Showing papers in "Current Medicinal Chemistry in 2020"

SARS-CoV-2: Recent Reports on Antiviral Therapies Based on Lopinavir/Ritonavir, Darunavir/Umifenovir, Hydroxychloroquine, Remdesivir, Favipiravir and other Drugs for the Treatment of the New Coronavirus.

Abstract: Here we report on the most recent updates on experimental drugs successfully employed in the treatment of the disease caused by SARS-CoV-2 coronavirus, also referred to as COVID-19 (COronaVIrus Disease-19). In particular, several cases of recovered patients have been reported after being treated with lopinavir/ritonavir [which is widely used to treat Human Immunodeficiency Virus (HIV) infection] in combination with the anti-flu drug oseltamivir. In addition, remdesivir, which has been previously administered to Ebola virus patients, has also proven effective in the U.S. against coronavirus, while antimalarial chloroquine and hydroxychloroquine, favipiravir and co-administered darunavir and umifenovir (in patient therapies) were also recently recorded as having anti-SARS-CoV-2 effects. Since the recoveries/deaths ratio in the last weeks significantly increased, especially in China, it is clear that the experimental antiviral therapy, together with the availability of intensive care unit beds in hospitals and rigorous government control measures, all play an important role in dealing with this virus. This also stresses the urgent need for the scientific community to devote its efforts to the development of other more specific antiviral strategies.

Metal-Organic Framework (MOF)-Based Drug Delivery

Abstract: Background Developing a controllable drug delivery system is imperative and important to reduce side effects and enhance the therapeutic efficacy of drugs. Metal-organic frameworks (MOFs) an emerging class of hybrid porous materials built from metal ions or clusters bridged by organic linkers have attracted increasing attention in the recent years owing to the unique physical structures possessed, and the potential for vast applications. The superior properties of MOFs, such as well-defined pore aperture, tailorable composition and structure, tunable size, versatile functionality, high agent loading, and improved biocompatibility, have made them promising candidates as drug delivery hosts. MOFs for drug delivery is of great interest and many very promising results have been found, indicating that these porous solids exhibit several advantages over existing systems. Objective This review highlights the latest advances in the synthesis, functionalization, and applications of MOFs in drug delivery, and has classified them using drug loading strategies. Finally, challenges and future perspectives in this research area are also outlined.

Aptamer-Based Targeted Drug Delivery Systems: Current Potential and Challenges.

Abstract: Aptamers are single-stranded DNA or RNA with 20-100 nucleotides in length that can specifically bind to target molecules via formed three-dimensional structures. These innovative targeting molecules have attracted an increasing interest in the biomedical field. Compared to traditional protein antibodies, aptamers have several advantages, such as small size, high binding affinity, specificity, good biocompatibility, high stability and low immunogenicity, which all contribute to their wide application in the biomedical field. Aptamers can bind to the receptors on the cell membrane and mediate themselves or conjugated nanoparticles to enter into cells. Therefore, aptamers can be served as ideal targeting ligands for drug delivery. Since their excellent properties, different aptamer-mediated drug delivery systems had been developed for cancer therapy. This review provides a brief overview of recent advances in drug delivery systems based on aptamers. The advantages, challenges and future prospectives are also discussed.

Unlocking the Potential of HK2 in Cancer Metabolism and Therapeutics.

Abstract: Glycolysis is a tightly regulated process in which several enzymes, such as Hexokinases (HKs), play crucial roles. Cancer cells are characterized by specific expression levels of several isoenzymes in different metabolic pathways and these features offer possibilities for therapeutic interventions. Overexpression of HKs (mostly of the HK2 isoform) have been consistently reported in numerous types of cancer. Moreover, deletion of HK2 has been shown to decrease cancer cell proliferation without explicit side effects in animal models, which suggests that targeting HK2 is a viable strategy for cancer therapy. HK2 inhibition causes a substantial decrease of glycolysis that affects multiple pathways of central metabolism and also destabilizes the mitochondrial outer membrane, ultimately enhancing cell death. Although glycolysis inhibition has met limited success, partly due to low selectivity for specific isoforms and excessive side effects of the reported HK inhibitors, there is ample ground for progress. The current review is focused on HK2 inhibition, envisaging the development of potent and selective anticancer agents. The information on function, expression, and activity of HKs is presented, along with their structures, known inhibitors, and reported effects of HK2 ablation/inhibition. The structural features of the different isozymes are discussed, aiming to stimulate a more rational approach to the design of selective HK2 inhibitors with appropriate drug-like properties. Particular attention is dedicated to a structural and sequence comparison of the structurally similar HK1 and HK2 isoforms, aiming to unveil differences that could be explored therapeutically. Finally, several additional catalytic- and non-catalytic roles on different pathways and diseases, recently attributed to HK2, are reviewed and their implications briefly discussed.

Antimicrobial Capacity of Plant Polyphenols against Gram-positive Bacteria: A Comprehensive Review.

Abstract: Background Multi-drug-resistant bacteria such as Methicillin-Resistant Staphylococcus aureus (MRSA) disseminate rapidly amongst patients in healthcare facilities and suppose an increasingly important cause of community-associated infections and associated mortality. The development of effective therapeutic options against resistant bacteria is a public health priority. Plant polyphenols are structurally diverse compounds that have been used for centuries for medicinal purposes, including infections treatment and possess, not only antimicrobial activity, but also antioxidant, anti-inflammatory and anticancer activities among others. Based on the existing evidence on the polyphenols' antibacterial capacity, polyphenols may be postulated as an alternative or complementary therapy for infectious diseases. Objective To review the antimicrobial activity of plant polyphenols against Gram-positive bacteria, especially against S. aureus and its resistant strains. Determine the main bacterial molecular targets of polyphenols and their potential mechanism of action. Methodology The most relevant reports on plant polyphenols' antibacterial activity and their putative molecular targets were studied. We also performed virtual screening of thousand different polyphenols against proteins involved in the peptidoglycan biosynthesis to find potential valuable bioactive compounds. The bibliographic information used in this review was obtained from MEDLINE via PubMed. Results Several polyphenols: phenolic acids, flavonoids (especially flavonols), tannins, lignans, stilbenes and combinations of these in botanical mixtures, have exhibited significant antibacterial activity against resistant and non-resistant Gram-positive bacteria at low μg/mL range MIC values. Their mechanism of action is quite diverse, targeting cell wall, lipid membrane, membrane receptors and ion channels, bacteria metabolites and biofilm formation. Synergic effects were also demonstrated for some combinations of polyphenols and antibiotics. Conclusion Plant polyphenols mean a promising source of antibacterial agents, either alone or in combination with existing antibiotics, for the development of new antibiotic therapies.

Bioactive Secondary Metabolites from Endophytic Fungi.

Abstract: Background Endophytes represent a complex community of microorganisms colonizing asymptomatically internal tissues of higher plants. Several reports have shown that endophytes enhance the fitness of their host plants by direct production of bioactive secondary metabolites, which are involved in protecting the host against herbivores and pathogenic microbes. In addition, it is increasingly apparent that endophytes are able to biosynthesize medicinally important "phytochemicals", originally believed to be produced only by their host plants. Objective The present review provides an overview of secondary metabolites from endophytic fungi with pronounced biological activities covering the literature between 2010 and 2017. Special focus is given on studies aiming at exploration of the mode of action of these metabolites towards the discovery of leads from endophytic fungi. Moreover, this review critically evaluates the potential of endophytic fungi as alternative sources of bioactive "plant metabolites". Results Over the past few years, several promising lead structures from endophytic fungi have been described in the literature. In this review, 65 metabolites are outlined with pronounced biological activities, primarily as antimicrobial and cytotoxic agents. Some of these metabolites have shown to be highly selective or to possess novel mechanisms of action, which hold great promises as potential drug candidates. Conclusion Endophytes represent an inexhaustible reservoir of pharmacologically important compounds. Moreover, endophytic fungi could be exploited for the sustainable production of bioactive "plant metabolites" in the future. Towards this aim, further insights into the dynamic endophyte - host plant interactions and origin of endophytic fungal genes would be of utmost importance.

Recent Progress in Histone Deacetylase Inhibitors as Anticancer Agents.

Abstract: Histone Deacetylase (HDAC) inhibitors are a relatively new class of anti-cancer agents that play important roles in epigenetic or non-epigenetic regulation, inducing death, apoptosis, and cell cycle arrest in cancer cells. Recently, their use has been clinically validated in cancer patients resulting in the approval by the FDA of four HDAC inhibitors, vorinostat, romidepsin, belinostat and panobinostat, used for the treatment of cutaneous/peripheral T-cell lymphoma and multiple myeloma. Many more HDAC inhibitors are at different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. Also, clinical trials of several HDAC inhibitors for use as anti-cancer drugs (alone or in combination with other anti-cancer therapeutics) are ongoing. In the intensifying efforts to discover new, hopefully, more therapeutically efficacious HDAC inhibitors, molecular modelingbased rational drug design has played an important role. In this review, we summarize four major structural classes of HDAC inhibitors (hydroxamic acid derivatives, aminobenzamide, cyclic peptide and short-chain fatty acids) that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility.

Comprehensive Review on Graphene Oxide for Use in Drug Delivery System.

Abstract: Motivated by the accomplishment of carbon nanotubes (CNTs), graphene and graphene oxide (GO) has been widely investigated in the previous studies as an innovative medication nanocarrier for the loading of a variety of therapeutics as well as anti-cancer medications, poor dissolvable medications, antibiotics, antibodies, peptides, DNA, RNA and genes. Graphene provides the ultra-high drug-loading efficiency due to the wide surface area. Graphene and graphene oxide have been widely investigated for biomedical applications due to their exceptional qualities: twodimensional planar structure, wide surface area, chemical and mechanical constancy, sublime conductivity and excellent biocompatibility. Due to these unique qualities, GO applications provide advanced drug transports frameworks and transports of a broad range of therapeutics. In this review, we discussed the latest advances and improvements in the uses of graphene and GO for drug transport and nanomedicine. Initially, we have described what is graphene and graphene oxide. After that, we discussed the qualities of GO as a drug carrier, utilization of GO in drug transport applications, targeted drug transport, transport of anticancer medications, chemical control medicine releasee, co-transport of different medications, comparison of GO with CNTs, nano-graphene for drug transport and at last, we have discussed the graphene toxicity. Finally, we draw a conclusion of current expansion and the potential outlook for the future.

Acyclovir in the Treatment of Herpes Viruses - A Review.

Abstract: Background Herpes Simplex (HSV) viruses are widely spread, highly contagious human pathogens. The statistics indicate that 50-90% of adults worldwide are seropositive for these viruses, mainly HSV-1 and HSV-2. The primary infection results in the appearance of watery blisters (cold sores) on the skin, lips, tongue, buccal mucosa or genitals. The ocular infection is the major cause of corneal blindness in the Western World. Once the HSV virus enters human body, it cannot be completely eradicated because HSV viruses are able to change into their latent form which can survive the treatment. The viron resides in trigeminal ganglia of the host, who becomes vulnerable to the reoccurrence of the disease during the whole lifespan. The neurotropic and neuro-invasive properties of HSV are responsible for neurodegenerative illnesses, such as Alzheimer's disease. Acyclovir and its analogues, being the inhibitors of the viral DNA replication, are the only approved medicines for HSV infection therapies. Objective The current paper presents the up-to-date overview of the important pharmacological features of acyclovir, its analogues and their delivery systems including the mechanism of action, routes of administration, absorption and metabolism, as well as side effects of the therapy. Conclusion Acyclovir remains the gold standard in the treatment of herpes virus infections, mainly due to the emerging of the new delivery systems improving considerably its bioavailability. The analogues of acyclovir, especially their esters, characterized by significantly higher bioavailability and safety, may gradually replace acyclovir in selected applications.

The role of diet related short-chain fatty acids in colorectal cancer metabolism and survival: prevention and therapeutic implications

Abstract: Colorectal Cancer (CRC) is a major cause of cancer-related death worldwide. CRC increased risk has been associated with alterations in the intestinal microbiota, with decreased production of Short Chain Fatty Acids (SCFAs). SCFAs produced in the human colon are the major products of bacterial fermentation of undigested dietary fiber and starch. While colonocytes use the three major SCFAs, namely acetate, propionate and butyrate, as energy sources, transformed CRC cells primarily undergo aerobic glycolysis. Compared to normal colonocytes, CRC cells exhibit increased sensitivity to SCFAs, thus indicating they play an important role in cell homeostasis. Manipulation of SCFA levels in the intestine, through changes in microbiota, has therefore emerged as a potential preventive/therapeutic strategy for CRC. Interest in understanding SCFAs mechanism of action in CRC cells has increased in the last years. Several SCFA transporters like SMCT-1, MCT-1 and aquaporins have been identified as the main transmembrane transporters in intestinal cells. Recently, it was shown that acetate promotes plasma membrane re-localization of MCT-1 and triggers changes in the glucose metabolism. SCFAs induce apoptotic cell death in CRC cells, and further mechanisms have been discovered, including the involvement of lysosomal membrane permeabilization, associated with mitochondria dysfunction and degradation. In this review, we will discuss the current knowledge on the transport of SCFAs by CRC cells and their effects on CRC metabolism and survival. The impact of increasing SCFA production by manipulation of colon microbiota on the prevention/therapy of CRC will also be addressed.

Polyoxometalates in Biomedicine: Update and Overview.

Abstract: Background Polyoxometalates (POMs) are negatively charged metal-oxo clusters of early transition metal ions in high oxidation states (e.g., WVI, MoVI, VV). POMs are of interest in the fields of catalysis, electronics, magnetic materials and nanotechnology. Moreover, POMs were shown to exhibit biological activities in vitro and in vivo, such as antitumor, antimicrobial, and antidiabetic. Methods The literature search for this peer-reviewed article was performed using PubMed and Scopus databases with the help of appropriate keywords. Results This review gives a comprehensive overview of recent studies regarding biological activities of polyoxometalates, and their biomedical applications as promising anti-viral, anti-bacterial, anti-tumor, and anti-diabetic agents. Additionally, their putative mechanisms of action and molecular targets are particularly considered. Conclusion Although a wide range of biological activities of Polyoxometalates (POMs) has been reported, they are to the best of our knowledge not close to a clinical trial or a final application in the treatment of diabetes or infectious and malignant diseases. Accordingly, further studies should be directed towards determining the mechanism of POM biological actions, which would enable fine-tuning at the molecular level, and consequently efficient action towards biological targets and as low toxicity as possible. Furthermore, biomedical studies should be performed on solutionstable POMs employing physiological conditions and concentrations.

The Role of Zinc and Copper in Insulin Resistance and Diabetes Mellitus.

Abstract: The prevalence of Type 2 Diabetes Mellitus (T2DM) is internationally ever-growing. Therefore, prevention, diagnostics, and control of insulin resistance and T2DM are of increasing importance. It has been suggested that mechanisms leading to insulin resistance and diabetes and its complications include high intake of refined and energy-rich food, which is presumed to be accompanied by suboptimal intake of trace elements, such as Zinc (Zn), Selenium (Se), Chromium (Cr), and Copper (Cu), which are essential and crucial for various biological processes. The purpose of this review is to highlight the role of Zn, Se, and Cu in T2DM. Diabetes seems prevalent when Zn, Se, and Cu are deficient, which may result from excessive intake of refined food. The literature search was conducted in PubMed and Scopus, supplemented with the reference lists of relevant articles and a Google Scholar search. We critically assessed all relevant citations, both review and research papers in English. The search terms that were used included Zn, Cu, diabetes, and diabetes mellitus. Research has shown that Zn, Se and Cu are involved in the pathogenesis of diabetes, but these trace elements can in excessive amounts be toxic. Zinc appears to activate key molecules that are involved in cell signaling, which maintain the homeostasis of glucose. Zinc also regulates insulin receptors, prolong the action of insulin, and promote healthy lipid profiles. Copper in excess can create oxidative stress, which is a factor in the onset and the progression of T2DM. Abnormal Zn and Cu metabolism appears to accompany and may also cause diabetes complications.

Anti-tumor Effects of Curcuminoids in Glioblastoma Multiforme: An Updated Literature Review

Abstract: Glioblastoma Multiforme (GBM) is a poorly curable brain tumor because of its extremely invasive nature. Curcuminoids, as potential phytochemicals extracted from Curcuma Longa L., have been documented for their chemopreventive and antitumor activities against several types of malignancies. These compounds exert these effects via modulation of multiple signaling pathways and molecular targets at different stages of tumor progression, proliferation, and metastasis. In experimental studies, curcuminoids have demonstrated promising therapeutic benefits to overcome GBM. Curcuminoids have been shown to exert their anti-GBM effects through regulation of angiogenesis, apoptosis, autophagy, metastasis, invasion as well as potential molecular targets, including receptor tyrosine kinases, Sonic Hedgehog, and NF-κB. This study reviews the observations regarding the impact of curcumin and its derivatives on GBM and the potential of translating the research findings into the clinic.

Ferroptosis: A Novel Mechanism of Artemisinin and its Derivatives in Cancer Therapy

Abstract: Background Artemisinin is a sesquiterpene lactone compound with a special peroxide bridge that is tightly linked to the cytotoxicity involved in fighting malaria and cancer. Artemisinin and its derivatives (ARTs) are considered to be potential anticancer drugs that promote cancer cell apoptosis, induce cell cycle arrest and autophagy, inhibit cancer cell invasion and migration. Additionally, ARTs significantly increase intracellular Reactive Oxygen Species (ROS) in cancer cells, which result in ferroptosis, a new form of cell death, depending on the ferritin concentration. Ferroptosis is regarded as a cancer suppressor and as well as considered a new mechanism for cancer therapy. Methods The anticancer activities of ARTs and reference molecules were compared by literature search and analysis. The latest research progress on ferroptosis was described, with a special focus on the molecular mechanism of artemisinin-induced ferroptosis. Results Artemisinin derivatives, artemisinin-derived dimers, hybrids and artemisinin-transferrin conjugates, could significantly improve anticancer activity, and their IC50 values are lower than those of reference molecules such as doxorubicin and paclitaxel. The biological activities of linkers in dimers and hybrids are important in the drug design processes. ARTs induce ferroptosis mainly by triggering intracellular ROS production, promoting the lysosomal degradation of ferritin and regulating the System Xc-/Gpx4 axis. Interestingly, ARTs also stimulate the feedback inhibition pathway. Conclusion Artemisinin and its derivatives could be used in the future as cancer therapies with broader applications due to their induction of ferroptosis. Meanwhile, more attention should be paid to the development of novel artemisinin-related drugs based on the mechanism of artemisinininduced ferroptosis.

Antiviral Activities of Human Host Defense Peptides.

Abstract: Peptides with broad-spectrum antimicrobial activity are found widely expressed throughout nature. As they participate in a number of different aspects of innate immunity in mammals, they have been termed Host Defense Peptides (HDPs). Due to their common structural features, including an amphipathic structure and cationic charge, they have been widely shown to interact with and disrupt microbial membranes. Thus, it is not surprising that human HDPs have activity against enveloped viruses as well as bacteria and fungi. However, these peptides also exhibit activity against a wide range of non-enveloped viruses as well, acting at a number of different steps in viral infection. This review focuses on the activity of human host defense peptides, including alpha- and beta-defensins and the sole human cathelicidin, LL-37, against both enveloped and non-enveloped viruses. The broad spectrum of antiviral activity of these peptides, both in vitro and in vivo suggest that they play an important role in the innate antiviral defense against viral infections. Furthermore, the literature suggests that they may be developed into antiviral therapeutic agents.

Advances in Docking.

Abstract: Background Design of small molecules which are able to bind to the protein responsible for a disease is the key step of the entire process of the new medicine discovery. Atomistic computer modeling can significantly improve effectiveness of such design. The accurate calculation of the free energy of binding a small molecule (a ligand) to the target protein is the most important problem of such modeling. Docking is one of the most popular molecular modeling methods for finding ligand binding poses in the target protein and calculating the protein-ligand binding energy. This energy is used for finding the most active compounds for the given target protein. This short review aims to give a concise description of distinctive features of docking programs focusing on computation methods and approximations influencing their accuracy. Methods This review is based on the peer-reviewed research literature including author's own publications. The main features of several representative docking programs are briefly described focusing on their characteristics influencing docking accuracy: force fields, energy calculations, solvent models, algorithms of the best ligand pose search, global and local optimizations, ligand and target protein flexibility, and the simplifications made for the docking accelerating. Apart from other recent reviews focused mainly on the performance of different docking programs, in this work, an attempt is made to extract the most important functional characteristics defining the docking accuracy. Also a roadmap for increasing the docking accuracy is proposed. This is based on the new generation of docking programs which have been realized recently. These programs and respective new global optimization algorithms are described shortly. Results Several popular conventional docking programs are considered. Their search of the best ligand pose is based explicitly or implicitly on the global optimization problem. Several algorithms are used to solve this problem, and among them, the heuristic genetic algorithm is distinguished by its popularity and an elaborate design. All conventional docking programs for their acceleration use the preliminary calculated grids of protein-ligand interaction potentials or preferable points of protein and ligand conjugation. These approaches and commonly used fitting parameters restrict strongly the docking accuracy. Solvent is considered in exceedingly simplified approaches in the course of the global optimization and the search for the best ligand poses. More accurate approaches on the base of implicit solvent models are used frequently for more careful binding energy calculations after docking. The new generation of docking programs are developed recently. They find the spectrum of low energy minima of a protein-ligand complex including the global minimum. These programs should be more accurate because they do not use a preliminary calculated grid of protein-ligand interaction potentials and other simplifications, the energy of any conformation of the molecular system is calculated in the frame of a given force field and there are no fitting parameters. A new docking algorithm is developed and fulfilled specially for the new docking programs. This algorithm allows docking a flexible ligand into a flexible protein with several dozen mobile atoms on the base of the global energy minimum search. Such docking results in improving the accuracy of ligand positioning in the docking process. The adequate choice of the method of molecular energy calculations also results in the better docking positioning accuracy. An advancement in the application of quantum chemistry methods to docking and scoring is revealed. Conclusion The findings of this review confirm the great demand in docking programs for discovery of new medicine substances with the help of molecular modeling. New trends in docking programs design are revealed. These trends are focused on the increase of the docking accuracy at the expense of more accurate molecular energy calculations without any fitting parameters, including quantum-chemical methods and implicit solvent models, and by using new global optimization algorithms which make it possible to treat flexibility of ligands and mobility of protein atoms simultaneously. Finally, it is shown that all the necessary prerequisites for increasing the docking accuracy can be accomplished in practice.

Terpenes, Phenylpropanoids, Sulfur and Other Essential Oil Constituents as Inhibitors of Cholinesterases.

Abstract: Essential oils constituents are a diverse family of low molecular weight organic compounds with comprehensive biological activity. According to their chemical structure, these active compounds can be divided into four major groups: terpenes, terpenoids, phenylpropenes, and "others". In addition, they may contain diverse functional groups according to which they can be classified as hydrocarbons (monoterpenes, sesquiterpenes, and aliphatic hydrocarbons); oxygenated compounds (monoterpene and sesquiterpene alcohols, aldehydes, ketones, esters, and other oxygenated compounds); and sulfur and/or nitrogen containing compounds (thioesters, sulfides, isothiocyanates, nitriles, and others). Compounds that act as cholinesterase inhibitors still represent the only pharmacological treatment of Alzheimer´s disease. Numerous in vitro studies showed that some compounds, found in essential oils, have a promising cholinesterase inhibitory activity, such as α-pinene, δ-3-carene, 1,8-cineole, carvacrol, thymohydroquinone, α- and β-asarone, anethole, etc. This review summarizes the most relevant research published to date on essential oil constituents and their acetylcholinesterase/butyrylcholinesterase inhibitory potential as well as their structure related activity, synergistic and antagonistic effects.

Natural Polymer-based Stimuli-responsive Hydrogels.

Abstract: The abilities of intelligent polymer hydrogels to change their structure and volume phase in response to external stimuli have provided new possibilities for various advanced technologies and great research and application potentials in the medical field. The natural polymer-based hydrogels have the advantages of environment-friendliness, rich sources and good biocompatibility. Based on their responsiveness to external stimuli, the natural polymer-based hydrogels can be classified into the temperature-responsive hydrogel, pH-responsive hydrogel, light-responsive hydrogel, electricresponsive hydrogel, redox-responsive hydrogel, enzyme-responsive hydrogel, magnetic-responsive hydrogel, multi-responsive hydrogel, etc. In this review, we have compiled some recent studies on natural polymer-based stimuli-responsive hydrogels, especially the hydrogels prepared from polysaccharides. The preparation methods, properties and applications of these hydrogels in the medical field are highlighted.

The Role of Matrix Gla Protein (MGP) in Vascular Calcification

Abstract: Matrix Gla protein (MGP) is a vitamin K-dependent protein, which is synthesized in bone and many other mesenchymal cells, which is also highly expressed by vascular smooth muscle cells (VSMCs) and chondrocytes. Numerous studies have confirmed that MGP acts as a calcification-inhibitor although the mechanism of action is still not fully understood. The modulation of tissue calcification by MGP is potentially regulated in several ways including direct inhibition of calcium-phosphate precipitation, the formation of matrix vesicles (MVs), the formation of apoptotic bodies (ABs), and trans-differentiation of VSMCs. MGP occurs as four species, i.e. fully carboxylated (cMGP), under-carboxylated, i.e. poorly carboxylated (ucMGP), phosphorylated (pMGP), and non-phosphorylated (desphospho, dpMGP). ELISA methods are currently available that can detect the different species of MGP. The expression of the MGP gene can be regulated via various mechanisms that have the potential to become genomic biomarkers for the prediction of vascular calcification (VC) progression. VC is an established risk factor for cardiovascular disease and is particularly prevalent in those with chronic kidney disease (CKD). The specific action of MGP is not yet clearly understood but could be involved with the functional inhibition of BMP-2 and BMP-4, by blocking calcium crystal deposition and shielding the nidus from calcification.

Pyridine and Pyrimidine Derivatives as Privileged Scaffolds in Biologically Active Agents

Abstract: Pyridine and pyrimidine derivatives have received great interest in recent pharmacological research, being effective in the treatment of various malignancies, such as myeloid leukemia, breast cancer and idiopathic pulmonary fibrosis. Most of the FDA approved drugs show a pyridine or pyrimidine core bearing different substituents. The aim of this review is to describe the most recent reports in this field, with reference to the newly discovered pyridineor pyrimidine-based drugs, to their synthesis and to the evaluation of the most biologically active derivatives. The corresponding benzo-fused heterocyclic compounds, i.e. quinolines and quinazolines, are also reported.

A Systematic Review on Anti-diabetic Properties of Chalcones

Abstract: The use of anti-diabetic drugs has been increasing worldwide and the evolution of therapeutics has been enormous. Still, the currently available anti-diabetic drugs do not present the desired efficacy and are generally associated with serious adverse effects. Thus, entirely new interventions, addressing the underlying etiopathogenesis of type 2 diabetes mellitus, are required. Chalcones, secondary metabolites of terrestrial plants and precursors of the flavonoids biosynthesis, have been used for a long time in traditional medicine due to their wide-range of biological activities, from which the anti-diabetic activity stands out. This review systematizes the information found in literature about the anti-diabetic properties of chalcones, in vitro and in vivo. Chalcones are able to exert these properties by acting in different therapeutic targets: Dipeptidyl Peptidase 4 (DPP-4); Glucose Transporter Type 4 (GLUT4), Sodium Glucose Cotransporter 2 (SGLT2), α-amylase, α-glucosidase, Aldose Reductase (ALR), Protein Tyrosine Phosphatase 1B (PTP1B), Peroxisome Proliferator-activated Receptor-gamma (PPARγ) and Adenosine Monophosphate (AMP)-activated Protein Kinase (AMPK). Chalcones are, undoubtedly, promising anti-diabetic agents, and some crucial structural features have already been established. From the Structure-Activity Relationships analysis, it can generally be stated that the presence of hydroxyl, prenyl and geranyl groups in their skeleton improves their activity for the evaluated anti-diabetic targets.

A Review: The Anti-inflammatory, Anticancer and Antibacterial Properties of Four Kinds of Licorice Flavonoids Isolated from Licorice

Abstract: Plants have always been an important source of medicines for humans, and licorice is a very significant herb in the development of humans. As a traditional herb, it is widely cultivated in China, Japan, Russia, Spain and India. With the development of organic chemistry and biochemistry, various chemical ingredients extracted from licorice have been studied and identified. Among them, many chemical components were considered to have strong pharmacological activities, such as anti-inflammatory, anti-ulcer, antibacterial, anticancer and so on. Based on those reports, licorice has attracted the attention of many researchers in recent years, and they are devoted to discovering the active ingredients and mechanism of action of active compounds. Licorice flavonoids are one of the main extracts of licorice root and stem and have many potential biological properties. This paper aims to summarize the four kinds of licorice flavonoids, including liquiritigenin, isoliquiritigenin, licochalcone (including licochalcone A and licochalcone B) and glabridin, about their biological activities of anti-inflammatory, anticancer, antibacterial.

Metabolic Routes in Inflammation: The Citrate Pathway and its Potential as Therapeutic Target.

Abstract: Significant metabolic changes occur in inflammation to respond to the new energetic needs of cells. Mitochondria are addressed not only to produce ATP, but also to supply substrates, such citrate, to produce pro-inflammatory molecules. In this context, most of the citrate is diverted from Krebs cycle and channeled into the "citrate pathway" leading to the increase in the export of citrate into cytosol by the Mitochondrial Citrate Carrier (CIC) followed by its cleavage into acetyl-CoA and oxaloacetate by ATP Citrate Lyase (ACLY). Acetyl- CoA is used to produce PGE2 and oxaloacetate to make NADPH needed for NO and ROS production. In addition, cytosolic citrate also provides precursors for itaconate synthesis. Citrate- derived itaconate acts as a negative regulator of inflammation by modulating the synthesis of the inflammatory mediators. Inhibition of CIC or ACLY by different synthetic and natural molecules results in the reduction of NO, ROS and PGE2 levels suggesting that the citrate pathway can be a new target to be addressed in inflammation. Beneficial effects can be obtained also in the oxidative stress and inflammatory conditions observed in Down syndrome.

B7-H3 Immune Checkpoint Protein in Human Cancer.

Abstract: B7-H3 belongs to the B7 family of immune checkpoint proteins, which are important regulators of the adaptive immune response and emerging key players in human cancer. B7-H3 is a transmembrane protein expressed on the surface of tumor cells, antigen presenting cells, natural killer cells, tumor endothelial cells, but can also be present in intra- and extracellular vesicles. Additionally, B7-H3 may be present as a circulating soluble isoform in serum and other body fluids. B7-H3 is overexpressed in a variety of tumor types, in correlation with poor prognosis. B7-H3 is a promising new immunotherapy target for anti-cancer immune response, as well as a potential biomarker. Besides its immunoregulatory role, B7-H3 has intrinsic pro-tumorigenic activities related to enhanced cell proliferation, migration, invasion, angiogenesis, metastatic capacity and anti-cancer drug resistance. B7-H3 has also been found to regulate key metabolic enzymes, promoting the high glycolytic capacity of cancer cells. B7-H3 receptors are still not identified, and little is known about the molecular mechanisms underlying B7-H3 functions. Here, we review the current knowledge on the involvement of B7-H3 in human cancer.

Osteoporosis: Current and Emerging Therapies Targeted to Immunological Checkpoints.

Abstract: Osteoporosis is a skeletal pathology characterized by compromised bone strength leading to increased risk of fracture, mainly the spine and hip fractures. Osteoporosis affects more than 200 million people worldwide and because of the skeletal fractures it causes, represents a major cause of morbidity, disability and mortality in older people. Recently, the new discoveries of osteoimmunology have clarified many of the pathogenetic mechanisms of osteoporosis, helping to identify new immunological targets for its treatment opening the way for new and effective therapies with biological drugs. Currently, there are basically two monoclonal antibodies for osteoporosis therapy: denosumab and romosozumab. Here, we focus on the modern approach to the osteoporosis management and in particular, on current and developing biologic drugs targeted to new immunological checkpoints, in the landscape of osteoimmunology.

Targeting n-3 Polyunsaturated Fatty Acids in Non-Alcoholic Fatty Liver Disease.

Abstract: Background Non-Alcoholic Fatty Liver Disease (NAFLD) is characterized by abnormal hepatic accumulation of triacylglycerides in the absence of alcohol consumption, in association with Oxidative Stress (OS), a pro-inflammatory state and Insulin Resistance (IR), which are attenuated by n-3 long-chain polyunsaturated Fatty Acids (FAs) C20-C22 (LCPUFAs) supplementation. Main causes of NAFLD comprise high caloric intake and a sedentary lifestyle, with high intakes of saturated FAs. Methods The review includes several searches considering the effects of n-3 LCPUFAs in NAFLD in vivo and in vitro models, using the PubMed database from the National Library of Medicine- National Institutes of Health. Result The LCPUFAs eicosapentaenoic acid (C20:5 n-3, EPA) and docosahexaenoic acid (C22:6 n- 3, DHA) have a positive effect in diminishing liver steatosis, OS, and the levels of aspartate aminotransferase, alanine aminotransferase and pro-inflammatory cytokines, with improvement of insulin sensitivity and adiponectin levels. The molecular pathways described for n-3 LCPUFAs in cellular and animal models and humans include peroxisome proliferator-activated receptor-α activation favouring FA oxidation, diminution of lipogenesis due to sterol responsive element binding protein-1c downregulation and inflammation resolution. Besides, nuclear factor erythroid-2-related factor-2 activation is elicited by n-3 LCPUFA-derived oxidation products producing direct and indirect antioxidant responses, with concomitant anti-fibrogenic action. Conclusion The discussed effects of n-3 LCPUFA supplementation support its use in NAFLD, although having a limited value in NASH, a contention that may involve n-3 LCPUFA oxygenated derivatives. Clinical trials establishing optimal dosages, intervention times, type of patients and possible synergies with other natural products are needed in future studies.

The Application of Hydrogels Based on Natural Polymers for Tissue Engineering.

Abstract: Hydrogels are known as polymer-based networks with the ability to absorb water and other body fluids. Because of this, the hydrogels are used to preserve drugs, proteins, nutrients or cells. Hydrogels possess great biocompatibility, and properties like soft tissue, and networks full of water, which allows oxygen, nutrients, and metabolites to pass. Therefore, hydrogels are extensively employed as scaffolds in tissue engineering. Specifically, hydrogels made of natural polymers are efficient structures for tissue regeneration, because they mimic natural environment which improves the expression of cellular behavior. Producing natural polymer-based hydrogels from collagen, hyaluronic acid (HA), fibrin, alginate, and chitosan is a significant tactic for tissue engineering because it is useful to recognize the interaction between scaffold with a tissue or cell, their cellular reactions, and potential for tissue regeneration. The present review article is focused on injectable hydrogels scaffolds made of biocompatible natural polymers with particular features, the methods that can be employed to engineer injectable hydrogels and their latest applications in tissue regeneration.

Advances in Pharmacological Activities and Mechanisms of Glycyrrhizic Acid.

Abstract: Licorice (Glycyrrhiza glabra L.) is widely regarded as an important medicinal plant and has been used for centuries in traditional medicine because of its therapeutic properties. Studies have shown that metabolites isolated from licorice have many pharmacological activities, such as antiinflammatory, anti-viral, participation in immune regulation, anti-tumor and other activities. This article gives an overview of the pharmacological activities and mechanisms of licorice metabolites and the adverse reactions that need attention. This review helps to further investigate the possibility of licorice as a potential drug for various diseases. It is hoped that this review can provide a relevant theoretical basis for relevant scholars' research and their own learning.

Exosomes and Lung cancer: Roles in pathophysiology, diagnosis and therapeutic applications.

Abstract: Lung cancer is a malignancy with a high morbidity and mortality rate, and affected patients have low survival and poor prognosis. The therapeutic approaches for the treatment of this cancer, including radiotherapy and chemotherapy, are not particularly effective partly due to late diagnosis. Therefore, the search for new diagnostic and prognostic tools is a critical issue. Novel biomarkers, such as exosomes, could be considered as potential diagnostic tools for malignancies, particularly lung cancer. Exosomes are nanovesicles, which are associated with different physiological and pathological conditions. It has been shown that these particles are released from many cells, such as cancer cells, immune cells and to some degree normal cells. Exosomes could alter the behavior of target cells through intercellular transfer of their cargo (e.g. DNA, mRNA, long non-coding RNAs, microRNAs and proteins). Thus, these vehicles may play pivotal roles in various physiological and pathological conditions. The current insights into lung cancer pathogenesis suggest that exosomes are key players in the pathogenesis of this cancer. Hence, these nanovesicles and their cargos could be used as new diagnostic, prognostic and therapeutic biomarkers in the treatment of lung cancer. Besides the diagnostic roles of exosomes, their use as drug delivery systems and as cancer vaccines is under investigation. The present review summarizes the current information on the diagnostic and pathogenic functions of exosomes in lung cancer.

Natural Polymers Based Hydrogels for Cell Culture Applications.

Abstract: It is well known that the extracellular matrix (ECM) plays a vital role in the growth, survival and differentiation of cells. Though two-dimensional (2D) materials are generally used as substrates for the standard in vitro experiments, their mechanical, structural, and compositional characteristics can alter cell functions drastically. Many scientists reported that cells behave more natively when cultured in three-dimensional (3D) environments than on 2D substrates, due to the more in vivo-like 3D cell culture environment that can better mimic the biochemical and mechanical properties of the ECM. In this regard, water-swollen network polymer-based materials called hydrogels are highly attractive for developing 3D ECM analogs due to their biocompatibility and hydrophilicity. Since hydrogels can be tuned and altered systematically, these materials can function actively in a defined culture medium to support long-term self-renewal of various cells. The physico-chemical and biological properties of the materials used for developing hydrogel should be tunable in accordance with culture needs. Various types of hydrogels derived either from natural or synthetic origins are currently being used for cell culture applications. In this review, we present an overview of various hydrogels based on natural polymers that can be used for cell culture, irrespective of types of applications. We also explain how each hydrogel is made, its source, pros and cons in biological applications with a special focus on regenerative engineering.