Brain Organoids: A Game-Changer for Drug Testing.

Neurological disorders are the second cause of death and the leading cause of disability worldwide. Unfortunately, no cure exists for these disorders, but the actual therapies are only able to ameliorate people's quality of life. Thus, there is an urgent need to test potential therapeutic approaches. Brain organoids are a possible valuable tool in the study of the brain, due to their ability to reproduce different brain regions and maturation stages; they can be used also as a tool for disease modelling and target identification of neurological disorders. Recently, brain organoids have been used in drug-screening processes, even if there are several limitations to overcome. This review focuses on the description of brain organoid development and drug-screening processes, discussing the advantages, challenges, and limitations of the use of organoids in modeling neurological diseases. We also highlighted the potential of testing novel therapeutic approaches. Finally, we examine the challenges and future directions to improve the drug-screening process.

S-Carboxymethyl Cysteine Protects against Oxidative Stress and Mitochondrial Impairment in a Parkinson's Disease In Vitro Model.

The mucolytic agent S-carboxymethylcysteine is widely used as an expectorant for the treatment of numerous respiratory disorders. The metabolic fate of S-carboxymethyl-L-cysteine is complex. Several clinical studies have demonstrated that the metabolism of this agent differs within the same individual, with sulfur oxygenated metabolites generated upon night-time administration. It has been indicated that this drug behaves like a free radical scavenger and that, in this regard, the sulfide is the active species with sulphoxide metabolites (already oxidized) being inactive. Consequently, a night-time consumption of the drug should be more effective upon daytime administration. Still, this diurnal variation in biotransformation (deactivation) is dependent on the genetic polymorphism on which relies the patient population capacities of S-carboxymethyl-L-cysteine sulphoxidation. It has been reported that those cohorts who are efficient sulfur oxidizers will generate inactive oxygenated metabolites. In contrast, those who have a relative deficiency in this mechanism will be subjected to the active sulfide for a more extended period. In this regard, it is noteworthy that 38-39% of Parkinson's disease patients belong to the poor sulphoxide cohort, being exposed to higher levels of active sulfide, the active antioxidant metabolite of S-carboxymethyl-L-cysteine. Parkinson's disease is a neurodegenerative disorder that affects predominately dopaminergic neurons. It has been demonstrated that oxidative stress and mitochondrial dysfunction play a crucial role in the degeneration of dopaminergic neurons. Based on this evidence, in this study, we evaluated the effects of S-carboxymethyl cysteine in an in vitro model of Parkinson's disease in protecting against oxidative stress injury. The data obtained suggested that an S-carboxymethylcysteine-enriched diet could be beneficial during aging to protect neurons from oxidative imbalance and mitochondrial dysfunction, thus preventing the progression of neurodegenerative processes.

The Great Escape: The Power of Cancer Stem Cells to Evade Programmed Cell Death.

Cancer is one of the primary causes of death worldwide. Tumour malignancy is related to tumor heterogeneity, which has been suggested to be due to a small subpopulation of tumor cells named cancer stem cells (CSCs). CSCs exert a key role in metastasis development, tumor recurrence, and also epithelial-mesenchymal transition, apoptotic resistance, self-renewal, tumorigenesis, differentiation, and drug resistance. Several current therapies fail to eradicate tumors due to the ability of CSCs to escape different programmed cell deaths. Thus, developing CSC-selective and programmed death-inducing therapeutic approaches appears to be of primary importance. In this review, we discuss the main programmed cell death occurring in cancer and the promising CSC-targeting agents developed in recent years. Even if the reported studies are encouraging, further investigations are necessary to establish a combination of agents able to eradicate CSCs or inhibit their growth and proliferation.

Olive leaf extract impairs mitochondria by pro-oxidant activity in MDA-MB-231 and OVCAR-3 cancer cells.

Breast and ovarian cancers are the leading and fifth reason for tumor death among females, respectively. Recently, many studies demonstrated antiproliferative activities of natural aliments in cancer. In this study, we investigated the antitumor potential of Olive Leaf Extract (OLE) in triple-negative breast and ovarian cancer cells. A HPLC/DAD analysis on OLE has been performed to assess the total polyphenolics and other secondary metabolites content. HCEpiC, MDA-MB-231, and OVCAR-3 cell lines were used. MTS, Cytofluorimetric, Western Blot analysis were performed to analyze cell viability, cell proliferation, apoptosis, and oxidative stress. Fluorimetric and IncuCyte® analyses were carried out to evaluate apoptosis and mitochondrial function. We confirmed that OLE, containing a quantity of oleuropein of 87 % of the total extract, shows anti-proliferative and pro-apoptotic activity on MDA-MB-231 cells. For the first time, our results indicate that OLE inhibits OVCAR-3 cell viability inducing cell cycle arrest, and it also increases apoptotic cell death up-regulating the protein level of cleaved-PARP and caspase 9. Moreover, our data show that OLE treatment causes a significant decrease in mitochondrial functionality, paralleled by a reduction of mitochondrial membrane potential. Interestingly, OLE increased the level of intracellular and mitochondrial reactive oxygen species (ROS) together with a decreased activity of ROS scavenging enzymes, confirming oxidative stress in both models. Our data demonstrate that mitochondrial ROS generation represented the primary mechanism of OLE antitumor activity, as pretreatment with antioxidant N-acetylcysteine prevented OLE-induced cell cycle arrest and apoptosis.

Potential Approaches Versus Approved or Developing Chronic Myeloid Leukemia Therapy.

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, continued use of these inhibitors has contributed to the increase in clinical resistance and the persistence of resistant leukemic stem cells (LSCs). So, there is an urgent need to introduce additional targeted and selective therapies to eradicate quiescent LSCs, and to avoid the relapse and disease progression. Here, we focused on emerging BCR-ABL targeted and non-BCR-ABL targeted drugs employed in clinical trials and on alternative CML treatments, including antioxidants, oncolytic virus, engineered exosomes, and natural products obtained from marine organisms that could pave the way for new therapeutic approaches for CML patients.

The emerging role of probiotics in neurodegenerative diseases: new hope for Parkinson's disease?

Neurodegenerative disease etiology is still unclear, but different contributing factors, such as lifestyle and genetic factors are involved. Altered components of the gut could play a key role in the gut-brain axis, which is a bidirectional system between the central nervous system and the enteric nervous system. Variations in the composition of the gut microbiota and its function between healthy people and patients have been reported for a variety of human disorders comprising metabolic, autoimmune, cancer, and, notably, neurodegenerative disorders. Diet can alter the microbiota composition, affecting the gut-brain axis function. Different nutraceutical interventions have been devoted to normalizing gut microbiome dysbiosis and to improving biological outcomes in neurological conditions, including the use of probiotics. Preclinical and clinical investigations discussed in this review strengthen the correlation between intestinal microbiota and brain and the concept that modifying the microbiome composition may improve brain neurochemistry, modulating different pathways. This review will discuss the potential use of probiotics for Parkinson's disease prevention or treatment or as adjuvant therapy, confirming that gut microbiota modulation influences different pro-survival pathways. Future investigations in Parkinson's disease should consider the role of the gut-brain axis and additional comprehension of the underlying mechanisms is extremely necessary.