Showing papers in "Current Medicinal Chemistry in 2017"

Glioblastoma Multiforme, Diagnosis and Treatment; Recent Literature Review.

Abstract: Background Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor, with an incidence of 3.19 cases per 100,000 person years and remarkably poor prognosis showing a 5-year survival rate of 4-5%, and only a 26-33% survival rate at 2 years in clinical trials. Objective In this paper, we review the different types of treatment modalities based on the relevant databases. Methods of diagnosis will be described briefly. Method Systemic compilation of the relevant literature. Results & conclusion Today's treatments cannot cure GBM patients but only extend their overall survival. The use of chemoradiation, immunotherapy, and radio sensitizers as an adjuvant therapy cannot reduce the high rates of recurrence within a few months after treatment. Radiotherapy will remain the backbone of the treatment but new treatment modalities must be developed.

Colorectal Cancer Chemotherapy: The Evolution of Treatment and New Approaches.

Abstract: Colorectal cancer (CRC) is one the greatest contributors to cancer related mortality. Although 5 year survival rate for patients at the early stage of CRC (stages I and II) is above 60%, more than 50% of patients are diagnosed at or beyond stage III when distant metastasis has already occurred, in which case 5 year survival rate drops to 10%. Chemotherapeutic intervention coupled with surgery is the backbone of metastatic CRC treatment and the only means of enhanced survival. For decades following its discovery, an antimetabolite 5- fluorouracil (5-FU) was the only chemotherapeutic agent available to successfully improve 12 month survival in CRC patients. Treatment of metastatic CRC has been considered palliative for many years; aiming to increase the duration and quality of the patient's remaining life, with little hope of cure, highlighting the need for novel DNA and RNA targeted therapies in the treatment of CRC. Over the last several decades, combinations of several chemotherapeutic agents have been incorporated into routine clinical practice. Combination regimes incorporating irinotecan, a semisynthetic inhibitor of topoisomerase, oxaliplatin, a third-generation platinum compound that causes mitotic arrest via the formation of DNA adducts, and capecitabine, a 5-FU prodrug, are now all established options for use as first-line, second-line and sequential treatment of CRC. This review provides a brief overview of the evolution of CRC chemotherapy as well as new and emerging treatment options.

The Antidiabetic Potential of Quercetin: Underlying Mechanisms.

Abstract: The dramatic increase in modern lifestyle diseases such as cancer, cardiovascular diseases and diabetes has renewed researchers' interest to explore nature as a source of novel therapeutic agents. Flavonoids are a large group of polyphenols that are widely present in the human diet. They have shown promising therapeutic activities against a wide variety of ailments. One of the most widely distributed and most extensively studied flavonoid is the flavonol quercetin. Its powerful antioxidant and anti-inflammatory activities are well documented and are thought to play a role in treating and protecting against diseases including diabetes, cancer, neurodegenerative and cardiovascular diseases. The purpose of this review is to shed light on quercetin therapeutic potential as an antidiabetic agent. Quercetin was reported to interact with many molecular targets in small intestine, pancreas, skeletal muscle, adipose tissue and liver to control whole-body glucose homeostasis. Mechanisms of action of quercetin are pleiotropic and involve the inhibition of intestinal glucose absorption, insulin secretory and insulin-sensitizing activities as well as improved glucose utilization in peripheral tissues. Initial studies suggested poor bioavailability of quercetin. However, recent reports have shown that quercetin was detected in the plasma after food or supplements consumption and has a long half-life in human body. Despite the wealth of in vitro and in vivo results supporting the antidiabetic potential of quercetin, its efficacy in diabetic human subjects is yet to be explored.

Targeting the Akt/PI3K Signaling Pathway as a Potential Therapeutic Strategy for the Treatment of Pancreatic Cancer.

Abstract: The phosphoinositide 3 kinase AKT mammalian target of rapamycin (PI3K-AKTmTOR) signaling pathway is an important in the aetiology of pancreatic cancer (PC) and is frequently activated in PC. It is then associated with a poorer prognosis. Aberrant activation of this pathway is involved in cell metabolism and survival, cell cycle progression, regulation of apoptosis, protein synthesis, and genomic instability. Several agents have been developed to target the Akt/PI3K pathways, including PI3K inhibitors, (e.g. LY294002, Wortmannin), PI3K/mTOR inhibitors (e.g. BEZ235), or Akt inhibitors (e.g. perifosine, MK2206), which have been tested alone or in combinations with DNA-targeted agents (e.g., gemcitabine and fluorouracil) in pancreatic ductal adenocarcinoma (PDAC). However, due to their unfavorable pharmaceutical activities, toxicity, and crossover inhibition of other lipid and protein kinases, these compounds have not been used in clinical studies. In this review, we focus on the progress in the development of Akt, PI3K and mTOR inhibitors for clinical applications, together with the need for the development of in PDAC and the need for the identification of predictive biomarkers and combination strategies with less toxicity in counteracting the mechanisms of resistance to the therapy.

Gut-brain Axis: Role of Lipids in the Regulation of Inflammation, Pain and CNS Diseases

Abstract: The human gut is a composite anaerobic environment with a large, diverse and dynamic enteric microbiota, represented by more than 100 trillion microorganisms, including at least 1000 distinct species. The discovery that a different microbial composition can influence behavior and cognition, and in turn the nervous system can indirectly influence enteric microbiota composition, has significantly contributed to establish the well-accepted concept of gut–brain axis. This hypothesis is supported by several evidence showing mutual mechanisms, which involve the vague nerve, the immune system, the hypothalamic-pituitary-adrenal (HPA) axis modulation and the bacteria-derived metabolites. Many studies have focused on delineating a role for this axis in health and disease, ranging from stress-related disorders such as depression, anxiety and irritable bowel syndrome (IBS) to neurodevelopmental disorders, such as autism, and to neurodegenerative diseases, such as Parkinson Disease, Alzheimer Disease etc. Based on this background, and considering the relevance of alteration of the symbiotic state between host and microbiota, this review focuses on the role and the involvement of bioactive lipids, such as the N-acylethanolamine (NAE) family whose main members are N-arachidonoylethanolamine (AEA), palmitoylethanolamide (PEA) and oleoilethanolamide (OEA), and short chain fatty acids (SCFAs), such as butyrate, belonging to a large group of bioactive lipids able to modulate peripheral and central pathologic processes. It is well established their effective role in inflammation, acute and chronic pain, obesity and central nervous system diseases. It has been shown a possible correlation between these lipids and gut microbiota through different mechanisms. Indeed, systemic administration of specific bacteria can reduce abdominal pain through the involvement of cannabinoid receptor 1 in rat; on the other hand, PEA reduces inflammation markers in a murine model of inflammatory bowel disease (IBD), and butyrate, producted by gut microbiota, is effective in reducing inflammation and pain in irritable bowel syndrome and IBD animal models. In this review, we underline the relationship among inflammation, pain, microbiota and the different lipids, focusing on a possible involvement of NAEs and SCFAs in the gut-brain axis and their role in central nervous system diseases.

Inorganic Nanoparticles for Cancer Therapy: A Transition from Lab to Clinic.

Abstract: Background Inorganic nanoparticles (NPs) including those derived from metals (e.g., gold, silver), semiconductors (e.g., quantum dots), carbon dots, carbon nanotubes, or oxides (e.g., iron oxide), have been deeply investigated recently for diagnostic and therapeutic purposes in oncology. Compared to organic nanomaterials, inorganic NPs have several advantages and unique characteristics for better imaging and drug delivery. Still, only a limited number of inorganic NPs are translated into clinical practice. Method In this review, we discuss the progression of inorganic NPs for cancer therapy and imaging, focusing our attention on opportunities, limitations and challenges for the main constituting nanomaterials, including metallic and magnetic NPs. In particular, the pre-clinical and clinical trials from the bench toward the clinic are here investigated. Results Over the last few decades, the development of wide range of NPs with the ability to tune size, composition and functionality, has provided an excellent resource for nanomedicine. Inorganic NPs provide a great opportunity as drug carriers, due to the easy modification of targeting molecules, the control of drug release by different stimuli, and the effective delivery to target sites, thus resulting in having an improved therapeutic efficacy and in reducing side effects. Inorganic NPs are investigated in preclinical and clinical studies for the detection, diagnosis and treatment of many diseases. The stability of inorganic NPs offers a potential advantage over the traditional delivery methods. Inorganic NPs could enhance and improve current imaging and diagnostic techniques, such as MRI or PET. Even though, they have not yet been approved for drug delivery applications, their ability to respond to external stimuli is now widely investigated in clinic. Conclusion The successful translation of inorganic NPs to the clinic requires the development of a simple, safe, cost-effective, ecofriendly mode of synthesis, and a better understanding of the safety mechanisms, biodistribution and the pharmacokinetics of NPs. However, more attention should be given to concerns on long-term toxicity, carcinogenesis, immunogenicity, inflammation and tissue damage. Although, some inorganic NPs, which were apparently promising in the preclinical phase, were found not to be successful when translated to the clinic, several encouraging NPs are currently being developed for treatment and cancer care and for a wide variety of other diseases.

Cannabis Phenolics and their Bioactivities

Abstract: Background Although Cannabis sativa L. is one of the most versatile plant species with multipurpose use both as medical, alimentary source and as psychoactive abuse, its biomedical relevance focused the attention on major cannabinoids. Phytochemical characterization of cannabis highlights the presence of various non-cannabinoids constituents including flavonoids, spiroindans, dihyrostilbenes, dihydrophenanthrenes, lignanamides, steroids and alkaloids. This review aims to identify polyphenols present in this plant, their biosynthesis, their bioactivities and their synthesis, when this occurred. Methods We undertook a systematic research focused on bibliographic databases including all noncannabinoids phenolics in various C. sativa strains from their isolation, structural elucidation, their biological activity to their synthesis. Result Nevertheless, attention has so far been focused only on cannabinoids (more than one hundred isolated), cannabis is a complex plant able to produce more than 480 chemical entities that represent almost all of the different biogenetic classes. Regarding phenolic compounds, the plant biosynthesises a plethora of unique non-cannabinoids second metabolites, such as prenylated flavonoids, stilbenoids derivatives and lignanammides. Conclusion Cannabis is a plant with high pharmacological and nutrition values, its potentialities and applications are not only circumscribed to cannabinoids biological activities, but also defined by noncannabinoid compounds. The combination of other cannabinoids together with noncannabinoid components could enhance the beneficial effects of THC and could reduce undesirable side effects.

Vanadium, Ruthenium and Copper Compounds: A New Class of Nonplatinum Metallodrugs with Anticancer Activity.

Abstract: Cancer is a group of diseases involving abnormal cell growth. The cells grow uncontrollably with the potential to invade and spread to other parts of the body. This disease is one of the principal death causes in the world, thus becoming a significant topic of scientific research. On the other hand, transition metals play a fundamental role in different living systems. In particular, Metallodrugs represent new and powerful tools for diverse therapeutic applications. To date, various metallodrugs display interesting biological activities for chemotherapy. In this field, cisplatin was the first inorganic compound with high relevance in cancer treatment. This compound was a leader agent in clinical use. Toxicity and resistance problems trigger the development of other platinum drugs with better clinical perspective and also raise the scientific interest for the putative antitumor properties of V, Ru and Cu compounds. Several scientific articles show that complexes of these metals are the new metal-based drugs used in the treatment of several cancers, such us, lung, colon, breast, bladder, etc. In this review we recapitulate current information and new advances on antitumor in vitro effects of several organic and inorganic compounds derived from copper, ruthenium and vanadium. These metal derived compounds targeting DNA or cell proteins involved in cell signaling pathways related to cancer. The mechanisms of cell death of these metallodrugs have also been comprehensibly reviewed. The knowledge of these mechanisms of death and the relationship between chemical structure and biological activity may be useful for the design of new metal-based drugs with promising pharmacologic applications as anticancer agents.

Sex Differences in Alcohol Use Disorder.

Abstract: Background: Alcohol use disorder (AUD) is a common and disabling mental disorder associated with a significant burden of medical consequences and high socioeconomic costs. Although a growing number of studies support the existence of sex differences in several aspects of alcohol consumption and AUD, the majority of investigations have been conducted in men. Objective: This article was aimed at reviewing sex differences in AUD, focusing on epidemiology, neurobiology, pharmacokinetics, susceptibility to medical consequences, and treatment. Results: Although AUD is more prevalent in men, the number of women with AUD is rapidly increasing, especially in adolescents. Women show a higher vulnerability to medical consequences induced by alcohol consumption, including alcohol-related liver disease, cardiomyopathy, and breast cancer. This observation is only partly explained by the sex differences observed in the pharmacokinetics of alcohol. Women also show an accelerated progression from the first use of alcohol to the onset of AUD and appear to be at higher risk of alcohol–medication interactions. Although AUD women are less likely to seek treatment than men, they achieve better results through dedicated programs taking into account the special needs of female patients. However, findings on the efficacy and safety of medications used to treat AUD mostly come from studies in which women were largely underrepresented. Conclusion: The sex differences observed suggest the urgent need to conduct studies recruiting adequate numbers of female subjects, to increase knowledge of sex differences in AUD, and to develop personalized and evidence-based approaches of prevention and treatment of AUD in women.

Bisphenol A in Reproduction: Epigenetic Effects.

Abstract: Background Bisphenol A (BPA) is an endocrine disrupting chemical widely used in the manufacture of polycarbonate plastic and epoxy resin to produce a multitude of consumer products, food and drink containers, and medical devices. BPA is similar to estradiol in structure and thus interferes in steroid signalling with different outcomes on reproductive health depending on doses, life stage, mode, and timing of exposure. In this respect, it has an emerging and controversial role as a "reproductive toxicant" capable of inducing short and long-term effects including the modulation of gene expression through epigenetic modification (i.e. methylation of CpG islands, histone modifications and production of non-coding RNA) with direct and trans-generational effects on exposed organisms and their offspring, respectively. Objective This review provides an overview about BPA effects on reproductive health and aims to summarize the epigenetic effects of BPA in male and female reproduction. Results BPA exerts epigenetic effects in both male and female reproduction. In males, BPA affects spermatogenesis and sperm quality and possible trans-generational effects on the reproductive ability of the offspring. In females, BPA affects ovary, embryo development, and gamete quality for successful in vivo and in vitro fertilization (IVF). Conclusion The exact mechanisms of BPA-mediated effects in reproduction are not fully understood; however, the environmental exposure to BPA - especially in fetal and neonatal period - deserves attention to preserve the reproductive ability in both sexes and to reduce the epigenetic risk for the offspring.

The Clinical Translation of Organic Nanomaterials for Cancer Therapy: A Focus on Polymeric Nanoparticles, Micelles, Liposomes and Exosomes.

Abstract: Background The application of nanotechnology in the medical field is called nanomedicine. Nowadays, this new branch of science is a point of interest for many investigators due to the important advances in which we assisted in recent decades, in particular for cancer treatment. Cancer nanomedicine has been applied in different fields such as drug delivery, nanoformulation and nanoanalytical contrast reagents. Nanotechnology may overcome many limitations of conventional approaches by reducing the side effects, increasing tumor drug accumulation and improving the efficacy of drugs. In the last two decades, nanotechnology has rapidly developed, allowing for the incorporation of multiple therapeutics, sensing and targeting agents into nanoparticles (NPs) for developing new nanodevices capable to detect, prevent and treat complex diseases such as cancer. Method In this review, we describe the main drug nanoformulations based on different types of organic NPs, the advantages that the new formulations present in comparison with their free drug counterparts and how nanodrugs have improved clinical care. We subdivided them into four main groups: polymeric NPs, liposomes, micelles and exosomes, a small subgroup that has only recently been used in clinical trials. Results The application of nanotechnology to pharmaceutical science has allowed us to build up nanosystems based on at least two stage vectors (drug/nanomaterial), which often shown better pharmacokinetics (PK), bioavailability and biodistribution. As a result of these advantages, the nanomaterials accumulate passively in the tumor (due to the enhanced permeability and retention, effect, EPR), thereby decreasing the side effects of free drug. Recently, many new drug formulations have been translated from bench to bedside. Conclusion It is important to underline that the translation of nanomedicines from the basic research phase to clinical use in patients is not only expensive and time-consuming, but that it also requires appropriate funding. After many years spent in the design of innovative nanomaterials, it is now the time for the research to take into consideration the biological obstacles that nanodrugs have to overcome. Barriers such as the mononuclear phagocyte system, intratumoral pressure or multidrug resistance are regularly encountered when a cancer patient is treated, especially in the metastatic setting.

Polyphenols in Food: Cancer Prevention and Apoptosis Induction.

Abstract: Polyphenols are a group of water-soluble organic compounds, mainly of natural origin. The compounds having about 5-7 aromatic rings and more than 12 phenolic hydroxyl groups are classified as polyphenols. These are the antioxidants which protect the body from oxidative damage. In plants, they are the secondary metabolites produced as a defense mechanism against stress factors. Antioxidant property of polyphenols is suggested to provide protection against many diseases associated with reactive oxygen species (ROS), including cancer. Various studies carried out across the world have suggested that polyphenols can inhibit the tumor generation, induce apoptosis in cancer cells and interfere in progression of tumors. This group of wonder compounds is present in surplus in natural plants and food products. Intake of polyphenols through diet can scavenge ROS and thus can help in cancer prevention. The plant derived products can also be used along with conventional chemotherapy to enhance the chemopreventive effects. The present review focuses on various in vitro and in vivo studies carried out to assess the anti-carcinogenic potential of polyphenols present in our food. Also, the pathways involved in cancer chemopreventive effects of various subclasses (flavonoids, lignans, stilbenes and phenolic acids) of polyphenols are discussed.

NGS Technologies as a Turning Point in Rare Disease Research , Diagnosis and Treatment

Abstract: Approximately 25-50 million Americans, 30 million Europeans, and 8% of the Australian population have a rare disease. Rare diseases are thus a common problem for clinicians and account for enormous healthcare costs worldwide due to the difficulty of establishing a specific diagnosis. In this article, we review the milestones achieved in our understanding of rare diseases since the emergence of next-generation sequencing (NGS) technologies and analyze how these advances have influenced research and diagnosis. The first half of this review describes how NGS has changed diagnostic workflows and provided an unprecedented, simple way of discovering novel disease-associated genes. We focus particularly on metabolic and neurodevelopmental disorders. NGS has enabled cheap and rapid genetic diagnosis, highlighted the relevance of mosaic and de novo mutations, brought to light the wide phenotypic spectrum of most genes, detected digenic inheritance or the presence of more than one rare disease in the same patient, and paved the way for promising new therapies. In the second part of the review, we look at the limitations and challenges of NGS, including determination of variant causality, the loss of variants in coding and non-coding regions, and the detection of somatic mosaicism variants and epigenetic mutations, and discuss how these can be overcome in the near future.

Cadmium, Organ Toxicity and Therapeutic Approaches: A Review on Brain, Kidney and Testis Damage.

Abstract: Background Cadmium (Cd) is a heavy metal particularly hazardous for human health, as it is highly diffused and, therefore, a ubiquitous environmental toxicant. In fact, in the general population, the main sources of exposure are food, cigarette smoking, inhalation of ambient air, drinking water, contaminated soil or dust. Furthermore, an occupational exposure usually involves human during mining, fume inhalation or manufacturing nickel-cadmium battery, electroplating and paint pigments that utilize Cd. Methods We undertook a structured search in literature about Cd. This metal is noxious on the cells of many organs, among which the kidney, the testis and the brain will be considered in this review. Results The toxic effects induced by Cd include many specific mechanisms, such as the oxidative stress, cellular death and inflammation. As no specific therapy for the prevention or treatment of the morbidity and mortality associated with Cd exposure is available, the state of the art of the therapeutic approaches is illustrated. Conclusion Nowadays, a therapy able to counteract Cd toxicity is still lacking and the development of new therapeutic agents is requested.

Snake Venom: From Deadly Toxins to Life-saving Therapeutics.

Abstract: Snakes are fascinating creatures and have been residents of this planet well before ancient humans dwelled the earth. Venomous snakes have been a figure of fear, and cause notable mortality throughout the world. The venom constitutes families of proteins and peptides with various isoforms that make it a cocktail of diverse molecules. These biomolecules are responsible for the disturbance in fundamental physiological systems of the envenomed victim, leading to morbidity which can lead to death if left untreated. Researchers have turned these life-threatening toxins into life-saving therapeutics via technological advancements. Since the development of captopril, the first drug that was derived from bradykininpotentiating peptide of Bothrops jararaca, to the disintegrins that have potent activity against certain types of cancers, snake venom components have shown great potential for the development of lead compounds for new drugs. There is a continuous development of new drugs from snake venom for coagulopathy and hemostasis to anti-cancer agents. In this review, we have focused on different snake venom proteins / peptides derived drugs that are in clinical use or in developmental stages till to date. Also, some commonly used snake venom derived diagnostic tools along with the recent updates in this exciting field are discussed.

Immune Checkpoint Inhibitors and Cardiac Toxicity: An Emerging Issue.

Abstract: Although survival of patients with different types of cancer has improved, cardiotoxicity induced by anti-neoplastic drugs remains a critical issue. Cardiac dysfunction after treatment with anthracyclines has historically been a major problem. However, also targeted therapies and biological molecules can induce reversible and irreversible cardiac dysfunction. Over the last years, cancer immunotherapies haverevolutionized the clinical management of a wide spectrum of solid and hematopoietic malignancies previously endowed with poor prognosis. Immune checkpoint inhibitors are at the forefront of immunotherapy: the two most prominent are the targeting of cytotoxic-T-lymphocyte-associated antigen 4 (CTLA- 4) and of programmed cell death 1 (PD-1) and its ligand PD-L1. Ipilimumab (anti-CTLA-4) is the godfather of checkpoint inhibitors, whereas several blocking monoclonal antibodies targeting PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab, durvalumab, avelumab, and BMS-946559) have been developed. Inhibitors of CTLA-4 and PD-1/PD-L1 pathway can unleash anti-tumor immunity and mediate cancer regressions. Although CTLA-4 inhibitors and PD-1 and PD-L1 blocking agents are frequently associated with a wide spectrum of immune-related adverse events, cardiac toxicity has been underestimated. However, early animal studies have demonstrated that after CTLA-4 inhibition and PD-1 deletion autoimmune myocarditis can occur. Moreover, PD-1 and PD-L1 can be expressed in rodent and human cardiomyocytes. During the last years several cases of fatal heart failure have been documented in melanoma patients treated with checkpoint inhibitors. The recent experience with cardiovascular toxic effects associated with checkpoint inhibitors introduces important concepts biologically and clinically relevant for future oncology trials and clinical practice.

Recent Advances and Perspectives in Liposomes for Cutaneous Drug Delivery.

Abstract: The cutaneous route is attractive for the delivery of drugs in the treatment of a wide variety of diseases. However the stratum corneum (SC) is an effective barrier that hampers skin penetration. Within this context, liposomes emerge as a potential carrier for improving topical delivery of therapeutic agents. In this review, we aimed to discuss key aspects for the topical delivery by drug-loaded liposomes. Phospholipid type and phase transition temperature have been shown to affect liposomal topical delivery. The effect of surface charge is subject to considerable variation depending on drug and composition. In addition, modified vesicles with the presence of components for permeation enhancement, such as surfactants and solvents, have been shown to have a considerable effect. These liposomes include: Transfersomes, Niosomes, Ethosomes, Transethosomes, Invasomes, coated liposomes, penetration enhancer containing vesicles (PEVs), fatty acids vesicles, Archaeosomes and Marinosomes. Furthermore, adding polymeric coating onto liposome surface could influence cutaneous delivery. Mechanisms of delivery include intact vesicular skin penetration, free drug diffusion, permeation enhancement, vesicle adsorption to and/or fusion with the SC, trans-appendageal penetration, among others. Finally, several skin conditions, including acne, melasma, skin aging, fungal infections and skin cancer, have benefited from liposomal topical delivery of drugs, with promising in vitro and in vivo results. However, despite the existence of some clinical trials, more studies are needed to be conducted in order to explore the potential of liposomes in the dermatological field.

Microneedle Patches as Drug and Vaccine Delivery Platform

Abstract: Background Transcutaneous delivery is the ideal method for delivering therapeutic reagents or vaccines into skin. With their promise of self-administration, cost-effective and high efficiency, microneedle patches have been studied intensively as therapeutic and vaccination delivery platform that replaces injection by syringe. This review aims to summarize the recent advancements of microneedle patches in application for drugs and vaccine delivery. Methods We reviewed the most of recently published papers on microneedle patches, summarized their evolution, classification, state-of the-art capabilities and discussed promising application in drugs and vaccine delivery. Results With the rapid development of nanotechnology, microneedle patches have been improved by switching from undissolving to dissolving microneedles, and their safety has also improved dramatically. As a drug delivery tool, microneedle patches can deliver bioactive molecular of different physical size. Additionally, microneedle patches can be coated or encapsulate with DNA vaccine, subunit antigen, inactivated or live virus vaccine. Combining clinical results with the results of patient interview, microneedle patches are found to be feasible and are predicated to soon be acceptable for the medical service. Conclusion In this review, we summarized the evolution, current and future application of microneedle patches as delivery vehicle for drugs and vaccines. Compared with traditional delivery tools, microneedle patches have many advantages, such as providing pain-free, non-invasive, convenient route for reagent administration and delivery, with no cold chain required for storage and transportation as well as decreasing sharp medical waste, needle-caused injury and transmission of blood-borne infectious disease in rural area. However, even though there are dramatic progress in preclinical investigation of microneedle patches, further testing will be required for clinical application. Further research should be implemented in multiple fields, such as vaccinology, immunology, and materials science, to improve this delivery platform. Because of their advantages in dose sparing, safety and treatment compliance, microneedle patches are expected to be widely applied in clinical treatment and vaccine administration in near future.

Nanocellulose and its Composites for Biomedical Applications

Abstract: Cellulose is a natural linear biopolymer, which is constituted of an assembly of cellulose nanofibrils in a hierarchical order. Nanocelluloses in particular show great promise as a cost-effective advanced material for biomedical applications because of their biocompatibility, biodegradability, and low cytotoxicity. Moreover, with their chemical functionality they can be easily modified to yield useful products. While nature uses the hierarchical nanostructure of cellulose as the load-bearing constituent in plants, a significant amount of research has been directed toward the fabrication of advanced cellulosic materials with various nanostructures and functional properties. Such nanocelluloses are widely applied in medical implants, tissue engineering, drug delivery, wound healing, diagnostics, and other medical applications with real examples in this field. There are also emerging fields being developed to use nanocelluloses and their composites in more novel ways in biomedical applications such as 3D printing and magnetically responsive materials. In this mini-review, recent advances in the design and fabrication of nanocellulose-based materials and composites are presented with a special emphasis on their suitability for material requirements for biomedical applications as well as the new directions and challenges that the materials might face in the future.

Circulating ACE2 in Cardiovascular and Kidney Diseases.

Abstract: Angiotensin converting enzyme (ACE) 2 is a homologue of ACE that catalyzes the conversion of Angiotensin (Ang) II into Ang1-7, which induces vasodilation, anti-fibrotic, anti-proliferative and anti-inflammatory effects Given that ACE2 counterbalances the effects of Ang II, it has been proposed as a biomarker in kidney disease patients Circulating ACE2 has been studied in human and experimental studies under physiological and pathological conditions and different techniques have been assessed to determine its enzymatic activity In patients with cardiovascular (CV) disease circulating ACE2 has been shown to be increased In addition, hypertensive and diabetic patients have also shown higher circulating ACE2 activities A study in type 1 diabetes patients found a negative association between circulating ACE2 and estimated glomerular filtration rate in male and female patients Recently, it has been demonstrated that circulating ACE2 is increased in male patients with chronic kidney disease (CKD) and that it is independently associated with other classical CV risk factors, such as advanced age and diabetes Furthermore, circulating ACE2 has been shown to be associated with silent atherosclerosis and CV outcomes in CKD patients In diabetic nephropathy, experimental studies have demonstrated an increase in circulating ACE2 activity both at early and late stages of the disease, as well as a direct association with increased urinary albumin excretion, suggesting that it may be increased as a renoprotective mechanism in these patients In this paper we will review the measurement of circulating ACE2 and its role in kidney disease, as well as its potential role as a renal and CV biomarker

Antimicrobial Peptides: A Promising Therapeutic Strategy in Tackling Antimicrobial Resistance.

Abstract: Background Antimicrobial resistance (AMR) has posed a serious threat to global public health and it requires immediate action, preferably long term. Current drug therapies have failed to curb this menace due to the ability of microbes to circumvent the mechanisms through which the drugs act. From the drug discovery point of view, the majority of drugs currently employed for antimicrobial therapy are small molecules. Recent trends reveal a surge in the use of peptides as drug candidates as they offer remarkable advantages over small molecules. Methods Newer synthetic strategies like organometalic complexes, Peptide-polymer conjugates, solid phase, liquid phase and recombinant DNA technology encouraging the use of peptides as therapeutic agents with a host of chemical functions, and tailored for specific applications. In the last decade, many peptide based drugs have been successfully approved by the Food and Drug Administration (FDA). This success can be attributed to their high specificity, selectivity and efficacy, high penetrability into the tissues, less immunogenicity and less tissue accumulation. Considering the enormity of AMR, the use of Antimicrobial Peptides (AMPs) can be a viable alternative to current therapeutics strategies. AMPs are naturally abundant allowing synthetic chemists to develop semi-synthetics peptide molecules. AMPs have a broad spectrum of activity towards microbes and they possess the ability to bypass the resistance induction mechanisms of microbes. Result The present review focuses on the potential applications of AMPs against various microbial disorders and their future prospects. Several resistance mechanisms and their strategies have also been discussed to highlight the importance in the current scenario. Conclusion Breakthroughs in AMP designing, peptide synthesis and biotechnology have shown promise in tackling this challenge and has revived the interest of using AMPs as an important weapon in fighting AMR.

Potential Anti-inflammatory Effects of Hesperidin from the Genus Citrus.

Abstract: Background The benefits of the Mediterranean diet for protecting against many diseases are usually attributed to high consumption of certain foods, characterized by the presence of bioactive substances such as polyphenols. Inflammation plays an important role in the pathogenesis of numerous diseases such as arthritis, allergies or neurodegenerative disorders. Dietary polyphenols constitute a large family of bioactive substances with potential beneficial effects against a broad group of diseases. Citrus fruits and juices are a rich source of vitamin C and flavonoids, with a potential effect on the inflammatory response. Objective The aim was to evidence the potential anti-inflammatory effects of the flavonoids hesperidin for its possible therapeutic application against diverse pathologies. Method In the present review, available literature about the anti-inflammatory effects of hesperidin is reported and discussed. Moreover, we also discuss the chemistry, bioavailability and proposed mechanisms of action of hesperidin. Results Hesperidin is a flavonoid present in high concentration in citrus species and has numerous biological properties, principally antioxidant and anti-inflammatory. Several studies have been performed in order to evaluate the effects of hesperidin as anti-inflammatory agent using cellular and animal models and few clinical trials. Hesperidin treatment decreased inflammatory mediators and exerted significant antioxidant effects. The molecular basis for its anti-inflammatory effects seems to be mediated by signalling pathways especially the nuclear factor κβ pathway. Conclusion Although hesperidin evidenced anti-inflammatory effects, the specific mechanism of action is not completely known and additional studies are required for elucidation of the molecular targets.

Anti-cancer Drug Delivery Using Metal Organic Frameworks (MOFs).

Abstract: Cancer is the uncontrolled growth of cells in the body and is considered as one of the major causes of death globally. There are several cytotoxic chemotherapeutic agents used to treat cancer including methotrexate, 5-fluorouracil, cisplatin, tamoxifen, doxorubicin and others. Although billions of dollars have been spent on cancer research to develop these chemotherapies, it still remains a major illness for mankind partly due to the shortcomings of these therapies. These shortcomings include low targeting specificity, severe side effects (due to high doses) and poor pharmacokinetics. To avoid these drawbacks, anti-cancer drug delivery systems have been developed recently using nanocarriers including liposomes, micelles, polyelectrolyte capsules and others. One of the recent class of nanoparticles investigated for chemotherapeutic use are metal organic frameworks (MOFs) which are hybrid polymers that consist of metal ions or clusters and organic ligands. MOFs are used in many applications including gas/vapor separation, gas storage, catalysis, luminescent materials, and biomedical imaging. These structures have additional features that promote their use as drug carriers in the biomedical field. First, they are nontoxic, biodegradable and have the ability to carry high loadings of the anti-neoplastic agent due to their porous nature. Also, they have well-defined crystalline structures that can be characterized by different analytical techniques and their sizes are suitable to control their in vivo drug release. This paper reviews the methods used to synthesize MOFs and their recent use as antineoplastic drug delivery carriers.

Piperine as a Potential Anti-cancer Agent: A Review on Preclinical Studies.

Abstract: Recently many studies showed anticancer activities of piperine, a pungent alkaloid found in black pepper and some other Piper species We attempted to summarize acquired data that support anticancer potential of this natural agent Piperine has been reported to possess effective chemopreventive activity It has been studied to affect via several mechanisms of action, in brief enhancing antioxidant system, increasing level and activity of detoxifying enzymes and suppressing stem cell self-renewal Moreover, piperine has been found to inhibit proliferation and survival of various cancerous cell lines via modulating cell cycle progression and exhibiting anti-apoptotic activity, respectively This compound has been shown to modify activity of various enzymes and transcription factors to inhibit invasion, metastasis and angiogenesis Interestingly, piperine has exhibited antimutagenic activity and also inhibited activity and expression of multidrug resistance transporters such as P-gp and MRP-1 Besides, about all reviewed studies have reported selective cytotoxic activity of piperine on cancerous cells in compared with normal cells Altogether, the studies completely underline promising candidacy of piperine for further development The collected preclinical data we provided in this article can be useful in the design of future researches especially clinical trials with piperine

Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions.

Abstract: Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR). When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis. The activities of ICL agents, in particular platinum-based therapies, establish a "molecular landscape," i.e., a pattern of DNA damage that can potentially be further exploited therapeutically with DDR-targeting agents. If the molecular landscape created by platinum-based agents could be better defined at the molecular level, a systematic, mechanistic rationale(s) could be developed for the use of DDR-targeting therapies in combination/maintenance protocols for specific, clinically advanced malignancies. New therapeutic drugs such as poly(ADP-ribose) polymerase (PARP) inhibitors are examples of DDR-targeting therapies that could potentially increase the DNA damage and replication stress imposed by platinum-based agents in tumor cells and provide therapeutic benefit for patients with advanced malignancies. Recent studies have shown that the use of PARP inhibitors together with platinum-based agents is a promising therapy strategy for ovarian cancer patients with "BRCAness", i.e., a phenotypic characteristic of tumors that not only can involve loss-of-function mutations in either BRCA1 or BRCA2, but also encompasses the molecular features of BRCA-mutant tumors. On the basis of these promising results, additional mechanism-based studies focused on the use of various DDR-targeting therapies in combination with platinum-based agents should be considered. This review discusses, in general, (1) ICL agents, primarily platinum-based agents, that establish a molecular landscape that can be further exploited therapeutically; (2) multiple points of potential intervention after ICL agent-induced crosslinking that further predispose to cell death and can be incorporated into a systematic, therapeutic rationale for combination/ maintenance therapy using DDR-targeting agents; and (3) available agents that can be considered for use in combination/maintenance clinical protocols with platinum-based agents for patients with advanced malignancies.

The Role of Oxidative Stress Modulators in Breast Cancer.

Abstract: Background Latest data from International Agency for Cancer Research shows that breast cancer is the leading cancer site in women and is the leading cause of death among female cancers. Induction of reactive oxygen species (ROS) and oxidative stress as a consequence of impaired balance between prooxidants and antioxidants are suggested to be involved in induction and progression of breast cancer. Cancer cells are found to exhibit higher levels of ROS compared to normal cells. However increased antioxidant defence which balances the oxidative status within the cancer cells suggests that high ROS levels may prevent tumorigenesis via various mechanisms. These contradictory roles of ROS and oxidative stress in breast cancer let scientists investigate potential oxidative stress modulators as anticancer strategies. Conclusions In the present review we address the mechanisms of ROS production in breast cancer cells, the role of impaired oxidative status as well as the benefits of introducing oxidative stress modulators in therapeutic strategies in breast cancer. This review is focusing more on melatonin which we have been working on during the last decade. Our data, in accordance with the literature, suggest an important role for melatonin in breast cancer prevention and adjuvant therapy.

P2X7 receptor orchestrates multiple signalling pathways triggering inflammation, autophagy and metabolic/trophic responses.

Abstract: P2X7 receptor is an ion channel activated by extracellular adenosine trisphosphate (eATP) that attracted increasing attention for its role in immune reactions, neurobiology and oncology. As receptor for an extracellular ligand, P2X7 activates a series of intracellular signalling pathways mainly via alterations of the ion permeability, but also through formation of a large unselective pore and direct interaction with other proteins. Here we wish to give an overview on the main biochemical paths initiated by P2X7 activation by revising recent and established literature on P2X7-triggered signalling cascades leading to cell death, inflammatory and immune response activation, proliferation and metabolism modulation. We will focus on the well-known P2X7 inflammasome/NF-kB and pro-apoptotic networks but also cover P2X7-activated emerging autophagic, pyroptotic and proliferativeoncogenic pathways, like beclin-1/LC3-II, caspase-11, Akt and VEGF axes.

Vitamin D/VDR, Probiotics, and Gastrointestinal Diseases

Abstract: Vitamin D is an important factor in regulating inflammation, immune responses, and carcinoma inhibition via action of its receptor, vitamin D receptor (VDR). Recent studies have demonstrated the role of vitamin D/VDR in regulating host-bacterial interactions. Probiotics are beneficial bacteria with the power of supporting or favoring life on the host. In the current review, we will discuss the recent progress on the roles of vitamin D/VDR in gut microbiome and inflammation. We will summarize evidence of probiotics in modulating vitamin D/VDR and balancing gut microbiota in health and gastrointestinal diseases. Moreover, we will review the clinical application of probiotics in prevention and therapy of IBD or colon cancer. Despite of the gains, there remain several barriers to advocate broad use of probiotics in clinical therapy. We will also discuss the limits and future direction in scientific understanding of probiotics, vitamin D/VDR, and host responses.

A Nanotechnology-based Strategy to Increase the Efficiency of Cancer Diagnosis and Therapy: Folate-conjugated Gold Nanoparticles.

Abstract: Background Gold nanoparticles (AuNPs), owing to their elegant physicochemical properties, have recently been introduced as promising theranostic nanoparticles. Folic acid is a necessary vitamin for cell proliferation. Accordingly, the surface functionalization of AuNP with folic acid may offer a great potential for the development of a strategy to increase the efficiency of cancer diagnosis and therapy based on the new nanotechnology. In this study, we have reviewed the recent progress made in the design and the biomedical application of various folate-conjugated gold nanoparticles (FAuNPs). Methods We performed a structured search in bibliographic databases and made a comprehensive list of relevant papers. The main subjects considered in this review included (1) methods for the preparation of F-AuNPs, (2) applications of F-AuNPs in computed tomography (CT), and (3) the use of F-AuNPs in targeted cancer therapy. Results As many as 96 papers were selected for the review. Accordingly, we explained the noncovalent and the covalent methods of fabricating the various types of F-AuNPs. Particular applications of F-AuNP in cancer diagnosis using the CT scan modality were described. In addition, the applications of F-AuNPs in targeted radiation therapy, chemotherapy, and hyperthermia were elucidated in depth. In the hyperthermia section, we presented certain extra explanations on F-AuNP-based laser, radiofrequency, and ultrasoundbased hyperthermia methods. Conclusion This review identifies the important roles of F-AuNPs in current cancer studies that are being undertaken worldwide. The findings of this review confirm that F-AuNP is a new theranostic agent, which has a great potential for simultaneous cancer therapy and diagnosis.

Phosphodiesterase 4 Inhibitors in Immune-mediated Diseases: Mode of Action, Clinical Applications, Current and Future Perspectives

Abstract: Phosphodiesterase (PDE) 4 is a superfamily of enzymes that catalyze the hydrolysis of cyclic adenosine 3',5'-monophosphate (cAMP), an intracellular second messenger and regulator of a wide array of genes and proteins. Increased levels of intracellular cAMP lead to activation of genes but also to inhibition of nuclear factor-kappa B, involved in pro-inflammatory responses. By increasing cAMP levels, PDE4 inhibitors, such as apremilast, reduced production of pro-inflammatory TNFα, IFNγ, and IL-17 and increased production of anti-inflammatory IL-10 in lipopolysaccharide-stimulated peripheral blood mononuclear cells, and in patients with psoriatic arthritis (PsA). Among PDE4 inhibitors, apremilast, roflumilast, and crisabolore have been approved for the treatment of psoriasis and PsA, chronic obstructive pulmonary disease, and atopic dermatitis, respectively. In a preliminary study on psoriasis and PsA we showed that at 6 months apremilast decreased IFNγ+CD3+ Th1 cells and IL- 17+CD3+ Th17 cells and increased regulatory B cells and regulatory T cells. In this review, we highlight recent findings of PDE4 inhibitors in atopic dermatitis, alopecia areata, uveitis, rheumatoid arthritis, psoriasis and PsA, systemic lupus erythematosus, vasculitis, systemic sclerosis, multiple sclerosis and inflammatory bowel disease. Given the role of cAMP as second messenger in diverse intracellular pathways, selective PDE4 inhibitors are likely to be therapeutic agents for various immune mediated diseases.