Molecular mechanisms of antiatherogenic drugs action

2021 ◽  
Vol 19 (3) ◽  
pp. 291-301
Author(s):  
Aleksey V. Lizunov ◽  
Evgenii R. Bychkov
Keyword(s):  
Lipid Metabolism ◽  
Molecular Mechanisms ◽  
Vascular Lesions ◽  
Atherosclerotic Plaques ◽  
General Description ◽  
Negative Effects ◽  
Atherosclerotic Lesions ◽  
Genetic Mechanisms ◽  
Biochemical Mechanisms ◽  
Antihyperlipidemic Agents

The purpose of this review is the analysis of the molecular mechanisms of lipid metabolism, their disorders leading to atherosclerosis, and the influence of modern antiatherogenic and antihyperlipidemic agents on atherogenic mechanisms. At the beginning of the review, a general description of atherosclerosis as pathology, its main characteristics and factors is given. The question of the complexity of the treatment of atherosclerosis and the problems arising in connection with the complexity is considered. Current models of the nature of atherosclerotic lesions are described. Next, we consider modern anti-atherosclerotic drugs used in clinical practice. Their nomenclature is given. Their basic biochemical mechanisms and the nature of their action are analyzed. Their negative effects and side effects are also considered. Then, the molecular and genetic mechanisms associated with atherosclerosis are analyzed in detail. The genes associated with lipid metabolism and the formation of atherosclerotic plaques, their expression and regulation are considered. The question of the influence of known anti-atherosclerotic agents on their expression is also covered. A group of azole drugs and their effect on lipid metabolism are considered in the context of the search for new anti-atherogenic drugs. The final part of the review examines the relevance of the search for new anti-atherosclerotic agents and methods for modeling dyslipidemia as a model of conditions that correlate with anti-atherosclerotic vascular lesions. It was concluded that the search for antiatherogenic drugs among imidazole derivatives is promising.

scholarly journals Hydroxytyrosol Plays Antiatherosclerotic Effects through Regulating Lipid Metabolism via Inhibiting the p38 Signal Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Xinxin Zhang ◽  
Yating Qin ◽  
Xiaoning Wan ◽  
Hao Liu ◽  
Chao Iv ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Fold Increase ◽  
Heart Tissue ◽  
Control Group ◽  
Atherosclerotic Lesions ◽  
Serum Crp

Purpose. Hydroxytyrosol (HT) processes multiaspect pharmacological properties such as antithrombosis and antidiabetes. The aim of this study was to explore the antistherosclerotic roles and relevant mechanisms of HT. Methods. Male apoE-/- mice were randomly divided into 2 groups: the control group and the HT group (10 mg/kg/day orally). After 16 weeks, blood tissue, heart tissue, and liver tissue were obtained to detect the atherosclerotic lesions, histological analysis, lipid parameters, and inflammation. And the underlying molecular mechanisms of HT were also studied in vivo and in vitro. Results. HT administration significantly reduced the extent of atherosclerotic lesions in the aorta of apoE-/- mice. We found that HT markedly lowered the levels of serum TG, TC, and LDL-C approximately by 17.4% (p=0.004), 15.2% (p=0.003), and 17.9% (p=0.009), respectively, as well as hepatic TG and TC by 15.0% (p<0.001) and 12.3% (p=0.003), respectively, while inducing a 26.9% (p=0.033) increase in serum HDL-C. Besides, HT improved hepatic steatosis and lipid deposition. Then, we discovered that HT could regulate the signal flow of AMPK/SREBP2 and increase the expression of ABCA1, apoAI, and SRBI. In addition, HT reduced the levels of serum CRP, TNF-α, IL-1β, and IL-6 approximately by 23.5% (p<0.001), 27.8% (p<0.001), 18.4% (p<0.001), and 19.1% (p<0.001), respectively, and induced a 1.4-fold increase in IL-10 level (p=0.014). Further, we found that HT might regulate cholesterol metabolism via decreasing phosphorylation of p38, followed by activation of AMPK and inactivation of NF-κB, which in turn triggered the blockade of SREBP2/PCSK9 and upregulation of LDLR, apoAI, and ABCA1, finally leading to a reduction of LDL-C and increase of HDL-C in the circulation. Conclusion. Our results provide the first evidence that HT displays antiatherosclerotic actions via mediating lipid metabolism-related pathways through regulating the activities of inflammatory signaling molecules.

scholarly journals Prevalence and typological characteristics of atherosclerotic lesions in carotid arteries associated with metabolic syndrome as revealed by multislice computed tomography

2017 ◽  
Vol 95 (1) ◽  
pp. 51-56
Author(s):  
Evgeniy A. Praskurnichiy ◽  
I. I. Aleksandrova ◽  
T. V. Kostycheva ◽  
A. N. Knyazev
Keyword(s):  
Computed Tomography ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Carotid Arteries ◽  
Multislice Computed Tomography ◽  
Vascular Lesions ◽  
Diabetic Patients ◽  
Atherosclerotic Plaques ◽  
Atherosclerotic Lesions

Aim. To study the character, prevalence, and typological structure of atherosclerotic changes in major arteries by multislice computed tomography in patients with various metabolic disorders. Material and Methods: Carotid arteries of 78 patients with metabolic syndrome or type 2 diabetes mellitus and without carbohydrate metabolism disorders were examined by multislice computed tomography. Results: The study revealed various types of atherosclerotic plaques differing in the composition of lipid, lipid-fibrotic and calcium components. The latter were especially well expressed in diabetes. Conclusion. All types of atherosclerotic plaques are roughly equally represented in the structure of atherosclerotic lesions of carotid arteries in patients with metabolic syndrome in the absence of type 2 diabetes. Diabetic patients had vascular lesions with especially high density of atherosclerotic plaques.

A Cytochemical Study of Glucose-6-Phosphatase (G-6-PASE) in Cells Participating in Atherogenesis of Rabbit Aorta

1975 ◽  
Vol 33 ◽  
pp. 460-461
Author(s):  
Sidney D. Kobernick ◽  
Edna A. Elfont ◽  
Neddra L. Brooks
Keyword(s):  
Lipid Metabolism ◽  
New Zealand ◽  
Aortic Wall ◽  
Rabbit Aorta ◽  
Plaque Formation ◽  
Metabolic Changes ◽  
Atherosclerotic Plaques ◽  
Cytochemical Study ◽  
Cellular Alteration ◽  
New Zealand White Rabbits

This cytochemical study was designed to investigate early metabolic changes in the aortic wall that might lead to or accompany development of atherosclerotic plaques in rabbits. The hypothesis that the primary cellular alteration leading to plaque formation might be due to changes in either carbohydrate or lipid metabolism led to histochemical studies that showed elevation of G-6-Pase in atherosclerotic plaques of rabbit aorta. This observation initiated the present investigation to determine how early in plaque formation and in which cells this change could be observed.Male New Zealand white rabbits of approximately 2000 kg consumed normal diets or diets containing 0.25 or 1.0 gm of cholesterol per day for 10, 50 and 90 days. Aortas were injected jin situ with glutaraldehyde fixative and dissected out. The plaques were identified, isolated, minced and fixed for not more than 10 minutes. Incubation and postfixation proceeded as described by Leskes and co-workers.

scholarly journals Insights into how environment shapes post-mortem RNA transcription in mouse brain

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Raphael Severino Bonadio ◽  
Larissa Barbosa Nunes ◽  
Patricia Natália S. Moretti ◽  
Juliana Forte Mazzeu ◽  
Stefano Cagnin ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Mouse Brain ◽  
Molecular Mechanisms ◽  
Cell Communication ◽  
Rna Degradation ◽  
The Body ◽  
Biological Processes ◽  
Post Mortem ◽  
Gene Expression Alterations ◽  
Upregulated Genes

AbstractMost biological features that occur on the body after death were already deciphered by traditional medicine. However, the molecular mechanisms triggered in the cellular microenvironment are not fully comprehended yet. Previous studies reported gene expression alterations in the post-mortem condition, but little is known about how the environment could influence RNA degradation and transcriptional regulation. In this work, we analysed the transcriptome of mouse brain after death under three concealment simulations (air exposed, buried, and submerged). Our analyses identified 2,103 genes differentially expressed in all tested groups 48 h after death. Moreover, we identified 111 commonly upregulated and 497 commonly downregulated genes in mice from the concealment simulations. The gene functions shared by the individuals from the tested environments were associated with RNA homeostasis, inflammation, developmental processes, cell communication, cell proliferation, and lipid metabolism. Regarding the altered biological processes, we identified that the macroautophagy process was enriched in the upregulated genes and lipid metabolism was enriched in the downregulated genes. On the other hand, we also described a list of biomarkers associated with the submerged and buried groups, indicating that these environments can influence the post-mortem RNA abundance in its particular way.

scholarly journals Comparative Transcriptome Analysis Reveals Genetic Mechanisms of Sugarcane Aphid Resistance in Grain Sorghum

2021 ◽  
Vol 22 (13) ◽  
pp. 7129
Author(s):  
Desalegn D. Serba ◽  
Xiaoxi Meng ◽  
James Schnable ◽  
Elfadil Bashir ◽  
J. P. Michaud ◽  
...  
Keyword(s):  
Differential Expression ◽  
Molecular Mechanisms ◽  
Grain Sorghum ◽  
Lipid Binding ◽  
Multiple Time ◽  
Melanaphis Sacchari ◽  
Resistant Genotype ◽  
Sugarcane Aphid ◽  
Genetic Mechanisms ◽  
Moderately Resistant

The sugarcane aphid, Melanaphis sacchari (Zehntner) (Hemiptera: Aphididae) (SCA), has become a major pest of grain sorghum since its appearance in the USA. Several grain sorghum parental lines are moderately resistant to the SCA. However, the molecular and genetic mechanisms underlying this resistance are poorly understood, which has constrained breeding for improved resistance. RNA-Seq was used to conduct transcriptomics analysis on a moderately resistant genotype (TAM428) and a susceptible genotype (Tx2737) to elucidate the molecular mechanisms underlying resistance. Differential expression analysis revealed differences in transcriptomic profile between the two genotypes at multiple time points after infestation by SCA. Six gene clusters had differential expression during SCA infestation. Gene ontology enrichment and cluster analysis of genes differentially expressed after SCA infestation revealed consistent upregulation of genes controlling protein and lipid binding, cellular catabolic processes, transcription initiation, and autophagy in the resistant genotype. Genes regulating responses to external stimuli and stress, cell communication, and transferase activities, were all upregulated in later stages of infestation. On the other hand, expression of genes controlling cell cycle and nuclear division were reduced after SCA infestation in the resistant genotype. These results indicate that different classes of genes, including stress response genes and transcription factors, are responsible for countering the physiological effects of SCA infestation in resistant sorghum plants.

Evaluation of Factors Associated With Elevated Levels of Platelet-Derived Microparticles in the Acute Phase of Cerebral Infarction

2009 ◽  
Vol 16 (1) ◽  
pp. 26-32 ◽  
Author(s):  
Nagato Kuriyama ◽  
Yoshinari Nagakane ◽  
Akiko Hosomi ◽  
Tomoyuki Ohara ◽  
Takashi Kasai ◽  
...  
Keyword(s):  
Cerebral Infarction ◽  
Acute Phase ◽  
Control Level ◽  
Intima Media Thickness ◽  
Vascular Lesions ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Large Artery ◽  
Vessel Occlusion ◽  
Atherosclerotic Lesions

Background: Platelet-derived microparticles (PDMPs) have attracted attention as blood coagulation-promoting, endothelial cell-activating factors. The objective of this study was to determine the parameters associated with elevated PDMP levels and examine their relationship with atherosclerotic lesions of main intracranial and extracranial arteries. Participants and Methods: Participants included a control group (C) of 61 patients with no apparent cerebral vascular lesions and 110 patients with acute-phase cerebral infarction, consisting of a small-vessel occlusion group (S) of 34 patients, a large-artery atherosclerosis group (L) of 41 patients, a cardioembolism group (CE) of 20 patients, and a stroke of undetermined etiology group (U) of 15 patients. Platelet-derived microparticle levels were measured using enzyme-linked immunosorbent assay (ELISA) at the time of admission, and the patients were reclassified into group CP (control level PDMPs), consisting of 70 patients with control PDMP levels, and group HP (high PDMPs), consisting of 40 patients with elevated PDMP levels. All patients underwent cranial magnetic resonance (MR) and carotid ultrasound examinations. Results: Platelet-derived microparticle levels were significantly higher in groups S and L than in group C (P < .01). Concomitant intima-media thickness (IMT; odds ratio [OR] = 1.29, P < .05) and concomitant intracranial stenosis (OR = 3.95, P < .01) were significantly correlated with elevated PDMP levels. Fibrinogen and high-sensitivity CRP levels were significantly higher in group HP than in group CP. Conclusion: Alterations in PDMP levels correlated with the presence of atherothrombotic lesions, and PDMP levels are expected to be useful as a clinical indicator, reflecting the presence of intracranial atherosclerotic lesions in the acute phase of cerebral infarction.

scholarly journals Regulation of Osteoclast Differentiation and Activity by Lipid Metabolism

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 89
Author(s):  
Haemin Kim ◽  
Brian Oh ◽  
Kyung-Hyun Park-Min
Keyword(s):  
Lipid Metabolism ◽  
Molecular Mechanisms ◽  
Bone Cells ◽  
Critical Role ◽  
Osteoclast Differentiation ◽  
Bone Diseases ◽  
Metabolic Reprogramming ◽  
Lipid Lowering ◽  
Metabolic Bone Diseases ◽  
Increased Risk

Bone is a dynamic tissue and is constantly being remodeled by bone cells. Metabolic reprogramming plays a critical role in the activation of these bone cells and skeletal metabolism, which fulfills the energy demand for bone remodeling. Among various metabolic pathways, the importance of lipid metabolism in bone cells has long been appreciated. More recent studies also establish the link between bone loss and lipid-altering conditions—such as atherosclerotic vascular disease, hyperlipidemia, and obesity—and uncover the detrimental effect of fat accumulation on skeletal homeostasis and increased risk of fracture. Targeting lipid metabolism with statin, a lipid-lowering drug, has been shown to improve bone density and quality in metabolic bone diseases. However, the molecular mechanisms of lipid-mediated regulation in osteoclasts are not completely understood. Thus, a better understanding of lipid metabolism in osteoclasts can be used to harness bone cell activity to treat pathological bone disorders. This review summarizes the recent developments of the contribution of lipid metabolism to the function and phenotype of osteoclasts.

Evolution of stickleback spines through independent cis-regulatory changes at HOXDB

2021 ◽  
Author(s):  
Julia I Wucherpfennig ◽  
Timothy R Howes ◽  
Jessica N Au ◽  
Eric H Au ◽  
Garrett A Roberts Kingman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Evolutionary Biology ◽  
Gasterosteus Aculeatus ◽  
Molecular Mechanisms ◽  
Wild Populations ◽  
Gene Variation ◽  
Regulatory Changes ◽  
Fundamental Goal ◽  
Apeltes Quadracus ◽  
Genetic Mechanisms

Understanding the genetic mechanisms leading to new traits is a fundamental goal of evolutionary biology. We show that HOXDB regulatory changes have been used repeatedly in different stickleback fish species to alter the length and number of bony dorsal spines. In Gasterosteus aculeatus, a variant HOXDB allele is genetically linked to shortening an existing spine and adding a spine. In Apeltes quadracus, a variant allele is associated with lengthening an existing spine and adding a spine. The alleles alter the same conserved non-coding HOXDB enhancer by diverse molecular mechanisms, including SNPs, deletions, and transposable element insertions. The independent cis-acting regulatory changes are linked to anterior expansion or contraction of HOXDB expression. Our findings support the long-standing hypothesis that natural Hox gene variation underlies key morphological patterning changes in wild populations and illustrate how different mutational mechanisms affecting the same region may produce opposite gene expression changes with similar phenotypic outcomes.

Abstract 2771: Incidence of High Risk Atherosclerotic Lesions in Intracranial and Extracranial Carotid Arteries in Patients with Acute Ischemic Stroke: A 3.0T Magnetic Resonance Imaging Study

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Xihai Zhao ◽  
Huilin Zhao ◽  
Feiyu Li ◽  
Jie Sun ◽  
Ye Cao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
High Risk ◽  
Carotid Artery ◽  
Acute Ischemic Stroke ◽  
Cerebral Artery ◽  
Carotid Arteries ◽  
Atherosclerotic Plaques ◽  
Slice Thickness ◽  
Atherosclerotic Lesions ◽  
Vascular Beds

Introduction Rupture of vulnerable atherosclerotic plaques in the intracranial and extracranial carotid arteries could trigger ischemic stroke. However, the incidence of high risk atherosclerotic lesions in these vascular beds is not well known. This study sought to investigate the incidence of high risk atherosclerotic lesions in intracranial and extracranial carotid arteries in stroke patients using magnetic resonance (MR) imaging. Methods Seventy-five patients (mean age 62.7 years, 56 males) with acute ischemic stroke underwent MR imaging for index carotid arteries, assigned as the same side as the brain lesions, with a Philips 3.0T MR scanner. Intracranial carotid MR angiography was performed using 3D TOF sequence with FOV of 23 × 23 cm 2 , matrix of 256 × 256, and a slice thickness of 1mm. The multi-contrast vessel wall images (3D TOF, T1W, T2W, and MP-RAGE) were acquired for extracranial carotid arteries with FOV of 14 × 14 cm 2 , matrix of 256 × 256, and slice thickness of 2 mm. The intracranial artery includes middle cerebral artery (MCA), anterior cerebral artery (ACA), and posterior cerebral artery (PCA). The extracranial carotid artery was divided into internal carotid artery (ICA), bulb, and common carotid artery (CCA). Luminal stenosis for each intracranial and extracranial carotid segment was measured and graded (normal or mild = 0-29%, moderate =30-69%, severe=70-99%). Normalized wall index (NWI = wall area/total vessel area × 100%), and presence/absence of calcification, lipid-rich necrotic core (LRNC), and intraplaque hemorrhage (IPH) and/or fibrous cap rupture in each extracranial carotid segment were determined. Results MCAs developed more severe stenotic lesions (24.6%), followed by extracranial carotids (16.5%), PCAs (5.4%), and ACAs (4.1%) in stroke patients ( Figure 1 A). For extracranial carotid arteries, ICAs showed the largest plaque burden as measured by NWI (44.3%±13.1%), followed by bulbs (39.4%±13%), and CCAs (37%±6.8%). Compared to CCAs, ICAs and bulb regions had more LRNCs (38.4% and 49.3% for ICA and bulb respectively) and IPH and/or rupture (11% and 9.6% for ICA and bulb respectively) ( Figure 1 B). Conclusions In patients with acute ischemic stroke, high risk atherosclerotic plaques can be found in both intracranial and extracranial carotid arteries, particularly in the MCA, ICA and bulb regions. Compared to extracranial carotid arteries, intracranial arteries develop more high risk lesions. The findings of this study suggest the necessity for early screening to detect high risk atherosclerotic lesions in these carotid vascular beds prior to cerebravascular events.

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