An investigation on interleukin 18 expression in cardiovascular diseases

Introduction: Interleukin 18 is a proinflammatory cytokine from IL-1 cytokine family and plays a central role in inflammation. In fact, it is an IFN-gamma-inducing factor (IGIF). Interleukin 18 increases the response of Th1 cells, cells that are dominant in atherogenesis and cause growth of atherosclerosis plaques. The concentration of circulating IL-18 predicts the probable mortality from cardiovascular problems in CAD patients and plays a key role in atherosclerosis, which is one of the reasons for CHF. Methods and Results: The proinflammatory cytokines of IL-1β, TNF-α, IL-6 and LPS induce IL-18 gene expression and IL-18 causes an increase in the proinflammatory cytokines of IL-1β, IL-6, TNF-α, GM-CSF growth factor, and nitric oxide and cyclooxygenase (cox-2) and thus interleukin 18 causes inflammatory diseases. The Heterodimeric IL-18 receptor is expressed in a variety of cells, including macrophages, T lymphocytes, and NK cells. These cells have a key role in atherosclerotic plaque rupture. The IL-18 binding protein, a natural endogenous inhibitor that is present in high concentration in the extracellular environment and is highly associated with IL-18, interferes with its receptor interaction, thus inhibits IL-18 activity. The level of IL-18 in coronary patients significantly increases and its serum level in CAD patients who die from cardiovascular problems is more than CAD patients who are still alive. In animal models, IL-18 administration has been shown to increase the size and number of clots associated with T lymphocytes and this effect has been eliminated in animals with interferon-gamma deficiency. Angiotensin II increases the expression of IL-18 in arterial smooth muscle cells by AT1 receptors. Losartan will slow down this process. We also know that losartan increases EF and decreases TNF-α and improves left ventricular function in HF patients. It has been shown in a study that stimulation of β-adrenergic receptors by isoproterenol during a series of events increases the transcription and expression of the IL-18 gene, and these events can occur similarly in HF. Conclusions: There is a strong association between serum IL-18 level and future cardiovascular problems so Inhibition of IL-18 signaling by IL-18 binding protein will be a new therapeutic strategy

Genetic variation in ACE A2350G: association with reduction in fasting blood glucose after fluoxetine therapy in depressed patients

Various studies have shown that genetic factors contribute substantially to the development and progression of diabetes. Renin-angiotensin system has long been proven to have a major role in cardiovascular physiology and pathology. Its major product Angiotensin II (Ang II) with pro oxidant properties has shown to predict the future risk of diabetes. Fluoxetine, a drug of choice in management of depression, was observed to reduce fasting blood sugar (FBS). In the present study, six common polymorphisms of genes encoding for RAS components were determined in DNAs extracted from venous blood of 100newly diagnosed depressed individuals taking 12 weeks of fluoxetine. Blood samples were collected prior and after the period of treatment in order to measure FBS. Our results indicate that carriers of GG genotype of ACE A2350G showed significantly lower FBS levels after fluoxetine treatment (P=0.043). On the other hand haplotype analysis designate a significant association between DTG carriers of ACE I/D, A-240T and A2350G (P=0.001) and reduced FBS levels. In conclusion, this study supports the hypothesis that RAS genetic variations affect blood glucose after a course of treatment in Iranian population with depressio

ACE genetic variability and response to fluoxetine: lack of association in depressed patients

Evidences suggest that besides the neurotransmitters contributing to the development of depression, renin-angiotensin system (RAS) may also have a substantial role. Certain polymorphisms of RAS are associated with over activity of RAS &amp; depression. Considering that antidepressants reduce the actions of angiotensin II, the main product of RAS, this may come into mind that genetic polymorphisms of the mentioned system may affect the outcome of therapy in depressed patients.In the present study, 100 newly diagnosed depressed patients, according to DSM-IV criteria, were treated with 20 mg of fluoxetine for 8-12 weeks. Patients were categorized into responsive and non-responsive groups according to 50% reduction in symptoms. Genotype frequencies of angiotensin-converting enzyme (ACE) gene [ACE (I/D, A-240T and A2350G)] were then determined in DNAs extracted from venous blood of the patients using polymerase chain reaction–restriction fragment length polymorphism (PCR– RFLP) and PCR.Results indicate that polymorphisms studied and their haplotypes were not associated with better response to fluoxetine. However, a strong association between age and treatment in depressed Iranian patients was observed (P=0.001).In conclusion, unlike previous reports, this study does not support the hypothesis of special genotypes of RAS contributing to a better response to antidepressants in depressed patients.</p

Drug-based therapeutic strategies for COVID-19-infected patients and their challenges

Emerging epidemic-prone diseases have introduced numerous health and economic challenges in recent years. Given current knowledge of COVID-19, herd immunity through vaccines alone is unlikely. In addition, vaccination of the global population is an ongoing challenge. Besides, the questions regarding the prevalence and the timing of immunization are still under investigation. Therefore, medical treatment remains essential in the management of COVID-19. Herein, recent advances from beginning observations of COVID-19 outbreak to an understanding of the essential factors contributing to the spread and transmission of COVID-19 and its treatment are reviewed. Furthermore, an in-depth discussion on the epidemiological aspects, clinical symptoms and most efficient medical treatment strategies to mitigate the mortality and spread rates of COVID-19 is presented

The effect of size, morphology and surface properties of mesoporous silica nanoparticles on pharmacokinetic aspects and potential toxicity concerns

Mesoporous silica nanoparticles (MSNs) are considered as suitable delivery vehicles considering their unique characteristics. Various physicochemical characteristics of MSNs govern their pharmacokinetic parameters which affect the disposition of these nanoparticles in the body. Along with the advantages of MSNs, the toxicity of nanoparticles entering the body is a major concern. Various factors such as particle size, surface charge, route of administration, etc., may affect organ toxicity of MSNs. The main target organs involved in the metabolism and elimination of MSNs are the kidney and the liver as well as the hematopoietic system. In this review, we first introduced the physicochemical characteristics of MSNs which affect the pharmacokinetic properties including drug absorption and bio-distribution. Thereafter, we discussed the mechanisms by which organ toxicity may occur. In this regard, the effects of various factors on organ-based MSNs toxicities and molecular mechanisms have been summarized. At last, we emphasized on the role of the physicochemical parameters on organ-based toxicities, and the proposed approaches to prevent or at least diminish MSN-related toxicities are discussed in detail

Combination of metformin and gallic acid induced autophagy and apoptosis in human breast cancer cells

Background and purpose: Breast cancer is the most common type of cancer and one of the major causes of death among women. Many reports propose gallic acid as a candidate for cancer treatment due to its biological and medicinal effects as well as its antioxidant properties. This study aimed to assess the effects of metformin and gallic acid on human breast cancer (MCF-7) and normal (MCF-10) cell lines. Experimental approach: MCF7 and MCF-10 cells were treated with various concentrations of metformin, gallic acid, and their combination. Cell proliferation, reactive oxygen species (ROS), as well as cell cycle arrest were measured. Autophagy induction was assessed using western blot analysis. Findings/Results: Metformin and gallic acid did not cause toxicity in normal cells. They had a stronger combined impact on ROS induction. Metformin and Gallic acid resulted in cell cycle arrest in the sub-G1 phase with G1 and S phase arrest, respectively. Increased levels of LC3 and Beclin-1 markers along with decreased P62 markers were observed in cancerous cells, which is consistent with the anticancer properties of metformin and gallic acid. Conclusion and implications: The effects of metformin and gallic acid on cancerous cells indicate the positive impact of their combination in treating human breast cancer

Modulation of ACE2/Ang1-7/Mas and ACE/AngII/AT1 axes affects anticancer properties of sertraline in MCF-7 breast cancer cells

The renin–angiotensin system (RAS) is best known for playing a major role in maintaining the physiology of the cardiovascular system. Dysregulation of the RAS pathway has been proposed as a link to some malignancies and contributes to cancer metastasis.Breast cancer is considered as one of the leading causes of cancer death in women and its prevention remains yet a challenge. Elements of RAS are expressed in both normal breast tissue and cancerous cells, signifying the essential role of RAS in breast cancer pathology. Sertraline, a widely used antidepressant, has shown anti-proliferative properties on a variety of malignancies.This study aimed to investigate the effect of sertraline and its combination with agonists and antagonists of RAS (A779, Ang 1–7 and losartan) on viability of MCF-7 cells along with their effect on apoptosis and distribution of cell cycle. Our results indicated that sertraline, losartan and Ang 1–7 significantly decreased cell viability, induced apoptosis and cell cycle arrest. A779 blunted the effect of sertraline on cell viability, ROS generation and cell cycle arrest. Combination treatment of sertraline with losartan as well as Ang 1–7 caused a remarkable decline in cell viability.In conclusion, results of the present study support the anti-cancer properties of sertraline, losartan and Ang 1–7 via induction of apoptosis and cell cycle arrest

FKBP5 blockade may provide a new horizon for the treatment of stress‐associated disorders: An in‐silico study

Abstract Objective We searched for, from the FDA (Food and Drug Administration‐USA)‐approved drugs, inhibitors of FKBP5 with tolerable adverse effect profiles (eg, mild headache, sedation, etc.) and with the ability to cross the blood brain barrier (BBB), using bio‐informatics tools (in‐silico). This may pave the road for designing clinical trials of such drugs in patients with functional seizures (FS) and other stress‐associated disorders. Methods Several databases were used to find all the approved drugs that potentially have interactions with FKBP51 protein [ie, CTD gene‐chemical interaction section of FKBP51 protein of Harmonizome of Mayaanlab, DrugCenteral database, PDID (Protein Drug Interaction Database), DGIdb (the Drug Gene Interaction database)]. Other databases were also searched [eg, clinicaltrials.gov; DRUGBANK (the FASTA format of the FKBP51 protein was imported to the target sequencing section of the database to find the associated drugs), and the STITCH database (to find the related chemical interaction molecules)]. Results After a comprehensive search of the designated databases, 28 unique and approved drugs were identified. Fluticasone propionate and Mifepristone and Ponatinib, Mirtazapine, Clozapine, Enzalutamide, Sertraline, Prednisolone, Fluoxetine, Dexamethasone, Clomipramine, Duloxetine, Citalopram, Chlorpromazine, Nefazodone, and Escitalopram are inhibitors of FKBP5 and have BBB permeability. Significance While the current in‐silico repurposing study could identify potential drugs (that are already approved and are widely available) for designing clinical trials in patients with stress‐associated disorders (eg, FS), any future clinical trial should consider the pharmacological profile of the desired drug and also the characteristics and comorbidities of the patients in order to foster a success

Association of renin–angiotensin–aldosterone system gene polymorphisms with left ventricular hypertrophy in patients with heart failure with preserved ejection fraction: A case–control study

Background: Heart failure with preserved ejection fraction (HFpEF) has close ties with hypertension, though risk factors to the development of HFpEF in hypertensive patients are not fully understood. Left ventricular hypertrophy (LVH) signifies the susceptibility toward diastolic heart dysfunction, and genetic determinants of LVH as a result may serve as risk predictors for HFpEF in hypertension. We investigated the role of three renin–angiotensin–aldosterone system (RAAS) gene polymorphisms in the development of LVH in hypertensive patients with a diagnosis of HFpEF. Methods: A total of 176 hypertensive patients with a diagnosis of HFpEF were divided to cases with LVH and controls without. rs4343 and rs4291 of angiotensin-converting enzyme (ACE) and rs5186 of angiotensin receptor type 1 were genotyped using PCR-RFLP method. Results: Genotypes and allele frequencies were significantly different between the case and control groups for rs4343 and rs4291, whereas no difference was observed for rs5186.Conclusion: Increased ACE activity explains the significant association of rs4343 and rs4291 polymorphisms with LVH in the carriers. Furthermore, findings support the pathophysiologic links between RAAS and increased LV mass in hypertension and suggest a genetic susceptibility to HFpEF. Such polymorphisms may serve as risk predictors of HFpEF in hypertensive patients

Genetic Variants of Angiotensin-Converting Enzyme Are Linked to Autism: A Case-Control Study.

BACKGROUND:Autism is a disease of complex nature with a significant genetic component. The importance of renin-angiotensin system (RAS) elements in cognition and behavior besides the interaction of angiotensin II (Ang II), the main product of angiotensin-converting enzyme (ACE), with neurotransmitters in CNS, especially dopamine, proposes the involvement of RAS in autism. Since the genetic architecture of autism has remained elusive, here we postulated that genetic variations in RAS are associated with autism. METHODS:Considering the relation between the three polymorphisms of ACE (I/D, rs4343 and rs4291) with the level of ACE activity, we have investigated this association with autism, in a case-control study. Genotype and allele frequencies of polymorphisms were determined in DNAs extracted from venous blood of 120 autistic patients and their age and sex-matched healthy controls, using polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods. RESULTS:There were strong associations between both DD genotype of ACE I/D and the D allele, with autism (P = 0.006, OR = 2.9, 95% CI = 1.64-5.13 and P = 0.006, OR = 2.18, 95% CI = 1.37-3.48 respectively). Furthermore, a significant association between the G allele of rs4343 and autism was observed (P = 0.006, OR = 1.84, 95%CI = 1.26-2.67). Moreover, haplotype analysis revealed an association between DTG haplotype and autism (P = 0.008). CONCLUSION:Our data suggests the involvement of RAS genetic diversity in increasing the risk of autism