scholarly journals RKIP is decreased in laboring myometrium and modulates inflammation-induced pro-labor mediators

Reproduction ◽  
2017 ◽  
Vol 153 (5) ◽  
pp. 545-553
Author(s):  
Martha Lappas
Keyword(s):  
Kinase Inhibitor ◽  
Mrna Abundance ◽  
Human Myometrium ◽  
Mrna Levels ◽  
Labor And Delivery ◽  
Myometrial Cells ◽  
Extracellular Signal ◽  
Human Labor ◽  
Significant Augmentation ◽  
Sirna Knockdown

Nuclear factor-kappa B (NF-κB)-induced inflammation plays a central role in the terminal process of human labor and delivery. Our previous studies show that IL1B induces NF-κB signaling through extracellular signal-regulated kinase (ERK; official gene symbol MAPK1), whereas TNF induces NF-κB-driven transcription of pro-labor mediators via an MAPK1-independent mechanism. Raf kinase inhibitor protein (RKIP) negatively regulates inflammation by inhibiting NF-κB activation directly or indirectly by inhibiting MAPK1. The role of RKIP in the processes of human labor and delivery is not known. The present study was performed to investigate the expression of RKIP in laboring and non-laboring human myometrium and determine the effect of siRNA knockdown of RKIP (siRKIP) on pro-labor mediators in human myometrial primary cells. Term labor was associated with a decrease in RKIP expression. Furthermore, RKIP expression was decreased in myometrial cells treated with IL1B and TNF, two likely factors contributing to preterm birth. The effect of siRKIP in primary myometrial cells was a significant augmentation of IL1B- and TNF-induced CXCL1 and CXCL8 mRNA abundance and secretion; PTGS2 mRNA levels and prostaglandin PGF2α release and MMP9 mRNA abundance and pro-MMP9 secretion. There was no effect of siRKIP on MAPK1 activation. On the other hand, RKIP knockdown was associated with increased activation of NF-κB RELA in the presence of IL1B and TNF. In conclusion, in human primary myometrial cells, RKIP negatively regulates IL1B- and TNF-induced expression and or secretion of pro-inflammatory and pro-labor mediators by inhibiting NF-κB RELA activation.

scholarly journals RAF1 is increased in labouring myometrium and modulates inflammation-induced pro-labour mediators

Reproduction ◽  
2016 ◽  
Vol 151 (4) ◽  
pp. 411-420 ◽  
Author(s):  
Martha Lappas
Keyword(s):  
Protein Expression ◽  
Interleukin 1 ◽  
Signalling Pathway ◽  
Mrna Abundance ◽  
Mrna Levels ◽  
Myometrial Cells ◽  
Human Labour ◽  
Prostaglandin Endoperoxide Synthase ◽  
Sirna Knockdown ◽  
Term Labour

Inflammation plays a central role in the terminal process of human labour and delivery, including myometrial contractions. RAF1 proto-oncogene serine/threonine-protein kinase (RAF1) can activate ERK (official gene symbolMAPK1) and/or nuclear factor-kappa B (NF-κB) to regulate genes involved in inflammation. There are, however, no studies on the role of RAF1 in the processes of human labour and delivery. Thus, the aims of this study were to determine the effect of i) human labour and pro-inflammatory cytokines interleukin 1 beta (IL1B) and tumour necrosis factor (TNF) alpha on RAF1 protein expression in myometrium and ii) siRNA knockdown ofRAF1on pro-inflammatory and pro-labour mediators in human myometrial primary cells. Term labour was associated with an increase in RAF1 protein expression. Furthermore, RAF1 protein expression was increased in myometrial cells treated with IL1B and TNF, two likely factors contributing to preterm birth. Knockdown ofRAF1by siRNA in primary myometrial cells significantly decreased IL1B- and TNF-inducedIL1A, IL1B, IL6,(C-X-C motif) ligand 8 (CXCL8)and chemokine (C-C motif) ligand 2 (CCL2) mRNA abundance and IL6, IL8 and CCL2; prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA levels and prostaglandin PGF2αrelease; and NF-κB activation. Furthermore,RAF1knockdown was associated with decreased activation of ERK in the presence of IL1B but not TNF. Concordantly, the ERK inhibitor U0126 significantly decreased IL1B-inducedIL6,CXCL8,CCL2andPTGS2mRNA abundance; IL6, CXCL8, CCL2 and PGF2αrelease; and NF-κB activation. In conclusion, IL1B induces the expression and secretion of pro-labour mediators through the RAF1–MAPK1–NF-κB signalling pathway. TNF, on the other hand, regulates pro-labour mediators through the RAF1–NF-κB signalling pathway via an MAPK1-independent mechanism.

scholarly journals The Onset of Labor Alters Corticotropin-Releasing Hormone Type 1 Receptor Variant Expression in Human Myometrium: Putative Role of Interleukin-1β

Endocrinology ◽  
2007 ◽  
Vol 148 (7) ◽  
pp. 3205-3213 ◽  
Author(s):  
Danijela Markovic ◽  
Manu Vatish ◽  
Mei Gu ◽  
Donna Slater ◽  
Rob Newton ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Nuclear Translocation ◽  
Fold Increase ◽  
Nuclear Factor Κb ◽  
Prolonged Treatment ◽  
Human Myometrium ◽  
Mrna Levels ◽  
Myometrial Cells ◽  
Important Regulator ◽  
R1 Gene

CRH targets the human myometrium during pregnancy. The efficiency of CRH actions is determined by expression of functional receptors (CRH-R), which are dynamically regulated. Studies in myometrial tissue biopsies using quantitative RT-PCR demonstrated that the onset of labor, term or preterm, is associated with a significant 2- to 3-fold increase in CRH-R1 mRNA levels. Detailed analysis of myometrial CRH-R1 mRNA variants showed a decline of the pro-CRH-R1 mRNA encoding the CRH-R1β variant during labor and increased mRNA levels of CRH-R1d mRNA. Studies in myometrial cells identified IL-1β as an important regulator of myometrial CRH-R1 gene expression because prolonged treatment of myometrial cells with IL-1β (1 ng/ml) for 18 h induced expression of CRH-R1 mRNA levels by 1.5- to 2-fold but significantly attenuated CRH-R1β mRNA expression by 70%. In contrast, IL-1β had no effect on CRH-R1d mRNA expression. Studies using specific inhibitors suggest that ERK1/2, p38 MAPK, and downstream nuclear translocation of nuclear factor-κB mediate IL-1β effects on myometrial CRH-R1 gene. However, the increased CRH-R1 mRNA expression was associated with a dampening of the receptor efficacy to activate the adenylyl cyclase/cAMP signaling cascade. Thus, our findings suggest that IL-1β is an important regulator of CRH-R1 expression and functional activity, and this interaction might play a role in the transition of the uterus from quiescence to active contractions necessary for the onset of parturition.

scholarly journals The Role of Cyclic-ADP-Ribose-Signaling Pathway in Oxytocin-Induced Ca2+ Transients in Human Myometrium Cells

Endocrinology ◽  
2004 ◽  
Vol 145 (2) ◽  
pp. 881-889 ◽  
Author(s):  
Hosana Barata ◽  
Michael Thompson ◽  
Weronika Zielinska ◽  
Young S. Han ◽  
Carlos B. Mantilla ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Uterine Contraction ◽  
Cyclase Activity ◽  
Human Myometrium ◽  
Mrna Levels ◽  
Myometrial Cells ◽  
Cd38 Expression ◽  
Cyclic Adp Ribose ◽  
Multiple Signaling

Abstract Human myometrial contraction plays a fundamental role in labor. Dysfunction of uterine contraction is an important cause of labor progression failure. Although the mechanisms controlling uterine contraction are not completely understood, intracellular Ca2+ mobilization plays an important role during uterine contraction. Several mechanisms of intracellular Ca2+ mobilization are present in smooth muscle, but in the human uterus, only 1,4,5-trisphosphate-induced Ca2+ release has been studied extensively. Ryanodine receptor channels are present in myometrium. We determined the role of the cyclic ADP-ribose (cADPR)-signaling pathway in oxytocin-induced intracellular Ca2+ [(Ca2+)i] transients in human myometrial cells. We found that oxytocin-induced Ca2+ transient is dependent on several sources of Ca2+, including extracellular Ca2+ and intracellular Ca2+ stores. In addition, we found that both the 1,4,5-trisphosphate- and the cADPR-induced Ca2+ releasing systems are important for the induction of [Ca2+]i transients by oxytocin in human myometrial cells. Furthermore, we investigated TNFα regulation of oxytocin-induced [Ca2+]i transients, CD38 cyclase activity, and CD38 expression in human myometrial cells. We found that oxytocin-induced [Ca2+]i transients were significantly increased by 50 ng/ml TNF. Similarly, CD38 mRNA levels, CD38 expression, and cyclase activity were increased by TNFα, thus increasing cADPR levels. We propose that a complex interaction between multiple signaling pathways is important for the development of intracellular Ca2+ transients induced by oxytocin and that TNFα may contribute for the myometrium preparation for labor by regulating the cADPR-signaling pathway. The observation that the cADPR-signaling pathway is important for the development of intracellular Ca2+ transients in human myometrial cells raises the possibility that this signaling pathway could serve as a target for the development of new therapeutic strategies for abnormal myometrial contraction observed during pregnancy.

scholarly journals TBX2, a Novel Regulator of Labour

Medicina ◽  
2021 ◽  
Vol 57 (6) ◽  
pp. 515
Author(s):  
Febilla Fernando ◽  
Geertruda J.M. Veenboer ◽  
Martijn A. Oudijk ◽  
Marlies A.M. Kampman ◽  
Karst Y. Heida ◽  
...  
Keyword(s):  
Preterm Labour ◽  
Therapeutic Interventions ◽  
Human Myometrium ◽  
Mrna Levels ◽  
Myometrial Cells ◽  
Cytokines And Chemokines ◽  
Term Labour ◽  
Upstream Regulators

Background and Objectives: Therapeutic interventions targeting molecular factors involved in the transition from uterine quiescence to overt labour are not substantially reducing the rate of spontaneous preterm labour. The identification of novel rational therapeutic targets are essential to prevent the most common cause of neonatal mortality. Based on our previous work showing that Tbx2 (T-Box transcription factor 2) is a putative upstream regulator preceding progesterone withdrawal in mouse myometrium, we now investigate the role of TBX2 in human myometrium. Materials and Methods: RNA microarray analysis of (A) preterm human myometrium samples and (B) myometrial cells overexpressing TBX2 in vitro, combined with subsequent analysis of the two publicly available datasets of (C) Chan et al. and (D) Sharp et al. The effect of TBX2 overexpression on cytokines/chemokines secreted to the myometrium cell culture medium were determined by Luminex assay. Results: Analysis shows that overexpression of TBX2 in myometrial cells results in downregulation of TNFα- and interferon signalling. This downregulation is consistent with the decreased expression of cytokines and chemokines of which a subset has been previously associated with the inflammatory pathways relevant for human labour. In contrast, CXCL5 (C-X-C motif chemokine ligand 5), CCL21 and IL-6 (Interleukin 6), previously reported in relation to parturition, do not seem to be under TBX2 control. The combined bioinformatical analysis of the four mRNA datasets identifies a subset of upstream regulators common to both preterm and term labour under control of TBX2. Surprisingly, TBX2 mRNA levels are increased in preterm contractile myometrium. Conclusions: We identified a subset of upstream regulators common to both preterm and term labour that are activated in labour and repressed by TBX2. The increased TBX2 mRNA expression in myometrium collected during a preterm caesarean section while in spontaneous preterm labour compared to tissue harvested during iatrogenic preterm delivery does not fit the bioinformatical model. We can only explain this by speculating that the in vivo activity of TBX2 in human myometrium depends not only on the TBX2 expression levels but also on levels of the accessory proteins necessary for TBX2 activity.

scholarly journals Adrenomedullin increases the expression of calcitonin-like receptor and receptor activity modifying protein 2 mRNA in human microvascular endothelial cells

2006 ◽  
Vol 190 (2) ◽  
pp. 505-514 ◽  
Author(s):  
Nele Schwarz ◽  
Derek Renshaw ◽  
Supriya Kapas ◽  
Joy P Hinson
Keyword(s):  
Endothelial Cells ◽  
Kinase Inhibitor ◽  
Receptor Activity ◽  
Microvascular Endothelial Cells ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Microvascular Endothelial

Adrenomedullin (AM) is a multifunctional peptide hormone, which plays a significant role in vasodilation and angiogenesis, implicating it in hypertension as well as in carcinogenesis. AM exerts its effects via the calcitonin receptor-like receptor (CRLR, now known as CL) complexed with either receptor activity modifying protein (RAMP) 2 or 3. We have investigated the effect of AM on immortalized human microvascular endothelial cells 1, since endothelial cells are a major source as well as a target of AM actions in vivo. Cells treated with AM showed elevated cAMP in a time (5–45 min)-dependent and dose (10−6–10−14 M)-dependent manner. Pre-treatment with the AM receptor antagonist AM22–52 partially suppressed the AM-induced increase in cAMP levels. An increase in extracellular signal-regulated kinase 1/2 phosphorylation was observed after 5 min of treatment with 10−8 M AM. This phosphorylation was specific, since we were able to block the AM-induced effect with 1 μM U0126, a specific mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor. Using real-time PCR, we were able to show for the first time that AM upregulates peptide and mRNA expression of vascular endothelial growth factor (VEGF). However, AM treatment of cells did not result in increased cell proliferation. Instead, we observed that AM and VEGF induced cell migration, which could be inhibited by the AM22–52 and anti-VEGF antibody respectively. AM also significantly elevated mRNA levels of CL (after 2 and 24 h treatment) and RAMP2 (after 1 and 24 h treatment). The upregulation of the AM receptor at two time points reflects possibly different cellular responses to short- and long-term exposure to AM.

scholarly journals Immune Aspects and Myometrial Actions of Progesterone and CRH in Labor

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Nikolaos Vrachnis ◽  
Fotodotis M. Malamas ◽  
Stavros Sifakis ◽  
Panayiotis Tsikouras ◽  
Zoe Iliodromiti
Keyword(s):  
Immune Responses ◽  
Critical Role ◽  
Progesterone Receptors ◽  
Human Myometrium ◽  
Myometrial Cells ◽  
Inflammatory Signals ◽  
Progesterone Metabolism ◽  
Human Labor ◽  
Pituitary Adrenal Axis

Progesterone and corticotropin-releasing hormone (CRH) have a critical role in pregnancy and labor, as changes related to these hormones are crucial for the transition from myometrial quiescence to contractility. The mechanisms related to their effect differ between humans and other species, thus, despite extensive research, many questions remain to be answered regarding their mediation in human labor. Immune responses to progesterone and CRH are important for labor. Progesterone acts as an immunomodulator which controls many immune actions during pregnancy, and its withdrawal releases the inhibitory action on inflammatory pathways. In humans, a “functional” progesterone withdrawal occurs with onset of labor through changes in progesterone metabolism, progesterone receptors, and other molecules that either facilitate or antagonize progesterone function. Placental CRH acts on the fetal pituitary-adrenal axis to stimulate adrenal production of androgens and cortisol and also acts directly on myometrial cells via its receptors. CRH also affects inflammatory signals and vice versa. Interactions between progesterone and CRH additionally occur during labor. We describe the role of these two hormones in human myometrium and their interactions with the immune system during labor.

scholarly journals Melatonin Sensitizes Human Myometrial Cells to Oxytocin in a Protein Kinase Cα/Extracellularly Regulated Kinase-Dependent Manner

2010 ◽  
Vol 24 (5) ◽  
pp. 1106-1106
Author(s):  
James T. Sharkey ◽  
Casey Cable ◽  
James Olcese
Keyword(s):  
Protein Kinase ◽  
Phospholipase C ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Human Myometrium ◽  
Dependent Manner ◽  
Uterine Contractility ◽  
Myometrial Cells

abstract Context: Studies have shown that labor occurs primarily in the night/morning hours. Recently, we identified the human myometrium as a target for melatonin (MEL), the neuroendocrine output signal coding for circadian night. Objective: The purpose of this study was to determine the signaling pathway underlying the effects of MEL on contractility and the contractile machinery in immortalized human myometrial cells. Design: To ascertain the signaling pathway of MEL leading to its effects on myometrial contractility in vitro, we performed gel retraction assays with cells exposed to iodo-MEL (I-MEL) with or without oxytocin and the Rho kinase inhibitor Y27632. I-MEL effects on inositol trisphosphate (IP3)/diacylglycerol (DAG)/protein kinase C (PKC) signaling were also investigated. Additionally, we assayed for caldesmon phosphorylation and ERK1/2 activation. Results: I-MEL was found to activate PKCα via the phospholipase C/IP3/DAG signaling pathway, which was confirmed by PKC enzyme assay. I-MEL did not affect myosin light chain phosphatase activity, and its effects on contractility were insensitive to Rho kinase inhibition. I-MEL did increase phosphorylation of ERK1/2 and caldesmon, which was inhibited by the MAPK kinase inhibitor PD98059 or the PKC inhibitor C1. Conclusions: MEL sensitizes myometrial cells to subsequent procontractile signals in vitro through activation of the phospholipase C/IP3/DAG signaling pathway, resulting in specific activation of PKCα and ERK1/2, thereby phosphorylating caldesmon, which increases actin availability for myosin binding and cross-bridging. In vivo, this sensitization would provide a mechanism for the increased nocturnal uterine contractility and labor that has been observed in late-term human pregnancy.

Abnormal EGF-dependent regulation of sodium absorption in ARPKD collecting duct cells

2005 ◽  
Vol 288 (3) ◽  
pp. F474-F482 ◽  
Author(s):  
I. Elias Veizis ◽  
Calvin U. Cotton
Keyword(s):  
Egf Receptor ◽  
Kinase Inhibitor ◽  
Collecting Duct ◽  
Apical Plasma Membrane ◽  
Sodium Absorption ◽  
Bathing Solution ◽  
Mrna Levels ◽  
Egf Receptors ◽  
Extracellular Signal ◽  
Erk Kinase

Amiloride-sensitive sodium entry, via the epithelial sodium channel (ENaC), is the rate-limiting step for Na+ absorption in kidney collecting ducts, and epidermal growth factor (EGF) inhibits Na+ transport and ENaC expression. A pathognomonic feature of polycystic kidney disease (PKD) is EGF receptor mislocalization to the apical plasma membrane and EGF/EGF receptor axis overactivity. Immunohistochemical and biochemical analysis revealed mislocalization of EGF receptor and excessive activation of the p42/44 extracellular signal-regulated protein kinase pathway (ERK1/2) in kidneys from cystic mice compared with noncystic littermates. Primary monolayer cultures of noncystic and cystic murine collecting duct principal cells were used to identify aberrant EGF-dependent ERK1/2 activation and regulation of Na+ transport associated with autosomal recessive PKD. Addition of EGF to the basolateral bathing solution of noncystic or cystic monolayers led to p42/44 phosphorylation and inhibition of Na+ transport (30–35%), whereas apical EGF was effective only in monolayers derived from cystic mice. p42/44 Phosphorylation and inhibition of Na+ transport were prevented by prior treatment of the cells with an ERK kinase inhibitor. Chronic treatment (24 h) of noncystic and cystic monolayers with basolateral EGF elicited sustained inhibition of Na+ absorption (50–55%) and a reduction in steady-state ENaC mRNA levels (50–75%). In contrast, addition of EGF to the apical bathing solution (24 h) had no effect in noncystic monolayers but led to inhibition of Na+ transport (50–60%) and decreased ENaC expression (45–60%) in cystic cells. Pretreatment of the monolayers with an ERK kinase inhibitor abolished the chronic effects of EGF on Na+ transport. The results of these studies reveal that the mislocalized apical EGF receptors are functionally coupled to the ERK pathway and that abnormal EGF-dependent regulation of ENaC function and expression may contribute to PKD pathophysiology.

scholarly journals VEGF Mediates Retinal Müller Cell Viability and Neuroprotection through BDNF in Diabetes

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 712
Author(s):  
Yun-Zheng Le ◽  
Bei Xu ◽  
Ana J. Chucair-Elliott ◽  
Huiru Zhang ◽  
Meili Zhu
Keyword(s):  
Specific Protein ◽  
Müller Cell ◽  
Dependent Manner ◽  
Vascular Abnormalities ◽  
Extracellular Signal ◽  
Muller Cell ◽  
Protein Kinase Akt ◽  
Sirna Knockdown ◽  
Endothelial Growth Factor ◽  
Dose Dependent

To investigate the mechanism of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) in Müller cell (MC) viability and neuroprotection in diabetic retinopathy (DR), we examined the role of VEGF in MC viability and BDNF production, and the effect of BDNF on MC viability under diabetic conditions. Mouse primary MCs and cells of a rat MC line, rMC1, were used in investigating MC viability and BDNF production under diabetic conditions. VEGF-stimulated BDNF production was confirmed in mice. The mechanism of BDNF-mediated MC viability was examined using siRNA knockdown. Under diabetic conditions, recombinant VEGF (rVEGF) stimulated MC viability and BDNF production in a dose-dependent manner. rBDNF also supported MC viability in a dose-dependent manner. Targeting BDNF receptor tropomyosin receptor kinase B (TRK-B) with siRNA knockdown substantially downregulated the activated (phosphorylated) form of serine/threonine-specific protein kinase (AKT) and extracellular signal-regulated kinase (ERK), classical survival and proliferation mediators. Finally, the loss of MC viability in TrkB siRNA transfected cells under diabetic conditions was rescued by rBDNF. Our results provide direct evidence that VEGF is a positive regulator for BDNF production in diabetes for the first time. This information is essential for developing BDNF-mediated neuroprotection in DR and hypoxic retinal diseases, and for improving anti-VEGF treatment for these blood–retina barrier disorders, in which VEGF is a major therapeutic target for vascular abnormalities.

scholarly journals Rho-kinase inhibitor hydroxyfasudil protects against HIV-1 Tat-induced dysfunction of tight junction and neprilysin/Aβ transfer receptor expression in mouse brain microvessels

2021 ◽  
Vol 476 (5) ◽  
pp. 2159-2170
Author(s):  
Qiangtang Chen ◽  
Yu Wu ◽  
Yachun Yu ◽  
Junxiang Wei ◽  
Wen Huang
Keyword(s):  
Tight Junction ◽  
Signaling Pathway ◽  
Mouse Brain ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Brain Microvessels ◽  
Rho Kinase Inhibitor ◽  
Hiv 1

AbstractHIV-1 transactivator protein (Tat) induces tight junction (TJ) dysfunction and amyloid-beta (Aβ) clearance dysfunction, contributing to the development and progression of HIV-1-associated neurocognitive disorder (HAND). The Rho/ROCK signaling pathway has protective effects on neurodegenerative disease. However, the underlying mechanisms of whether Rho/ROCK protects against HIV-1 Tat-caused dysfunction of TJ and neprilysin (NEP)/Aβ transfer receptor expression have not been elucidated. C57BL/6 mice were administered sterile saline (i.p., 100 μL) or Rho-kinase inhibitor hydroxyfasudil (HF) (i.p., 10 mg/kg) or HIV-1 Tat (i.v., 100 μg/kg) or HF 30 min before being exposed to HIV-1 Tat once a day for seven consecutive days. Evans Blue (EB) leakage was detected via spectrophotometer and brain slides in mouse brains. The protein and mRNA levels of zonula occludens-1 (ZO-1), occludin, NEP, receptor for advanced glycation end products (RAGE), and low-density lipoprotein receptor-related protein 1 (LRP1) in mouse brain microvessels were, respectively, analyzed by Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. Exposure of the mice to HIV-1 Tat increased the amount of EB leakage, EB fluorescence intensity, blood–brain barrier (BBB) permeability, as well as the RAGE protein and mRNA levels, and decreased the protein and mRNA levels of ZO-1, occludin, NEP, and LRP1 in mouse brain microvessels. However, these effects were weakened by Rho-kinase inhibitor HF. Taken together, these results provide information that the Rho/ROCK signaling pathway is involved in HIV-1 Tat-induced dysfunction of TJ and NEP/Aβ transfer receptor expression in the C57BL/6 mouse brain. These findings shed some light on potentiality of inhibiting Rho/Rock signaling pathway in handling HAND.

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