Novel Regioisomeric Analogues of Naphthyl-N-Acylhydrazone Derivatives and Their Anti-Inflammatory Effects.

BACKGROUND: When homeostasis is disturbed it can result in a pathological event named inflammation. The main drugs used in the treatment consist of non-steroidal and steroidal anti-inflammatory drugs. However, the side effects remain an obstacle during the treatments. In this study, we aimed to evaluate three new regioisomers analogues of naphthyl-N-acylhydrazone derivatives. METHODS: Acute models of inflammation in vivo (formalin-induced licking and carrageenan-induced inflammation) as well as in vitro were used to evaluate the effects of LASSBio-2039, LASSBio-2040, and LASSBio-2041. RESULTS: All three substances (at 1, 10 or 30 µmol/kg) presented significant effects in the in vivo model reducing leukocyte migration, nitric oxide (NO) and interleukin-1ß production. It was observed that only LASSBio-2039 significantly reduced cell migration in vitro. None of the LASSBios affected inducible nitric oxide synthase activity nor presented nitric oxide (NO) scavenger effect. No toxic effect was observed, either in vivo or in vitro. The new regioisomers analogues of naphthyl-N-acylhydrazone derivatives presented significant anti-inflammatory activity, suggesting LASSBio-2039 has a direct effect in leukocytes migratory capacity. CONCLUSIONS: Taken together, the data indicate that these substances present promising effects for the development of a prototype for new drugs.

Novel p38 Mitogen-Activated Protein Kinase Inhibitor Reverses Hypoxia-Induced Pulmonary Arterial Hypertension in Rats.

Mitogen-activated protein kinase (MAPK) signaling is strongly implicated in cardiovascular remodeling in pulmonary hypertension (PH) and right ventricle (RV) failure. The effects of a newly designed p38 inhibitor, LASSBio-1824, were investigated in experimentally induced PH. Male Wistar rats were exposed to hypoxia and SU5416 (SuHx), and normoxic rats were used as controls. Oral treatment was performed for 14 days with either vehicle or LASSBio-1824 (50 mg/kg). Pulmonary vascular resistance and RV structure and function were assessed by echocardiography and catheterization. Histological, immunohistochemical and Western blot analysis of lung and RV were performed to investigate cardiovascular remodeling and inflammation. Treatment with LASSBio-1824 normalized vascular resistance by attenuating vessel muscularization and endothelial dysfunction. In the heart, treatment decreased RV systolic pressure, hypertrophy and collagen content, improving cardiac function. Protein content of TNF-α, iNOS, phosphorylated p38 and caspase-3 were reduced both in lung vessels and RV tissues after treatment and a reduced activation of transcription factor c-fos was found in cardiomyocytes of treated SuHx rats. Therefore, LASSBio-1824 represents a potential candidate for remodeling-targeted treatment of PH.

Identifying strategies to improve PANSS based dimensional models in schizophrenia: Accounting for multilevel structure, Bayesian model and clinical staging.

BACKGROUND: Dimensional approaches can decompose a construct in a set of continuous variables, improving the characterization of complex phenotypes, such as schizophrenia. However, the five-factor model of the Positive and Negative Syndrome Scale (PANSS), the most used instrument in schizophrenia research, yielded poor fits in most confirmatory factor analysis (CFA) studies, raising concerns about its applications. Thus, we aimed to identify dimensional PANSS CFA models with good psychometric properties by comparing the traditional CFA with three methodological approaches: Bayesian CFA, multilevel modeling, and Multiple Indicators Multiple Causes (MIMIC) modeling. METHODS: Clinical data of 700 schizophrenia patients from four centers were analyzed. We first performed a traditional CFA. Next, we tested the three techniques: 1) a Bayesian CFA; 2) a multilevel analysis using the centers as level; and 3) a MIMIC modeling to evaluate the impact of clinical staging on PANSS factors and items. RESULTS: CFA and Bayesian CFA produced poor fit models. However, when adding a multilevel structure to the CFA model, a good fit model emerged. MIMIC modeling yielded significant differences in the factor structure between the clinical stages of schizophrenia. Sex, age, age of onset, and duration of illness did not significantly affect the model fit. CONCLUSION: Our comparison of different CFA methods highlights the need for multilevel structure to achieve a good fit model and the potential utility of staging models (rather than the duration of illness) to deal with clinical heterogeneity in schizophrenia. Large prospective samples with biological data should help to understand the interplay between psychometrics concerns and neurobiology research.