RESUMO
Polyunsaturated fatty acids (PUFAs) and cholesterol are lipids implicated in suicide risk. We prospectively studied plasma glycerophospholipid PUFAs and cholesterol as putative predictors of suicide attempts. In a multicenter cohort study, we enrolled 123 patients admitted to the emergency department (ED) for suicidal ideation or suicide attempt. Clinical assessments were performed, with follow-up telephone evaluations 6, 12, 18, and 24 months later. Blood samples were obtained in the ED and assayed for PUFAs. Using survival analysis, suicide events were not predicted by eicosapentaenoic acid (EPA, HR: -0.83, 95%CI: 0.39-1.76, p = 0.621) or docosahexaenoic acid (DHA, HR: -0.60, 95%CI: 0.19-1.86, p = 0.371). However, higher arachidonic acid (AA) was a trend for a protective factor (HR=0.30, 95%CI: 0.08-1.08, p = 0.065) in the entire trans-diagnostic sample. This protective effect was significant in all participants with a prior suicide attempt history (n = 85; HR=0.16, 95%CI: 0.04-0.67, p = 0.012), and in the subgroup of attempters with major depressive disorder (MDD; n = 55, HR=0.15, 95%CI:0.03-0.76, p = 0.002). Total LDL- and HDL-cholesterol did not predict subsequent suicide events. AA, but not DHA or EPA, positively correlated with baseline depression severity in MDD patients (r = 0.3, p = 0.006). Contrary to our hypothesis that low n-3 PUFA levels would create risk, we found that while higher AA was associated with greater depression severity at baseline, low AA unexpectedly predicted subsequent suicide attempts, the more so in higher-risk patients. Although surprising, this result agrees with a minority of reports concerning n-6 PUFAs and may represent complex interactions with sample characteristics.
Assuntos
Ácido Araquidônico/sangue , Biomarcadores/sangue , Transtorno Depressivo Maior/sangue , Ácidos Docosa-Hexaenoicos/sangue , Ácido Eicosapentaenoico/sangue , Tentativa de Suicídio/estatística & dados numéricos , Adulto , Argentina , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Serviço Hospitalar de Emergência , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ideação Suicida , Análise de SobrevidaRESUMO
Multiple sclerosis (MS) is a highly disabling neurodegenerative autoimmune condition in which an unbalanced immune response plays a critical role. Although the mechanisms remain poorly defined, helminth infections are known to modulate the severity and progression of chronic inflammatory diseases. The tyrosine kinase receptors TYRO3, AXL, and MERTK (TAM) have been described as inhibitors of the immune response in various inflammatory settings. We show here that patients with concurrent natural helminth infections and MS condition (HIMS) had an increased expression of the negative regulatory TAM receptors in antigen-presenting cells and their agonist GAS6 in circulating CD11bhigh and CD4+ T cells compared to patients with only MS. The Th17 subset was reduced in patients with HIMS with a subsequent downregulation of its pathogenic genetic program. Moreover, these CD4+ T cells promoted lower levels of the co-stimulatory molecules CD80, CD86, and CD40 on dendritic cells compared with CD4+ T cells from patients with MS, an effect that was GAS6-dependent. IL-10+ cells from patients with HIMS showed higher GAS6 expression levels than Th17 cells, and inhibition of phosphatidylserine/GAS6 binding led to an expansion of Th17 effector genes. The addition of GAS6 on activated CD4+ T cells from patients with MS restrains the Th17 gene expression signature. This cohort of patients with HIMS unravels a promising regulatory mechanism to dampen the Th17 inflammatory response in autoimmunity.
Assuntos
Helmintíase/complicações , Helmintíase/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/parasitologia , Células Th17/imunologia , Adulto , Animais , Feminino , Humanos , MasculinoRESUMO
The New World arenavirus Junin (JUNV) is the etiological agent of Argentine hemorrhagic fever (AHF). Previous studies of human macrophage infection by the Old-World arenaviruses Mopeia and Lassa showed that while the non-pathogenic Mopeia virus replicates and activates human macrophages, the pathogenic Lassa virus replicates but fails to activate human macrophages. Less is known in regard to the impact of New World arenavirus infection on the human macrophage immune response. Macrophage activation is critical for controlling infections but could also be usurped favoring immune evasion. Therefore, it is crucial to understand how the JUNV infection modulates macrophage plasticity to clarify its role in AHF pathogenesis. With this aim in mind, we compared infection with the attenuated Candid 1 (C#1) or the pathogenic P strains of the JUNV virus in human macrophage cultures. The results showed that both JUNV strains similarly replicated and induced morphological changes as early as 1 day post-infection. However, both strains differentially induced the expression of CD71, the receptor for cell entry, the activation and maturation molecules CD80, CD86, and HLA-DR and selectively modulated cytokine production. Higher levels of TNF-α, IL-10, and IL-12 were detected with C#1 strain, while the P strain induced only higher levels of IL-6. We also found that C#1 strain infection skewed macrophage polarization to M1, whereas the P strain shifted the response to an M2 phenotype. Interestingly, the MERTK receptor, that negatively regulates the immune response, was down-regulated by C#1 strain and up-regulated by P strain infection. Similarly, the target genes of MERTK activation, the cytokine suppressors SOCS1 and SOCS3, were also increased after P strain infection, in addition to IRF-1, that regulates type I IFN levels, which were higher with C#1 compared with P strain infection. Together, this differential activation/polarization pattern of macrophages elicited by P strain suggests a more evasive immune response and may have important implications in the pathogenesis of AHF and underpinning the development of new potential therapeutic strategies.
Assuntos
Febre Hemorrágica Americana/imunologia , Vírus Junin/imunologia , Ativação de Macrófagos , Macrófagos/imunologia , Animais , Antígeno B7-1/imunologia , Antígeno B7-2/imunologia , Chlorocebus aethiops , Cricetinae , Citocinas/imunologia , Antígenos HLA-DR/imunologia , Febre Hemorrágica Americana/patologia , Humanos , Especificidade da Espécie , Células VeroRESUMO
Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12, the only polyamine transporter described in T. cruzi. After a screening of 3000 FDA-approved drugs, 7 retinoids with medical use were retrieved and used for molecular docking assays with TcPAT12. From the docked molecules, isotretinoin, a well-known drug used for acne treatment, showed the best interaction score with TcPAT12 and was selected for further in vitro studies. Isotretinoin inhibited the polyamine transport, as well as other amino acid transporters from the same protein family (TcAAAP), with calculated IC50 values in the range of 4.6-10.3 µM. It also showed a strong inhibition of trypomastigote burst from infected cells, with calculated IC50 of 130 nM (SI = 920) being significantly less effective on the epimastigote stage (IC50 = 30.6 µM). The effect of isotretinoin on the parasites plasma membrane permeability and on mammalian cell viability was tested, and no change was observed. Autophagosomes and apoptotic bodies were detected as part of the mechanisms of isotretinoin-induced death indicating that the inhibition of transporters by isotretinoin causes nutrient starvation that triggers autophagic and apoptotic processes. In conclusion, isotretinoin is a promising trypanocidal drug since it is a multi-target inhibitor of essential metabolites transporters, in addition to being an FDA-approved drug largely used in humans, which could reduce significantly the requirements for its possible application in the treatment of Chagas disease.
Assuntos
Transporte Biológico/efeitos dos fármacos , Isotretinoína/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/enzimologia , Aminoácidos/metabolismo , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Poliaminas/metabolismoRESUMO
OBJECTIVE: Our purpose was to determine the presence of alpha(1)-adrenoceptor messenger RNA subtypes and extend the pharmacologic characterization of alpha(1)-adrenoceptors involved in human umbilical vein (HUV) contraction. STUDY DESIGN: Cords (n=124) from healthy patients after term vaginal or cesarean deliveries were used. The vein was carefully dissected out of cords and used for reverse transcription combined with polymerase chain reaction (RT-PCR) to amplify alpha(1)-adrenoceptor transcripts. In isolated organ baths, HUV rings were mounted and cumulative concentration-response curves were constructed either for epinephrine or the selective alpha(1A)-adrenoceptor agonist, A-61603. In other series of experiments, the effects of the selective alpha(1A)- and alpha(1B)-adrenoceptor antagonists (RS-100329 or B8805-033 or spiperone, AH11110A and cyclazosin, respectively) were evaluated to estimate its blocking potencies on epinephrine concentration-response curves. RESULTS: By means of RT-PCR technique alpha(1a)- and alpha(1b)-adrenoceptor transcripts were detected in the HUV. The blocking potency values of RS-100329 or B8805-033 against responses mediated by epinephrine were not consistent with the activation of an alpha(1A)-adrenoceptor population. Moreover, the low potency of the agonist A-61603 was not in accordance with an alpha(1A)-adrenoceptor interaction. On the other hand, the antagonist potencies of spiperone, AH11110A and cyclazosin were in agreement with an interaction on alpha(1B)-adrenoceptor subtype. CONCLUSION: Although alpha(1a)- and alpha(1b)-adrenoceptor messenger RNAs are detected in the HUV, only alpha(1B)-adrenoceptors are involved in epinephrine vasoconstrictor action.