Current Medicinal Chemistry - Volume 28, Issue 20, 2021

SUMOylation has emerged as an important post-translational modification that involves the covalent attachment of the Small Ubiquitin-like Modifier (SUMO) polypeptide to a lysine residue of a target protein. The enzymatic pathway of SUMOylation is very similar to ubiquitinylation and involves an activating enzyme, a conjugating enzyme, ligases, and deconjugating enzymes. SUMOylation modulates the function of a number of proteins associated with various pathways, and in fact, dysregulation of the SUMOylation pathway is observed in both cancer and neurological diseases. In many cancers, the SUMO enzymes are upregulated, and SUMO levels correlate directly with prognosis and disease progression. As a result, there has been an emphasis on the discovery and development of inhibitors of SUMOylation. In this review, the latest advances in SUMOylation inhibitors are described alongside the methods used to discover small molecule SUMOylation inhibitors, which include natural products, peptidomimetics, as well as synthetic derivatives identified via virtual screens.

Glycosphingolipids (GSLs) are ubiquitous components on animal cell membranes, and exposed on the outer surface. Various studies have demonstrated that they play key roles in cell proliferation, adhesion, motility and differentiation. Usually, the specific types of GSLs are expressed more highly in tumors than in normal tissues, which are known as tumorassociated antigens. It has been revealed that most tumor cells show altered GSLs patterns on their surface, abnormal GSLs signaling and biosynthesis, which together play a major role in tumor development. Tumor-associated GSL antigens have been used in the development of antitumor vaccines. There is no doubt that GSLs play a crucial role in tumor progression and would be a promising target for cancer treatment.

Cyclosporine A (CsA) is a cyclic undecapeptide with strong immunosuppressive potency. Firstly marketed in the mid-1980s, CsA was widely used in transplantation and greatly improved the survival rates of patients and grafts after solid-organ transplantation. Unfortunately, CsA administration can be associated with a number of side effects due to its high toxicity. These side effects seriously limited the clinical use of CsA. Therefore, it is important to understand the serious side effects of CsA in patients, especially in transplantation. In this review article, the chemistry and most known toxic effects of CsA, including the nephrotoxic, hepatotoxic, neurotoxic, and cardiotoxic effects, are summarized. Its available toxicity data (different species, different administration routes), published formerly, are also summarized. In addition, the molecular pathways of toxicity induced by CsA are also discussed in detail. It is hoped that this review will help to further understand the source, chemistry, and clinical application of CsA in patients as well as the potential mechanisms of CsA-induced toxicity.

Background: The incidence of diabetes mellitus (DM) is ever-increasing and along with its microvascular and macrovascular complications, it is associated with a high morbidity and mortality burden globally. Major components of diabetes pathophysiology include glucotoxicity, lipotoxicity and insulin resistance, disturbing the vascular wall integrity and leading to endothelial dysfunction and platelet hyper aggregation. Objective: This review aims to identify and summarize the effect of novel anti-diabetic agents (glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter -2 inhibitors) on endothelial (EF) and platelet function (PF) and evaluate the consistency with the results of cardiovascular outcomes studies. Methods: We performed a structured search of the PubMed database for peer-reviewed research of the literature between 1981 and 2020 regarding the effect of DM and novel antidiabetic agents on EF and PF. Results: We analyzed data regarding the effect of novel anti-diabetic agents on EF and PF as well as the pathophysiological interplay between DM, PF, and EF. The available studies use different methods to evaluate these outcomes and the results of different studies are rather conflicting as a result of different study designs, combinations of drugs tested, small study samples and patient population heterogeneity. Conclusion: The currently available data do not unequivocally support a consistent effect of novel antidiabetic agents on EF and PF. Further study is required ideally for the validation of the results with clinical outcomes.

In December 2019, a novel respiratory coronavirus named SARS-CoV-2 appeared in China, causing the disease termed COVID-19 that has caused millions of infections worldwide. In this article, we have analyzed existing evidence on the immune response against SARS coronaviruses in order to understand the possible outcome of a vaccine for COVID-19. From our analysis, it becomes clear that there is a big difference in the immune response against SARS in children, young adults and the elderly, both at the innate and adaptive levels. Taking this information into account, we have studied the strategies that are being used for the development of COVID-19 vaccines. We discussed the perspectives for obtention and worldwide distribution of reliable vaccines using this perspective. The conclusion is that different vaccines may be protective for different age segments within the population, depending on the strategy used for their design. Therefore, it will become necessary for several vaccines to reach the finish line, not only to ensure availability, but also to guarantee an adequate immune response at the individual level.

Immobilization techniques have been popularly used to preserve the operational stability of the enzymes for industrial applications. The three main components of an immobilized enzyme system are the enzyme, the matrix/support, and the technique of immobilization. So far, different supports have been developed to improve the efficiency of the immobilized enzymes. But in the recent decade, nanotechnology has been of considerable research interest in the field of immobilized enzyme carriers. The materials at the nano-scale, due to their unique physicochemical properties, including; specific surface area, mass transfer limitation, and effective enzyme loading, are considered interesting matrices for enzyme immobilization. This review describes techniques employed to immobilize enzymes, and provides an integrated focus on the most common nanoparticles for enzyme conjugation. Additionally, the pros and cons of nanoparticles as immobilization matrices are also discussed. Depending on the type of enzyme and its application, in this review, the researchers are directed to select an appropriate method and support for enzyme immobilization in terms of enzyme stability and functionality.

Obesity is a major health concern for a growing fraction of the population, as its prevalence and related metabolic disorders are not fully understood. Over the last decade, many attempts have been undertaken to understand the mechanisms at the basis of this condition, in which the accumulation of fat occurring in adipose tissue leads to the pathogenesis of obesity- related disorders. Among the most recent studies, those on Peroxisome Proliferator Activated Receptors (PPARs) revealed that these nuclear receptor proteins acting as transcription factors, among others, regulate the expression of genes involved in energy, lipid, and glucose metabolisms, and chronic inflammation. The three different isotypes of PPARs, with different tissue expression and ligand binding specificity, exert similar or overlapping functions directly or indirectly linked to obesity. In this study, we reviewed the available scientific reports concerning the PPARs structure and functions, especially in obesity, considering both natural and synthetic ligands and their role in the therapy of obesity and obesity-associated disorders. On the whole, the collected data suggest that there are both natural and synthetic compounds that show beneficial and promising activity as PPAR agonists in chronic diseases related to obesity.

The prostate-specific antigen (PSA) has been considered a crucial serological marker for distinguishing prostate based cancer. This survey shows recent progress in the construction of nanomaterial-based electrochemical immunosensors for a PSA. This review (from 2015 to 2020) reports the latest progress in PSA sensing based on the employ of different types of nanostructured materials. The most popular used nanostructured materials are metal, metal oxide, carbon-based nanomaterials, and their hybrid architectures utilized for distinct amplification protocols. In this review, the electrochemical immunosensors for prostate-specific antigen sensing are classified into three categories such as sandwich type@labeled, label free@nonlabeled and aptamer-based electrochemical immunosensor.

Background: It is estimated that the average time between the diagnosis of Alzheimer’s disease (AD) and the patient’s death is 5-9 years. Therefore, both the initial phase of the disease and the preclinical state can be included in the critical period in disease diagnosis. Accordingly, huge progress has recently been observed in biomarker research to identify risk factors for dementia in older people with normal cognitive functions and mild cognitive impairments. Methods: Electrochemical biosensors are excellent analytical tools that are used in the detection of AD biomarkers as they are easy to use, portable, and can do analysis in real time. and mild cognitive impairments. Results: This review presents the analytical techniques currently used to determine AD biomarkers in terms of their advantages and disadvantages; the most important clinical biomarkers of AD and their role in the disease. All recently used biorecognition molecules in electrochemical biosensor development, i.e., receptor protein, antibodies, aptamers and nucleic acids, are summarized for the first time. Novel electrochemical biosensors for AD biomarker detection, as ideal analytical platforms for point-of-care diagnostics, are also reviewed. and mild cognitive impairments. Conclusion: The article focuses on various strategies of biosensor chemical surface modifications to immobilize biorecognition molecules, enabling specific, quantitative AD biomarker detection in synthetic and clinical samples. In addition, this is the first review that presents innovative single-platform systems for simultaneous detection of multiple biomarkers and other important AD-associated biological species based on electrochemical techniques. The importance of these platforms in disease diagnosis is discussed.

Background: Numerous studies have demonstrated that halogenated agents elicit myocardial conditioning effects when administered perioperatively in cardiac surgery. Recent evidence has been published on the benefits of maintaining exposure to halogenated agents during the early postoperative period. The enzymatic mechanisms by which this beneficial effect is exerted were explained recently. Objectives: Our study was performed to investigate whether this phenomenon is mediated by either the activation or suppression of miRNAs targeted by halogenated anesthetics. Methods: A double-blind, two-stage trial was conducted. The results of the first stage of the trial are presented in this paper. The sample was composed of patients undergoing off-pump myocardial revascularization surgery. Patients were randomized to receive either sevoflurane [S] or propofol [P] during the intraoperative and early postoperative period (during the first six hours after the intervention). Hemodynamics (heart rate, blood pressure, central venous pressure, cardiac index, systolic volume index, LVEF) and myocardial enzymes (troponin I) were monitored at six hour intervals during the first 48 hours. In the first stage of the trial, blood was drawn for gene sequencing from eight patients (four per group) at baseline and at 24 h. In the second stage of the study, a qPCR analysis was performed of the miRNAs identified as significant by gene sequencing. Levels of cardioprotective enzymes (serine/threonine protein kinase (Akt), tumor necrosis factor alpha (TNFα), extracellular regulated protein kinase (ERK 1/2), and caspase 3) were measured to assess their role in myocardial conditioning pathways. The purpose was to identify the miRNAs that play a major role in myocardial conditioning induced by halogenated agents. Concentrations of cardioprotective enzymes were higher in patients who received sevoflurane than the patients who were administered propofol. Results: NGS differences were observed between baseline and 24-h values in the two study groups. In group P, miRNA 197-3p was overexpressed, whereas miRNAs 4443 and 1294, 708-3p were underexpressed. In group S, miRNAs 615-3p, 4466, 29, 937-3p, 636, 197-3P, 184, 4685, 296-3p, 147b, 3199, 6815, 1294 and 3176 were underexpressed; whereas 708-3p was overexpressed. qPCR showed significant variations in miRNAs 197-3p, 4443, 708-3p and 1294 in the P group, and in miRNAs 937-3p, 636, 197- 3p, 296-3p and 708-3p in the S group. Conclusion: In the P Group, changes in the expression of some miRNAs were associated with lower concentrations of the enzymes involved in myocardial pre- and postconditioning. In contrast, in Group S, variations in miRNAs were associated with the activation of mediators of anesthetic-induced pre- and post-conditioning, a reduction in cell apoptosis, and a decrease in caspase and TnBF alpha concentrations. Changes in these miRNAs were associated with better prognosis in patients with ischemic heart disease. The main limitation of this study will be overcome in the second stage of the trial, where the specific role of each miRNA will be determined.