Antimicrobial properties of the medicinal plant Cardiospermum halicacabum L: new evidence and future perspectives.

The emergence and rapid spread of multidrug-resistance in human pathogenic microorganisms urgently require the development of novel therapeutic strategies for the treatment of infectious diseases. From this perspective, the antimicrobial properties of the natural plant-derived products may represent an important alternative therapeutic option to synthetic drugs. Among medicinal plants, the Cardiospermum halicacabum L. (C. halicacabum), belonging to Sapindaceae family, could be a very promising candidate for its antimicrobial activity against a wide range of microorganisms, including both Gram-positive and Gram-negative bacteria, as well as fungal pathogens. Although the antimicrobial properties of C. halicacabum have been intensively studied, the mechanism/s by which it exerts the inhibitory activity towards the pathogenic microbes have not yet been completely understood. This review focuses on the main antimicrobial activities displayed in vitro by the plant extract, with particular attention on our recent advances. We demonstrated that C. halicacabum is able to exert in vitro a dose-dependent fungistatic effect against Trychophyton rubrum (T. rubrum) through molecular interaction with the fungal heat shock protein (Hsp)-90 chaperone. These findings are supported by a growing body of research indicating the crucial role played by the Hsp90 in the virulence of the pathogenic microorganisms, including fungal pathogens. The possible future use of C. halicacabum for treating a wide range of infectious diseases is also discussed.

Structural insights into the multi-determinant aggregation of TDP-43 in motor neuron-like cells.

TDP-43 is aggregated in patients with ALS and FLTD through mechanisms still incompletely understood. Since aggregation in the cytosol is most probably responsible for the delocalization and loss of proper RNA-binding function of TDP-43 in the nucleus, interception of the formation of aggregates may represent a useful therapeutic option. In this study, we investigated the relative importance of the N-terminal and C-terminal moieties of TDP-43 in the aggregation process and the weight of each of the six cysteine residues in determining unfolding and aggregation of the different domains. We report that cytoplasmic inclusions formed by WT and mutant TDP-43 in motor neuron-like NSC34 cells are redox-sensitive only in part, and contain at least two components, i.e. oligomers and large aggregates, that are made of different molecular species. The two N-terminal cysteine residues contribute to the seeding for the first step in oligomerization, which is then accomplished by mechanisms depending on the four cysteines in the RNA-recognition motifs. Cysteine-independent large aggregates contain unfolded isoforms of the protein, held together by unspecific hydrophobic interactions. Interestingly, truncated isoforms are entrapped exclusively in oligomers. Ab initio modeling of TDP-43 structure, molecular dynamics and molecular docking analysis indicate a differential accessibility of cysteine residues that contributes to aggregation propensity. We propose a model of TDP-43 aggregation involving cysteine-dependent and cysteine-independent stages that may constitute a starting point to devise strategies counteracting the formation of inclusions in TDP-43 proteinopathies.

A model for the relationship between the arterial pressure and the heart period.

This paper provides a simple model for predicting the relationship between steady-state heart rate and arterial blood pressure. Two current state-of-the-art models of the cardiovascular system as a pump operating in its circuit are reformulated and combined in order to highlight the role of the duration of the heart cycle. The proposed model establishes that the cardiac cycle lengthens linearly with the inverse of the average blood pressure. Experimental data are reported for sixteen preoperated conscious dogs resting quietly on their sides. Vagal and sympathetic blocks have been produced in four dogs in order to obtain a wide range of sympathetic and parasympathetic tones, namely, to cover the entire range of physiological values of the heart rate. For these dogs a comparison between the experimental values and the theoretical predictions shows a good agreement, the results of the linear regression model being statistically significant at the p = 0.001 level for three dogs and at the p = 0.01 level for the fourth dog.