Article by Disease | Statins in Aortic Disease

Bentham Cardiovascular Disorders Collection | Cardiovascular Disorders | Aortic Coarctation 

 

Abstract:

Background: Numerous studies indicate that statins have multiple beneficial actions (known as ‘pleiotropic actions’) on cardiovascular system through the improvement of endothelial dysfunction, inflammation, oxidative stress, excessive arterial thrombosis, and stabilization of the atherosclerotic plaque. Aortic disease primarily consists of aortic valve stenosis, aortic valve regurgitation, aneurysm disease, and genetic disorders such as Marfan syndrome, bicuspid aortic valve and aortic coarctation. Many studies have revealed the cardioprotective actions of statins in aortic disease.

Objective: Our aim was to present current data concerning the value of treatment with statins in aortic diseases.

Methods: A thorough search of PubMed and the Cochrane Database was conducted to identify the studies and novel articles related to the use of statins in aortic disease.

Results: Numerous studies in animals and humans indicate a beneficial effect of treatment with statins in the previous conditions apart from a few conflicting data.

Conclusion: There is a need of further investigation in this field, especially for the estimation of the optimal type and dose of statins required in each clinical condition of aortic disease.

 

Read out more at: http://www.eurekaselect.com/node/157165/article

Press Release | Tumor necrosis associate with atherosclerotic lipid accumulation

 

The article by Dr. Alexander N. Orekhov et al. is published in Current Pharmaceutical Design, 2018

Inflammation is currently a well-documented component of atheroslcerosis pathogenesis, which plays a role at each stage of the disease development. Local activation of endothelial cells causing increase endothelial permeability, infiltration of intima with atherogenic low-density lipoprotein (LDL), and recruitment of circulating immune cells is regarded as a first step of atherosclerotic plaque development. Circulating modified LDL is immunogenic, and forms highly atherogenic aggregates with antibodies that are later accumulated in the arterial wall. In growing plaques, circulating monocytes are attracted to the lesions site by cytokine signalling. In the arterial wall, monocyte-derived macrophages play an active role in lipid accumulation, internalizing large associates of lipoprotein particles by means of phagocytosis. Phagocytic cells with cytoplasm filled by stored lipid droplets called foam cells can be found in developing plaques in large quantities. There is evidence that lipid accumulation in the arterial wall cells in its turn activates cytokine signalling leading to a vicious cycle and further aggravating the disease. However, the immune response in atherosclerosis is not limited to enhanced inflammation, since anti-inflammatory cytokines and alternatively-activated (M2) macrophages are also present in atherosclerotic plaques. Anti-inflammatory M2 macrophages are likely to be responsible for hte resolution of the inflammatory response and tissue remodelling observed in advancing plaques. At later stages of lesion development, lipofibrous plaquest with high lipid contents and cell counts give rise to fibrous plaques that contain less cells and lipids, but more extracellular matrix material.

Although the involvement of cytokines in atherosclerotic lesion development is currently beyond doubt, quantitative evaluation of the expression of pro- and anti-inflammatory cytokines in the plaque remains to be studied in detail. In this study, we analyzed the distribution of two cytokines, pro-inflammatory TNFα and anti-inflammatory CCL18, in sections of human carotid atherosclerotic plaques at different stages of development. Our results demonstrated that both pro- and anti-inflammatory cytokines were present in the plaques, although differently distributed and likely expressed by different cells, and appeared to be enriched as compared to grossly normal intima taken as a control. To test whether the expression of TNFα and CCL18 is increased in atherosclerotic lesions, we performed gene expression analysis by means of quantitative PCR. We found that the expression of both cytokines was indeed increased in different types of atherosclerotic lesions. Moreover, it followed a bell-shaped distribution across the 4 studied plaque stages, gradually increasing from the early initial lesions to fatty streaks, reaching maximum in lipofibrous plaques, and decreasing again in fibrous plaques. This distribution was consistent with our previously published observations of bell-shaped changes of atherosclerotic lesion cellularity, proliferative activity, collagen synthesis and lipid content at different stages of the development. For TNFα, the maximal increase in atherosclerotic lesions reached 2 folds as compared to normal tissue, while for CCL18, this number was 1.5 folds.

We next investigated the relationship between pro- and anti-inflammatory cytokine production and lipid accumulation in cells. To that end, we used cultured human monocyte-derived macrophages with lipid accumulation induced by incubation with atherogenic LDL obtained from atheroslcerosis patients’ blood serum. Non-atherogenic LDL obtained from healthy donors, which did not cause cholesterol accumulation in cultured cells, was used as a control. We found that cholesterol accumulation in macrophages caused by atherogenic LDL treatment was associated with up-regulation of both TNFα and CCL18. The increase in relative gene expression was statistically significant (p=0.05 for TNFα and p=0.023 for CCL18) as compared to non-atherogenic LDL treatment.

In this work, we report the increased expression of pro-inflammatory cytokine TNFα and anti-inflammatory CCL18 in human atherosclerotic lesions, which could be observed microscopically and in gene expression analysis by means of quantitative PCR. Furthermore, we demonstrate that the increase of pro- and anti-inflammatory cytokines expression is associated with cholesterol accumulation caused by atherogenic LDL in cultured cells. It is likely that lipid accumulation is the trigger of cytokine expression in atherosclerotic lesions, since the maximum of expression is observed in atherosclerotic lesions most enriched in lipids. We discuss the implications of these findings for atheroslcerosis pathogenesis, postulating that a splash of cytokine signalling occurs in lesions with the highest lipid contents. We hypothesize that both pro- and anti-inflammatory responses take place in human atherosclerotic lesions, but are probably characterized by different dynamics. While pro-inflammatory signalling occurs rapidly in response to triggering stimuli and is transient, anti-inflammatory response is relatively slow and long-lasting. Under favorable conditions, resolution of inflammation should lead to a healing process and plaque stabilization, while chronic inflammation may aggravate the disease development.

Browse the Article at: http://www.eurekaselect.com/165293/article

Press Release | Modified LDL particles activate inflammatory pathways in monocyte-derived macrophages

The article by Dr. . Alexander N. Orekhov et al. is published in Current Pharmaceutical Design, 2018

 

One of the main characteristics of atherosclerosis is the accumulation of lipids in the intimal layer of the arterial wall. In atherosclerotic plaques, phagocytic cells, such as macrophages, engulf atherogenic low-density lipoprotein (LDL) particles, but are unable to process them, and thus become foam cells, having cytoplasm packed with lipid droplets. Foam cells are characterized by several typical features: they have decreased ability to migrate, while displaying enhanced production of pro-inflammatory cytokines. Therefore foam cells participate in maintaining chronic inflammation in the lesion. Such changes of phenotype in comparison to normal macrophages should be based on changes in gene expression patterns of these cells. The study of foam cell formation is of key importance to our understanding of atherosclerosis pathogenesis and for the development of novel diagnostic and therapeutic tools. However, little is known so far on gene expression changes that take place during conversion of macrophages to foam cells.

Previous studies have shown several clusters of genes up- or down-regulated in macrophages in response to oxidized LDL, which is known to be atherogenic. Among the up-regulated genes were scavenger receptors SCA and CD36, nuclear receptors PPARγ, LXRα and RXRγ, and cholesterol efflux protein ABCA1. Regarding the inflammatory response, modified LDL appeared to trigger up-regulation of genes with anti-inflammatory activities, such as IL1-RA, DSCR1, annexin 1, and the Burton’s tyrosine kinase repressor SH3 protein, and down-regulation of a number of pro-inflammatory genes, including leukotriene A4 hydrolase, cathepsin G, elastase 2, RNase A family 2 and 3 proteins, cytochromeb-245, and CD64. However, modern powerful tools, such as transcriptome analysis, may provide more detailed data on change of gene expression patterns during atherosclerotic plaque development and reveal causative relationships between gene expression patterns and pathologic phenotypic alterations.

We performed a transcriptome analysis of macrophages treated with atherogenic LDL that causes intracellular cholesterol accumulation. We used the strategy of upstream analysis for causal interpretation of the expression changes. This strategy has three major steps: (1) analysis of promoters and enhancers of identified differentially expressed genes to identify transcription factors involved in the process under study; (2) reconstruction of signaling pathways that activate these transcription factors; and (3) identification of master-regulators of these pathways.

In this study, we used human monocyte-derived macrophages treated with different lipoprotein-containing samples : high-density lipoprotein (HDL), native LDL, which does not induce cholesterol accumulation in cultured cells, and 3 types of modified atherogenic LDL (oxidized LDL, acetylated LDL and desialylated LDL). In this experiment, low concentrations of native LDL and HDL did not increase the total or esterified cholesterol content in cultured macrophages. After incubation with the substances, mRNA was isolated from the cells and analysed using high-throughput sequencing on HiSeq 1500.

In this study, we discovered 27 transcription factors, including c-Ets, GR-alpha, BRCA1, E2F-1, E2F-6 and EGR-1, that were potentially responsible for the changes in gene expression induced by modified atherogenic LDL. These transcription factors were used for identifying the master-regulators (genes and proteins) responsible for regulation of large cascades of differentially expressed genes. The most reliable of identified master-regulators were IL7R, TIGIT, CXCL8, F2RL1, EIF2AK3, IL7, TSPYL2, ANXA1, DUSP1 and IL15. In the Discussion section of our paper, we give more detail on each of these master-regulators. In general, the genes that were up-regulated in response to lipid accumulation in macrophages induced by atherogenic LDL were mostly involved in inflammation and immune response, and not in cholesterol metabolism. Our results suggest a possibility that it is not cholesterol accumulation that causes an innate immunity response, but rather the immune response is a consequence of a cellular reaction to modified LDL. These results highlight the importance of the inflammatory component in the pathogenesis of atherosclerosis.

ARTICLE BY DISEASE – The Prevalence of the Classical and Non-Classical Cardiovascular Risk Factors in Multiple Sclerosis Patients

 

ARTICLE BY DISEASE ON “ACOUSTIC NEUROMA”

 

Background: Inflammation is known to play a role in cererovascular risk. Multiple sclerosis (MS) is a neurodegenerative disease that is initially characterized by inflammatory changes in the brain. We hypothesized that due to chronic inflammation, MS patients would present with a higher levels of cardiovascular (CV) risk factors than non-MS patients.

Methods: We performed a retrospective chart review on 206 MS patients and 142 control patients suffering from meningiomas and acoustic neuromas, non inflammatory, non autoimmune diseases of the brain. The obtained data included fasting lipid profiles, plasma glucose, systolic and diastolic blood pressure (BP), serum levels of homocysteine and uric acid, data on iron status, smoking habit, and list of medications. In addition, data on indicators of MS disease severity was obtained for MS patients.

Results: MS patients had significantly higher total plasma cholesterol, p = 0.01, and plasma high density lipoprotein, P <0.001, but lower plasma glucose, P <0.001, and systolic BP, P = 0.001, than non-MS patients. In addition, MS patients had lower erythrocyte sedimentation rate and serum vitamin B12, but higher serum folic acid and vitamin D3 than non-MS patients. A positive correlation was observed between plasma glucose and the extended disability status scale (EDSS), P = 0.008, and between plasma glucose and the rate of clinical relapse, P = 0.001.

Conclusion: The MS pathophysiology may be among factors for the lower CV risk factors in MS patients. Future studies should examine whether the chronic use of many pharmacological agents influence CV risk factors in MS patients.

 

For more details, please visit: http://www.eurekaselect.com/node/107982/article

ARTICLES BY DISEASE – The Prevalence of the Classical and Non-Classical Cardiovascular Risk Factors in Multiple Sclerosis Patients

ARTICLE BY DISEASE ON “ACOUSTIC NEUROMA

 

Abstract:

Background: Inflammation is known to play a role in cererovascular risk. Multiple sclerosis (MS) is a neurodegenerative disease that is initially characterized by inflammatory changes in the brain. We hypothesized that due to chronic inflammation, MS patients would present with a higher levels of cardiovascular (CV) risk factors than non-MS patients.

Methods: We performed a retrospective chart review on 206 MS patients and 142 control patients suffering from meningiomas and acoustic neuromas, non inflammatory, non autoimmune diseases of the brain. The obtained data included fasting lipid profiles, plasma glucose, systolic and diastolic blood pressure (BP), serum levels of homocysteine and uric acid, data on iron status, smoking habit, and list of medications. In addition, data on indicators of MS disease severity was obtained for MS patients.

Results: MS patients had significantly higher total plasma cholesterol, p = 0.01, and plasma high density lipoprotein, P <0.001, but lower plasma glucose, P <0.001, and systolic BP, P = 0.001, than non-MS patients. In addition, MS patients had lower erythrocyte sedimentation rate and serum vitamin B12, but higher serum folic acid and vitamin D3 than non-MS patients. A positive correlation was observed between plasma glucose and the extended disability status scale (EDSS), P = 0.008, and between plasma glucose and the rate of clinical relapse, P = 0.001.

Conclusion: The MS pathophysiology may be among factors for the lower CV risk factors in MS patients. Future studies should examine whether the chronic use of many pharmacological agents influence CV risk factors in MS patients

For more details, please visit: http://www.eurekaselect.com/node/107982/article

EDITORS CHOICE ARTICLE – A Potential Therapeutic Target RNA-binding Protein, Arid5a for the Treatment of Inflammatory Disease Associated with Aberrant Cytokine Expression

Journal Name: Current Pharmaceutical Design

Author(s): Kazuya Masuda*, Tadamitsu Kishimoto.

 

 

Abstract:

Background: Infection, tissue damage and aging can cause inflammation with high levels of inflammatory cytokines. Overproduction of inflammatory cytokines often leads to systemic inflammatory response syndrome (SIRS), severe sepsis, and septic shock. However, prominent therapeutic targets have not been found, although the incidence of sepsis is likely to increase annually. Our recent studies indicate that some RNA-binding proteins, which control gene expression of inflammatory cytokines at the post-transcriptional level, may play a critical role in inflammatory diseases such as sepsis.

Results: 1) One of the RNA-binding proteins, AT-rich interactive domain-containing 5a (Arid5a) promotes cytokine production through control of mRNA half-lives of pro-inflammatory molecules such as IL-6, STAT3, T-bet, and OX40 in activated macrophages and T cells. Arid5a KO mice are refractory to endotoxin shock, bleomycininduced lung injury, and inflammatory autoimmune disease. 2) Chlorpromazine (CPZ), which is recognized as a psychotic drug, impairs post-transcriptional gene expression of Il6 in LPS-stimulated macrophages: CPZ inhibits the binding activity of Arid5a to the 3’UTR of Il6 mRNA, thereby destabilizing Il6 mRNA possibly through suppression of Arid5a expression. 3) CPZ has strong suppressive effects on cytokine production such as TNF-α in vivo. Mice with treatment of CPZ are resistant to lipopolysaccharide (LPS)-induced shock.

Conclusion: Thus, Arid5a contributes to the activation of macrophages and T cells through positive control of mRNA half-lives of inflammatory cytokines and its related molecules, which might lead to cytokine storm. Interestingly, Arid5a was identified from an inhibitory effect of CPZ on IL-6 production in macrophages activated by LPS. Therefore, CPZ derivatives or Arid5a inhibitors may have a potential to suppress severe sepsis through control of post-transcriptional gene expression.

READ MORE HERE: http://www.eurekaselect.com/161575/article

EDITOR’S CHOICE – Novel Patents Targeting Interleukin-17A; Implications in Cancer and Inflammation

Journal: Recent Patents on Anti-Cancer Drug Discovery

Author(s): Juan F. Santibanez*, Suncica Bjelica

Abstract:

Background: IL-17A is a founding member of the IL-17 family that has been implicated in the pathogenesis of inflammatory-associated diseases such as cancer and autoimmune disease. In cancer, IL-17A participates in many key events for tumor development, in part by affecting innate and adaptive immune system and also by direct modulation of many pro-tumor events. Moreover, IL-17A dysregulation at the site of inflammation is associated with rheumatoid arthritis, multiple sclerosis, psoriasis, among others. IL-17A has emerged as a topic of interest and is under profound investigation for its involvement in several types of inflammatory-associated diseases.

Objective: This review aims to present an overview of the state of the art of IL-17A role in cancer and inflammation, as well as to describe recent patents targeting IL-17A with relevant clinical and biological properties for the prevention and treatment of cancer and inflammatory diseases.

Methods: Relevant information was obtained by searching in PubMed using IL-17A or IL-17, cancer and inflammation as keywords, while relevant patents were obtained mainly from Google Patents.

Results: Literature data indicated IL-17A as important biomolecule in the physiopathology of cancer and inflammatory diseases. Whereas, novel patents (2010 to 2017) targeting IL-17A are focused mainly on describing strategies to modulate IL-17A per se, co-modulation by bispecific antibodies to blocking IL-17A and important cytokines for IL-17A functions, upstream mechanisms and compounds to regulate IL-17A expression.

Conclusion: The promising effects of patented agents against IL-17A may open new opportunities to therapeutic intervention targeting at different levels of involvement in the pathogenesis of cancer and inflammatory diseases.

Read more here: http://www.eurekaselect.com/159948/article

 

PRESS RELEASE – Targeting inflammation to prevent preterm birth

A molecule named rytvela decreases uteroplacental inflammation, prevents preterm birth and improves perinatal outcomes through biased antagonism of the IL-1 receptor (functional selectivity)

Preterm birth (PTB) affects more than 10% of pregnancies worldwide and is the leading cause of neonatal mortality. Current treatments target myometrial contractility and are largely ineffective at improving perinatal outcomes. Myometrial contractions represent the final stage of a long process of uterine activation orchestrated by in utero inflammatory processes. If triggered prematurely (e.g. by infection), inflammation inevitably leads to preterm labor, with the timing of onset being inversely correlated with adverse neonatal outcomes and associated lifelong complications. Interleukin-1 (IL-1) is a major proinflammatory cytokine that has been firmly linked to human PTB and fetal organ injuries.

In a review article published in Current Pharmaceutical Design, Nadeau-Vallée et al. summarize the most recent evidence on the efficacy of molecules that target IL-1 to prevent PTB. Of all inhibitors of IL-1, the selective IL-1 receptor inhibitor rytvela (all-d heptapeptide) stands out preclinically as superiorly potent, effective, and safe in the prevention of PTB and its consequences. “Rytvela exerts benefits in decreasing uteroplacental inflammation, decreasing premature birth, prolonging gestation, increasing fetal survival, and improving fetal and neonatal outcome including that of the neurodevelopment” says Dr. Sylvain Chemtob, neonatologist, researcher, and principal author of the article. “Other than preventing preterm labor, rytvela also decreases inflammation inside the fetal compartment and in fetal organs, which is of significant importance because numerous neonatal conditions have been linked to inflammation independent of prematurity. Antenatal treatment with rytvela results in normalisation of lung, intestine and cerebral pathology scores during development and at adulthood”.

The effects of rytvela have been validated in vitro in murine and human uterine and immune cells, and in vivo in numerous murine models of PTB. Mechanistically, rytvela binds on a site remote from the binding site of IL-1 and act as a biased ligand by selectively inhibiting the p38/JNK/AP-1 pathway while preserving the activity of transcription factor NF-kB. This innovative mechanism of action may help decrease adverse effects (e.g. immunosuppression) which are particularly undesirable in the context of pregnancy.

Read more here: http://www.eurekaselect.com/155176

EDITOR’S CHOICE – Macrophage Polarization as a Therapeutic Target in Myocardial Infarction – Current Drug Targets

Journal: Current Drug Targets

Author(s): Yuanyuan Cheng, Jianhui Rong*

Graphical Abstract:

 

Abstract:

Background: Myocardial infarction is characterized by the interruption of blood flow through the heart, directly causing mortality and disability worldwide. Cardiac macrophages exhibit distinct phenotypes (e.g., M1 or M2) and functions (e.g., proinflammatory or anti-inflammatory) in response to the alterations of myocardial microenvironment, and subsequently exacerbate or resolve inflammation in the infarcted hearts. Regulation of macrophage polarization was implicated in myocardial infarction for the quality and outcome of cardiac healing.

Objective: The purpose of this review was to summarise the current understanding on the regulation of macrophage polarization in myocardial infarction and highlight the therapeutic potential of pharmacological regulators in the treatment of myocardial injury via modulating macrophage polarization.

Results: Timely control of M2/M1 ratio by endogenous mediators and pharmacological regulators should help the resolution of inflammation, promote wound healing and prevent cardiac fibrosis after myocardial infarction.

Conclusion: Macrophage polarization deserves better investigations as the therapeutic target for the development of novel drugs against myocardial injury.

Read more here: http://www.eurekaselect.com/156685/article

 

OPEN ACCESS ARTICLE – An Inflammation-related Nutrient Pattern is Associated with Both Brain and Cognitive Measures in a Multiethnic Elderly Population – Current Alzheimer Research

Journal: Current Alzheimer Research

Author(s): Yian Gu*, Jennifer J. Manly, Richard P. Mayeux, Adam M. Brickman

 

Abstract:

Background: Accumulating evidence suggests that dietary factors are associated with Alzheimer’s disease, cognition, and brain health in older adults. It is however unclear whether inflammation explains this association.

Objective: To examine whether an inflammation-related nutrient pattern (INP) was associated with neuroimaging and cognitive measures of brain health.

Method: The current cross-sectional study included 330 non-demented elderly (mean age 79 years at MRI scan) participants in a multi-ethnic, community-based cohort study who had information on nutritional intake (estimated from food frequency questionnaire), circulating C-reactive protein and interleukin- 6 (measured by ELISA), MRI scans, and cognition. Diet and blood samples were collected approximately 5.3 years prior to the MRI and cognitive test visit. We used a reduced rank regression model to derive an INP based on 24 nutrients’ relationship with CRP and interleukin-6. We examined the association of the INP with brain and cognitive measures using regression models adjusted for age, sex, race/ethnicity, education, caloric intake, APOE genotype, body mass index, and vascular burden, as well as intracranial volume for the brain MRI measures.

Results: The INP was characterized by low intake (effect loading <-0.15) of calcium, vitamins (D, E, A, B1, B2, B3, B5, B6), folate, Ω-3 poly-unsaturated fatty acids, and high intake (>0.15) of cholesterol. As designed, this INP was positively correlated with CRP (Pearson’s r=0.25 p=0.005) and interleukin-6 (r=0.30, p<0.0001). Each unit increase in INP was associated with 36.8 cm3 (p=0.023) smaller total brain volume and 0.21 (p=0.038) lower visuospatial z-score. Mediation analysis showed that TGMV (b=0.002, p=0.003) was associated with visuospatial cognitive function, and there was a significant mediation effect by TGMV (indirect effect: -0.049, 95% CI: -0.1121 ~ -0.0131) for the association between INP and visuospatial cognitive score.

Conclusions: Among older adults, a diet with high inflammatory potential is associated with less favorable brain and cognitive health.

Read more here: http://www.eurekaselect.com/158749

 

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