Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus (HIV) infection has been associated with periodontal diseases in HIV-seropositive patients. In periodontal diseases, matrix metalloproteinases (MMPs) may play key roles in the extracellular matrix, basement membrane, serpin degradation, and modification of cytokine action. We characterized the 72 kDa type IV collagenase (gelatinase A, MMP-2) and 92 kDa type IV collagenase (gelatinase B, MMP-9) in the saliva of HIV-seropositive patients and seronegative healthy controls by activity measurements and quantitative immunoblotting. Immunoblot analysis with specific antibodies against MMP-2 and MMP-9 and their tissue inhibitors (TIMP-1, TIMP-2) disclosed that, independent of the phase of the patients' HIV infection, their salivary samples contained higher amounts of MMP-2 and MMP-9 immunoreactivities in pro- and active forms and the TIMP-1 and TIMP-2 inhibitors than did the control samples. Healthy control saliva contained only slight immunoreactivities for gelatinases and TIMPs. However, as judged by the studied clinical and microbiologic indicators, HIV-seropositive patients showed only a slight tendency to develop periodontitis. Overall, an increased amount of gelatinases in saliva may reflect increased host response and defense activities in HIV infection.
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PMID:72-kDa and 92-kDa gelatinases in saliva of patients with human immunodeficiency virus infection. 968 21

Chemotactic cytokines or chemokines form a family of proinflammatory proteins that are functionally linked to various classes of proteases, including matrix metalloproteinases (MMPs). Both families of molecules are key players in the migration of inflammatory cells in autoimmune diseases and in invasive cancers. For example, the chemokine interleukin-8 acts as a fast secretagogue of gelatinase B in granulocytes and is increased in the synovial fluid of arthritis patients and may locally recruit and activate neutrophils. The latter are the most abundant inflammatory cell type in the joints of patients with rheumatoid arthritis. In the case of the inflamed joint, the contribution of matrix remodeling enzymes in the breakdown of cartilage and bone is trivial. Gelatinase B (MMP-9) was documented in autoimmune diseases and cancer by immunohistochemistry with the use of monoclonal antibodies. Studies in rheumatoid arthritis and multiple sclerosis led us to postulate the "Remnant Epitopes Generate Autoimmunity" or REGA model for autoimmunity. This model is based on the pathophysiological role of three major classes of molecules involved in aspecific primary immune defense mechanisms: the cytokines, the chemokines and the proteases. The REGA model has proven to be useful for the development of disease treatment strategies. Particular cytokines are disease-limiting and may thus be used for the treatment of autoimmune disorders. Cytokines and chemokines that induce enzymes promote disease and may be antagonized. Along this line of research, we have recently identified natural and biosynthetic chemokine antagonists. Some of these have shown potent antiviral activity against human immunodeficiency virus. It is expected that these might also become useful in the treatment of autoimmune diseases and invasive cancers. A similar effect may be expected by the antagonization of damaging proteases or with the use of recombinant or synthetic enzyme inhibitors.
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PMID:Chemokines and proteinases in autoimmune diseases and cancer. 1208 66

The introduction of potent antiretroviral drugs for the treatment of patients with human immunodeficiency virus (HIV) infection has dramatically reduced the prevalence of HIV-associated neurological disorders. Such diseases can be mediated by proteolytic enzymes, i.e. matrix metalloproteinases (MMPs) and, in particular gelatinases, released from glial cells. The aim of this study was to investigate whether the antiretroviral drugs commonly used for the treatment of HIV-infected patients modulate the activity of MMPs in astrocyte and microglial cultures. Primary cultures of rat astrocyte and microglia were treated with different doses of zidovudine (AZT) or indinavir (IDV) for 20 h and simultaneously activated by exposure to lipopolysaccharide (LPS). Culture supernatants collected from astrocytes and microglia after 24 h incubation were subjected to gelatin zymography and western blot analysis for the assessment of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) protein levels. Total RNA was extracted from glial cells and used for reverse transcriptase-polymerase chain reaction for the assessment of mRNA expression. Our results indicate that both astrocyte and microglial cells constitutively express MMP-2 mRNA and protein. LPS treatment increased MMP-2 mRNA and protein expression in astrocytes, but not in microglial cells. The treatment with both AZT and IDV dose-dependently inhibited the expression of MMP-2 in astrocytes, whereas it had no effect on microglial cells. The expression of MMP-9 in both astrocytes and microglia was induced by LPS treatment and was dose-dependently inhibited by AZT and IDV treatment in LPS-stimulated astrocytes and microglia. These results raise the possibility that AZT and IDV interfere directly with MMP production in glial cells and independently from their antiviral activity, thus suggesting the possible therapeutical use in neurological diseases associated with MMPs involvement.
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PMID:Anti-HIV drugs decrease the expression of matrix metalloproteinases in astrocytes and microglia. 1466 18

Neurotoxic secretory products from virus-infected mononuclear phagocytes (MP; perivascular macrophages and microglia) orchestrate the neuropathogenesis of human immunodeficiency virus type one (HIV-1) infection. To uncover such MP products and their relationship to disease, we used a proteomics platform consisting of one dimensional polyacrylamide gel electrophoresis (1-DE), mass spectrometry peptide sequencing, and bioinformatics in order to identify from HIV-1-infected monocyte-derived macrophages (MDM) secretions. Matrix metalloproteinase 9 (MMP 9) secreted in abundance in MDM was markedly down-regulated following viral infection. A negative correlation between MMP 9 and HIV-1 reverse transcriptase activity was shown by quantitative Western blot assays. These data further demonstrate immunoregulatory activities of HIV-1-infected MDM providing unique insights into cellular function in disease.
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PMID:Diminished matrix metalloproteinase 9 secretion in human immunodeficiency virus-infected mononuclear phagocytes: modulation of innate immunity and implications for neurological disease. 1557 75

In a previous publication, we reported that human immunodeficiency virus (HIV) protease inhibitors (PIs) inhibited the differentiation of human preadipocytes in primary culture, reducing the expression and secretion of matrix metalloproteinase 9 (MMP-9). The present work was performed to clarify this mechanism. Interestingly, HIV-PIs have been reported to be inhibitors of the proteasome complex, which is known to regulate nuclear factor (NF)-kappaB activation and transcription of its target genes, among them MMP-9. We thus investigated the potential involvement of the proteasome in the antiadipogenic effects of HIV-PIs. The effect of four HIV-PIs was tested on preadipocyte proteasomal activity, and chronic treatment with the specific proteasome inhibitor lactacystin was performed to evaluate alterations of adipogenesis and MMP-9 expression/secretion. Finally, modifications of the NF-kappaB pathway induced by either HIV-PIs or lactacystin were studied. We demonstrated that preadipocyte proteasomal activity was decreased by several HIV-PIs and that chronic treatment with lactacystin mimicked the effects of HIV-PIs by reducing adipogenesis and MMP-9 expression/secretion. Furthermore, we observed an intracellular accumulation of the NF-kappaB inhibitor, IkappaBbeta, with chronic treatment with HIV-PIs or lactacystin as well as a decrease in MMP-9 expression induced by acute tumor necrosis factor-alpha stimulation. These results indicate that inhibition of the proteasome by specific (lactacystin) or nonspecific (HIV-PIs) inhibitors leads to a reduction of human adipogenesis, and they therefore implicate deregulation of the NF-kappaB pathway and the related decrease of the key adipogenic factor, MMP-9. This study adds significantly to recent reports that have linked HIV-PI-related lipodystrophic syndrome with altered proteasome function, endoplasmic reticulum stress, and metabolic disorders.
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PMID:Inhibition of human preadipocyte proteasomal activity by HIV protease inhibitors or specific inhibitor lactacystin leads to a defect in adipogenesis, which involves matrix metalloproteinase-9. 1703 10

It was previously reported that human immunodeficiency virus type 1 (HIV-1) spreads in CD4 lymphocytes through cell-to-cell transmission. Here we report that HIV-1-infected macrophages, but not lymphocytes, transmit HIV-1 products to CD4-negative cells of either epithelial, neuronal, or endothelial origin in the absence of overt HIV-1 infection. This phenomenon was detectable as early as 1 h after the start of cocultivation and depended on cell-to-cell contact but not on the release of viral particles from donor cells. Transfer of HIV-1 products occurred upon their polarization and colocalization within zones of cell-to-cell contact similar to virological synapses. Neither HIV-1 Env nor Nef expression was required but, interestingly, we found that an HIV-1-dependent increase in matrix metalloproteinase 9 production from donor cells significantly contributed to the cell-to-cell transmission of the viral products. The macrophage-driven transfer of HIV-1 products to diverse CD4-negative cell types may have a significant role in AIDS pathogenesis.
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PMID:Macrophages transmit human immunodeficiency virus type 1 products to CD4-negative cells: involvement of matrix metalloproteinase 9. 1758 88