Background: Immune stress induced by lipopolysaccharide(LPS) influences the gonadotropin-releasing hormone(GnRH)/luteinizing hormone(LH) secretion. Presence of LPS interacting Toll-like receptor(TLR) 4 in the hypothal...Background: Immune stress induced by lipopolysaccharide(LPS) influences the gonadotropin-releasing hormone(GnRH)/luteinizing hormone(LH) secretion. Presence of LPS interacting Toll-like receptor(TLR) 4 in the hypothalamus may enable the direct action of LPS on the GnRH/LH secretion. So, the aim of the study was to investigate the influence of intracerebroventricular(icv) injection of TLR4 antagonist on GnRH/LH secretion in anestrous ewes during LPS-induced central inflammation. Animals were divided into three groups icv-treated with: Ringer-Locke solution, LPS and TLR4 antagonist followed by LPS.Results: It was demonstrated that TLR4 antagonist reduced LPS-dependent suppression of GnRH gene expression in the preoptic area and in the medial basal hypothalamus, and suppression of receptor for GnRH gene expression in the anterior pituitary gland. It was also shown that TLR4 antagonist reduced suppression of LH release caused by icv injection of LPS. Central administration of LPS stimulated TLR4 gene expression in the medial basal hypothalamus.Conclusions: It was indicated that blockade of TLR4 prevents the inhibitory effect of centrally acting LPS on the GnRH/LH secretion. This suggests that some negative effects of bacterial infection on the hypothalamic-pituitary-gonadal axis activity at the hypothalamic level may be caused by central action of LPS acting through TLR4.展开更多
A series of thiourea derivatives have been synthesized. Their structures were confirmed by MS and 1H NMR. Several compounds showed potent activities as antagonists of CCR4 receptor.
CC chemokine receptor 4(CCR4)is a kind of G-protein-coupled receptor,which plays a pivotal role in allergic inflammation.The interaction between 2-(2-(4-chloro-phenyl)-5-{[(naphthalen-1-ylmethyl)-carbamlyl]-methyl-4-o...CC chemokine receptor 4(CCR4)is a kind of G-protein-coupled receptor,which plays a pivotal role in allergic inflammation.The interaction between 2-(2-(4-chloro-phenyl)-5-{[(naphthalen-1-ylmethyl)-carbamlyl]-methyl-4-oxo-thiazolidin-3-yl)-N-(3-morpholin-4-yl-propyi)-acetamide(S009)and the N-terminal extracellular tail(ML40)of CCR4 has been validated to be high affinity by capillary zone electrophoresis(CZE).The S009 is a known CCR4 antagonist.Now,a series of new thiourea derivatives have been synthesized.Compared with positive control S009,they were screened using ML40 as target by CZE to find some new drugs for allergic inflammation diseases.The synthesized compounds XJH-5,XJH-4,XJH-17 and XJH-1 displayed the interaction with ML40,but XJH-9,XJH-10,XJH-I 1,XJH-12,XJH-13,XJH-14,XJH-3,XJH-8,XJH-6,XJH-7,XJH-15,XJH-16 and XJH-2 did not bind to ML40.Both qualification and quantification characterizations of the binding were determined.The affinity of the four compounds was valued by the binding constant,which was similar with the results of chemotactic experiments.The established CEZ method is capable of sensitive and fast screening for a series of lactam analogs in the drug discovery for allergic inflammation diseases.展开更多
基金supported by the National Science Centre,Poland,Grant No.2013/09/N/NZ9/00212
文摘Background: Immune stress induced by lipopolysaccharide(LPS) influences the gonadotropin-releasing hormone(GnRH)/luteinizing hormone(LH) secretion. Presence of LPS interacting Toll-like receptor(TLR) 4 in the hypothalamus may enable the direct action of LPS on the GnRH/LH secretion. So, the aim of the study was to investigate the influence of intracerebroventricular(icv) injection of TLR4 antagonist on GnRH/LH secretion in anestrous ewes during LPS-induced central inflammation. Animals were divided into three groups icv-treated with: Ringer-Locke solution, LPS and TLR4 antagonist followed by LPS.Results: It was demonstrated that TLR4 antagonist reduced LPS-dependent suppression of GnRH gene expression in the preoptic area and in the medial basal hypothalamus, and suppression of receptor for GnRH gene expression in the anterior pituitary gland. It was also shown that TLR4 antagonist reduced suppression of LH release caused by icv injection of LPS. Central administration of LPS stimulated TLR4 gene expression in the medial basal hypothalamus.Conclusions: It was indicated that blockade of TLR4 prevents the inhibitory effect of centrally acting LPS on the GnRH/LH secretion. This suggests that some negative effects of bacterial infection on the hypothalamic-pituitary-gonadal axis activity at the hypothalamic level may be caused by central action of LPS acting through TLR4.
基金supported by the National High-Tech Research and Development Program of China(863 Program)(No.2006AA10A201)National Natural Science Foundation(No.30472093).
文摘A series of thiourea derivatives have been synthesized. Their structures were confirmed by MS and 1H NMR. Several compounds showed potent activities as antagonists of CCR4 receptor.
基金supported by the National Key New Drug Creation Program of China(2009ZX09103-724)the National Natural Science Foundation of China grants(30872292,90813025 and 81072612)+2 种基金the Natural Science Foundation of Beijing(7102107)the Open Foundation of State Key Laboratory of Natural and Biomimetic Drugs(K20090207)the National New Drug Research and Development Project of China(2009ZX09301-010)
文摘CC chemokine receptor 4(CCR4)is a kind of G-protein-coupled receptor,which plays a pivotal role in allergic inflammation.The interaction between 2-(2-(4-chloro-phenyl)-5-{[(naphthalen-1-ylmethyl)-carbamlyl]-methyl-4-oxo-thiazolidin-3-yl)-N-(3-morpholin-4-yl-propyi)-acetamide(S009)and the N-terminal extracellular tail(ML40)of CCR4 has been validated to be high affinity by capillary zone electrophoresis(CZE).The S009 is a known CCR4 antagonist.Now,a series of new thiourea derivatives have been synthesized.Compared with positive control S009,they were screened using ML40 as target by CZE to find some new drugs for allergic inflammation diseases.The synthesized compounds XJH-5,XJH-4,XJH-17 and XJH-1 displayed the interaction with ML40,but XJH-9,XJH-10,XJH-I 1,XJH-12,XJH-13,XJH-14,XJH-3,XJH-8,XJH-6,XJH-7,XJH-15,XJH-16 and XJH-2 did not bind to ML40.Both qualification and quantification characterizations of the binding were determined.The affinity of the four compounds was valued by the binding constant,which was similar with the results of chemotactic experiments.The established CEZ method is capable of sensitive and fast screening for a series of lactam analogs in the drug discovery for allergic inflammation diseases.
