Spiro-containing derivatives show antiparasitic activity against trypanosoma brucei through inhibition of the trypanothione reductase enzyme

Trypanothione reductase (TR) is a key enzyme that catalyzes the reduction of trypa-nothione, an antioxidant dithiol that protects Trypanosomatid parasites from oxidative stress induced by mammalian host defense systems. TR is considered an attractive target for the development of novel anti-parasitic agents as it is essential for parasite survival but has no close homologue in humans. We report here the identification of spiro-containing derivatives as inhibitors of TR from Trypanosoma brucei (TbTR), the parasite responsible for Human African Trypanosomiasis. The hit series, identified by high throughput screening, was shown to bind TbTR reversibly and to compete with the trypanothione (TS2) substrate. The prototype compound 1 from this series was also found to impede the growth of Trypano-soma brucei parasites in vitro. The X-ray crystal structure of TbTR in complex with compound 1 solved at 1.98 Å allowed the identification of the hydrophobic pocket where the inhibitor binds, placed close to the catalytic histidine (His 461’) and lined by Trp21, Val53, Ile106, Tyr110 and Met113. This new inhibitor is specific for TbTR and no activity was detected against the structurally similar human glutathione reductase (hGR). The central spiro scaffold is known to be suitable for brain active compounds in humans thus represent-ing an attractive starting point for the future treatment of the central nervous system stage of T. brucei infections

Theory of mind in Parkinson’s disease: evidences in drug-naïve patients and longitudinal effects of dopaminergic therapy

Theory of mind (ToM) is the ability to attribute mental states to one self and others and to understand that others have beliefs different from one’s own. Different subcomponents of ToM have also been identified: cognitive and affective. Cognitive ToM refers to the capacity to infer others’ beliefs and intentions, while affective ToM implies the ability to appreciate others’ emotional states. The aim of this study was to explore ToM in drug-naïve Parkinson’s disease (PD) patients and to investigate the effects of chronic dopaminergic therapy on different subcomponents of ToM during a 3 months and 1 year of follow-up. We examined 16 PD patients in three conditions: before (un-medicated) and after dopaminergic therapy (medicated 3 months: T1 and medicated 1 year: T2). We also compared our PD’s ToM abilities with 11 healthy individuals. ToM was explored with 5 different tasks: Faux Pas Test, Picture Sequencing Task Capture Story, Emotion Attribution Task, Strange Stories Task, and Karolinska Directed Emotional Faces. Our study confirms that PD patients present deficits in cognitive components of ToM and preserved performances in the affective ones in early stages of disease. We also find a significant effect of dopaminergic therapy on ToM already after 3 months with a good persistency after 1 year of treatment

Benign versus malignant Parkinson disease: the unexpected silver lining of motor complications.

OBJECTIVE: We sought to evaluate demographic, clinical, and habits/occupational variables between phenotypic extremes in Parkinson's disease (PD). METHODS: Databases from nine movement disorders centers across seven countries were retrospectively searched for subjects meeting criteria for very slowly progressive, benign, PD (bPD) and rapidly progressive, malignant, PD (mPD). bPD was defined as Hoehn and Yahr (H&Y) stage ≤ 3, normal cognitive function, and Schwab and England (S&E) score ≥ 70 after ≥ 20 years of PD (≥ 10 years if older than 60 at PD onset); mPD as H&Y > 3, S&E score  68-year-old). CONCLUSIONS: Phenotypic PD extremes showed distinct demographic, clinical, and habits/occupational factors. Motor complications may be conceived as markers of therapeutic success given their attenuating effects on the odds of mPD

Homeobox gene expression profile indicates HOXA5 as a candidate prognostic marker in oral squamous cell carcinoma

The search for molecular markers to improve diagnosis, individualize treatment and predict behavior of tumors has been the focus of several studies. This study aimed to analyze homeobox gene expression profile in oral squamous cell carcinoma (OSCC) as well as to investigate whether some of these genes are relevant molecular markers of prognosis and/or tumor aggressiveness. Homeobox gene expression levels were assessed by microarrays and qRT-PCR in OSCC tissues and adjacent non-cancerous matched tissues (margin), as well as in OSCC cell lines. Analysis of microarray data revealed the expression of 147 homeobox genes, including one set of six at least 2-fold up-regulated, and another set of 34 at least 2-fold down-regulated homeobox genes in OSCC. After qRT-PCR assays, the three most up-regulated homeobox genes (HOXA5, HOXD10 and HOXD11) revealed higher and statistically significant expression levels in OSCC samples when compared to margins. Patients presenting lower expression of HOXA5 had poorer prognosis compared to those with higher expression (P=0.03). Additionally, the status of HOXA5, HOXD10 and HOXD11 expression levels in OSCC cell lines also showed a significant up-regulation when compared to normal oral keratinocytes. Results confirm the presence of three significantly upregulated (>4-fold) homeobox genes (HOXA5, HOXD10 and HOXD11) in OSCC that may play a significant role in the pathogenesis of these tumors. Moreover, since lower levels of HOXA5 predict poor prognosis, this gene may be a novel candidate for development of therapeutic strategies in OSCC