PPARγ up-regulates TGFβ/smad signal pathway repressor c-Ski / 生理学报

TGFβ/smad pathway is recognized as an important signal pathway to promote the pathogenesis of atherosclerosis (AS). Peroxisome proliferator-activated receptor γ (PPARγ) activation is considered to be important in modulating AS. Herein, we investigated the regulation of PPARγ on c-Ski, the repressor of TGFβ/smad pathway, in rat AS model and cultured vascular smooth muscle cells (VSMCs). c-Ski mRNA and protein expression were detected by real-time PCR and Western blot, respectively, in vivo and in vitro with treatment of PPARγ agonist rosiglitazone and antagonist GW9662. The proliferation and collagen secretion of VSMCs after c-Ski transfection were investigated. The underlying mechanism was further investigated by online program NUBIScan and luciferase reporter gene analysis. Results showed that both mRNA and protein expressions of c-Ski in the AS lesions was down-regulated in vivo, while in cultured VSMCs, c-Ski transfection significantly suppressed the proliferation and collagen secretion of rat VSMCs. Rosiglitazone significantly up-regulated mRNA and protein levels of c-Ski in VSMCs, which could be blocked by GW9662. Online NUBIScan analysis suggested possible PPARγ binding sites in the promoter region of c-Ski. In addition, luciferase activity of c-Ski reporter gene was also increased obviously in the presence of rosiglitazone. These results indicate that c-Ski is one of the newly found target genes of PPARγ and thus involved in the anti-AS effect of PPARγ.

Effect of (S)-4C3HPG on brain damage in the acute stage of moderate traumatic brain injury model of mice and underlying mechanism / 生理学报

The aim of this study is to investigate the effect of (S)-4-carboxy-3-hydroxy-phenylglycine [(S)-4C3HPG], a mixed group I glutamate metabotropic receptor antagonist and a group II agonist, on impairment in a cortical impact model of traumatic brain injury (TBI) in mice and to elucidate the possible mechanisms. Mice were injected (i.p.) with saline, 1 mg/kg (S)-4C3HPG, 5 mg/kg (S)-4C3HPG and 10 mg/kg (S)-4C3HPG (n=10 per group), respectively, at 30 min before moderate TBI. Neurological deficit scores, water content in injured brain and glutamate concentration in cerebral spinal fluid (CSF) were detected at 24 h after TBI. The expressions of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) mRNA in injured cortex were also detected by real-time RT-PCR. The results showed that the neurological deficits and cerebral edema were significantly attenuated in mice pretreated with (S)-4C3HPG (5 and 10 mg/kg respectively) compared with those in mice pretreated with saline. Furthermore, (S)-4C3HPG treatment also decreased the glutamate concentration in CSF and the expressions of TNF-α and IL-1β mRNA remarkably in a dose-dependent manner. These results suggest that (S)-4C3HPG treatment attenuates cortical impact-induced brain injury possibly via suppression of glutamate release and inhibition of excessive inflammatory cytokine production. These findings highlight the potential benefit of glutamate metabotropic receptor ligand for preventing TBI.

Different effects of adenosine A2A receptors in the models of traumatic brain injury and peripheral tissue injury / 生理学报

Recently, activation of the adenosine A2A receptors has been shown to exert protection against peripheral tissue injuries but aggravation in the central nervous system (CNS) injuries. To explore the different effects of adenosine A2A receptors and try to perform some new treatment strategies for peripheral tissue and CNS traumas, we constructed the mouse models of skin trauma, skin combined radiation-impaired wound and traumatic brain injury (TBI), respectively. Wild type mice and A2A receptor gene knockout mice were both used in the experiments. In skin trauma and combined radiation-impaired wound models, the time of wound healing was observed, while in TBI model, neurological deficit scores, water content in injured brain and glutamate concentration in cerebral spinal fluid (CSF) were detected at 24 h after TBI. The results showed that in skin trauma and combined radiation-impaired wound models, CGS21680 (an agonist of the A2A receptors) promoted while A2A receptor gene knockout delayed the course of skin wound healing. On the contrary, in TBI model, A2A receptor gene knockout, not CGS21680, showed a protective role by inhibition of glutamate release. These data further indicate that promoting glutamate release may account for the different effects of A2A receptor activation in CNS injury and peripheral tissue injury models. These findings may provide some experimental evidence and a new strategy for clinical treatment of peripheral tissue damages by agonists of A2A receptors, while treatment of CNS injuries by antagonists of A2A receptors.

Establishment of a selective inactivation adenosine A2A receptors mice model / 中华血液学杂志

<p><b>OBJECTIVE</b>To establish a mice model with selective inactivation adenosine A2A receptors (A2ARs) in peripheral white blood cells (PWBC).</p><p><b>METHODS</b>A2ARs were selectively inactivated in PWBCs by transplanting bone marrow cells (BMCs) from A2AR knockout (KO) mice into their wild type (WT) littermates after a single total body irradiation of 9.5 Gy or fractionated total body irradiation of 6.2 Gy x 2. The efficiency of reconstitution of bone marrow-derived cells in chimeric mice was assessed.</p><p><b>RESULTS</b>PCR band patterns changed from the recipient pattern (one band of 330 bp) to the donor (two bands of 300 and 330 bp) pattern. Immunohistochemistry analysis showed that 10.21% of cells were A2AR+ in PWBCs in KO--> WT mice, whereas 96.72% of cells were A2AR+ in WT mice. The survival rates of mice irradiated with 6.2 Gy x 2 and transplanted with more than 6 x 10(6) BMCs were about 91%.</p><p><b>CONCLUSION</b>A murine model of selective inactivation adenosine A2A receptors in PWBCs was established successfully.</p>