Current Pharmaceutical Design - Volume 25, Issue 3, 2019

Macrophages are key players in human innate immunity that protect the organism from pathologic agents, including infection and malignant cells. The spectrum of their functions includes initiation and maintaining of inflammation, cleaning of pathogens and cell debris, as well as inflammation resolution and tissue remodeling and repair. Such a wide spectrum is reflected by the great variety of macrophage phenotypes based on the activation of distinct transcription patterns in response to different stimuli. Studying this complexity requires an integrated approach, such as transcriptome studies. For many genes, the exact role in macrophage biology remains unknown, although clear associations with pro- or anti-inflammatory macrophage polarization could be demonstrated. These findings reveal the novel directions for future research. In this review, we describe the known mechanisms of macrophage polarization and the new insights available from transcriptome studies.

Background: Hereditary component plays a significant role in the formation of insulin resistance (IR) - one of the pathogenetic links of arterial hypertension (AH) and type 2 diabetes mellitus (DM2). However, the genetic predisposition to IR can not be realized and does not manifest itself clinically in the absence of appropriate factors of the environment (excessive nutrition, low physical activity, etc.). Objective: The review summarizes the results of studies which describe the contribution of genetic polymorphism to the formation and progression of AH, DM2 and their comorbidity in various populations. Results: In many studies, it has been established that genetic polymorphism of candidate genes is influenced by the formation, course and complication of AH and DM2. According to research data, the modulating effect of polymorphism of some genetic markers of AH and DM2 on metabolism and hemodynamics has been established. The results of numerous studies have shown a higher frequency of occurrence of AH and DM2, as well as their more severe course with adverse genetic polymorphisms. At the same time, the role of genetic polymorphism in the formation of AH and DM2 differs in different populations. Conclusion: Contradictory data on the influence of gene polymorphisms on the formation of AH and DM2 in different populations, as well as a small number of studies on the combined effects of several polymorphisms on the formation of comorbidity, determine the continuation of research in this direction.

Background: It is well known that long living individuals are a model of successful ageing and that the identification of both genetic variants and environmental factors that predispose to a long and healthy life is of tremendous interest for translational medicine. Methods: We present the preliminary findings obtained from an ongoing study on longevity conducted on a sample of Sicilian long-lived individuals. Results: We review the characteristics of longevity in Sicily, taking into account lifestyle, environment, genetics, hematochemical values, body composition and immunophenotype. In addition, we discuss the possible implications of our data for the prevention and/or treatment of age-related diseases. Conclusion: As widely discussed in this review, the explanation of the role of genetics and lifestyle in longevity can provide important information on how to develop drugs and/or behaviours that can slow down or delay ageing. Thus, it will be possible to understand, through a “positive biology” approach, how to prevent and/or reduce elderly frailty and disability.

Abnormal activation of the immune system plays an important role in the pathogenesis of aplastic anemia (AA). Various immune cells and cytokines constitute a complex immune network, leading to bone marrow failure. The known pathogenesis is an increase of the myeloid dendritic cell (mDC)/ plasmacytoid dendritic cell (pDC) ratio, which causes the ratio of T helper (Th)1/Th2 to be skewed in favor of Th1 and eventually leads to an abnormal activation of cytotoxic T lymphocyte (CTL). The antigens that stimulate T cells in the context of AA remain unknown. In this process, regulatory T (Treg), Th17, natural killer (NK) cell, memory T cell and negative hematopoietic regulatory factors are also involved. In addition, genetic background (e.g., chromosomal abnormalities, telomere attrition, somatic cell mutations), abnormal bone marrow hematopoietic microenvironment and viral infection may also contribute to the pathogenesis of AA. This review summarizes the recent studies of the pathogenesis of AA and the current status of AA research.

Background: Thromboembolic ischemic stroke, which is mainly caused by hypertension, as well as plasma dyslipidemia, arterial fibrillation and diabetes, is a leading cause of death in the US and other countries. Numerous clinical trials for thrombolytic drugs, which aimed to pharmacologically dissolve thrombi, were conducted in the 1950s, when the first thrombolytic therapy was performed. Methods: In this study, we summarize the pathophysiologic features of ischemic stroke, and the history of thrombolytic therapy, and discuss the recent progress that has been made in the ongoing development of thrombolytic drugs. Conclusion: Thrombolytic therapy is sometimes accompanied by harmful hemorrhagic insults; accordingly, a window of time wherein therapy can safely be performed has been established for this approach. Several basic and clinical studies are ongoing to develop next-generation thrombolytic drugs to expand the time window.

From the viewpoint of the general pathology, most of the human diseases are associated with a limited number of pathogenic processes such as inflammation, tumor growth, thrombosis, necrosis, fibrosis, atrophy, pathological hypertrophy, dysplasia and metaplasia. The phenomenon of chronic low-grade inflammation could be attributed to non-classical forms of inflammation, which include many neurodegenerative processes, pathological variants of insulin resistance, atherosclerosis, and other manifestations of the endothelial dysfunction. Individual and universal manifestations of cellular stress could be considered as a basic element of all these pathologies, which has both physiological and pathophysiological significance. The review examines the causes, main phenomena, developmental directions and outcomes of cellular stress using a phylogenetically conservative set of genes and their activation pathways, as well as tissue stress and its role in inflammatory and para-inflammatory processes. The main ways towards the realization of cellular stress and its functional blocks were outlined. The main stages of tissue stress and the classification of its typical manifestations, as well as its participation in the development of the classical and non-classical variants of the inflammatory process, were also described. The mechanisms of cellular and tissue stress are structured into the complex systems, which include networks that enable the exchange of information with multidirectional signaling pathways which together make these systems internally contradictory, and the result of their effects is often unpredictable. However, the possible solutions require new theoretical and methodological approaches, one of which includes the transition to integral criteria, which plausibly reflect the holistic image of these processes.

Base excision DNA repair (BER) is a vitally important pathway that protects the cell genome from many kinds of DNA damage, including oxidation, deamination, and hydrolysis. It involves several tightly coordinated steps, starting from damaged base excision and followed by nicking one DNA strand, incorporating an undamaged nucleotide, and DNA ligation. Deficiencies in BER are often embryonic lethal or cause morbid diseases such as cancer, neurodegeneration, or severe immune pathologies. Starting from the early 1980s, when the first mammalian cell lines lacking BER were produced by spontaneous mutagenesis, such lines have become a treasure trove of valuable information about the mechanisms of BER, often revealing unexpected connections with other cellular processes, such as antibody maturation or epigenetic demethylation. In addition, these cell lines have found an increasing use in genotoxicity testing, where they provide increased sensitivity and representativity to cell-based assay panels. In this review, we outline current knowledge about BER-deficient cell lines and their use.

Pigment epithelium-derived factor (PEDF) is one of the serine protease inhibitors with multifunctional properties, which is produced by various types of organs and tissues. There is an accumulating body of evidence that PEDF plays an important role in the maintenance of tissue homeostasis. Indeed, PEDF not only works as an endogenous inhibitor of angiogenesis, but also suppresses oxidative stress, inflammatory and thrombotic reactions in cell culture systems, animal models, and humans. Furthermore, we, along with others, have found that PEDF inhibits proliferation of, and induces apoptotic cell death in, numerous kinds of tumors. In addition, circulating as well as tumor expression levels of PEDF have been inversely associated with tumor growth and metastasis. These observations suggest that supplementation of PEDF proteins and/or enhancement of endogenous PEDF expression could be a novel therapeutic strategy for the treatment of cancer. Therefore, in this paper, we review the effects of PEDF on diverse types of cancer, and discuss its therapeutic perspectives.

Iron deficiency, one of the most common nutritional deficient disorders, frequently affects infants, adolescents and pregnant women and impairs growth, development and immune responses. Iron deficiency may also be secondary to gastrointestinal conditions such as gastrectomy and inflammatory bowel disease, as well as cancer and chronic uremia. Iron supplementation is the most commonly selected treatment option for iron deficiency. This review summarizes the iron compounds currently recommended for the iron fortification of foods and for clinical use. Additionally, this review discusses and compares the important aspects of high-quality iron compounds/products and classes of compounds that enhance iron bioavailability. The development of efficient iron fortification methods remains the most cost-effective and long-term approach to the treatment of iron deficiency or related anemia. To date, no orally administered options for iron fortification can sufficiently replace the parenteral administration of iron supplements, which includes the intramuscular injection of iron-dextran to neonatal piglets and intravenous injection of iron supplements to patients with gastrointestinal disorders. Iron bioavailability may be enhanced by encouraging customers to ingest iron-enriched foods together with dietary sources of vitamin C, folic acid and/or oligosaccharides.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor. Despite standard multimodality treatment, the highly aggressive nature of GBM makes it one of the deadliest human malignancies. The anti-cancer effects of dietary phytochemicals like curcumin provide new insights to cancer treatment. Evaluation of curcumin’s efficacy against different malignancies including glioblastoma has been a motivational research topic and widely studied during the recent decade. In this review, we discuss the recent observations on the potential therapeutic effects of curcumin against glioblastoma. Curcumin can target multiple signaling pathways involved in developing aggressive and drug-resistant features of glioblastoma, including pathways associated with glioma stem cell activity. Notably, combination therapy with curcumin and chemotherapeutics like temozolomide, the GBM standard therapy, as well as radiotherapy has shown synergistic response, highlighting curcumin’s chemo- and radio-sensitizing effect. There are also multiple reports for curcumin nanoformulations and targeted forms showing enhanced therapeutic efficacy and passage through blood-brain barrier, as compared with natural curcumin. Furthermore, in vivo studies have revealed significant anti-tumor effects, decreased tumor size and increased survival with no notable evidence of systemic toxicity in treated animals. Finally, a pharmacokinetic study in patients with GBM has shown a detectable intratumoral concentration, thereby suggesting a potential for curcumin to exert its therapeutic effects in the brain. Despite all the evidence in support of curcumin’s potential therapeutic efficacy in GBM, clinical reports are still scarce. More studies are needed to determine the effects of combination therapies with curcumin and importantly to investigate the potential for alleviating chemotherapy- and radiotherapy-induced adverse effects.

Background: Valproic acid (VPA) as a widely used primary medication in the treatment of epilepsy is associated with reversible or irreversible hepatotoxicity. Long-term VPA therapy is also related to increased risk for the development of non-alcoholic fatty liver disease (NAFLD). In this review, metabolic elimination pathways of VPA in the liver and underlying mechanisms of VPA-induced hepatotoxicity are discussed. Methods: We searched in PubMed for manuscripts published in English, combining terms such as “Valproic acid”, “hepatotoxicity”, “liver injury”, and “mechanisms”. The data of screened papers were analyzed and summarized. Results: The formation of VPA reactive metabolites, inhibition of fatty acid β-oxidation, excessive oxidative stress and genetic variants of some enzymes, such as CPS1, POLG, GSTs, SOD2, UGTs and CYPs genes, have been reported to be associated with VPA hepatotoxicity. Furthermore, carnitine supplementation and antioxidants administration proved to be positive treatment strategies for VPA-induced hepatotoxicity. Conclusion: Therapeutic drug monitoring (TDM) and routine liver biochemistry monitoring during VPA-therapy, as well as genotype screening for certain patients before VPA administration, could improve the safety profile of this antiepileptic drug.

Ischemia, referring to reduction and restriction of perfusion to myocardial tissue which involves coronary artery through the formation of misplaced clots and thrombosis, is one of the most important cardiovascular diseases. Plant-based compounds help to improve or prevent disease by affecting the factors involved in the disease. This review was conducted to report the medicinal plants and factors effective in cardiac ischemiareperfusion (I/R) injury to supplement the knowledge about this disease and its prevention and treatment using certain medicinal plants and their active compounds. For this purpose, medicinal plants and their potential antioxidant activities, effects on lipid levels and plaque formation, atherosclerosis and development of cardiovascular diseases and ischemia were reviewed. Methods: To conduct this review, relevant articles published between 1983 and 2018 were retrieved from the Google Scholar, PubMed, Scientific Information Database, Web of Science, and Scopus using search terms antioxidant, ischemia, reperfusion, heart, infarct, inflammation, cholesterol and medicinal plants. Then, the eligible articles were reviewed. Results: The active compounds of plants, including phenolic compounds, flavonoids, and antioxidant compounds, can be effective on certain pathogenic factors particularly in decreasing cholesterol and blood pressure, preventing an increase in free radicals and ultimately reducing blood clots and vascular resistance to reduce and prevent ischemic disease and its harmful effects. Conclusion: Medicinal plants discussed in this article seem to be able to prevent cardiac damage and the disease progression via affecting the factors that are involved in ischemia.

Prunella vulgaris (PV) is a perennial herb belonging to the Labiate family and is widely distributed in the northeastern Asian countries such as Korea, Japan, and China. It is reported to display diverse biological activities including anti-microbial, anti-cancer, and anti-inflammation as determined by in vitro or in vivo studies. So far, about 200 compounds have been isolated from PV plant and a majority of these have been characterized mainly as triterpenoids, sterols and flavonoids, followed by coumarins, phenylpropanoids, polysaccharides and volatile oils. This review summarizes and analyzes the current knowledge on the chemical constituents, pharmacological activities, mechanisms of action and clinical applications of the PV plant including its potential as a future medicinal plant. Although some of the chemical constituents of the PV plant and their mechanisms of action have been investigated, the biological activities of many of these remain unknown and further clinical trials are required to further enhance its reputation as a medicinal plant.