Mohamad Sadikin

Biochemical studies of membrane bound Plasmodium falciparum mitochondrial L-malate:quinone oxidoreductase, a potential drug target

Plasmodium falciparum is an apicomplexan parasite that causes the most severe malaria in humans. Due to a lack of effective vaccines and emerging of drug resistance parasites, development of drugs with novel mechanisms of action and few side effects are imperative. To this end, ideal drug targets are those essential to parasite viability as well as absent in their mammalian hosts. The mitochondrial electron transport chain (ETC) of P. falciparum is one source of such potential targets because enzymes, such as L-malate:quinone oxidoreductase (PfMQO), in this pathway are absent humans. PfMQO catalyzes the oxidation of L-malate to oxaloacetate and the simultaneous reduction of ubiquinone to ubiquinol. It is a membrane protein, involved in three pathways (ETC, the tricarboxylic acid cycle and the fumarate cycle) and has been shown to be essential for parasite survival, at least, in the intra-erythrocytic asexual stage. These findings indicate that PfMQO would be a valuable drug target for development of antimalarial with novel mechanism of action. Up to this point in time, difficulty in producing active recombinant mitochondrial MQO has hampered biochemical characterization and targeted drug discovery with MQO. Here we report for the first time recombinant PfMQO overexpressed in bacterial membrane and the first biochemical study. Furthermore, about 113 compounds, consisting of ubiquinone binding site inhibitors and antiparasitic agents, were screened resulting in the discovery of ferulenol as a potent PfMQO inhibitor. Finally, ferulenol was shown to inhibit parasite growth and showed strong synergism in combination with atovaquone, a well-described anti-malarial and bc1 complex inhibitor.

The role of autosuggestion in geriatric patients' quality of life: a study on psycho-neuro-endocrine-immunology pathway.

ABSTRACT Background: There has been no study conducted about the effect of autosuggestion on quality of life for geriatric patients. Our aim was to evaluate the efficacy of autosuggestion for geriatric patients’ quality of life and its impact on psycho-neuro-endocrine-immune pathway. Methods: Sixty geriatric patients aged ≥60 years in a ward were randomly assigned to either receive autosuggestion or not. Autosuggestion was recorded in a tape to be heard daily for 30 days. Both groups received the standard medical therapy. Primary outcome was quality of life by COOP chart. Secondary outcomes were serum cortisol level, interleukin-2, interleukin-6, interferon-γ, and N-acetylaspartate/creatine ratio in limbic/paralimbic system by magnetic resonance spectroscopy. The study was single blinded due to the nature of the intervention studied. Results: Out of 60 subjects, 51 finished the study. The autosuggestion group reported better scores than the control one for quality of life, COOP chart 1.95 vs. 2.22 (95% CI, p = 0.02). There were increments of serum cortisol (p = 0.03) and interleukin-6 in the autosuggestion group (p = 0.04). Interleukin-2, interferon-γ, and N-acetylaspartate/creatine ratio in prefrontal cortex showed a tendency to increase in the autosuggestion groups. Conclusion: Autosuggestion is associated with improvement of geriatrics’ quality of life, serum cortisol level, and adaptive immunity. There is a better trend for neuroplasticity in prefrontal cortex in the autosuggestion group.