In vitro antileishmanial activity and phytochemical analysis of Carissa edulis against Leishmania major

Background: However, there is need to carry out scientific studies in order to confirm the medicinal properties of many plants used traditionally. Carissa edulis Forskk. (Gentiales: Apocynaceae) used by local communities for the treatment of various diseases has showed antiviral, antibacterial and antiprotozoal properties although there are no studies demonstrating its antileishmanial activity. Objective: To investigate in vitro antileishmanial activity of extracts of Carissa edulis on promastigote and amastigote forms of Leishmania major. Methodology: Solvent extraction of the stem parts of C. edulis was performed using water, methanol, petroleum ether, dichloromethane and ethyl acetate. Minimum inhibitory concentration (MIC), anti-amastigote and nitric oxide production assays were carried out to demonstrate antileishmanial activity of C. edulis extracts against the two forms of L. major parasite species: promastigote and amastigote. The extracts were also screened for phytochemical constituents present. Cytotoxicity assay was then done to assess their safe use as herbal medicinal products. Results: The C. edulis petroleum ether extract showed the strongest antileishmanial activity against L. major promastigotes (MIC=625μg/ml) with the water, dichloromethane and ethyl acetate extracts recording the weakest activity (MIC=2500μg/ml). The successive methanol extract reduced the number L. major amastigotes by 88.29% compared to the negative control (RPMI). The water (13.37μM), petroleum ether (12.93μM) and successive methanol extracts (12.82μM) produced nitrite values lower than the standard drugs Pentostam® (14.35μM) and Amphotericin B (14.13μM). Discussion: All C. edulis extracts have potential antileishmanial activity against L. major. Preliminary phytochemical screening of these extracts showed presence of alkaloids, terpenoids, phenols, anthraquinones and saponins. These phytochemicals were previously reported to have antileishmanial activity. Therefore, the plant extracts could offer an opportunity to develop cheaper antileishmanial alternatives to the more expensive pentavalent antimonials. Key words: C. edulis, L. major, promastigote, amastigot

Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects

Omenn syndrome (OS) is caused by hypomorphic Rag mutations and characterized by a profound immunodeficiency associated with autoimmune-like manifestations. Both in humans and mice, OS is mediated by oligoclonal activated T and B cells. The role of microbial signals in disease pathogenesis is debated. Here, we show that Rag2R229Q knock-in mice developed an inflammatory bowel disease affecting both the small bowel and colon. Lymphocytes were sufficient for disease induction, as intestinal CD4 T cells with a Th1/Th17 phenotype reproduced the pathological picture when transplanted into immunocompromised hosts. Moreover, oral tolerance was impaired in Rag2R229Q mice, and transfer of wild-type (WT) regulatory T cells ameliorated bowel inflammation. Mucosal immunoglobulin A (IgA) deficiency in the gut resulted in enhanced absorption of microbial products and altered composition of commensal communities. The Rag2R229Q microbiota further contributed to the immunopathology because its transplant into WT recipients promoted Th1/Th17 immune response. Consistently, long-term dosing of broad-spectrum antibiotics (ABXs) in Rag2R229Q mice ameliorated intestinal and systemic autoimmunity by diminishing the frequency of mucosal and circulating gut-tropic CCR9+ Th1 and Th17 T cells. Remarkably, serum hyper-IgE, a hallmark of the disease, was also normalized by ABX treatment. These results indicate that intestinal microbes may play a critical role in the distinctive immune dysregulation of OS

High H1-affinity antidepressants and risk of metabolic syndrome in bipolar disorder

Rationale Metabolic syndrome (MetS) is common in patients with bipolar disorder, with a relative risk of 1.6\u20132 compared to the general population. The increased risk is believed to be due to unhealthy lifestyles and use of medications. Although antipsychotics and mood stabilizers have been associated with weight gain and MetS, the impact of antidepressants has not been comprehensively evaluated. Objective The objective of the study is to assess the risk of MetS in patients exposed to different types of antidepressants. Methods In this cross-sectional study, 294 patients with bipolar disorder were consecutively recruited. MetS was diagnosed according to NCEP ATP-III modified criteria. Antidepressants used by the patients were classified according to the usual nomenclature (SSRI, TCA, SNRI, and other antidepressants) and a pharmacodynamic classification taking into account histamine 1-receptor (H1-R) affinity. Results Use of antidepressants in general was not associated with MetS (prevalence ratio [PR], 1.08; 95% confidence interval, 0.73 to 1.62; p\u2009=\u20090.70). However, subjects using H1-R high-affinity antidepressants (N\u2009=\u200915) showed a substantial increase in the prevalence of MetS (PR, 2.17; 95 % confidence interval, 1.24 to 3.80; p\u2009=\u20090.007). When we included the inhibition constant (Ki) as a continuous covariate in the models, we found an inverse association between Ki and prevalence of MetS (p\u2009=\u20090.004). Conclusion We observed for the first time in a clinical setting that a pharmacodynamic-based classification of antidepressants could be more useful than the traditional one to predict the risk of MetS in patients with bipolar disorder. Clinical consequences may be relevant. However larger studies are warranted to generalize these results

Clinical correlates of age at onset distribution in bipolar disorder: a comparison between diagnostic subgroups

Abstract Background Admixture analysis of age at onset (AAO) has helped delineating the clinical profile of early onset (EO) bipolar disorder (BD). However, there is scarce evidence comparing the distributional properties of AAO as well as the clinical features of EO BD type 1 (BD1) with EO BD type 2 (BD2). To this end, we studied 515 BD patients (224 BD1, 279 BD2, and 12 BD not otherwise specified [NOS]) diagnosed according to DSM-IV-TR criteria. Methods AAO was defined as the first reliably diagnosed hypo/manic or depressive episode according to diagnostic criteria. We used normal distribution mixture analysis to identify subgroups of patients according to AAO. Models were chosen according to the Schwarz’s Bayesian information criteria (BIC). Clinical correlates of EO were analysed using univariate tests and multivariate logistic regression models. Results A two normal components model best fitted the observed distribution of AAO in BD1 (BIC = −1599.3), BD2 (BIC = −2158.4), and in the whole sample (BIC = −3854.9). A higher number of EO BD2 patients had a depression-(hypo)mania-free interval (DMI) course, while a higher rate of (hypo)mania-depression-free interval (MDI) course was found in EO BD1. EO BD2 had also a higher rate of comorbidity with alcohol dependence compared to EO BD1. The latter finding was confirmed by multivariate logistic regression analysis. Conclusions In conclusion, both BD1 and BD2 had bimodal AAO distributions, but EO subgroups had a diagnostic-specific clinical delineation

Coregulation in human leukocytes of the long pentraxin PTX3 and TSG-6

The prototypic long PTX3 is a multifunctional protein involved in innate resistance to pathogens and in controlling inflammation. TSG-6 is a hyaluronan-binding protein that is involved in ECM remodeling and has anti-inflammatory and chondroprotective functions. PTX3 and TSG-6 are coregulated by growth differentiation factor-9 in granulosa cells, where they are produced during the periovulatory period and play essential roles in the incorporation of hyaluronan into the ECM during cumulus expansion. The present study was designed to assess whether PTX3 and TSG-6 are coregulated in leukocytes, in particular, in phagocytes and DC. Monocytes, macrophages, and myeloid DC were found to produce high levels of TSG-6 and PTX3 in response to proinflammatory mediators (LPS or cytokines). Unstimulated neutrophil polymorphonuclear granulocytes expressed high levels of TSG-6 mRNA, but not PTX3 transcript, and stored both proteins in granules. In contrast, endothelial cells expressed substantial amounts of PTX3 mRNA and low levels of TSG-6 transcript under the conditions tested. Anti-inflammatory cytokines, such as IL-4, dampened LPS-induced TSG-6 and PTX3 expression. Divergent effects were observed with IL-10, which synergizes with TLR-mediated PTX3 induction but inhibits LPS-induced TSG-6 transcription. Immunohistochemical analysis confirms the colocalization of the two proteins in inflammatory infiltrates and in endothelial cells of inflamed tissues. Thus, here we show that myelomonocytic cells and MoDC are a major source of TSG-6 and that PTX3 and TSG-6 are coregulated under most of the conditions tested. The coordinated expression of PTX3 and TSG-6 may play a role in ECM remodeling at sites of inflammatio

Clinical correlates of age at onset distribution in bipolar disorder: a comparison between diagnostic subgroups

Background: Admixture analysis of age at onset (AAO) has helped delineating the clinical pro le of early onset (EO) bipolar disorder (BD). However, there is scarce evidence comparing the distributional properties of AAO as well as the clinical features of EO BD type 1 (BD1) with EO BD type 2 (BD2). To this end, we studied 515 BD patients (224 BD1, 279 BD2, and 12 BD not otherwise speci ed [NOS]) diagnosed according to DSM-IV-TR criteria. Methods: AAO was de ned as the rst reliably diagnosed hypo/manic or depressive episode according to diagnos- tic criteria. We used normal distribution mixture analysis to identify subgroups of patients according to AAO. Models were chosen according to the Schwarz\u2019s Bayesian information criteria (BIC). Clinical correlates of EO were analysed using univariate tests and multivariate logistic regression models. Results: A two normal components model best tted the observed distribution of AAO in BD1 (BIC = 121599.3), BD2 (BIC = 122158.4), and in the whole sample (BIC = 123854.9). A higher number of EO BD2 patients had a depression- (hypo)mania-free interval (DMI) course, while a higher rate of (hypo)mania-depression-free interval (MDI) course was found in EO BD1. EO BD2 had also a higher rate of comorbidity with alcohol dependence compared to EO BD1. The latter nding was con rmed by multivariate logistic regression analysis. Conclusions: In conclusion, both BD1 and BD2 had bimodal AAO distributions, but EO subgroups had a diagnostic- specic clinical delineation