Current Pharmaceutical Design - Volume 22, Issue 31, 2016

Heart failure is one of the devastating public health problems with high mortality. Among various contributing factors for heart failure, severe dilated cardiomyopathy is the most common indication for cardiac transplantation. Recent evidence revealed that RBM20 mutation represents one main cause for familial dilated cardiomyopathy with a 3% prevalence in all forms of dilated cardiomyopathy. Further scrutiny of molecular mechanisms suggests a role for RBM20 as a functional splicing factor for protein isoform transition, indicating the clinical value of RBM20 mutations in the diagnosis and treatment of heart diseases. RBM20 alternatively splices a set of genes including titin, CaMKIID, and GIT2 at the post transcriptional level to yield diverse isoforms. These target proteins are necessary for cardiac homeostasis including structure and signal transduction. Mutations in RBM20 cause dilated cardiomyopathy along with dysregulated isoform switch. This review aims to summarize the current knowledge of RBM20-related dilated cardiomyopathy and heart failure as well as the underlying mechanism. We will emphasize and thoroughly discuss two splicing targets including titin and CaMKII which are known to play a vital role in dilated cardiomyopathy and heart failure.

Advances in pharmacotherapy as well as device therapy in common cardiovascular diseases, especially implementation of rapid coronary reperfusion as a key management strategy in acute ischemic disease, improved overall survival. Yet, this success contributes to increased number of patients susceptible to heart failure development due to damaged myocardium. Although survival after heart failure diagnosis has improved over time, the death rate remains high: ≈50% of people diagnosed with this disease will die within 5 years. Thus, not only there is a space for novel concepts and strategies in the treatment of symptomatic heart failure, but also they are urgently needed. The mechanisms underlying the development of heart failure are multiple, complex, and not well understood. However, regardless of the cause of heart failure, or whether its presentation is acute or chronic, altered mitochondrial function/bioenergetics appears to play a substantial role in its pathophysiology. As such, the mitochondria are potentially promising, but still underused, target for new HF therapies. This review will focus on changes that occur in the mitochondria of failing myocardium, as well as on targets and approaches that suggest potential therapeutic effect in this ominous disease.

Background: Mitochondria fulfill the massive energy demands of the human heart through oxidative phosphorylation (OXPHOS) which couples nutrient oxidation and the reduction of molecular oxygen (O2) to the phosphorylation of ADP. Reactive oxygen species (ROS) are also generated during OXPHOS which can be damaging at high levels but serve as secondary messengers when produced in a controlled manner. Methods: Here, I review how disruption of control over mitochondrial ROS production can lead to the pathogenesis of a range of cardiovascular diseases (CVD) including decompensated left ventricular hypertrophy, alcoholic and diabetic hypertrophy, myocardial infarction (MI), ischemic-reperfusion injury (IR), and heart failure. In particular I focus on the function of protein S-glutathionylation (PGlu) reactions, a rapid and reversible redox signaling mechanism that involves the conjugation and removal of glutathione from cysteine switches, in the modulation of ROS production in myocardial mitochondria and how these reactions become deregulated in heart disease. I also discuss the use of mitochondria penetrating antioxidants in the treatment of heart disease. Results: I propose that heart disease related to deregulated PGlu reactions can be treated with a novel and hypothetical class of mitochondria penetrating reduced glutathione (GSH) molecules called MitoGSH. This synthetic form of GSH can be tagged with either SS peptides or triphenylphosphonium ions to ensure accumulation in mitochondria which could restore glutathione levels and preserve redox buffering networks. Conclusion: Mitochondria penetrating antioxidants have been shown to be efficient at restoring mitochondrial antioxidant defense in CVD. However, CVD and various other disorders are associated with a depletion of GSH pools. Use of mitochondria-targeted GSH analogs could serve as a more efficient means of treating heart disease since it would allow for the direct restoration of GSH levels and preserve mitochondrial redox buffering and signaling capacity.

The survival of patients with pulmonary arterial hypertension is closely related with right ventricular function. During the progression of right ventricular remodeling, energetic metabolism shifts from oxidative mitochondrial metabolism to glycolysis. In normal physiological conditions, cardiomyocytes use major sources of glucose and fatty acids to sustain a continuous systolic workload and energy supply. This allows the heart to choose the most efficient substrate to response to environmental stimuli. Therefore, ATP production of glucose is the preferred energy source than fatty acids in right ventricular remodeling. However, the metabolic fate of glucose altered because mitochondrial metabolism is actively suppressed. Metabolic shift towards aerobic glycolysis and down-regulation of mitochondrial oxidation, is called the Warburg effect. Studies on animal models and human RVF suggest that there is reduced glucose oxidation and increased glycolysis in both adaptive and maladaptive right ventricular failure. Accordingly, a gate-keeping enzyme, pyruvate dehydrogenase kinase (PDK) is activated and inhibited pyruvate into the mitochondria with increased lactate dehydrogenase. Therefore, augmentation of glucose oxidation is beneficial in right ventricular remodeling and can be achieved by inhibition of PDK and fatty acid oxidation. As a PDK inhibitor, Dicholoracetate (DCA) can reduce pyruvate dehydrogenase phosphorylation and partially restore RV structure and function by promoting glucose and mitochondrial oxidation. Moreover, the partial inhibitors of fatty acid oxidation would be offered the utilization to improve right ventricular function. Although metabolic targeting drugs can be beneficial to right ventricular remodeling, the advantage of modulating metabolic shift into an enhanced clinical performance still remains to be determined.

Background: Heart failure (HF) is characterized by cardiac functional and structural alterations, progressively leading to clinical symptoms and signs. Certain neurohormonal systems (i.e. the sympathetic nervous system, the reninangiotensin-aldosterone system and the natriuretic peptide system) as well as interactions between endothelial, monocytes/macrophages and myocardial cells are involved in the process. Methods: The present narrative review discusses the relationships between lipids, statins and HF. Results: Lipid metabolism is involved in cardiac function. Inflammation, oxidative stress, endothelial and platelet dysfunction, activation of neurohormonal systems, adverse cardiac remodeling, haemodynamic disorders and arrhythmogenesis predispose to HF development and progression. Statins have been shown to reduce HF incidence possibly via their pleiotropic actions on the above mentioned mechanisms. Other cardiovascular (CV) risk factors affecting HF prevalence and outcomes include metabolic syndrome, non-alcoholic fatty liver disease, chronic kidney disease, hyperuricaemia, epicardial fat and increased arterial stiffness that are improved following statin therapy. Conclusion: Lipid disorders are involved in HF development and progression. Statins may beneficially affect these disorders as well as other CV risk factors linked to HF. However, the impact of statins in patients with established HF has yet to be determined. Further studies are needed to unveil potential benefits of statin therapy (or some statins) in specific groups of HF patients.

Background: Mitochondria are cellular organelles responsible for energy production, calcium handling, controlled synthesis of reactive oxygen species (ROS), and regulation of apoptosis. All these functions are crucial for cardiac homeostasis, and may be impaired in chronic heart failure (CHF). Therefore, mitochondrial dysfunction might represent a crucial element in the onset and progression of CHF and, as such, a promising therapeutic target. Methods: Original articles and review on the treatment of mitochondrial dysfunction in CHF were searched on Medline and Scopus. Results: The present review summarizes the current knowledge about mitochondrial modulation as a therapeutic strategy for CHF, and proposes some perspectives for future studies. Mitochondrial dysfunction can be ascribed to neuro-humoral activation and cardiac remodeling associated with CHF. Conceptually, the correction of mitochondrial dysfunction could provide an additive benefit to optimal CHF treatment. Increasing glucose metabolism and reducing oxidative stress within mitochondria are the two most promising approaches, even though further studies are required before implementing new treatments in the setting of CHF. On the other hand, inhibition of apoptosis, and normalization of calcium and mitochondrial dynamics have been assessed almost exclusively in ex vivo models, and mostly in settings other than CHF. Conclusion: Mitochondrial modulation in CHF is an intriguing example of translational research and a potentially rewarding field.

Heart failure (HF) is a major global problem in public health with no curative treatment currently available. Energy remodeling is one of the features in HF, preceding cardiac structure remodeling. As an important energy organelle, mitochondrion plays critical roles in the progress of HF. This review focuses on the potential mechanisms linking mitochondrial functions and energy remodeling in HF including the energy starvation theory and energy substrate metabolism. It also highlights the potentials of novel drugs targeting HF energy metabolism.

Osteosarcoma is the most common type of primary bone tumor in adolescents and young adults. The dysregulation of cell cycle control and cell division often results in the aberrant growth of osteosarcoma cells. The primary proteins involved in cell cycle control and cell division include checkpoint kinases (CHKs), cyclin-dependent kinases (CDKs), polo-like kinases (PLKs) and aurora kinases (AURKs). In recent years, a large number of these protein kinase inhibitors have been identified in osteosarcoma. In this review, we highlight the current drugs being developed to target these protein kinases in osteosarcoma.

Influenza virus can cause epidemics and pandemics of flu. A highly variable virus genome is responsible for the existence of different viral strains and acquired resistance to antiviral drugs. Today, only one class of therapeutics, neuraminidase inhibitors, is efficient and proved for influenza prophylaxis and treatment; whereas M2 protein inhibitors became inefficient due to evolving drug resistance. Therefore, there is an urgent need for the development of novel therapeutics. Aptamers are promising molecular recognition elements of high specificity and low toxicity, but only a few of them are under development as therapeutics. After selection of primary aptamers, there are sophisticated steps of further adjustments to the target and meeting requirements for therapeutics. In the last decade, dozens of DNA and RNA aptamers to various influenza types have been selected, but no comparative analyses have been performed yet. Most of aptamers were selected to hemagglutinin, a viral surface protein, which supports the first stages of virus invasion into the host cell. In the review, all available data on aptamers to hemagglutinin are analyzed. Aptamer specificity and affinity are discussed, as well as examples of aptamer applications for virus detection and virus infection inhibition. In summary, aptamers can be selected for hemagglutinin recognition, aptamers to hemagglutinin can recognize viruses with different specificity, and some aptamers can neutralize virus in vitro, ex vivo and in vivo. Special sections of the review are dedicated to the original structural analyses. Some structural similarities among different aptamers have been revealed suggesting involvement into the target recognition.

The labeling of biomolecule using 99mTc-tricarbonyl is an interesting tool for the diagnosis of diseases. This labeling startegy has several advantages as compared to other common radiolabeling techniques. This review is a complete overview of synthesis and chemistry of 99mTc-tricarbonyl molecule for labeling peptides and proteins. Also, the effect of ligand type on the stability and in vivo biodistribution of 99mTc-tricarbonyl labeled biomolecules are discussed. Chemistries of cyclopentadienyl and hexa histidine tag as two important bifunctional chelating agents (BFCA) are presented. The in vitro and in vivo behaviors of some 99mTc-tricarbonyl labeled peptides and proteins are explained. Preclinical outcomes revealed that these labeled compounds are biologically, kinetically and thermodynamically stable. Findings showed that 99mTc-tricarbonyl labeled biomolecules are promising tools for future clinical applications in image diagnosis.

Introduction: MicroRNA-208a (miR-208a) exacerbated cardiomyocyte apoptosis via inhibiting nemo-like kinase (NLK). miR-208a is a crucial molecule in the regulation of heart diseases, however, the biological function and underlying mechanism of miR-208a in the progression of cardiomyocyte apoptosis is not clearly elucidated. We hypothesized that miR-208a might potentiate cardiomyocyte apoptosis through inhibiting NLK. Methods: Male Sprague-Dawley rats were underwent permanent coronary artery ligation to establish myocardial infarction (MI) model. The quantitative real-time RT-PCR (qRT-PCR) was used to evaluate the expression of miR-208a and NLK mRNA. Western blot was applied to detect NLK and Bcl-2 proteins expression. Luciferase reporter assay was performed to indentify NLK as a target of miR-208a. The apoptosis of H9C2 cells was assessed by flow cytometry (FCM). Results: miR-208a was upregulated accompanying with a significant decrease of NLK in response to MI, and stronger miR-208a staining was detected by in situ hybridization in the cytoplasm of cardiomyocytes in MI group compared to the sham group. In vitro, overexpression of miR-208a greatly enhance Ang II-induced the apoptosis of H9C2 cells through downregulating of NLK and the anti-apoptosis protein Bcl-2 expression, whereas these effects were reversed when miR-208a was downregulated. Dual luciferase reporter assay and western blot results demonstrated that NLK was a direct target of miR-208a. Interestingly, upregulation of NLK obviously increased Bcl-2 expression and reduced the percentage of apoptotic cells, while attenuation of NLK reduced the level of Bcl-2 and cells apoptosis after treatment with Ang II. Conclusions: miR-208a can promote Ang II-induced cardiomyocyte apoptosis via negatively regulating NLK expression, and inhibition of miR-208a may provide a novel therapeutic target for cardiomyocyte apoptosis.

Aims: The main aim of this study was to verify the effect of natalizumab on the levels of circulating catecholamines and indolamine and their possible relation with MS. Methods: For this purpose, 12 healthy individuals (control group) and 12 relapsing-remitting multiple sclerosis patients (RR-MS) were selected. The patients were treated with 300 mg of natalizumab during 56 weeks (1 dose/4 weeks) (MS-56). This selection was based on the McDonalds revision criterion and scheduled to star treatment with natalizumab. Blood samples were taken before treatment (basal level) and after 56 weeks of using natalizumab. Melatonin was measured in serum and in plasma, catecholamines (dopamine, epinephrine, and norepinephrine), carbonylated proteins, 8-hydroxy-2’deoxyguanosine (8OH-dG) and the ratio reduced glutathione/oxidised glutathione (GSH/GSSG). Results: The epinephrine and dopamine levels diminished in the basal group with respect to the control and did not recover normal levels with the treatment. The melatonin was decreased in RR-MS patients and went back to its normal levels with natalizumab. Norepinephrine was increased in RR-MS and decreased in MS-56 until it equalled the control group. Conclusion: Natalizumab normalizes altered melatonin and norepinephrine levels in MS.