Pathogenesis of HIV-associated dementia and its potential drug targets

HIV-associated dementia (HAD) is a serious complication of AIDS patients. With the wide application of highly active antiretroviral therapy (HAART), the replication of HIV is under effective control and the incidence of HAD is also declined. However, a relatively mild HIV-associated symptom of dementia, called minor cognitively motor disorder (MCMD), become the problem and can not be neglected in the treatment of AIDS. The neural injury caused by HIV may be mediated mainly by macrophages, microglia and astrocytes, though we can not rule out the direct damage on neurons by HIV proteins. To date, the precise mechanism of neural damage caused by HIV remains unclear. The present review tries to figure out the recent progress of pathogenesis and potential drug targets for HAD.     

Central roles for IL-2 and MCP-1 following intranasal exposure to SEB: a new mouse model

Murine models for bacterial superantigens like staphylococcal enterotoxin B (SEB) have to date been rather cumbersome. The reasons include: (1) necessary use of potentiating agents such as actinomycin D, d-galactosamine, lipopolysaccharide (LPS), or viruses; (2) high toxin amounts required to elicit effects; and/or (3) generation of phenotypic-stable transgenic animals. Our study employed readily available C3H/HeJ (TLR4 negative, LPS-nonresponsive) mice with intranasal and intraperitoneal administration of low microgram quantities of SEB. These animals responded to SEB with severe lung inflammation and hypothermia, culminating in death. A survey of cytokines/chemokines in sera and lungs after lethal intoxication revealed that monocyte chemoattractant protein-1 and interleukin-2 were associated with effects in this model. In contrast, SEB had minimal effects upon congenic (TLR4 positive, LPS-responsive) C3H/OuJ mice. Lethality of SEB in C3H/HeJ mice was neutralized with SEB-specific antibodies, suggesting potential utility of this model for future therapeutic studies.     

Therapeutic effect of MCP-1 mediated macrophages on ovarian epithelial carcinoma

AIM: To investigate the therapeutic effect of MCP-1 mediated macrophages on ovarian epithelial carcinoma and its mechanisms.METHODS: Retorviral expression vectors pLXSN/MCP-1 was transfected into the packaging cell line PA317 by lipofectin-mediated gene transfer system. The virus particles containing MCP-1 gene were collected to infect NuTu-19. RT-PCR and Boyden Chamber were used to confirm the expression of MCP-1. Rat Fischer344 spleen macrophages were isolated. MTT method was applied to investigate the tumoricidal effect of macrophages. The survival time of the intraperitoneal disseminating ovarian cancer animal model was observed, and flow cytometry method was applied to analyze the expression of CD25 or CD44v6, and then the anti-tumor mechanisms of gene modified tumor cell lines were discussed. RESULTS: Stable MCP-1 expression in the cell line NuTu-19/MCP-1 possessed the chemotatic activity. The maximum killing ratio of macrophages on NuTu-19/MCP-1 cells was 28%. In the animal models immunized by MCP-1 expressing cells, prolonged survival time was showed which had statistical significance compared with that in the control group (P<0.05). The expression rate of CD25 (25.82%) in the NuTu-19/MCP-1 cells was higher than that in NuTu-19/neo cells (8.73%). The expression of CD44v6 in NuTu-19/MCP-1 cells was significantly lower than that in control NuTu-19/neo cells. CONCLUSION: MCP-1 mediates macrophages and suppresses the growth of NuTu-19. MCP-1 gene modified tumor cells can induce anti-tumor immunity. This strategy would be used as a promising approach for the treatment of ovarian cancer.     

Inhibitory effect of simvastatin on TNF-α-induced chemokines secretion in rheumatoid arthritis fibroblast like synoviocytes via inhibition of RhoA activation

AIM: To investigate the effect of simvastatin (SMV) on tumor necrosis factor α (TNF-α)-induced chemokine secretion in rheumatoid arthritis fibroblast-like synoviocytes (RA FLS).METHODS: RhoA activity was determined by pull-down assay. Chemokine secretion was measured by ELISA. MTT test was used to detect cell viability.RESULTS: Simvastatin attenuated TNF-α-induced interleukin-8(IL-8) and monocyte chemotactic protein-1(MCP-1) secretion as well as RhoA activation in RA FLS. The inhibitory effects of SMV were completely reversed by mevalonate (MEVA) and geranylgeranyl pyrophosphate (GGPP). Suppression of RhoA activation with a specific inhibitor depressed the secretion of IL-8 and MCP-1 in TNF-α-induced RA FLS.CONCLUSION: Simvastatin inhibits TNF-α-induced secretion of IL-8 and MCP-1 in RA FLS through inhibition of RhoA activation, indicating a novel strategy for anti-inflammatory effects of statins on treatment of RA.     

Expression and clinical significance of chemokine receptor CXCR6 in primary colorectal cancer

AIM: To investigate the expression of chemokine receptor CXCR6 in primary colorectal cancer and determine the association between CXCR6 expression and synchronous liver metastasis/prognosis. METHODS: The colorectal cancer tissues from 143 patients were collected from August 2004 to December 2008 in the First Affiliated Hospital, Sun Yat-sen University. Twenty-night cases of the adjacent normal colorectal tissues were enrolled as controls. The expression of CXCR6 was detected by immunohistochemistry and the mean intergrated absorbance ( mIA ) was calculated by Image-Pro Plus 6.0 software. The relationship between CXCR6 expression and synchronous liver metastasis/prognosis was analyzed. RESULTS: The CXCR6 staining was mainly positive in colorectal cancer tissues but not in adjacent normal colorectal tissues. The mIA of CXCR6 in colorectal cancer was 1.54±0.04 (range: 0.41~2.84), and was 1.63±0.05 and 1.41±0.08 (P<0.05) in the cases with (n=83) or without (n=60) synchronous liver metastasis, respectively. According to the mean mIA of CXCR6 (1.54), the cases was divided into high CXCR6 group (mIA≥1.54) and low CXCR6 group ( mIA <1.54). The overall survival rate in high CXCR6 group was significantly lower than that in low CXCR6 group (P<0.05). In multivariate Cox regression models, age (P<0.05), lymph node metastasis (P<0.05) and synchronous liver metastasis (P<0.01) but not CXCR6 were identified as independent risk factors for poor outcome. In subgroup analysis, high CXCR6 expression was associated with poorer survival in the patients with stage I~III colorectal cancer (P<0.01) but not those with synchronous liver metastasis (P>0.05).CONCLUSION: CXCR6 in primary colorectal cancer tissues is associated with liver metastasis. It may become a potential target for the treatment of colorectal cancer liver metastasis.     

Expression of MIP-1α and RANTES gene and protein in the bronchus of murine asthma

AIM: To study the role of the gene and protein expression of MIP-1α and RANTES in the bronchus of murine asthma. METHODS: 20 male BALB/C mice were randomly divided into two groups: the control group (A₀ group) and asthma group (B₀ group). In the experiment, the mice model of asthma was established by the ovalbumin (OVA) challenge methods. The protein expression of MIP-1α and RANTES were detected by immunohistochemistry methods. The gene expressions of MIP-1α and RANTES were detected by in situ hybridization methods. RESULTS: Immunohistochemistry showed that the expressions of MIP-1α protein and RANTES protein around the bronchus of group B₀ were significantly higher than those of group A₀ (P<0.01), the epithelial cells were the chief expression cells; (2) In situ hybridization showed that the expressions of MIP-1α gene and RANTES gene around the bronchus of group B₀ were significantly higher compared to those of group A₀ (P<0.01), the epithelial cells were the chief expression cells. CONCLUSION: MIP-1α and RANTES are high expression in the bronchus epithelial cells in experimental murine asthma.     

Effect of fractalkine on neuroprotection

The chemokine fractalkine primarily involves in chemotaxis,adherence and inflammation.Recently it has been discovered owning the ability of inhibiting cell death in neurons and glial cells,as well as protecting central nervous system from toxic damage.Fractalkine reduces the toxicity to neurons and glial cells mediated by excessive Fas L,glutamate (Glu) or lipopolysaccharide (LPS).In vivo neutralization of endogenous brain fractalkine signal pathway increases inflammatory cytokines secretion and neuronal cell death induced by LPS.Fractalkine may achieve its neuroprotective property through influencing expression of pro-apoptotic and anti-apoptotic proteins,intracellular Ca2+ level and inflammatory cytokines secretion via protein kinase B (PKB)/Akt and extracellular signal-regulated kinase (ERK)/MAPK pathways.