Pharmacology

What We Can Learn from Current Inflammatory Bowel Disease (IBD) Biological Therapy—Dose Regimen and Others Abstract Purpose of Review Inflammatory bowel disease (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC), is an unmet need as indicated by less than ideal remission rates with current treatments. Understanding the clinical development of approved IBD biological therapy, particularly dose selection, may help improve future biologic development. Recent Findings Seven biologics have been approved for CD and/or UC in the last two decades (as of January 2019), including anti-tumor necrosis factors (anti-TNFs) (infliximab, adalimumab, certolizumab, and golimumab), anti-integrins (natalizumab and vedolizumab), and anti-interleukin (IL)-12/IL-23 (ustekinumab). These agents demonstrate effectiveness in inducing sustained clinical remission despite the high and variable "placebo" response. Side effects such as infections and malignancies can occur for biologics partly due to the long-term immunosuppression. IBD biologics typically employ an intensive induction followed by maintenance therapy. Approved dose regimen (especially induction) tends to be the same or close to the highest doses that have been evaluated in clinical development, indicating a limited dose range tested. Biologics approved for CD and UC use the same dose regimen though a given drug may not work equally effectively for both indications. Summary Lessons learned from current IBD biological therapy may help enhance the clinical development efficiency of future biologics, e.g., test a wide dose range; characterize full dose-response for desirable and untoward effects; understand influencing factors to the treatment (and placebo) effect; and leverage dose-ranging learning between CD and UC.

A Small Green Red-Ox Carries a Bright Medical Future for Sub-Saharan Africa Abstract Purpose of Review Redox-related diseases are prevalent globally. Given the cost of allopathic medicines, "green preparations" are often relied on in economically developing countries. This review sought to identify medicinal plants of sub-Saharan Africa which have scientifically validated antioxidant properties, the compounds responsible for these properties, and to highlight the role of nanosizing of such plant materials in the medical future for the region. Recent Findings Eighteen plants (from 13 families) with reported antioxidant properties were identified. The Euphorbiaceae (3 plants) and Capparaceae (2 plants) were the most represented families. Most of the plants were reported to be used in folk medicine for the treatment of infections and inflammation, and water and methanol were the most widely used solvents for preparing the bioactive extracts. In vitro studies (13 cases) predominated. Forty-six different bioactive compounds were reported in the 18 plants identified. Catechin/epicatechin (13 plants), gallic acid (7 plants), caffeic acid, chlorogenic acid, and vitexin/isovitexin (5 plants each) were the most widely reported antioxidant phytochemicals. Given that synergism can occur to enhance the antioxidant activities of phytochemicals, nanosizing the plant leaves identified may open new vistas of opportunities in the development of redox active green pharmaceuticals. Summary Given the abundance of antioxidant phenolics in the plants of sub-Saharan Africa, and the challenges of solvent extraction techniques (with respect to upscaling), nanosizing presents an eco-friendly means of sustainably exploiting these plant resources for medicinal purposes. Therefore, it appears that "a small green red-ox carries a bright medical future for sub-Saharan Africa."

Electrochemical Potential-Biological Activity Relationships of Cyclic Sulfur-Containing Molecules Against Steinernema feltiae , Botrytis cinerea , and Neuro 2a Cell Line Abstract Purpose of Review This article provides a brief overview of electrochemical potential-biological activity relationships of natural and synthetic cyclic sulfur-containing molecules against Steinernema feltiae, Botrytis cinerea, and Neuro 2a cell line (from murine neuroblastoma). Recent Findings This article finds natural cyclic sulfur-containing molecules and their synthetic analogues were more reducing than glutathione (GSH) and therefore apparently did not react with GSH. The nematicidal assay indicated that cyclic disulfide compound of 1 (3-vinyl-4H-1,2-dithiin, 1,2-VDT) was more active against Steinernema feltiae with the LD50 value 151.93 ± 1.3 μM, while dithiole thione group compounds showed moderate activity against this nematode. The article also finds compound 7 (3H-1,2-dithiole-3-thione or dithiolethione, DT) has a strong activity against all different strains of Botrytis cinerea in the range concentration of 0.1–0.5 mM. This article also finds that compounds 3 (1,2-dithiane, 1,2-DT), 4 (1,5-dithiacyclooctane, 1,5-DTCO), and 7 (3H-1,2-dithiole-3-thione or dithiolethione, DT) possess some moderate activity on Neuro 2a cell lines. Summary Antinematode, antifungal, and anticancer activity of cyclic sulfur-containing molecules indicated that they could be promising candidates for "green pesticides" or phytoprotectans and for cancer prevention.

Focusing on the Pharmacological Effects of Iridoids and Crocetin and Its Ester Derivatives of Gardenia jasminoides Abstract Gardenia jasminoides (G. jasminoides), grown in multiple regions in China, was commonly used as a natural yellow dye but has been one of the popular traditional Chinese medicines since the discovery of its biological property few decades ago. It has been reported that G. jasminoides possesses multiple bioactivities, such as anti-oxidant property, hypoglycemic effect, and inhibition of inflammation, anti-depression, and improving sleeping quality. In this review, we aimed to have a comprehensive summary of its phytochemistry including the extraction, isolation, and characterization of volatiles and bioactive molecules in G. jasminoides, focusing on the two major phytochemicals, iridoids and crocetin, and its ester derivatives, which exhibit potential medicinal properties. Furthermore, this work attempted to establish a structure activity relationship (SAR) between the two major series of derivatives with different molecular skeletons and their biological activities, which would serve further exploration of the health-promoting potentials of phyto-compounds in G. jasminoides as dietary supplements or functional ingredients in medical foods. Graphical Abstract .

Selenoneine: a Unique Reactive Selenium Species From the Blood of Tuna With Implications for Human Diseases Abstract Purpose of Review The trace element selenium is found in many dietary components, from grains to Brazil nuts. In humans, this chalcogen is essential for many physiological processes. A couple of years ago, selenoneine, a rather unusual seleno-histidine derivative, has been isolated from tuna. Recent Findings Whilst there is a limited number of other naturally occurring small selenium compounds, large quantities of selenoneine can be generated in genetically engineered microorganisms and via chemical synthesis. Due to a rare selenol/selenone tautomerism, this compound exhibits unique redox properties and promising biological activities, which range of traditional antioxidant action to the interaction and subsequent protection of metal ions. Summary Selenoneine may indeed provide a promising lead for a new generation of selenium supplements and chemopreventive agents.

Protection from DNA Damage by Use of an Aronia Food Supplement—Results from a Pilot Human Intervention Study Abstract Purpose of Review Polyphenols from fruits and other plant sources exhibit protective effects against DNA damage and markers of oxidative stress. Meanwhile, previous investigations tested rather large volumes of polyphenol-rich fruit juices; hence, there is a lack of information on the efficacy of small-volume supplementation concepts suitable for daily routine. We designed a 6-week pilot study on the use of such a food supplement (aronia+) including ten healthy male volunteers and tested for effects on DNA integrity, oxidation-related parameters (Nrf2, SOD, GPx, CAT, and oxidized LDL), and blood lipids. Recent Findings Tendencies towards a decrease were observed for both total and background DNA strand breaks but were not significant after 4-week consumption of the food supplement. Transcription levels of Nrf2 were elevated; meanwhile, Nrf2/ARE-related enzymes were not affected (GPx) or even slightly decreased (SOD, CAT). Marginal reduction was observed for total and LDL cholesterol, whereas other parameters remained almost unchanged. Summary This explorative study yields first indications on protective effects on DNA damage after intake of even small volumes of polyphenol-rich food supplements. These observations must be confirmed in a follow-up study with a higher number of included volunteers and an integration of a control group in order to clearly assess the effect of the intervention.

Polymethoxyflavones: Chemistry and Molecular Mechanisms for Cancer Prevention and Treatment Abstract Polymethoxyflavones (PMFs) are one group of the flavonoid compounds, with tangeretin (Tan) and nobiletin (Nob) being the most abundant PMFs in citrus peel. Numerous biological activities of PMFs have been intensively studied, including anti-inflammatory and anticancer activities. Because of their methoxy groups, PMFs are more lipophilic than hydroxyl flavones, which may affect their biological activities. In addition, researchers found that hydroxylated PMFs (HPMFs) are one of the major metabolites of PMFs in animal urine and feces. Although PMF and HPMFs do show anticancer activity against different types of cancers, but their low hydrophilicity is still a crucial factor that may affect their biological effectiveness. Therefore, from the pharmaceutical aspect, chemical modifications of PMFs have been carried out to obtain acetylated PMFs (Ac-PMFs) for enhancing their biological effects. From the past centuries to the present, cancer is still a critical disease that needs to be solved. Carcinogenesis can be simply divided into three stages: initiation, promotion, and progression. These three stages involve different biological events, such as DNA mutation, cell proliferation, cell growth, and metastasis. In this paper, we aim to illustrate the biological effects of different PMFs, HPMFs, PMF derivatives, and metabolites against different types of cancer and related molecular mechanisms.

Dyslipidemia: Contemporary Therapy Options in Terms of Worldwide Guidelines Abstract Purpose of Review Statins represent a golden standard for treating patients with dyslipidemia. At half of the treated patients, the targeted level of LDL cholesterol is not achieved. Numerous studies which promote new medications have been published in the past several years. Therefore, the objective of this paper is to consider the new possibilities of treating dyslipidemia in terms of various dyslipidemia guidelines. Recent Findings Randomized clinical trials have shown that most positive effects are achieved by lowering the level of LDL cholesterol, and thus the guidelines define the target LDL value. Numerous guidelines in the field of dyslipidemia have been published, but there are some differences which will be analyzed in this review paper. Even if the target LDL cholesterol level is reached, there is still a residual lipid risk for the occurrence of cardiovascular diseases. Therefore, lipid factors, such as high level of triglycerides, low HDL cholesterol, LP(a), etc., play a very important role. Nowadays, there are numerous potent medications which are used in statin and non-statin therapies. PCSK9 inhibitors, which are in the special focus of this paper, have been tested in the past few years. The paper offers an overview of traditionally used medications, as well as new experimental medications. Moreover, the paper emphasizes the importance of non-adherence to antilipemic medications, which is an important issue which reduces the favorable effects of the treatment. Summary Nowadays, there are drugs which, combined with statins, may reduce HDL-C level to very low values. The studies have shown inconsistent results in terms of solving the issue of residual lipid risk. Research in this field may significantly reduce lipid risk for cardiovascular events.

Role of Reactive Oxygen Species in Cancer Progression Abstract Purpose of Review Although there are significant improvements in diagnosis and therapeutics tools, cancer remained a major cause of deaths in developing and developed countries. Among others, endogenously or exogenously generating reactive oxygen species (ROSs) are considered a crucial cause for tumor initiation, development, and survival. Unhealthy lifestyle, exposure to various carcinogens, ionizing radiations, and chemotherapy drugs are the main factors for ROS production. Recent Findings Reactive oxygen species cause genetic instability due to DNA damage or mutation load. Exposer to ROS also modulates the expression of various transcription factors such as Sp1, AP1, and NF-κβ implicated in proliferation, metastasis, and cancer stem cell maintenance. It is suggested that ROSs are involved in various cancer-related process including apoptosis, angiogenesis, metastasis, and inflammation. Numerous data from several studies suggest ROS as one of the therapeutic targets for cancer prevention and cure. Summary The current review summarizing the interactions of ROSs with various cellular molecules involved in angiogenesis, metastasis, and inflammation.

Role of Histone Acetylation and Methylation in Obesity Abstract Purpose of Review This review gives an overview of the roles of histone acetylation and methylation in obesity and related metabolic diseases. Recent Findings Nutrition can change gene expression via epigenetics such as DNA methylation and post-translational modifications of histones. A growing number of both experimental and clinical studies suggested that histone modifications are very sensitive to changes in nutritional availability and potentially impact the development and progression of metabolic disorders. Recent advances in proteomic studies provided evidence linking histone modifications to over-nutrition and metabolic dysregulation. In this review, we will summarize the recent findings on two classical histone modifications, i.e., acetylation and methylation and the related findings from clinical studies and potential applications. Summary The involvement of histone modifications in the progression of metabolic diseases is now widely appreciated. Over the recent years, mass spectrometry-based proteomics approaches discovered and mapped different kind of histone modifications linking obesity and metabolic diseases. The list of these modifications is evergrowing; however, their functions and roles in obesity are not well understood. Same as for the most well studied histone modifications, namely acetylation and methylation. Although much has been learnt from these two modifications, their contributions in regulation of metabolism are still largely unknown. It will be necessary to carry out more studies to further dissect the importance of the availability of substrates and activities of the enzymes for histone acetylation and methylation in the metabolic tissues.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
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2841026182

6948891480

alsfakia@gmail.com