RESUMO
The efficacy of the routinely used anti-HIV (Human Immunodeficiency Virus) therapy based on nucleoside reverse transcriptase inhibitors (NRTIs) is limited by the poor cellular uptake of the active triphosphorylated metabolites and the low efficiency of intracellular phosphorylation of their prodrugs. Nanoparticles of iron(iii) polycarboxylate Metal-Organic Frameworks (nanoMOFs) are promising drug nanocarriers. In this study, two active triphosphorylated NRTIs, azidothymidine triphosphate (AZT-Tp) and lamivudine triphosphate (3TC-Tp), were successfully co-encapsulated into the biocompatible mesoporous iron(iii) trimesate MIL-100(Fe) nanoMOF in order to improve anti-HIV therapies. The drug loaded nanoMOFs could be stored for up to 2-months and reconstituted after freeze drying, retaining similar physicochemical properties. Their antiretroviral activity was evidenced in vitro on monocyte-derived macrophages experimentally infected with HIV, making these co-encapsulated nanosystems excellent HIV-microbicide candidates.
RESUMO
Prions cause various transmissible spongiform encephalopathies. They are highly resistant to the chemical and physical decontamination and sterilization procedures routinely used in healthcare facilities. The decontamination procedures recommended for the inactivation of prions are often incompatible with the materials used in medical devices. In this study, we evaluated the use of low-temperature hydrogen peroxide gas plasma sterilization systems and other instrument-processing procedures for inactivating human and animal prions. We provide new data concerning the efficacy of hydrogen peroxide against prions from in vitro or in vivo tests, focusing on the following: the efficiency of hydrogen peroxide sterilization and possible interactions with enzymatic or alkaline detergents, differences in the efficiency of this treatment against different prion strains, and the influence of contaminating lipids. We found that gaseous hydrogen peroxide decreased the infectivity of prions and/or the level of the protease-resistant form of the prion protein on different surface materials. However, the efficiency of this treatment depended strongly on the concentration of hydrogen peroxide and the delivery system used in medical devices, because these effects were more pronounced for the new generation of Sterrad technology. The Sterrad NX sterilizer is 100% efficient (0% transmission and no protease-resistant form of the prion protein signal detected on the surface of the material for the mouse-adapted bovine spongiform encephalopathy 6PB1 strain and a variant Creutzfeldt-Jakob disease strain). Thus, gaseous or vaporized hydrogen peroxide efficiently inactivates prions on the surfaces of medical devices.
Assuntos
Anti-Infecciosos Locais/farmacologia , Descontaminação/métodos , Peróxido de Hidrogênio/farmacologia , Príons/efeitos dos fármacos , Esterilização/métodos , Animais , Bioensaio , Cricetinae , Detergentes/farmacologia , Interações Medicamentosas , Contaminação de Equipamentos/prevenção & controle , Feminino , Gases/farmacologia , Humanos , Mesocricetus , Doenças Priônicas/prevenção & controle , Doenças Priônicas/transmissão , Aço Inoxidável , Resultado do TratamentoRESUMO
With the detection of prions in specific tissues in variant and sporadic Creutzfeldt-Jakob diseases, efficient decontamination for human transmissible spongiform encephalopathy (TSE) agents, that is compatible with medical equipment, has become a major issue. We previously described the cleavage of prions on exposure to copper (Cu) and hydrogen peroxide (H(2)O(2)) and have used this property to develop efficient prion decontamination processes. To validate this approach, in-vitro assays on genuine human and animal prions using both brain homogenates and steel wires to mimic contamination of medical equipment were conducted. In-vivo experiments using steel wire in the hamster 263 K model were then used to evaluate the effect on prion infectivity. Assays on classical pathogens following international norms completed these prion experiments. In-vitro data confirmed the full decontamination efficacy of H(2)O(2)/Cu on different TSE strains. Combination of Cu with peracetic acid, used for endoscope disinfection, also revealed improved prion decontamination. Animal assay demonstrated efficacy on TSE infectivity of H(2)O(2)/Cu alone or in combination with detergents (reduction factor > or =5.25 log(10)). Assays on classical pathogens confirmed the disinfection properties of the different processes. Taken together, these new disinfection processes are efficient for both conventional and prion infectious agents and are, compatible with thermosensitive medical equipment. They can be adapted to hospitals' and practitioners' routine use, and they present reduced risks for the environment and for healthcare professionals.
Assuntos
Infecção Hospitalar/prevenção & controle , Desinfecção/métodos , Equipamentos e Provisões Hospitalares , Doenças Priônicas/prevenção & controle , Príons/efeitos dos fármacos , Animais , Bactérias/efeitos dos fármacos , Cobre/farmacologia , Cricetinae , Desinfetantes/farmacologia , Fungos/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Mesocricetus , Camundongos , Vírus/efeitos dos fármacosRESUMO
Tau interferon (IFN-tau) was shown to inhibit human immunodeficiency virus (HIV) replication in vitro more strongly than human IFN-alpha, particularly in human macrophages. IFN-tau efficiently inhibited the early steps of HIV biological cycle, decreasing intracellular HIV RNA and inhibiting the initiation of the reverse transcription of viral RNA into proviral DNA. In this study, the in vitro immunomodulatory effects of IFN-tau were explored in human macrophages. We found that IFN-tau increased the synthesis of the cellular antiviral factors, such as 2',5'-oligoadenylate synthetase/RNase L and MxA protein. These results suggested that IFN-tau induces the same antiviral pathways in macrophages as other type I IFNs. We found that IFN-tau increased the production of interleukins (IL)-10 and IL-6, but not of IL-1ss or TNF-alpha, in not infected and in in vitro HIV-1/Ba-L-infected macrophages. We also found that the neutralization of IL-6 biological activity in the cell culture supernatants of IFN-tau-treated macrophages led to a decrease in the antiretroviral effects of IFN-tau towards HIV RNA. In conclusion, anti-HIV effects of IFN-tau are mediated by several modes of action, mediated either directly by IFN-tau or via other cytokines, such as IL-6, also known to be induced by IFN-alpha.
Assuntos
HIV-1/fisiologia , Interferon Tipo I/farmacologia , Interleucina-6/fisiologia , Macrófagos/efeitos dos fármacos , Proteínas da Gravidez/farmacologia , Replicação Viral/efeitos dos fármacos , Anticorpos Monoclonais/farmacologia , Diferenciação Celular , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/virologia , Citocinas/metabolismo , Endorribonucleases/biossíntese , Endorribonucleases/genética , Proteínas de Ligação ao GTP/biossíntese , Proteínas de Ligação ao GTP/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Transcriptase Reversa do HIV/metabolismo , Humanos , Interferon-alfa/fisiologia , Interleucina-10/biossíntese , Interleucina-10/genética , Interleucina-10/farmacologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Interleucina-6/genética , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Macrófagos/virologia , Monócitos/citologia , Monócitos/efeitos dos fármacos , Proteínas de Resistência a Myxovirus , Receptores de HIV/fisiologia , Proteínas Recombinantes de Fusão/farmacologiaRESUMO
Abstract We evaluated the prognostic value of different mediators of inflammation: TNF-alpha and its soluble receptor p75, platelet-activating factor, and glutathione tripeptide in a case-control study nested within a cohort of 1281 patients infected by the human immunodeficiency virus (HIV) started on highly active antiretroviral treatment (HAART). During the first year of HAART, 16 cases experienced an AIDS-defining event and 6 experienced an evolution of T CD4(+) cell count <100/mm(3). Forty-four controls who did not progress during the same follow-up period were matched for age, baseline CD4(+), and HIV-RNA. In the control group, plasma levels of TNF-alpha and its soluble receptor p75 decreased significantly from baseline to month 4: from 11.0 to 8.7 pg/ml (p < 0.001) and from 27.3 to 22.8 pg/ml (p < 0.003), respectively. Furthermore the decrease of TNF-alpha soluble receptor p75 was larger in nonprogressors than in progressors (p = 0.003). Measurement of TNF-alpha soluble receptor p75 may be of interest as an additional marker of early antiretroviral effect.
Assuntos
Terapia Antirretroviral de Alta Atividade , Progressão da Doença , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Adulto , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Humanos , Masculino , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue , Carga ViralRESUMO
BACKGROUND AND PURPOSE: 5-HT (serotonin) is known to be involved in neuroinflammation and immunoregulation. The human immunodeficiency virus (HIV) targets cells such as monocytes/macrophages, which colocalize with 5-HT-releasing cell types, mostly platelets. In this study, we investigated the effects of 5-HT on HIV-1-infected macrophages in vitro. EXPERIMENTAL APPROACH: Human macrophages cultured in serum-free medium were treated over 7 days with 5-HT at three concentrations (0.01, 1 and 100 microM) with or without agonists and antagonists of 5-HT(1A) and 5-HT(2) receptors. After 7 days of treatment, macrophages were infected with HIV-1/Ba-L and virus replication was monitored over 16 days and expression of proviral HIV DNA was investigated by PCR after 24 h of infection. Cell surface expression of HIV-1/Ba-L receptor (CD4) and coreceptor (CCR5) was investigated by flow cytometry. The CCR5 ligand, macrophage inflammatory protein-1alpha (MIP-1alpha), was quantified by ELISA in cell culture supernatants and MIP-1alpha mRNA expression was assessed by reverse transcriptase-PCR. KEY RESULTS: In vitro, 5-HT downregulated the membranous expression of CCR5 and led to a decrease of HIV-1 infection, probably through its action on 5-HT(1A) receptors. 5-HT (100 microM) was also able to induce overexpression of MIP-1alpha mRNA leading to an increase of MIP-1alpha secretion by human macrophages. CONCLUSIONS AND IMPLICATIONS: The effects of 5-HT on HIV infection could be a consequence of the increase in MIP-1alpha concentrations and/or CCR5 receptor downregulation. These results suggest that 5-HT can inhibit the replication of HIV-1 in primary culture of human macrophages through its action on 5-HT(1A) receptors.
Assuntos
HIV-1/efeitos dos fármacos , Macrófagos/virologia , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Antígenos CD4/biossíntese , Células Cultivadas , DNA Viral/biossíntese , Humanos , Piperazinas/farmacologia , Piridinas/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores CCR5/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Replicação Viral/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Antioxidant molecules can be used both to replenish the depletion of reduced glutathione (GSH) occurring during HIV infection, and to inhibit HIV replication. The purpose of this work was to assess the efficacy of two pro-GSH molecules able to cross the cell membrane more easily than GSH. We used an experimental animal model consisting of C57BL/6 mice infected with the LP-BM5 viral complex; the treatments were based on the intramuscular administration of I-152, a pro-drug of N-acetylcysteine and S-acetyl-beta-mercaptoethylamine, and S-acetylglutathione, an acetylated GSH derivative. The results show that I-152, at a concentration of 10.7 times lower than GSH, caused a reduction in lymph node and spleen weights of about 55% when compared to infected animals and an inhibition of about 66% in spleen and lymph node virus content. S-acetylglutathione, at half the concentration of GSH, caused a reduction in lymph node weight of about 17% and in spleen and lymph node virus content of about 70% and 30%, respectively. These results show that the administration of pro-GSH molecules may favorably substitute for the use of GSH as such.
Assuntos
Acetilcisteína/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Cisteamina/análogos & derivados , Glutationa/análogos & derivados , Síndrome de Imunodeficiência Adquirida Murina/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Animais , Fármacos Anti-HIV/farmacologia , Proliferação de Células/efeitos dos fármacos , Cisteamina/farmacologia , Cisteamina/uso terapêutico , DNA Viral/efeitos dos fármacos , DNA Viral/genética , Modelos Animais de Doenças , Feminino , Glutationa/farmacologia , Glutationa/uso terapêutico , Hipergamaglobulinemia/tratamento farmacológico , Imunoglobulina G/sangue , Vírus da Leucemia Murina/efeitos dos fármacos , Vírus da Leucemia Murina/genética , Vírus da Leucemia Murina/isolamento & purificação , Linfonodos/efeitos dos fármacos , Linfonodos/fisiopatologia , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Reação em Cadeia da Polimerase , Pró-Fármacos/farmacologia , Baço/efeitos dos fármacos , Baço/fisiopatologiaRESUMO
Sodium valproate (VPA) has been reported to increase the accumulation of the pathologic isoform of prion protein (PrPsc) in scrapie-infected murine neuroblastoma cells. In this study, the effect of VPA on PrPsc accumulation was investigated in murine N2a neuroblastoma cells chronically infected with scrapie strain 22L (N2a-22L). No accumulation of PrPsc was detected after short-term (3 days) or long-term (21 days) treatment of N2a-22L cells with 4.8, 12, 18 or 24 microM VPA. Higher VPA concentrations (240 and 600 microM) also failed to augment PrPsc expression. In conclusion, in our experimental conditions, no deleterious effect was induced by VPA on prions replication.
Assuntos
Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Neuroblastoma/metabolismo , Príons/metabolismo , Ácido Valproico/farmacologia , Animais , Linhagem Celular Tumoral , Clorpromazina/farmacologia , Antagonistas de Dopamina/farmacologia , Camundongos , Neuroblastoma/microbiologia , Scrapie/virologia , Fatores de TempoRESUMO
The neurotransmitter 5-hydroxytryptamine (5-HT), commonly known as serotonin, is released at peripheral sites from activated platelets. At inflammatory sites, macrophages and lymphocytes could be exposed to 5-HT concentrations up to 100 microM. Moreover, 5-HT could modulate cytokine secretion by monocytes/macrophages and immune functions through the uptake of 5-HT at these inflammatory sites from T cells and dendritic cells. HIV infection is also under the control of inflammatory processes (including T cell proliferation and cytokines secretion). On this basis, we studied explored herein the effects of 5-HT on HIV-1/Ba-L (macrophage-tropic virus) replication in primary cultures of human macrophages. This pharmacological study with isotype-selective receptor agonists and antagonist allowed us to show that the 100 microM 5-HT concentration via 5-HT(1A) subtype receptors could decrease HIV replication. This observation was associated with an increase of MIP-1alpha secretion such as an increase of MIP-1alpha mRNA production and with a decrease of HIV-coreceptor CCR5 cell surface expression. Our results point out for the first time the inhibitory effects of 5-HT on HIV replication in primary culture of human macrophages via activation of 5-HT(1A) subtype receptors.
Assuntos
HIV/fisiologia , Macrófagos/virologia , Receptor 5-HT1A de Serotonina/fisiologia , Serotonina/farmacologia , Replicação Viral/efeitos dos fármacos , Antivirais/uso terapêutico , HIV/efeitos dos fármacos , Humanos , Monócitos/virologia , Viroses/diagnóstico , Viroses/tratamento farmacológicoRESUMO
Reduced glutathione (GSH) is present in millimolar concentrations in mammalian cells. It is involved in many cellular functions such as detoxification, amino acid transport, production of coenzymes, and the recycling of vitamins E and C. GSH acts as a redox buffer to preserve the reduced intracellular environment. Decreased glutathione levels have been found in numerous diseases such as cancer, viral infections, and immune dysfunctions. Many antioxidant molecules, such as GSH and N-acetylcysteine (NAC), have been demonstrated to inhibit in vitro and in vivo viral replication through different mechanisms of action. Accumulating evidence suggests that intracellular GSH levels in antigen-presenting cells such as macrophages, influence the Th1/Th2 cytokine response pattern, and more precisely, GSH depletion inhibits Th1-associated cytokine production and/or favours Th2 associated responses. It is known that GSH is not transported to most cells and tissues in a free form. Therefore, a number of different approaches have been developed in the last years to circumvent this problem. This review discusses the capacity of some new molecules with potent pro-GSH effects either to exert significant antiviral activity or to augment GSH intracellular content in macrophages to generate and maintain the appropriate Th1/Th2 balance. The observations reported herein show that pro-GSH molecules represent new therapeutic agents to treat antiviral infections and Th2-mediated diseases such as allergic disorders and AIDS.
Assuntos
Adjuvantes Imunológicos/farmacologia , Antivirais/farmacologia , Glutationa/farmacologia , Animais , Glutationa/fisiologia , Humanos , Camundongos , Células Th1/imunologia , Células Th2/imunologia , Viroses/fisiopatologiaRESUMO
BACKGROUND: The purpose of this study was to describe child deliveries in French Guyana and describe changes in perinatal mortality in different population groups between 1992 and 1999. MATERIAL AND METHODS: All deliveries in health centers and maternity wards in French Guyana between January 1, 1992 and December 31, 1999 were included in the study. Social, demographic, and clinical data were collected at the time of delivery. Infants with a birth weight of 500 g or term 22 weeks were included. RESULTS: From 1992 to 1995, the number of deliveries in health centers declined 5.7% and the number in public maternity wards increased 69.7%. The same trend was observed in 1998 - 1999 (2.4% and 85.7% respectively), an expression of the policy of antenatal referral implemented by the network of childbirth professionals. Perinatal mortality decreased significantly between 1995 and 1998 from 35.4 to 15.2 for the Creole population (p=0.06), from 46 to 16.5 for the Black-Marron Surinam population (p<0.0007), and from 36 to 10.2 for the Black-Marron French population (p<0.009). This drop in mortality in high-risk population groups may have contributed to the overall decline in perinatal mortality observed over the study period. The rate of preterm birth remained stable (at 13.5%) and the proportion of low-weight infants increased only slightly (12.8% to 13.7%). Mortality among preterm infants declined considerably, undoubtedly because of improved neonatal intensive care. CONCLUSION: Despite significant improvement, the perinatal mortality in French Guyana (18.9 in 1999) remains almost three times that in metropolitan France (7.4 in 1999). The mothers are young (17% aged less than 20 years) and the proportion of primiparous and grand multiparous mothers is high. With the absence or insufficiency of prenatal care, the problem of perinatal mortality remains a public health priority and challenge in French Guyana.
Assuntos
Parto Obstétrico/tendências , Mortalidade Infantil/tendências , Assistência Perinatal/tendências , Coeficiente de Natalidade , Peso ao Nascer , Parto Obstétrico/métodos , Feminino , Morte Fetal/epidemiologia , Guiana Francesa/epidemiologia , Idade Gestacional , Política de Saúde/tendências , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Idade Materna , Trabalho de Parto Prematuro/epidemiologia , Paridade , Vigilância da População , Gravidez , Gravidez de Alto Risco , Encaminhamento e Consulta/tendências , Características de Residência/estatística & dados numéricos , Fatores SocioeconômicosRESUMO
In this study, we investigated the cytokine profiles of 14 treatment-naive HIV-infected patients on the initiation of highly active antiretroviral therapy (HAART). At baseline, plasma levels of TNF-alpha and its mRNA in peripheral blood mononuclear cells (PBMC) were highest in the most severely immunocompromised patients (<200 CD4+ cells/mm3). After 12 months of HAART, the virus was undetectable in the plasma of all patients (<200 copies/ml), and median CD4 T cell counts had increased (+164 cells/mm3). We also observed a gradual decrease in the number of proviral DNA copies in PBMC and in immune activation, with lower levels of IFN-gamma mRNA in PBMC associated with weaker activation of CD8+ T cells and lower levels of plasma TNF-alpha. IL-2 mRNA levels in PBMC were found to increase in parallel. The decrease in TNF-alpha and IFN-gamma levels and the increase in IL-2 production appear to be correlated with the efficacy of HAART in naive immunocompromised HIV-infected individuals.
Assuntos
Terapia Antirretroviral de Alta Atividade , Citocinas/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Feminino , Seguimentos , Infecções por HIV/virologia , Humanos , Imunofenotipagem , Interferon gama/biossíntese , Interferon gama/genética , Interleucina-2/biossíntese , Interleucina-2/genética , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Mensageiro/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Carga ViralRESUMO
Anti-myelin basic protein (MBP) autoreactive T cells play a key role in the pathogenesis of multiple sclerosis. Thus, we applied the Immunoscope strategy to cerebrospinal fluid (CSF) and peripheral blood lymphocytes (PBLs) of an HLA-DR2 patient. Both compartments showed major expansion for the V(beta)13S5 chain, which was associated in peripheral blood with significant proliferation of PBLs in response to MBP and the 84-102 HLA-DR2-restricted peptide. Sequencing revealed a unique nucleotide sequence in the CSF that gives rise to the amino acid sequence V(beta)13S5-RPGQGDQETQ-J(beta)2.5 if translated. This CDR3 sequence had already been reported to be reactive against the 84-102 peptide. This specific sequence was not detected in PBLs on day 0, whereas it was readily detectable on day 6 culture samples. Thus, cell culture may lead to enrichment in a T cell clone identified as autoreactive.
Assuntos
Células Clonais/imunologia , Antígeno HLA-DR2/imunologia , Esclerose Múltipla/imunologia , Proteína Básica da Mielina/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Linfócitos T/imunologia , Adulto , Sequência de Aminoácidos , Autoanticorpos/sangue , Autoanticorpos/líquido cefalorraquidiano , Autoanticorpos/imunologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Células Cultivadas , Humanos , Masculino , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Proteína Básica da Mielina/farmacologia , Fragmentos de Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismoRESUMO
Cysteine is the limiting precursor for glutathione synthesis. Because of its low bioavailability, cysteine is generally produced from cystine, which may be taken up through two different transporters. The cystine/glutamate antiporter (x system) transports extracellular cystine in exchange for intracellular glutamate. The X(AG) transport system takes up extracellular cystine, glutamate, and aspartate. Both are sensitive to competition between cystine and glutamate, and excess extracellular glutamate thus inhibits glutathione synthesis, a nonexcitotoxic mechanism for glutamate toxicity. We demonstrated previously that human macrophages express the glutamate transporters excitatory amino acid transporter (EAAT)1 and EAAT2 (which do not transport cystine, X system) and overcome competition for the use of cystine transporters. We now show that macrophages take up cystine through the x and not the X(AG) system. We also found that glutamate, although competing with cystine uptake, dose-dependently increases glutathione synthesis. We used inhibitors to demonstrate that this increase is mediated by EAATs. EAAT expression in macrophages thus leads to glutamate-dependent enhancement of glutathione synthesis by providing intracellular glutamate for direct insertion in glutathione and also for fueling the intracellular pool of glutamate and trans-stimulating the cystine/glutamate antiporter.
Assuntos
Sistema y+ de Transporte de Aminoácidos , Proteínas de Transporte/metabolismo , Transportador 1 de Aminoácido Excitatório/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/metabolismo , Glutationa/metabolismo , Macrófagos/metabolismo , Células Cultivadas , Cistina/metabolismo , Cistina/farmacologia , Transportador 1 de Aminoácido Excitatório/antagonistas & inibidores , Transportador 2 de Aminoácido Excitatório/antagonistas & inibidores , Ácido Glutâmico/farmacologia , Humanos , Modelos BiológicosRESUMO
Oxidative stress and glutathione deficiency seem to play a major role in the pathogenesis of HIV infection, as suggested by the increased survival of HIV-infected patients treated with N-acetylcysteine, a prodrug of glutathione. However, beneficial effects of GSH-replenishing drugs are restricted in vivo by the high concentrations needed to obtain biological effects and their low bioavailability. In this study, we evaluated the antiretroviral and antioxidant activities of new more lipophilic GSH-replenishing molecules, in macrophages infected in vitro with HIV-1. In these experimental conditions, a prodrug of N-acetylcystéine and beta-mercaptoethylamine, I-152 demonstrated a potent anti-HIV activity, increased intracellular GSH level, and decreased TNF-alpha production. Altogether, these results suggest that I-152 could be beneficial as adjuvant therapy of antiretrovirals in HIV-infected patients, especially in those with damages to the central nervous system or with mitochondrial damages associated with highly active antiretroviral therapy.
Assuntos
Acetilcisteína/análogos & derivados , Acetilcisteína/farmacologia , Fármacos Anti-HIV/farmacologia , Antioxidantes/farmacologia , Cisteamina/análogos & derivados , Cisteamina/farmacologia , Glutationa/fisiologia , HIV-1/efeitos dos fármacos , Macrófagos/virologia , Pró-Fármacos/farmacologia , Acetilcisteína/toxicidade , Butionina Sulfoximina/farmacologia , Células Cultivadas , Cisteamina/toxicidade , Avaliação Pré-Clínica de Medicamentos , HIV-1/fisiologia , Humanos , Macrófagos/metabolismo , Estresse Oxidativo , Fator de Necrose Tumoral alfa/biossíntese , Replicação Viral/efeitos dos fármacosRESUMO
Neurological disorders represent one of the most common disturbances accompanying HIV infection. In the past few years, highly antiretroviral active therapy has significantly reduced the incidence of HIV-related diseases. However, neurological dysfunction in AIDS patients still remains an unresolved problem. Oxidative stress, which occurs in brain tissues of patients undergoing HIV infection and is implicated in cell death of both astroglia and neurones, has recently been suggested to play a role in the pathogenesis of neuroAIDS. Thus, a better understanding of the processes that trigger and modulate free radical formation in brain tissues of AIDS patients might help in a successful therapeutic approach to the neuropathogenesis of HIV infection.
Assuntos
Complexo AIDS Demência/metabolismo , Antioxidantes/metabolismo , Barreira Hematoencefálica/fisiologia , Radicais Livres/metabolismo , Estresse Oxidativo/fisiologia , Complexo AIDS Demência/tratamento farmacológico , Complexo AIDS Demência/fisiopatologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Catalase/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Produtos do Gene tat/metabolismo , Glutationa/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Infecções por HIV/fisiopatologia , Humanos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Compostos Organometálicos/farmacologia , Compostos Organometálicos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência HumanaRESUMO
I-152 is a prodrug of NAC and MEA with potent pro-GSH effects in human macrophages, astrocytes and lymphocytes. This molecule could be of interest in HIV infection in respect to its antioxidant and anti-HIV activities, but also in other diseases to counteract oxidative stress, that is, inflammation, cardiovascular diseases, and neurodegenerative diseases.
Assuntos
Acetilcisteína/síntese química , Acetilcisteína/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Cisteamina/síntese química , Cisteamina/farmacologia , Glutationa/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Acetilcisteína/análogos & derivados , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Cisteamina/análogos & derivados , Infecções por HIV/metabolismo , Humanos , Indicadores e Reagentes , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismoRESUMO
We assessed the anti-human immunodeficiency virus (anti-HIV) activity in vitro of new platelet-activating factor (PAF) receptor antagonists, as PAF and viral replication are thought to be involved in HIV neuropathogenesis. We found that PMS-601 inhibited proinflammatory cytokine synthesis and HIV replication in macrophages and potentiated the antiretroviral activity of zidovudine. These results suggest that PMS-601 is of potential value as an adjuvant treatment for HIV infection.
Assuntos
Fármacos Anti-HIV/farmacologia , HIV/efeitos dos fármacos , Macrófagos/virologia , Piperazinas/farmacologia , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Receptores de Superfície Celular , Receptores Acoplados a Proteínas G , Sinergismo Farmacológico , HIV/fisiologia , Humanos , Macrófagos/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Zidovudina/farmacologiaRESUMO
Haemophagocytic syndrome (HPS) and HIV infection are both associated with cytokine network dysregulation. We therefore analysed plasma levels and mRNA synthesis in peripheral blood mononuclear cells (PBMC) of cytokines, chemokines and chemokine receptors in one HIV-infected patient with HPS. We compared the results with those for eight HIV-infected patients with similar CD4+ T cell counts (207/mm3 versus controls: median 214/mm3) and plasma virus load (4.1 log copies/ml, versus controls: median 4.2 log copies/ml). The HPS patient had a lower viral DNA load in PBMC and higher plasma levels of interferon-gamma, IL-10, and macrophage inflammatory protein (MIP)-1beta. No difference in plasma tumour necrosis factor-alpha (TNF-alpha), IL-6 and MIP-1alpha concentration was observed between the HPS patient and control patients. No difference was observed in TNF-alpha, IL-1beta, IL-10, IL-4, MIP-1alpha, MIP-1beta, RANTES, CXCR-4, and CCR-5 mRNA levels in PBMC, but IL-6 levels were higher in the HPS patient. Our results emphasize the role of IL-10 in the control of immune hyperactivation that is observed in HPS.