Current Drug Targets - Volume 19, Issue 9, 2018

Post-translational modification represents an important mechanism to regulate protein function in cardiac cells. Ubiquitin (Ub) and ubiquitin-like proteins (UBLs) are a family of protein modifiers that share a certain extent of sequence and structure similarity. Conjugation of Ub or UBLs to target proteins is dynamically regulated by a set of UBL-specific enzymes and modulates the physical and physiological properties of protein substrates. Ub and UBLs control a strikingly wide spectrum of cellular processes and not surprisingly are involved in the development of multiple human diseases including cardiac diseases. Further identification of novel UBL targets will expand our understanding of the functional diversity of UBL pathways in physiology and pathology. Here we review recent findings on the mechanisms, proteome and functions of a subset of UBLs and highlight their potential impacts on the development and progression of various forms of cardiac diseases.

Coronary artery disease and atherothrombosis are complex pathologic entities leading to poor clinical outcome and high cardiac mortality. Coronary artery revascularization strategies, such as percutaneous coronary intervention (PCI) in an effort to restore myocardial blood reperfusion, may only partially treat ischemic heart disease. PCI has revolutionized the revascularization for ischemiarelated cardiovascular diseases such as stable angina and acute coronary syndrome. Post-PCI restenosis, however, remains a major problem to overcome. Following the mechanical stretch, restenosis takes place in concert with the proliferation and migration of smooth muscle cells (SMCs) from the tunica media through the disruption of intima or endothelial barrier, and eventually leads to narrowed vascular lumen and obstruction. As the central pathogenetic event of restenosis, vascular neointimal hyperplasia occurs gradually as a result of the imbalance between SMC death and proliferation. Despite ample efforts, the precise mechanisms underscoring transition from initial apoptosis of vascular SMCs to apoptosis resistant proliferation remains unclear. As a conservative regulatory avenue found in nearly all mammalian cell types, autophagy plays a unique role in the delicate control on cell fate in the development of neointimal hyperplasia in post-PCI restenosis. In this mini-review, we will focus on how apoptosis, autophagy, and the cross-talk between the two govern cell death or proliferation in restenosis pathogenesis, particularly in neointimal hyperplasia involving SMCs.

Autophagy is an evolutionarily conserved degradation process in triggered by metabolic stress or environmental changes. Autophagy involves formation of autophagosomes, which fuse with lysosomes and degrade encapsulated intracellular components, such as long-lived and misfolded proteins, as well as intracellular organelles. Autophagy has been implicated in a wide variety of physiological and pathological conditions, and was recently implicated in the regulation of immunity and inflammation. Rheumatic diseases are a group of disorders characterized by immune system malfunctions in which the body attacks its own tissues. These diseases can seriously threaten human health if untreated. Although the underlying pathophysiology of autoimmune diseases has not yet been fully elucidated, autophagy has been implicated in their progression. In this article, we review the basics of autophagy, and the functional role of autophagy in the pathogenesis of rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Crohn's disease and ankylosing spondylitis (AS). Moreover, we reviewed the role of autophagy and autophagy-related genes (Atgs) in innate and adaptive immunity, as well as the pathogenic crosstalk between autophagy and apoptosis. Our findings should provide valuable insights into the role of autophagy in the pathogenesis of rheumatic diseases. In addition, identification of novel autophagy-associated target proteins may offer a promising target for drugs treating human rheumatic disorders.

Pancreatic cancer is predicted to be the second deadliest malignancy (a median survival of 4-6 months and a 5-year survival of less than 5%) in the USA by 2020. Although current medical detection technologies have dramatically improved the survival rate for patients with other gastrointestinal malignancies, the dismal clinical outcome remains somewhat unchanged for patients with pancreatic cancer. Preclinical evidence suggests that pancreatic cancer may be benefited from early administration of systemic therapy in addition to surgery. New biomarkers should help to identify those patients possibly candidates for various systemic therapy including chemotherapy. Classical anticancer drugs such as FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin), and nabpaclitaxel plus gemcitabine only produced some modest improvements in survival. To this end, novel therapeutic avenues are sought for pancreatic cancer. This mini-review summarizes the state-of-the-art of pancreatic cancer treatment, and possible role of autophagy in therapeutics against pancreatic cancer.

The latter half of the twentieth century has witnessed a humongous spurt in the use of synthetic chemicals in a wide variety of industrial and agricultural applications leading to specific perturbations affecting every trophic level of the ecosystems due to unmitigated environmental contamination. Despite the incremental usefulness of endocrine disrupting chemicals (EDCs) such as pesticides and plasticizers, their statutory impact on environmental health is assuming worrisome proportions. The EDCs can disrupt physiological homeostasis resulting in developmental and reproductive abnormalities. Both preclinical animal experiments, as well as epidemiological studies, have correlated EDC exposure with metabolic disorders such as metabolic syndrome, type 2 diabetes as well as cardiovascular health. Here we briefly review the statutory impact of EDCs on metabolic disruption as well as their impact on environmental health. Finally, difficulties pertaining to the categorization of EDC induced metabolic diseases as risk factors for global disease burden have been addressed taking into account the complexity of such interactions.

Alzheimer disease (AD) is most common neurodegenerative disorder of dementia, as we all know that ApoE4 is the greatest genetic risk factor of late-onset Alzheimer's disease (LOAD). Coronary heart disease (CHD) leads to one-fourth of all deaths in industrialized countries, it is reported that ApoE4 increases the risk of coronary heart disease as well. Furthermore, evidence show that coronary heart disease also increases the incidence of Alzheimer's disease. Whether ApoE4 is a bridge connecting AD with CHD or not? And what are the special mechanism and therapeutic methods? Researchers found that cholesterol metabolic disorder is the common cause and risk factor of AD and CHD. Epidemiological studies demonstrate that carriers of the ApoE4 allele have higher cholesterol plasma concentration. More evidence indicate that hypercholesterolemia accelerates the progression of coronary atherosclerosis, damages the central nervous system blood-brain barrier, promotes Aβ protein production and Tau deposition in brain. Therefore, ApoE4 is likely to be the bridge between AD and CHD, and may be a potentially promising therapeutic target.

Diabetes is an important cause of morbidity and mortality worldwide. Management of blood glucose is critical for diabetic patients since diabetes carries a risk for many diseases and disorders. Although there are several antidiabetic agents in the markets for a long time, some of the agents have dose-limiting side effects, such as hypoglycemia and weight gain which limits their ability to reduce cardiovascular complications. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents which exerts their effects insulin-independent mechanism, therefore, they do not cause hypoglycemia in the diabetic patients. Due to the unique class-dependent mechanism, they can be adjunct to the standard therapy of the diabetic patients. Recent studies have speculated that SGLT2 inhibitors have some beneficial effects other than hypoglycemic effects in diabetic patients like lowering body weight, reducing blood pressure and hyperuricemia. This review aims to discuss the pleiotropic effects of SGLT2 inhibitors and gives an avenue for new research ideas.

Cardiovascular complications are among the main reasons for the high morbidity and mortality in patients with type 2 diabetes, making the management of cardiovascular complications an integral component in the treatment of type 2 diabetes. Along the same line, the US Food and Drug Administration mandated all new diabetic drugs and therapies have a safe cardiovascular profile. Among various drugs available for the treatment against type 2 diabetes, the sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a class of newly developed anti-diabetic agents with properties of mitigating cardiovascular risk in patients with type 2 diabetes. Evidence from clinical trials has suggested that the SGLT2 inhibitors empagliflozin and canagliflozin are capable of reducing the overall risk of cardiovascular events and mortality in type 2 diabetic patients. In this mini-review, we will briefly discuss the various cardiovascular benefits of SGLT2 inhibitors, and the underlying mechanisms involved.

Despite the intensive research and progress in modern pharmacotherapy, hypercholesterolemia and related cardiovascular complications remain one of the leading causes of mortality and disability in the modern world. A significant contribution to the treatment of hypercholesterolemia was made by the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9). This enzyme is responsible for the degradation of the low-density lipoprotein (LDL) receptor (LDLR) found at the surface of the plasma membrane in the liver and directly associated with serum LDL level. Limitations in standard therapy used in the treatment of lipid disorders have led to the development of new drugs, such as an inhibitor of PCSK9. Over the past years, the greatest achievement in discovering the PCSK9 inhibitor was made by designing monoclonal antibodies that disable PCSK9 to bind LDLR and RNA interference to reduce PCSK9 production, but one of the main disadvantages is costeffectiveness. In this review, we will summarize the most recent findings of basic and clinical studies which focus on PCSK9 function, regulation and therapeutic target for the treatment of hypercholesterolemia and associated cardiovascular diseases.

Iron is an essential mineral required for a variety of vital biological functions. Despite being vital for life, iron also has potentially toxic aspects. Iron has been investigated as a risk factor for coronary artery disease (CAD), however, iron's toxicity in CAD patients still remains controversial. One possible mechanism behind the toxicity of iron is “ferroptosis”, a newly described form of irondependent cell death. Ferroptosis is an iron-dependent form of regulated cell death that is distinct from apoptosis, necroptosis, and other types of cell death. Ferroptosis has been reported in ischemiareperfusion (I/R) injury and several other diseases. Recently, we reported that ferroptosis is a significant form of cell death in cardiomyocytes. Moreover, myocardial hemorrhage, a major event in the pathogenesis of heart failure, could trigger the release of free iron into cardiac muscle and is an independent predictor of adverse left ventricular remodeling after myocardial infarction. Iron deposition in the heart can now be detected with advanced imaging methods, such as T2 star (T2*) cardiac magnetic resonance imaging, which can non-invasively predict iron levels in the myocardium and detect myocardial hemorrhage, thus existing technology could be used to assess myocardial iron. We will discuss the role of iron in cardiovascular diseases and especially with regard to myocardial I/R injury.

Heart failure represents a challenging clinical and public health problem and is associated with significant morbidity and mortality. Mechanistically, loss of cardiomyocytes leads to decompensated ventricular remodeling, which eventually progresses to cardiac failure. Regenerative medicine aimed to supplement functional cardiomyocytes is supposedly a promising approach for the effective treatment of heart failure. Over the past decades, investigations on heart regeneration have revealed the regulating networks of cardiomyocyte proliferation. Recently, the research effort has been directed to non-cardiomyocytes for heart regeneration, including cardiac fibroblasts, epicardial cells, endothelial cells, stem/progenitor cells, and immune cells. Cardiac fibroblasts not only substantially influence the composition of extracellular matrix deposition which is vital for the function and proliferation of cardiomyocytes, but also directly convert into cardiomyocytes. The epicardium is functionally important since it is involved in the cardiac development and regeneration via epicardial-mesenchymal transformation. Moreover, several immune cell lineages are found to be interspersed in heart tissue. Immune cell infiltration in combination with inflammatory reaction is found to stimulate the regenerative response in neonatal mouse heart after injury. In this review, we presented and discussed recent development in the studies on non-cardiomyocytes that directly regulate cardiomyocyte proliferation and differentiation during postnatal cardiac regeneration, with an attempt to provide information on the potential targets for the treatment of heart failure.

Non-alcoholic fatty liver disease (NAFLD) is a common public health issue and is considered a main drive for liver diseases. However, the basic mechanisms that trigger the development of NAFLD still remain somewhat elusive. Endoplasmic reticulum (ER) stress facilitates the unfolded protein response (UPR) and contributes to the etiology of steatosis, nonalcoholic steatohepatitis and ultimately hepatocarcinoma. Although ER stress may lead to a cascade of compensatory responses that help to restore ER homeostasis, cell survival and adaptation, prolonged ER stress is known to impose detrimental pathological outcome, involving insulin resistance, ectopic fat deposition, inflammation, apoptosis, and dysregulated autophagy. All of these processes are capable of provoking the onset and development of NAFLD. To this end, it is pertinent to understand the role of ER stress in the onset and progression of NAFLD for proper management of this devastating metabolic disease. Here in this review, we will summarize available information on the recent advances in the potential role for ER stress in the etiology of NAFLD.

Background: There are accumulating studies reporting that vitamin E in general exhibits bone protective effects. This systematic review, however discusses the effects of a group of vitamin E isomers, tocotrienols in preventing bone loss through osteoclast differentiation and activity suppression. Objective: This review is aimed to discuss the literature reporting the effects of tocotrienols on osteoclasts, the cells specialized for resorbing bone. Results: Out of the total 22 studies from the literature search, only 11 of them were identified as relevant, which comprised of eight animal studies, two in vitro studies and only one combination of both. The in vivo studies indicated that tocotrienols improve the bone health and reduce bone loss via inhibition of osteoclast formation and resorption activity, which could be through regulation of RANKL and OPG expression as seen from their levels in the sera. This is well supported by data from the in vitro studies demonstrating the suppression of osteoclast formation and resorption activity following treatment with tocotrienol isomers. Conclusion: Thus, tocotrienols are suggested to be potential antioxidants for prevention and treatment of bone-related diseases characterized by increased bone loss.