Deficiency in Androgen Receptor Aggravates Traumatic Brain Injury-Induced Pathophysiology and Motor Deficits in Mice

Chen, Yu‐Hsin; Chen, Yen-Chou; Hwang, Ling Ling; Yang, Liang-Yo; Lu, Dah‐Yuu

doi:10.3390/molecules26206250

Cited by 3 publications

(3 citation statements)

References 90 publications

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“…With the GFAP promoter containing no known binding sites for AR, Androgen/Androgen Receptor complex indirectly and negatively regulates GFAP expression and further, it can be speculated that this regulation is weak due to western blot data displaying decreased GFAP protein in the presence in VSV-G/Gagi infected U373 compared to VSV-G/Gagi.Nef-infected U373 cells (Fig. 6) [112][113][114].…”

Section: Discussionmentioning

confidence: 99%

HIV Nef Expression Down-modulated GFAP Expression and Altered Glutamate Uptake and Release and Proliferation in Astrocytes

Wilson¹,

He²

2023

Aging and disease

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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.

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Section: Discussionmentioning

confidence: 99%

HIV Nef Expression Down-modulated GFAP Expression and Altered Glutamate Uptake and Release and Proliferation in Astrocytes

Wilson¹,

He²

2023

Aging and disease

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“…T mediates this effect if given following injury 50 . Both 5α‐DHT and T bind to androgen receptors which play a crucial role in TBI 51,52 …”

Section: Introductionmentioning

confidence: 99%

“…50 Both 5α-DHT and T bind to androgen receptors which play a crucial role in TBI. 51,52 Progesterone (P4) has also been studied for its role in TBI recovery. Among steroids, P4 was one of the first investigated in the context of TBI.…”

mentioning

confidence: 99%

Steroid profiling in brain and plasma of adult zebra finches following traumatic brain injury

Duncan

2022

J Neuroendocrinology

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Traumatic brain injury (TBI) is a serious health concern and a leading cause of death. Emerging evidence strongly suggests that steroid hormones (estrogens, androgens, and progesterone) modulate TBI outcomes by regulating inflammation, oxidative stress, free radical production, and extracellular calcium levels. Despite this growing body of evidence on steroid‐mediated neuroprotection, very little is known about the local synthesis of these steroids following injury. Here, we examine the effect of TBI on local neurosteroid levels around the site of injury and in plasma in adult male and female zebra finches. Using ultrasensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS), we examined estrogens, androgens, and progesterone in the entopallium and plasma of injured and uninjured animals. Three days after injury, elevated levels of 17β‐estradiol (E2), estrone (E1), and testosterone (T) were detected near injured brain tissue with a corresponding increase in E2 also detected in plasma. Taken together, these results provide further evidence that TBI alters neurosteroid levels and are consistent with studies showing that neurosteroids provide neuroprotection following injury.

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Neurosteroid Receptor Modulators for Treating Traumatic Brain Injury

Verdoorn,

Parry,

Pinna

et al. 2023

Neurotherapeutics

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Traumatic brain injury (TBI) triggers wide-ranging pathology that impacts multiple biochemical and physiological systems, both inside and outside the brain. Functional recovery in patients is impeded by early onset brain edema, acute and chronic inflammation, delayed cell death, and neurovascular disruption. Drug treatments that target these deficits are under active development, but it seems likely that fully effective therapy may require interruption of the multiplicity of TBI-induced pathological processes either by a cocktail of drug treatments or a single pleiotropic drug. The complex and highly interconnected biochemical network embodied by the neurosteroid system offers multiple options for the research and development of pleiotropic drug treatments that may provide benefit for those who have suffered a TBI. This narrative review examines the neurosteroids and their signaling systems and proposes directions for their utility in the next stage of TBI drug research and development.

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Deficiency in Androgen Receptor Aggravates Traumatic Brain Injury-Induced Pathophysiology and Motor Deficits in Mice

Cited by 3 publications

References 90 publications

HIV Nef Expression Down-modulated GFAP Expression and Altered Glutamate Uptake and Release and Proliferation in Astrocytes

HIV Nef Expression Down-modulated GFAP Expression and Altered Glutamate Uptake and Release and Proliferation in Astrocytes

Steroid profiling in brain and plasma of adult zebra finches following traumatic brain injury

Neurosteroid Receptor Modulators for Treating Traumatic Brain Injury

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