Current Pharmaceutical Design - Volume 25, Issue 35, 2019

The prevalence of several diseases increases by age, including cardiovascular diseases, which are the leading cause of morbidity and mortality worldwide. Aging, as a complex process characterized by senescence, triggers various pathways, such as oxidative stress, systemic inflammation, metabolism dysfunction, telomere shortening, mitochondrial dysfunction and deregulated autophagy. A better understanding of the mechanisms underlying senescence may lead to the development of new therapeutic targets and strategies for age-related pathologies and extend the healthy lifespan. Modulating lifestyle risk factors and adopting healthy dietary patterns remain significant tools in delaying the aging process, decreasing age-associated comorbidities and mortality, increasing life expectancy and consequently, preventing the development of cardiovascular disease. Furthermore, such a strategy represents the most cost-effective approach, and the quality of life of the subjects may be significantly improved. An integrated, personalized approach targeting cardiometabolic aging and frailty is suggested in daily clinical practice. However, it should be initiated from an early age. Moreover, there is a need for further well designed and controlled studies in order to elucidate a link between the time of feeding, longevity and cardiovascular prevention. In the future, it is expected that the pharmacological treatment in cardioprotective management will be necessary, accompanied by equally important lifestyle interventions and adjunctive exercise.

Cardiovascular (CV) diseases are the most common health problems worldwide, with a permanent increase in incidence. Growing evidence underlines that insulin-like growth factor 1 (IGF-1) is a very important hormone responsible for normal CV system physiology. IGF-1 is an anabolic growth hormone, responsible for cell growth, differentiation, proliferation, and survival. Despite systemic effects, IGF-1 exerts a wide array of influences in the CV system affecting metabolic homeostasis, vasorelaxation, cardiac contractility and hypertrophy, autophagy, apoptosis, and antioxidative processes. The vasodilatory effect of IGF-1, is achieved through the regulation of the activity of endothelial nitric oxide synthase (eNOS) and, at least partly, through enhancing inducible NOS (iNOS) activity. Also, IGF-1 stimulates vascular relaxation through regulation of sodium/potassiumadenosine- triphosphatase. Numerous animal studies provided evidence of diverse influences of IGF-1 in the CV system such as vasorelaxation, anti-apoptotic and prosurvival effects. Human studies indicate that low serum levels of free or total IGF-1 contribute to an increased risk of CV and cerebrovascular disease. Large human trials aiming at finding clinical efficacy and outcome of IGF-1-related therapy are of great interest. We look forward to the development of new IGF 1 therapies with minor side effects. In this review, we discuss the latest literature data regarding the function of IGF-1 in the CV system in the physiological and pathophysiological conditions.

Acute ST-segment elevation myocardial infarction (STEMI) remains a leading cause of morbidity and mortality around the world. A large number of STEMI patients after the infarction gradually develop heart failure due to the infarcted myocardium. Timely reperfusion is essential to salvage ischemic myocardium from the infarction, but the restoration of coronary blood flow in the infarct-related artery itself induces myocardial injury and cardiomyocyte death, known as ischemia/reperfusion injury (IRI). The factors contributing to IRI in STEMI are complex, and microvascular obstruction, inflammation, release of reactive oxygen species, myocardial stunning, and activation of myocardial cell death are involved. Therefore, additional cardioprotection is required to prevent the heart from IRI. Although many mechanical conditioning procedures and pharmacological agents have been identified as effective cardioprotective approaches in animal studies, their translation into the clinical practice has been relatively disappointing due to a variety of reasons. With new emerging data on cardioprotection in STEMI over the past few years, it is mandatory to reevaluate the effectiveness of “old” cardioprotective interventions and highlight the novel therapeutic targets and new treatment strategies of cardioprotection.

Oleanolic acid is an analogue of pentacyclic triterpenoids. It has been used as a hepatic drug for over 20 years in China. Currently, there are only five approved drugs derived from pentacyclic triterpenoids, including oleanolic acid (liver diseases), asiaticoside (wound healing), glycyrrhizinate (liver diseases), isoglycyrrhizinate (liver disease) and sodium aescinate (hydrocephalus). To understand more about the bioactivity and functional mechanisms of oleanolic acid, it can be developed as a potent therapeutic agent, in particular, for the prevention and treatment of heart diseases that are the leading cause of death for people worldwide. The primary aim of this mini-review is to summarize the new applications of oleanolic acid and its derivatives as cardioprotective agents reported in recent years and to highlight their therapeutic perspectives in cardiovascular diseases.

Exercise has long been recognized as a beneficial living style for cardiovascular health. It has been applied to be a central component of cardiac rehabilitation for patients with chronic heart failure (CHF), coronary heart disease (CHD), post-acute coronary syndrome (ACS) or primary percutaneous coronary intervention (PCI), post cardiac surgery or transplantation. Although the effect of exercise is multifactorial, in this review, we focus on the specific contribution of regular exercise on the heart and vascular system. We will summarize the known result of clinical findings and possible mechanisms of chronic exercise on the cardiovascular system.

Background and Aim: Gynura segetum (Tusanqi or Jusanqi) is widely used in China as a herbal remedy, however, it has often been associated with hepatic sinusoidal obstruction syndrome (HSOS). Its extent in inducing hepatotoxicity is not sufficiently understood. Hence, we aimed to identify the characteristic features of Gynura segetum associated HSOS. Methods: A total of 64 patients diagnosed with HSOS induced by gynura segetum were enrolled from eight Chinese tertiary care hospitals between 2008 and 2018. General information regarding diagnosis, disease history, suspected drug use, symptoms and signs, biochemical index, imaging data, liver histology, treatment methods, severity and prognosis were collected and analyzed. Results: The mean age of the enrolled patients were 58.07±11.44 years. Male patients accounted for 64.1% of HSOS patients. The median latency period was 75 days. The number of patients with a definite diagnosis from the eight hospitals was 5 (7.81%), with a misdiagnosis rate of 92.18%. Hepatomegaly, splenomegaly, ascites and lower limbs edema were present in 89.1%, 76.6%, 81.3% and 43.8% of the patients, respectively. The imaging characteristic changes were liver parenchyma echo thickening, uneven density, and hepatic vein stenosis and occlusion. Liver biopsies had characteristic pathological changes. Except for ALT and D-Dimer, liver function and coagulation index at admission and before discharge were not significantly different (p>0.05). The 6-month mortality rate was 77.55%, with upper-gastrointestinal bleeding being the leading cause of death (42.11%). The second leading cause of death was a secondary infection (36.84%), while the third was hepatorenal syndrome (21.05%). Conclusion: Gynura segetum related HSOS often presents as progressive hepatic congestion, portal hypertension and liver failure, and has a high mortality and misdiagnosis rate.

Background: Progression of aortic valve calcifications (AVC) leads to aortic valve stenosis (AS). Importantly, the AVC degree has a great impact on AS progression, treatment selection and outcomes. Methods of AVC assessment do not provide accurate quantitative evaluation and analysis of calcium distribution and deposition in a repetitive manner. Objective: We aim to prepare a reliable tool for detailed AVC pattern analysis with quantitative parameters. Methods: We analyzed computed tomography (CT) scans of fifty patients with severe AS using a dedicated software based on MATLAB version R2017a (MathWorks, Natick, MA, USA) and ImageJ version 1.51 (NIH, USA) with the BoneJ plugin version 1.4.2 with a self-developed algorithm. Results: We listed unique parameters describing AVC and prepared 3D AVC models with color pointed calcium layer thickness in the stenotic aortic valve. These parameters were derived from CT-images in a semi-automated and repeatable manner. They were divided into morphometric, topological and textural parameters and may yield crucial information about the anatomy of the stenotic aortic valve. Conclusion: In our study, we were able to obtain and define quantitative parameters for calcium assessment of the degenerated aortic valves. Whether the defined parameters are able to predict potential long-term outcomes after treatment, requires further investigation.

Background: Resveratrol was demonstrated to act as partial agonist of PPAR-γ receptor, which opens up the possibility for its use in the treatment of metabolic disorders. Considering the poor bioavailability of resveratrol, particularly due to its low aqueous solubility, we aimed to identify analogues of resveratrol with improved pharmacokinetic properties and higher binding affinities towards PPAR-γ. Methods: 3D structures of resveratrol and its analogues were retrieved from ZINC database, while PPAR-γ structure was obtained from Protein Data Bank. Docking studies were performed using Molegro Virtual Docker software. Molecular descriptors relevant to pharmacokinetics were calculated from ligand structures using VolSurf+ software. Results: Using structural similarity search method, 56 analogues of resveratrol were identified and subjected to docking analyses. Binding energies were ranged from -136.69 to -90.89 kcal/mol, with 16 analogues having higher affinities towards PPAR-γ in comparison to resveratrol. From the calculated values of SOLY descriptor, 23 studied compounds were shown to be more soluble in water than resveratrol. However, only two tetrahydroxy stilbene derivatives, piceatannol and oxyresveratrol, had both better solubility and affinity towards PPAR-γ. These compounds also had more favorable ADME profile, since they were shown to be more metabolically stable and wider distributed in body than resveratrol. Conclusion: Piceatannol and oxyresveratrol should be considered as potential lead compounds for further drug development. Although experimental validation of obtained in silico results is required, this work can be considered as a step toward the discovery of new natural and safe drugs in treatment of metabolic disorders.

Background: Multi-center, randomized-controlled trials and observational studies have demonstrated that, in severe asthmatic patients receiving omalizumab treatment, the frequency of exacerbations, the number of urgent adverse events, and the need for oral steroids tend to decrease. Materials and Methods: This study included a total of 32 patients. The patients were divided into two groups as Group IA (pre-omalizumab) and Group IB (post-omalizumab). Serum IL-25 and IL-33 levels were measured and the number of emergency admissions, length of hospitalization (day), Asthma Control Test (ACT) scores, eosinophil cationic protein (ECP), and fractional exhaled nitric oxide (FeNO) value were analyzed. Results: ACT and FeNO values increased after omalizumab treatment, while IL-33, IL-25 levels decreased after the completion of omalizumab treatment. Furthermore, there was a weak, positive, and significant relationship between the changes in the ECP levels and IL-33 levels (r=0.38, p=0.03). Conclusion: To the best of our knowledge, this is the first study to compare circulating IL-25 and IL-33 levels with specific IgE synthesis in the literature. Multivariate correlation analysis showed that the changes in serum IL-33 levels were significantly correlated with the changes in the mite sIgE levels and length of hospital stay (Fmodel=11.2, p=0.01, r2=0.45). On the other hand, there was no significant relationship between the other variables and changes in the IL-25 levels.