Cocaine abuse hastens the neurodegeneration often associated with advanced HIV-1 infection. The mechanisms, in part, revolve around the neuroinflammatory processes mediated by the chemokine monocyte chemotactic protein-1 (MCP-1/ CCL2). Understanding factors that modulate MCP-1 and, in turn, facilitate monocyte extravasation in the brain is thus of paramount importance. We now demonstrate that cocaine induces MCP-1 in rodent microglia through translocation of the sigma receptor to the lipid raft microdomains of the plasma membrane.Sequential activation of Src, mitogenactivated protein kinases (MAPKs), and phosphatidylinositol-3 kinase (PI3K)/Akt and nuclear factor B (NF-B) pathways resulted in increased MCP-1 expression. Furthermore, conditioned media from cocaine-exposed microglia increased monocyte transmigration, and thus was blocked by antagonists for CCR2 or sigma receptor. These findings were corroborated by demonstrating increased monocyte transmigration in mice exposed to cocaine, which was attenuated by pretreatment of mice with the sigma receptor antagonist. Interestingly, cocaine-mediated transmigratory effects were not observed in CCR2 knockout mice. We conclude that cocaine-mediated induction of MCP-1 accelerates monocyte extravasation across the endothelium. Understanding the regulation of MCP-1 expression and functional changes by cocaine/sigma receptor system may provide insights into the development of potential therapeutic targets for HIV-1-associated neurocognitive disorders. IntroductionHIV-1-associated neurocognitive disorders (HANDs) remain a common complication of viral infection despite the advent of antiretroviral therapies (ARTs). One contributing factor is the use of illicit drugs, including but not limited to cocaine. The mechanism by which cocaine augments HANDs has been the subject of intense research. 1,2 One possibility rests in the idea that the drug can "open" the blood brain barrier (BBB), which, in turn, can facilitate transmigration of bloodborne inflammatory monocytes into the brain. 3,4 Although considerable efforts have been made to best understand the cellular and molecular mechanisms underlying the effects of cocaine on proinflammatory factor secretion and BBB function, 5 there exists a paucity of information on the mechanisms by which cocaine influences chemokine secretion and cell migration into and within the central nervous system (CNS).Common neuropathologic correlates for HANDs include BBB disruption, glial activation, neuroinflammation (proinflammatory factors and chemokines), viral replication, and neuronal aberrations. The key factor mediating monocyte-macrophage transmigration across the BBB is the CC chemokine, monocyte chemoattractant protein-1 (MCP-1/CCL2), 6 which mediates its effects by binding to its cognate receptor CCR2. 7 Moreover, the best correlate for cognitive impairment remains the numbers of immune competent brain mononuclear phagocytes (MPs; bloodborne macrophages and microglia). Exploration of mechanisms that modulate MCP-1 in the brain is thus...
is essential for mammalian ovary maintenance. Although sexually dimorphic expression of was observed in many teleosts, its role and regulative mechanism in fish remained largely unclear. In this study, we first identified two transcript variants of and its homologous gene in zebrafish, and revealed their specific expression in follicular layer cells in a sequential and divergent fashion during ovary differentiation, maturation, and maintenance. Then, homozygous mutants () and mutants () were constructed and detailed comparisons, such as sex ratio, gonadal histological structure, transcriptome profiling, and dynamic expression of gonadal development-related genes, were carried out. Initial ovarian differentiation and oocyte development occur normally both in and mutants, but and disruptions result in premature ovarian failure and partial sex reversal, respectively, in adult females. In female mutants,/ signaling was upregulated at 150 days postfertilization (dpf) and subsequently oocyte apoptosis was triggered after 180 dpf. In contrast, expression was greater at 105 dpf and increased several 100-fold in mutated ovaries at 270 dpf, along with other testis-related genes. Finally, homozygous / double mutants were constructed in which complete sex reversal occurs early and testis-differentiation genes robustly increase at 60 dpf. Given mutual compensation between and in and mutants, we proposed a model in which and cooperate to regulate zebrafish ovary development and maintenance, with potentially having a dominant role in preventing the ovary from differentiating as testis, as compared to.
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