Current Medicinal Chemistry - Volume 26, Issue 29, 2019

Therapeutic hypothermia has consistently been shown to be a robust neuroprotectant in many labs studying different models of neurological disease. Although this therapy has shown great promise, there are still challenges at the clinical level that limit the ability to apply this routinely to each pathological condition. In order to overcome issues involved in hypothermia therapy, understanding of this attractive therapy is needed. We review methodological concerns surrounding therapeutic hypothermia, introduce the current status of therapeutic cooling in various acute brain insults, and review the literature surrounding the many underlying molecular mechanisms of hypothermic neuroprotection. Because recent work has shown that body temperature can be safely lowered using pharmacological approaches, this method may be an especially attractive option for many clinical applications. Since hypothermia can affect multiple aspects of brain pathophysiology, therapeutic hypothermia could also be considered a neuroprotection model in basic research, which would be used to identify potential therapeutic targets. We discuss how research in this area carries the potential to improve outcome from various acute neurological disorders.

This review article is an attempt to summarize the current state of knowledge of the impact of Vanadium (V) on Oxidative Stress (OS) markers in vivo. It shows the results of our studies and studies conducted by other researchers on the influence of different V compounds on the level of selected Reactive Oxygen Species (ROS)/Free Radicals (FRs), markers of Lipid peroxidation (LPO), as well as enzymatic and non-enzymatic antioxidants. It also presents the impact of ROS/peroxides on the activity of antioxidant enzymes modulated by V and illustrates the mechanisms of the inactivation thereof caused by this metal and reactive oxygen metabolites. It also focuses on the mechanisms of interaction of V with some nonenzymatic compounds of the antioxidative system. Furthermore, we review the routes of generation of oxygen-derived FRs and non-radical oxygen derivatives (in which V is involved) as well as the consequences of FR-mediated LPO (induced by this metal) together with the negative/ positive effects of LPO products. A brief description of the localization and function of some antioxidant enzymes and low-molecular-weight antioxidants, which are able to form complexes with V and play a crucial role in the metabolism of this element, is presented as well. The report also shows the OS historical background and OS markers (determined in animals under V treatment) on a timeline, collects data on interactions of V with one of the elements with antioxidant potential, and highlights the necessity and desirability of conducting studies of mutual interactions between V and antioxidant elements.

A number of papers reporting antimicrobial properties of extracts, essential oils, resins and various classes of compounds isolated from higher plants have been published in recent years; however, a comprehensive analysis of plant-derived antimicrobial agents currently applied in practice for the improvement of human health is still lacking. This review summarizes data on clinical efficacy, antimicrobial effects and the chemistry of commercially available antibacterial and antifungal agents of plant origin currently used in the prevention and treatment of gastrointestinal, oral, respiratory, skin, and urinary infections. As a result of an analysis of the literature, more than 40 plant-derived over-the-counter pharmaceuticals, dietary supplements, cosmetics, herbal medicines, and functional foods containing complex mixtures (e.g. Glycyrrhiza glabra extract, Melaleuca alternifolia essential oil, and Pistacia lentiscus resin), pure compounds (e.g. benzoic acid, berberine, eucalyptol, salicylic acid and thymol) as well as their derivatives and complexes (e.g. bismuth subsalicylate and zinc pyrithione) have been identified. The effectiveness of many of these products is illustrated by results of clinical trials and supported by data on there in vitro antimicrobial activity. A broad spectrum of various commercial products currently available on the market and their welldocumented clinical efficacy suggests that plants are prospective sources for the identification of new types of antimicrobial agents in future. Innovative approaches and methodologies for effective proof-of-concept research and the development of new types of plant-derived products effective against recently emerging problems related to human microbial diseases (e.g. antimicrobial resistance) are also proposed in this review.

Diabetes mellitus, commonly referred to as diabetes, is the 8th leading cause of death worldwide. As of 2015, approximately 415 million people were estimated to be diabetic worldwide, type 2 diabetes being the most common accounting for approximately 90-95% of all diagnosed cases with increasing prevalence. Fructose-1,6-bisphosphatase is one of the important therapeutic targets recently discovered to treat this chronic disease. In this focused review, we have highlighted recent advances and structure-activity relationship studies in the discovery and development of different fructose-1,6-bisphosphatase inhibitors reported since the year 2000.

Background: Despite optimal management of diabetic kidney disease (DKD) with intensive glycemic control and administration of agents blocking the renin-angiotensinaldosterone- system, the residual risk for nephropathy progression to end-stage-renal-disease (ESRD) remains high. Sodium-glucose co-transporter type 2 (SGLT-2)-inhibitors represent a newly-introduced anti-diabetic drug class with pleiotropic actions extending above their glucose-lowering efficacy. Herein, we provide an overview of preclinical and clinical-trial evidence supporting a protective effect of SGLT-2 inhibitors on DKD. Methods: A systematic literature search of bibliographic databases was conducted to identify preclinical studies and randomized trials evaluating the effects SGLT-2 inhibitors on DKD. Results: Preclinical studies performed in animal models of DKD support the renoprotective action of SGLT-2 inhibitors showing that these agents exert albuminuria-lowering effects and reverse glomerulosclerosis. The renoprotective action of SGLT-2 inhibitors is strongly supported by human studies showing that these agents prevent the progression of albuminuria and retard nephropathy progression to ESRD. This beneficial effect of SGLT-2 inhibitors is not fully explained by their glucose-lowering properties. Attenuation of glomerular hyperfiltration and improvement in a number of surrogate risk factors, including associated reduction in systemic blood pressure, body weight, and serum uric acid levels may represent plausible mechanistic explanations for the cardio-renal protection offered by SGLT-2 inhibitors. Furthermore, the tubular cell metabolism seems to be altered towards a ketone-prone pathway with protective activities. Conclusion: SGLT-2 inhibition emerges as a novel therapeutic approach of diabetic with anticipated benefits towards cardio-renal risk reduction. Additional research efforts are clearly warranted to elucidate this favorable effect in patients with overt DKD.

Background: Clinical evaluation of the Endothelial Function (EF) is becoming an essential step in the quality assessment of cardiovascular risk prevention and rational pharmacotherapy of cardiovascular disorders. The existing pieces of evidence suggested that Calcium Channel Blockers (CCB) can induce positive effects on impaired EF. Objective: To evaluate the effects of CCB on EF, we performed a meta-analysis of available data from randomized and placebo-controlled or other treatment-controlled clinical studies encompassing effects of CCB on EF, as measured by Flow-Mediated Dilation (FMD) of the brachial artery. Methods: The relevant clinical studies were searched by systematic exploration of the appropriate databases until November 30, 2017. A random-effect model was conducted. The primary outcome was the percentage change in FMD between the baseline and the final levels in response to investigated drugs. Results: Fifteen randomized clinical studies with 33 arms were identified. CCB improved FMD more pronounced than thiazide diuretics - TD (3 studies, 157 participants, WMD=2.08%, 95% CI=0.35-3.80%; P=0.02). Oppositely, ACE Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB) notably improved FMD if compared to CCB (CCB vs. ACEI: 5 studies, 533 participants, WMD = -1.62%, 95% CI = -2.74% to -0.50%; P=0.005; and CCB vs. ARB: 9 studies, 669 participants, WMD = -1.52%, 95% CI = -2.22% to -0.81%; P=0.0001). CCB effects on EF were similar to those evoked by beta blockers or placebo. Conclusion: CCB improved EF to a more prominent extent only if paralleled to TD, while inversely; ACEI and ARB were more effective in augmenting FMD.