VEGF-ERK1/2 pathway.

OBJECTIVE: To study the effect of estrogen on anovulatory dysfunctional uterine bleeding (ADUB). METHODS: Primary endometrial epithelial cells of Hainan Lizu female was cultured and hydrolytic activity of gelatinase was determined by gelatin zymography analysis. Cellular mRNA and protein synthesis was blocked respectively to determine whether the increased expression of MMP-2/9 was induced by estrogen. The expression of VEGF was blocked by siRNA. After treatment with various factors, MMP-9, VEGF, total Erk and phosphorylated Erk expression in primary uterine epithelial cells was detected by Western blotting analysis. Cell MMP-2/9mRNA levels was measured by real-time RT-PCR. RESULTS: The activity and expression of MMP2/9 was increased in the endometrium of patients with ADUB. Estrogen could up-regulate the expression of VEGF and activate Erk 1/2-Elk1 signal path. After interference by siRNA, ERK1/2 pathway was blocked in cells, and the expression of MMP-2/9 was down-regulated. ERK1/2 specific blocker U0126 blocked ERK phosphorylation, and it could down-regulate the expression of MMP-2/9. CONCLUSIONS: The results showed that the estrogen can increase the expression of VEGF, and thus activate ERK1/2 pathway to induce MMP-2/9 expression.

Effects of selenium intervention on chronic fluorosis-induced renal cell apoptosis in rats.

This study aims to explore the effect of selenium in fluoride-induced renal cell apoptosis in rats and determine the optimal level of selenium in drinking water to prevent fluorosis. Experimental animals were divided into a control group, a sodium fluoride-treated group (NaF, 50 mg/L), three sodium selenite-treated groups (Na2SeO3, 0.375, 0.75, and 1.5 mg/L), and three selenium + NaF-treated groups (Na2SeO3, 0.375, 0.75, and 1.5 mg/L; NaF, 50 mg/L). Ultrastructural changes in the kidney tissues of each group were observed by transmission electron microscopy. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and the expressions of Bcl-2 and Bax proteins were detected by immunohistochemical methods. The expressions of Bcl-2 and Bax mRNA were detected by reverse transcription-polymerase chain reaction. The results showed that Bcl-2, Bax, and Bax/Bcl-2 protein expressions in the fluoride and high selenium groups were highly elevated compared with the control group (P < 0.01). Bax expression in the low selenium group and Bcl-2, Bax, and Bax/Bcl-2 protein expressions in the moderate selenium groups were observably elevated (P < 0.05). Bax and Bax/Bcl-2 expressions in the fluoride group and Bax mRNA expression in the high selenium group were highly elevated (P < 0.01). Bax/Bcl-2 mRNA expression in the high selenium group was also highly elevated (P < 0.05). Compared with the fluoride group, the group treated with low selenium has Bax protein expression that was observably reduced (P < 0.05); the group treated with moderate selenium has Bcl-2 protein expression that was observably elevated (P < 0.05), Bax protein expression that was highly reduced (P < 0.01), and Bax/Bcl-2 protein expression that was observably reduced (P < 0.05); the group treated with high selenium has Bcl-2 protein expression that was highly elevated (P < 0.01), Bax protein expression that was highly elevated (P < 0.01), and Bax/Bcl-2 protein expression that was highly reduced (P < 0.01); the groups treated with moderate selenium and high selenium have Bax mRNA expression that was highly reduced (P < 0.01), and the groups treated with high selenium have Bax/Bcl-2 mRNA expression that was observably reduced (P < 0.05). Selenium may inhibit the apoptosis of renal cells in fluorosis rats by regulating the expressions of Bcl-2 and Bax. The optimal dose of Na2SeO3 to protect against fluoride-induced renal cell apoptosis was determined to be 1.5 mg/L.

Safety assessment of ovarian cryopreservation and transplantation in nude mice bearing human epithelial ovarian cancer.

OBJECTIVE: Nude mice with orthotopic transplantation of human ovarian epithelial cancer were used to investigate screening criteria for paraneoplastic normal ovarian tissue and the security of the freezing and thawing for ovarian tissue transplantation. METHODS: Expression of CK-7, CA125, P53, survivin, MMP-2/TIMP- 2 in paraneoplastic normal ovarian tissues were detected by RT-PCR as well as immunohistochemistry. The tissues of the groups with all negative indicators of RT-PCR, all negative indicators of immunohistochemistry, negative expression of CK-7, CA125 and survivin, positive expression of CK-7, CA125 and survivin, cancer tissues and normal ovarian tissues of nude mice were used for freezing and thawing transplantation, to analyze overt and occult carcinogenesis rates after transplantation. RESULTS: When all indicators or the main indicators, CK-7, CA125 and survivin, were negative, tumorigenesis did not occur after transplantation. In addition the occult carcinogenesis rate was lower than in the group with positive expression of CK-7, CA125 and survivin (P<0.01). After subcutaneous and orthotopic transplantation of ovarian tissues, rates did not change (P>0.05). There was no statistical significance among rates after transplantation of ovarian tissues which were obtained under different severity conditions (P>0.05). CONCLUSION: Negative expression of CK-7, CA125 and survivin can be treated as screening criteria for security of ovarian tissues for transplantation. Immunohistochemical methods can be used as the primary detection approach. Both subcutaneous and orthotopic transplantation are safe. The initial severity does not affect the carcinogenesis rate after tissue transplantation. Freezing and thawing ovarian tissue transplantation in nude mice with human epithelial ovarian carcinoma is feasible and safe.

[Adsorption kinetics of phenol on organic modified Lou soil].

Using batch experiment, the adsorption kinetics of phenol on both tillage layer (TL) and clay layer (CL) of Lou soil modified with cetyltrimethylammonium bromide (CTMAB, CB) at various ratio (100 CB and 50 CB) and cetyltrimethylammonium bromide + sodium dodecylsulphonate (CTMAB + SDS, CS) mixture were carried out, and its mechanism was discussed also. The results showed that two adsorption velocity parameters of phenol, total-adsorption-velocity (Vt) and fast-adsorption-velocity (Vf), on both layers of modified soil are 2.64-3.31 microg x (g x h)(-1), 39.19-61.23 microg (g x h)(-1) at low added phenol concentration respectively and 13.09-16.30 microg (g x h)(-1), 247.87-325.64 microg (g x h)(-1) at high added phenol concentration respectively at two experimental temperature, moreover, the two velocity parameters have a same sequence in different modification treatments, i.e., ordered by 100 CB > 120 CS > 50 CB > CK in TL treatment and by 100 CB > 50 CB > 120 CS> CK in CL treatment. These outcomes indicated that the modification on the both layers of Lou soil increases significantly the adsorption velocity of phenol. The adsorption of phenol is divided into two stages, fast adsorption and slow adsorption, in which the adsorption of phenol is primarily decided by the fast adsorption while it is affected little by slow adsorption. Therefore, the velocity parameters that relate with the fast adsorption have better correlation between them. The time of conversion (t(c)) between fast adsorption and slow adsorption in modified soil is less than 2 h, and shows a reverse sequence in different modification treatments compared to the adsorption velocity parameters. The adsorption velocity of modified CL to phenol is higher than that of modified TL. The adsorption velocity of organic modified soil to phenol can be increased by an increase of both temperature and added concentration of phenol. The exponential II kinetic model is the best model to describe the adsorption kinetic curves of phenol on modified soil, furthermore, the fitted parameter A has better correlation with the velocity parameters related to the fast adsorption while the fitted parameter--B, which can become a characteristic parameter to describe the adsorption velocity, has better correlation with the time of conversion to. The adsorption of phenol on the modified soil is primarily decided by the hydrophobic adsorption of organic phase on the surface of modified soil.