Background and Purpose-Angiotensin-converting enzyme inhibitors have been shown to protect against stroke in hypertensive rats and to improve neurological outcome after cerebral ischemia in normotensive rats. The present study was designated to test the hypothesis that blockade of brain AT 1 receptors improves the recovery from focal cerebral ischemia and reduces expression of AP-1 transcription factors c-Fos and c-Jun, which have been associated with programmed cell death and neurodegeneration. Methods-Experiments were carried out in normotensive male Wistar rats. Focal cerebral ischemia was induced by middle cerebral artery occlusion lasting for 90 minutes and followed by reperfusion. The selective AT 1 receptor antagonist irbesartan was infused intracerebroventricularly over a 5-day period before the induction of ischemia at a dose that inhibited brain but not vascular AT 1 receptors. Twenty-four hours after ischemia, neurological outcome was evaluated and expression of c-Fos and c-Jun proteins in the brain was studied immunocytochemically. Results-Focal

Di-(2-ethylhexyl) phthalate (DEHP) is one of the most commonly used plasticizers, and it is widely applied in various plastic products. DEHP is an endocrine-disrupting chemical (EDC) that has been shown to disrupt the function of reproductive system in females. Although many studies have shown that DEHP potentially causes female reproductive toxicity, including depletion of the primordial follicle and decreased sex hormone production, the specific mechanisms by which DEHP affects female reproduction remain unknown. In recent years, research focused on the intestinal flora has provided an idea to eliminate our confusion, and gut bacterial dysbiosis may contribute to female reproductive toxicity. In the present study, the feces of DEHP-exposed mice were collected and analyzed using 16S rRNA amplicon sequencing and untargeted global metabolite profiling of metabolomics. DEHP obviously causes reproductive toxicity, including the ovarian organ coefficient, estradiol level, histological features of the ovary and estrus. Furthermore, DEHP exposure alters the structure of the intestinal microbiota community and fecal metabolite profile in mice, suggesting that the reproductive toxicity may be caused by gut bacterial dysbiosis and altered metabolites, such as changes in the levels of short-chain fatty acid (SCFA). Additionally, it is well known that changes in gut microbiota and fecal metabolites cause inflammation and tissue oxidative stress, expectedly, we found oxidative stress in the ovary and systemic inflammation in DEHP exposed mice. Thus, based on our findings, DEHP exposure may cause gut bacterial dysbiosis and altered metabolite profiles, particularly SCFA profiles, leading to oxidative stress in the ovary and systemic inflammation to ultimately induce female reproductive toxicity.

Abstract-Stlmulatlon of bram penventncular and hypothalamic substance P receptors mduces a pressor response and tachycardla associated with mesentenc and renal vasoconstrlctlon and hmdhmb vasodllatlon resembhng thus the classical defense reaction This cardiovascular response 1s brought about by the activation of the sympathoadrenal system and 1s accompanied by groommg behavior To address the role of oxytocmerglc pathways m the brain m the medlatlon of these responses, we mvestlgated the effects of central pretreatment of rats with oxytocm annsense, mlxed base, and sense ohgodeoxynucleotldes on mean artenal pressure, heart rate, and grooming behavior mduced by mtracerebroventncular inJections of substance P (50 pmol) Central pretreatment of conscious rats with the oxytocm antisense ohgodeoxynucleotlde (mtracerebroventncular mJectlons, 8 and 4 hours before admmlstratlon of substance P) attenuated the mean arterial pressure (by 55%) and heart rate responses (by 58'Y) o as well as grooming behavior induced by the peptlde A complete recovery of all substance P-induced responses was observed 28 hours after antisense ohgodeoxynucleottde pretreatment Intracerebroventncular pretreatment of rats with nuxed base and sense ohgodeoxynucleotldes &d not affect the cardiovascular and behavioral responses to substance P. The signal for oxytocm mRNA m the paraventrlcular nucleus was reduced only m rats pretreated with the antlsense ohgodeoxynucleotlde These results demonstrate that oxytocm neurons m the paraventncular nucleus, which innervate the cardiovascular centers m the hmdbram and the spinal cord, mediate the Increases m blood pressure and heart rate induced by stlmulatlon of substance P receptors m the forebram These neurons may also transmt signals, which are generated by substance P m the hypothalamus and are responsible for the sympathoadrenal activation m response to stress (Hypertension. 1998;31[part 2]:480-486.)Key Words: substance P w blood pressure H heart rate w behavior n oxytocm n brain N umerous studies have postulated a link between stress, sympathoadrenal actlvatlon, and the pathogenesls of artenal hypertension ' 2 The sympathoadrenal outflow and blood pressure are prmclpally controlled by complex mteractlons between areas localized m the lower brain stem, the hypothalamus, and the mtermedlolateral column of the spinal cord 3*4 A number of neurotransmltters and neuromodulators m the brain participate m the regulation of autonomic functions Substance P (SP), a natural hgand for NK, receptors, acts m the forebrain as a potent activator of the sympathoadrenal system Stlmulatlon ofpenventncular SP receptors or direct mlcromJectlons of the peptlde mto vanous hypothalamic regons mduce an elevation of artenal blood pressure, tachycardla, increase m cardiac output, vasodllatlon m skeletal muscles, and vasoconstnctlon m the splanchmc area and m the kidney 5,6 The central cardiovascular responses produced by SP are brought about by sympathoadrenal stlmulatlon as evidenced by increases m efferent splanchmc and renal ner...

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