Poly-ε-Caprolactone Implants for Benznidazole Prolonged Release: An Alternative to Chagas Disease Oral Treatment.

Benznidazole (BZ) tablets are the currently prescribed treatment for Chagas disease. However, BZ presents limited efficacy and a prolonged treatment regimen with dose-dependent side effects. The design and development of new BZ subcutaneous (SC) implants based on the biodegradable poly-ɛ-caprolactone (PCL) is proposed in this study for a controlled release of BZ and to improve patient compliance. The BZ-PCL implants were characterized by X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy, which indicated that BZ remains in its crystalline state dispersed in the polymer matrix with no polymorphic transitions. BZ-PCL implants, even at the highest doses, induce no alteration of the levels of hepatic enzymes in treated animals. BZ release from implants to blood was monitored in plasma during and after treatment in healthy and infected animals. Implants at equivalent oral doses increase the body's exposure to BZ in the first days compared with oral therapy, exhibiting a safe profile and allowing sustained BZ concentrations in plasma to induce a cure of all mice in the experimental model of acute infection by the Y strain of T. cruzi. BZ-PCL implants have the same efficacy as 40 daily oral doses of BZ. Biodegradable BZ implants are a promising option to reduce failures related to poor adherence to treatment, with more comfort for patients, and with sustained BZ plasma concentration in the blood. These results are relevant for optimizing human Chagas disease treatment regimens.

Guarana (Paullinia cupana) Extract Protects Caenorhabditis elegans Models for Alzheimer Disease and Huntington Disease through Activation of Antioxidant and Protein Degradation Pathways.

Guarana (Paullinia cupana) is largely consumed in Brazil in high energy drinks and dietary supplements because of its stimulant activity on the central nervous system. Although previous studies have indicated that guarana has some protective effects in Parkinson's (PD), Alzheimer's (AD), and Huntington's (HD) disease models, the underlying mechanisms are unknown. Here, we investigated the protective effects of guarana hydroalcoholic extract (GHE) in Caenorhabditis elegans models of HD and AD. GHE reduced polyglutamine (polyQ) protein aggregation in the muscle and also reduced polyQ-mediated neuronal death in ASH sensory neurons and delayed ß-amyloid-induced paralysis in a caffeine-independent manner. Moreover, GHE's protective effects were not mediated by caloric restriction, antimicrobial effects, or development and reproduction impairment. Inactivation of the transcription factors SKN-1 and DAF-16 by RNAi partially blocked the protective effects of GHE treatment in the AD model. We show that the protective effect of GHE is associated with antioxidant activity and modulation of proteostasis, since it increased the lifespan and proteasome activity, reduced intracellular ROS and the accumulation of autophagosomes, and increased the expression of SOD-3 and HSP-16.2. Our findings suggest that GHE has therapeutic potential in combating age-related diseases associated with protein misfolding and accumulation.

Carqueja (Baccharis trimera) Protects against Oxidative Stress and ß-Amyloid-Induced Toxicity in Caenorhabditis elegans.

Carqueja (Baccharis trimera) is a native plant found throughout South America. Several studies have shown that Carqueja has antioxidant activity in vitro, as well as anti-inflammatory, antidiabetic, analgesic, antihepatotoxic, and antimutagenic properties. However, studies regarding its antioxidant potential in vivo are limited. In this study, we used Caenorhabditis elegans as a model to examine the antioxidant effects of a Carqueja hydroalcoholic extract (CHE) on stress resistance and lifespan and to investigate whether CHE has a protective effect in a C. elegans model for Alzheimer's disease. Here, we show for the first time, using in vivo assays, that CHE treatment improved oxidative stress resistance by increasing survival rate and by reducing ROS levels under oxidative stress conditions independently of the stress-related signaling pathways (p38, JNK, and ERK) and transcription factors (SKN-1/Nrf and DAF-16/Foxo) tested here. CHE treatment also increased the defenses against ß-amyloid toxicity in C. elegans, in part by increasing proteasome activity and the expression of two heat shock protein genes. Our findings suggest a potential neuroprotective use for Carqueja, supporting the idea that dietary antioxidants are a promising approach to boost the defensive systems against stress and neurodegeneration.

Açaí (Euterpe oleracea Mart.) modulates oxidative stress resistance in Caenorhabditis elegans by direct and indirect mechanisms.

Açaí (Euterpe oleracea Mart.) has recently emerged as a promising source of natural antioxidants. Despite its claimed pharmacological and nutraceutical value, studies regarding the effects of açaí in vivo are limited. In this study, we use the Caenorhabditis elegans model to evaluate the in vivo antioxidant properties of açaí on an organismal level and to examine its mechanism of action. Supplementation with açaí aqueous extract (AAE) increased both oxidative and osmotic stress resistance independently of any effect on reproduction and development. AAE suppressed bacterial growth, but this antimicrobial property did not influence stress resistance. AAE-increased stress resistance was correlated with reduced ROS production, the prevention of sulfhydryl (SH) level reduction and gcs-1 activation under oxidative stress conditions. Our mechanistic studies indicated that AAE promotes oxidative stress resistance by acting through DAF-16 and the osmotic stress response pathway OSR-1/UNC-43/SEK-1. Finally, AAE increased polyglutamine protein aggregation and decreased proteasome activity. Our findings suggest that natural compounds available in AAE can improve the antioxidant status of a whole organism under certain conditions by direct and indirect mechanisms.