41 results on '"He, Johnny J."'
Search Results
2. Metformin Treatment Leads to Increased HIV Transcription and Gene Expression through Increased CREB Phosphorylation and Recruitment to the HIV LTR Promoter.
- Author
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Rezaei, Sahar, Timani, Khalid A., and He, Johnny J.
- Subjects
ANTIRETROVIRAL agents ,PHOSPHORYLATION ,COMORBIDITY - Abstract
Antiretroviral therapy has effectively suppressed HIV infection and replication and prolonged the lifespan of HIV-infected individuals. In the meantime, various complications including type 2 diabetes associated with the long-term antiviral therapy have shown steady increases. Metformin has been the front-line anti-hyperglycemic drug of choice and the most widely prescribed medication for the treatment of type 2 diabetes. However, little is known about the effects of Metformin on HIV infection and replication. In this study, we showed that Metformin treatment enhanced HIV gene expression and transcription in HIV-transfected 293T and HIV-infected Jurkat and human PBMC. Moreover, we demonstrated that Metformin treatment resulted in increased CREB expression and phosphorylation, and TBP expression. Furthermore, we showed that Metformin treatment increased the recruitment of phosphorylated CREB and TBP to the HIV LTR promoter. Lastly, we showed that inhibition of CREB phosphorylation/activation significantly abrogated Metformin-enhanced HIV gene expression. Taken together, these results demonstrated that Metformin treatment increased HIV transcription, gene expression, and production through increased CREB phosphorylation and recruitment to the HIV LTR promoter. These findings may help design the clinical management plan and HIV cure strategy of using Metformin to treat type 2 diabetes, a comorbidity with an increasing prevalence, in people living with HIV. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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3. Tat expression led to increased histone 3 tri-methylation at lysine 27 and contributed to HIV latency in astrocytes through regulation of MeCP2 and Ezh2 expression
- Author
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Liu, Ying, Niu, Yinghua, Li, Lu, Timani, Khalid A., He, Victor L., Sanburns, Chris, Xie, Jiafeng, and He, Johnny J.
- Published
- 2019
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4. Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model
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Langford, Dianne, oh Kim, Byung, Zou, Wei, Fan, Yan, Rahimain, Pejman, Liu, Ying, and He, Johnny J.
- Published
- 2018
- Full Text
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5. Function of ubiquitin (Ub) specific protease 15 (USP15) in HIV-1 replication and viral protein degradation
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Pyeon, Dohun, Timani, Khalid Amine, Gulraiz, Fahad, He, Johnny J., and Park, In-Woo
- Published
- 2016
- Full Text
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6. Tip110: Physical properties, primary structure, and biological functions
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Whitmill, Amanda, Timani, Khalid Amine, Liu, Ying, and He, Johnny J.
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- 2016
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- View/download PDF
7. The anticancer drug sunitinib promotes autophagyand protects from neurotoxicity in an HIV-1 Tat model of neurodegeneration
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Fields, Jerel A., Metcalf, Jeff, Overk, Cassia, Adame, Anthony, Spencer, Brian, Wrasidlo, Wolfgang, Florio, Jazmin, Rockenstein, Edward, He, Johnny J., and Masliah, Eliezer
- Published
- 2017
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8. Exosome-associated release, uptake, and neurotoxicity of HIV-1 Tat protein
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Rahimian, Pejman and He, Johnny J.
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- 2016
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9. HIV/neuroAIDS biomarkers
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Rahimian, Pejman and He, Johnny J.
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- 2017
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10. HIV Tat Expression and Cocaine Exposure Lead to Sex- and Age-Specific Changes of the Microbiota Composition in the Gut.
- Author
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Li, Lu, Zhao, Xiaojie, and He, Johnny J.
- Subjects
GENE expression ,AMINO acid metabolism ,HIV ,GUT microbiome ,COCAINE ,HIV infections ,LIPID metabolism - Abstract
The balance of microbial communities in the gut is extremely important for normal physiological function. Disruption of the balance is often associated with various disorders and diseases. Both HIV infection and cocaine use are known to change the gut microbiota and the epithelial barrier integrity, which contribute to inflammation and immune activation. Our recent study shows that Tat expression and cocaine exposure result in changes of genome-wide DNA methylation and gene expression and lead to worsen the learning and memory impairments. In the current study, we extended the study to determine effects of Tat and cocaine on the gut microbiota composition. We found that both Tat expression and cocaine exposure increased Alteromonadaceae in 6-month-old female/male mice. In addition, we found that Tat, cocaine, or both increased Alteromonadaceae, Bacteroidaceae, Cyanobiaceae, Erysipelotrichaceae, and Muribaculaceae but decreased Clostridiales_vadinBB60_group, Desulfovibrionaceae, Helicobacteraceae, Lachnospiraceae, and Ruminococcaceae in 12-month-old female mice. Lastly, we analyzed changes of metabolic pathways and found that Tat decreased energy metabolism and nucleotide metabolism, and increased lipid metabolism and metabolism of other amino acids while cocaine increased lipid metabolism in 12-month-old female mice. These results demonstrated that Tat expression and cocaine exposure resulted in significant changes of the gut microbiota in an age- and sex-dependent manner and provide additional evidence to support the bidirectional gut–brain axis hypothesis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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11. HIV Nef Expression Down-modulated GFAP Expression and Altered Glutamate Uptake and Release and Proliferation in Astrocytes.
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Wilson, Kelly M. and He, Johnny J.
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HIV infections , *GLIAL fibrillary acidic protein , *ASTROCYTES - Abstract
HIV infection of astrocytes leads to restricted gene expression and replication but abundant expression of HIV early genes Tat, Nef and Rev. A great deal of neuroHIV research has so far been focused on Tat protein, its effects on astrocytes, and its roles in neuroHIV. In the current study, we aimed to determine effects of Nef expression on astrocytes and their function. Using transfection or infection of VSVG-pseudotyped HIV viruses, we showed that Nef expression down-modulated glial fibrillary acidic protein (GFAP) expression. We then showed that Nef expression also led to decreased GFAP mRNA expression. The transcriptional regulation was further confirmed using a GFAP promoter-driven reporter gene assay. We performed transcription factor profiling array to compare the expression of transcription factors between Nef-intact and Nef-deficient HIV-infected cells and identified eight transcription factors with expression changes of 1.5-fold or higher: three up-regulated by Nef (Stat1, Stat5, and TFIID), and five down-regulated by Nef (AR, GAS/ISRE, HIF, Sp1, and p53). We then demonstrated that removal of the Sp1 binding sites from the GFAP promoter resulted in a much lower level of the promoter activity and reversal of Nef effects on the GFAP promoter, confirming important roles of Sp1 in the GFAP promoter activity and for Nef-induced GFAP expression. Lastly, we showed that Nef expression led to increased glutamate uptake and decreased glutamate release by astrocytes and increased astrocyte proliferation. Taken together, these results indicate that Nef leads to down-modulation of GFAP expression and alteration of glutamate metabolism in astrocytes, and astrocyte proliferation and could be an important contributor to neuroHIV. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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12. Cell–cell contact viral transfer contributes to HIV infection and persistence in astrocytes
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Luo, Xiaoyu and He, Johnny J.
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- 2015
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13. Nef inhibits HIV transcription and gene expression in astrocytes and HIV transmission from astrocytes to CD4+ T cells.
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Kandel, Suresh R., Luo, Xiaoyu, and He, Johnny J.
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HIV infection transmission ,GENE expression ,HIV ,MOLECULAR cloning ,ASTROCYTES ,REPORTER genes ,T cells - Abstract
HIV infects astrocytes in a restricted manner but leads to abundant expression of Nef, a major viral factor for HIV replication and disease progression. However, the roles of Nef in HIV gene expression and replication in astrocytes and viral transfer from astrocytes to CD4
+ T cells remain largely unclear. In this study, we attempted to address these issues by transfecting human primary astrocytes with HIV molecular clones with intact Nef and without Nef (a nonsense Nef mutant) and comparing gene expression and replication in astrocytes and viral transfer from astrocytes to CD4+ T cells MT4. First, we found that lack of Nef expression led to increased extracellular virus production from astrocytes and intracellular viral protein and RNA expression in astrocytes. Using a HIV LTR-driven luciferase reporter gene assay, we showed that ectopic Nef expression alone inhibited the HIV LTR promoter activity in astrocytes. Consistent with the previously established function of Nef, we showed that the infectivity of HIV derived from astrocytes with Nef expression was significantly higher than that with no Nef expression. Next, we performed the co-culture assay to determine HIV transfer from astrocytes transfected to MT4. We showed that lack of Nef expression led to significant increase in HIV transfer from astrocytes to MT4 using two HIV clones. We also used Nef-null HIV complemented with Nef in trans in the co-culture assay and demonstrated that Nef expression led to significantly decreased HIV transfer from astrocytes to MT4. Taken together, these findings support a negative role of Nef in HIV replication and pathogenesis in astrocytes. [ABSTRACT FROM AUTHOR]- Published
- 2022
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14. A Unique Robust Dual-Promoter-Driven and Dual-Reporter-Expressing SARS-CoV-2 Replicon: Construction and Characterization.
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Liu, Ying, Li, Lu, Timani, Khalid A., and He, Johnny J.
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SARS-CoV-2 ,RNA viruses ,SEMLIKI Forest virus ,GREEN fluorescent protein ,REPORTER genes ,DRUG development - Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, SARS2) remains a great global health threat and demands identification of more effective and SARS2-targeted antiviral drugs, even with successful development of anti-SARS2 vaccines. Viral replicons have proven to be a rapid, safe, and readily scalable platform for high-throughput screening, identification, and evaluation of antiviral drugs against positive-stranded RNA viruses. In the study, we report a unique robust HIV long terminal repeat (LTR)/T7 dual-promoter-driven and dual-reporter firefly luciferase (fLuc) and green fluorescent protein (GFP)-expressing SARS2 replicon. The genomic organization of the replicon was designed with quite a few features that were to ensure the replication fidelity of the replicon, to maximize the expression of the full-length replicon, and to offer the monitoring flexibility of the replicon replication. We showed the success of the construction of the replicon and expression of reporter genes fLuc and GFP and SARS structural N from the replicon DNA or the RNA that was in vitro transcribed from the replicon DNA. We also showed detection of the negative-stranded genomic RNA (gRNA) and subgenomic RNA (sgRNA) intermediates, a hallmark of replication of positive-stranded RNA viruses from the replicon. Lastly, we showed that expression of the reporter genes, N gene, gRNA, and sgRNA from the replicon was sensitive to inhibition by Remdesivir. Taken together, our results support use of the replicon for identification of anti-SARS2 drugs and development of new anti-SARS strategies targeted at the step of virus replication. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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15. Tip110/SART3-Mediated Regulation of NF-κB Activity by Targeting IκBα Stability Through USP15.
- Author
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Timani, Khalid Amine, Rezaei, Sahar, Whitmill, Amanda, Liu, Ying, and He, Johnny J.
- Subjects
DEUBIQUITINATING enzymes ,NUCLEAR proteins ,EMBRYONIC stem cells ,PROTEIN stability ,KNOCKOUT mice - Abstract
To date, there are a small number of nuclear-restricted proteins that have been reported to play a role in NF-κB signaling. However, the exact molecular mechanisms are not fully understood. Tip110 is a nuclear protein that has been implicated in multiple biological processes. In a previous study, we have shown that Tip110 interacts with oncogenic ubiquitin specific peptidase 15 (USP15) and that ectopic expression of Tip110 leads to re-distribution of USP15 from the cytoplasm to the nucleus. USP15 is known to regulate NF-κB activity through several mechanisms including modulation of IκBα ubiquitination. These findings prompted us to investigate the role of Tip110 in the NF-κB signaling pathway. We showed that Tip110 regulates NF-κB activity. The expression of Tip110 potentiated TNF-α-induced NF-κB activity and deletion of the nuclear localization domain in Tip110 abrogated this potentiation activity. We then demonstrated that Tip110 altered IκBα phosphorylation and stability in the presence of TNF-α. Moreover, we found that Tip110 and USP15 opposingly regulated NF-κB activity by targeting IκBα protein stability. We further showed that Tip110 altered the expression of NF-κB-dependent proinflammatory cytokines. Lastly, by using whole-transcriptome analysis of Tip110 knockout mouse embryonic stem cells, we found several NF-κB and NF-κB-related pathways were dysregulated. Taken together, these findings add to the nuclear regulation of NF-κB activity by Tip110 through IκBα stabilization and provide new evidence to support the role of Tip110 in controlling cellular processes such as cancers that involve proinflammatory responses. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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16. Tip110 Expression Facilitates the Release of HEXIM1 and pTEFb from the 7SK Ribonucleoprotein Complex Involving Regulation of the Intracellular Redox Level.
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Ying Liu, Lu Li, Timani, Khalid, White, Carl, and He, Johnny J.
- Subjects
NUCLEOPROTEINS ,GENETIC transcription ,HIV infection genetics - Abstract
HIV-1 Tat-interacting protein of 110 kDa (Tip110; p110
nrb /SART3) has been identified to be important for HIV gene transcription and several host gene expression. In this study, we showed that Tip110 was present in the 7SK snRNP through direct binding to MEPCE, a component of the 7SK snRNP complex. In addition, we found a positive association between Tip110 expression, change of HEXIM1 from dimer/oligomer to monomer, and release of HEXIM1 and P-TEFb from the 7SK snRNP complex. A similar association was also noted specifically in nuclear matrix as well as in chromatin where the free HEXIM1 and 7SK snRNP-bound HEXIM1 are located. Moreover, we demonstrated that Tip110 expression was linked to the glutathione metabolic pathway and the intracellular redox level, which in turn regulated HEXIM1 dimerization/oligomerization. Lastly, we performed the FRET microscopic analysis and confirmed the direct relationship between Tip110 expression and HEXIM1 dimerization/oligomerization in vivo. Taken together, these results identified a new mechanism governing HEXIM1 dimerization/oligomerization and the release of HEXIM1 and P-TEFb from the 7SK snRNP complex. These results also yield new insights to the roles of Tip110 in HIV gene transcription and replication. [ABSTRACT FROM AUTHOR]- Published
- 2021
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17. Activation of α7 nicotinic acetylcholine receptor ameliorates HIV-associated neurology and neuropathology.
- Author
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Zhao, Xiaojie, Wilson, Kelly, Uteshev, Victor, and He, Johnny J
- Subjects
NICOTINIC acetylcholine receptors ,TRANSGENIC mice ,NEUROLOGICAL disorders ,NEUROBEHAVIORAL disorders ,KNOCKOUT mice ,AIDS dementia complex ,CHOLINERGIC receptors ,ANIMAL experimentation ,GENES ,RESEARCH funding ,MICE - Abstract
HIV-associated neurocognitive disorders (HAND) in the era of combination antiretroviral therapy are primarily manifested as impaired behaviours, glial activation/neuroinflammation and compromised neuronal integrity, for which there are no effective treatments currently available. In the current study, we used doxycycline-inducible astrocyte-specific HIV Tat transgenic mice (iTat), a surrogate HAND model, and determined effects of PNU-125096, a positive allosteric modulator of α7 nicotinic acetylcholine receptor (α7 nAChR) on Tat-induced behavioural impairments and neuropathologies. We showed that PNU-125096 treatment significantly improved locomotor, learning and memory deficits of iTat mice while inhibited glial activation and increased PSD-95 expression in the cortex and hippocampus of iTat mice. Using α7 nAChR knockout mice, we showed that α7 nAChR knockout eliminated the protective effects of PNU-125096 on iTat mice. In addition, we showed that inhibition of p38 phosphorylation by SB239063, a p38 MAPK-specific inhibitor exacerbated Tat neurotoxicity in iTat mice. Last, we used primary mouse cortical individual cultures and neuron-astrocytes co-cultures and in vivo staining of iTat mouse brain tissues and showed that glial activation was directly involved in the interplay among Tat neurotoxicity, α7 nAChR activation and the p38 MAPK signalling pathway. Taken together, these findings demonstrated for the first time that α7 nAChR activation led to protection against HAND and suggested that α7 nAChR modulator PNU-125096 holds significant promise for development of therapeutics for HAND. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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18. Unraveling neuroHIV in the Presence of Substance Use Disorders.
- Author
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Lin, Yu, He, Johnny J., Sorensen, Roger, and Chang, Linda
- Abstract
This special issue contains 10 invited review papers that highlighted and extended the presentations at the NIDA-sponsored workshop "Unraveling NeuroAIDS in the Presence of Substance Use Disorders" at the 25th Society on NeuroImmune Pharmacology conference in 2019. The topics covered by these papers focused on the interactive, additive or synergistic effects of substance use disorders (SUD) with HIV infection on the immune system and on neuropathogenesis. These papers reviewed four categories of substances of abuse (opioids, tobacco, stimulants, and cannabis) and how comorbid HIV infection (including models with HIV proteins, HIV transgenic rodent models and SIV) might further impact the dysregulated dopaminergic and immune systems, and the subsequent neuropathogenesis and behavioral disorders known as HIV-associated neurological disorders (HAND). These reviews provided detailed background knowledge regarding how each of these addictive substances and HIV individually or collectively affected the immune system at the cellular, molecular and system levels, and the subsequent clinical and behavioral outcomes. The authors also identified gaps, confounds or constraints in the current disease models and approaches, and proposed future research directions. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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19. Independent and Combined Effects of Nicotine or Chronic Tobacco Smoking and HIV on the Brain: A Review of Preclinical and Clinical Studies.
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Chang, Linda, Liang, Huajun, Kandel, Suresh R., and He, Johnny J.
- Abstract
Tobacco smoking is highly prevalent among HIV-infected individuals. Chronic smokers with HIV showed greater cognitive deficits and impulsivity, and had more psychopathological symptoms and greater neuroinflammation than HIV non-smokers or smokers without HIV infection. However, preclinical studies that evaluated the combined effects of HIV-infection and tobacco smoking are scare. The preclinical models typically used cell cultures or animal models that involved specific HIV viral proteins or the administration of nicotine to rodents. These preclinical models consistently demonstrated that nicotine had neuroprotective and anti-inflammatory effects, leading to cognitive enhancement. Although the major addictive ingredient in tobacco smoking is nicotine, chronic smoking does not lead to improved cognitive function in humans. Therefore, preclinical studies designed to unravel the interactive effects of chronic tobacco smoking and HIV infection are needed. In this review, we summarized the preclinical studies that demonstrated the neuroprotective effects of nicotine, the neurotoxic effects of the HIV viral proteins, and the scant literature on nicotine or tobacco smoke in HIV transgenic rat models. We also reviewed the clinical studies that evaluated the neurotoxic effects of tobacco smoking, HIV infection and their combined effects on the brain, including studies that evaluated the cognitive and behavioral assessments, as well as neuroimaging measures. Lastly, we compared the different approaches between preclinical and clinical studies, identified some gaps and proposed some future directions. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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20. Long-term HIV-1 Tat Expression in the Brain Led to Neurobehavioral, Pathological, and Epigenetic Changes Reminiscent of Accelerated Aging.
- Author
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Xiaojie Zhao, Yan Fan, Vann, Philip H., Wong, Jessica M., Sumien, Nathalie, and He, Johnny J.
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HIV-positive persons ,HIGHLY active antiretroviral therapy ,DNA methylation - Abstract
HIV infects the central nervous system and causes HIV/neuroAIDS, which is predominantly manifested in the form of mild cognitive and motor disorder in the era of combination antiretroviral therapy. HIV Tat protein is known to be a major pathogenic factor for HIV/neuroAIDS through a myriad of direct and indirect mechanisms. However, most, if not all of studies involve short-time exposure of recombinant Tat protein in vitro or short-term Tat expression in vivo. In this study, we took advantage of the doxycycline-inducible brainspecific HIV-1 Tat transgenic mouse model, fed the animals for 12 months, and assessed behavioral, pathological, and epigenetic changes in these mice. Long-term Tat expression led to poorer short-and long-term memory, lower locomotor activity and impaired coordination and balance ability, increased astrocyte activation and compromised neuronal integrity, and decreased global genomic DNA methylation. There were sex- and brain region-dependent differences in behaviors, pathologies, and epigenetic changes resulting from long-term Tat expression. All these changes are reminiscent of accelerated aging, raising the possibility that HIV Tat contributes, at least in part, to HIV infection-associated accelerated aging in HIV-infected individuals. These findings also suggest another utility of this model for HIV infection-associated accelerated aging studies. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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- View/download PDF
21. Regulation of Constitutive Tip110 Expression in Human Cord Blood CD34+ Cells Through Selective Usage of the Proximal and Distal Polyadenylation Sites Within the 3′Untranslated Region.
- Author
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Liu, Ying, Huang, Xinxin, Timani, Khalid A., Broxmeyer, Hal E., and He, Johnny J.
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- 2018
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22. Tip110 Deletion Impaired Embryonic and Stem Cell Development Involving Downregulation of Stem Cell Factors Nanog, Oct4, and Sox2.
- Author
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Whitmill, Amanda, Liu, Ying, Timani, Khalid Amine, Niu, Yinghua, and He, Johnny J.
- Abstract
HIV-1 Tat-interacting protein of 110 kDa, Tip110, plays important roles in multiple biological processes. In this study, we aimed to characterize the function of Tip110 in embryonic development. Transgenic mice lacking expression of a functional Tip110 gene (Tip110
-/- ) died post-implantation, and Tip110-/- embryos exhibited developmental arrest between 8.5 and 9.5 days post coitum. However, in vitro cultures of Tip110-/- embryos showed that Tip110 loss did not impair embryo growth from the zygote to the blastocyst. Extended in vitro cultures of Tip110-/- blastocysts showed that Tip110 loss impaired both blastocyst outgrowth and self-renewal and survival of blastocyst-derived embryonic stem cells. Microarray analysis of Tip110-/- embryonic stem cells revealed that Tip110 loss altered differentiation, pluripotency, and cycling of embryonic stem cells and was associated with downregulation of several major stem cell factors including Nanog, Oct4, and Sox2 through a complex network of signaling pathways. Taken together, these findings document for the first time the lethal effects of complete loss of Tip110 on mammalian embryonic development and suggest that Tip110 is an important regulator of not only embryonic development but also stem cell factors. S tem C ells 2017;35:1674-1686 [ABSTRACT FROM AUTHOR]- Published
- 2017
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23. HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway.
- Author
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Yan Fan, Xiang Gao, Jinhui Chen, Ying Liu, and He, Johnny J.
- Subjects
DEVELOPMENTAL neurobiology ,LIGANDS (Biochemistry) ,HIV ,TYROSINEMIA ,MYELINATION ,SCHWANN cells - Abstract
Alterations in adult neurogenesis have been noted in the brain of HIV-infected individuals and are likely linked to HIV-associated neurocognitive deficits, including those in learning and memory. But the underlying molecular mechanisms are not fully understood. In the study, we took advantage of doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) and determined the relationship between Tat expression and neurogenesis. Tat expression in astrocytes was associated with fewer neuron progenitor cells (NPCs), fewer immature neurons, and fewer mature neurons in the dentate gyrus of the hippocampus of the mouse brain. In vitro NPC-derived neurosphere assays showed that Tat-containing conditioned media from astrocytes or recombinant Tat protein inhibited NPC proliferation and migration and altered NPC differentiation, while immunodepletion of Tat from Tat-containing conditioned media or heat inactivation of recombinant Tat abrogated those effects. Notch signaling downstream gene HesI promoter-driven luciferase reporter gene assay and Western blotting showed that recombinant Tat or Tat-containing conditioned media activated Hesl transcription and protein expression, which were abrogated by Tat heat inactivation, immunodepletion, and cysteine mutation at position 30. Last, Notch signaling inhibitor N-[W-(3,5-difluorophenacetyl)-Lalanyl]- S-phenylglycine t butyl ester (DAPT) significantly rescued Tat-impaired NPC differentiation in vitro and neurogenesis in vivo. Together, these results show that Tat adversely affects NPCs and neurogenesis through Notch signaling and point to the potential of developing Notch signaling inhibitors as HIV/neuroAIDS therapeutics. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
24. HIV-1 Tat Induces Unfolded Protein Response and Endoplasmic Reticulum Stress in Astrocytes and Causes Neurotoxicity through Glial Fibrillary Acidic Protein (GFAP) Activation and Aggregation.
- Author
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Yan Fan and He, Johnny J.
- Subjects
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MOLECULAR chaperones , *ENDOPLASMIC reticulum , *GLIAL fibrillary acidic protein , *NEUROTOXICOLOGY , *ASTROCYTES , *WOUNDS & injuries , *PREVENTION - Abstract
HIV-1 Tat is a major culprit for HIV/neuroAIDS. One of the consistent hallmarks of HIV/neuroAIDS is reactive astrocytes or astrocytosis, characterized by increased cytoplasmic accumulation of the intermediate filament glial fibrillary acidic protein (GFAP).Wehave shown that that Tat induces GFAP expression in astrocytes and that GFAP activation is indispensable for astrocyte-mediated Tat neurotoxicity. However, the underlying molecular mechanisms are not known. In this study, we showed that Tat expression or GFAP expression led to formation of GFAP aggregates and induction of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress in astrocytes. In addition, we demonstrated that GFAP up-regulation and aggregation in astrocytes were necessary but also sufficient for UPR/ER stress induction in Tat-expressing astrocytes and for astrocyte-mediated Tat neurotoxicity. Importantly, we demonstrated that inhibition of Tat- or GFAP-induced UPR/ER stress by the chemical chaperone 4-phenylbutyrate significantly alleviated astrocyte-mediated Tat neurotoxicity in vitro and in the brain of Tat-expressing mice. Taken together, these results show that HIV-1 Tat expression leads to UPR/ER stress in astrocytes, which in turn contributes to astrocyte-mediated Tat neurotoxicity, and raise the possibility of developing HIV/neuroAIDS therapeutics targeted at UPR/ER stress. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
25. HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity.
- Author
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Yan Fan and He, Johnny J.
- Subjects
- *
TYROSINEMIA , *NEUROTOXICOLOGY , *ENDOPLASMIC reticulum , *ENZYME analysis , *PROTEIN synthesis , *PREVENTION - Abstract
Tat interaction with astrocytes has been shown to be important for Tat neurotoxicity and HIV/neuroAIDS. We have recently shown that Tat expression leads to increased glial fibrillary acidic protein (GFAP) expression and aggregation and activation of unfolded protein response/endoplasmic reticulum (ER) stress in astrocytes and causes neurotoxicity. However, the exact molecular mechanism of astrocyte-mediated Tat neurotoxicity is not defined. In this study, we showed that neurotoxic factors other than Tat protein itself were present in the supernatant of Tat-expressing astrocytes. Two-dimensional gel electrophoresis and mass spectrometry revealed significantly elevated lysosomal hydrolytic enzymes and plasma membraneassociated proteins in the supernatant of Tat-expressing astrocytes. We confirmed that Tat expression and infection of pseudotyped HIV.GFP led to increased lysosomal exocytosis from mouse astrocytes and human astrocytes. We found that Tatinduced lysosomal exocytosis was tightly coupled to astrocytemediated Tat neurotoxicity. In addition, we demonstrated that Tat-induced lysosomal exocytosis was astrocyte-specific and required GFAP expression and was mediated by ER stress. Taken together, these results show for the first time that Tat promotes lysosomal exocytosis in astrocytes and causes neurotoxicity through GFAP activation and ER stress induction in astrocytes and suggest a common cascade through which aberrant astrocytosis/GFAP up-regulation potentiates neurotoxicity and contributes to neurodegenerative diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
26. HIV-1 Tat-shortened neurite outgrowth through regulation of microRNA-132 and its target gene expression.
- Author
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Rahimian, Pejman and He, Johnny J.
- Subjects
- *
HIV , *BRAIN-derived neurotrophic factor , *NOGO protein , *NEUROTOXICOLOGY , *GENE expression , *CELL metabolism , *NEURAL physiology , *PROTEIN metabolism , *RNA metabolism , *ANIMAL experimentation , *ANTIBIOTICS , *CELLS , *CYTOKINES , *CYTOSKELETAL proteins , *EPITHELIAL cells , *GENES , *GLIOMAS , *MICE , *NEUROBLASTOMA , *NEURONS , *PROTEINS , *RESEARCH funding , *RNA , *TRANSFERASES , *DOXYCYCLINE , *PHARMACODYNAMICS - Abstract
Background: Synaptodendritic damage is a pathological hallmark of HIV-associated neurocognitive disorders, and HIV-1 Tat protein is known to cause such injury in the central nervous system. In this study, we aimed to determine the molecular mechanisms of Tat-induced neurite shortening, specifically the roles of miR-132, an important regulator of neurite morphogenesis in this process.Methods: The relationship between Tat expression and miR-132 expression was first determined using reverse transcription quantitative PCR (qRT-PCR) in Tat-transfected astrocytes and neurons, astrocytes from Tat-transgenic mice, and HIV-infected astrocytes. qRT-PCR and Western blotting were performed to determine Tat effects on expression of miR-132 target genes methyl CpG-binding protein 2, Rho GTPase activator p250GAP, and brain-derived neurotrophic factor. Exosomes were isolated from Tat-expressing astrocytes, and exosomal microRNA (miRNA) uptake into neurons was studied using miRNA labeling and flow cytometry. The lactate dehydrogenase release was used to determine the cytotoxicity, while immunostaining was used to determine neurite lengths and synapse formation. Tat basic domain deletion mutant and miR-132 mimic and inhibitor were used to determine the specificity of the relationship between Tat and miR-132 and its effects on astrocytes and neurons and the underlying mechanisms of Tat-induced miR-132 expression.Results: Tat significantly induced miR-132 expression, ensuing down-regulation of miR-132 target genes in astrocytes and neurons. miR-132 induction was associated with phosphorylation of cAMP response element-binding protein and required the basic domain of Tat. miRNA-132 induction had no effects on astrocyte activation or survival but was involved in the direct neurotoxicity of Tat. miR-132 was present in astrocyte-derived exosomes and was taken up by neurons, causing neurite shortening.Conclusions: Tat-induced miR-132 expression contributes to both direct and astrocyte-mediated Tat neurotoxicity and supports the important roles of miR-132 in controlling neurite outgrowth. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
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27. Role of Tat-interacting protein of 110 kDa and microRNAs in the regulation of hematopoiesis.
- Author
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Ying Liu, He, Johnny J., and Liu, Ying
- Published
- 2016
- Full Text
- View/download PDF
28. MicroRNA-124 Targets Tip110 Expression and Regulates Hematopoiesis.
- Author
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Liu, Ying, Huang, Xinxin, Timani, Khalid Amine, Broxmeyer, Hal E., and He, Johnny J.
- Published
- 2015
- Full Text
- View/download PDF
29. Tip110 Regulates the Cross Talk between p53 and Hypoxia-Inducible Factor 1α under Hypoxia and Promotes Survival of Cancer Cells.
- Author
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Timani, Khalid Amine, Ying Liu, Yan Fan, Mohammad, Khalid S., and He, Johnny J.
- Subjects
PROTEIN expression ,PROTEOLYSIS ,P53 antioncogene ,HYPOXIA-inducible factor 1 ,BIOLOGICAL crosstalk ,CANCER cells - Abstract
Hypoxia often occurs under various physiological and pathophysiological conditions, including solid tumors; it is linked to malignant transformation, metastatic progression, and treatment failure or resistance. Tip110 protein plays important roles in several known physiological and pathophysiological processes, including cancers. Thus, in the present study we investigated the regulation of Tip110 expression under hypoxia. Hypoxia led to Tip110 protein degradation through the ubiquitin-proteasome system. Under hypoxia, Tip110 stabilized p53, which in return destabilized Tip110. In addition, Tip110 regulated hypoxia-inducible factor 1α (HIF-1α), likely through enhancement of its protein stability. Furthermore, Tip110 upregulated p300, a known coactivator for both p53 and HIF-1α. Expression of a p53(22/23) mutant deficient in p300 binding accelerated Tip110 degradation under hypoxia. Tip110 knockdown resulted in the inhibition of cell proliferation and cell death in the presence of p53. Finally, significantly less Tip110, p53, and HIF-1α was detected in the hypoxic region of bone metastasis tumors in a mouse model of human melanoma cells. Taken together, these results suggest Tip110 is an important mediator in the cross talk between p53 and HIF-1α in response to hypoxic stress. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
30. Tip110 binding to U6 small nuclear RNA and its participation in pre-mRNA splicing.
- Author
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Ying Liu, Jinfeng Liu, Zenyuan Wang, and He, Johnny J.
- Subjects
RNA-protein interactions ,RNA splicing ,GENE expression ,NUCLEOPROTEINS ,SMALL nuclear RNA ,EUKARYOTIC cells ,SPLICEOSOMES - Abstract
Background: RNA-protein interactions play important roles in gene expression control. These interactions are mediated by several recurring RNA-binding motifs including a well-known and characterized ribonucleoprotein motif or so-called RNA recognition motif (RRM). Results: In the current study, we set out to identify the RNA ligand(s) of a RRM-containing protein Tip110, also known as p110
nrb , SART3, or p110, using a RNA-based yeast three-hybrid cloning strategy. Six putative RNA targets were isolated and found to contain a consensus sequence that was identical to nucleotides 34-46 of U6 small nuclear RNA. Tip110 binding to U6 was confirmed to be specific and RRM-dependent in an electrophoretic mobility shift assay. Both in vitro pre-mRNA splicing assay and in vivo splicing-dependent reporter gene assay showed that the pre-mRNA splicing was correlated with Tip110 expression. Moreover, Tip110 was found in the spliceosomes containing prespliced pre-mRNA and spliced mRNA products. Nonetheless, the RRM-deleted mutant (ΔRRM) that did not bind to U6 showed promotion in vitro pre-mRNA splicing, whereas the nuclear localization signal (NLS)-deleted mutant ΔNLS that bound to U6 promoted the pre-mRNA splicing both in vitro and in vivo. Lastly, RNA-Seq analysis confirmed that Tip110 regulated a number of gene pre-mRNA splicing including several splicing factors. Conclusions: Taken together, these results demonstrate that Tip110 is directly involved in constitutive eukaryotic pre-mRNA splicing, likely through its binding to U6 and regulation of other splicing factors, and provide further evidence to support the global roles of Tip110 in regulation of host gene expression. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
31. Exosomes Are Unlikely Involved in Intercellular Nef Transfer.
- Author
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Luo, Xiaoyu, Fan, Yan, Park, In-Woo, and He, Johnny J.
- Subjects
EXTRACELLULAR matrix ,HIV infections ,AIDS ,CD4 antigen ,CELL lines ,BIOMARKERS - Abstract
HIV-1 Nef is an important pathogenic factor for HIV/AIDS pathogenesis. Several recent studies including ours have demonstrated that Nef can be transferred to neighboring cells and alters the function of these cells. However, how the intercellular Nef transfer occurs is in dispute. In the current study, we attempted to address this important issue using several complementary strategies, a panel of exosomal markers, and human CD4+ T lymphocyte cell line Jurkat and a commonly used cell line 293T. First, we showed that Nef was transferred from Nef-expressing or HIV-infected Jurkat to naïve Jurkat and other non-Jurkat cells and that the transfer required the membrane targeting function of Nef and was cell density-dependent. Then, we showed that Nef transfer was cell-cell contact-dependent, as exposure to culture supernatants or exosomes from HIV-infected Jurkat or Nef-expressing Jurkat and 293T led to little Nef detection in the target cells Jurkat. Thirdly, we demonstrated that Nef was only detected to be associated with HIV virions but not with acetylcholinesterase (AChE+) exosomes from HIV-infected Jurkat and not in the exosomes from Nef-expressing Jurkat. In comparison, when it was over-expressed in 293T, Nef was detected in detergent-insoluble AChE+/CD81
low /TSG101low exosomes, but not in detergent-soluble AChE-/CD81high /TSG101high exosomes. Lastly, microscopic imaging showed no significant Nef detection in exosomal vesicle-like structures in and out 293T. Taken together, these results show that exosomes are unlikely involved in intercellular Nef transfer. In addition, this study reveals existence of two types of exosomes: AChE+/CD81low /TSG101low exosomes and AChE-/CD81high /TSG101high exosomes. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
32. HIV-1 Tat Alters Neuronal Autophagy by Modulating Autophagosome Fusion to the Lysosome: Implications for HIV-Associated Neurocognitive Disorders.
- Author
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Fields, Jerel, Dumaop, Wilmar, Elueteri, Simona, Campos, Sofia, Serger, Elisabeth, Trejo, Margarita, Kosberg, Kori, Adame, Anthony, Spencer, Brian, Rockenstein, Edward, He, Johnny J., and Masliah, Eliezer
- Subjects
HIV-positive persons ,NEURODEGENERATION ,TAT protein ,AUTOPHAGY ,LYSOSOMES ,ANTIRETROVIRAL agents ,HEALTH - Abstract
Antiretroviral therapy has increased the life span of HIV+ individuals; however, HIV-associated neurocognitive disorder (HAND) occurrence is increasing in aging HIV patients. Previous studies suggest HIV infection alters autophagy function in the aging CNS and HIV-1 proteins affect autophagy in monocyte-derived cells. Despite these findings, the mechanisms leading to dysregulated autophagy in the CNS remain unclear. Here we sought to determine how HIV Tat dysregulates autophagy in neurons. Tat caused a dose-dependent decrease in autophagosome markers, microtubule-associated protein-1 light chain β II (LC3II), and sequestosome 1(SQSTM1), in a membrane-enriched fraction, suggesting Tat increases autophagic degradation. Bafilomycin A1 increased autophagosome number, LC3II, and SQSTM1 accumulation; Tat cotreatment diminished this effect. Tat had no effect when 3-methyladenine or knockdown of beclin 1 blocked early stages of autophagy. Tat increased numbers of LC3 puncta and resulted in the formation of abnormal autophagosomes in vitro. Likewise, in vivo studies in GFAP-Tat tg mice showed increased autophagosome accumulation in neurons, altered LC3II levels, and neurodegeneration. These effects were reversed by rapamycin treatment. Tat colocalized with autophagosome and lysosomal markers and enhanced the colocalization of autophagosome with lysosome markers. Furthermore, co-IP studies showed that Tat interacts with lysosomal-associated membrane protein 2A (LAMP2A) in vitro and in vivo, and LAMP2A overexpression reduces Tat-induced neurotoxicity. Hence, Tat protein may induce autophagosome and lysosome fusion through interaction with LAMP2A leading to abnormal neuronal autophagy function and dysregulated degradation of critical intracellular components. Therapies targeting Tat-mediated autophagy alterations may decrease neurodegeneration in aging patients with HAND. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
33. HIV Tat and cocaine interactively alter genome-wide DNA methylation and gene expression and exacerbate learning and memory impairments.
- Author
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Zhao, Xiaojie, Zhang, Fan, Kandel, Suresh R., Brau, Frédéric, and He, Johnny J.
- Abstract
Cocaine use is a major comorbidity of HIV-associated neurocognitive disorder (HAND). In this study, we show that cocaine exposure worsens the learning and memory of doxycycline-inducible and brain-specific HIV Tat transgenic mice (iTat) and results in 14,838 hypermethylated CpG-related differentially methylated regions (DMRs) and 15,800 hypomethylated CpG-related DMRs, which are linked to 52 down- and 127 upregulated genes, respectively, in the hippocampus of iTat mice. These genes are mostly enriched at the neuronal function-, cell morphology-, and synapse formation-related extracellular matrix (ECM) receptor-ligand interaction pathway and mostly impacted in microglia. The accompanying neuropathological changes include swollen dendritic spines, increased synaptophysin expression, and diminished glial activation. We also find that sex (female) and age additively worsen the behavioral and pathological changes. These findings together indicate that chronic cocaine and long-term Tat expression interactively contribute to HAND, likely involving changes of DNA methylation and ECM receptor-ligand interactions. [Display omitted] • Cocaine use worsens impaired learning and memory in brain-specific Tat transgenic mice • Cocaine/Tat alters gene expression in ECM receptor pathways and microglia • Cocaine/Tat changes dendritic spines, synaptophysin expression, and glial activation • Sex and age are both important contributing factors to cocaine and Tat interaction Zhao et al. investigate combined effects of HIV Tat and cocaine on HIV-associated neurocognitive disorder and the underlying molecular mechanisms, using doxycycline-inducible and brain-specific HIV Tat transgenic mice. They uncover specific changes in behavior, neuropathologies, genome-wide DNA methylation, gene expression, and processes affected by combined cocaine and Tat. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
34. Leishmaniac Quest for Developing a Novel Vaccine Platform. Is a Roadmap for Its Advances Provided by the Mad Dash to Produce Vaccines for COVID-19?
- Author
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Chang, Kwang Poo, Reynolds, Joseph M., Liu, Ying, and He, Johnny J.
- Subjects
VACCINE development ,COVID-19 vaccines ,CANCER vaccines ,COMPARATIVE method ,REACTIVE oxygen species - Abstract
"Bugs as drugs" in medicine encompasses the use of microbes to enhance the efficacy of vaccination, such as the delivery of vaccines by Leishmania—the protozoan etiological agent of leishmaniasis. This novel approach is appraised in light of the successful development of vaccines for Covid-19. All relevant aspects of this pandemic are summarized to provide the necessary framework in contrast to leishmaniasis. The presentation is in a side-by-side matching format with particular emphasis on vaccines. The comparative approach makes it possible to highlight the timeframe of the vaccine workflows condensed by the caveats of pandemic urgency and, at the same time, provides the background of Leishmania behind its use as a vaccine carrier. Previous studies in support of the latter are summarized as follows. Leishmaniasis confers life-long immunity on patients after cure, suggesting the effective vaccination is achievable with whole-cell Leishmania. A new strategy was developed to inactivate these cells in vitro, rendering them non-viable, hence non-disease causing, albeit retaining their immunogenicity and adjuvanticity. This was achieved by installing a dual suicidal mechanism in Leishmania for singlet oxygen (
1 O2 )-initiated inactivation. In vitro cultured Leishmania were genetically engineered for cytosolic accumulation of UV-sensitive uroporphyrin I and further loaded endosomally with a red light-sensitive cationic phthalocyanine. Exposing these doubly dye-loaded Leishmania to light triggers intracellular production of highly reactive but extremely short-lived1 O2 , resulting in their rapid and complete inactivation. Immunization of susceptible animals with such inactivated Leishmania elicited immunity to protect them against experimental leishmaniasis. Significantly, the inactivated Leishmania was shown to effectively deliver transgenically add-on ovalbumin (OVA) to antigen-presenting cells (APC), wherein OVA epitopes were processed appropriately for presentation with MHC molecules to activate epitope-specific CD8+ T cells. Application of this approach to deliver cancer vaccine candidates, e.g., enolase-1, was shown to suppress tumor development in mouse models. A similar approach is predicted to elicit lasting immunity against infectious diseases, including complementation of the spike protein-based vaccines in use for COVID-19. This pandemic is devastating, but brings to light the necessity of considering many facets of the disease in developing vaccination programs. Closer collaboration is essential among those in diverse disciplinary areas to provide the roadmap toward greater success in the future. Highlighted herein are several specific issues of vaccinology and new approaches worthy of consideration due to the pandemic. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
35. Tip110/SART3 regulates IL-8 expression and predicts the clinical outcomes in melanoma.
- Author
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Timani, Khalid Amine, Győrffy, Balázs, Liu, Ying, Mohammad, Khalid S., and He, Johnny J.
- Subjects
ONCOGENIC proteins ,CELL proliferation ,GENE expression ,CELL lines ,T cells - Abstract
Tip110, an important regulator of several oncogenic proteins, was significantly downregulated in human metastatic melanoma cells exposed to a hypoxic condition. Therefore, in this study, we set to determine whether differential expression of Tip110 could be an important indicator for melanoma tumorigenesis and metastasis. We found that in melanoma, but not in other cancer types, Tip110 knockdown enhanced significant expression and secretion of IL-8 and melanoma cells invasions. This induction was further potentiated under hypoxia and by inflammatory cytokine and found independent of TNF-α autocrine signaling. We further showed that Tip110 knockdown-mediated IL-8 induction involved IL-8 mRNA stability. Furthermore, the transcriptomic profiling data and survival from 455 melanoma patients demonstrated that the correlation between Tip110 expression and the clinical outcomes in melanoma was stage-dependent. These findings uncover important roles of Tip110 in melanoma tumorigenesis and metastasis through regulation of IL-8 and hope to provide new clues for future therapeutic strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
36. Abstracts from the Joint Meeting of the International Society for NeuroVirology (ISNV) and the Society on NeuroImmune Pharmacology (SNIP) April 10-14, 2018, Chicago, Illinois, USA.
- Published
- 2018
- Full Text
- View/download PDF
37. Neo-clerodane diterpenoids from the whole plants of Scutellaria formosana.
- Author
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Chen, Xin, Chen, Wenhao, Chen, Guangying, Han, Changri, He, Johnny J., Zhou, Xueming, Yu, Zhangxin, Dai, Chunyan, and Song, Xiaoping
- Subjects
- *
SCUTELLARIA , *NEO-clerodanes , *DITERPENES , *CELL-mediated cytotoxicity , *ANTI-HIV agents , *STEREOCHEMISTRY - Abstract
Scuteformoids A-J, ten previously undescribed neo- clerodane diterpenoids along with one known analogue, were isolated from petroleum ether soluable fraction of the whole plants of Scutellaria formosana . The differences among these compounds are the substituents and stereochemistry at C-13. Their structures were elucidated by 1D and 2D NMR experiments, and the absolute configurations of Scuteformoids A, C, E, F, and I were further confirmed by single-crystal X-ray diffraction. Scuteformoids A, C, D, F, H, and I were evaluated for their inhibitory effects against HIV lytic replication and cytotoxic activities. All of them showed weak anti-HIV activities, with EC 50 values ranging from 48.24 to 79.17 μg/mL. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
38. Volume 35 Author Index.
- Published
- 2017
- Full Text
- View/download PDF
39. Ionic derivatives of betulinic acid exhibit antiviral activity against herpes simplex virus type-2 (HSV-2), but not HIV-1 reverse transcriptase.
- Author
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Visalli, Robert J., Ziobrowski, Hannah, Badri, Kameswara R., He, Johnny J., Zhang, Xiugen, Arumugam, Sri Ranjini, and Zhao, Hua
- Subjects
- *
BETULIN , *ANTIVIRAL agents , *HERPES simplex virus , *REVERSE transcriptase , *CHEMICAL derivatives , *DRUG solubility , *THERAPEUTICS - Abstract
Betulinic acid ( 1 ) has been modified to ionic derivatives ( 2 – 5 ) to improve its water solubility and biological activities. The binding properties of these derivatives with respect to human serum albumin (HSA) was examined and found to be similar to current anti-HIV drugs. These compounds did not inhibit HIV reverse transcriptase, however, 1 , 2 and 5 inhibited herpes simplex type 2 (HSV-2) replication at concentrations similar to those reported for acyclovir (IC 50 ∼0.1–10 μM) and with minimal cellular cytotoxicity. IC 50 values for antiviral activity against HSV-2 186 were 1.6, 0.6, 0.9, 7.2, and 0.9 μM for compounds 1 – 5 , respectively. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
40. Exosome-associated hepatitis C virus in cell cultures and patient plasma.
- Author
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Liu, Ziqing, Zhang, Xiugen, Yu, Qigui, and He, Johnny J.
- Subjects
- *
EXOSOMES , *HEPATITIS C , *BLOOD plasma , *CELL communication , *TRANSMISSION electron microscopy , *ANTIVIRAL agents - Abstract
Hepatitis C virus (HCV) infects its target cells in the form of cell-free viruses and through cell–cell contact. Here we report that HCV is associated with exosomes. Using highly purified exosomes and transmission electron microscopic imaging, we demonstrated that HCV occurred in both exosome-free and exosome-associated forms. Exosome-associated HCV was infectious and resistant to neutralization by an anti-HCV neutralizing antibody. There were more exosome-associated HCV than exosome-free HCV detected in the plasma of HCV-infected patients. These results suggest exosome-associated HCV as an alternative form for HCV infection and transmission. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
41. Regulation of ubiquitin-proteasome system-mediated Tip110 protein degradation by USP15.
- Author
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Timani, Khalid Amine, Liu, Ying, Suvannasankha, Attaya, and He, Johnny J.
- Subjects
- *
UBIQUITIN , *PROTEASOME regulation , *GENETIC transcription , *MESSENGER RNA , *NUCLEAR proteins , *RNA splicing , *STEM cells , *PHYSIOLOGY - Abstract
Tip110 is a nuclear protein and has been shown to function in tumor antigenicity, regulation of gene transcription, pre-mRNA splicing, stem cell proliferation and differentiation, and embryonic development. To characterize the in vivo functions of Tip110, a transgene cassette expressing human Tip110 protein (hTip110) was used to generate hTip110 transgenic (Tg) mice. Unexpectedly, only Tip110 mRNA but not Tip110 protein was expressed in Tg MEF and tissues. Treatment of Tg MEF with proteasome inhibitors led to detection of hTip110 protein, which prompted us to investigate the regulatory mechanisms of Tip110 degradation in mouse cells. We found that hTip110 was more sensitive to ubiquitin-proteasome system (UPS)-mediated protein degradation than mouse Tip110 (mTip110), likely resulting from more hTip110 ubiquitination. Using affinity chromatography and proteomics, we identified USP15, a deubiquitinating enzyme, to be associated with Tip110. Tip110 expression led to re-distribution of USP15 from the cytoplasm to the nucleus and complete co-localization of Tip110 with USP15 in the nucleus, whereas USP15 expression resulted in hTip110 deubiquitination. Interestingly, USP15 knockdown restored hTip110 protein expression in Tg MEF and USP15 expression had little effects. Taken together, these results provide insights into the regulatory mechanism of human Tip110 degradation by USP15. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
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