Current Pharmaceutical Design - Volume 24, Issue 26, 2018

A group of stimulus-responsive biopolymers developed from the hydrophobic domain of tropoelastin is collectively known as elastin-like polypeptides (ELPs). These peptides generally consist of repeated pentapeptide units of the form (VPGXG)n, where X can be any amino acid with the exception of proline. ELPs present wide-ranging possibilities in biomedicine due to their many beneficial characteristics, including tunable phase transition behavior and biological compatibility, along with the absence of immunogenic and pyrogenic characteristics. The present paper reviews the physicochemical characteristics of ELPs and outlines a range of applications in biotechnology and medicine.

Prediction of pharmacokinetics and drug targeting is a challenge in drug design. There are different types of software that can help to predict the pharmacokinetic profile of a drug. Quantitative structure-activity relationship (QSAR) modeling is used for drug design with less cost. Drug-excipient interactions are predicted by docking tools. Computerized drug target prediction and docking programs offer additional options to predict potential effects and adverse reactions of a given candidate as well as the best orientation of the compound on the receptor active site. Information on the absorption, distribution, metabolism and excretion of the drug in the body can enhance prediction of drug release and distribution in the blood and central nervous system (CNS). Computer- aided drug design and delivery can help to save the time and cost in the process of rational drug development.

The article is an overview of author's data obtained in the framework of the project “The Creation of dipeptide preparations” at the V.V. Zakusov Institute of Pharmacology, Moscow, Russia. Advantages of dipeptides over longer peptides consist in that they are orally active owing to higher stability and ability to penetrate biological barriers due to the presence of specific ATP–dependent transporters in enterocytes and blood-brain barrier. Two original approaches for dipeptide drugs design have been developed. Both of them are based on the idea of a leading role of central dipeptide fragment of the peptide chain beta-turn in the peptide-receptor interaction. The first approach, named "peptide drug-based design" represents the transformation of known nonpeptide drug into its dipeptide topological analog. The latter usually corresponds to a beta-turn of some regulatory peptide. The second approach represents the design of tripeptoide mimetic of the beta-turn of regulatory peptide or protein. The results of the studies, which led to the discovery of endogenous prototypes of the known non-peptide drugs piracetam and sulpiride, are presented herein. The paper discusses the process, based on the abovementioned principles, that was used in designing of nontoxic, orally available, highly effective dipeptide drugs: nootropic noopept, dipeptide analog of piracetam; antipsychotic dilept, neurotensin tripeptoid analog; selective anxiolytic GB-115, tripeptoid analog of CCK-4, and potential neuroprotector GK-2, homodimeric dipeptide analog of NGF.

The issue of vitamin deficiency persists to be a major health issue worldwide despite the advancements in medicine. At the same time, the effect of marginal vitamin deficiency status on physiological processes is proven. However, general methods such as immune-enzyme and fluorescence analysis, microbiological assays, for example, have limitations in vitamin status assessment and are not able to reliably reflect personal vitamin demand. The potential usefulness of modern metabolomics methods in vitamin status assessment is described in this review. These methods can be used for vitamin metabolites detection as well as for comprehensive metabolic phenotyping that makes them even more valuable.

Background: R. Schofield (1978) proposed a hypothesis of hematopoietic stem cells (HSCs) niche (specialized cell microenvironment). An existence of osteoblastic and vascular niches for HSCs has been postulated since 2003. At the same time, the discussion about the existence and functioning of niche for multipotent mesenchymal stromal cells (MMSCs) is just beginning to develop. The design of artificial materials capable of biomimetical reproductionof the cellular and tissue microenvironment based on ideas and main elements borrowed from wildlife is an experimental approach in search of the stem cell niches. Results: Recent attempts to model the microterritories (niches) for HSCs have been undertaken and the behavior of cells in such structures has been investigated. However, the main quantitative factors involved in the original design of stem cell microterritories remain unknown. At the modern stage, the topography, hierarchy, and the size of the niches have to be determined, because the definition of the niches as morphological (structural and functional) units (microterritories), which provides the conditions for vital activity of stem cells, implies finite values of its parameters. The aim of this review was the critical review of key milestones of the niche concept for HSCs and MMSCs as we understood it. Conclusion: We speculated our definition of the stem cell niche, proposed and described certain stages (postulation; morphofunctional; topographical; quantitative; bioengineering) of the niche theory development. Prospective directions of the niche designing for cell-based diagnostics and regenerative medicine were noted.

Atrial fibrillation (AF) is the most common and significant cardiac arrhythmia in clinical practice, however the pathophysiological mechanism of AF has not been fully explained. At present, there are no available treatment options that can target the underlying pathophysiological processes of AF. Research on improving management strategies for AF can start with a further understanding of the changes of cells in AF. Mitochondria play central roles in the function of cardiac myocytes and many of the pathophysiological processes implicated in AF are relative to mitochondrial function, including formation of reactive oxygen species (ROS), calcium homeostasis, and alterations of oxygen consumption. The changes of levels of phosphocreatine, electron transfer chain proteins and differences in mitochondrial distribution further imply that mitochondria play a role in AF. Related studies of recent years are summarized, in order to elucidate the causal relationship between mitochondria and AF, and provide potential therapeutic target for the treatment and prevention of AF in clinical practice. In the article, we summarize the direct or indirect factors that affect mitochondria function and thus cause AF, including anticancer agents, surgery, gene, age, air pollution, oxidative stress, and β3-adrenoceptor (β3-AR). There is a close relationship between mitochondrial dysfunction and the occurrence of AF, which cannot be ignored, and further research in this area is needed.

Atrial fibrillation (AF) is a frequent cardiac arrhythmia. It is a common major cause of serious diseases and is an increasing health-care burden. AF is associated with an excess amount of reactive oxygen species. In this review, we summarize several possible reactive oxygen species pathways that induce AF based on atrial electrical and structural remodeling data. The sources and factors implicated in AF-related oxidative stress include NADPH oxidase activation, calcium overloading and mitochondrial damage, angiotensin system activation, nitric oxide synthase uncoupling, and xanthine oxidase activation-associated cardiovascular conditions. Scavenging oxidative stress markers and related substances are essential aspects of these molecular mechanisms, and may be a therapeutic target in AF.

Background: The incidence and prevalence of diabetes mellitus are increasing globally at alarming rates. Cardiovascular and renal complications are the major cause of morbidity and mortality in patients with diabetes. Methylglyoxal (MG) - a highly reactive dicarbonyl compound – is increased in patients with diabetes and has been implicated to play a detrimental role in the etiology of cardiovascular and renal complications. Derived from glucose, MG binds to arginine and lysine residues in proteins, and the resultant end products serve as surrogate markers of MG generation in vivo. Under normal conditions, MG is detoxified by the enzyme glyoxalase 1 (Glo1), using reduced glutathione as a co-factor. Elevated levels of MG is known to cause endothelial and vascular dysfunction, oxidative stress and atherosclerosis; all of which are risk factors for cardiovascular diseases. Moreover, MG has also been shown to cause pathologic structural alterations and impair kidney function. Conversely, MG scavengers (such as N-acetylcysteine, aminoguanidine or metformin) or Nrf2/Glo1 activators (such as trans-resveratrol / hesperetin) are shown to be useful in preventing MG-induced cardiovascular and renal complications in diabetes. However, clinical evidence supporting the MG lowering properties of these agents are limited and hence, need further investigation. Conclusion: Reducing MG levels directly using scavengers or indirectly via activation of Nrf2/Glo1 may serve as a novel and potent therapeutic strategy to counter the deleterious effects of MG in diabetic complications.

Hypertension is a non-transmissible chronic disease with a high prevalence, morbidity, and mortality. Different strategies for the treatment of hypertension are employed worldwide, but the control of hypertension remains a major challenge for global health. Many unsuccessful unconventional therapies have been proposed in recent years, including herbal medicines and the development of small molecules or antibodies that seek to disrupt the disease's pathogenesis. Cell-based therapies may be used as replacement or complementary treatment strategies. The results of recent preclinical studies of cell-based therapies are promising. However, human clinical trials are scarce, the data are insipid, and many issues have been raised about the safety and efficacy of cell-based therapies. The present review summarizes research on cell-based therapy for hypertension. We also briefly summarize relevant clinical trials and discuss future perspectives and possible clinical applications.

Hair loss may not be recognized as a life-threatening disorder. However, it has a great harm to a person's self-respect, mental health, and entirety quality of life. Androgenic alopecia (AGA) is the most common type of hair loss, which affects a great number of both men and women. Alopecia can be treated with various hair loss strategies, including hair transplant, cosmetics and medication. Medical treatment shows the outstanding ability in improving hair growth. Plenty of drugs prevents alopecia by inhibiting the secretion of male hormone. But these medicines exhibit some undesirable side effects. Since hair loss requires a long-term treatment and minimizing adverse side effects is extremely urgent in drug development. Accordingly, new agents are obtained from natural products with less adverse effects. Traditional Chinese medicines exhibit unique advantages in hair loss treatment. This review generalizes and analyzes the recent progress of medicinal plants for the treatment of hair loss, suggested mechanisms and outlines a number of trials taken or underway to optimize the treatment.

For nearly a century, the adult heart was considered as a post-mitotic organ. The discovery of a resident cardiac stem cell (CSC) population in the heart has dramatically undermined this notion with the support of encouraging preclinical and clinical studies aiming to regenerate the damaged heart after a myocardial infarction (MI). There are two ways to obtain CSCs for transplantation: Allogeneic and autologous sources. Autologous cells may be obtained from the patients' own tissue. Obtaining cells from diseased patients may contain a risk for altered stem cell characteristics. In addition to MI, these patients may also suffer from pathological conditions such as hypertension, diabetes mellitus, heart failure, congenital heart disease or cancer, which are known to alter CSC characteristics. It is also known that physiological conditions such as aging and death affect CSC functions in the heart. Our knowledge about the CSC characteristics in various physiological and pathological conditions may shed light on our opinion about the regenerative capacity and biological activity of these cells in these situations. Defining these properties may guide the researchers and clinicians in choosing and obtaining the most qualified CSC populations for cardiac regenerative medicine therapies. The purpose of this review is to describe the alterations in CSC characteristics in various physiological and pathological conditions.

Killer immunoglobulin-like receptors (KIRs) regulate the activation of natural killer cells through their interaction with human leucocyte antigens (HLA). KIRs and HLA loci are highly polymorphic, and some of their combinations have been found to protect against viral infections or to predispose to autoimmune disorders. In particular, some activating KIRs profiles may be detrimental in autoimmune pathogenesis, and specific KIRs may be particularly aggressive in the clearance of different microorganisms, protecting individuals in the control of a given pathogen. So, considering that in the pathogenesis of many autoimmune disorders and infections innate immunity plays a key role, the recent development for KIRs characterization, diseases monitoring, and treatment becomes obvious. Here, we reviewed a growing body of evidence supporting the influence of KIRs variants and their interaction with ligands in the development of the main human autoimmune and viral diseases, highlighting the main applications in clinical practice.

Atherosclerosis is an inflammatory vascular disease that is characterized by progressive accumulation of cholesterol in the arterial walls and it is a major cause of cardiovascular disease. Issues related to the side effects of synthetic drugs have in recent times, led to the misuse of drugs, a lack of patient consultations, and consequently, a disruption in meticulous disease control. Therefore, a new insight into medicinal plants has recently emerged and much research has been conducted on these herbs in an attempt to prepare novel naturally based drugs. The aim of this review article was to scrutinize the molecular mechanisms of medicinal plants possessing effectiveness against atherosclerosis. To conduct the review, electronic searches were performed to retrieve potentially relevant publications, indexed within internet databases and reference textbooks concerning the effects and underlying molecular mechanisms of plants or their constituents used to treat atherosclerosis. Overall, medicinal plants facilitate atherosclerosis treatment through a variety of mechanisms which include the regulation of expression of inflammatory factors, stimulation of peroxisome proliferator-activated receptors (PPARs), inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), promotion of ATP-binding cassette transporter A1 (ABCA1) as well as ATP-binding cassette transporter G (ABCG), facilitation of adiponectin activity, reduction of sterol regulatory element-binding proteins (SREBPs) and antioxidant activity. An increased perception of these herbal mechanistic links is an important prelude to the design of novel plant based drugs.

Ischemic Heart Disease (IHD) has been recognized as the main cause of mortality in the modern world. Application of cell therapy technologies for the IHD treatment has been actively studied from the beginning of 2000s. The review is dedicated to the use of mesenchymal stem cells (MSC) in the therapy of IHD. The strategies of the MSC modification in vitro for improvement of their regenerative potential are extensively discussed, including preconditioning to enhance the cell survival, boosting their paracrine effect and manipulating their cardiomyogenic differentiation. The optimization of the MSC delivery and opportunities related to the use of biomaterials as cell carriers are also discussed. The results of the most important clinical studies on the MSC-based IHD therapy are presented, including those completed and published in the literature and the ongoing clinical trials registered at clinicaltrials.gov by June 2018.

Background: A hallmark of atherosclerosis is its complex pathogenesis, which is dependent on altered cholesterol metabolism and inflammation. Both arms of pathogenesis involve myeloid cells. Monocytes migrating into the arterial walls interact with modified low-density lipoprotein (LDL) particles, accumulate cholesterol and convert into foam cells, which promote plaque formation and also contribute to inflammation by producing proinflammatory cytokines. A number of studies characterized transcriptomics of macrophages following interaction with modified LDL, and revealed alteration of the expression of genes responsible for inflammatory response and cholesterol metabolism. However, it is still unclear how these two processes are related to each other to contribute to atherosclerotic lesion formation. Methods: We attempted to identify the main mater regulator genes in macrophages treated with atherogenic modified LDL using a bioinformatics approach. Results: We found that most of the identified genes were involved in inflammation, and none of them was implicated in cholesterol metabolism. Among the key identified genes were interleukin (IL)-7, IL-7 receptor, IL- 15 and CXCL8. Conclusion: Our results indicate that activation of the inflammatory pathway is the primary response of the immune cells to modified LDL, while the lipid metabolism genes may be a secondary response triggered by inflammatory signalling.