1. Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing.
作者:Wei Datsen George , Chiang Vicki , Fyne Elizabeth , Balakrishnan Mini , Barnes Tiffany , Graupe Michael , Hesselgesser Joseph , Irrinki Alivelu , Murry Jeffrey P , Stepan George , Stray Kirsten M , Tsai Angela , Yu Helen , Spindler Jonathan , Kearney Mary , Spina Celsa A , McMahon Deborah , Lalezari Jacob , Sloan Derek , Mellors John , Geleziunas Romas , Cihlar Tomas
期刊:PLoS pathogens
日期:2014-04-10
DOI :10.1371/journal.ppat.1004071
Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 µM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART.
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1区Q1影响因子: 4.8
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2. Delta EEG band as a marker of left hypofrontality for language in schizophrenia patients.
Frontal hypoactivation has consistently been demonstrated in schizophrenia patients. We hypothesized that this well-known deficit is asymmetrical, ie, centered over left frontal locations and, in-line with Crow's theory, associated with both loss of linguistic asymmetry and correlated with positive symptoms. Electroencephalography delta band was used as a quantitative index of cortical inhibition in 17 paranoid schizophrenia patients with prevailing positive symptoms and 17 matched control subjects. Delta amplitude was measured by 38 electrodes, while participants performed 3 linguistic tasks, visuoperceptual, rhyming, and semantic judgment. Compared with control subjects, patients did not show overall delta band differences, revealing no detrimental effects of pharmacological treatment. In healthy participants, analysis of 4 quadrants/regions of interest revealed higher delta amplitude in right vs left anterior sites, indicating significant left anterior disinhibition during linguistic processing. Instead, patients showed bilateral delta band distribution and, compared with control subjects, significant greater delta amplitude (ie, brain inhibition) in linguistic left anterior centers. Patients' left hypofrontality was functionally related to their lack of hemispheric specialization for language and was positively correlated with higher levels of delusions (P1) and conceptual disorganization (P2) Positive and Negative Syndrome Scale subscales. Results suggest, in schizophrenia patients, a functional deficit of Broca's area, a region playing a fundamental hierarchical role between and within hemispheres by integrating many basic processes in linguistic and conceptual organization. The significant correlation between lack of anterior asymmetry and increased positive symptoms is in-line with Crow's hypothesis postulating the etiological role of disrupted linguistic frontal asymmetry on the onset of the key symptoms of schizophrenia.
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3区Q1影响因子: 5.3
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3. The advances of methotrexate resistance in rheumatoid arthritis.
作者:Yu Jun , Zhou Peng
期刊:Inflammopharmacology
日期:2020-08-05
DOI :10.1007/s10787-020-00741-3
Rheumatoid arthritis (RA) is a systemic autoimmune disease, which is characterized by a chronic fluctuating course and immune dysfunction, resulting in affecting the health and life quality of RA patients. Methotrexate (MTX), as the standard gold treatment of RA, has received more and more clinical applications and basic pharmacological research. In several observational studies, MTXR, and treatment responses in RA patients show that the ratio of MTXR and non- response is about 30%-50%, namely MTX resistance (MTXR). Extensive efforts have been made into the investigation of the mechanism and effective biomarkers in MTXR of RA. In this paper, we discuss the recent findings regarding the critical signaling pathways of MTXR in RA. Provide research targets and directions for a drug therapy that develop preventive strategies and effective treatments of MTXR.
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3区Q1影响因子: 5.9
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4. Animal models of drug-induced pulmonary fibrosis: an overview of molecular mechanisms and characteristics.
期刊:Cell biology and toxicology
日期:2021-11-05
DOI :10.1007/s10565-021-09676-z
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by progressive loss of pulmonary function. Drug-induced interstitial lung disease has been reported as a severe adverse effect of some drugs, such as bleomycin, amiodarone, and methotrexate. Based on good characteristics, drug-induced pulmonary fibrosis (PF) animal model has played a key role in our understanding of the molecular mechanisms of PF pathogenesis and recapitulates the specific pathology in patients and helps develop therapeutic strategies. Here, we summarize the mechanisms and characteristics of given fibrotic drug-induced animal models for PFs. Together with the key publications describing these models, this brief but detailed overview would be helpful for the pharmacological research with animal models of PFs. Potential mechanisms underlying drug induced lung toxicity.