Our previous study demonstrated that phosphodiesterase 8(PDE8)could work as a potential target for vascular dementia(Va D)using a chemical probe 3a.However,compound 3a is a chiral compound which was obtained by chiral...Our previous study demonstrated that phosphodiesterase 8(PDE8)could work as a potential target for vascular dementia(Va D)using a chemical probe 3a.However,compound 3a is a chiral compound which was obtained by chiral resolution on HPLC,restricting its usage in clinic.Herein,a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors.Lead 15 exhibited potent inhibitory activity against PDE8A(IC_(50)=11 nmol/L),high selectivity over other PDEs,and remarkable drug-like properties(worthy to mention is that its bioavailability was up to 100%).Oral administration of 15 significantly improved the c AMP level of the right brain and exhibited dosedependent effects on cognitive improvement in a Va D mouse model.Notably,the X-ray crystal structure of the PDE8A—15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shapedπ—πinteractions with Phe785 as well as a unique H-bond network,which have never been observed in other PDE-inhibitor complex before,providing new strategies for the further rational design of novel selective inhibitors against PDE8.展开更多
OBJECTIVE： The leaves of Parquetina nigrescens have been claimed in folk medicine to be useful for managing sexual dysfunction, but there is inadequate scientific evidence for this claim. This investigation was condu...OBJECTIVE： The leaves of Parquetina nigrescens have been claimed in folk medicine to be useful for managing sexual dysfunction, but there is inadequate scientific evidence for this claim. This investigation was conducted to assess the effects of aqueous leaf extract of Parquetina nigrescens （AEPN） in rats induced with sexual dysfunction. METHODS： Male rats were allocated into various groups after being induced into sexual dysfunction with paroxetine hydrochloride. The groups were treated with distilled water, PowMaxM （reference drug）, and the AEPN at 20, 40 and 80 mg/kg body weight （BW） respectively for 7 d. Frequencies of mount （MF）, intromission （IF）, ejaculation （EF）, as well as latencies of mount （ML）, intromission （IL） and post - ejaculatory interval （PEI） were progressively monitored with receptive female rats on days 1, 3 and 7. The precentage of mounted, intromitted, and ejaculated rats, intromission ratio （IR）, copulatory efficiency （CE） and intercopulatory interval （ICI） were also computed. Standard methods were employed to determine the levels of serum luteinizing and follicle stimulating hormones （LH and FSH）, testosterone, nitric oxide （NO） and the activity of phosphodiesterase V （PDE5）. RESULTS： The plant contained alkaloids, saponins, flavonoids, cardiac glycosides, steroids, tannins, phlobatannins, cardenolides, phenolics, anthraquinones and triterpenes with alkaloids （2.32 mg/g） occurring in greatest quantity while flavonoids, anthraquinones and cardenolides （0.01 mg/g, each） were the least. All the 20 standard amino acids were detected in the plant leaf, with the lowest concentration being 0.30 mg/g for methionine and the highest being 2.12 mg/g for cysteine. Furthermore, P. nigrescens leaves contained Na, K, Fe, Mg, Zn, Ca, Cu, Mn, P, Pb, Cd, Ni, Cr, and Co, with Fe present in the highest and Co the lowest concentrations. Paroxetine significantly （P〈0.05） reduced MF, IF, EF, percentage mounted, intromitted, ejaculat展开更多
为研究猪链球菌2型(Streptococcus suis serotype 2,SS2)环二腺苷酸(c-di-AMP)水解蛋白GdpP的生化特性,根据已公布的SS2中国强致病株98HAH33全基因组中的gdpP序列信息设计引物,以SS2强致病株HA9801基因组为模板,通过PCR方法克隆获得了SS...为研究猪链球菌2型(Streptococcus suis serotype 2,SS2)环二腺苷酸(c-di-AMP)水解蛋白GdpP的生化特性,根据已公布的SS2中国强致病株98HAH33全基因组中的gdpP序列信息设计引物,以SS2强致病株HA9801基因组为模板,通过PCR方法克隆获得了SS2的c-di-AMP水解蛋白基因gdpP完整序列,其阅读框由1 965个核苷酸组成,编码654个氨基酸。应用大肠杆菌重组表达系统,表达、纯化了GdpP,进而分析了其体外生物活性,结果显示纯化的重组蛋白可以在体外水解c-di-AMP形成pApA。其水解酶活性在碱性环境条件下(pH 8.0)相对较强,而在酸性环境下(pH 6.0,6.5)未检测到活性;同时,水解酶活性还依赖于二价金属离子Mg2+、Mn2+以及Co2+的存在,且在Mn2+存在的条件下相对活性最强,而在Ca2+、Fe2+和Cu2+存在的条件下则均未表现出活性。上述结果为进一步深入研究c-di-AMP在猪链球菌2型中发挥的生物学功能奠定了基础。展开更多
基金supported by the Natural Science Foundation of China(21877134,22077143,81903542,and 21977127)Science Foundation of Guangzhou City(201904020023,China)+3 种基金Fundamental Research Funds for Hainan University(KYQD(ZR)21031,China)Science Foundation of Guangdong Province(2019A1515011883,China)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093,China)Guangdong Province Higher Vocational Colleges&Schools Pearl River Scholar Funded Scheme(2016,China)。
文摘Our previous study demonstrated that phosphodiesterase 8(PDE8)could work as a potential target for vascular dementia(Va D)using a chemical probe 3a.However,compound 3a is a chiral compound which was obtained by chiral resolution on HPLC,restricting its usage in clinic.Herein,a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors.Lead 15 exhibited potent inhibitory activity against PDE8A(IC_(50)=11 nmol/L),high selectivity over other PDEs,and remarkable drug-like properties(worthy to mention is that its bioavailability was up to 100%).Oral administration of 15 significantly improved the c AMP level of the right brain and exhibited dosedependent effects on cognitive improvement in a Va D mouse model.Notably,the X-ray crystal structure of the PDE8A—15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shapedπ—πinteractions with Phe785 as well as a unique H-bond network,which have never been observed in other PDE-inhibitor complex before,providing new strategies for the further rational design of novel selective inhibitors against PDE8.
文摘OBJECTIVE： The leaves of Parquetina nigrescens have been claimed in folk medicine to be useful for managing sexual dysfunction, but there is inadequate scientific evidence for this claim. This investigation was conducted to assess the effects of aqueous leaf extract of Parquetina nigrescens （AEPN） in rats induced with sexual dysfunction. METHODS： Male rats were allocated into various groups after being induced into sexual dysfunction with paroxetine hydrochloride. The groups were treated with distilled water, PowMaxM （reference drug）, and the AEPN at 20, 40 and 80 mg/kg body weight （BW） respectively for 7 d. Frequencies of mount （MF）, intromission （IF）, ejaculation （EF）, as well as latencies of mount （ML）, intromission （IL） and post - ejaculatory interval （PEI） were progressively monitored with receptive female rats on days 1, 3 and 7. The precentage of mounted, intromitted, and ejaculated rats, intromission ratio （IR）, copulatory efficiency （CE） and intercopulatory interval （ICI） were also computed. Standard methods were employed to determine the levels of serum luteinizing and follicle stimulating hormones （LH and FSH）, testosterone, nitric oxide （NO） and the activity of phosphodiesterase V （PDE5）. RESULTS： The plant contained alkaloids, saponins, flavonoids, cardiac glycosides, steroids, tannins, phlobatannins, cardenolides, phenolics, anthraquinones and triterpenes with alkaloids （2.32 mg/g） occurring in greatest quantity while flavonoids, anthraquinones and cardenolides （0.01 mg/g, each） were the least. All the 20 standard amino acids were detected in the plant leaf, with the lowest concentration being 0.30 mg/g for methionine and the highest being 2.12 mg/g for cysteine. Furthermore, P. nigrescens leaves contained Na, K, Fe, Mg, Zn, Ca, Cu, Mn, P, Pb, Cd, Ni, Cr, and Co, with Fe present in the highest and Co the lowest concentrations. Paroxetine significantly （P〈0.05） reduced MF, IF, EF, percentage mounted, intromitted, ejaculat
基金supported by the Special Fund for Basic Scientific Research of Central Colleges,South-Central University for Nationalities(CZY11004)in part by the National Institutes of Health(RC1MH088480)+1 种基金Natural Science Foundation(CHE-1111761)National Natural Science Foundation of China(20602014,20503008,20372023,21273089)
