Current Medicinal Chemistry (v.24, #14)
Emerging Insight into MAPK Inhibitors and Immunotherapy in Colorectal Cancer by Massimo Pancione, Guido Giordano, Pietro Parcesepe, Luigi Cerulo, Luigi Coppola, Anais Del Curatolo, Fabiana Conciatori, Michele Milella, Almudena Porras (1383-1402).
Our understanding of the genetic and non-genetic molecular alterations associated with colorectal cancer (CRC) progression and therapy resistance has markedly expanded in the recent years. In addition to their effects on tumor biology, targeted therapies can have effects on host immune responses. However, the mechanisms by which immune cells organize tumor microenvironments to regulate T-cell activity need to be comprehensively defined. There is good evidence in the literature that alterations in different members of the MAPK superfamily (mainly ERKs and p38 MAPKs) modify the inflammatory response and antitumor immunity, enhancing metastatic features of the tumors. In addition, a plethora of alterations that emerge at relapse often converge on the activation of MAPKs, particularly, ERKs, which act in concert with other oncogenic signals to modulate cellular homeostasis and clonal evolution during targeted therapies. Herein, we discuss how this knowledge can be translated into drug development strategies aimed at increasing tumor antigenicity and antitumor immune responses. Insights from these studies could provide a framework for considering additional combinations of targeted therapies and immunotherapies for the treatment of CRC.
Treatment with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors to Reduce Cardiovascular Inflammation and Outcomes by Luca Liberale, Fabrizio Montecucco, Giovanni G. Camici, Franco Dallegri, Alessandra Vecchie, Federico Carbone, Aldo Bonaventura (1403-1416).
Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is a serine protease involved in cholesterol homeostasis. After binding to the complex low-density lipoprotein (LDL)-receptor, PCSK9 induces its intracellular degradation, thus reducing serum LDL clearance. PCSK9 is mainly secreted by the liver, but it is also expressed to a lesser extent in other organs. Apart from the well-known activity concerning hepatic LDL receptor-mediated pathway, PCSK9 has been supposed to potentially interfere with vascular inflammation in atherogenesis. Vascular smooth muscle cells have been demonstrated to produce higher amounts of PCSK9 as compared to endothelial cells especially in an inflammatory microenvironment. Low shear stress regions increase PCSK9 expression within SMCs, while higher shear stress gradually reduced PCSK9 expression. Moreover, a crosstalk between PCSK9 and reactive oxygen species has been also described. Oxidized LDL was shown to up regulate the expression of PCKS9 by influencing dose-dependently the secretion of interleukin (IL)-1α, IL-6, and tumor necrosis factor-α. After the identification of gene loss-of-function mutations and no detectable circulating protein levels, PCSK9 has attracted a great interest as an effective target for cholesterol-lowering therapies. Different strategies have been implemented to block the effects of both intracellular and circulating PCSK9. In particular, monoclonal antibodies represent the most promising approach and two of these, alirocumab and evolocumab, have been approved for clinical use in patients affected by familial hypercholesterolemia with encouraging results. In the next future, the improvement of the knowledge of the 'pleiotropic' effects of PCSK9 inhibitors might unveil therapeutic potential on cardiovascular outcome independently on the cholesterol lowering activity.
Role of Hepcidin-25 in Chronic Kidney Disease: Anemia and Beyond by Norishi Ueda, Kazuya Takasawa (1417-1452).
Iron is an essential element for all living organisms, but produces toxic oxidants. Thus, iron homeostasis is tightly regulated in mammals. Hepcidin-25 (hepcidin) has emerged as a molecule that regulates iron metabolism. Binding of hepcidin to its receptor, ferroportin, inhibits intestinal iron absorption and iron efflux from hepatocytes and macrophages. Decreased hepcidin enhances iron absorption and efflux. Hepcidin could be predictive of iron status and the response to iron supplementation or erythropoietin-stimulating agents. Monitoring hepcidin is helpful for the management of anemia. Thus, it is urgent to obtain normal reference values in a large population of healthy subjects and to standardize various hepcidin assays, which enables to compare the data measured by different methods. Anemia is an important and common problem associated with chronic kidney disease (CKD), which is caused by erythropoietin deficiency, iron-restricted erythropoiesis, inflammation, hypoxia, vitamin D deficiency, hyperparathyroidism, and obesity. Anemia causes poor quality of life, progression of CKD, increased risk of cardiovascular events, and mortality. Besides its role in anemia, recent evidence suggests that hepcidin-25 plays a role in the pathogenesis and progression of kidney injury via modulation of iron-mediated oxidant injury. Despite accumulating experimental data, information about clinical significance of hepcidin-25 for anemia and kidney injury in CKD patients is scarce, especially in children. This review summarizes the current knowledge of the role of hepcidin-25 in the regulation of anemia and kidney injury in children and adults with CKD. Strategy for modulating hepcidin-25 to prevent anemia and kidney injury associated with CKD is also discussed.
Therapeutic Strategies of Plant-derived Compounds for Diabetes Via Regulation of Monocyte Chemoattractant Protein-1 by Magdalena Czemplik, Anna Kulma, Yu Fu Wang, Jan Szopa (1453-1468).
Background: Monocyte chemoattractant protein-1 (MCP-1) is a member of the CC chemokine family that plays a key role in the inflammatory process. It has been broadly studied in the aspect of its role in obesity and diabetes related diseases. MCP-1 causes the infiltration of macrophages into obese adipose tissue via binding to the CCR2 receptor and is involved in the development of insulin resistance. Methods: We reviewed the available literature regarding the importance of plant metabolites that regulate MCP-1 activity and are used in the treatment of diabetic disorders. The characteristics of screened papers were described and the important findings were included in this review. Results: This mini-review provides a summary of functions and therapeutic strategies of this chemokine, with a special focus on plant-derived compounds that possess a putative antidiabetic function via a mechanism of MCP-1 interaction. The highlights of this review include the roles of MCP-1 in development of diabetes, the evaluation of plant metabolites that specifically or non-specifically inhibit MCP-1 overproduction, and the molecular mechanisms of this activity. Among these metabolites, we particularly focused on phenolic acids and their derivatives, flavonoids, stilbenes, anthocyanins, capsaicin, alkaloids, plant sterols, terpenes, saponins, unsaturated fatty acids and plant-derived extracts. Conclusion: Regarding the increasing number of diabetic patients yearly, the recent progress in the putative therapies needs to be summarized. This article underlines the significance and involvement of the chemokine MCP-1 in the development of obesity, type 2 diabetes, and diabetic complications, with an emphasis on the role of plant metabolites in the regulation of this chemokine and thus the role in the prevention or therapy of diabetes. We suggest that MCP-1 might be a molecular marker of type 2 diabetes.
Role of Oxidative Stress in Renal Transplantation: Bases for an n-3 PUFA Strategy Against Delayed Graft Function by Camilo G. Sotomayor, Ignacio Cortés, Juan Guillermo Gormaz, Sergio Vera, Matías Libuy, Nicolás Valls, Ramón Rodrigo (1469-1485).
Renal transplantation (RT) is considered the 'gold standard' treatment for end-stage renal disease patients. Efforts should be made to reduce ischaemia-reperfusion (IR) injury, which unavoidably occurs in RT as long as several clinical settings, i.e. open-heart surgeries, prosthesis implantation, among others. It is well known that IR is primarily responsible for injury associated with RT. Consequently, tissue inflammation and organ dysfunction will ensue due to the occurrence of oxidative stress (OS) in the reperfused tissue, a condition generated when endogenous antioxidant defences become overwhelmed by a massive production of reactive oxygen species. Furthermore, OS is involved in the impairment of renal function, leading to deleterious conditions such as delayed graft function (DGF), which is a common clinical expression of IR injury in RT. Omega-3 polyunsaturated fatty acids (n -3 PUFA) have been widely used in different clinical settings to counteract the deleterious effects of OS. Thus, based on the currently available literature, the central aim of this review was to propose an n-3 PUFAbased strategy targeting the key role of OS in the pathophysiology of renal IR injury in order to encourage protection against the occurrence of DGF.