The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16␣-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7␣-hydroxylase (Cyp7a1) and the Na ؉ -independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.

We aimed to determine the relative role of quinolinic acid synthesis in purified human microglia, monocyte-derived macrophages and astrocytes in the human brain following immune stimulation. Microglia and macrophages significantly increased quinolinic acid synthesis from tryptophan following activation by either lipopolysaccharide or interferon-gamma. Quinolinic acid synthesis by individual microglia was heterogeneous, and its production by activated macrophages was approximately 32-fold greater than its microglial synthesis. Quinolinic acid synthesis by astrocytes was undetectable. Microglia may, therefore, be the primary endogenous cell type responsible for quinolinic acid synthesis in the brain parenchyma. However, under pathological conditions which precipitate blood-brain barrier compromise and/or leukocytic infiltration, intracerebral quinolinic acid may be derived chiefly from cells of the peripheral immune system such as activated macrophages.

Cells maintain membrane fluidity by regulating lipid saturation, but the molecular mechanisms of this homeoviscous adaptation remain poorly understood. We have reconstituted the core machinery for regulating lipid saturation in baker's yeast to study its molecular mechanism. By combining molecular dynamics simulations with experiments, we uncover a remarkable sensitivity of the transcriptional regulator Mga2 to the abundance, position, and configuration of double bonds in lipid acyl chains, and provide insights into the molecular rules of membrane adaptation. Our data challenge the prevailing hypothesis that membrane fluidity serves as the measured variable for regulating lipid saturation. Rather, we show that Mga2 senses the molecular lipid-packing density in a defined region of the membrane. Our findings suggest that membrane property sensors have evolved remarkable sensitivities to highly specific aspects of membrane structure and dynamics, thus paving the way toward the development of genetically encoded reporters for such properties in the future.

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A human immunodeficiency virus type 1 (HIV) -seropositive, antiretroviral-naive patient presented with significant cognitive dysfunction. Neuropsychologic, neuroradiologic, immunologic, and virologic studies confirmed HIV-associated dementia (HAD). After 12 weeks of highly active antiretroviral therapy (HAART) with ibuprofen, dramatic improvements were demonstrated in neurologic function and were sustained for ú1 year. HIV-1 RNA in cerebrospinal fluid (CSF) decreased from 10 5 to 10 4 copies/mL after 4 weeks. After 20 weeks of therapy, plasma viremia decreased from 10 6 copies/mL to undetectable (õ96 copies/mL). Assays of neurotoxins (tumor necrosis factor-a, quinolinic acid, and nitric oxide) in plasma and CSF were considerably elevated at presentation and significantly decreased after therapy. Baseline plasma and CSF demonstrated neurotoxic activities in vitro, which also reduced markedly. These data, taken together, support the notion that HAD is a reversible metabolic encephalopathy fueled by viral replication. HAART used with nonsteroidal antiinflammatory agents leads to the suppression of inflammatory neurotoxins and can markedly improve neurologic function in HAD.Human immunodeficiency virus type 1 (HIV)-associated deproteins such as gp120, tat, and nef [18][19][20][21][22]. High levels of these macrophage-produced neurotoxic factors have been found mentia (HAD) is characterized by cognitive and motor impairment in 15%-20% of infected patients [1][2][3][4]. Neurologic defiin the brains and cerebrospinal fluid (CSF) of patients with HAD [23][24][25][26]. These factors produce an encephalopathy with cortical cits have been classified by the American Academy of Neurology, and an algorithm has been developed for mild disand subcortical neuronal damage [27] and induce a breakdown of the blood-brain barrier (BBB) [28, 29]. ease (minor cognitive/motor disorder) or more severe impairment (HAD) [1]. Dementia can occur with few neuropathologic HIV RNA levels in CSF correlate with the presence and severity of cognitive dysfunction [30 -33]. If a central nervous changes or with encephalitis characterized by multinucleated giant cells, astrocytosis, microglial nodules, myelin pallor, and system virus is both necessary and sufficient to induce neurologic impairment, therapy for HAD should of necessity target neuronal loss [5,6]. Of interest, clinical disease is not caused by active HIV replication in neural cells. The virus's target cells HIV. Inhibitors of HIV protease in combination with nucleoside analogue reverse transcriptase (RT) inhibitors can dramatiare mononuclear phagocytes (brain macrophages and microglia) [7,8]. Once infected, these cells become immunoactive and cally reduce levels of plasma viremia [34,35]. Unfortunately, many of these agents are highly plasma protein bound and have produce a variety of neurotoxic secretory products [9]. These include but are not limited to cytokines such as tumor necrosis limited BBB penetration [36]. Zidovudine remains the only drug to date with documented efficacy for H...

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Electrolytic lesions of the nucleus raphe dorsalis and medianus reduce the concentration of serotonin (5-hydroxytryptamine) within rat brain intraparenchymal blood vessels. The concentration of serotonin within these vessels increases or decreases after the administration of drugs that modify the biosynthesis and degradation of serotonin or destroy nerve terminals by an uptake-dependent mechanism. These studies provide evidence for the existence of a serotonin-containing pathway seemingly analogous to the neuronal projection that terminates on small parenchymal blood vessels from noradrenergic neurons of the locus coeruleus.