The Yin and Yang of toll-like receptors in endothelial dysfunction.

Endothelial cells (ECs) play a critical role in health and disease due to their widespread distribution and unique location. Although ECs are not regarded as classical immune cells, they actively participate in innate immune and inflammatory responses. EC function is affected by exogenous activators (i.e., infectious agents) and endogenous triggers (i.e., damage-associated molecular pattern molecules (DAMPs) released by stressed or injured cells). Toll-like receptors (TLRs) can recognize both infectious agents and DAMPs and play a key role in activating innate mechanisms in ECs. Endothelial dysfunction (EDF) may lead to tissue damage in various inflammatory and autoimmune diseases through TLRs. This review summarizes the current knowledge about the role of TLRs in a variety of EDF-related conditions, including autoimmunity and graft rejection, cancer, cardiovascular diseases, diabetes and related complications, ischemia and related injuries, and sepsis.

The role of microRNAs in multiple sclerosis.

Despite numerous studies on multiple sclerosis (MS) and understanding many aspects of this disease, researchers still struggle to find proper biomarkers that facilitate diagnosis; prognosis and monitoring of treatment efficacy in MS. MicroRNAs (miRNAs) are considered as endogenous, comparatively stable and small non-coding RNAs involved in various biological and pathological signaling pathways. Interestingly, miRNAs have been emerged as a potential biomarker for monitoring novel therapies in MS patients. In this review, we described the miRNAs alteration in the MS patients as well as their altered expression in patients under common MS therapies.

The role of inflammasomes in multiple sclerosis.

Multiple sclerosis (MS) is considered as an inflammatory autoimmune disease of the central nervous system (CNS), with a complex and heterogenic etiology. However, the involvement of inflammation in its pathophysiology is well documented and current therapies for MS are mainly immunosuppressive drugs. Although the available drugs reduce new lesions and relapses, their long-term outcome is not completely satisfactory. Inflammasomes are multimeric protein complexes that play a critical role in the inflammatory process. Several lines of evidence suggest an association between inflammasome activation and MS. In this paper, we have reviewed current studies that demonstrate the involvement of inflammasomes in MS development, in both animal model and MS patients. Furthermore, prior studies about the effect of inflammasome inhibitor drugs on development and progression of MS are discussed.

Angiotensin-converting enzyme 2 (ACE2) receptor and SARS-CoV-2: Potential therapeutic targeting.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta coronavirus that uses the human angiotensin-converting enzyme 2 (ACE2) receptor as a point of entry. The present review discusses the origin and structure of the virus and its mechanism of cell entry followed by the therapeutic potentials of strategies directed towards SARS-CoV2-ACE2 binding, the renin-angiotensin system, and the kinin-kallikrein system. SARS-CoV2-ACE2 binding-directed approaches mainly consist of targeting receptor binding domain, ACE2 blockers, soluble ACE2, and host protease inhibitors. In conclusion, blocking or manipulating the SARS-CoV2-ACE2 binding interface perhaps offers the best tactic against the virus that should be treated as a fundamental subject of future research.

Update on neurological manifestations of COVID-19.

Novel coronavirus (severe acute respiratory syndrome coronavirus-2: SARS-CoV-2) has a high homology with other cousin of coronaviruses such as SARS and Middle East respiratory syndrome-related coronavirus (MERS). After outbreak of the SARS-CoV-2 in China, it has spread so fast around the world. The main complication of coronavirus disease 2019 (COVID-19) is respiratory failure, but several patients have also been admitted to the hospital with neurological symptoms. Direct invasion, hematogenic rout, retrograde and anterograde transport along peripheral nerves are considered as main neuroinvasion mechanisms of SARS-CoV-2. In the present study, we describe the possible routes for entering of SARS-CoV-2 into the nervous system. Then, the neurological manifestations of the SARS-CoV-2 infection in the central nervous system (CNS) and peripheral nervous system (PNS) are reviewed. Furthermore, the neuropathology of the virus and its impacts on other neurological disorders are discussed.

Direct conversion of somatic cells towards oligodendroglial lineage cells: A novel strategy for enhancement of myelin repair.

Oligodendrocyte precursor cells (OPCs) are considered as the main cell source for myelination in the central nervous system. Following demyelination, proliferation, migration, and differentiation capability of endogenous OPCs remarkably increase leading to remyelination in damaged areas. Despite the beneficial impacts of resident OPCs for myelin repair, the capacity of endogenous repair is low and insufficient. Therefore, several strategies have been developed to improve endogenous myelin repair. Although stem cell therapy has been introduced as a promising strategy for neurodegenerative disorders, but several limitations such as cell rejection, teratoma formation, and ethical concerns have hampered the extensive application of stem cells in clinic. In recent years, direct conversion of fully differentiated somatic cells into desired cells in the lesion area has opened a new era in regenerative medicine. In addition to direct reprogramming of somatic cells to neurons, recent evidence have also demonstrated that somatic cells, including fibroblasts and astrocytes, can be directly reprogrammed to OPC-like cells by overexpression of some specific transcription factors, microRNAs, or application of small molecules. Interestingly, induced OPCs differentiated to myelinating oligodendrocytes that could effectively ensheath the host axons. In the present review article, the current advancements in direct conversion of somatic cells towards oligodendroglial cells have been discussed both in vitro and in vivo.

Direct reprogramming of terminally differentiated cells into neurons: A novel and promising strategy for Alzheimer's disease treatment.

Glial activation is a common pathological process of the central nervous system (CNS) in disorders such as Alzheimer's disease (AD). Several approaches have been used to reduce the number of activated astrocytes and microglia in damaged areas. In recent years, various kinds of fully differentiated cells have been successfully reprogrammed to a desired type of cell in lesion areas. Interestingly, internal glial cells, including astrocytes and NG2 positive cells, were efficiently converted to neuroblasts and neurons by overexpression of some transcription factors (TFs) or microRNAs (miRNAs). Notably, some specific subtypes of neurons have been achieved by in vivo reprogramming and the resulting neurons were successfully integrated into local neuronal circuits. Furthermore, somatic cells from AD patients have been converted to functional neurons. Although direct reprogramming of a patient's own internal cells has revolutionized regenerative medicine, but there are some major obstacles that should be examined before using these induced cells in clinical therapies. In the present review article, we aim to discuss the current studies on in vitro and in vivo reprogramming of somatic cells to neurons using TFs, miRNAs or small molecules in healthy and AD patients.

Curcumin-loaded nanoparticles: a novel therapeutic strategy in treatment of central nervous system disorders.

Curcumin as a hydrophobic polyphenol is extracted from the rhizome of Curcuma longa. Curcumin is widely used as a dietary spice and a topical medication for the treatment of inflammatory disorders in Asia. This compound also possesses remarkable anti-inflammatory and neuroprotective effects with the ability to pass from the blood brain barrier. Based on several pharmacological activities of curcumin, it has been introduced as an ideal candidate for different neurological disorders. Despite the pleiotropic activities of curcumin, poor solubility, rapid clearance and low stability have limited its clinical application. In recent years, nano-based drug delivery system has effectively improved the aqueous solubility and bioavailability of curcumin. In this review article, the effects of curcumin nanoparticles and their possible mechanism/s of action has been elucidated in various central nervous system (CNS)-related diseases including Parkinson's disease, Huntington disease, Alzheimer's disease, Multiple sclerosis, epilepsy and Amyotrophic Lateral Sclerosis. Furthermore, recent evidences about administration of nano-curcumin in the clinical trial phase have been described in the present review article.