RESUMO
The association between the pro-inflammatory state of schizophrenia and increased tryptophan degradation into kynurenine has been reported. However, the relationship between metabolites from subdivisions of the kynurenine pathway, kynurenic acid and 3-hydroxykynurenine, remains unknown. The present study tested the relationship between these kynurenine metabolites in the plasma of medication-naïve (n=35) or medication-free (n=18) patients with schizophrenia at admission and following 6-week antipsychotic treatment compared to healthy controls (n=48). The plasma concentrations of kynurenic acid (nmol/l) were lower (difference=-8.44 (-13.22 to -3.65); p=0.001) and of 3-hydroxykynurenine (nmol/l) were higher (difference=11.24 (8.11-14.37); p<0.001) in the patients compared with the healthy controls. The kynurenic acid/kynurenine (difference=-2.75 (-5.115 to -0.336); p=0.026) and kynurenic acid/3-hydroxykynurenine (difference=-1.08 (-1.431 to -0.729); p<0.001) ratios were also lower in the patients. After the 6-week treatment, the patients' plasma kynurenic acid levels (difference=3.85 (-0.23 to 7.94); p=0.064) showed a trend towards an increase, whereas plasma 3-hydroxykynurenine levels (difference=22.41 (19.76-25.07); p<0.001) decreased. As a consequence, the kynurenic acid/3-hydroxykynurenine ratio (difference=-4.41 (-5.51 to -3.3); p<0.001) increased. Higher initial plasma kynurenic acid levels on admission or increased kynurenic acid/kynurenine ratio after treatment were associated with reduction of clinical symptoms scores upon discharge although higher kynurenic acid/kynurenine on admission may induce higher positive symptoms score. In contrast, higher 3-hydroxykynurenine is associated with lower positive symptoms score. These results indicate that there is an imbalance in the kynurenine pathway in schizophrenia. The 6-week antipsychotic treatment may partially reverse the imbalance in kynurenine metabolism and that in turn induces clinical response.
Assuntos
Antipsicóticos/efeitos adversos , Ácido Cinurênico/metabolismo , Cinurenina/análogos & derivados , Esquizofrenia/metabolismo , Adulto , Algoritmos , Antipsicóticos/uso terapêutico , Cromatografia Líquida de Alta Pressão , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Cinurenina/metabolismo , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Espectrofotometria Ultravioleta , Resultado do Tratamento , Triptofano/metabolismoRESUMO
Abnormal activity in peripheral blood of the cytosolic enzyme prolyl endopeptidase (PEP, EC 3.4.21.26, post prolyl cleaving enzyme, prolyl oligopeptidase) has been found in patients with a variety of psychiatric disorders, most consistently in mood disorders. Mood disturbance is a well-known side effect of immunotherapy with interferon-alpha (IFN-alpha). Earlier, we documented a decrease in serum PEP activity in the first 4 weeks of treatment with IFN-alpha. In 24 patients (16 men, 8 women, median age 60.5 years, range 47-72 years) with metastatic renal cell carcinoma (RCC), psychiatric assessment and blood sampling were performed before and at 4 and 8 weeks and at 6 months after initiation of treatment with IFN-alpha. No episodes of depression were observed, and the sum score and the scores on the subscales for depression and hostility of the Symptom Check List-90 (SCL-90) did not change during follow-up, whereas the anxiety scores were somewhat lower at 4 and 8 weeks compared with baseline. No change in plasma PEP activity and no relationships between change in psychiatric parameters and change in plasma PEP activity were found. As more subtle relationships between PEP activity and psychiatric status could have easily been obscured, a role for PEP in the pathophysiology of IFN-alpha-induced mood disturbance can neither be confirmed nor excluded.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/psicologia , Imunoterapia , Interferon-alfa/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/psicologia , Serina Endopeptidases/sangue , Idoso , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/enzimologia , Feminino , Seguimentos , Humanos , Neoplasias Renais/sangue , Neoplasias Renais/enzimologia , Masculino , Pessoa de Meia-Idade , Prolil Oligopeptidases , PsicopatologiaRESUMO
UNLABELLED: CD26/Dipeptidyl peptidase (DPP) IV is an integral membrane protein of lymphocytes that modulates the activities of chemokines, interleukins, and neuropeptides. We investigated the effect of enzymatic DPP IV inhibition on ischemia/reperfusion injury after extended ischemia prior to transplantation. MATERIALS AND METHODS: We used a syngeneic rat (Lewis) orthotopic left lung transplantation model. In the control group (group I), donor lungs were flushed and preserved in Perfadex for 18 hours at 4 degrees C, then transplanted and reperfused for 2 hours. Group II donor lungs were perfused with and stored in Perfadex +25mol/L AB192 (bis(4-acetamidophenyl) 1-(S)-prolylpyrrolidine-2(R,S)-phosphonate), a small molecular weight DPP IV inhibitor. After 2-hour reperfusion, we measured blood gas, peak airway pressure, and thiobarbituric acid reactive substances. RESULTS: Grafts from group II versus group I showed a significantly increased oxygenation capacity (II: 298.4 +/- 87.6 mm Hg vs 120.9 +/- 48.0, P < .01), lower peak airway pressure (11.8 +/- 0.9 mm Hg vs 16.0 +/- 1.4, P < .01), and less lipid peroxidation (9.3 +/- 2.0 micromol/L vs 13.8 +/- 1.8, P < .01). CONCLUSION: Inhibition of intragraft DPP IV enzymatic activity significantly reduced ischemia/reperfusion-associated pulmonary injury, allowing for successful transplantation after 18 hours of ischemia.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Transplante de Pulmão/fisiologia , Organofosfonatos/uso terapêutico , Prolina/análogos & derivados , Traumatismo por Reperfusão/prevenção & controle , Animais , Inibidores Enzimáticos/uso terapêutico , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/fisiologia , Transplante de Pulmão/patologia , Prolina/uso terapêutico , Ratos , Ratos Endogâmicos Lew , Transplante IsogênicoRESUMO
A carboxypeptidase capable of cleaving basic amino acids from synthetic peptide substrates is present in fresh human serum, and not in human heparinized plasma. Its activity is generated during the process of coagulation. Because of its unstability at room temperature and at 37 degrees C, we named it unstable carboxypeptidase (carboxypeptidase U). Carboxypeptidase U was partially purified from fresh human serum by chromatography on DEAE-cellulose and Mono-Q sepharose and was found to be a 435 kDa protein. We compared this enzyme with carboxypeptidase N, purified from human serum by a two-step affinity chromatography on arginine-Sepharose 4B, followed by ion-exchange chromatography on Mono-Q sepharose. Carboxypeptidase U cleaves hippuryl-L-arginine and hippuryl-L-lysine, but at a different relative rate than carboxypeptidase N, and has no esterase activity on hippuryl-L-argininic acid. Its activity was inhibited by o-phenanthroline, DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid, CoCl2, 2-mercaptoethanol, dithiothreitol and 4-chloromercuribenzoic acid. These characteristics differentiate carboxypeptidase U from carboxypeptidase N and other known carboxypeptidases.
Assuntos
Carboxipeptidases/isolamento & purificação , Lisina Carboxipeptidase/isolamento & purificação , Cromatografia de Afinidade , Ativação Enzimática , Estabilidade Enzimática , Humanos , Lisina Carboxipeptidase/antagonistas & inibidores , Lisina Carboxipeptidase/sangue , Peso MolecularRESUMO
Human DPP IV, isolated from seminal plasma by means of immobilised adenosine deaminase, occurs in different forms which are distinguishable by net charge and native molecular weight. Charge differences arise primarily from different degrees of glycosylation containing various amounts of sialic acid. The majority of DPP IV isolated from total seminal plasma consists of the extracellular part of the protein starting at Gly-31. It is a very stable protein resisting high concentrations of denaturant. Unfolding experiments under reducing conditions are indicative of the existence of at least two domains which function independently. One of these domains is highly stabilised by disulfide bonds. Disruption of the disulfide bonds does not affect the activity, the dimeric state nor the adenosine deaminase binding properties of the protein but renders it more susceptible to proteolysis. The low-angle X-ray scattering spectrum is consistent with a model for a protein containing two subunits, each composed of three domains linked by flexible regions with low average mass. The secondary structure composition, determined by FTIR spectrometry, indicates that 45% of the protein consists of beta-sheets, which is higher than expected from computed secondary structure predictions. Our results provide compelling experimental evidence for the three-domain structure of the extracellular part of DPP IV.
Assuntos
Dipeptidil Peptidase 4/química , Sêmen/enzimologia , Sequência de Aminoácidos , Dipeptidil Peptidase 4/isolamento & purificação , Glicosilação , Guanidina , Guanidinas , Humanos , Dados de Sequência Molecular , Dobramento de Proteína , Estrutura Secundária de Proteína , UreiaRESUMO
A number of dipeptide diphenyl phosphonate esters were studied as inhibitors of dipeptidyl peptidase IV, focusing on the role of the P2 residue in the inactivation process. The active compounds were slow irreversible inhibitors of the catalytic activity of the enzyme. With proline (or alanine) in the P1 position, the rate constants of inactivation correlated with the acylation rate constants reported for homologous dipeptide derived substrates. The kinetic data indicate that the mechanism of inhibition consists of the formation of a fairly weak initial complex, followed by a slow irreversible inactivation step. This indicates that, as in the case of trypsin-like proteinases, dipeptide diphenyl phosphonate esters form a covalent adduct with the catalytic site of DPP IV, even though this enzyme belongs to a completely distinct class of serine peptidases. Enantioselectivity and secondary specificity further support the evidence that diphenyl phosphonate esters are mechanism-based inhibitors. The dipeptide diphenyl phosphonate esters had a half-life of 3-10 h at 37 degrees C in Tris buffer. The inhibitors were degraded in human plasma, depending on the type of amino-terminal amino acid. The compound with proline in the P2 position was the most resistant to degradation in plasma. Due to their stability and the irreversible nature of the inhibition, the diphenyl phosphonate esters promise to be useful tools in the continuing investigation of the physiological function of dipeptidyl peptidase IV.
Assuntos
Dipeptidil Peptidase 4/efeitos dos fármacos , Compostos Organofosforados/farmacologia , Inibidores de Serina Proteinase/farmacologia , Sítios de Ligação , Dipeptidil Peptidase 4/sangue , Ésteres , Humanos , Cinética , EstereoisomerismoRESUMO
OBJECTIVE: To investigate the seasonal variation in levels of plasma L-tryptophan and competing amino acids (CAAs) in healthy humans in relation to climatic variables, total serum protein levels, and violent suicide occurrence. METHODS: Twenty-six healthy volunteers (13 men and 13 women; mean [+/- SD] age, 38.7 +/- 13.4 years) had monthly blood samplings for assays of L-tryptophan, valine, leucine, isoleucine, tyrosine, and phenylalanine during 1 calendar year. RESULTS: Significant annual rhythms were detected in L-tryptophan, the L-tryptophan/CAA ratio, phenylalanine, valine, and leucine, and semiannual rhythms in L-tryptophan values and in L-tryptophan/CAA ratios. Plasma L-tryptophan and the L-tryptophan/CAA ratio were significantly lower in the spring than in the other seasons. The peak-trough differences in the yearly variation expressed as a percentage of the mean were 17.1% and 16.1% for L-tryptophan values and L-tryptophan/CAA ratios, respectively. The amplitude of the yearly variation in all CAAs was low, ie, less than 7%. An important part of the variance in L-tryptophan availability (ie, 12% to 14%) could be explained by the composite effects of present and past climatic factors; higher ambient temperature and relative humidity in the face of lower air pressure are the most important predictors of low L-tryptophan availability. Important and positive time relationships were noted between total serum protein level and all amino acid concentrations, and a significant time relationship was also noted between the seasonal variation in L-tryptophan availability and the occurrence of violent suicide in Belgium. CONCLUSION: Our results show a bimodal seasonal pattern in the availability of plasma L-tryptophan that matches seasonal patterns in the prevalence of violent suicide in the local population and depression in other studies.
Assuntos
Estações do Ano , Suicídio/estatística & dados numéricos , Triptofano/sangue , Violência , Adulto , Aminoácidos/sangue , Proteínas Sanguíneas/análise , Encéfalo/metabolismo , Ritmo Circadiano , Transtorno Depressivo/epidemiologia , Feminino , Humanos , Masculino , Prevalência , Análise de Regressão , Triptofano/metabolismo , Tempo (Meteorologia)RESUMO
An immunofluorescence study of the adherent layer of human long-term bone marrow cultures (HLTBMC) revealed the following surface markers on the different stromal cell populations: stromal fibroblastic cells CD10+, FIB86.3+, CD13+, CD71+; adipocytes CD10+, FIB86.3-, CD13+, CD71-/+; and macrophages CD10-/+, FIB86.3+, CD13+, CD71-/+, CD14+, CD33+, CD25+, HLA-DR+, CD4+, CD19+, CD45+. The markers of the stromal fibroblastic cells in HLTBMC were similar to those of twice-passaged fibroblasts not only from bone marrow and spleen, but also from a hemopoietic non-supportive organ such as the skin. Some of the cultured human umbilical vein endothelial cells used as controls were found to be CD25+, demonstrating for the first time the interleukin-2 receptor p55 chain on normal non-hemopoietic cells. The stromal fibroblastic cells are overrepresented compared to the small non-macrophage hemopoietic cell population in the adherent layer of HLTBMC. In addition, silver staining revealed an increased reticulin content in most of the HLTBMC. An excessive growth of stromal fibroblastic cells and an excessive deposition of their product, the reticulin fibers, are the hallmark of myelofibrosis. The finding of equivalent observations in HLTBMC suggests that the hitherto unexplained, premature quenching of hemopoiesis in HLTBMC might at least partly be due to mechanisms similar to those operating in myelofibrosis in vivo.
Assuntos
Células da Medula Óssea , Mielofibrose Primária/etiologia , Antígenos CD/análise , Antígenos de Diferenciação/análise , Antígenos de Diferenciação de Linfócitos B/análise , Antígenos de Neoplasias/análise , Antígenos de Superfície/análise , Medula Óssea/enzimologia , Medula Óssea/imunologia , Células Cultivadas , Fibroblastos/imunologia , Hematopoese , Humanos , Neprilisina , Peptidil Dipeptidase A/análise , Receptores da TransferrinaRESUMO
It was previously shown that CD26 (DPP IV, EC 3.4.14.5) is a binding site for adenosine deaminase (ADA, EC 3.5.4.4) on T cells and that costimulation by some anti-CD26 monoclonal antibodies (mAbs) and anti-CD3 induces CD4+ T cell proliferation. The CD26 epitopes involved in costimulation, the precise sequence of the events preceding proliferation, and the response of CD8+ compared with CD4+ T cells to CD26 were not extensively studied. We therefore compared the effects of the novel TA5.9 anti-CD26 mAb, recognizing an ADA-binding epitope, and the clearly distinct anti-Ta1 reference anti-CD26 mAb for their costimulatory properties in various T cell subsets. Both purified CD4+ and CD8+ T cells proliferated upon costimulation with anti-CD3 and either anti-CD26 mAb, but anti-TA5.9 mAb induced a more potent response than anti-Ta1. Either anti-CD26 mAb, together with anti-CD3, caused a similar sequential up-regulation of CD69, CD25 (IL-2R alpha), and CD71 (transferrin receptor) expression on CD4+ and CD8+ T cells. The activation markers appeared faster on the CD45R0+ than on the CD45R0- subsets. After costimulation, CD4+ T cell cultures contained significant amounts of the Th1 cytokines IL-2, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha). In CD8+ T cell cultures relatively more IFN-gamma and TNF-alpha but almost no IL-2 was measured after triggering of CD3 and CD26. Our data demonstrate that the recognition of the ADA-binding epitope is not a prerequisite for the costimulatory capacity of anti-CD26 mAbs. Both CD4+ and CD8+ T cells and their CD45R0- and CD45R0+ subsets are sensitive to various aspects of activation via CD26, but the magnitude and/or kinetics differ according to the anti-CD26 used and the T cell subset studied.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Dipeptidil Peptidase 4/imunologia , Ativação Linfocitária , Adenosina Desaminase/metabolismo , Complexo CD3/fisiologia , Humanos , Técnicas In Vitro , Interferon gama/biossíntese , Interleucina-2/biossíntese , Interleucina-5/biossíntese , Transdução de Sinais , Fatores de Tempo , Fator de Necrose Tumoral alfa/biossínteseRESUMO
To clarify the different anti-CD26 mAbs corresponding different functions of CD26, the correlation of the epitopes defined by anti-CD26 mAbs and the functions of CD26 have been studied. Using truncated, human-rat CD26 swap mutants and cross-blocking studies, 13 anti-CD26 mAbs were divided into 5 separate groups. These 5 epitopes were localized between the 1-247th, 248-358th, 359-449th (closer to the 359th amino acid), 450-577th and 359 653th amino acid regions. MAbs against two of these five epitopes, the 248-358th and 359-449th amino acid regions, were associated with inducing modulation of CD26 and T-cell costimulation through the CD3 pathway. Furthermore, mAbs against one of these epitopes, the 359-449th amino acid region, appeared to encompass the ADA binding domain. Analysing the avidity of each mAb to the CD26 molecule using DPPIV enzymatic activity as an indicator, we found that the function of CD26 had little correlation with the avidity of anti-CD26 mAbs, suggesting that distinct epitopes defined by anti-CD26 mAbs appeared to be associated with different functions of CD26. These results will be very useful in the further definition of the functional domains of CD26.
Assuntos
Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Dipeptidil Peptidase 4/imunologia , Epitopos/imunologia , Animais , Dipeptidil Peptidase 4/genética , Epitopos/genética , Humanos , Ativação Linfocitária , Mutação , Engenharia de Proteínas , Ratos , Proteínas Recombinantes de Fusão/imunologia , Deleção de Sequência , Especificidade da Espécie , Linfócitos T/imunologiaRESUMO
Recently, it was found that major depression is accompanied by an acute phase (AP) response with increased haptoglobin (Hp) plasma levels and various indices of systemic immune stimulation. The present study has been carried out in order to determine the relationships between hyperhaptoglobinemia and indices of systemic immune activation in severe depression. Toward this end, the authors investigated the relationships between Hp levels and number of leukocytes, monocytes, neutrophils, lymphocytes, and activated T lymphocytes (CD25+, HLA-DR+), in depression. Hp plasma levels were significantly higher in major depressed subjects as compared to healthy controls and minor depressives. There was a significant positive correlation between Hp levels and severity of illness. Hp plasma levels showed significant and positive relationships with the absolute number of leukocytes, neutrophils, monocytes, CD25+ and HLA-DR+ T cells. Up to 35% of the variance in Hp levels could be explained by the regression on the number of neutrophils and HLA-DR+ T cells. The results show that hyperhaptoglobinemia in major depression is significantly related to activation of cell-mediated immunity.
Assuntos
Transtornos de Adaptação/imunologia , Transtorno Depressivo/imunologia , Haptoglobinas/metabolismo , Imunidade Celular/imunologia , Adulto , Feminino , Humanos , Contagem de Leucócitos , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Inventário de Personalidade , Linfócitos T/imunologiaRESUMO
In order to investigate the relationships between the hypothalamic-pituitary-adrenal (HPA)-axis activity, the central serotonergic neurotransmission, and the peripheral metabolism of l-tryptophan (L-TRP), the authors measured the following: the postdexamethasone cortisol values, the cortisol responses to 125 mg 5-hydroxy-L-tryptophan (L-5-HTP) orally, and the total L-TRP/competing amino acids (CAA) ratio in 64 depressed females. Severely depressed females showed significantly lower values for L-TRP/CAA, significantly higher postdexamethasone cortisol values, and cortisol responses to L-5-HTP as compared with minor depressives. Dexamethasone nonsuppressors showed significantly lower L-TRP/CAA values as compared with suppressors. The cortisol responses to dexamethasone were significantly and negatively correlated with the availability of L-TRP. The cortisol responses to L-5-HTP were not related to either the availability of L-TRP or to the postdexamethasone cortisol values.
Assuntos
5-Hidroxitriptofano , Transtorno Depressivo/diagnóstico , Dexametasona , Hidrocortisona/sangue , Triptofano/sangue , Adulto , Transtorno Depressivo/sangue , Transtorno Depressivo/psicologia , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Pessoa de Meia-Idade , Testes de Personalidade , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Receptores de Serotonina/fisiologiaRESUMO
Prolyl endopeptidase (PEP) is a serine proteinase, which may cleave peptides that are involved in the pathophysiology of major depression, such as arginine vasopressin, beta-endorphin, luteinizing hormone-releasing hormone, thyrotropin-releasing hormone, and maybe corticotropin-releasing hormone. PEP may be involved in activation of cell-mediated immunity, autoimmune and inflammatory responses, which repeatedly occur in severe depression. The present study investigates serum PEP activity in 33 normal controls, 16 minor, 14 simple major, and 18 melancholic depressed subjects. Pre-dexamethasone and post-dexamethasone (DST) intact adrenocorticotropic hormone (ACTH) and cortisol values were determined in 33 depressed subjects. Serum PEP activity was significantly lower in depressed subjects compared to normal controls and in melancholic depressed subjects compared to minor and simple major depressed subjects. Up to 61.1% of the melancholic patients had serum PEP activities below the mean PEP values of normal controls minus two SDs. In the depressed study group, significant negative correlations between serum PEP activity and severity of illness, post-DST cortisol, and ACTH values were observed. There was a trend toward higher serum PEP activity with increasing age. It is hypothesized that lower serum PEP activity, and lower serum activity of other peptidases, may play a role in the neuroendocrine and immune pathophysiology of major depression.
Assuntos
Transtorno Depressivo/fisiopatologia , Serina Endopeptidases/sangue , Hormônio Adrenocorticotrópico/sangue , Adulto , Idoso , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/psicologia , Dexametasona , Feminino , Humanos , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/fisiopatologia , Prolil OligopeptidasesRESUMO
It has been recently shown that severe depression is characterized by immune dysfunctions such as blunted mitogen-induced blast transformation, which is linked to interleukin-2 (IL-2) mechanisms, and to autoimmune responses. In order to explore one of the putative pathophysiological mechanisms underlying both factors, we have measured the predexamethasone and postdexamethasone serum dipeptidyl-peptidase IV (DPP IV) activity in depressed inpatients and normal controls. This enzyme is an important mediator of IL-2-related blast proliferation, and it may play a role in autoimmunity. We found significantly lower DPP IV levels in major depressives as compared with healthy controls, and melancholics exhibited significantly lower enzyme activity than minor depressives. There was a significant negative correlation between serum DPP IV activity and the severity of illness. However, we were unable to detect any significant relationships between DPP IV on the one hand, and mitogen-induced blast transformation, soluble IL-2 receptor accumulation in PHA culture supernatant, total number of leukocytes and lymphocytes, T lymphocytes, CD4+ and CD25+ cells, on the other. Men exhibited significantly higher serum DPP IV levels than women.
Assuntos
Transtornos de Adaptação/diagnóstico , Transtornos de Adaptação/enzimologia , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/enzimologia , Dipeptidil Peptidases e Tripeptidil Peptidases/sangue , Transtornos de Adaptação/psicologia , Adulto , Antígenos CD/análise , Transtorno Depressivo/psicologia , Dexametasona , Dipeptidil Peptidase 4 , Feminino , Humanos , Contagem de Leucócitos , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Testes de Personalidade , Receptores de Interleucina-2/imunologia , Valores de ReferênciaRESUMO
Recently, some authors have reported defective neutrophil phagocytosis during depression. The present study investigated neutrophil function in 19 healthy controls and in 41 depressed inpatients categorized according to DSM-III into minor, simple major, and melancholic depression. We determined neutrophil function by means of phagocytosis, chemotaxis, and superoxide release. The results show no significant differences in neutrophil function among any of the subtypes of depression and normal volunteers. This suggests that overall neutrophil function is normal during depression. Thus, neutrophils are unlikely to be involved in the increased susceptibility to physical illness of patients with depression.
Assuntos
Quimiotaxia de Leucócito/imunologia , Transtorno Depressivo/imunologia , Neutrófilos/imunologia , Superóxidos/sangue , Adulto , Quimiotaxia de Leucócito/efeitos dos fármacos , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Psicotrópicos/uso terapêutico , Valores de ReferênciaRESUMO
BACKGROUND: The aim of the present study was to examine the production of interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-6 (IL-6), IL-10, IL-4, IL-5, IL-1 receptor antagonist (IL-1RA), and prostaglandin E2 in relation to the number of leukocytes in the blood of detoxified, chronic alcoholic patients without apparent liver disease (AWLD). METHODS: Phytohemagglutinin + lipopolysaccharide-induced production of the above variables as well as the number of white blood cells and differentials were determined in detoxified AWLD patients and normal volunteers. RESULTS: Detoxified AWLD patients have a significantly higher production of IL-6, IL-10, TNF-alpha, GM-CSF, and IL-1RA and significantly increased numbers of leukocytes and neutrophils compared to normal volunteers. CONCLUSIONS: Detoxified AWLD patients show an increased production of proinflammatory cytokines, i.e., IL-6, TNF-alpha, and GM-CSF, as well as negative immunoregulatory proteins, such as IL-10 and IL-1RA.
Assuntos
Alcoolismo/metabolismo , Citocinas/biossíntese , Citocinas/metabolismo , Adulto , Análise de Variância , Doença Crônica , Transtorno Depressivo/metabolismo , Feminino , Humanos , Hepatopatias/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
The human cDNA encoding prolyl endopeptidase, a cytoplasmic endoprotease which hydrolyses the peptide bond at the C-terminal side of proline, was sequenced. After the isolation of the 3' terminal fragment of the pep cDNA sequence from a human lymphocyte cDNA library, an approach based on the polymerase chain reaction (PCR) was undertaken to obtain the complete pep cDNA. Overlapping DNA fragments were generated by PCR from cDNA synthesized from human lymphocyte mRNA. The DNA fragments were subcloned and sequenced. The complete cDNA is 2562 nucleotides (nt) in length and contains an open reading frame coding for a protein of 710 amino acids (aa). Comparison of the primary PEP sequences from human lymphocyte and pig brain shows 97% identify. The aa sequence analysis shows homology with bacterial PEPs and with protease II from Escherichia coli. Asp641 probably participates in the active site of PEP.
Assuntos
Hominidae/genética , Linfócitos/enzimologia , Serina Endopeptidases/biossíntese , Serina Endopeptidases/genética , Sequência de Aminoácidos , Animais , Bactérias/enzimologia , Bactérias/genética , Sequência de Bases , Encéfalo/enzimologia , Clonagem Molecular , Citoplasma/enzimologia , Primers do DNA , Escherichia coli/enzimologia , Escherichia coli/genética , Humanos , Dados de Sequência Molecular , Fases de Leitura Aberta , Reação em Cadeia da Polimerase , Prolil Oligopeptidases , Homologia de Sequência de Aminoácidos , SuínosRESUMO
OBJECTIVE: There is extensive evidence that major depression, and particularly melancholia, is characterized by hypothalamic-pituitary-adrenal (HPA) axis hyperactivity as well as systemic immune activation, which may be accompanied by increased interleukin-1 beta production. Interleukin-1 beta is known to enhance HPA axis activity during an immune response. This study investigated whether interleukin-1 beta production is related to HPA axis activity in depressed subjects. METHOD: The subjects were 28 inpatients with major or minor depression and 10 normal comparison subjects. The authors measured 1) the subjects' cortisol levels after an overnight 1-mg dexamethasone suppression test (DST) and 2) mitogen-stimulated supernatant interleukin-1 beta production by peripheral blood mononuclear cells. RESULTS: Statistically significant positive correlations between interleukin-1 beta production and post-DST cortisol values were found in the study group as a whole and in the depressed and normal subgroups separately. CONCLUSIONS: It is suggested that constituents of the immune response (such as interleukin-1 beta) in major depression may contribute to HPA axis hyperfunction in that illness.
Assuntos
Transtorno Depressivo/diagnóstico , Dexametasona , Hidrocortisona/sangue , Interleucina-1/sangue , Adulto , Transtorno Depressivo/imunologia , Hospitalização , Humanos , Ativação Linfocitária , Linfócitos/química , Linfócitos/imunologia , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Studies from the authors' laboratory have shown that major depression is accompanied by significantly increased plasma concentrations of positive acute-phase proteins such as haptoglobin. Haptoglobin is characterized by a molecular variation with three known phenotypes (Hp 1-1, Hp 2-1, and Hp 2-2). This study investigated haptoglobin plasma levels and phenotype and gene frequencies in unipolar major depression. METHOD: Haptoglobin plasma levels of 22 healthy volunteers, 32 patients with minor depression, and 72 patients with major depression were determined by means of a laser nephelometric method. Haptoglobin phenotyping of these 126 subjects and 200 healthy blood donors was also carried out. RESULTS: The patients with major depression exhibited significantly higher haptoglobin plasma levels than the healthy comparison subjects and the patients with minor depression. Subjects with the haptoglobin phenotype Hp 2-2 had significantly lower haptoglobin levels than the phenotype Hp 1-1 and Hp 2-1 carriers. The frequencies of haptoglobin phenotypes Hp 2-1 (61.1%) and Hp 2-2 (20.8%) in the patients with major depression were significantly higher and lower, respectively, than the frequencies in the normal population (i.e., the blood donors: 48.0% and 37.0%, respectively). The frequency of the Hp-1 gene was significantly greater in the patients with major depression (48.6%) than in the normal population (39.0%). CONCLUSIONS: Major depression is characterized by a hyperhaptoglobinemia that is largely independent of haptoglobin phenotypes. This altered distribution of haptoglobin phenotypes and genes suggests that genetic variation on chromosome 16 may be associated with that illness.
Assuntos
Transtorno Depressivo/genética , Frequência do Gene , Haptoglobinas/genética , Fenótipo , Adulto , Doadores de Sangue , Cromossomos Humanos Par 16 , Transtorno Depressivo/sangue , Feminino , Variação Genética , Haptoglobinas/análise , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Dipeptidyl-peptidase IV (DPPIV/CD26) metabolizes neuropeptides regulating insulin secretion. We studied the in vitro steady-state kinetics of DPPIV/CD26-mediated truncation of vasoactive intestinal peptide (VIP), pituitary adenylyl cyclase-activating peptide (PACAP27 and PACAP38), gastrin-releasing peptide (GRP) and neuropeptide Y (NPY). DPPIV/CD26 sequentially cleaves off two dipeptides of VIP, PACAP27, PACAP38 and GRP. GRP situates between the best DPPIV/CD26 substrates reported, comparable to NPY. Surprisingly, the C-terminal extension of PACAP38, distant from the scissile bond, improves both PACAP38 binding and turnover. Therefore, residues remote from the scissile bond can modulate DPPIV/CD26 substrate selectivity as well as residues flanking it.