scholarly journals Claudins: Beyond Tight Junctions in Human IBD and Murine Models

2021 ◽  
Vol 12 ◽  
Author(s):  
Snježana Čužić ◽  
Maja Antolić ◽  
Anja Ognjenović ◽  
Darija Stupin-Polančec ◽  
Adriana Petrinić Grba ◽  
...  
Keyword(s):  
Animal Models ◽  
Mononuclear Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Mrna Level ◽  
Cell Lineage ◽  
Inflammatory Cells ◽  
Transfer Model ◽  
Mrna Levels ◽  
Junction Protein ◽  
Mesodermal Origin

Claudins are transmembrane proteins constituting one of three tight junction protein families. In patients with inflammatory bowel disease (IBD), disease activity–dependent changes in expression of certain claudins have been noted, thus making certain claudin family members potential therapy targets. A study was undertaken with the aim of exploring expression of claudins in human disease and two different animal models of IBD: dextrane sulfate sodium–induced colitis and adoptive transfer model of colitis. The expression of sealing claudin-1, claudin-3, claudin-4, and claudin-8, and pore-forming claudin-2 in humans and rodents has been evaluated by immunohistochemistry and quantitative polymerase chain reaction. Claudins were expressed by epithelial and cells of mesodermal origin and were found to be situated at the membrane, within the cytoplasm, or within the nuclei. Claudin expression by human mononuclear cells isolated from lamina propria has been confirmed by Western blot and flow cytometry. The claudin expression pattern in uninflamed and inflamed colon varied between species and murine strains. In IBD and both animal models, diverse alterations in claudin expression by epithelial and inflammatory cells were recorded. Tissue mRNA levels for each studied claudin reflected changes within cell lineage and, at the same time, mirrored the ratio between various cell types. Based on the results of the study, it can be concluded that 1) claudins are not expressed exclusively by epithelial cells, but by certain types of cells of mesodermal origin as well; 2) changes in the claudin mRNA level should be interpreted in the context of overall tissue alterations; and 3) both IBD animal models that were analyzed can be used for investigating claudins as a therapy target, respecting their similarities and differences highlighted in this study.

scholarly journals Decreased levels of miR-28-5p and miR-361-3p and increased levels of insulin-like growth factor 1 mRNA in mononuclear cells from patients with hereditary hemorrhagic telangiectasia

2019 ◽  
Vol 97 (6) ◽  
pp. 562-569 ◽  
Author(s):  
Anthony Cannavicci ◽  
Qiuwang Zhang ◽  
Si-Cheng Dai ◽  
Marie E. Faughnan ◽  
Michael J.B. Kutryk
Keyword(s):  
Growth Factor ◽  
Peripheral Blood ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Mononuclear Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Clinical Manifestations ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Peripheral Blood Mononuclear ◽  
Micro Rnas

Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disorder inherited in an autosomal dominant manner. Patients with HHT can develop vascular dysplasias called telangiectasias and arteriovenous malformations (AVMs). Our objective was to profile and characterize micro-RNAs (miRNAs), short noncoding RNAs that regulate gene expression posttranscriptionally, in HHT patient-derived peripheral blood mononuclear cells (PBMCs). PBMCs, comprised mostly of lymphocytes and monocytes, have been reported to be dysfunctional in HHT. A total of 40 clinically confirmed HHT patients and 22 controls were enrolled in this study. PBMCs were isolated from 16 mL of peripheral blood and purified for total RNA. MiRNA expression profiling was conducted with a human miRNA array analysis. Select dysregulated miRNAs and miRNA targets were validated with reverse transcription–quantitative polymerase chain reaction. Of the 377 miRNAs screened, 41 dysregulated miRNAs were identified. Both miR-28-5p and miR-361-3p, known to target insulin-like growth factor 1 (IGF1), a potent angiogenic growth factor, were found to be significantly downregulated in HHT patients. Consequently, IGF1 mRNA levels were found to be significantly elevated. Our research successfully identified miRNA dysregulation and elevated IGF1 mRNA levels in PBMCs from HHT patients. This novel discovery represents a potential pathogenic mechanism that could be targeted to alleviate clinical manifestations of HHT.

Increased NOX1 and DOUX2 Expression in the Colonic Mucosa of Patients with Chronic Functional Constipation

2021 ◽  
Author(s):  
Xiuqin Wei ◽  
Chunbo Kang ◽  
Lei Gao ◽  
Mengqiao Zhang ◽  
Mei Xue ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Healthy Subjects ◽  
Mrna Level ◽  
Functional Constipation ◽  
Inflammatory Cells ◽  
Histological Structure ◽  
Mrna Levels ◽  
Significant Difference ◽  
And Control ◽  
Colonic Biopsies

Abstract Aim To determine whether oxidative stress and inflammation are associated with constipation by examining the expression of the main producers of reactive oxygen species, NADPH oxidases, and pro-inflammatory cytokines in the colon of patients with chronic functional constipation. Methods The colonic biopsies were collected from 32 patients with chronic functional constipation and 30 healthy subjects who underwent colonoscopy. Colonic mucosal histology was observed. IL-1β, IL-6, IL-8 mRNA, and four members of NADPH oxidase (NOX1, NOX2, DOUX2 and NOX4) protein and mRNA were assessed by immunohistochemistry, western blotting and RT-PCR. Results The tissues from both patients and healthy subjects showed normal histological structure without increase of inflammatory cells. NOX1 protein and mRNA levels were significantly increased compared to controls (P<0.05). DOUX2 protein, but not mRNA, was increased by twofold compared to controls (P<0.05). The levels of NOX2 and NOX4 protein and mRNA demonstrated no significant difference between patients and control subjects. The levels of IL-1β and IL-6 mRNA were significantly higher in constipation patients (P<0.05), while IL-8 mRNA level was no different between the two groups. Conclusion NADPH oxidase and pro-inflammatory cytokine might be involved in the pathogeneses of chronic functional constipation.

Expression of P73 Splice Variants Correlates to Resistance to DNA Damaging Drugs in Childhood T-Lineage Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 995-995
Author(s):  
Marrit Meier ◽  
Monique L. Den Boer ◽  
Jules P.P. Meijerink ◽  
Monique Passier ◽  
Elisabeth R. Van Wering ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Mononuclear Cells ◽  
Splice Variants ◽  
Lymphoblastic Leukemia ◽  
Mrna Level ◽  
Dominant Negative ◽  
Leukemic Cells ◽  
Mrna Levels ◽  
Transactivation Domain ◽  
Loss Of Function

Abstract Children with T-lineage Acute Lymphoblastic Leukemia (T-ALL) have a higher relapse-risk and are in-vitro more resistant to therapeutic drugs compared to ALL patients with a precursor-B phenotype. Cellular resistance to anti-cancer agents has previously shown to be associated with failure of P53 family member signaling by abrogation of P53 function due to loss-of-function mutations or dominant-negative inhibition by isoforms of P73 lacking (part of) the N-terminal transactivation domain (P73ΔEX2, P73ΔEX2/3, ΔN-P73 and ΔN’-P73). Since p53 mutations are not commonly found in T-ALL, we investigated the expression levels of p73 splice variants in relation to drug resistance in children with T-ALL. Splice variants were quantitatively measured at the mRNA level in leukemic cells of 55 T-ALL patients and mononuclear cells of 12 non-leukemic controls. TA-p73 (transactivation competent), p73Δex2, p73Δex2/3, ΔN-p73 and ΔN’-p73 were all found to be present at a relatively higher mRNA level in T-ALL patients than controls (P < 0.05 for all), suggesting that expression of the TP73 gene is deregulated in T-ALL. Resistance of T-ALL cells to the DNA damaging drug daunorubicin correlated with mRNA levels of the dominant-negative variants of p73, i.e. ΔN-p73 and ΔN’-p73 (Rs = 0.38, P = 0.03). In contrast, expression of none of the variants, including ΔN-p73 and ΔN’-p73, was related to resistance of T-ALL cells to non-DNA damaging drugs (prednisolone, vincristine and L-asparaginase). In conclusion, high expression of ΔN-p73 and ΔN’-p73 variants possibly contributes to resistance to DNA damaging drugs in childhood T-ALL.

Prognostic Significance of WT1 mRNA and Anti-WT1 Antibody Levels in Peripheral Blood in Patients with Myelodysplastic Syndromes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3821-3821
Author(s):  
Hideto Tamura ◽  
Kazuo Dan ◽  
Norio Yokose ◽  
Rika Iwakiri ◽  
Masatsugu Ohta ◽  
...  
Keyword(s):  
Immune Response ◽  
Mrna Expression ◽  
Myelodysplastic Syndromes ◽  
Peripheral Blood ◽  
Quantitative Polymerase Chain Reaction ◽  
Mrna Level ◽  
Prognostic Significance ◽  
Refractory Anemia ◽  
Mrna Levels ◽  
Disease Subtype

Abstract Abstract 3821 Poster Board III-757 (INTRODUCTION) The Wilms tumor gene (WT1) message is overexpressed in tumor cells from various solid cancers as well as hematologic malignancies including myelodysplastic syndromes (MDS). We reported previously that WT1 mRNA expression in peripheral blood mononuclear cells (PBMCs) as well as bone marrow (BM) cells increased with the aggressiveness of MDS disease subtype as defined by the French-American-British (FAB) classification and that a humoral immune response, IgG- or IgM-type anti-WT1 antibody (Ab) expression, was detected in sera from most MDS patients. In this study, we investigated whether WT1 mRNA expression and anti-WT1 Ab titers in PB were associated with prognosis in MDS patients by examining their long-term follow-up data. (METHODS AND RESULTS) (1) WT1 mRNA expression in PBMCs was examined in 80 patients: 35 with refractory anemia (RA); 5 with RA with ringed sideroblasts (RARS); 24 with RA with excess blasts (RAEB); 5 with RAEB in transformation (RAEB-t); and 11 with acute myeloid leukemia transformed from MDS (AML-MDS). Levels of WT1 mRNA expression were assessed using the real-time quantitative polymerase chain reaction [Tamaki H, et al, Leukemia 1999]. WT1 mRNA levels increased with the aggressiveness of disease subtype (mean: RA, 220.9; RARS, 129.4; RAEB, 5,554.3; RAEB-t, 14,284.0; AML-MDS, 56,272.7 copies/μg) and with the aggressiveness of the International Prognostic Scoring System (IPSS) category (mean: low, 114.5; intermediate-1, 360.8; intermediate-2, 12,041.6; high, 7,357.9 copies/μg) in these patients. (2) IgG- and IgM-type anti-WT1 Ab titers were determined using the dot-blot assay [Elisseeva OA, Blood 2002] in sera from 45 of the 80 patients: 15 RA; 3 RARS; 18 RAEB; 3 RAEB-t; and 6 AML-MDS. IgM and IgG WT1 Abs were detected in 31 (79.5%) and 34 (87.2%) MDS patients, and 5 (83.3%) and 6 (100%) AML-MDS patients, respectively. WT1 Abs levels were not correlated with FAB subtype, IPSS, or WT1 mRNA expression in PBMCs. (3) When patients were divided into three groups based on the WT1 mRNA level (fewer than 100 copies/μg, 100 to 10,000 copies/μg, and more than 10,000 copies/μg), their survival rates differed significantly (P = 0.0186): survival was worse in those with increased WT1 mRNA levels. Specifically, a high WT1 mRNA level was a strong predictor of rapid AML transformation even if adjusted by the IPSS (P = 0.0005). Furthermore, patients with high levels of either IgM or IgG WT1 Abs had significantly better survival compared with those whose IgM and IgG WT1 Abs values were both low (P = 0.0007) even when adjusted by the IPSS (P = 0.0019). (CONCLUSIONS) This study showed for the first time that high WT1 mRNA expression and high WT1 Ab titers in PB affected the prognosis of MDS patients negatively and positively, respectively, suggesting that an optimal immune response against WT1 may beneficial. Recently, clinical trials of WT1 peptide-based immunotherapy have been conducted for various malignancies including MDS. Our data presented here may provide a rationale for anti-WT1 immunotherapy in MDS. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Role of interleukin-33 in the clinical pathogenesis of chronic apical periodontitis

2019 ◽  
Vol 47 (7) ◽  
pp. 3332-3343
Author(s):  
Tana Gegen ◽  
Yanxia Zhu ◽  
Qinnuan Sun ◽  
Benxiang Hou
Keyword(s):  
Inflammatory Cell ◽  
Mrna Level ◽  
Rank Correlation ◽  
Inflammatory Cells ◽  
Apical Periodontitis ◽  
Mrna Levels ◽  
Interleukin 33 ◽  
Receptor Activator ◽  
Hematoxylin And Eosin

Objective This study investigated interleukin (IL)-33 expression in chronic apical periodontitis (CAP) lesions and possible relationships with receptor activator of nuclear factor κ-Β ligand (RANKL) and osteoprotegerin (OPG). Methods Inflammatory cell infiltration in CAP lesions and samples of healthy periapical tissue (n = 30 each) was evaluated by hematoxylin and eosin staining. IL-33, RANKL, and OPG expression levels were assessed by immunohistochemistry and real-time PCR. In CAP lesions alone, relationships between mRNA level of IL-33 and mRNA levels of both RANKL and OPG were analyzed by Spearman rank correlation. Results Histological analysis revealed a large number of inflammatory cells in CAP lesions, and immunohistochemistry revealed IL-33-positive cells. There were more IL-33- and RANKL-positive cells in CAP lesions than in healthy periapical tissue, whereas there were fewer OPG-positive cells in CAP lesions than in healthy periapical tissue. In CAP lesions alone, IL-33 mRNA level was negatively correlated with mRNA level of RANKL and positively correlated with mRNA level of OPG. Conclusions IL-33 is highly expressed in CAP lesions, where it is negatively correlated with RANKL and positively correlated with OPG expression. IL-33 may protect against bone resorption via RANKL suppression and OPG induction, and constitutes a potential target for CAP treatment.

Hypomethylation and Overexpression of CD70 in CD4+ T Cells of the Patients with Immuno-Related Pancytopenia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5157-5157
Author(s):  
Zonghong Shao ◽  
Yue Ren ◽  
Rong Fu
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Methylation Level ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Quantitative Polymerase Chain Reaction ◽  
Gradient Centrifugation ◽  
Mrna Level ◽  
Venous Blood ◽  
Normal Controls

Abstract Objective To study the expression of CD 70 and the methylation level of CD70 promoter in immuno-related pancytopenia (IRP) patients, and explore the role of CD70 in the pathogenesis of IRP. Methods Thirty-five IRP patients and fifteen healthy donors were enrolled in this study. Peripheral blood mononuclear cells were isolated from venous blood by density gradient centrifugation and CD4+ T cells were isolated by immunomagnetic beads.The mRNA level and the percentage of CD70 of CD4+ T cells were measured by real-time quantitative polymerase chain reaction (RT-PCR) and flow cytometry respectively. Methylation-Specific PCR (MSP) was performed to determine the methylation level of CD70 promoter. Results The percentage of CD70 expression on CD4+ T cells of untreated IRP patients[(7.46±1.51)%] was significantly higher than that of recovered IRP patients [(5.95±1.34) %] and normal controls [(1.83±0.6)%] and the result of recovered IRP patients was significantly higher than that of normal controls (P<0.05).The relative expressions of CD70 mRNA in CD4+ T cells were [2.314(0.200~6.084)]A[1.021 (0.135~3.434)]A [0.353 (0.008~2.258)] in three groups respectively. The differences between untreated IRP patients,recovered IRP patients and normal controls were significant (P<0.05). The CD70 promoter methylation level in CD4+ T cells of all IRP patients was significantly lower than that of normal controls (p<0.05). The expression of CD70 positively correlated to the ratio of CD5+ B cells (r=0.533, p<0.001). Conclusions The overexpression of CD70 may lead to immunologic disarrangement and patients and it may play important role in the pathogenesis of IRP. Disclosures No relevant conflicts of interest to declare.

Evaluation of apoptotic caspase levels in estimation of the wound age

2017 ◽  
Vol 43 (2) ◽  
pp. 126-133
Author(s):  
Taner Akar ◽  
Atiye Seda Yar Saglam ◽  
Pınar Uyar Göçün ◽  
Ebru Alp ◽  
Ece Konac ◽  
...  
Keyword(s):  
Immunohistochemical Staining ◽  
Caspase 3 ◽  
Mononuclear Cells ◽  
Mrna Level ◽  
Skin Wound ◽  
Wound Age ◽  
Mrna Levels ◽  
Caspase 9 ◽  
Protein Levels ◽  
Potential Tool

AbstractObjectives:We aimed to investigate the potential use of the expression of apoptotic signaling pathway genes of rat in skin wound age estimation.Material and methods:For this purpose, we formed cutting tool injuries using a scalpel in an experimental model. Then, we assessed Caspase 3, 8 and 9 mRNA levels by using quantitative real-time PCR and protein levels by using immunohistochemistry in rat skin wounds. In addition, we used TUNEL assay to detect apoptotic cells.Results:We observed that Caspase 3 mRNA level significantly increased (2.1±0.4 folds) on day 3 (p<0.05) and Caspase 8 mRNA level significantly increased (1.8±0.2 folds) on day 5 (p<0.05). Caspase 9 mRNA level increased (1.9±0.1 folds) on day 3 and (2.5±0.4 folds) on day 5 (p<0.05). The percentage values of polymorphonuclear leukocytes (PMNLs) and inflammatory mononuclear cells (IMCs) were observed after immunohistochemical staining by Caspase 3, 8, 9 antibodies. Our immunohistochemistry results were found to be consistent with the mRNA results observed. We reported a statistically significant increase in Caspase 3, 8 and 9-positive cells on days 3 and 5 after immunohistochemical staining as well.Conclusion:Our results suggest that time-dependent features of apoptotic factors might offer a potential tool in estimating wound age.

scholarly journals Evaluation of Plasma MMP-9 and VEGF-A mRNAs as Non-invasive Diagnostic Biomarkers in Women with Endometriosis

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Sepideh Abdollahi ◽  
Pantea Izadi ◽  
Shahla Noori Ardebili ◽  
Samaneh Chegeni ◽  
Mir Saead Yekaninejad
Keyword(s):  
Plasma Level ◽  
Quantitative Polymerase Chain Reaction ◽  
Mrna Level ◽  
Control Group ◽  
P Value ◽  
Mrna Levels ◽  
Diagnostic Biomarker ◽  
Diagnostic Biomarkers ◽  
Non Invasive ◽  
Significant Difference

Background: Endometriosis is one of the common gynecological diseases and can lead to pelvic pain, dysmenorrhea, dyspareunia, and infertility in women. Thus, accurate and early diagnosis is a pivotal issue and an essential need for managing this disorder. At the present, the gold standard diagnostic method for endometriosis is laparoscopic surgery that is an invasive method and can lead to delay in diagnosis. Thus, there is an immediate necessity to search for non-invasive diagnostic biomarkers, such as blood-based ones. Objectives: Matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor-A (VEGF-A) have essential roles in the pathogenesis of endometriosis. Therefore, in this study, we evaluated the plasma mRNA levels of MMP-9 and VEGF-A, as potential non-invasive diagnostic biomarkers for endometriosis. Methods: This study included 48 women (24 cases and 24 controls) who underwent laparoscopy for suspected endometriosis. Preoperative plasma samples were collected, and after RNA extraction, the levels of MMP-9 and VEGF-A mRNAs were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results: Plasma MMP-9 mRNA level was statistically higher in endometriosis patients compared with the control group (P value = 0.01). However, plasma VEGF-A mRNA level did not show a significant difference between the two groups (P value =0.5). Conclusions: It seems that the plasma level of MMP-9 mRNA in endometriosis patients is significantly higher than in non-endometriosis women. This finding can provide new insights regarding this mRNA’s applicability as a non-invasive diagnostic biomarker for discovering new cases of endometriosis (newly diagnosed). According to our results, despite the suggested role of VEGF-A in endometriosis pathogenesis, it seems that the plasma level of VEGF-A mRNA does not have the potential to be used as a non-invasive diagnostic biomarker.

Inflammatory and redox responses to ischaemia/reperfusion in human skeletal muscle

2004 ◽  
Vol 107 (5) ◽  
pp. 497-503 ◽  
Author(s):  
Ruksana HUDA ◽  
Daneshvari R. SOLANKI ◽  
Mali MATHRU
Keyword(s):  
Skeletal Muscle ◽  
Superoxide Dismutase ◽  
Manganese Superoxide Dismutase ◽  
Mononuclear Cells ◽  
Glutathione Transferase ◽  
Mrna Level ◽  
Plasma Concentrations ◽  
Mrna Levels ◽  
Ischaemia Reperfusion ◽  
Tnf Α

The objective of this study was to identify cellular and plasma marker(s) of post-I/R (ischaemia/reperfusion) in patients undergoing elective knee surgery where a tourniquet was used to facilitate a bloodless surgical field. We evaluated the inflammatory and redox response by measuring the mRNA levels of ICAM-1 (intercellular cell-adhesion molecule-1), MnSOD (manganese superoxide dismutase), GST-μ (glutathione transferase-μ) and Cu/ZnSOD (copper/zinc superoxide dismutase) in the operated muscle and blood cells pre-operatively (pre-tourniquet) and at various times after reperfusion (tourniquet release). We also measured plasma concentrations of IL (interleukin)-6, IL-8, sICAM-1 (soluble ICAM-1), IL-1β and TNF-α (tumour necrosis factor-α) using ELISA. Our results show a strong induction of MnSOD and GST-μ in granulocytes (but not in mononuclear cells or muscle) after reperfusion (2 and 4 h). There was no change in the mRNA level of Cu/ZnSOD after reperfusion. An up-regulation of membrane ICAM-1 in muscle and a decrease in sICAM-1 in plasma were detected after reperfusion. Plasma IL-6 and IL-8 levels (but not TNF-α or IL-1β) increased significantly over baseline at 2 and 4 h after reperfusion. Elevated expression of ICAM-1 in muscle, MnSOD and GST-μ in granulocytes and increased levels of plasma IL-6 and IL-8 may be considered as phase- and cell-specific markers of post-I/R of skeletal muscle in humans.

scholarly journals HIV-1 Tat Protein-Induced Alterations of ZO-1 Expression are Mediated by Redox-Regulated ERK1/2 Activation

2005 ◽  
Vol 25 (10) ◽  
pp. 1325-1335 ◽  
Author(s):  
Hong Pu ◽  
Jing Tian ◽  
Ibolya E Andras ◽  
Kentaro Hayashi ◽  
Govinder Flora ◽  
...  
Keyword(s):  
Specific Inhibitor ◽  
Inflammatory Cells ◽  
Mrna Levels ◽  
Tat Protein ◽  
Extracellular Signal ◽  
Junction Protein ◽  
The Central Nervous System ◽  
The Right ◽  
The Brain ◽  
Hiv 1

HIV-1 Tat protein plays an important role in inducing monocyte infiltration into the brain and may alter the structure and functions of the blood—brain barrier (BBB). The BBB serves as a frontline defense system, protecting the central nervous system from infected monocytes entering the brain. Therefore, the aim of the present study was to examine the mechanisms of Tat effect on the integrity of the BBB in the mouse brain. Tat was injected into the right hippocampi of C57BL/6 mice and expression of tight junction protein zonula occludens-1 (ZO-1) was determined in control and treated mice. Tat administration resulted in decreased mRNA levels of ZO-1 and marked disruption of ZO-1 continuity. These changes were associated with accumulation of inflammatory cells in brain tissue of Tat-treated mice. Further experiments indicated that Tat-mediated alterations of redox-related signaling may be responsible for decreased ZO-1 expression. Specifically, injections with Tat resulted in activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and pretreatment with U0126, a specific inhibitor of ERK kinase, effectively ameliorated the Tat-induced diminished ZO-1 levels. In addition, administration of N-acetylcysteine (NAC), a precursor of glutathione and a potent antioxidant, attenuated both Tat-induced ERK1/2 activation and alterations in ZO-1 expression. These results indicate that Tat-induced oxidative stress can play an important role in affecting the integrity of the BBB through the ERK1/2 pathway.

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