By using a cre-lox conditional knockout strategy, we report here the generation of androgen receptor knockout (ARKO) mice. Phenotype analysis shows that ARKO male mice have a female-like appearance and body weight. Their testes are 80% smaller and serum testosterone concentrations are lower than in wild-type (wt) mice. Spermatogenesis is arrested at pachytene spermatocytes. The number and size of adipocytes are also different between the wt and ARKO mice. Cancellous bone volumes of ARKO male mice are reduced compared with wt littermates. In addition, we found the average number of pups per litter in homologous and heterozygous ARKO female mice is lower than in wt female mice, suggesting potential defects in female fertility and/or ovulation. The cre-lox ARKO mouse provides a much-needed in vivo animal model to study androgen functions in the selective androgen target tissues in female or male mice

The roles of the androgen receptor (AR) in female fertility and ovarian function remain largely unknown. Here we report on the generation of female mice lacking AR (AR ؊/؊ ) and the resulting influences on the reproductive system. Female AR ؊/؊ mice appear normal but show longer estrous cycles and reduced fertility. The ovaries from sexually mature AR ؊/؊ females exhibited a marked reduction in the number of corpora lutea. After superovulation treatment, the AR ؊/؊ ovaries produced fewer oocytes and also showed fewer corpora lutea. During the periovulatory period, an intensive granulosa apoptosis event occurs in the AR ؊/؊ preovulatory follicles, concurrent with the down-regulation of p21 and progesterone receptor expression. Furthermore, the defective conformation of the cumulus cell-oocyte complex from the AR ؊/؊ females implies a lower fertilization capability of the AR ؊/؊ oocytes. In addition to insufficient progesterone production, the diminished endometrial growth in uteri in response to exogenous gonadotropins indicates that AR ؊/؊ females exhibit a luteal phase defect. Taken together, these data provide in vivo evidence showing that AR plays an important role in female reproduction.

Four new guaiane-type sesquiterpenes (1S,4S,5S,10R)-zedoarondiol, zedoalactones D, E, and F (1-4), along with 10 known ones (5-14), were isolated from Curcuma wenyujin Y.H. Chen et C. Ling. The structures of these new compounds were elucidated by spectroscopic methods. The inhibitory effects of compounds 1-14 on nitric oxide production in lipopolysaccharide-activated macrophages were evaluated.

No abstract

Mitochondrial fission catalyzed by dynamin-related protein 1 (Drp1) is necessary for mitochondrial biogenesis and maintenance of healthy mitochondria. However, excessive fission has been associated with multiple neurodegenerative disorders, and we recently reported that mice with smaller mitochondria are sensitized to ischemic stroke injury. Although pharmacological Drp1 inhibition has been put forward as neuroprotective, the specificity and mechanism of the inhibitor used is controversial. Here, we provide genetic evidence that Drp1 inhibition is neuroprotective. Drp1 is activated by dephosphorylation of an inhibitory phosphorylation site, Ser637. We identify Bb2, a mitochondria-localized protein phosphatase 2A (PP2A) regulatory subunit, as a neuron-specific Drp1 activator in vivo. Bb2 KO mice of both sexes display elongated mitochondria in neurons and are protected from cerebral ischemic injury. Functionally, deletion of Bb2 and maintained Drp1 Ser637 phosphorylation improved mitochondrial respiratory capacity, Ca 21 homeostasis, and attenuated superoxide production in response to ischemia and excitotoxicity in vitro and ex vivo. Last, deletion of Bb2 rescued excessive stroke damage associated with dephosphorylation of Drp1 S637 and mitochondrial fission. These results indicate that the state of mitochondrial connectivity and PP2A/Bb2-mediated dephosphorylation of Drp1 play a critical role in determining the severity of cerebral ischemic injury. Therefore, Bb2 may represent a target for prophylactic neuroprotective therapy in populations at high risk of stroke.

The present study focused on the involvement of gamma-aminobutyric acid transporter I (GAT1) in pain. We found that GABA uptake was increased in mouse spinal cord at 20 min and 120 min after formalin injection and in mouse brain at 120 min, but not 20 min, after formalin injection. In addition, the antinociceptive effects of GAT1-selective inhibitors were examined using assays of thermal (tail-flick) and chemical (formalin and acetic acid) nociception in C57BL/6J mice. The GAT1-selective inhibitors, ethyl nipecotate and NO-711, exhibited significant antinociceptive effects in these nociceptive assays. To study further the effects of GAT1 on pain, we used two kinds of GAT1-overexpressing transgenic mice (under the control of a CMV promoter or a NSE promoter) to examine the nociceptive responses in these mice. In the thermal, formalin, and acetic acid assays, both kinds of transgenic mice displayed significant hyperalgesia after nociceptive stimuli. In addition, the micro opioid receptor antagonist naloxone had no influence on nociceptive responses in wild-type and transgenic mice. The results indicate that GAT1 is involved in the regulation of pain processes, and point to the possibility of developing analgesic drugs that target GAT1 other than opioid receptors.

ABSTRACT:The androgen receptor (AR), a member of the nuclear receptor superfamily, is a ligand-dependent transcription factor involved in regulating expression of an array of androgen-responsive genes. AR-mediated androgen actions play the important roles in male and female reproductive development and function. AR mutations can cause a diverse range of diseases, such as testicular feminization mutation (Tfm) syndrome, prostate cancer, and Kennedy's disease. However, because of a lack of genetic models, the molecular mechanisms involved in the physiological and pathological effects of androgen-AR function in male and female reproductive health remains largely unknown. To get a better insight into the molecular working mechanisms of the AR, a global and several cellspecific conditional knockout mouse models have been developed. These models are reviewed here, and the phenotypes of the different cell-specific androgen receptor knockout (ARKO) mice are compared with those of the global ARKO mice.

γ-Aminobutyric acid and GABAergic receptors were previously reported to be distributed in reproductive systems besides CNS and predicted to participate in the modulation of testicular function. γ-Aminobutyric acid transporter was implicated to be involved in this process. However, the potential role of γ-aminobutyric transporter in testis has not been explored. In this study, we investigated the existence of mouse gaminobutyric acid transporter subtype I (mGAT1) in testis. Wild-type and transgenic mice, which overexpressing mGAT1 in a variety of tissues, especially in testis, were primarily studied to approach the profile of mGAT1 in testis. Mice with overexpressed mGAT1 develop normally but with reduced mass and size of testis as compared with wild-type. Testicular morphology of transgenic mice exhibited overt abnormalities including focal damage of the spermatogenic epithelium accompanied by capillaries proliferation and increased diameter of seminiferous tubules lumen. Reduced number of spermatids was also found in some seminiferous tubules. Our results clearly demonstrate the presence of GAT1 in mouse testis and imply that GAT1 is possibly involved in testicular function.