Showing papers in "Current Pharmaceutical Design in 2020"

Pathophysiology of Ischemic Stroke: Role of Oxidative Stress.

Abstract: Stroke is the second leading cause of mortality and the major cause of adult physical disability worldwide. The currently available treatment to recanalize the blood flow in acute ischemic stroke is intravenous administration of tissue plasminogen activator (t-PA) and endovascular treatment. Nevertheless, those treatments have the disadvantage that reperfusion leads to a highly harmful reactive oxygen species (ROS) production, generating oxidative stress (OS), which is responsible for most of the ischemia-reperfusion injury and thus causing brain tissue damage. In addition, OS can lead brain cells to apoptosis, autophagy and necrosis. The aims of this review are to provide an updated overview of the role of OS in brain IRI, providing some bases for therapeutic interventions based on counteracting the OS-related mechanism of injury and thus suggesting novel possible strategies in the prevention of IRI after stroke.

Wnt/beta-catenin and PI3K/Akt/mTOR Signaling Pathways in Glioblastoma: Two Main Targets for Drug Design: A Review.

Abstract: Glioblastoma (GBM) is the most common and malignant astrocytic glioma, accounting for about 90% of all brain tumors with poor prognosis. Despite recent advances in understanding molecular mechanisms of oncogenesis and the improved neuroimaging technologies, surgery, and adjuvant treatments, the clinical prognosis of patients with GBM remains persistently unfavorable. The signaling pathways and the regulation of growth factors of glioblastoma cells are very abnormal. The various signaling pathways have been suggested to be involved in cellular proliferation, invasion, and glioma metastasis. The Wnt signaling pathway with its pleiotropic functions in neurogenesis and stem cell proliferation is implicated in various human cancers, including glioma. In addition, the PI3K/Akt/mTOR pathway is closely related to growth, metabolism, survival, angiogenesis, autophagy, and chemotherapy resistance of GBM. Understanding the mechanisms of GBM's invasion, represented by invasion and migration, is an important tool in designing effective therapeutic interventions. This review will investigate two main signaling pathways in GBM: PI3K/Akt/mTOR and Wnt/beta-catenin signaling pathways.

Neurofilament Proteins as Prognostic Biomarkers in Neurological Disorders.

Abstract: Neurofilaments: light, medium, and heavy (abbreviated as NF-L, NF-M, and NF-H, respectively), which belong to Type IV intermediate filament family (IF), are neuron-specific cytoskeletal components. Neurofilaments are axonal structural components and integral components of synapses, which are important for neuronal electric signal transmissions along the axons and post-translational modification. Abnormal assembly of neurofilaments is found in several human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy (SMA), and hereditary sensory-motor neuropathy (HSMN). In addition, those pathological neurofilament accumulations are known in α-synuclein in Parkinson's disease (PD), Aβ and tau in Alzheimer's disease (AD), polyglutamine in CAG trinucleotide repeat disorders, superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP43), neuronal FUS proteins, optineurin (OPTN), ubiquilin 2 (UBQLN2), and dipeptide repeat protein (DRP) in amyotrophic lateral sclerosis (ALS). When axon damage occurs in central nervous disorders, neurofilament proteins are released and delivered into cerebrospinal fluid (CSF), which are then circulated into blood. New quantitative analyses and assay techniques are well-developed for the detection of neurofilament proteins, particularly NF-L and the phosphorylated NF-H (pNF-H) in CSF and serum. This review discusses the potential of using peripheral blood NF quantities and evaluating the severity of damage in the nervous system. Intermediate filaments could be promising biomarkers for evaluating disease progression in different nervous system disorders.

Pathophysiological Functions of the lncRNA TUG1.

Abstract: Background Long non-coding RNAs (lncRNAs) with little or no coding capacity are associated with a plethora of cellular functions, participating in various biological processes. Cumulative study of lncRNA provides explanations to the physiological and pathological processes and new perspectives to the diagnosis, prevention, and treatment of some clinical diseases. Long non-coding RNA taurine-upregulated gene 1(TUG1) is one of the first identified lncRNAs associated with human disease, which actively involved in various physiological processes, including regulating genes at epigenetics, transcription, post-transcription, translation, and posttranslation. The aim of this review was to explore the molecular mechanism of TUG1 in various types of human diseases. Methods In this review, we summarized and analyzed the latest findings related to the physiologic and pathophysiological processes of TUG1 in human diseases. The related studies were retrieved and selected the last six years of research articles in PubMed with lncRNA and TUG1 as keywords. Results TUG1 is a valuable lncRNA that its dysregulated expression and regulating the biological processes were found in a variety of human diseases. TUG1 is found to exhibit aberrant expression in a variety of malignancies. Dysregulation of TUG1 has been shown to contribute to proliferation, migration, cell cycle changes, inhibited apoptosis, and drug resistance of cancer cells, which revealed an oncogenic role for this lncRNA, but some reports have shown downregulation of TUG1 in lung cancer samples compared with noncancerous samples. In addition, the molecular and biological functions of TUG1 in physiology and disease (relevant to endocrinology, metabolism, immunology, neurobiology) have also been highlighted. Finally, we discuss the limitations and tremendous diagnostic/therapeutic potential of TUG1 in cancer and other diseases. Conclusion Long non-coding RNA-TUG1 likely served as useful disease biomarkers or therapy targets and effectively applied in different kinds of diseases, such as human cancer and cardiovascular diseases.

Excitotoxicity as a Target Against Neurodegenerative Processes.

Abstract: The global burden of neurodegenerative diseases is alarmingly increasing in parallel to the aging of population. Although the molecular mechanisms leading to neurodegeneration are not completely understood, excitotoxicity, defined as the injury and death of neurons due to excessive or prolonged exposure to excitatory amino acids, has been shown to play a pivotal role. The increased release and/or decreased uptake of glutamate results in dysregulation of neuronal calcium homeostasis, leading to oxidative stress, mitochondrial dysfunctions, disturbances in protein turn-over and neuroinflammation. Despite the anti-excitotoxic drug memantine has shown modest beneficial effects in some patients with dementia, to date, there is no effective treatment capable of halting or curing neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, Huntington's disease or amyotrophic lateral sclerosis. This has led to a growing body of research focusing on understanding the mechanisms associated with the excitotoxic insult and on uncovering potential therapeutic strategies targeting these mechanisms. In the present review, we examine the molecular mechanisms related to excitotoxic cell death. Moreover, we provide a comprehensive and updated state of the art of preclinical and clinical investigations targeting excitotoxic- related mechanisms in order to provide an effective treatment against neurodegeneration.

Emerging Potential of Naturally Occurring Autophagy Modulators Against Neurodegeneration

Abstract: Background: Naturally-occurring products derived from living organisms have been shown to modulate various pharmacological and biological activities. Natural products protect against various diseases, which could be used for therapeutic assistance. Autophagy, a lysosome-mediated self-digestion pathway, has been implicated in a range of pathophysiological conditions and has recently gained attention for its role in several neurodegenerative diseases. Methods: In this current review, we emphasized the recent progress made in our understanding of the molecular mechanism of autophagy in different cellular and mouse models using naturally-occurring autophagy modulators for the management of several neurodegenerative diseases. Results: Accumulating evidence has revealed that a wide variety of natural compounds such as alkaloids, polyphenols, terpenoids, xanthonoids, flavonoids, lignans, disaccharides, glycolipoproteins, and saponins are involved in the modulation of the autophagy signaling pathway. These natural products have been used to treat various neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, spinocerebellar ataxia, neuroblastoma, and glioblastoma. Although a number of synthetic autophagy regulators have been recognized as encouraging neurodegenerative therapeutic candidates, natural autophagy-regulating compounds have been of further interest as potential disease therapeutics, as they cause insignificant side effects. Conclusion: Existing in vitro and in vivo data are promising and highlight that naturally-occurring autophagy-regulating compounds play an important role in the prevention and treatment of neurodegenerative disorders.

Vaccinium myrtillus L. Fruits as a Novel Source of Phenolic Compounds with Health Benefits and Industrial Applications - A Review.

Abstract: Consumers' demand for healthier foods with functional properties has had a clear influence on the food industry and in this sense, they have been attaching natural sources of bioactive ingredients into food products. Vaccinium myrtillus L. (bilberry) is known to be a functional food, presenting its fruits in the form of a small dark blueberry. This coloration is due to its high content in anthocyanin, being also associated with bilberries' beneficial health effects. In the bilberry industry, there is a very high annual loss of this fruit due to the less aesthetic shape or appearance, in which they cannot be considered suitable for sale and are therefore disposed of as biological waste. Therefore, it is of great importance to valorize this fruit and this review aimed to completely characterize the fruits of V. myrtillus in order to comprehend the relationship between their consumption and the beneficial effects regarding consumer's health. Thus, this review provides a description of the nutritional and bioactive compounds present in bilberry fruits, followed by their beneficial health effects. An overview of the natural pigments present in these fruits was also explored, focusing particularly in the anthocyanins composition, which represents the most widely studied class of bioactive compounds of V. myrtillus fruits. Finally, industrial applications of these fruits and by-products, as an efficient approach to the production of value-added products with economical and environmental impact, were also discussed. In general, V. myrtillus is a rich source of micronutrients and phytochemical compounds, such as organic acids, sugars, vitamins, fibers and phenolic compounds (anthocyanin and non-anthocyanin compounds), with nutritional and functional properties, that justify the growing interest in these berries, not only for food applications, but also in the pharmaceutical industry.

Natural Compounds as Inhibitors of SARS-CoV-2 Main Protease (3CLpro): A Molecular Docking and Simulation Approach to Combat COVID-19

Abstract: The emergence and dissemination of SARS-CoV-2 has caused high mortality and enormous economic loss. Rapid development of new drug molecules is the need of hour to fight COVID-19. However, the conventional approaches of drug development are time consuming and expensive. Here, we have adopted a computational approach to identify lead molecules from nature. Ligands from natural compounds library available at Selleck Inc (L1400) have been screened for their ability to bind and inhibit the main protease (3CLpro) of SARS-CoV-2. We found that Kaempferol, Quercetin, and Rutin were bound at the substrate binding pocket of 3CLpro with high affinity (105-106 M-1) and interact with the active site residues such as His41 and Cys145 through hydrogen bonding and hydrophobic interactions. In fact, the binding affinity of Rutin (~106 M-1) was much higher than Chloroquine (~103 M-1) and Hydroxychloroquine (~104 M-1), and the reference drug Remdesivir (~105 M-1). The results suggest that natural compounds such as flavonoids have the potential to be developed as novel inhibitors of SARS-CoV-2 with a comparable/higher potency as that of Remdesivir. However, their clinical usage on COVID-19 patients is a subject of further investigations and clinical trials.

Lipid-Based Nanosystem As Intelligent Carriers for Versatile Drug Delivery Applications.

Abstract: The contemporary drug discovery research shows that most of the drug candidates are highly potent, but showing poor aqueous solubility leads a variety of challenges for formulation scientists to develop a suitable formulation to improve the systemic bioavailability of such drugs. Lipid-based nanocarriers act as a major and most projecting approach overcoming the limitations which affect several physiochemical properties of drug such as the solubility, partition coefficient and bioavailability or absorption. This also fulfills a variety of product requirements and helps to overcome several limitations as decided by symptoms of the disease, various routes of administration of drug, price concern, increasing strength of product, noxious or harmful effect of drug, and dose efficacy. The lipidic nanosystem formulates aqueous drug in lipid base and is also a commercially feasible approach for the formulation of different dosage forms meant for topical or transdermal, oral, ocular, pulmonary, and parenteral delivery. This review provides a brief on lipid-based drug delivery nanocarrier and the mechanisms by which lipids and lipidic excipients improve the oral absorption of drugs with poor aqueous solubility and also provide a viewpoint on the promising applications of lipidic nanoparticulate systems.

Artemia species: An Important Tool to Screen General Toxicity Samples

Abstract: Medicinal plants are a good source of novel therapeutic drugs, due to the phytochemicals present. Artemia, commonly known as brine shrimp, is a tiny halophilic invertebrate belonging to class Crustacean, which plays an important role in saline aquatic and marine eco-systems. Besides its usage in aquaculture, it is also highly valued for its application in toxicity detection and it is used in areas such as Ecology, Physiology, Ecotoxicology, Aquaculture and Genetics. Furthermore, Artemia based lethality assay (brine shrimp lethality assay, BSLA) is rapid, convenient and low cost. Presently, brine shrimp lethality assays are enormously employed in research and applied toxicology. It has been used in the study of natural products as a preliminary toxicity assay to screen a large number of extracts and compounds for drug discovery in medicinal plants. The aim of this review paper is to collect, organize, select and discuss the existing knowledge about the different uses of Artemia salina as a bench-top bioassay for the discovery and purification of bioactive natural products.

Epidemiology of Non-alcoholic Fatty Liver Disease in North America.

Abstract: Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common cause of chronic liver disease worldwide. This is primarily driven by the global epidemic of obesity and diabetes as well as the aging of the general population. Most of the epidemiology data of NAFLD for North America are published from studies originating in the United States (U.S.). The overall prevalence of NAFLD in the U.S. is estimated to be 24%. Hispanic Americans have a higher prevalence of NAFLD, whereas African Americans have a lower prevalence of NAFLD. The exact contributions of genetic and environmental factors on these differences in the prevalence rates have not been determined. From the spectrum of NAFLD, patients with non-alcoholic steatohepatitis (NASH) are at the highest risk of progression to cirrhosis and hepatocellular carcinoma (HCC). The most recent data regarding the progression of NASH suggest a complex pattern of progression and regression of fibrosis. Factors influencing the progression and regression of NASH have not been fully described. More research is needed to better understand NAFLD in Mexico and Canada.

Tribolium castaneum: A Model for Investigating the Mode of Action of Insecticides and Mechanisms of Resistance.

Abstract: The red flour beetle, Tribolium castaneum, is a worldwide insect pest of stored products, particularly food grains, and a powerful model organism for developmental, physiological and applied entomological research on coleopteran species. Among coleopterans, T. castaneum has the most fully sequenced and annotated genome and consequently provides the most advanced genetic model of a coleopteran pest. The beetle is also easy to culture and has a short generation time. Research on this beetle is further assisted by the availability of expressed sequence tags and transcriptomic data. Most importantly, it exhibits a very robust response to systemic RNA interference (RNAi), and a database of RNAi phenotypes (iBeetle) is available. Finally, classical transposonbased techniques together with CRISPR/Cas-mediated gene knockout and genome editing allow the creation of transgenic lines. As T. castaneum develops resistance rapidly to many classes of insecticides including organophosphates, methyl carbamates, pyrethroids, neonicotinoids and insect growth regulators such as chitin synthesis inhibitors, it is further a suitable test system for studying resistance mechanisms. In this review, we will summarize recent advances in research focusing on the mode of action of insecticides and mechanisms of resistance identified using T. castaneum as a pest model.

Vitamin D and Sleep Regulation: Is there a Role for Vitamin D?

Abstract: Background Vitamin D exerts multiple pleiotropic effects beyond its role in calcium-phosphate metabolism. Growing evidence suggests an association between hypovitaminosis D and sleep disorders, thus increasing the interest in the role of this vitamin in the regulatory mechanisms of the sleep-wake cycle. Objective The study aimed to explore and summarize the current knowledge about the role of vitamin D in sleep regulation and the impact of vitamin D deficiency on sleep disorders. Methods The main regulatory mechanisms of vitamin D on sleep are explained in this study. The literature was scanned to identify clinical trials and correlation studies showing an association between vitamin D deficiency and sleep disorders. Results Vitamin D receptors and the enzymes that control their activation and degradation are expressed in several areas of the brain involved in sleep regulation. Vitamin D is also involved in the pathways of production of Melatonin, the hormone involved in the regulation of human circadian rhythms and sleep. Furthermore, vitamin D can affect sleep indirectly through non-specific pain disorders, correlated with alterations in sleep quality, such as restless legs syndrome and obstructive sleep apnea syndrome. Conclusion Vitamin D has both a direct and an indirect role in the regulation of sleep. Although vitamin D deficiency has been associated to sleep disorders, there is still scant evidence to concretely support the role of vitamin D supplementation in the prevention or treatment of sleep disturbances; indeed, more intervention studies are needed to better clarify these aspects.

Polymer-Lipid Hybrid Nanoparticles: A Next-Generation Nanocarrier for Targeted Treatment of Solid Tumors.

Abstract: At present, cancer is the most deadly disease and one of the most common causes of death worldwide providing different obstacles to chemotherapy including non-specific biodistribution of chemotherapeutic drugs, dose-related adverse effects, development of metastasis and chemoresistance. Nanoparticle-based targeted delivery of chemotherapeutics gained enormous attention in the treatment of solid tumors as they provide many significant advantages including prolonged drug release, enhanced systemic half-life, decreased toxicity and targeted drug delivery. Polymer-lipid hybrid nanoparticles (PLHNPs) are the most effective nanoplatform that develop from building blocks of polymers and lipids. PLHNPs combine the unique advantages of both lipid-based nanoparticles as well as polymeric nanoparticles. PLHNPs integrate biocompatible polymers and biomimetic lipids in their architecture, which imparts PLHNPs with wide versatility for delivering chemotherapeutic drugs of different physicochemical characteristics to their target site of action. The hybrid architecture of PLHNPs provides many exceptional advantages such as small particle size, encapsulation of more than one anticancer drugs, high drug loading capacity and modified drug release profile. Furthermore, the surface decoration of PLHNPs improves the therapeutic potential of the chemotherapeutic drug by selective targeting of tumor tissue and reduces the side effects by decreasing non-specific biodistribution. This review highlights the challenges in the treatment of solid tumors by using nanoparticles system, rationale and targeting strategies of PLHNPs in the targeted treatment of solid tumors, and current progress of PLHNPs in the management of different types of solid tumors.

Dietary Amino Acids and Immunonutrition Supplementation in Cancer-Induced Skeletal Muscle Mass Depletion: A Mini-Review

Abstract: Cancer patients display systemic inflammation, which leads to an increase in protein catabolism, thus promoting the release of free amino acids to further support metabolism and remodelling of muscle proteins. Inflammation associated with tumor growth leads to malnutrition, a factor that increases the risk of developing cachexia. With cancer-induced cachexia, nutritional interventions have gained traction as a preventative method to manage this condition. Currently, cancer consensus recommendations suggest a protein intake above 1.0 g/kg.day-1 up to 2.0 g/k.day-1 for cancer patients, although an ideal amount for some amino acids in isolation has yet to be determined. Due to controversy in the literature regarding the benefits of the biochemical mechanisms of various muscle mass supplements, such as L-leucine (including whey protein and BCAA), β-hydroxy-beta-methyl butyrate (HMβ), arginine, glutamine and creatine, several studies have carefully examined their effects. L-leucine and its derivatives appear to regulate protein synthesis by direct or indirect activation of the mTORC1 pool of kinases, further promoting muscle protein balance. Arginine and glutamine may act by reducing inflammation and infection progression, thus promoting improvements in food intake. Creatine exerts anabolic activity, acting as an immediate energy substrate to support muscle contraction further increasing lean mass, mainly due to greater water uptake by the muscle. In this narrative review, we highlighted the main findings regarding protein consumption and amino acids to mitigate cancer-induced skeletal muscle depletion.

Nanostructured Lipid Carriers as Potential Drug Delivery Systems for Skin Disorders.

Abstract: Background Skin diseases affect all the age groups of people and have an impact on patients' physical, mental, and emotional status. Conventional topical preparation is limited with its efficacy due to low permeation, frequent application, and poor adherence to the therapy for prolong time. Objective The objective of this review article is to address the emerging trends of nanotechnology derived lipidic carrier systems for an effective treatment for skin disorders. Methodology Various research and review articles from reputed international journals were referred and compiled. Results and discussion Topical drug delivery systems were found to be more effective than oral and parenteral drug delivery systems for treating skin diseases due to targeted localized applications with reduced side effects. Lipid-based nanoparticles have been found to have the potential in treating skin diseases due to the biocompatibility and the versatility of the lipids. Nanostructured lipid carriers (NLCs) have gained much attention in treating skin diseases due to improved stability of the drugs, enhanced skin permeation, retention, and better therapeutic efficacy. The review summarizes the NLCs characteristics and their application for topical delivery of various therapeutics in skin disorders. NLCs have shown great potential in effective drug delivery for the treatment of psoriasis, dermatitis, bacterial infections, and skin cancer. Its cosmetic application has opened a new area for skincare. Furthermore, safety and clinical status revealed its future commercial acceptability. Conclusion NLCs have been found as effective lipid nanocarriers for the delivery of topical therapeutics.

Current Nanoparticle Approaches in Nose to Brain Drug Delivery and Anticancer Therapy - A Review

Abstract: Nanoparticles (NPs) are unique may be organic or inorganic, play a vital role in the development of drug delivery targeting the central nervous system (CNS). Intranasal drug delivery has shown to be an efficient strategy with attractive application for drug delivery to the CNS related diseases, such as Parkinson's disease, Alzheimer 's disease and brain solid tumors. Blood brain barrier (BBB) and blood-cerebrospinal fluid barriers are natural protective hindrances for entry of drug molecules into the CNS. Nanoparticles exhibit excellent intruding capacity for therapeutic agents and overcome protective barriers. By using nanotechnology based NPs targeted, drug delivery can be improved across BBB with discharge drugs in a controlled manner. NPs confer safe from degradation phenomenon. Several kinds of NPs are used for nose to the brain (N2B) enroute, such as lipidemic nanoparticles, polymeric nanoparticles, inorganic NPs, solid lipid NPs, dendrimers. Among them, popular lipidemic and polymeric NPs are discussed, and their participation in anti-cancer activity has also been highlighted in this review.

β-amyloid and oxidative stress: Perspectives in drug development

Abstract: Alzheimer's Disease (AD) is a slow-developing neurodegenerative disorder in which the main pathogenic role has been assigned to β-amyloid protein (Aβ) that accumulates in extracellular plaques. The mechanism of action of Aβ has been deeply analyzed and several membrane structures have been identified as potential mediators of its effect. The ability of Aβ to modify neuronal activity, receptor expression, signaling pathways, mitochondrial function, and involvement of glial cells have been analyzed. In addition, extensive literature deals with the involvement of oxidative stress in Aβ effects. Herein we focus more specifically on the reciprocal regulation of Aβ, that causes oxidative stress, that favors Aβ aggregation and toxicity and negatively affects the peptide clearance. Analysis of this strict interaction may offer novel opportunities for therapeutic intervention. Both common and new molecules endowed with antioxidant properties deserve attention in this regard.

Nanomedicines in Diagnosis and Treatment of Cancer: An Update.

Abstract: Nanomedicine has revolutionized the field of cancer detection and treatment by enabling the delivery of imaging agents and therapeutics into cancer cells. Cancer diagnostic and therapeutic agents can be either encapsulated or conjugated to nanosystems and accessed to the tumor environment through the passive targeting approach (EPR effect) of the designed nanomedicine. It may also actively target the tumor exploiting conjugation of targeting moiety (like antibody, peptides, vitamins, and hormones) to the surface of the nanoparticulate system. Different diagnostic agents (like contrast agents, radionuclide probes and fluorescent dyes) are conjugated with the multifunctional nanoparticulate system to achieve simultaneous cancer detection along with targeted therapy. Nowadays targeted drug delivery, as well as the early cancer diagnosis is a key research area where nanomedicine is playing a crucial role. This review encompasses the significant recent advancements in drug delivery as well as molecular imaging and diagnosis of cancer exploiting polymer-based, lipid-based and inorganic nanoparticulate systems.

The Role of Chloroquine and Hydroxychloroquine in Immune Regulation and Diseases.

Abstract: Chloroquine (CQ) and hydroxychloroquine (HCQ) are derivatives of the heterocyclic aromatic compound quinoline. These economical compounds have been used as antimalarial agents for many years. Currently, they are used as monotherapy or in conjunction with other therapies for the treatment of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's syndrome (SS) and antiphospholipid antibody syndrome (APS). Based on its effects on the modulation of the autophagy process, various clinical studies suggest that CQ and HCQ could be used in combination with other chemotherapeutics for the treatment of various types of cancer. Furthermore, the antiviral effects showed against Zika, Chikungunya, and HIV are due to the annulation of endosomal/lysosomal acidification. Recently, CQ and HCQ were approved for the U.S. Food and Drug Administration (FDA) for the treatment of infected patients with the coronavirus SARSCoV- 2, causing the disease originated in December 2019, namely COVID-2019. Several mechanisms have been proposed to explain the pharmacological effects of these drugs: 1) disruption of lysosomal and endosomal pH, 2) inhibition of protein secretion/expression, 3) inhibition of antigen presentation, 4) decrease of proinflammatory cytokines, 5) inhibition of autophagy, 6) induction of apoptosis and 7) inhibition of ion channels activation. Thus, evidence has shown that these structures are leading molecules that can be modified or combined with other therapeutic agents. In this review, we will discuss the most recent findings in the mechanisms of action of CQ and HCQ in the immune system, and the use of these antimalarial drugs on diseases.

Exosomes and Bone Disease.

Abstract: Exosomes, which mediate cell-to-cell communications and provide a novel insight into information exchange, have drawn increasing attention in recent years. The homeostasis of bone metabolism is critical for bone health. The most common bone diseases such as osteoporosis, osteoarthritis and bone fractures have apparent correlations with exosomes. Accumulating evidence has suggested the potential regenerative capacities of stem cell-derived exosomes. In this review, we summarise the pathophysiological mechanism, clinical picture and therapeutic effects of exosomes in bone metabolism. We introduce the advantages and challenges in the application of exosomes. Although the exact mechanisms remain unclear, miRNAs seem to play major roles in the exosome.

New Insights about Regulatory T Cells Distribution and Function with Exercise: The Role of Immunometabolism

Abstract: A lack of physical activity is linked to the development of many chronic diseases through a chronic low-grade inflammation state. It is now well accepted that the immune system plays a central role in the development of several chronic diseases, including insulin resistance, type 2 diabetes, atherosclerosis, heart failure and certain types of cancer. Exercise elicits a strong anti-inflammatory response independently of weight loss and can be a useful non-pharmacologic strategy to counteract the low-grade inflammation. The CD4+CD25+CD127- FoxP3+ Regulatory T (Treg) cells are a unique subset of helper T-cells, which regulate immune response and establish self-tolerance through the secretion of immunoregulatory cytokines, such as IL-10 and TGF-β, and the suppression of the function and activity of many immune effector cells (including monocytes/macrophages, dendritic cells, CD4+ and CD8+ T cells, and Natural Killers). The metabolic phenotype of Tregs are regulated by the transcription factor Foxp3, providing flexibility in fuel choice, but a preference for higher fatty acid oxidation. In this review, we focus on the mechanisms by which exercise - both acute and chronic - exerts its antiinflammatory effects through Treg cells mobilization. Furthermore, we discuss the implications of immunometabolic changes during exercise for the modulation of Treg phenotype and its immunosuppressive function. This narrative review focuses on the current knowledge regarding the role of Treg cells in the context of acute and chronic exercise using data from observational and experimental studies. Emerging evidence suggests that the immunomodulatory effects of exercise are mediated by the ability of exercise to adjust and improve Tregs number and function.

BPC 157 Rescued NSAID-cytotoxicity Via Stabilizing Intestinal Permeability and Enhancing Cytoprotection.

Abstract: The stable gastric pentadecapeptide BPC 157 protects stomach cells, maintains gastric integrity against various noxious agents such as alcohol, nonsteroidal anti-inflammatory drugs (NSAIDs), and exerts cytoprotection/ adaptive cytoprotection/organoprotection in other epithelia, that is, skin, liver, pancreas, heart, and brain. Especially BPC 157 counteracts gastric endothelial injury that precedes and induces damage to the gastric epithelium and generalizes "gastric endothelial protection" to protection of the endothelium of other vessels including thrombosis, prolonged bleeding, and thrombocytopenia. In this background, we put the importance of BPC 157 as a possible way of securing GI safety against NSAIDs-induced gastroenteropathy since still unmet medical needs to mitigate NSAIDs-induced cytotoxicity are urgent. Furthermore, gastrointestinal irritants such as physical or mental stress, NSAIDs administration, surfactants destroyer such as bile acids, alcohol can lead to leaky gut syndrome through increasing epithelial permeability. In this review article, we described the potential rescuing actions of BPC 157 against leaky gut syndrome after NSAIDs administration for the first time.

Pathophysiology of Contrast-Induced Acute Kidney Injury (CIAKI).

Abstract: Contrast-induced acute kidney injury (CIAKI) is a severe complication associated with the use of iodinated contrast media (CM); a sudden but potentially reversible fall in glomerular filtration rate (GFR) typically occurring 48-72 hours after CM administration. Principal risk factors related with the presentation of CIAKI are preexisting chronic kidney disease and diabetes mellitus. Studies on CIAKI present considerable complexity because of differences in CM type and dose, controversies in definition and baseline comorbidities. Despite that, it should be noted that CIAKI poses a serious health problem because it is a very common cause of hospitalacquired AKI, linked to increased morbidity and mortality and utilizing growing healthcare resources. The pathogenesis of CIAKI is heterogeneous and, thus, is incompletely understood. Three basic mechanisms appear to simultaneously occur for CIAKI development: Renal vasoconstriction and medullary hypoxia, tubular cell toxicity and reactive oxygen species formation. The relative contribution of each one of these mechanisms is unknown but they ultimately lead to epithelial and endothelial cell apoptosis and GFR reduction. Further research is needed in order to better clarify CIAKI pathophysiology and accordingly introduce effective preventive and therapeutic strategies.

Insect Cuticular Chitin Contributes to Form and Function.

Abstract: Chitin contributes to the rigidity of the insect cuticle and serves as an attachment matrix for other cuticular proteins. Deficiency of chitin results in abnormal embryos, cuticular structural defects and growth arrest. When chitin is not turned over during molting, the developing insect is trapped inside the old cuticle. Partial deacetylation of cuticular chitin is also required for proper laminar organization of the cuticle and vertical pore canals, molting, and locomotion. Thus, chitin and its modifications strongly influence the structure of the exoskeleton as well as the physiological functions of the insect. Internal tendons and specialized epithelial cells called "tendon cells" that arise from the outer layer of epidermal cells provide attachment sites at both ends of adult limb muscles. Membrane processes emanating from both tendon and muscle cells interdigitate extensively to strengthen the attachment of muscles to the extracellular matrix (ECM). Protein ligands that bind to membrane-bound integrin complexes further enhance the adhesion between muscles and tendons. Tendon cells contain F-actin fiber arrays that contribute to their rigidity. In the cytoplasm of muscle cells, proteins such as talin and other proteins provide attachment sites for cytoskeletal actin, thereby increasing integrin binding and activation to mechanically couple the ECM with actin in muscle cells. Mutations in integrins and their ligands, as well as depletion of chitin deacetylases, result in defective locomotion and muscle detachment from the ECM. Thus, chitin in the cuticle and chitin deacetylases strongly influence the shape and functions of the exoskeleton as well as locomotion of insects.

Scutellaria barbata: A Review on Chemical Constituents, Pharmacological Activities and Clinical Applications.

Abstract: Scutellaria barbata has a long history of medical use in Traditional Chinese Medicine for removing heat and toxic material, promoting blood circulation and removing blood stasis, and inducing diuresis to reduce edema. Recent pharmacology investigations have provided evidence for its anti-cancer, bacteriostasis, anti-virus, anti-inflammation, anti-oxidation and immunity enhancement properties. The efficacy of activating blood circulation and removing blood stasis has unique advantages in the treatment of cardiovascular and cerebrovascular diseases. A total of 84 compounds have been isolated from S. barbata and are characterized mainly as flavonoids, diterpenoids, followed by polysaccharide, volatile oil and steroids. Peer-reviewed articles published over the last few years were gathered by consulting the databases PubMed, Elsevier, Springer, and Chinese Herbal Classics. This review mainly focuses on the pharmacologically active constituents isolated from S. barbata，which have been subjected to in vitro and/or in vivo studies. Although, the chemical components, pharmacological activities, toxicology, clinical applications and mechanisms of action of S. barbata have been investigated, many constituents remain unknown. Further investigations are required to investigate the medicinal properties of S. barbata.

The Blood-Brain Barrier Interface in Diabetes Mellitus: Dysfunctions, Mechanisms and Approaches to Treatment.

Abstract: Diabetes mellitus (DM) is one of the most common diseases in the world. Among its effects are an increase in the risk of cognitive impairment, including Alzheimer's disease, and blood-brain barrier (BBB) dysfunction. DM is characterized by high blood glucose levels that are caused by either lack of insulin (Type I) or resistance to the actions of insulin (Type II). The phenotypes of these two types are dramatically different, with Type I animals being thin, with low levels of leptin as well as insulin, whereas Type II animals are often obese with high levels of both leptin and insulin. The best characterized change in BBB dysfunction is that of disruption. The brain regions that are disrupted, however, vary between Type I vs Type II DM, suggesting that factors other than hyperglycemia, perhaps hormonal factors such as leptin and insulin, play a regionally diverse role in BBB vulnerability or protection. Some BBB transporters are also altered in DM, including P-glycoprotein, lowdensity lipoprotein receptor-related protein 1, and the insulin transporter as other functions of the BBB, such as brain endothelial cell (BEC) expression of matrix metalloproteinases (MMPs) and immune cell trafficking. Pericyte loss secondary to the increased oxidative stress of processing excess glucose through the Krebs cycle is one mechanism that has shown to result in BBB disruption. Vascular endothelial growth factor (VEGF) induced by advanced glycation endproducts can increase the production of matrix metalloproteinases, which in turn affects tight junction proteins, providing another mechanism for BBB disruption as well as effects on P-glycoprotein. Through the enhanced expression of the redox-related mitochondrial transporter ABCB10, redox-sensitive transcription factor NF-E2 related factor-2 (Nrf2) inhibits BEC-monocyte adhesion. Several potential therapies, in addition to those of restoring euglycemia, can prevent some aspects of BBB dysfunction. Carbonic anhydrase inhibition decreases glucose metabolism and so reduces oxidative stress, preserving pericytes and blocking or reversing BBB disruption. Statins or N-acetylcysteine can reverse the BBB opening in some models of DM, fibroblast growth factor-21 improves BBB permeability through an Nrf2-dependent pathway, and nifedipine or VEGF improves memory in DM models. In summary, DM alters various aspects of BBB function through a number of mechanisms. A variety of treatments based on those mechanisms, as well as restoration of euglycemia, may be able to restore BBB functions., including reversal of BBB disruption.

Specificity and Continuity of Schizophrenia and Bipolar Disorder: Relation to Biomarkers.

Abstract: Schizophrenia and bipolar disorder overlap considerably in terms of symptoms, familial patterns, risk genes, outcome, and treatment response. This article provides an overview of the specificity and continuity of schizophrenia and mood disorders on the basis of biomarkers, such as genes, molecules, cells, circuits, physiology and clinical phenomenology. Overall, the discussions herein provided support for the view that schizophrenia, schizoaffective disorder and bipolar disorder are in the continuum of severity of impairment, with bipolar disorder closer to normality and schizophrenia at the most severe end. This approach is based on the concept that examining biomarkers in several modalities across these diseases from the dimensional perspective would be meaningful. These considerations are expected to help develop new treatments for unmet needs, such as cognitive dysfunction, in psychiatric conditions.

Protective Effects and Mechanisms of Action of Ulinastatin against Cerebral Ischemia-Reperfusion Injury.

Abstract: Background Cerebral ischemia-reperfusion injury is an extremely complicated pathological process that is clinically characterized by high rates of disability and mortality. It is imperative to explore some effective neuroprotective agents for its treatment. Ulinastatin is a protease inhibitor with anti-inflammatory and antioxidant activity. For the past few years, new studies of ulinastatin for the treatment of ischemic brain injury have emerged. Objective We conducted a review to summarize the mechanisms of ulinastatin and analyze its neuroprotective action against cerebral ischemia-reperfusion injury. Methods We reviewed and summarized pertinent reports published between 1993 and 2019 from PubMed, Web of Science, and Embaseby searching for the scientific terms ulinastatin, cerebral ischemia-reperfusion injury, neuroprotective, stroke, cardiac arrest, and brain edema. Results The protective mechanisms of ulinastatin in the key steps of cerebral ischemia-reperfusion injury include inhibition of inflammatory response, oxidative stress, neuronal apoptosis, neuronal autophagy, and aquaporin- 4 expression as well as improvement in blood-brain barrier permeability. In addition, we provide a perspective on potential research directions and clinical safety. Conclusion Ulinastatin seems to have the potential to alleviate cerebral ischemia-reperfusion injury. These findings may be valuable to further promote the research and development of drug candidates and provide novel and reliable references for rational drug use.

Solid Lipid Nanoparticles for Topical Drug Delivery: Mechanisms, Dosage Form Perspectives, and Translational Status

Abstract: Solid lipid nanoparticles (SLNs) have shown potential as a novel lipid-based drug delivery system for the topical applications of innumerable therapeutic compounds. However, the mechanisms governing the absorption and cellular uptake of SLNs through topical route, along with the mechanism of drug release from SLNs are still ambiguous, and require further investigation. In addition, the selection of an appropriate dosage form/formulation base is essential for ease of application of SLNs and to enhance dermal and transdermal delivery. Upscaling and regulatory approvals are other challenges that may impede the clinical translation of SLNs. Therefore, this review focusses on different mechanisms involved in skin penetration and cellular uptake of SLNs. This is followed by a comprehensive discussion on the physicochemical properties of SLNs including various formulation and dosage form factors, which might influence the absorption of SLNs through the skin. Finally, translational status with respect to scale-up and regulatory aspects are also discussed. This review will be useful to researchers with an interest in topical applications of SLNs for the efficient delivery of drugs and cosmetics.