Showing papers in "Current Pharmaceutical Design in 2015"
TL;DR: Mechanistic evidence illustrates plausible pathways by which acute and chronic exposures to air pollutants might disrupt hemodynamic balance favoring vasoconstriction, including autonomic imbalance and augmented release of various pro-oxidative, inflammatory and/or hemodynamically-active mediators.
Abstract: Both high arterial blood pressure (BP) and elevated levels of fine particulate matter (PM2.5) air pollution have been associated with an increased risk for several cardiovascular (CV) diseases, including stroke, heart failure, and myocardial infarction. Given that PM2.5 and high BP are each independently leading risk factors for premature mortality worldwide, a potential relationship between these factors would have tremendous public health repercussions. Therefore, the aim of this review is to summarize recent evidence linking air pollution and BP. Epidemiological findings demonstrate that particulate pollutants cause significant increases in BP parameters in relation to both short and long-term exposures, with robust evidence for exposures to PM2.5. Moreover, recent epidemiological studies suggest a positive association between residence within regions with higher levels of ambient PM and an increased incidence and prevalence of overt hypertension. Studies provide consistent results that elevated concentrations of pollutants increase hospital admissions and/or emergency visits for hypertensive disorders and also support that PM levels increases BP in vulnerable subsets of individuals (pregnant women, high CV risk individuals). In this context, PM-mediated BP elevations may be an important pathway which acts as a potential triggering factor for acute CV events. Mechanistic evidence illustrates plausible pathways by which acute and chronic exposures to air pollutants might disrupt hemodynamic balance favoring vasoconstriction, including autonomic imbalance and augmented release of various pro-oxidative, inflammatory and/or hemodynamically-active mediators. Together these responses may underlie PM-induced BP elevations; however, full details regarding the responsible mechanisms require further studies. As a consequence of the ubiquity of air pollution, even a small effect on raising BP and/or the prevalence of hypertension, i.e. the major risk factor for mortality and morbidity worldwide, would have enormous global public health implications.
207 citations
TL;DR: This review gives a detailed account of commonly used methods for synthesising nanoparticles of various ceramic materials, along with an overview of their recent research status in the field of drug delivery.
Abstract: Ceramic nanoparticles are primarily made up of oxides, carbides, phosphates and carbonates of metals and metalloids such as calcium, titanium, silicon, etc. They have a wide range of applications due to a number of favourable properties, such as high heat resistance and chemical inertness. Out of all the areas of ceramic nanoparticles applications, biomedical field is the most explored one. In the biomedical field, ceramic nanoparticles are considered to be excellent carriers for drugs, genes, proteins, imaging agents etc. To be able to act as a good and successful drug delivery agent, various characteristics of nanoparticles need to be controlled, such as size range, surface properties, porosity, surface area to volume ratio, etc. In achieving these properties on the favourable side, the method of preparation and a good control over process variables play a key role. Choosing a suitable method to prepare nanoparticles, along with loading of significant amount of drug(s) leads to development of effective drug delivery systems which are being explored to a great extent. Ceramic nanoparticles have been successfully used as drug delivery systems against a number of diseases, such as bacterial infections, glaucoma, etc., and most widely, against cancer. This review gives a detailed account of commonly used methods for synthesising nanoparticles of various ceramic materials, along with an overview of their recent research status in the field of drug delivery.
190 citations
TL;DR: This paper reviewed the recently published papers on the effects of herbal medicines on PD alongside the pathogenesis of PD with regard to oxidative stress and revealed new perspectives of research and therapy.
Abstract: Parkinson's disease (PD) is a neurodegenerative disorder due to dopamine deficit in substatia nigra. PD is mainly a sporadic disease with unestablished etiology. However, exposure to environmental toxins, head trauma, inflammation, and free radicals are potential reasons. Recently, the role of oxidative stress in neurological abnormalities, including PD, has been particularly addressed. Antioxidant remedies, particularly herbal antioxidants, have revealed new perspectives of research and therapy as possible preventive and therapeutic approaches for PD. In this paper, we reviewed the recently published papers on the effects of herbal medicines on PD alongside the pathogenesis of PD with regard to oxidative stress.
189 citations
TL;DR: Emerging knowledge regarding the plasticity of cancer stem cells and the role that this plasticity plays in tumor metastasis are discussed.
Abstract: Over the past several decades the traditional view of cancer being a homogeneous mass of rapid proliferating malignant cells is being replaced by a model of ever increasing complexity, which points out that cancers are complex tissues composed of multiple cell types. A large variety of immune and other host cells constitute the tumor microenvironment, which supports the growth and progression of the tumor where individual cancer cells evolve with increasing phenotypic and genetic heterogeneity. Furthermore, it has also become clear that, in addition to this cellular and genetic heterogeneity, most tumors exhibit a hierarchical organization composed of tumor cells displaying divergent lineage markers and at the apex of this hierarchy are cells capable of self-renewal. These "cancer stem cells" not only drive tumor growth, but also mediate metastasis and contribute to treatment resistance. Besides displaying remarkable genetic and phenotypic heterogeneity, cancer stem cells maintain plasticity to transition between mesenchymal-like (EMT) and epithelial-like (MET) states in a process regulated by the tumor microenvironment. These stem cell state transitions may play a fundamental role in the process of tumor metastasis. In this review, we will discuss emerging knowledge regarding the plasticity of cancer stem cells and the role that this plasticity plays in tumor metastasis. We also discuss the implications of these findings for the development of cancer stem cell targeted therapeutics.
179 citations
TL;DR: This review will cover fatty acid chain and posttranslational modifications of HSA that potentially modulate how HSA interacts with various pharmacological drugs, including glycation, cysteinylation, S-nitrosylation,S-transnitrosation and S-guanylation.
Abstract: Human serum albumin (HSA) regulates the transport and availability of numerous chemical compounds and molecules in the blood vascular system. While previous HSA research has found that HSA interacts with specific varieties of ligands, new research efforts aim to expand HSA's ability to interact with more different drugs in order to improve the delivery of various pharmacological drugs. This review will cover fatty acid chain and posttranslational modifications of HSA that potentially modulate how HSA interacts with various pharmacological drugs, including glycation, cysteinylation, S-nitrosylation, S-transnitrosation and S-guanylation.
176 citations
TL;DR: OLP is often used in cases of therapeutic dead-ends or for specific disorders with few or no currently approved medications, however, other OLP practices only reflect temporary prescription trends for mild symptoms, which may induce safety concerns.
Abstract: Introduction: New antipsychotics continuously arrive on the market, which thereby influences the approved and off-label prescribing (OLP) schemes. We aimed to identify the recent trends in the OLP of antipsychotics. We conducted a literature review based on three different populations: adult, pediatric, and elderly patients. Methods: A literature search was performed in the PubMed and ScienceDirect databases using the following keyword algorithm: “offlabel” AND (“antipsychotic*” OR “neuroleptic*”). The period investigated ranged from January 2000 to January 2015. Only Englishwritten pharmacoepidemiological studies were included. Results: Seventy-seven relevant results were identified. Among adults, OLP consisted of 40 to 75% of all antipsychotic prescriptions. The main indications were mood disorders, anxiety disorders, insomnia and agitation. Quetiapine was the most frequently prescribed offlabel antipsychotic, especially for anxiety and insomnia. Among children, OLP was estimated between 36 and 93.2% of all antipsychotic prescriptions. Risperidone and aripiprazole were primarily used and were most often prescribed for attention deficit hyperactivity disorder, anxiety, or mood disorders. Among elderly individuals, OLP consisted of 22 to 86% of all antipsychotic prescriptions. Antipsychotic OLP was particularly frequent for agitation; however, a recent decrease in this OLP was identified. Discussion: Antipsychotics have largely been prescribed off-label in recent years. The types of antipsychotic OLP practices differ according to the age category of patients. OLP is often used in cases of therapeutic dead-ends or for specific disorders with few or no currently approved medications. However, other OLP practices only reflect temporary prescription trends for mild symptoms, which may induce safety concerns.
154 citations
TL;DR: Focus of the discussion is on the various challenges researchers face when developing lipid-based RNA nanocarriers, such as the toxicity of cationic lipids and issues related to PEGylated lipids, as well as the strategies employed in tackling these challenges.
Abstract: RNA-interference (RNAi) agents such as small-interfering RNA (siRNA) and micro-RNA (miRNA) have strong potential as therapeutic agents for the treatment of a broad range of diseases such as malignancies, infections, autoimmune diseases and neurological diseases that are associated with undesirable gene expression. In recent years, several clinical trials of RNAi therapeutics especially siRNAs have been conducted with limited success so far. For systemic administration of these poorly permeable and easily degradable macromolecules, it is obvious that a safe and efficient delivery platform is highly desirable. Because of high biocompatibility, biodegradability and solid track record for clinical use, nanocarriers made of lipids and/or phospholipids have been commonly employed to facilitate RNA delivery. In this article, the key features of the major sub-classes of lipid-based nanocarriers, e.g. liposomes, lipid nanoparticles and lipid nanoemulsions, will be reviewed. Focus of the discussion is on the various challenges researchers face when developing lipid-based RNA nanocarriers, such as the toxicity of cationic lipids and issues related to PEGylated lipids, as well as the strategies employed in tackling these challenges. It is hoped that by understanding more about the pros and cons of these most frequently used RNA delivery systems, the pharmaceutical scientists, biomedical researchers and clinicians will be more successful in overcoming some of the obstacles that currently limit the clinical translation of RNAi therapy.
146 citations
TL;DR: The mechanisms of various environmental parameters functioning as stimuli to tailor the release rates of smart electrospun nanofibers are reviewed.
Abstract: In biological systems, chemical molecules or ions often release upon certain conditions, at a specific location, and over a desired period of time. Electrospun nanofibers that undergo alterations in the physicochemical characteristics corresponding to environmental changes have gained considerable interest for various applications. Inspired by biological systems, therapeutic molecules have been integrated with these smart electrospun nanofibers, presenting activation-modulated or feedback-regulated control of drug release. Compared to other materials like smart hydrogels, environment-responsive nanofiber-based drug delivery systems are relatively new but possess incomparable advantages due to their greater permeability, which allows shorter response time and more precise control over the release rate. In this article, we review the mechanisms of various environmental parameters functioning as stimuli to tailor the release rates of smart electrospun nanofibers. We also illustrate several typical examples in specific applications. We conclude this article with a discussion on perspectives and future possibilities in this field.
129 citations
TL;DR: Current studies related to EMT and CSCs in tumor progression and therapeutic resistance are reviewed, with a special focus on the common characteristics and links between these processes, and the importance of these links in the development of improved antitumor therapies is explored.
Abstract: The epithelial-mesenchymal transition (EMT) is a highly conserved cellular process that transforms epithelial cells into mesenchymal cells; EMT is involved in normal embryogenesis and tissue repair and contributes to tumor progression, including tumor metastasis, therapy resistance and disease recurrence. Cancer stem cells (CSCs) represent a fraction of undifferentiated cancer cells that exhibit stem cell-like features. They have the ability to self-renew and can seed new tumors. Thus, CSCs might represent the cellular resource that causes metastases and accounts for therapy resistance. Recent studies have highlighted a link between EMT and CSC formation. EMT is relevant to the acquisition and maintenance of stem cell-like characteristics and is sufficient to endow differentiated normal and cancer cells with stem cell properties. Moreover, CSCs often exhibit EMT properties. This reciprocal relationship between EMT and CSCs might have many implications in tumor progression. In this paper, we review current studies related to EMT and CSCs in tumor progression and therapeutic resistance, with a special focus on the common characteristics and links between these processes, and explore the importance of these links in the development of improved antitumor therapies.
127 citations
TL;DR: A self-assembly mechanism for small molecules used in the peptide hydrogels is introduced, and recent methods for controlling the assembly of molecular hydrogelations are described, placing particular emphasis on recent advances in the use of different types of peptidehydrogels as drug delivery carriers.
Abstract: Molecular hydrogels have been widely explored in various biomedical applications, such as cell culture, tissue engineering and drug delivery. Peptide-based hydrogel nanoparticles represent a promising alternative to current drug delivery approaches and cell carriers for tissue engineering, due to their encapsulation stability, water solubility and biocompatibility. This review focuses on recent advances in the use of self-assembling peptide nanogels for applications in drug delivery. We firstly introduce a self-assembly mechanism for small molecules used in the peptide hydrogel, and then describe recent methods for controlling the assembly of molecular hydrogelations. A particular emphasis is placed on recent advances in the use of different types of peptide hydrogels as drug delivery carriers. Lastly, the current challenges and future perspectives for self-assembling peptide hydrogels in drug delivery applications are discussed.
115 citations
TL;DR: A review examines the involvement of the GABAergic system in both cognitive and non-cognitive behavioural symptoms in AD, providing some pointers for rational drug development.
Abstract: Alzheimer’s disease (AD) is the most common form of dementia in the elderly. Research focused on identifying compounds that restore cognition and memory in AD patients is a very active investigational pursuit, but unfortunately, it has been only successful in terms of developing symptomatic treatments. Aβ deposition and neurofibrillary tangles along with neuron and synapse loss are associated with neurotransmitter dysfunction and have been recognized as hallmarks of AD. Furthermore, clinical and preclinical studies point to this neurotransmitter dysfunction as a main factor underlying both cognitive and neuropsychiatric symptoms of the illness. Cholinergic deficit in AD prompted the use of cholinesterase inhibitors as the symptomatic treatment of cognitive decline in AD, however this therapeutic approach provides only modest benefit in the majority of patients. Hence, nowadays research is focused on investigating compounds that could restore cognition and memory in AD patients. GABA is the primary inhibitory neurotransmitter in the central nervous system and GABAergic neurons provide extensive innervation to cholinergic and glutamatergic neurons. It has been shown that dysfunction of the GABAergic system may contribute to cognitive impairment in humans. Significant reductions in GABA levels have been described in severe cases of AD, which could be underlying the behavioral and psychological symptoms of AD. This review examines the involvement of the GABAergic system in both cognitive and non-cognitive behavioural symptoms in AD, providing some pointers for rational drug development.
TL;DR: The aim of this review is to briefly summarize the key pharmacological properties of GABA receptors, and to present selected novel findings with the potential to open new perspectives in the development of more effective therapeutic strategies.
Abstract: Gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, plays a key role in the regulation of neuronal transmission throughout the brain, affecting numerous physiological and psychological processes. Changes in GABA levels provoke disbalance between excitatory and inhibitory signals, and are involved in the development of numerous neuropsychiatric disorders. GABA exerts its effects via ionotropic (GABAA) and metabotropic (GABAB) receptors. Both types of receptors are targeted by many clinically important drugs that affect GABAergic function and are widely used in the treatment of anxiety disorder, epilepsy, insomnia, spasticity, aggressive behaviour, and other pathophysiological conditions and diseases. Of particular importance are drugs that modulate GABAA receptor complex, such as benzodiazepines, barbiturates, neuroactive steroids, intravenous and inhalational anesthetics, and ethanol. Molecular interactions and subsequent pharmacological effects induced by drugs acting at GABAA receptors are extremely complex due to structural heterogeneity of GABAA receptors and existence of numerous allosterically interconnected binding sites and various chemically distinct ligands that are able to bound to them. There is a growing interest in the development and application of subtype-selective drugs that will achieve specific therapeutic benefits without undesirable side effects. The aim of this review is to briefly summarize the key pharmacological properties of GABA receptors, and to present selected novel findings with the potential to open new perspectives in the development of more effective therapeutic strategies.
TL;DR: Ginkgo biloba is one of the most effective plants with an old history of applications in neuropsychological disorders which recently is used for autism and the promising results of herbal remedies are addressed.
Abstract: Autism is a comprehensive growth abnormality in which social skills, language, communication, and behavioral skills are developed with delay and as diversionary. The reasons for autism are unclear, but various theories of genetics, immunity, biological, and psychosocial factors have been proffered. In fact, autism is a complex disorder with distinct causes that usually co-occur. Although no medicine has been recognized to treat this disorder, pharmacological treatments can be effective in reducing its signs, such as self-mutilation, aggression, repetitive and stereotyped behaviors, inattention, hyperactivity, and sleeping disorders. Recently, complementary and alternative approaches have been considered to treat autism. Ginkgo biloba is one of the most effective plants with an old history of applications in neuropsychological disorders which recently is used for autism. The present review discusses the recent findings, pathophysiology, and etiology of autism and thereafter addresses the promising results of herbal remedies.
TL;DR: It is beyond any doubt that statins do slightly increase the incidence of type 2 diabetes mellitus in people with two or more components of metabolic syndrome but the cardiovascular benefits of such a treatment by far exceed this risk.
Abstract: Statins reduce cardiovascular mortality and morbidity as well as cardiovascular events in patients with a very high risk of cardiovascular disease (CVD) and also in subjects with high or moderate risk by reducing the levels of low-density lipoprotein cholesterol (LDL-C). Although they are considered to be drugs with a very good safety profile, because of their wide use there are many concerns that their adverse effects might compromise their proven beneficial effects. Therefore this article reviews all the data and provides an evidence- based insight what are the proven adverse effects of statins and what are the "myths" about them. The most important side effects include myopathy and rhabdomyolysis. Another side effect is increased activity of liver tests which occurs occasionally and is reversible. However, recent studies even suggest that statin therapy can improve hepatic steatosis. It is beyond any doubt that statins do slightly increase the incidence of type 2 diabetes mellitus in people with two or more components of metabolic syndrome but the cardiovascular benefits of such a treatment by far exceed this risk. Statin therapy has also been associated with some adverse renal effects, eg. acute renal failure, but recent data suggest even a possible protective effect of these drugs on renal dysfunction. Concerns that statins might increase cancer have not been proven. On the contrary, several studies have indicated a possible benefit of these drugs in patients with different types of cancer. Early concerns about cognitive dysfunction and memory loss associated with statins use could not be proven and most recent data even suggest a possible beneficial effect of statins in the prevention of dementia. Systematic reviews and clinical guidelines suggest that the cardiovascular benefits of statins by far out-weight non-cardiovascular harms in patients with cardiovascular risk.
TL;DR: Conventional as well as novel antioxidants have been discussed with special emphasis for the treatment of CVD and the critical challenges for antioxidant delivery and various novel carriers including, liposomes and nanoparticles explored for their efficient delivery in the therapeutic management ofCVD are highlighted.
Abstract: Cardiovascular disorders or cardiovascular diseases (CVD) are major illness associated with heart and blood vessels. Reactive oxygen species (ROS), generated during excessive oxidative stress, are responsible for the pathophysiology of various cardiovascular disorders including atherosclerosis, cardiac hypertrophy, cardiomyopathy, heart failure, ventricular remodeling, ischemia/reperfusion injury and myocardial infarction. Cellular "redox homeostasis" generally maintains the healthy physiology in cardiac myocytes and endothelial cells. However, during excessive oxidative stress body's endogenous system fails to maintain normal physiology hence antioxidant supplementation is necessary, which could scavenge the free radicals and other toxic radicals. Several antioxidants such as CoQ10, beta carotene, lycopene, quercetin, reserveterol, vitamin C and vitamin E have shown preventive and therapeutic benefits in different forms of CVD. However, poor biopharmaceutical properties and variable pharmacokinetics of several antioxidants limits their use as therapeutic agents. Hence delivery of stable antioxidants at their site of action is a need of current scenario. Several novel carriers based approaches have shown considerable benefits for the systemic and site specific delivery of antioxidants for the preventive and therapeutic treatment of several cardiovascular diseases. In the present review, conventional as well as novel antioxidants have been discussed with special emphasis for the treatment of CVD. Further, the current review also highlights the critical challenges for antioxidant delivery and various novel carriers (nanoformulations) including, liposomes and nanoparticles explored for their efficient delivery in the therapeutic management of CVD.
TL;DR: The most recent and promising astrocyte-based therapeutic approaches - from fundamental discoveries to clinical trials - that intent to sustain neuronal health and function in neurodegenerative disorders are presented.
Abstract: The causes of neurodegenerative disorders are multiple, and for most of them a mechanistic understanding is still lacking. However, neurodegenerative diseases such as Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) all share common features that include elevated oxidative stress levels and impaired energy metabolism in the nervous system. Most of the current treatments are only successful at alleviating some of the pathological symptoms, but fail at preventing neurodegeneration. There is therefore an urgent need for innovative and more efficient treatments for neurodegenerative disorders. We review here the central role played by astrocytes in the regulation of brain homeostasis, protection and function by supporting neuronal health and activity. In particular, astrocytes are key partners of neuronal metabolism, notably through activation of the astrocyteneuron lactate shuttle (ANLS). They also control the levels of extracellular glutamate, production of antioxidant molecules, disposal of neuronal waste products, storage of energy in the form of glycogen, and expression of neurotrophic factors. These mechanisms, which are key for brain activity and cognition, also largely contribute to neuronal degeneration in pathological situations. Thus, as astrocytes appear to play a key role in the etiology of neurodegenerative disorders, a growing interest has arisen for astrocytemediated pathways as targets for drugs that aim at treating the root causes of the pathology. We present here the most recent and promising astrocyte-based therapeutic approaches - from fundamental discoveries to clinical trials - that intent to sustain neuronal health and function in neurodegenerative disorders.
TL;DR: This review will focus on the relationships between the structure of DSPEPEG and its noticeable effects on these nanocarriers' properties, and the recent progress on the development of the material and its derivatives in delivery systems.
Abstract: 1, 2-Distearoyl-sn-glycero-3-phosphoethanolamine-Poly(ethylene glycol) (DSPE- PEG) is a widely used phospholipids-polymer conjugate in drug delivery applications. It is a biocompatible, biodegradable and amphiphilic material which can also be functionalized with various biomolecules for specific functions. With the emerging interest in use of nanocarriers for therapeutic drug delivery and imaging DSPE-PEG has become a very useful material for the formulation of these nanocarriers for achieving prolonged blood circulation time, improved stability and enhanced encapsulation efficiency. This review will focus on the relationships between the structure of DSPEPEG and its noticeable effects on these nanocarriers' properties, and the recent progress on the development of DSPE-PEG and its derivatives in delivery systems.
TL;DR: A review of physiological regulation of both myocardial fatty acid and glucose oxidation in the heart and pharmacological interventions that target enzymes involved in fatty acid uptake, fatty acid oxidation, transcriptional regulation of fatty acids oxidation, and glucose oxide to treat heart failure.
Abstract: Despite recent advances in therapy, heart failure remains a major cause of mortality and morbidity and is a growing healthcare burden worldwide. Alterations in myocardial energy substrate metabolism are a hallmark of heart failure, and are associated with an energy deficit in the failing heart. Previous studies have shown that a metabolic shift from mitochondrial oxidative metabolism to glycolysis, as well as an uncoupling between glycolysis and glucose oxidation, plays a crucial role in the development of cardiac inefficiency and functional impairment in heart failure. Therefore, optimizing energy substrate utilization, particularly by increasing mitochondrial glucose oxidation, can be a potentially promising approach to decrease the severity of heart failure by improving mechanical cardiac efficiency. One approach to stimulating myocardial glucose oxidation is to inhibit fatty acid oxidation. This review will overview the physiological regulation of both myocardial fatty acid and glucose oxidation in the heart, and will discuss what alterations in myocardial energy substrate metabolism occur in the failing heart. Furthermore, lysine acetylation has been recently identified as a novel post-translational pathway by which mitochondrial enzymes involved in all aspects of cardiac energy metabolism can be regulated. Thus, we will also discuss the effect of acetylation of metabolic enzymes on myocardial energy substrate preference in the settings of heart failure. Finally, we will focus on pharmacological interventions that target enzymes involved in fatty acid uptake, fatty acid oxidation, transcriptional regulation of fatty acid oxidation, and glucose oxidation to treat heart failure.
TL;DR: A summary on current understanding of MALAT1 in different physiological or pathophysiological processes is made and the potential therapeutic applications based on MALat1 detection and inhibition are discussed.
Abstract: Genome-wide studies have identified thousands of noncoding RNAs (ncRNAs) with no protein coding capacity. Among them, the long non-coding RNAs (lncRNAs), which are more than 200 nucleotides in length, recently are widely concerned for their crucial role in regulating biological processes and diseases. However, most lncRNAs are expressed at a very low level, and generally exhibit poor primary sequence conservation over evolution. Long non-coding RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), also known as NEAT2 (nuclear-enriched abundant transcript 2), is outstanding among the lncRNA family due to its evolutionarily high conservation and abundant expression throughout diferent mammalian species. Meanwhile, MALAT1 was one of the first lncRNAs that was demonstrated to be associated with a disease, namely non-small cell lung cancer (NSCLC). Subsequently, MALAT1 was identified in multiple types of physiological processes, such as alternative splicing, nuclear organization, epigenetic modulating of gene expression, and so on. Moreover, a growing number of evidences indicated that MALAT1 was also closely related to various pathological processes, ranging from diabetes complications to cancers.In this review, we will make a summary on current understanding of MALAT1 in different physiological or pathophysiological processes and discuss the potential therapeutic applications based on MALAT1 detection and inhibition.
TL;DR: Results from these studies have demonstrated that PEI-based nanocarriers are promising delivery systems because of their efficient gene transfection, negligible toxicity, capability to co-deliver nucleic acids and chemotherapy drugs, ease of modification with the targeting molecules, and good responsiveness to external stimulus.
Abstract: There is a tremendous progress in the design and synthesis of nano-scaled, non-viral carriers in the previous two decades. The nanodelivery systems can significantly improve biopharmaceutical features, pharmacokinetic properties and therapeutic efficacy of entrapped drugs. Branched polyethylenimine (PEI) is a cationic polymer that contains primary, secondary and tertiary amino groups. Such type of water-soluble polymer having high density of amines is one of the most promising cationic vectors for gene delivery. Hence, constructing nanocarriers that contain PEI have attracted much research effort in gene therapy because of the synergy effects of PEI molecules for their efficient transfection and the multi-functionality of nanoparticles in delivery. In this review, we focus on the recent development on the design and synthesis of four types of PEI-based nanocarriers: 1) PEI-based polymeric micelles systems; 2) PEI-based polymeric nanoparticle system; 3) PEI/silica nanoparticle systems; and 4) PEI/metal nanoparticle systems. Their in vitro gene transfaction and in vivo gene therapy will be also discussed. Results from these studies have demonstrated that PEI-based nanocarriers are promising delivery systems because of their efficient gene transfection, negligible toxicity, capability to co-deliver nucleic acids and chemotherapy drugs, ease of modification with the targeting molecules, and good responsiveness to external stimulus.
TL;DR: The findings on the health benefits of Chlorella supplementation and the molecular mechanisms underlying these effects are summarized.
Abstract: Chlorella vulgaris is a green unicellular microalgae with biological and pharmacological properties important for human health. C. vulgaris has a long history of use as a food source and contains a unique and diverse composition of functional macro- and micro-nutrients including proteinsChlorella vulgaris is a green unicellular microalgae with biological and pharmacological properties important for human health. C. vulgaris has a long history of use as a food source and contains a unique and diverse composition of functional macro- and micro-nutrients including proteins, omega-3 polyunsaturated fatty acids, polysaccharides, vitamins and minerals. Clinical trials have suggested that supplementation with C. vulgaris can ameliorate amelioration hyperlipidemia and hyperglycemia, and protect against oxidative stress, cancer and chronic obstructive pulmonary disease. In this review, we summarize the findings on the health benefits of Chlorella supplementation and the molecular mechanisms underlying these effects., omega-3 polyunsaturated fatty acids, polysaccharides, vitamins and minerals. Clinical trials have suggested that supplementation with C. vulgaris can ameliorate amelioration hyperlipidemia and hyperglycemia, and protect against oxidative stress, cancer and chronic obstructive pulmonary disease. In this review, we summarize the findings on the health benefits of Chlorella supplementation and the molecular mechanisms underlying these effects.
TL;DR: Several recent preclinical and clinical studies on the role of miRNAs in myocardial infarction are highlighted; novel miRNA-based therapeutic approaches for therapeutic intervention, and potential circulating miRNA to be served as biomarkers in patients with suspected MI are highlighted.
Abstract: MicroRNAs (miRNAs) are a class of small regulatory RNAs that control several cellular processes that may contribute to development of cardiovascular disease (CVD) and the pathophysiological consequences of myocardial infarction (MI). Only a very small-numbers of biomarkers in MI (e.g., Troponin) have been identified, which are sufficiently sensitive, specific and robust. There is growing evidence of an association between specific miRNAs in the pathogenesis of MI. miRNAs are transported within the systemic circulation via exosomes and microparticles, and are therefore detectable in blood, urine, saliva, and other fluid compartments. Dysregulation of myocardial-derived miRNAs, such as miR-1, miR-133, miR-499, and miR-208, have been identified as potential biomarkers in MI. Furthermore, alteration of the levels of some miRNAs during stress-induced apoptosis is reported as a novel therapeutic strategy for cardiac disease. Modulation of mir-24 appears to inhibit cardiomyocyte apoptosis, attenuate infarct size, and reduce cardiac dysfunction. A greater knowledge on the molecular mechanism underlying the functional role of emerging miRNAs, could provide novel insights into identifying of new biomarkers. This review highlights several recent preclinical and clinical studies on the role of miRNAs in myocardial infarction; novel miRNA-based therapeutic approaches for therapeutic intervention, and potential circulating miRNA to be served as biomarkers in patients with suspected MI.
TL;DR: How prolonged stressful events during childhood or adolescence can lead to increased oxidative stress in the CNS and enhance the risk to develop psychiatric diseases such as anxiety, depression, drug abuse or psychosis is discussed.
Abstract: Stress is an inevitable part of human life and it is experienced even before birth. Stress to some extent could be considered normal and even necessary for the survival and the regular psychological development during childhood or adolescence. However, exposure to prolonged stress could become harmful and strongly impact mental health increasing the risk of developing psychiatric disorders. Recent studies have attempted to clarify how the human central nervous system (CNS) reacts to early life stress, focusing mainly on neurobiological modifications. Oxidative stress, defined as a disequilibrium between the oxidant generation and the antioxidant response, has been recently described as a candidate for most of the observed modifications. In this review, we will discuss how prolonged stressful events during childhood or adolescence (such as early maternal separation, parental divorce, physical violence, sexual or psychological abuses, or exposure to war events) can lead to increased oxidative stress in the CNS and enhance the risk to develop psychiatric diseases such as anxiety, depression, drug abuse or psychosis. Defining the sources of oxidative stress following exposure to early life stress might open new beneficial insights in therapeutic approaches to these mental disorders.
TL;DR: HEP and its constituents exhibited a variety of anti-resorptive and bone formation-stimulating effects, which target different pathways in the bone remodeling cycle, and may provide new perspectives in alternative treatment regimes and reveal novel chemical scaffolds for the development ofAnti-osteoporotic drugs.
Abstract: Herba Epimedii (HEP) known as YinYangHuo in Chinese is the dried leaf of the Epimediium, and has been historically used in combination with other herbs to treat skeletal diseases in traditional Chinese medicine (TCM). Here, we review the historical TCM interpretation of the action of HEP, its use in clinical trials, its main phytochemical constituents and its pharmacological findings. 85 clinical trials were identified which used HEP in TCM prescriptions with other herbs to treat primary and secondary osteoporosis from 2005 to now. More than 60 individual compounds were isolated and characterized from HEP and studied in various animal and cell models. HEP and its constituents exhibited a variety of anti-resorptive and bone formation-stimulating effects, which target different pathways in the bone remodeling cycle. These compounds may provide new perspectives in alternative treatment regimes and reveal novel chemical scaffolds for the development of anti-osteoporotic drugs. These approaches are also useful for guiding our research to employ an integrative therapeutic approach to treat complex diseases such as osteoporosis diseases which could be superior to the conventional single target – single drug approach.
TL;DR: This review focuses on recent mouse models of primary SjS xerostomia and describes them under three categories of spontaneous, genetically engineered, and experimentally induced models.
Abstract: Sjogren's syndrome (SjS) is a chronic autoimmune disorder characterized by immune cell infiltration and progressive injury to the salivary and lacrimal glands. As a consequence, patients with SjS develop xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). SjS is the third most common rheumatic autoimmune disorder, affecting 4 million Americans with over 90% of patients being female. Current diagnostic criteria for SjS frequently utilize histological examinations of minor salivary glands for immune cell foci, serology for autoantibodies, and dry eye evaluation by corneal or conjunctival staining. SjS can be classified as primary or secondary SjS, depending on whether it occurs alone or in association with other systemic rheumatic conditions, respectively. Clinical manifestations typically become apparent when the disease is relatively advanced in SjS patients, which poses a challenge for early diagnosis and treatment of SjS. Therefore, SjS mouse models, because of their close resemblance to the human SjS, have been extremely valuable to identify early disease markers and to investigate underlying biological and immunological dysregulations. However, it is important to bear in mind that no single mouse model has duplicated all aspects of SjS pathogenesis and clinical features, mainly due to the multifactorial etiology of SjS that includes numerous susceptibility genes and environmental factors. As such, various mouse models have been developed in the field to try to recapitulate SjS. In this review, we focus on recent mouse models of primary SjS xerostomia and describe them under three categories of spontaneous, genetically engineered, and experimentally induced models. In addition, we discuss future perspectives highlighting pros and cons of utilizing mouse models and current demands for improved models.
TL;DR: Different sources of ROS are examined from the point of view of their participation in pathogenesis of atherosclerosis and related cardiovascular risk, including mitochondria, NADPH-oxidase, xanthine oxidase, peroxidases, NO-synthases, cytochrome P450, cyclooxygenase, lipoxygenases, and hemoglobin of red blood cells.
Abstract: The volume of publications on the role of reactive oxygen species (ROS) in biological processes has been increasing exponentially over the last decades. ROS in large amounts clearly have detrimental effects on cell physiology, whereas low concentrations of ROS are permanently produced in cells and play a role as signaling molecules. An imbalance in ROS production and defense mechanisms can lead to pathological vascular remodeling, atherosclerosis being among them. The aim of this review is to examine different sources of ROS from the point of view of their participation in pathogenesis of atherosclerosis and related cardiovascular risk. Among the possible sources of ROS discussed here are mitochondria, NADPH-oxidases, xanthine oxidase, peroxidases, NO-synthases, cytochrome P450, cyclooxygenases, lipoxygenases, and hemoglobin of red blood cells. A great challenge for future research is to establish interrelations, feedback and feed-forward regulation mechanisms of various sources of ROS in development of atherosclerosis and other vascular pathologies.
TL;DR: In this article, drug repurposing efforts that lead to the discovery of prior non-antibiotic drugs can be used in clinical applicable ranges to treat patients of bacterial infection.
Abstract: Disclosed herewith is drug repurposing efforts that lead to the discovery of prior non-antibiotic drugs can be used in clinical applicable ranges to treat patients of bacterial infection. These repurposed drug can be used either alone or in combination with traditional antibiotic drugs to treat bacterial strains that may develop or already have developed drug resistance.
TL;DR: In this review, critical particulate properties that affect aerosol performance are discussed and recent advances in powder production and particle engineering techniques are assessed, aiming to develop new inhaled powder formulations or improve the aerosolisation efficiency of existing products.
Abstract: Dry powder inhalers have become increasingly attractive for pulmonary delivery of locally and systemically effective medications. In comparison to the liquid counterparts, such as nebulisation and pressurised metered dose inhalers, the powder form generally offers better chemical stability, improved portability and potentially superior patient adherence. Currently, the aerosol performance between dry powder inhalers varies to a large extent due to differences in the design of inhaler device and formulation. The particulate properties have a significant influence on the inter-particle interactions, which impacts on the aerosolisation of the inhaled powder. In this review, critical particulate properties that affect aerosol performance are discussed. Recent advances in powder production and particle engineering techniques are also assessed, aiming to develop new inhaled powder formulations or improve the aerosolisation efficiency of existing products.
TL;DR: An overview into different vesicle-based gene delivery systems is provided and how various modifications in their structure and formulations could improve the transfection efficiency and decrease the toxicity is discussed.
Abstract: Synthetic and biological vesicular carriers have been recognized as attractive and intelligent systems for delivery of a verity of bioactive molecules. The importance of such delivery systems can be mostly due to their physicochemical properties, i.e. a lipid bilayer surrounding an aqueous core which allows encapsulation and protection of active hydrophilic molecules such as nucleic acids. Synthetic vesicles such as liposomes have been studied as gene delivery systems for decades. However, due to their fast clearance, toxicity and immunogenicity which impose restrictions on clinical applications, some other natural lipid vesicles such as exosomes have been considered as alternatives. Attractive features of nature's own 'nano-vesicles' such as exosomes, virosomes, bacterial ghosts and erythrocyte ghosts include efficient cellular entry, physicochemical properties and evading immune responses. Nevertheless, there are advantages and disadvantages with both synthetic and biological vesicular systems. Here, we provide an overview into different vesicle-based gene delivery systems and discuss how various modifications in their structure and formulations could improve the transfection efficiency and decrease the toxicity.
TL;DR: The present review focuses on the current state of drug - HSA binding studies and the most extensive studied topics in the area are discussed including quantitative characterization of drug- HSA complexation, identification of the binding sites, stereoselectivity of drug – HSA interactions, and thermodynamic characterization of thebinding process.
Abstract: Human serum albumin (HSA) is the major plasma protein with vital functions acting as depot and career for many endogenous (fatty acids, bilirubin, etc.) and exogenous substances (drugs, nutrients, etc.) in the blood. Binding to HSA controls the free, active concentration of the drug and may affect considerably the overall pharmacodynamic and pharmacokinetic profile. Studies on drug - protein binding are important from both theoretical and practical point of view as they allow better understanding of the processes underlying drug disposition and elimination and the effect of several pathological states or co-administered drugs on drug delivery and efficacy. The present review focuses on the current state of drug - HSA binding studies. The major functions and consequences of drug - protein binding are described. The X-ray structure of HSA is discussed focusing on the location and the architecture of the primary drug and fatty acids binding sites. Some of the most commonly used methods for drug - HSA binding assay are presented together with examples for their application. The most extensive studied topics in the area are discussed including quantitative characterization of drug - HSA complexation, identification of the binding sites, stereoselectivity of drug - HSA interactions, and thermodynamic characterization of the binding process. A short section is devoted to in silico prediction of drug - HSA binding as an important step in drug design and development.