Contribution of Extracellular Vesicles and Molecular Chaperones in Age-Related Neurodegenerative Disorders of the CNS.

Many neurodegenerative disorders are characterized by the abnormal aggregation of misfolded proteins that form amyloid deposits which possess prion-like behavior such as self-replication, intercellular transmission, and consequent induction of native forms of the same protein in surrounding cells. The distribution of the accumulated proteins and their correlated toxicity seem to be involved in the progression of nervous system degeneration. Molecular chaperones are known to maintain proteostasis, contribute to protein refolding to protect their function, and eliminate fatally misfolded proteins, prohibiting harmful effects. However, chaperone network efficiency declines during aging, prompting the onset and the development of neurological disorders. Extracellular vesicles (EVs) are tiny membranous structures produced by a wide range of cells under physiological and pathological conditions, suggesting their significant role in fundamental processes particularly in cellular communication. They modulate the behavior of nearby and distant cells through their biological cargo. In the pathological context, EVs transport disease-causing entities, including prions, α-syn, and tau, helping to spread damage to non-affected areas and accelerating the progression of neurodegeneration. However, EVs are considered effective for delivering therapeutic factors to the nervous system, since they are capable of crossing the blood-brain barrier (BBB) and are involved in the transportation of a variety of cellular entities. Here, we review the neurodegeneration process caused mainly by the inefficiency of chaperone systems as well as EV performance in neuropathies, their potential as diagnostic biomarkers and a promising EV-based therapeutic approach.

Structural and Dynamic Disturbances Revealed by Molecular Dynamics Simulations Predict the Impact on Function of CCT5 Chaperonin Mutations Associated with Rare Severe Distal Neuropathies.

Mutations in genes encoding molecular chaperones, for instance the genes encoding the subunits of the chaperonin CCT (chaperonin containing TCP-1, also known as TRiC), are associated with rare neurodegenerative disorders. Using a classical molecular dynamics approach, we investigated the occurrence of conformational changes and differences in physicochemical properties of the CCT5 mutations His147Arg and Leu224Val associated with a sensory and a motor distal neuropathy, respectively. The apical domain of both variants was substantially but differently affected by the mutations, although these were in other domains. The distribution of hydrogen bonds and electrostatic potentials on the surface of the mutant subunits differed from the wild-type molecule. Structural and dynamic analyses, together with our previous experimental data, suggest that genetic mutations may cause different changes in the protein-binding capacity of CCT5 variants, presumably within both hetero- and/or homo-oligomeric complexes. Further investigations are necessary to elucidate the molecular pathogenic pathways of the two variants that produce the two distinct phenotypes. The data and clinical observations by us and others indicate that CCT chaperonopathies are more frequent than currently believed and should be investigated in patients with neuropathies.

Calorie restriction promotes remyelination in a Cuprizone-Induced demyelination mouse model of multiple sclerosis.

Over the past few decades several attempts have been made to introduce a potential and promising therapy for Multiple sclerosis (MS). Calorie restriction (CR) is a dietary manipulation to reduce calorie intake which has been shown to improve neuroprotection and attenuate neurodegenerative disorders. Here, we evaluated the effect of 33% CR regimen for 4 weeks on the remyelination capacity of Cuprizone (CPZ) induced demyelination in a mouse model of MS. Results showed that CR induced a significant increase in motor coordination and balance performance in CPZ mice. Also, luxol fast blue (LFB) staining showed that CR regimen significantly improved the remyelination in the corpus callosum of CPZ + CR mice compared to the CPZ group. In addition, CR regimen significantly increased the transcript expression levels of BDNF, Sox2, and Sirt1 in the corpus callosum of CPZ mice, while decreasing the p53 levels. Moreover, CR regimen significantly decreased the apoptosis rate. Furthermore, astrogliosis (GFAP + astrocytes) and microgliosis (Iba-1 + microglia) were significantly decreased by CR regimen while oligodendrogenesis (Olig2+) and Sirt1 + cell expression were significantly increased in the corpus callosum of CPZ + CR mice compared to the CPZ group. In conclusion, CR regimen can promote remyelination potential in a CPZ-demyelinating mouse model of MS by increasing oligodendrocyte generation while decreasing their apoptosis.

Extracellular Vesicles-Based Drug Delivery Systems: A New Challenge and the Exemplum of Malignant Pleural Mesothelioma.

Research for the most selective drug delivery to tumors represents a fascinating key target in science. Alongside the artificial delivery systems identified in the last decades (e.g., liposomes), a family of natural extracellular vesicles (EVs) has gained increasing focus for their potential use in delivering anticancer compounds. EVs are released by all cell types to mediate cell-to-cell communication both at the paracrine and the systemic levels, suggesting a role for them as an ideal nano-delivery system. Malignant pleural mesothelioma (MPM) stands out among currently untreatable tumors, also due to the difficulties in achieving an early diagnosis. Thus, early diagnosis and treatment of MPM are both unmet clinical needs. This review looks at indirect and direct evidence that EVs may represent both a new tool for allowing an early diagnosis of MPM and a potential new delivery system for more efficient therapeutic strategies. Since MPM is a relatively rare malignant tumor and preclinical MPM models developed to date are very few and not reliable, this review will report data obtained in other tumor types, suggesting the potential use of EVs in mesothelioma patients as well.

Putative Roles and Therapeutic Potential of the Chaperone System in Amyotrophic Lateral Sclerosis and Multiple Sclerosis.

The putative pathogenic roles and therapeutic potential of the chaperone system (CS) in amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are reviewed to provide a bibliographic and conceptual platform for launching research on the diagnostic and therapeutic applications of CS components. Various studies suggest that dysfunction of the CS contributes to the pathogenesis of ALS and MS, and here, we identify some of the implicated CS members. The physiology and pathophysiology of the CS members can be properly understood if they are studied or experimentally or clinically manipulated for diagnostic or therapeutic purposes, bearing in mind that they belong to a physiological system with multiple interacting and dynamic components, widespread throughout the body, intra- and extracellularly. Molecular chaperones, some called heat shock protein (Hsp), are the chief components of the CS, whose canonical functions are cytoprotective. However, abnormal chaperones can be etiopathogenic factors in a wide range of disorders, chaperonopathies, including ALS and MS, according to the data reviewed. Chaperones typically form teams, and these build functional networks to maintain protein homeostasis, the canonical role of the CS. However, members of the CS also display non-canonical functions unrelated to protein homeostasis. Therefore, chaperones and other members of the CS, if abnormal, may disturb not only protein synthesis, maturation, and migration but also other physiological processes. Thus, in elucidating the role of CS components in ALS and MS, one must look at protein homeostasis abnormalities and beyond, following the clues emerging from the works discussed here.

Effects of illicit drugs on structural and functional impairment of testis, endocrinal disorders, and molecular alterations of the semen.

Illicit drug use is growing among young people, which is one of the major problems in today's society that can be associated with many medical issues, including infertility. Amphetamines, cocaine, opioids, and marijuana are the most common and the most used illicit drugs worldwide. The purpose of this review was to collect as much literature as possible about the impact of illicit drugs on male fertility and summarize their valuable data. Original studies and reviews were collected by searching the keywords "illicit drugs (all kinds of that) and male infertility". The obtained information was also categorized based on the content of the "Infertility in the Male" book. Almost all studies suggested that taking all kinds of illicit drugs with the effects on different parts of the male reproductive system can result in subfertility or complete infertility in the consumers. Although the data in this field are not decisive and there are some confounding factors in human studies, it can be inferred that the use of any illicit drug with an effect on male sexual health reduces fertility potency. Therefore, it is recommended that couples, who are planning to conceive, avoid taking any illicit drugs before and during treatment.

Intrathecal administration of the extracellular vesicles derived from human Wharton's jelly stem cells inhibit inflammation and attenuate the activity of inflammasome complexes after spinal cord injury in rats.

Activation of inflammasome complexes during spinal cord injury (SCI) lead to conversion of pro-inflammatory cytokines, interleukin-1beta (IL-1ß) and interleukin-18 (IL-18) to their active form to initiates the neuroinflammation. Mesenchymal stem cells (MSCs) showed anti-inflammatory properties through their extracellular vehicles (EVs). We investigated immunomodulatory potential of human Wharton's jelly mesenchymal stem cells derived extracellular vesicles (hWJ-MSC-EVs) on inflammasome activity one week after SCI in rats. The gene expression and protein level of IL-1ß, IL-18, tumor necrosis factor alpha (TNF-α) and caspase1, were assessed by QPCR and western blotting. Immunohistochemistry (IHC) was done to measure the glial fibrillary acidic protein (GFAP) and Nestin expression. Cell death, histological evaluation and hind limb locomotion was studied by TUNEL assay, Nissl staining and Basso, Beattie, Bresnaham (BBB), respectively. Our finding represented that intrathecally administrated of hWJ-MSC-EVs significantly attenuated expression of the examined factors in both mRNA (P < 0.05 and P ≤ 0.01) and protein levels (P < 0.05 and P ≤ 0.01), decreased GFAP and increased Nestin expression (P < 0.05), reduced cell death and revealed the higher number of typical neurons in ventral horn of spinal cord. Consequently, progress in locomotion. We came to the conclusion that hWJ-MSC-EVs has the potential to control the inflammasome activity after SCI in rats. Moreover, EVs stimulated the neural progenitor cells and modulate the astrocyte activity.

Biomedical features of flaxseed against different pathologic situations: A narrative review.

Flaxseed is a plant that grows and is cultivated in more than 50 countries; the main flax producer countries are Canada, China, the United States, and India. The purpose of the present study was to overview the source, chemical compounds, and mechanisms of the therapeutic effects of this valuable plant. For writing this manuscript, we made a list of relevant keywords and phrases, and then we started searching for studies in PubMed, Scopus, and Web of Science databases. The main constituents of flaxseed include lipids, proteins, lignans, fibers, and minerals. Flaxseed is full of antioxidants such as tocopherols, betacarotene, cysteine, and methionine which result in a decrease in blood pressure, heart disease, hepatic and neurological disorders, and increased insulin sensitivity. Flaxseed is commonly used for its antidiabetic and anticancer activities and also it is beneficial for cardiovascular, gastrointestinal, hepatic, urological, and reproductive disorders, and because of these beneficial effects, it is recognized as a medical plant.