Current Medicinal Chemistry - Volume 26, Issue 22, 2019

Type 2 diabetes mellitus is a metabolic disease widely spread across industrialized countries. Sedentary lifestyle and unhealthy alimentary habits lead to obesity, boosting both glucose and fatty acid in the bloodstream and eventually, insulin resistance, pancreas inflammation and faulty insulin production or secretion, all of them very well-defined hallmarks of type 2 diabetes mellitus. miRNAs are small sequences of non-coding RNA that may regulate several processes within the cells, fine-tuning protein expression, with an unexpected and subtle precision and in time-frames ranging from minutes to days. Since the discovery of miRNA and their possible implication in pathologies, several groups aimed to find a relationship between type 2 diabetes mellitus and miRNAs. Here we discuss the pattern of expression of different miRNAs in cultured cells, animal models and diabetic patients. We summarize the role of the most important miRNAs involved in pancreas growth and development, insulin secretion and liver, skeletal muscle or adipocyte insulin resistance in the context of type 2 diabetes mellitus.

A large number of studies have been focused on investigating serum biomarkers associated with risk or diagnosis of type-2 diabetes mellitus. In the last decade, promising studies have shown that circulating levels of adipokines could be used as a relevant biomarker for diabetes mellitus progression as well as therapeutic future targets. Here, we discuss the possible use of recently described adipokines, including apelin, omentin-1, resistin, FGF-21, neuregulin-4 and visfatin, as early biomarkers for diabetes. In addition, we also include recent findings of other well known adipokines such as leptin and adiponectin. In conclusion, further studies are needed to clarify the pathophysiological significance and clinical value of these biological factors as potential biomarkers in type-2 diabetes and related dysfunctions.

Enhanced platelet activation and thrombosis are linked to various cardiovascular diseases (CVD). Among other mechanisms, oxidative stress seems to play a pivotal role in platelet hyperactivity. Indeed, upon stimulation by physiological agonists, human platelets generate and release several types of reactive oxygen species (ROS) such as O2 -, H2O2 or OH-, further amplifying the platelet activation response via various signalling pathways, including, formation of isoprostanes, Ca2+ mobilization and NO inactivation. Furthermore, excessive platelet ROS generation, incorporation of free radicals from environment and/or depletion of antioxidants induce pro-oxidant, pro-inflammatory and platelet hyperaggregability effects, leading to the incidence of cardiovascular events. Here, we review the current knowledge regarding the effect of oxidative stress on platelet signaling pathways and its implication in CVD such as type 2 diabetes mellitus. We also summarize the role of natural antioxidants included in vegetables, fruits and medicinal herbs in reducing platelet function via an oxidative stress-mediated mechanism.

The pathophysiology linking diabetes and cardiovascular disease (CVD) is complex and multifactorial. The specific type of cardiomyopathy associated with diabetes, known as diabetic cardiomyopathy (DCM), is recognized as asymptomatic progression of structural and functional remodeling in the heart of diabetic patients in the absence of coronary atherosclerosis and hypertension. In other words, the presence of heart disease specifically in diabetic patients is also known as diabetic heart disease. This article reviews the impact of diabetes in heart and vascular beds focusing on molecular mechanisms involving the oxidative stress, the inflammation, the endothelium dysfunction and the alteration of the homeostasis of calcium, among others mechanisms. Understanding these mechanisms will help identify and treat CVD in patients with diabetes, as well as to plan efficient strategies to mitigate DCM impact in those patients.

All living organisms exhibit circadian rhythms, which govern the majority of biological functions, including metabolic processes. Misalignment of these circadian rhythms increases the risk of developing metabolic diseases. Thus, disruption of the circadian system has been proven to affect the onset of type 2 diabetes mellitus (T2DM). In this context, the pineal indoleamine melatonin is a signaling molecule able to entrain circadian rhythms. There is mounting evidence that suggests a link between disturbances in melatonin production and impaired insulin, glucose, lipid metabolism, and antioxidant capacity. Besides, several genetic association studies have causally associated various single nucleotide polymorphysms (SNPs) of the human MT2 receptor with increased risk of developing T2DM. Taken together, these data suggest that endogenous as well as exogenous melatonin may influence diabetes and associated metabolic disturbances not only by regulating insulin secretion but also by providing protection against reactive oxygen species (ROS) since pancreatic β-cells are very susceptible to oxidative stress due to their low antioxidant capacity.

The alarming increase in the number of diabetic patients worldwide raises concerns regarding the impact of the disease on global health, not to mention on social and economic aspects. Furthermore, the association of this complex metabolic disorder with male reproductive impairment is worrying, mainly due to the increasing chances that young individuals, at the apex of their reproductive window, could be affected by the disease, further contributing to the disturbing decline in male fertility worldwide. The cornerstone of diabetes management is glycemic control, proven to be effective in avoiding, minimizing or preventing the appearance or development of disease-related complications. Nonetheless, the possible impact of these therapeutic interventions on male reproductive function is essentially unexplored. To address this issue, we have made a critical assessment of the literature on the effects of several antidiabetic drugs on male reproductive function. While the crucial role of insulin is clear, as shown by the recovery of reproductive impairments in insulin-deficient individuals after treatment, the same clearly does not apply to other antidiabetic strategies. In fact, there is an abundance of controversial reports, possibly related to the various study designs, experimental models and compounds used, which include biguanides, sulfonylureas, meglitinides, thiazolidinediones/glitazones, bile acid sequestrants, amylin mimetics, as well as sodiumglucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP1), α-glucosidase inhibitors and dipeptidyl peptidase 4 (DPP4) inhibitors. These aspects constitute the focus of the current review.

The Tear Film (TF) is a trilaminar and dynamic fluid covering the entire Ocular Surface (OS), consisting of a mucus, aqueous, and lipid layer deeply interacting between them. Because of its structure and functions, TF plays a pivotal role in the preservation of the OS integrity and the quality of vision. Medical therapy for glaucoma is recognized to profoundly disturb the OS homeostasis by altering all components of the ocular surface unit, including TF. The presence of preservatives, the number of daily eye drops instillations, and the duration of therapy are the main contributors to TF changes. From the physio-pathological side, TF alterations are induced by toxic and allergic mechanisms and result from goblet cell and Meibomian gland loss, dysfunction of accessory lacrimal glands, and epithelial disruption. In detail, TF changes are represented by mucus layer thinning, reduced mucin concentration, aqueous layer volume reduction, and lipid layer thinning with increased tear evaporation. Hyper- osmolarity and instability represent the main hallmarks of these changes and are an expression of a iatrogenic form of dry eye. TF undergoes also molecular modifications that primarily reflect a therapy- or disease-induced inflammatory status of the OS. Over the last years, this field of research aimed a progressively growing interest since molecular variations may be considered as potential candidate biomarkers of glaucoma. The aim of this review is to report the main TF changes occurring during glaucoma, exploring the relationship they may have with the glaucoma-related ocular surface disease and the patient quality of life, and their utility as potential biomarkers of disease.

Glaucoma is the second leading cause of blindness in the world, affecting more than 60 million people globally. In order to reduce the progression of the disease, both medical and surgical treatments are used. Frequent side effects of both treatments include a range of modifications of the ocular surface grouped as the Ocular Surface Disease (OSD), which include Dry Eye Disease (DED). DED and other OSD negatively impact on the success of anti-glaucoma treatments and reduce the adherence to medical therapies. Tear film osmolarity (TFO) is a relatively novel test which has become a hallmark of DED. The aim of this paper was to review the association between OSD, DED and glaucoma in view of published TFO data, and to discuss future fields of research and treatments on the topic of glaucoma iatrogenic damage.

Ocular surface disease is characterized by tear film instability and histopathologic and clinical changes of the ocular surface. Glaucoma patients often suffer from ocular surface disease caused by the chronic use of preserved medical treatment to reduce intraocular pressure. Benzalkonium chloride is the preservative most frequently used in glaucoma medications. Its effect on tear film, conjunctiva and cornea and the consequences in glaucoma management are discussed in this mini-review.

Kinetoplastid and apicomplexan parasites comprise a group of protozoans responsible for human diseases, with a serious impact on human health and the socioeconomic growth of developing countries. Chemotherapy is the main option to control these pathogenic organisms and nucleotide metabolism is considered a promising area for the provision of antimicrobial therapeutic targets. Impairment of thymidylate (dTMP) biosynthesis severely diminishes the viability of parasitic protozoa and the absence of enzymatic activities specifically involved in the formation of dTMP (e.g. dUTPase, thymidylate synthase, dihydrofolate reductase or thymidine kinase) results in decreased deoxythymidine triphosphate (dTTP) levels and the so-called thymineless death. In this process, the ratio of deoxyuridine triphosphate (dUTP) versus dTTP in the cellular nucleotide pool has a crucial role. A high dUTP/dTTP ratio leads to uracil misincorporation into DNA, the activation of DNA repair pathways, DNA fragmentation and eventually cell death. The essential character of dTMP synthesis has stimulated interest in the identification and development of drugs that specifically block the biochemical steps involved in thymine nucleotide formation. Here, we review the available literature in relation to drug discovery studies targeting thymidylate biosynthesis in kinetoplastid (genera Trypanosoma and Leishmania) and apicomplexan (Plasmodium spp and Toxoplasma gondii) protozoans. The most relevant findings concerning novel inhibitory molecules with antiparasitic activity against these human pathogens are presented herein.

The role metals play in living organisms is well established and subject to extensive research. Some of them participate in electron-exchange reactions. Such reactions cause generation of free radicals that can adversely impact biological systems, as a result of oxidative stress. The impact of ‘non-biological’ metals on oxidative stress is also a worthy pursuit due to the crucial role they play in modern civilization. Lanthanides (Ln) are widely used in modern technology. As a result, human exposure to them is increasing. They have a number of established medical applications and are being extensively researched for their potential antiviral, anticancer and anti-inflammatory properties. The present review focuses on lanthanum (La) and its impact on oxidative stress. Another metal, widely used in modern high-tech is gallium (Ga). In some respects, it shows certain similarities to La, therefore it is a subject of the present review as well. Both metals exhibit ionic mimicry which allows them to specifically target malignant cells, initiating apoptosis that makes their simple salts and coordination complexes promising candidates for future anticancer agents.