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1.
HIV Med ; 20(10): 681-690, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31424619

RESUMO

OBJECTIVES: The aim of this study was to evaluate the circulating levels of CD40 ligand (CD40 L), Dickkopf-1 (DKK-1) and P-selectin, their relationships and their contributions to cardiovascular risk in subjects with HIV infection. METHODS: The study population included 80 HIV-infected patients, 14 (17.5%) of whom had diabetes mellitus (DM) and 32 (40.0%) of whom had arterial hypertension (AH). The HIV-infected patients were compared with a control group with similar demographic and clinical features. CD40L, DKK-1 and P-selectin levels were measured using an enzyme-linked immunosorbent assay. RESULTS: The HIV-infected patients showed higher levels of all the cardiovascular disease (CVD) markers. Both serum CD40L and DKK-1 were significantly higher in HIV-infected patients than in the HIV-negative controls (P < 0.001), while soluble P-selectin showed no significant between-group difference (P = 0.133), reflecting the role of HIV infection in CVD. In the HIV-infected group, patients with DM showed lower levels of CD40L and DKK-1 in comparison with the nondiabetic patients and patients with AH (P < 0.05, with Bonferroni correction). In contrast, patients with AH showed higher levels of CD40L and DKK-1 in comparison to patients without DM or AH (P < 0.05, with Bonferroni correction). Patients with AH showed higher levels of CD40L and DKK-1 than patients with DM (P < 0.05, with Bonferroni correction). CONCLUSIONS: In this study, we found that HIV-infected patients displayed significantly higher circulating levels of both CD40L and DKK-1, which were linearly and directly correlated, when compared to HIV-negative patients. The presence of diabetes was associated with lower levels of both CD40L and DKK-1, whereas the presence of hypertension was associated with higher levels of CD40L.


Assuntos
Ligante de CD40/sangue , Doenças Cardiovasculares/sangue , Infecções por HIV/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Selectina-P/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Diabetes Mellitus/sangue , Feminino , Humanos , Hipertensão/sangue , Masculino , Pessoa de Meia-Idade
2.
J Antimicrob Chemother ; 71(3): 739-50, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26679249

RESUMO

OBJECTIVES: This study aims to evaluate the reliability and clinical utility of NS3 sequencing in hepatitis C virus (HCV) 1-infected patients who were candidates to start a PI-containing regimen. METHODS: NS3 protease sequencing was performed by in-house-developed HCV-1 subtype-specific protocols. Phylogenetic analysis was used to test sequencing reliability and concordance with previous genotype/subtype assignment by commercial genotyping assays. RESULTS: Five hundred and sixty-seven HCV plasma samples with quantifiable HCV-RNA from 326 HCV-infected patients were collected between 2011 and 2014. Overall, the success rate of NS3 sequencing was 88.9%. The success rate between the two subtype protocols (HCV-1a/HCV-1b) was similarly high for samples with HCV-RNA >3 log IU/mL (>92% success rate), while it was slightly lower for HCV-1a samples with HCV-RNA ≤3 log IU/mL compared with HCV-1b samples. Phylogenetic analysis confirmed the genotype/subtype given by commercial genotyping assays in 92.9% (303/326) of cases analysed. In the remaining 23 cases (7.1%), 1 was HCV-1g (previously defined as subtype 1a), 1 was HCV-4d (previously defined as genotype 1b) and 1 was HCV-1b (previously defined as genotype 2a/2c). In the other cases, NS3 sequencing precisely resolved the either previous undetermined/discordant subtype 1 or double genotype/subtype assignment by commercial genotyping assays. Resistance-associated variants (RAVs) to PI were detected in 31.0% of samples. This prevalence changed according to PI experience (17.1% in PI-naive patients versus 79.2% in boceprevir/telaprevir/simeprevir-failing patients). Among 96 patients with available virological outcome following boceprevir/telaprevir treatment, a trend of association between baseline NS3 RAVs and virological failure was observed (particularly for HCV-1a-infected patients: 3/21 failing patients versus 0/22 achieving sustained virological response; P = 0.11). CONCLUSIONS: HCV-NS3 sequencing provides reliable results and at the same time gives two clinically relevant pieces of information: a correct subtype/genotype assignment and the detection of variants that may interfere with the efficacy of PI.


Assuntos
Farmacorresistência Viral , Técnicas de Genotipagem/métodos , Hepacivirus/classificação , Hepacivirus/efeitos dos fármacos , Hepatite C/virologia , Mutação , Proteínas não Estruturais Virais/genética , Genótipo , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Humanos , RNA Viral/genética , Estudos Retrospectivos , Análise de Sequência de DNA
3.
Infection ; 41(6): 1103-9, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23839213

RESUMO

PURPOSE: Our aim was to explore the interplay between human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections in the expression of cognitive disorders. METHODS: We performed a multi-centre cross-sectional study, enrolling three groups of asymptomatic outpatients matched for age and education: (1) HIV mono-infected; (2) HCV mono-infected; (3) HIV-HCV co-infected. All subjects were subjected to the Zung depression scale and a comprehensive neuropsychological battery. RESULTS: A total of 50 patients for each group were enrolled. Patients in the three groups did not significantly differ in the main common demographic and clinical characteristics, except for a lower proportion of past injecting drug use (IDU) in group 1 (4 %) in comparison to groups 2 (38 %, p < 0.001) and 3 (78 %, p < 0.001), a longer duration of HIV infection in group 3 in comparison to group 1 (p < 0.001) and a longer duration of HCV infection in group 3 in comparison to group 2 (p = 0.028). Overall, 39.3 % of patients showed minor cognitive impairment, with a higher proportion in group 3 (54 %) when compared to groups 1 (28 %, p = 0.015) or 2 (36 %, p = 0.108). Patients in group 3 [odds ratio (OR) 3.35, p = 0.038 when compared to group 1] and those with higher depression scores (OR 1.05, p = 0.017) showed an increased risk of cognitive impairment after adjusting for education and past injection drug use. In particular, group 3 showed worse performance in psychomotor speed tasks when compared to group 1 (p = 0.033). CONCLUSIONS: A worse cognitive performance in HIV-HCV co-infected patients was observed, suggesting an additive role of the two viruses in the pathogenesis of cognitive disorders.


Assuntos
Transtornos Cognitivos/psicologia , Transtornos Cognitivos/virologia , Coinfecção/psicologia , Infecções por HIV/psicologia , Hepatite C/psicologia , Análise de Variância , Coinfecção/virologia , Estudos Transversais , Feminino , Infecções por HIV/virologia , Hepatite C/virologia , Humanos , Masculino , Testes Psicológicos , Fatores de Risco
4.
Eur Rev Med Pharmacol Sci ; 16(4): 491-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22696876

RESUMO

BACKGROUND: There is increasing evidence of hypertension and microalbuminuria in HIV-infected patients, and these are two important risk factors for renal and cardiovascular disease. Anti-hypertensive drugs inhibiting the renin-angiotensin system exert an antiproteinuric effect. Telmisartan, an angiotensin II receptor blocker and partial peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist that is approved for the treatment of hypertension, appears to exert a nephroprotective effect independent of blood pressure reduction in the general population. OBJECTIVE: The aim of this preliminary study was to evaluate possible nephroprotective effects of telmisartan in hypertensive HIV-positive patients with microalbuminuria. PATIENTS AND METHODS: Caucasian male patients with HIV infection (n=13) receiving stable combined antiretroviral therapy (without therapeutic changes for > 12 months) and a recent diagnosis of grade 1 hypertension were treated with daily oral telmisartan 80 mg for 6 months. Patients had suppressed viremia and a CD4 cell count > 300 cells/mL for 6 months, and microalbuminuria > 5 mg/dL. Systolic and diastolic blood pressure (SBP, DBP), triglycerides, total cholesterol, HDL cholesterol and LDL cholesterol, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), microalbuminuria, Modification of Diet Renal Disease-Glomerular Filtration Rate (MDRD-GFR), vascular endothelial growth factor (VEGF) and endothelin-1 were measured at baseline and at one, three and six months. All statistical analyses were performed using SAS 9.2. RESULTS: A significant reduction of microalbuminuria (p < 0.001) with stable MDRD-GFR was observed, although the main indices of renal function showed no substantial change. A significant reduction in mean SBP and DBP was observed at T1 and confirmed at T3 and T6 (SBP p < 0.001 and DBP p < 0.001), and there was BP normalization. Metabolic assessments showed an improvement in lipid parameters, and a significant decrease in insulin resistance assessed by the homeostasis model assessment index-insulin resistance (HOMA-IR) (p = 0.04). In addition, there was a statistically significant reduction in ESR (p = 0.02) and a non significant reduction in CRP. Other results included a significant reduction in serum VEGF and endothelin-1 levels (p < 0.001). CONCLUSIONS: From these preliminary findings, telmisartan has demonstrated efficacy in the control of hypertension and microalbuminuria in HIV-infected patients. Decreased microalbuminuria with stable MDRD-GFR may be indicative of a nephroprotective effect of telmisartan; mechanisms causing microalbuminuria in patients with HIV could be related to infection, chronic inflammation, and endothelial dysfunction. The decreased endothelin-1 and VEGF levels in patients in this study may be related to an endothelial protective effect of telmisartan. This study reports the first observation of renal and endothelial protective effects of telmisartan in HIV-positive patients.


Assuntos
Albuminúria/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Benzimidazóis/uso terapêutico , Benzoatos/uso terapêutico , Infecções por HIV/complicações , Hipertensão/tratamento farmacológico , Adulto , Albuminúria/sangue , Albuminúria/diagnóstico , Albuminúria/fisiopatologia , Albuminúria/virologia , Terapia Antirretroviral de Alta Atividade , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Infecções por HIV/sangue , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Humanos , Hipertensão/sangue , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Hipertensão/virologia , Resistência à Insulina , Itália , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Telmisartan , Fatores de Tempo , Resultado do Tratamento
5.
J Biol Regul Homeost Agents ; 24(2): 131-5, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20487626

RESUMO

Interleukin 12 (IL 12) p35/p40 is a heterodimeric cytokine which plays a critical role in inflammation, immunity and tissue proliferation, and also plays a relevant function in T helper (Th) cell polarization and Th1 T-cell differentiation. IL-12 family members, IL-12p70, IL-23, IL-27 and IL-35, play an important role in influencing helper T-cell differentiation. EBV-induced gene 3 can be associated with the p35 subunit of IL-12 to form the EBI3/p35 heterodimer, also called IL-35. It has been shown that IL-35 has biological activity and able to expand CD4+CD25+ Treg cells, suppress the proliferation of CD4+CD25- effector cells and inhibit Th17 cell polarization. IL-35 has been shown to be constitutively expressed by regulatory T (Treg) cells CD4(+)CD25(+)Foxp3(+) and suggested to contribute to their suppressive activity. IL-35 is a crucial mediator which provokes CD4+CD25+ T cell proliferation and IL-10 generation, another well-known anti-inflammatory cytokine, along with TGFbeta cytokine. These studies suggest that IL-35, together with other successfully discovered cytokine inhibitors, represents a new potential therapeutic cytokine for chronic inflammation, autoimmunity and other immunological disorders.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucinas/farmacologia , Interleucinas/fisiologia , Linfócitos T Reguladores/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Diferenciação Celular , Divisão Celular/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Citocinas/fisiologia , Humanos , Inflamação/fisiopatologia , Interleucina-12/farmacologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/fisiologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos
6.
Int J Immunopathol Pharmacol ; 22(3): 853-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19822103

RESUMO

In HIV-infected patients with metabolic disorders, as in the general population, there is evidence of hypertension requiring pharmacological treatment. The presence of diabetes constitutes a cluster of particularly high cardiovascular risks in patients, both regarding diabetic damage and hypertensive damage. We used telmisartan to manage high blood pressure values in an HIV-positive patient with insulin-dependent diabetes. Surprisingly, insulin therapy had to be suspended because of hypoglycemic fits and treatment with metformin was started. In conclusion, telmisartan was effective and well tolerated for the control of hypertension in this case and improved sensitivity to insulin. There are interesting effects of this drug in HIV-positive diabetic patients. Thus, if further studies confirm these effects, telmisartan may be the anti-hypertensive drug of first choice in HIV-infected subjects on combined antiretroviral therapy affected with diabetes and metabolic disorders.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Benzimidazóis/uso terapêutico , Benzoatos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Infecções por HIV/complicações , Hipertensão/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Hemoglobinas Glicadas/metabolismo , Infecções por HIV/sangue , Infecções por HIV/fisiopatologia , Humanos , Hipertensão/sangue , Hipertensão/etiologia , Hipertensão/fisiopatologia , Hipoglicemia/etiologia , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Lipídeos/sangue , Masculino , Metformina/uso terapêutico , Telmisartan , Resultado do Tratamento
7.
Int J Immunopathol Pharmacol ; 22(3): 795-807, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19822097

RESUMO

Chronic fatigue syndrome (CFS) is a disabling condition characterized by unexplained chronic fatigue that impairs normal activities. Many body systems are affected and etiology has not yet been identified. In addition to immunological and psychological aspects, skeletal muscle symptoms are prominent in CFS patients. In an effort to establish which pathways might be involved in the onset and development of muscle symptoms, we used global transcriptome analysis to identify genes that were differentially expressed in the vastus lateralis muscle of female and male CFS patients. We found that the expression of genes that play key roles in mitochondrial function and oxidative balance, including superoxide dismutase 2, were altered, as were genes involved in energy production, muscular trophism and fiber phenotype determination. Importantly, the expression of a gene encoding a component of the nicotinic cholinergic receptor binding site was reduced, suggesting impaired neuromuscular transmission. We argue that these major biological processes could be involved in and/or responsible for the muscle symptoms of CFS.


Assuntos
Síndrome de Fadiga Crônica/genética , Perfilação da Expressão Gênica , Músculo Quadríceps/química , Adulto , Atrofia/genética , Biópsia , Estudos de Casos e Controles , Reparo do DNA/genética , Metabolismo Energético/genética , Síndrome de Fadiga Crônica/metabolismo , Síndrome de Fadiga Crônica/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Junção Neuromuscular/genética , Análise de Sequência com Séries de Oligonucleotídeos , Estresse Oxidativo/genética , Fenótipo , Músculo Quadríceps/patologia
8.
Int J Immunopathol Pharmacol ; 22(1): 15-9, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19309548

RESUMO

Autism spectrum disorder is of interest neurochemically because it represents a relatively homogeneous disorder with regard to disease development, abnormal cognitive development and intellectual development disturbance. A consistent finding in autistic children is a high number of mast cells and a high level of serotonin which is also found at elevated concentrations in the urine of autistic patients. In addition, a dysfunction of clinical conditions, such as gastrointestinal and immunological symptoms, is frequently noted in autistic children, however, IgE does not appear to be prevalent in these children but probably an increase of cytokines/chemokines produced by mast cells at an early age may play an important role. Therefore an immune hypothesis, involving also autoimmunity, is one possible pathogenetic mechanism in autism. In conclusion, mast cell activation could contribute to immune and neuroinflammatory abnormalities that are evident in patients with autism spectrum disorders.


Assuntos
Transtorno Autístico/imunologia , Imunidade , Amônia/sangue , Citocinas/biossíntese , Humanos , Mastócitos/fisiologia , Serotonina/fisiologia
9.
J Biol Regul Homeost Agents ; 23(1): 11-4, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19321041

RESUMO

IL-33, a member of IL-1 family, induces the differentiation of T-cells (depending on the phosphorylation of MAPKs and NF-kB) and is involved in T-cell mediated immune responses. IL-33 is also involved in the production of IL-5, IL-4 and IL-13 and several chemokines. In this editorial we show the importance of IL-33 in allergic diseases and its role as an inflammatory cytokine. In addition, the induction of certain chemokines by IL-33 may candidate this new cytokine as a mediator in inflammatory and autoimmune diseases and may prove to be a therapeutic target for the prevention of these diseases.


Assuntos
Interleucina-1/imunologia , Interleucinas/imunologia , Mastócitos/imunologia , Animais , Asma/imunologia , Aterosclerose/imunologia , Camundongos
10.
J Biol Regul Homeost Agents ; 23(3): 141-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19828090

RESUMO

IL-32, a newly-discovered proinflammatory cytokine that activates the p38MAPK and NF-kappaB pathways, is an important player in innate and adaptive immune response. IL-32, a cytokine produced mainly by T, natural killer, and epithelial cells induces significant amounts of TNFalpha and MIP-2 and increases the production of both cytokines in a dose-dependent manner. IL-32 has been implicated in inflammatory disorders, mycobacterium tuberculosis infections, inflammatory bowel disease, and influenza A virus infection, as well as in some autoimmune diseases, such as rheumatoid arthritis, ulcerative colitis and Crohn?s disease and in human stomach cancer, human lung cancer and breast cancer tissues. Moreover, it has been reported that IL-32 has pro-inflammatory effects on myeloid cells and causes the differentiation of osteoclast precursors into multinucleated cells expressing specific osteoclast markers. We recently found that human IL-32 has the capacity to provoke histamine release in human-derived cord blood mast cells (HDCBMC), but not in LAD 2 cells nor in rat peritoneal mast cells (RPMC), showing that IL-32 may be specie specific and act more in mature human mast cells (HDCBMC) than in transformed mast cells (LAD 2 cells). Certainly, IL-32 is another potent proinflammatory cytokine, however, the specific role of this newly-discovered protein in the network of cytokine biology remains to be determined.


Assuntos
Mediadores da Inflamação/metabolismo , Interleucinas/metabolismo , Animais , Diferenciação Celular , Humanos , Imunidade , NF-kappa B/metabolismo
11.
Int J STD AIDS ; 20(8): 580-1, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19625595

RESUMO

Compared with healthy controls, HIV patients already have abnormal lipoprotein concentrations before the initiation of highly active antiretroviral therapy (HAART), which worsen with the therapy. HAART-associated dyslipidaemia features fundamental proatherogenic changes such as increased plasma triglycerides (TGs), increased total cholesterol and low-density lipoprotein cholesterol as well as decreased high-density lipoprotein cholesterol (HDL-C). The current guidelines for managing HIV-associated dyslipidaemia recommend diet and exercise counselling, alteration of HAART regimen or addition of lipid-lowering medications such as statins, fibrates and omega-3 (OM-3) fatty acids. Given that cardiovascular risk significantly increases with elevated lipid levels, selecting a drug to manage dyslipidaemia is particularly important. A case is described of an HIV patient who had severe hypertriglyceridaemia and bad metabolic parameters treated with rosuvastatin and OM-3 fatty acids. So we obtained a more marked reduction of TG levels than has never been described before in the literature, associated with a significant increase in HDL-C levels.


Assuntos
Ácidos Graxos Ômega-3/administração & dosagem , Fluorbenzenos/administração & dosagem , Infecções por HIV/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipertrigliceridemia/tratamento farmacológico , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Quimioterapia Combinada , Humanos , Masculino , Rosuvastatina Cálcica
12.
Infez Med ; 17(1): 38-40, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19359825

RESUMO

Complications in urinary tract nervous routes due to herpes viruses as VZV and HSV-2 are well known. Acute urinary retention and chronic neuropathic pain are not rare when sacral dermatomes are involved by these viruses. However, an analogous condition has not yet been clearly ascribed to HSV-1 infection. We present a 32-year-old immunocompetent patient with fever, lumbar pain and acute urinary retention who had never had herpetic clinical manifestations. Urodynamic studies diagnosed a neurologic bladder with an absent filling sensation. Cystoscopic assessment revealed the presence of reddened and isolated small mucosal areas in the bladder walls. The search for herpes viruses in plasma and CSF by PCR assay were positive for HSV-1. After treatment with antiviral therapy the disease resolved. Intermittent catheterization was necessary and voiding dysfunction resolved after three weeks by its appearance. Neurological damage to the central nervous system (CNS) and/or PNS due to HSV-1 seems to be the most likely reason. The course of disease was benign and self-remitting.


Assuntos
Cistite/virologia , Herpes Simples/complicações , Herpesvirus Humano 1/patogenicidade , Mielite/virologia , Retenção Urinária/etiologia , Dor Abdominal/etiologia , Adulto , Anticorpos Antivirais/sangue , Cistite/complicações , Feminino , Febre/etiologia , Hematúria/etiologia , Herpes Simples/virologia , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/isolamento & purificação , Humanos , Imunoglobulina G/sangue , Ceratite Herpética/complicações , Dor Lombar/etiologia , Mielite/líquido cefalorraquidiano , Mielite/complicações , Viremia/complicações , Viremia/virologia
13.
Clin Microbiol Infect ; 25(7): 906.e1-906.e7, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30472417

RESUMO

OBJECTIVE: We aimed to investigate HBx genetic elements correlated with hepatitis B virus (HBV) -related hepatocellular carcinoma (HCC) and their impact on (a) HBV replicative efficiency, (b) HBx binding to circular covalently closed DNA (cccDNA), (c) apoptosis and cell-cycle progression, and (d) HBx structural stability. METHODS: This study included 123 individuals chronically infected with HBV: 27 with HCC (77.9% (21/27) genotype D; 22.1% (6/27) genotype A) and 96 without HCC (75% (72/96) genotype D; 25.0% (24/96) genotype A). HepG2 cells were transfected by wild-type or mutated linear HBV genome to assess pre-genomic RNA (pgRNA) and core-associated HBV-DNA levels, HBx-binding onto cccDNA by chromatin immunoprecipitation-based quantitative assay, and rate of apoptosis and cell-cycle progression by cytofluorimetry. RESULTS: F30V was the only HBx mutation correlated with HCC (18.5% (5/27) in HCC patients versus 1.0% (1/96) in non-HCC patients, p 0.002); a result confirmed by multivariate analysis. In vitro, F30V determined a 40% and 60% reduction in pgRNA and core-associated HBV-DNA compared with wild-type (p <0.05), in parallel with a significant decrease of HBx binding to cccDNA and decreased HBx stability. F30V also decreased the percentage of apoptotic cells compared with wild-type (14.8 ± 6.8% versus 19.1 ± 10.1%, p <0.01, without affecting cell-cycle progression) and increased the probability of HBx-Ser-31 being phosphorylated by PI3K-Akt kinase (known to promote anti-apoptotic activity). CONCLUSIONS: F30V was closely correlated with HBV-induced HCC in vivo, reduced HBV replicative efficiency by affecting HBx-binding to cccDNA and increased anti-apoptotic HBx activity in vitro. This suggests that F30V (although hampering HBV's replicative capacity) may promote hepatocyte survival, so potentially allowing persistent production of viral progeny and initiating HBV-driven hepatocarcinogenesis. Investigation of viral genetic markers associated with HCC is crucial to identify those patients at higher risk of HCC, who hence deserve intensive liver monitoring and/or early anti-HBV therapy.


Assuntos
Apoptose , Carcinoma Hepatocelular/virologia , Vírus da Hepatite B/genética , Neoplasias Hepáticas/virologia , Transativadores/genética , Replicação Viral , Adulto , Idoso , DNA Viral/genética , Feminino , Genótipo , Células Hep G2 , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/virologia , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Homologia Estrutural de Proteína , Transativadores/química , Proteínas Virais Reguladoras e Acessórias
14.
Int J Immunopathol Pharmacol ; 21(2): 255-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18547468

RESUMO

The tridecapeptide neurotensin (NT) acts in the mammalian brain as a primary neurotransmitter or neuromodulator of classical neurotransmitters. Morphological and functional in vitro and in vivo studies have demonstrated the existence of close interactions between NT and dopamine both in limbic and in striatal brain regions. Additionally, biochemical and neurochemical evidence indicates that in these brain regions NT also plays a crucial role in the regulation of the aminoacidergic signalling. Immune cells, such as lymphocytes, macrophages and mast cells are reported to be activated by neuropeptides, such as neurotensin; this activation leads to cytokine and immunoglobulin production. In addition, neurotensin increases calcium level and the production of nitric oxide. Therefore neurotensin is deeply involved in immunity and inflammation but its real function still remains to be elucidated.


Assuntos
Neurotensina/fisiologia , Neurotransmissores/fisiologia , Animais , Comportamento/fisiologia , Química Encefálica , Trato Gastrointestinal/fisiologia , Humanos , Neurotensina/imunologia , Neurotensina/metabolismo , Neurotransmissores/metabolismo , Distribuição Tecidual
15.
J Clin Virol ; 106: 49-52, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30075459

RESUMO

BACKGROUND: Recent studies suggest that transmitted drug resistance (TDR) may be decreasing in latest years, likely because of the reduced frequency of acquired resistance. However, specific risk factors, geographical areas and special HIV-infected populations may be disproportionally affected by TDR. OBJECTIVES: Correlates of TDR and time trends were evaluated from 2007 to 2014. STUDY DESIGN: We evaluated the genotypic results of 2155 naïve patients enrolled in the I.Co.N.A cohort at 23 clinical Centers in Italy between 2007 and 2014. A weighted analysis was performed to account for the patients enrolled in the cohort in each clinical Centre at each biennium (total number of patients: 3737). RESULTS: Overall prevalence of TDR was 10.7%. Independent predictors of TDR were sexual risk factor (OR 2.315, p = 0.020) and non-Italian geographical origin (OR 1.57, p = 0.038). The weighted prevalence of TDR was 10.5% with a stable proportion over calendar years. Generally, TDR prevalence was numerically higher, although not significantly, in clinical Centers of metropolitan areas with more than 3 millions of residents as compared to others (11.3% vs. 9.2%). The difference in TDR prevalence between these Centers decreased in more recent years. CONCLUSIONS: A stable frequency of TDR was observed during the most recent years in Italy, with opposite and converging trends in large metropolitan areas as compared to the rest of the country, suggesting a more homogeneous spread of TDR across the country in latest years. Concerns remain for sexual route of infection and non-Italian origin, reinforcing the need for specific prevention strategies prioritizing specific populations.


Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/genética , Genótipo , Infecções por HIV/transmissão , HIV-1/efeitos dos fármacos , Adulto , Feminino , Infecções por HIV/epidemiologia , Soropositividade para HIV , HIV-1/genética , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Análise Espaço-Temporal , Fatores de Tempo , Adulto Jovem
16.
Int J Biol Markers ; 22(3): 226-31, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17922468

RESUMO

Inducible nitric oxide synthase (iNOS) is one of three enzymes generating nitric oxide (NO) from the amino acid L-arginine. iNOS-derived NO plays an important role in several physiological and pathophysiological conditions. NO is a free radical which produces many reactive intermediates that account for its bioactivity. In the human lung, the alveolar macrophage is an important producer of cytokines and this production may be modified by NO. Moreover, high concentrations of NO have been shown to increase nuclear factor kappaB (NF-kB) activation. Recent investigations of NO expression in tumor tissue indicated that, at least for certain tumors, NO may mediate one or more roles during the growth of human cancer. We have studied iNOS in two tissue groups: normal human lung tissue and human lung cancer tissue. We localized iNOS in these tissues by immunohistochemistry and tested the mRNA expression by RT-PCR, the protein level by Western blot, and the protein activity by radiometric analysis. The results demonstrate different expression, localization and activity of iNOS in normal versus tumor tissue. This is suggestive of a role for NO production from iNOS in human lung cancer because high concentrations of this short molecule may transform to highly reactive compounds such as peroxynitrite (ONOO-); moreover, through the upregulator NF-kB, they can induce a chronic inflammatory state representing an elevated risk for cell transformation to cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/enzimologia , Pulmão/enzimologia , Óxido Nítrico Sintase Tipo II/metabolismo , Apoptose/fisiologia , Western Blotting , Citocinas/biossíntese , Humanos , Imuno-Histoquímica , Pulmão/citologia , Neoplasias Pulmonares/patologia , NF-kappa B/biossíntese , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Int J Immunopathol Pharmacol ; 20(3): 519-27, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17880765

RESUMO

In this cross-sectional study, we evaluate potential predictors of Metabolic Syndrome (MS) in a group of 54 Caucasian chronically HIV-infected patients with lipodystrophy. According to ATP-III criteria, 22 patients were affected by MS and 32 were not. The mean age of the sample was 41.2+/-8.6 years, and most patients were males (74.1%); the two groups were homogeneous for gender, age, viro-immunologic status and the duration of antiviral therapy. The independent association between MS and several factors including demographic characteristics, type of highly-active antiviral therapy (HAART), viro-immunologic response, common cardiovascular risk factors (including Framingham scores), and selected cytokines (IFN-gamma, TNF-alpha, IL-2, IL-4, IL-6, IL-10 and IL-18), was investigated using stepwise forward logistic regression. At multivariate analysis, the only independent predictors of the metabolic syndrome were triglycerides and IL-18. A 10 mg/dL increase in triglycerides corresponds to an adjusted risk ratio for MS of 1.11 (95 percent IC: 1.04-1.19); and patients in the top tertile of IL-18 (those with IL-18 >/= 530 pg/L) had more than three times the likelihood of MS, as compared to the bottom and medium tertiles of IL-18 (patients with IL-18< 530 pg/L). This relationship was not attenuated by the inclusion of any other variable in the multivariate model. However, the association between metabolic syndrome and IL-18 is no longer significant when IL-18 is treated as a continuous variable (trend p = 0.087). Our results on HIV patients with lipodystrophy confirm previous findings on a strong independent association between IL-18 and MS in the general population. Further research is needed to clarify the mechanism of this association and its role in the development of cardiovascular disease in HIV patients.


Assuntos
Doenças Cardiovasculares/etiologia , Infecções por HIV/complicações , Síndrome Metabólica/etiologia , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Doenças Cardiovasculares/diagnóstico , Estudos Transversais , Citocinas/sangue , Citocinas/imunologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Síndrome de Lipodistrofia Associada ao HIV/etiologia , Síndrome de Lipodistrofia Associada ao HIV/imunologia , Síndrome de Lipodistrofia Associada ao HIV/metabolismo , Humanos , Metabolismo dos Lipídeos , Masculino , Síndrome Metabólica/imunologia , Síndrome Metabólica/metabolismo , Prognóstico , Risco , Triglicerídeos/sangue , Carga Viral
18.
J Biol Regul Homeost Agents ; 20(1-2): 15-23, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-18088550

RESUMO

Regulated on activation, normal T-cell expressed and presumably secreted (RANTES), which generally mediates monocyte-macrophage (MO) activation and recruitment, is a protein of 8-10 kD that chemoattracts eosinophils, monocytes and certain T leukocyte subsets. RANTES is coded for by a gene cluster located on human chromosome 17 and is a human T-cell specific molecule. RANTES is a member of a beta intercrine subfamily reported to be a selective chemoattractant for human monocytes rather than neutrophils, and is also a chemoattractant for memory T lymphocytes, CD4+ cells. RANTES is a modulator of many important macrophage functions in addition to aggregation, such as chemotaxis and phagocytosis. Our investigations focussed on the ability to modulate the aggregation of macrophages induced by calcium ionophore A23187. The ionophore A23187 directly induced potent aggregation of MO which was markedly enhanced when the cells were pretreated with RANTES. However, the addition of RANTES in the absence of other co-stimuli did not directly induce aggregation. Additional cytokines examined for possible induction of macrophage aggregation were interleukin-1 (IL-1), tumor necrosis alpha (TNF-alpha), and IL-6; all proved to be incapable of inducing aggregation directly, nor did they enhance the effects of A23187 on macrophage aggregation. Additionally, we found that RANTES can directly stimulate MO to activate specific pathways of arachidonic acid cascade, inducing a synthesis and release of thromboxane (TxA2) and leukotriene B4 (LTB4). RANTES did not augment the potent ability of A23187 to induce increased production of LTB4 or TxA2 by human MO. These data suggest that RANTES can contribute directly to monocyte-leukocyte-activation during inflammatory responses, resulting in greater cell aggregation, activation, and specific pro-inflammatory arachidonic acid products release, such as TxA2 and LTB4.


Assuntos
Ácido Araquidônico/metabolismo , Calcimicina/farmacologia , Quimiocina CCL5/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Cultivadas , Humanos
19.
J Biol Regul Homeost Agents ; 20(3-4): 47-52, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-18187018

RESUMO

An investigated flavonoid, quercetin, is reviewed in this article. Quercetin is a bioflavonoid found in red wine, grapefruit, onions, apples, black tea, and, in lesser amounts, in leafy green vegetables and beans. Quercetin has an antioxidant and anti-inflammatory activity and prevents cancer. Quercitin inhibits the growth of certain malignant cells in vitro, and histamine and most cyclin-dependent kinases and also displays unique anticancer properties. Quercetin is a natural compound that blocks substances involved in allergies and is able to act as an inhibitor of mast cell secretion, causes a decrease in the release of tryptase, MCP-1 and IL-6 and the down-regulation of histidine decarboxylase (HDC) mRNA from few mast cell lines. Quercetin is a safe, natural therapy that may be used as primary therapy or in conjunction with conventional methods.


Assuntos
Quercetina , Triptases , Humanos , Hipersensibilidade/metabolismo , Inflamação/metabolismo , Mastócitos/efeitos dos fármacos
20.
Clin Exp Med ; 6(4): 150-6, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17191106

RESUMO

Mast cells are involved in inflammatory processes and in allergic reactions where immunologic stimulation leads to degranulation and generation of numerous cytokines and inflammatory mediators. Mast cells have been proposed as an immune gate to the brain, as well as sensors of environmental and emotional stress, and are likely involved in neuropathologic processes such as multiple sclerosis. Among mast cell products, the protease tryptase could be associated with neurodegenerative processes through the activation of specific receptors (PARs) expressed in the brain, while interleukin (IL)-6 likely causes neurodegeneration and exacerbates dysfunction induced by other cytokines; or it could have a protective effect against demyelinisation. In this report we show that quercetin, a natural compound able to act as an inhibitor of mast cell secretion, causes a decrease in the release of tryptase and IL-6 and the down-regulation of histidine decarboxylase (HDC) mRNA from human mast cell (HMC)-1 cells. As quercetin dramatically inhibits mast cell tryptase and IL-6 release and HDC mRNA transcription by HMC-1 cell line, these results nominate quercetin as a therapeutical compound in association with other therapeutical molecules for neurological diseases mediated by mast cell degranulation.


Assuntos
Inibidores Enzimáticos/farmacologia , Histidina Descarboxilase/metabolismo , Interleucina-6/metabolismo , Mastócitos/efeitos dos fármacos , Quercetina/farmacologia , Triptases/metabolismo , Northern Blotting , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Histidina Descarboxilase/biossíntese , Histidina Descarboxilase/genética , Humanos , Mastócitos/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Transcrição Gênica
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