The mitochondrial calcium signaling, regulation, and cellular functions: A novel target for therapeutic medicine in neurological disorders.

Mitochondrial calcium (Ca2+ ) dynamics play critical roles in regulating vital physiological conditions in the brain. Importantly, Mitochondria-associated endoplasmic reticulum (ER) membranes serve different cellular functions including Ca2+ signaling, bioenergetics, phospholipid biosynthesis, cholesterol esterification, programmed cell death, and communication between the two organelles. Several Ca2+ -transport systems specialize at the mitochondria, ER, and their contact sites that provide tight control of mitochondrial Ca2+ signaling at the molecular level. The biological function of Ca2+ channels and transporters as well as the role of mitochondrial Ca2+ signaling in cellular homeostasis can open new perspectives for investigation and molecular intervention. Emerging evidence suggests that abnormalities in ER/mitochondrial brain functions and dysregulation of Ca2+ homeostasis are neuropathological hallmarks of neurological disorders like Alzheimer's disease, but little evidence is available to demonstrate their relationship to disease pathogenesis and therapeutic approaches. In recent years, the detection of the molecular mechanism regulating cellular Ca2+ homeostasis and also mitochondrial functions have expanded the number of targeted treatments. The main experimental data identify beneficial effects, whereas some scientific trials did not meet the expectations. Together with an overview of the important function of mitochondria, this review paper introduced the possible tested therapeutic approaches that target mitochondria in the context of neurodegenerative diseases. Since these treatments in neurological disorders have shown different degrees of progress, it is essential to perform a detailed assessment of the significance of mitochondrial deterioration in neurodegenerative diseases and of a pharmacological treatment at this stage.

Adult neurogenesis and the molecular signalling pathways in brain: the role of stem cells in adult hippocampal neurogenesis.

Molecular signalling pathways are an evolutionarily conserved multifaceted pathway that can control diverse cellular processes. The role of signalling pathways in regulating development and tissue homeostasis as well as hippocampal neurogenesis is needed to study in detail. In the adult brain, the Notch signalling pathway, in collaboration with the Wnt/ß-catenin, bone morphogenetic proteins (BMPs), and sonic hedgehog (Shh) molecular signalling pathways, are involved in stem cell regulation in the hippocampal formation, and they also control the plasticity of the neural stem cells (NSCs) or neural progenitor cells (NPCs) which involved in neurogenesis processes. Here we discuss the distinctive roles of molecular signalling pathways involved in the generation of new neurons from a pool of NSCs in the adult brain. Our approach will facilitate the understanding of the molecular signalling mechanism of hippocampal neurogenesis during NSCs development in the adult brain using molecular aspects coupled with cell biological and physiological analysis.

Microglia in Alzheimer's Disease: The Role of Stem Cell-Microglia Interaction in Brain Homeostasis.

Microglia as resident cells of the brain can regulate neural development and maintenance of neuronal networks. Any types of pathologic events or changes in brain homeostasis are involved in the activation of microglia. This activation depends on the context, type of the stressor, or pathology. Due to the release of a plethora of substances such as chemokines, cytokines, and growth factors, microglia able to influence the pathologic outcome. In Alzheimer's disease (AD) condition, the deposition of amyloid-ß (Aß) result in provokes the phenotypic activation of microglia and their elaboration of pro-inflammatory molecules. New investigations reveal that cellular therapy with stem cells might have therapeutic effects in preventing the pathogenesis of AD. Although many strategies have focused on the use of stem cells to regenerate damaged neurons, new researches have demonstrated the immune-regulatory feature of stem cells which can modulate the activity state of microglia as well as mediates neuroinflammation. Hence, understanding the molecular mechanisms involved in the brain homeostasis by the protective features of mesenchymal stem cells (MSCs) could lead to remedial treatment for AD.

Stem cell-based therapy as a promising approach in Alzheimer's disease: current perspectives on novel treatment.

Alzheimer's disease (AD) is a neuronal disorder with insidious onset and slow progression, leading to growing global concern with huge implications for individuals and society. The occurrence of AD has been increased and has become an important health issue throughout the world. In recent years, the care of more than 35 million patients with AD costs over $ 600 billion per year, it is approximately 1 percent of the global Gross Domestic Product. Currently, the therapeutic approach is not effective for neurological deficits especially after the development of these major neurological disorders. The discovery of the technique called cell-based therapy has shown promising results and made important conclusions beyond AD using the stem cells approach. Here we review recent progress on stem cell-based therapy in the context of AD.

Protective effects of mesenchymal stem cells on ischemic brain injury: therapeutic perspectives of regenerative medicine.

Cerebral ischemic injury as the main manifestation of stroke can occur in stroke patients (70-80%). Nowadays, the main therapeutic strategy used for ischemic brain injury treatment aims to achieve reperfusion, neuroprotection, and neurorecovery. Also, angiogenesis as a therapeutic approach maybe represents a promising tool to enhance the prognosis of cerebral ischemic stroke. Unfortunately, although many therapeutic approaches as a life-saving gateway for cerebral ischemic injuries like pharmacotherapy and surgical treatments are widely used, they all fail to restore or regenerate damaged neurons in the brain. So, the suitable therapeutic approach would focus on regenerating the lost cells and restore the normal function of the brain. Currently, stem cell-based regenerative medicine introduced a new paradigm approach in cerebral ischemic injuries treatment. Today, in experimental researches, different types of stem cells such as mesenchymal stem cells have been applied. Therefore, stem cell-based regenerative medicine provides the opportunity to inquire and develop a more effective and safer therapeutic approach with the capability to produce and regenerate new neurons in damaged tissues.

Novel application of adipose-derived mesenchymal stem cells via producing antiangiogenic factor TSP-1 in lung metastatic melanoma animal model.

Human adipose tissue derived mesenchymal stem cells (hAD-MSCS) with suppressive immunogenicity, homing to injury, inflammatory, and cancer sites can be suitable for gene therapy. PiggyBac (PB) is a type of transposon vector applied in mammalian systems and could overcome some limitations of other transposon and viral vectors. In this study, the therapeutic potential hAD-MSCs expressing thrombospondin-1 (TSP-1) is assessed through tail vein injection in C57BL/6 models bearing melanoma mice. Twenty days after injection, antiangiogenic effects and number of activated T. cells are assessed by Immunohistochemistry (IHC) method. Apoptosis value is analyzed by tunnel assay. Mice survival and numbers of nodules in mice lungs also are assessed. By western blotting, value of TSP-1, Bax and Bcl2 expression are assessed. The result revealed that hAD-MSCs.TSP-1 can inhibit angiogenesis and induce apoptosis and activated T. cells in a significant manner in C57BL/6 mice models bearing melanoma. Survival also significantly increased and number of nodules decreased, value of Bax and TSP-1 expression increased and value of Bcl2 expression decreased. In conclusion, our result showed that hAD-MSC. TSP-1 can be applied as an effective delivery vehicle in lung metastatic melanoma therapy.

Stem cell-based therapy for Parkinson's disease with a focus on human endometrium-derived mesenchymal stem cells.

Parkinson's disease (PD) as an increasing clinical syndrome is a multifunctional impairment with systemic involvement. At present, therapeutic approaches such as l-3,4-dihydroxy-phenylalanine replacement therapy, dopaminergic agonist administration, and neurosurgical treatment intend to relieve PD symptoms which are palliative and incompetent in counteracting PD progression. These mentioned therapies have not been able to replace the lost cells and they could not effectively slow down the relentless neurodegenerative process. Till now, there is a lack of eligible treatment for PD, and stem cells therapy recently has been considered for PD treatment. In this review, we demonstrate how human stem cell technology especially human endometrium-derived stem cells have made advancement as a therapeutic source for PD compared with other treatments.

Intranasal administration of endometrial mesenchymal stem cells as a suitable approach for Parkinson's disease therapy.

This study aimed to investigate the therapeutic effects of intranasal administration of human endometrium-derived stem cells (HEDSCs) in the mouse model of Parkinson's disease (PD). Thirty days after intrastriatal injection of 6-OHDA, HEDSCs were administrated intranasally in three doses (104, 5 × 104 and 105 cells µl-1). During 120 days after stem cell administration, behavioral tests were examined. Then the mice were sacrificed and the fresh section of the substantia nigra pars compacta (SNpc) was used for detection of HEDSCs-GFP labeled by fluorescence microscopy method. In addition, immunohistochemistry was used to assay GFP, human neural Nestin, and tyrosine hydroxylase (TH) markers in the fixed brain tissue at the SNpc. Our data revealed that behavioral parameters were significantly improved after cell therapy. Fluorescence microscopy assay in fresh tissue and GFP analysis in fixed tissue were showed that the HEDSCs-GFP labeled migrated to SNpc. The data from immunohistochemistry revealed that the Nestin as a differential neuronal biomarker was expressed in SNpc. Also, TH as a dopaminergic neuron marker significantly increased after HEDSCs therapy in an optimized dose 5 × 104 cells µl-1. Our results suggest that intranasal administration of HEDSCs improve the PD symptoms in the mouse model of PD dose-dependent manner as a noninvasive method.

Bee venom as a promising therapeutic strategy in central nervous system diseases.

Central nervous system (CNS) disorders are one of the leading health problems today, accounting for a large proportion of global morbidity and mortality. Most these disorders are characterized by high levels of oxidative stress and intense inflammatory responses in degenerated neuronal tissues. While extensive research has been conducted on CNS diseases, but few breakthroughs have been made in treatment methods. To date, there are no disease-modifying drugs available for CNS treatment, underscoring the urgent need for finding effective medications. Bee venom (BV), which is produced by honeybee workers' stingers, has been a subject of interest and study across various cultures. Over the past few decades, extensive research has focused on BV and its therapeutic potentials. BV consists a variety of substances, mainly proteins and peptides like melittin and phospholipase A2 (PLA2). Research has proven that BV is effective in various medical conditions, including pain, arthritis and inflammation and CNS disorders such as Multiple sclerosis, Alzheimer's disease and Parkinson's disease. This review provides a comprehensive overview of the existing knowledge concerning the therapeutic effects of BV and its primary compounds on various CNS diseases. Additionally, we aim to shed light on the potential cellular and molecular mechanisms underlying these effects.

A review of the advances, insights, and prospects of gene therapy for Alzheimer's disease: A novel target for therapeutic medicine.

Neurodegenerative diseases such as Alzheimer's disease (AD) are still an important issue for scientists because it is difficult to cure with the available molecular medications and conventional treatments. Due to the complex nature of the brain structures and heterogeneous morphological and physiological properties of neuronal cells, interventions for cerebral-related disorders using surgical approaches, and classical and ongoing treatments remain hard for physicians. Furthermore, the development of newly designed medications attempts to target AD are not successful in improving AD, because abnormalities of tau protein, aggregation of amyloid ß (Aß) peptide, inflammatory responses, etc lead to advanced neurodegeneration processes that conventional treatments cannot stop them. In recent years, novel diagnostic strategies and therapeutic approaches have been developed to identify and cure early pathological events of AD. Accordingly, many gene-based therapies have been developed and introduce the therapeutic potential to prevent and cure AD. On the other hand, genetic investigations and postmortem assessments have detected a large number of factors associated with AD pathology. Also, genetically diverse animal models of AD help us to detect and prioritize novel resilience mechanisms. Hence, gene therapy can be considered an effective and powerful tool to identify and treat human diseases. Ultimately, gene study and gene-based therapy with a critical role in the detection and cure of various human disorders will have a fundamental role in our lives forever. This scientific review paper discusses the present status of different therapeutic strategies, particularly gene-based therapy in treating AD, along with its challenges.

Nanocurcumin prevents memory impairment, hippocampal apoptosis, Akt and CaMKII-α signaling disruption in the central STZ model of Alzheimer's disease in rat.

The central route of streptozotocin (STZ) administration has been introduced as a rat model of sporadic Alzheimer's disease (AD). Curcumin was suggested to possess possible neuroprotective effects, which may be profitable in AD. However, the low bioavailability of curcumin hinders its beneficial effects in clinical studies. Earlier studies suggested that a bovine serum albumin-based nanocurcumin, produces superior neuroprotective effects compared to natural curcumin. In the present study, the protective effect of nanocurcumin in rat model of central STZ induced memory impairment was assessed. In addition, due to the importance of the hippocampus in memory, the amounts of hippocampal active caspase-3, Akt, and CaMKII-α were evaluated. Adult male Wistar rats weighing 250-300 g were used. STZ (icv) was injected during days 1 and 3 (3 mg/kg in divided), and nanocurcumin or curcumin 50 mg/kg/oral gavage was administered daily during days 4-14. Morris water maze training was performed on days 15-17, and the retention memory test was achieved on the 18th day. Following memory assessment, the rats were sacrificed and the hippocampi were used to assess caspase-3 cleavage, Akt, and CaMKII-α signaling. The findings revealed that nanocurcumin ingestion (but not natural curcumin) in the dose of 50 mg/kg was capable to prevent the impairment of water maze learning and memory induced by central STZ. Molecular assessments indicated that STZ treatment increased the caspase-3 cleavage in the hippocampus while deactivating Akt and CaMKII-α. Nanocurcumin reduced caspase-3 cleavage to a non-significant level compared to control group and restored Akt and CaMKII-α within the hippocampus while natural curcumin exerted no significant effect. These findings might suggest that nanocurcumin can restore memory deficit, hippocampal apoptosis as well as Akt and CaMKII-α signaling disruption associated with brain insulin resistance.

Activation of the BMP2/SMAD4 signaling pathway for enhancing articular cartilage regeneration of mesenchymal stem cells utilizing chitosan/alginate nanoparticles on 3D extracellular matrix scaffold.

This study investigated the efficacy of using chitosan/alginate nanoparticles loaded with recombinant human bone morphogenetic-2 (rhBMP-2) and SMAD4 encoding plasmid to enhance the chondrogenesis of human bone marrow mesenchymal stem cells (hBM-MSCs) seeded on an extracellular matrix (ECM). The research treatments included the stem cells treated with the biological cocktail (BC), negative control (NC), hBM-MSCs with chondrogenic medium (MCM), hBM-MSCs with naked rhBMP-2 and chondrogenic medium (NB/C), and hBM-MSCs with naked rhBMP-2 and chondrogenic medium plus SMAD4 encoding plasmid transfected with polyethyleneimine (PEI) (NB/C/S/P). The cartilage differentiation was performed with real-time quantitative PCR analysis and alizarin blue staining. The data indicated that the biological cocktail (BC) exhibited significantly higher expression of cartilage-related genes compared to significant differences with MCM and negative control (NC) on chondrogenesis. In the (NB/C/S/P), the expression levels of SOX9 and COLX were lower than those in the BC group. The expression pattern of the ACAN gene was similar to COL2A1 changes suggesting that it holds promising potential for cartilage regeneration.

Developing nanosize carrier systems for Amphotericin-B: A review on the biomedical application of nanoparticles for the treatment of leishmaniasis and fungal infections.

New formulations of Amphotericin-B (Am-B), the most popular therapeutic drug for many human infections such as parasitic and fungal pathogens, are safe, economical, and effective in the world. Several newly designed carrier systems for Am-B can also be considered orally with sufficient gastrointestinal permeability and good solubility. However, the clinical application of several new formulations of Am-B with organ cytotoxicity, low bioavailability, high costs, and technical problems have caused some issues. Therefore, more attention and scientific design are required to progress safe and effective drug delivery systems. Currently, the application of nano-based technology and nanomaterials in the advancement of drug delivery systems exhibits promising outcomes to cure many human systemic infections. Designing novel drug delivery systems including solid lipid nanostructured materials, lipo-polymersomes, drug conjugates and microneedles, liposomes, polymer and protein-based nanostructured materials, dendrimers, emulsions, mixed micelles, polymeric micelles, cyclodextrins, nanocapsules, and nanocochleate for Am-B has many advantages to reducing several related issues. The unique properties of nanostructured particles such as proper morphology, small size, surface coatings, and, electrical charge, permit scientists to design new nanocomposite materials against microorganisms for application in various human diseases. These features have made these nanoparticles an ideal candidate for drug delivery systems in clinical approaches to cure a number of human disorders and currently, several therapeutic nanostructured material formulations are under different stages of clinical tests. Hence, this scientific paper mainly discussed the advances in new formulations of Am-B for the treatment of human systemic infections and related clinical tests.

The distribution of neurotransmitters in the brain circuitry: Mesolimbic pathway and addiction.

Understanding the central nervous system (CNS) circuitry and its different neurotransmitters that underlie reward is essential to improve treatment for many common health issues, such as addiction. Here, we concentrate on understanding how the mesolimbic circuitry and neurotransmitters are organized and function, and how drug exposure affects synaptic and structural changes in this circuitry. While the role of some reward circuits, like the cerebral dopamine (DA)/glutamate (Glu)/gamma aminobutyric acid (GABA)ergic pathways, in drug reward, is well known, new research using molecular-based methods has shown functional alterations throughout the reward circuitry that contribute to various aspects of addiction, including craving and relapse. A new understanding of the fundamental connections between brain regions as well as the molecular alterations within these particular microcircuits, such as neurotrophic factor and molecular signaling or distinct receptor function, that underlie synaptic and structural plasticity evoked by drugs of abuse has been made possible by the ability to observe and manipulate neuronal activity within specific cell types and circuits. It is exciting that these discoveries from preclinical animal research are now being applied in the clinic, where therapies for human drug dependence, such as deep brain stimulation and transcranial magnetic stimulation, are being tested. Therefore, this chapter seeks to summarize the current understanding of the important brain regions (especially, mesolimbic circuitry) and neurotransmitters implicated in drug-related behaviors and the molecular mechanisms that contribute to altered connectivity between these areas, with the postulation that increased knowledge of the plasticity within the drug reward circuit will lead to new and improved treatments for addiction.

Processing and post-processing of fish skin as a novel material in tissue engineering.

As a natural material, fish skin contains significant amounts of collagen I and III, and due to its biocompatible nature, it can be used to regenerate various tissues and organs. To use fish skin, it is necessary to perform the decellularization process to avoid the immunological response of the host body. In the process of decellularization, it is crucial to conserve the extracellular matrix (ECM) three-dimensional (3D) structure. However, it is known that decellularization methods may also damage ECM strands arrangement and structure. Moreover, after decellularization, the post-processing of fish skin improves its mechanical and biological properties and preserves its 3D design and strength. Also, sterilization, which is one of the post-processing steps, is mandatory in pre-clinical and clinical settings. In this review paper, the fish skin decellularization methods performed and the various post-processes used to increase the performance of the skin have been studied. Moreover, multiple applications of acellular fish skin (AFS) and its extracted collagen have been reviewed.

The role of microRNAs in the pathophysiology of human central nervous system: A focus on neurodegenerative diseases.

microRNAs (miRNAs) are suggested to play substantial roles in regulating the development and various physiologic functions of the central nervous system (CNS). These include neurogenesis, cell fate and differentiation, morphogenesis, formation of dendrites, and targeting non-neural mRNAs. Notably, deregulation of an increasing number of miRNAs is associated with several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and CNS tumors. They are particularly known to affect the amyloid ß (Aß) cleavage and accumulation, tau protein homeostasis, and expression of alpha-synuclein (α-syn), Parkin, PINK1, and brain-derived neurotrophic factor (BDNF) that play pivotal roles in the pathogenesis of neurodegenerative diseases. These include miR-16, miR-17-5p, miR-20a, miR-106a, miR-106b, miR-15a, miR-15b, miR-103, miR-107, miR-298, miR-328, miR-195, miR-485, and miR-29. In CNS tumors, several miRNAs, including miR-31, miR-16, and miR-21 have been identified to modulate tumorigenesis through impacting tumor invasion and apoptosis. In this review article, we have a look at the recent advances on our knowledge about the role of miRNAs in human brain development and functions, neurodegenerative diseases, and their clinical potentials.

microRNA-382 as a tumor suppressor? Roles in tumorigenesis and clinical significance.

MicroRNAs (miRNAs) are small single-stranded RNAs belonging to a class of non-coding RNAs with an average length of 18-22 nucleotides. Although not able to encode any protein, miRNAs are vastly studied and found to play role in various human physiologic as well as pathological conditions. A huge number of miRNAs have been identified in human cells whose expression is straightly regulated with crucial biological functions, while this number is constantly increasing. miRNAs are particularly studied in cancers, where they either can act with oncogenic function (oncomiRs) or tumor-suppressors role (referred as tumor-suppressor/oncorepressor miRNAs). miR-382 is a well-studied miRNA, which is revealed to play regulatory roles in physiological processes like osteogenic differentiation, hematopoietic stem cell differentiation and normal hematopoiesis, and liver progenitor cell differentiation. Notably, miR-382 deregulation is reported in pathologic conditions, such as renal fibrosis, muscular dystrophies, Rett syndrome, epidural fibrosis, atrial fibrillation, amelogenesis imperfecta, oxidative stress, human immunodeficiency virus (HIV) replication, and various types of cancers. The majority of oncogenesis studies have claimed miR-382 downregulation in cancers and suppressor impact on malignant phenotype of cancer cells in vitro and in vivo, while a few studies suggest opposite findings. Given the putative role of this miRNA in regulation of oncogenesis, assessment of miR-382 expression is suggested in a several clinical investigations as a prognostic/diagnostic biomarker for cancer patients. In this review, we have an overview to recent studies evaluated the role of miR-382 in oncogenesis as well as its clinical potential.

Non-coding RNAs: A new frontier in benzene-mediated toxicity.

One of the most frequent environmental contaminants, benzene is still widely used as an industrial solvent around the world, especially in developing nations, posing a serious occupational risk. While the processes behind the toxicity of benzene grounds are not fully understood, it is generally accepted that its metabolism, which involves one or more reactive metabolites, is crucial to its toxicity. In order to evaluate the many ways that benzene could influence gene regulation and thus have an impact on human health, new methodologies have been created. The pathophysiology of the disorder may result from epigenetic reprogramming caused by exposure to benzene, including changes in non-coding RNA (ncRNA) markers, according to recent studies. We are interested in the identification of hazardous regulatory ncRNAs, the identification of these ncRNAs' targets, and the comprehension of the significance of these interactions in the mechanisms behind benzene toxicity. Hence, the focus of recent research is on long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs), and some of the more pertinent articles are also discussed.

microRNA-184 in the landscape of human malignancies: a review to roles and clinical significance.

MicroRNAs (miRNAs) are a class of non-coding RNAs (ncRNAs) with a short length of 19-22 nucleotides. miRNAs are posttranscriptional regulators of gene expression involved in various biological processes like cell growth, apoptosis, and angiogenesis. miR-184 is a well-studied miRNA, for which most studies report its downregulation in cancer cells and tissues and experiments support its role as a tumor suppressor inhibiting malignant biological behaviors of cancer cells in vitro and in vivo. To exert its functions, miR-184 affects some signaling pathways involved in tumorigenesis like Wnt and ß-catenin, and AKT/mTORC1 pathway, oncogenic factors (e.g., c-Myc) or apoptotic proteins, such as Bcl-2. Interestingly, clinical investigations have shown miR-184 with good performance as a prognostic/diagnostic biomarker for various cancers. Additionally, exogenous miR-184 in cell and xenograft animal studies suggest it as a therapeutic anticancer target. In this review, we outline the studies that evaluated the roles of miR-184 in tumorigenesis as well as its clinical significance.