Pharmacokinetics and Pharmacodynamics of a Nanostructured Lipid Carrier Co-Encapsulating Artemether and miRNA for Mitigating Cerebral Malaria.

Cerebral malaria (CM), a severe neurological pathology caused by Plasmodium falciparum infection, poses a significant global health threat and has a high mortality rate. Conventional therapeutics cannot cross the blood-brain barrier (BBB) efficiently. Therefore, finding effective treatments remains challenging. The novelty of the treatment proposed in this study lies in the feasibility of intranasal (IN) delivery of the nanostructured lipid carrier system (NLC) combining microRNA (miRNA) and artemether (ARM) to enhance bioavailability and brain targeting. The rational use of NLCs and RNA-targeted therapeutics could revolutionize the treatment strategies for CM management. This study can potentially address the challenges in treating CM, allowing drugs to pass through the BBB. The NLC formulation was developed by a hot-melt homogenization process utilizing 3% (w/w) precirol and 1.5% (w/v) labrasol, resulting in particles with a size of 94.39 nm. This indicates an effective delivery to the brain via IN administration. The results further suggest the effective intracellular delivery of encapsulated miRNAs in the NLCs. Investigations with an experimental cerebral malaria mouse model showed a reduction in parasitaemia, preservation of BBB integrity, and reduced cerebral haemorrhages with the ARM+ miRNA-NLC treatment. Additionally, molecular discoveries revealed that nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) and Interleukin-6 (IL-6) levels were reduced in the treated groups in comparison to the CM group. These results support the use of nanocarriers for IN administration, offering a viable method for mitigating CM through the increased bioavailability of therapeutics. Our findings have far-reaching implications for future research and personalized therapy.

Trimethylamine-N-oxide and cerebral stroke risk: A review.

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced by the action of gut microbiota and the hepatic enzyme Flavin Mono­oxygenase 3 (FMO3). TMAO level has a positive correlation with the risk of cardiovascular events, including stroke, and their level is influenced mainly by dietary choice and the action of liver enzyme FMO3. TMAO plays a role in the development of atherosclerosis plaque, which is one of the causative factors of the stroke event. Preclinical and clinical investigations on the TMAO and associated stroke risk, severity, and outcomes are summarised in this review. In addition, mechanisms of TMAO-driven vascular dysfunction are also discussed, such as inflammation, oxidative stress, thrombus and foam cell formation, altered cholesterol and bile acid metabolism, etc. Post-stroke inflammatory cascades involving activation of immune cells, i.e., microglia and astrocytes, result in Blood-brain-barrier (BBB) disruption, allowing TMAO to infiltrate the brain and further aggravate inflammation. This event occurs as a result of the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway through the release of inflammatory cytokines and chemokines that further aggravate the BBB and initiate further recruitment of immune cells in the brain. Thus, it's likely that maintaining TMAO levels and associated gut microbiota could be a promising approach for treating and improving stroke complications.

Polyphenols, Autophagy and Neurodegenerative Diseases: A Review.

Polyphenols are secondary metabolites from plant origin and are shown to possess a wide range of therapeutic benefits. They are also reported as regulators of autophagy, inflammation and neurodegeneration. The autophagy pathway is vital in degrading outdated organelles, proteins and other cellular wastes. The dysregulation of autophagy causes proteinopathies, mitochondrial dysfunction and neuroinflammation thereby contributing to neurodegeneration. Evidence reveals that polyphenols improve autophagy by clearing misfolded proteins in the neurons, suppress neuroinflammation and oxidative stress and also protect from neurodegeneration. This review is an attempt to summarize the mechanism of action of polyphenols in modulating autophagy and their involvement in pathways such as mTOR, AMPK, SIRT-1 and ERK. It is evident that polyphenols cause an increase in the levels of autophagic proteins such as beclin-1, microtubule-associated protein light chain (LC3 I and II), sirtuin 1 (SIRT1), etc. Although it is apparent that polyphenols regulate autophagy, the exact interaction of polyphenols with autophagy markers is not known. These data require further research and will be beneficial in supporting polyphenol supplementation as a potential alternative treatment for regulating autophagy in neurodegenerative diseases.