Type 2 diabetes (T2D) is a heterogeneous disorder that is characterized by chronic hyperglycemia and its prevalence reaches epidemic proportions worldwide. T2D is characterized by a progressive loss of the first phase of insulin secretion in early stages of the disease. The origin of insulin secretion failure is still unknown. As hyperglycemia becomes chronic, pancreatic β-cell undergoes deterioration and destruction. β-Cell destruction by glucolipotoxic-mediated apoptosis and by proinflammatory cytokines actions is important etiological factor in the progression of the disease. The focus of this review is on the signaling pathways engaged by G-protein coupled receptors and tyrosine-kinase receptors which control β-cell function and survival through cell kinases (i.e., cAMP/PKA, IRS/PI3-kinase, and ERK1/2), and as well as on pathways implicated in β-cell dysfunction and death, among them glucotoxicity and lipotoxicity. A better knowledge of these pathways (and of their dysfunctions) will have significant implications for the prevention and management of T2D (patents and design of new drug targets for therapeutic approach), as well as for our general understanding of β-cell failure in this disease. Finally, the current and future molecular targets for designing innovative therapeutic agents with the aim to restore β-cell mass and insulin secretion are reviewed.
The gastrointestinal tract has a crucial role in the control of energy homeostasis through the action of multiple peptides known as incretins that act on distant target sites to promote the efficient uptake and storage of energy. In particular, GLP-1, an incretin hormone secreted from the intestinal mucosa in response to meal ingestion, is shown to augment the magnitude of meal-stimulated insulin secretion from islet β cells in a glucose-dependent manner and thus proved to be a novel candidate for treatment in patients with diabetes mellitus. This article reviews the biological actions of GLP-1 regulating glucose homeostasis, with an emphasis on mechanisms of action and the emerging therapeutic roles of GLP-1 analogues, and DPP-4 inhibitors for the treatment of diabetes mellitus.
There is compelling evidence for tomatoes to be considered as cardiovascular protective foods, due to the presence in tomatoes of many nutrients which have been associated with theoretical or proven effects on the cardiovascular system. However, despite an inverse association found for high intakes of tomato-based products, dietary lycopene was not strongly associated with the risk of cardiovascular disease (CVD). This indicates that other unidentified compounds in tomatoes may have cardioprotective effects. We identified potent anti-platelet factors in tomato extracts, which inhibited platelet aggregation and discussed recent patents in this field. There is increasing evidence that acute clinical manifestations of coronary atherosclerotic disease are caused by plaque disruption and subsequent plateletthrombus formation. Platelet activity can influence the progression of disease as well as the stability of atherosclerotic plaques. The observed cardiovascular benefits attributed to the tomato could be linked to antiplatelet activity and thus suppression of platelet function in vivo. This type of natural anti-thrombotic agent could have an application in primary prevention of CVD.
Sepsis is one of the most studied diseases in intensive care medicine nowadays, mainly due to the severe morbidity associated with this condition. Among the several mediators evaluated in the context of sepsis, the study of reactive oxygen and nitrogen species has achieved considerable interest, mostly regarding their effects in direct cytotoxicity as well as altered cell signaling. These compounds have also been associated with vascular and organ dysfunction of sepsis. The discovery of precise mechanisms of free radical-induced organ dysfunction may lead to the discovery of therapeutic strategies able to reduce the severe effects of sepsis in the organism. In this context, the administration of antioxidants has been tested in experimental and clinical studies of sepsis in order to restore their adequate levels that are frequently diminished during the course of disease. This review will focus on mechanisms associated with increased oxidative stress in sepsis, as well as therapeutic strategies concerning antioxidant therapy during sepsis and multisystem organ failure. The most recent patents related to the clinical use of antioxidants in this field will also be discussed.
Year 2007 is the golden anniversary for the discovery of the sodium- and potassium adenosine triphosphatase, i.e., Na+, K+-ATPase, or Na+-pump by Jens Skou who shared the 1997 Nobel Prize in Chemistry for his discovery. Prior to identification of the enzymatic basis of Na+ and K+ active transport by Skou, the physiological and pharmacological manifestations of such a system had long been evident. Since 1957, there has been a dramatic increase in the knowledge of the physical, chemical, and kinetic properties of the pump and recognition of its basis for a wide range of physiological, pathological, and pharmacological aspects of the cardiovascular system. The Na+-pump has recently been identified as a key partner in a wide array of cell signaling pathways related to hypertrophy and expression of its marker genes. Taken together, these facts make it evident that the pump is a prime target for pharmacological interventions of cardiovascular diseases such as hypertrophy, hypertension, congestive heart failure (CHF), and preeclampsia. This review couples basic attributes of the Na+-pump with pathophysiological etiologies and clinical management of cardiovascular related maladies, and also discusses related patents.
In the past decade the involvement of inflammatory responses with metabolic disorders became well established, more specifically the insulin resistance, responsible for Type-2 diabetes. The major evidence for insulin resistance is the deactivation of insulin receptors substrates (IRS) trough inflammatory activated pathways and the presence of pro-inflammatory cytokines, especially tumor necrosis factor alpha (TNFα) at adipose tissues. The intracellular regulation of TNFα is mediated by several processes, thus the knowledge about these pathways may provide targets to inhibit TNFα synthesis, such as mitogen activated protein kinases (MAPK) cascades and nuclear factor kappa B (NF-κB) activation pathways. Natural anti-inflammatory pathways can also be activated in order to treat or ameliorate these disorders, such as peroxisome proliferator-activated receptors (PPAR) and suppressors of cytokine signaling (SOCS) families. It is discussed here international bibliography regarding insulin resistance related to inflammation and also patent literature disclosing methods to treat Type-2 diabetes targeting immune systems molecules and pathways.