Effects of statins on the biological features of mesenchymal stem cells and therapeutic implications.

Statins are well-known lipid-lowering drugs. The pleiotropic effects of statins have brought about some beneficial effects on improving the therapeutic outcomes of cell therapy and tissue engineering approaches. In this review, the impact of statins on mesenchymal stem cell behaviors including differentiation, apoptosis, proliferation, migration, and angiogenesis, as well as molecular pathways which are responsible for such phenomena, are discussed. A better understanding of pathways and mechanisms of statin-mediated effects on mesenchymal stem cells will pave the way for the expansion of statin applications. Furthermore, since designing a suitable carrier for statins is required to maintain a sufficient dose of active statins at the desired site of the body, different systems for local delivery of statins are also reviewed.

Prospects for the potential of RNA interference in the treatment of autoimmune diseases: Small interfering RNAs in the spotlight.

The identification of RNA interference (RNAi) has caused a growing interest in harnessing its potential in the treatment of different diseases. Modulation of dysregulated genes through targeting by RNAi represents a potential approach with which to alter the biological pathways at a post-transcriptional level, especially as it pertains to autoimmunity and malignancy. Short hairpin RNAs (shRNA), short interfering RNAs (siRNA), and microRNAs (miRNA) are mainly involved as effector mechanisms in the targeting of RNAi biological pathways. The manipulation and delivery of these molecules in an efficient way promotes the specificity and stability of RNAi-based systems, while minimizing the unwanted adverse reactions by the immune system and reducing cytotoxicity and off-target effects. Advances made to date in identifying the etiopathogenesis of autoimmune diseases has prompted the utilization of RNAi-based systems in vitro and in vivo. Future investigations aimed at deciphering the molecular basis of RNAi and optimizing the delivery of RNAi-based targeting systems will hopefully promote the applicability of such regulatory mechanisms and, ultimately, transfer the acquired knowledge from bench-to-bedside to ameliorate human diseases. In this review, we seek to clarify the potential of RNAi, with a focus on siRNAs, in designing therapeutics for potential treatment of human autoimmune disorders.

The pivotal role of CD69 in autoimmunity.

Autoimmune disorders are outcomes of impaired activity of the immune system regarding the maintenance of tolerance, which results in tissue damage secondary to an excess in the inflammatory response. Under normal conditions, the cells in the adaptive immune system are highly controlled to remain unresponsive against self-antigens (self-Ags) through various mechanisms and during different stages of maturation. CD69 (cluster of differentiation 69), a C-type lectin disulfide-linked homodimer, is expressed on different leukocytes, including newly-activated lymphocytes, certain subtypes of memory T-cells, infiltrating lymphocytes isolated from patients with chronic inflammatory disorders, and regulatory T-cells (Tregs). Cumulative evidence from in vitro and in vivo studies has revealed an immunoregulatory role for CD69. This marker has been reported to play a controversial role in chronic human inflammatory disorders. Many investigations have linked the absence of CD69 with a predisposition to inflammatory and/or autoimmune conditions, which indicates an immunoregulatory function for CD69 by mechanisms such as controlling the balance between differentiation of Th/Treg cells and enhancing the suppressive activity of Tregs. However, some reports from human studies have indicated that CD69 may exert a stimulatory effect on the inflammatory response. In this review, we first present a brief summary of the concept of 'immune tolerance' and, subsequently, review previous studies to uncover the details that underlie the immunoregulatory effects of CD69.

Anti-fibrotic effects of curcumin and some of its analogues in the heart.

Cardiac fibrosis stems from the changes in the expression of fibrotic genes in cardiac fibroblasts (CFs) in response to the tissue damage induced by various cardiovascular diseases (CVDs) leading to their transformation into active myofibroblasts, which produce high amounts of extracellular matrix (ECM) proteins leading, in turn, to excessive deposition of ECM in cardiac tissue. The excessive accumulation of ECM elements causes heart stiffness, tissue scarring, electrical conduction disruption and finally cardiac dysfunction and heart failure. Curcumin (Cur; also known as diferuloylmethane) is a polyphenol compound extracted from rhizomes of Curcuma longa with an influence on an extensive spectrum of biological phenomena including cell proliferation, differentiation, inflammation, pathogenesis, chemoprevention, apoptosis, angiogenesis and cardiac pathological changes. Cumulative evidence has suggested a beneficial role for Cur in improving disrupted cardiac function developed by cardiac fibrosis by establishing a balance between degradation and synthesis of ECM components. There are various molecular mechanisms contributing to the development of cardiac fibrosis. We presented a review of Cur effects on cardiac fibrosis and the discovered underlying mechanisms by them Cur interact to establish its cardio-protective effects.

The Effect of Curcumin on the Differentiation of Mesenchymal Stem Cells into Mesodermal Lineage.

Curcumin has been placed at the forefront of the researcher's attention due to its pleiotropic pharmacological effects and health benefits. A considerable volume of articles has pointed out curcumin's effects on the fate of stem cell differentiation. In this review, a descriptive mechanism of how curcumin affects the outcome of the differentiation of mesenchymal stem cells (MSCs) into the mesodermal lineage-i.e., adipocyte, osteocyte, and chondrocyte differentiation-is compiled from the literature. The sections include the mechanism of inhibition or induction of MSCs differentiation to each lineage, their governing molecular mechanisms, and their signal transduction pathways. The effect of different curcumin doses and its structural modifications on the MSCs differentiation is also discussed.

The regenerative potential of glial progenitor cells and reactive astrocytes in CNS injuries.

Cell therapeutic approaches focusing on the regeneration of damaged tissue have been a popular topic among researchers in recent years. In particular, self-repair scarring from the central nervous system (CNS) can significantly complicate the treatment of an injured patient. In CNS regeneration schemes, either glial progenitor cells or reactive glial cells have key roles to play. In this review, the contribution and underlying mechanisms of these progenitor/reactive glial cells during CNS regeneration are discussed, as well as their role in CNS-related diseases.

The Bumpy Road to Stem Cell Therapies: Rational Design of Surface Topographies to Dictate Stem Cell Mechanotransduction and Fate.

Cells sense and respond to a variety of physical cues from their surrounding microenvironment, and these are interpreted through mechanotransductive processes to inform their behavior. These mechanisms have particular relevance to stem cells, where control of stem cell proliferation, potency, and differentiation is key to their successful application in regenerative medicine. It is increasingly recognized that surface micro- and nanotopographies influence stem cell behavior and may represent a powerful tool with which to direct the morphology and fate of stem cells. Current progress toward this goal has been driven by combined advances in fabrication technologies and cell biology. Here, the capacity to generate precisely defined micro- and nanoscale topographies has facilitated the studies that provide knowledge of the mechanotransducive processes that govern the cellular response as well as knowledge of the specific features that can drive cells toward a defined differentiation outcome. However, the path forward is not fully defined, and the "bumpy road" that lays ahead must be crossed before the full potential of these approaches can be fully exploited. This review focuses on the challenges and opportunities in applying micro- and nanotopographies to dictate stem cell fate for regenerative medicine. Here, key techniques used to produce topographic features are reviewed, such as photolithography, block copolymer lithography, electron beam lithography, nanoimprint lithography, soft lithography, scanning probe lithography, colloidal lithography, electrospinning, and surface roughening, alongside their advantages and disadvantages. The biological impacts of surface topographies are then discussed, including the current understanding of the mechanotransductive mechanisms by which these cues are interpreted by the cells, as well as the specific effects of surface topographies on cell differentiation and fate. Finally, considerations in translating these technologies and their future prospects are evaluated.

Implications for the role of lipopolysaccharide in the development of atherosclerosis.

Mounting scientific evidence over decades has established that atherosclerosis is a chronic inflammatory disorder. Among the potentially critical sources of vascular inflammation during atherosclerosis are the components of pathogenic bacteria, especially lipopolysaccharide (LPS). Toll-like receptor (TLR)-4, expressed on different inflammatory cells involved with the recognition of bacterial LPS, has been recognized to have mutations that are prevalent in a number of ethnic groups. Such mutations have been associated with a decreased risk of atherosclerosis. In addition, epidemiological investigations have proposed that LPS confers a risk factor for the development of atherosclerosis. Gram-negative bacteria are the major source of LPS in an individual's serum, which may be generated during subclinical infections. The major cell receptors on inflammatory cells involved in the pathogenesis of atherosclerosis, like macrophages, monocytes, and dendritic cells (DCs), are CD14, MD-2, and LPS binding protein (LBP). These receptors have been blamed for the development of atherosclerosis through dysregulated activation following LPS recognition. Lipoproteins may also play a role in modulating the LPS-induced inflammatory events during atherosclerosis development. In this review article, we attempt to clarify the role of LPS in the initiation and progression of atherosclerotic lesion development.

Biomaterials and stem cells as drug/gene-delivery vehicles for Parkinson's treatment: an update.

By introducing biomaterials and stem cells into Parkinson's disease (PD), therapeutic approaches have led to promising results due to facilitating brain targeting and blood-brain barrier permeation of the drugs and genes. Here, after reviewing the most recent drug- and gene-delivery vehicles including liposomes, exosomes, natural/synthetic polymeric particles/fibers, metallic/ceramic nanoparticles and microbubbles, used for Parkinson's disease treatment, the effect of stem cells as a reservoir of neurotrophic factors and exosomes is provided.

Mesenchymal Stem Cell-Derived Exosomes for COVID-19 Therapy, Preclinical and Clinical Evidence.

Since the emergence of the novel coronavirus, named COVID-19, researchers are looking for a treatment to stop the devastating pandemic. During these efforts, mesenchymal stem cells (MSCs), the potential next generation of therapeutic methods with wide application for diseases, have successfully controlled cytokine storm following the virus infection. However, the use of MSCs has been limited due to the ethical issues, immunogenicity, and genetic modifications. Therefore, exosomes were introduced as a suitable substitute for the MSCs. In the case of COVID-19 treatment, both MSCs and exosomes exert their beneficial effect mainly through the management of the cytokine storm. This study provided the underlying mechanisms for the effect of exosomes on COVID-19 treatment and presented several preclinical and clinical studies of exosomes for COVID-19 treatment.

Effects of Statins on Renin-Angiotensin System.

Statins, a class of drugs for lowering serum LDL-cholesterol, have attracted attention because of their wide range of pleiotropic effects. An important but often neglected effect of statins is their role in the renin-angiotensin system (RAS) pathway. This pathway plays an integral role in the progression of several diseases including hypertension, heart failure, and renal disease. In this paper, the role of statins in the blockade of different components of this pathway and the underlying mechanisms are reviewed and new therapeutic possibilities of statins are suggested.

Implications on the Therapeutic Potential of Statins via Modulation of Autophagy.

Statins, which are functionally known as 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) inhibitors, are lipid-lowering compounds widely prescribed in patients with cardiovascular diseases (CVD). Several biological and therapeutic functions have been attributed to statins, including neuroprotection, antioxidation, anti-inflammation, and anticancer effects. Pharmacological characteristics of statins have been attributed to their involvement in the modulation of several cellular signaling pathways. Over the past few years, the therapeutic role of statins has partially been attributed to the induction of autophagy, which is critical in maintaining cellular homeostasis and accounts for the removal of unfavorable cells or specific organelles within cells. Dysregulated mechanisms of the autophagy pathway have been attributed to the etiopathogenesis of various disorders, including neurodegenerative disorders, malignancies, infections, and even aging. Autophagy functions as a double-edged sword during tumor metastasis. On the one hand, it plays a role in inhibiting metastasis through restricting necrosis of tumor cells, suppressing the infiltration of the inflammatory cell to the tumor niche, and generating the release of mediators that induce potent immune responses against tumor cells. On the other hand, autophagy has also been associated with promoting tumor metastasis. Several anticancer medications which are aimed at inducing autophagy in the tumor cells are related to statins. This review article discusses the implications of statins in the induction of autophagy and, hence, the treatment of various disorders.

Statins Attenuate Fibrotic Manifestations of Cardiac Tissue Damage.

Cardiac fibrosis is a maladaptive condition secondary to cardiomyopathy caused by a wide spectrum of stimuli, including myocardial infarction (MI), pressure overload, hyperglycemia, aging, and other factors. Despite having been supposed to be a reparative mechanism, the development of cardiac fibrosis can result in undesirable outcomes like the disruption of excitation-contraction coupling and ventricular hypertrophy, leading finally to heart failure (HF). Statins are known as potent cardioprotective agents widely used to control dyslipidemia; these drugs have exhibited protective effects against manifestations of cardiac fibrosis and hypertrophy. Cumulative evidence has suggested that statins attenuate the severity of fibrotic and hypertrophic manifestations of cardiac damage by affecting a variety of mechanisms like differentiation of myofibroblasts and crosstalk between cells in cardiac tissue as well as altering the expression and function of different molecules involved in cardiac remodeling, including inflammatory cytokines and signaling molecules. It seems that statins can inhibit cardiac fibrosis and hypertrophy not only through their ability to inhibit hydroxymethylglutaryl-CoA reductase but also by their pleiotropic properties. This review aims to discuss the effects of statins on molecular pathways involved in the inhibition of fibrotic and hypertrophic remodeling in the heart, thereby potentially helping to recover proper cardiac size, plasticity, and functioning.

A comprehensive review on the lipid and pleiotropic effects of pitavastatin.

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, are administered as first line therapy for hypercholesterolemia, both in primary and secondary prevention. There is a growing body of evidence showing that beyond their lipid-lowering effect, statins have a number of additional beneficial properties. Pitavastatin is a unique lipophilic statin with a strong effect on lowering plasma total cholesterol and triacylglycerol. It has been reported to have pleiotropic effects such as decreasing inflammation and oxidative stress, regulating angiogenesis and osteogenesis, improving endothelial function and arterial stiffness, and reducing tumor progression. Based on the available studies considering the risk of statin-associated muscle symptoms it seems to be also the safest statin. The unique lipid and non-lipid effects of pitavastatin make this molecule a particularly interesting option for the management of different human diseases. In this review, we first summarized the lipid effects of pitavastatin and then strive to unravel the diverse pleiotropic effects of this molecule.

The potential of mitochondrial modulation by neuroglobin in treatment of neurological disorders.

Neuroglobin is the third member of the globin family to be identified in 2000 in neurons of both human and mouse nervous systems. Neuroglobin is an oxygen-binding globin found in neurons within the central nervous system as well as in peripheral neurons, that produces a protective effect against hypoxic/ischemic damage induced by promoting oxygen availability within the mitochondria. Numerous investigations have demonstrated that impaired neuroglobin functioning is implicated in the pathogenesis of multiple neurodegenerative disorders. Several in vitro and animal studies have reported the potential of neuroglobin upregulation in improving the neuroprotection through modulation of mitochondrial functions, such as ATP production, clearing reactive oxygen species (ROS), promoting the dynamics of mitochondria, and controlling apoptosis. Neuroglobin acts as a stress-inducible globin, which has been associated hypoxic/ischemic insults where it acts to protect the heart and brain, providing a wide range of applicability in the treatment of human disorders. This review article discusses normal physiological functions of neuroglobin in mitochondria-associated pathways, as well as outlining how dysregulation of neuroglobin is associated with the pathogenesis of neurodegenerative disorders.

The Role of MicroRNAs in Regulating Cytokines and Growth Factors in Coronary Artery Disease: The Ins and Outs.

Coronary artery diseases (CAD), as a leading cause of mortality around the world, has attracted the researchers' attention for years to find out its underlying mechanisms and causes. Among the various key players in the pathogenesis of CAD cytokines, microRNAs (miRNAs) are crucial. In this study, besides providing a comprehensive overview of the involvement of cytokines, growth factors, and miRNAs in CAD, the interplay between miRNA with cytokine or growth factors during the development of CAD is discussed.

Targeted and Controlled Drug Delivery to a Rat Model of Heart Failure Through a Magnetic Nanocomposite.

As a novel cardiac myosin activator, Omecamtive Mecarbil (OM) has shown promising results in the management of systolic heart failure in clinical examinations. However, the need for repeated administration along with dose-dependent side effects made its use elusive as a standard treatment for heart failure (HF). We hypothesized that improved cardiac function in systolic HF models would be achieved in lower doses by targeted delivery of OM to the heart. To test this hypothesis, a nanocomposite system was developed by composing chitosan and a magnetic core (Fe3O4), loaded with OM, and directed toward the rats' heart via a 0.3 T magnet. HF-induced rats were injected with saline, OM, and OM-loaded nanocomposite (n = 8 in each group) and compared with a group of healthy animals (saline injected, n = 8). Knowing the ejection fraction (EF) of healthy (93.68 ± 1.37%) and HF (71.7 ± 1.41%) rats, injection of nanocomposites was associated with improved EF (EF = 89.6 ± 1.40%). Due to increased heart targeting of nanocomposite (2.5 folds), improved cardiac function was seen with only 4% of the OM dose required for infusion, while injecting the same dose of OM without targeting was unable to stop HF progression (EF = 55.33 ± 3.16%) during 7 days. In conclusion, heart nanocomposites targeting improves the EF by up to 18% by only using 4% of the doses traditionally used in treating the HF.

Antiviral effects of statins.

Introducing statins as possible widely-available drugs for the treatment of viral infections requires an in depth review of their antiviral properties. Despite some inconsistency, a large body of literature data from experimental and clinical studies suggest that statins may have a role in the treatment of viral infections due to their immunomodulatory properties as well as their ability to inhibit viral replication. In the present review, the role that statins may play while interacting with the immune system during viral infections and the possible inhibitory effects of statins on different stages of virus cell cycle (i.e., from fusion with host cell membranes to extracellular release) and subsequent virus transmission are described. Specifically, cholesterol-dependent and cholesterol-independent mechanisms of the antiviral effects of statins are reported.

A new approach to the diagnosis and treatment of atherosclerosis: the era of the liposome.

The consequences of atherosclerotic cardiovascular disease (ASCVD) include myocardial infarction, ischemic stroke, and angina pectoris, which are major causes of mortality and morbidity worldwide. Despite current therapeutic strategies to reduce risk, patients still experience the consequences of ASCVD. Consequently, a current goal is to enhance visualization of early atherosclerotic lesions to improve residual ASCVD risk. The uses of liposomes, in the context of ASCVD, can include as contrast agents for imaging techniques, as well as for the delivery of antiatherosclerotic drugs, genes, and cells to established sites of plaque. Additionally, liposomes have a role as vaccine adjuvants against mediators of atherosclerosis. Here. we review the scientific and clinical evidence relating to the use of liposomes in the diagnosis and management of ASCVD.