Abstract P280: CCL5 Causes Vascular Injury Via CCR5 And Nadph Oxidase 1- Derived Ros

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Shubhnita Singh ◽  
Ariane Bruder Nascimento ◽  
Anita Bargaje ◽  
Thiago Bruder Nascimento
Keyword(s):  
Vascular Injury ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Vascular Inflammation ◽  
Fold Increase ◽  
Cellular Migration ◽  
Vascular Growth ◽  
Aortic Smooth Muscle ◽  
The Family ◽  
Nadph Oxidase 1

Chemokine (C-Cmotif) ligand 5 (CCL5) and its receptor CCR5 belong to the family of chemokines and are expressed and active in the vasculature. NADPH oxidases (Noxs) are the major source of reactive oxygen species (ROS) in vascular cells, but whether the activation of these oxidases is CCL5/CCR5 sensitive and whether such interaction participates in the genesis of vascular disease is not fully known. We investigated whether CCL5/CCR5 leads to vascular injury by activating Nox1. Carotid ligation model (CL, for 2-weeks) was used to induce pathological vascular growth in 10-weeks old (C57BL6/J) mice. Rat aortic smooth muscle cells (RASMC) were treated with recombinant CCL5 (100ng/mL) to study the molecular mechanisms. CL induces neointima formation, which was associated with increase in IL1β, TNFα, CCR3, CCR5 (3-fold increase), CCL5, and Nox1 gene expression. No difference was observed for Nox2 and 4. Treatment with CCR5 blocker (maraviroc, 25mg/Kg/day i.p) partially inhibited CL-induced vascular injury (media/intima ratio, CL: 1.2 ± 0.2 vs CL + maraviroc: 0.7 ± 0.2) and Nox1 expression (Fold changes: CL: 2.1 ± 0.4 vs CL + maraviroc: 1.2 ± 0.4). In RASMC, CCL5 induced Nox1 expression, which was blunted by pre-treating cells with maraviroc (10uM). Also, it increases p47phox content in membrane fraction (index of Nox activation), and elevated ROS production, analyzed by L012. CCL5 also induced cell migration, measured by transwell assay (number of cells per spot, control: 21.3 ± 3.1 vs CCL5: 31.1 ± 2.4), proliferation, analyzed by Edu+ cells (% of cells per spot, control: 10.6 ± 4.3 vs CCL5: 22.8 ± 5.1), and inflammation (studied by IL1β and TNFα levels). Lastly, CCL5 elevated NF-κB translocation into the nucleus, indicating NF-κB activation. Strikingly, inhibition of Nox1 (GKT771, 10uM), blocked CCL5-induced vascular migration, proliferation, and inflammation, as well as NF-κB activation. We propose that CCL5 activates Nox1 in the vasculature leading to local injury characterized by vascular inflammation and cellular migration and proliferation, perhaps by activating NF-κB signaling. Herein, we place CCR5 signaling as possible therapeutic target to reduce the cardiovascular risk in inflammatory diseases associated with dysregulation of CCL5 and/or CCR5

scholarly journals Sulfonylureas for Treatment of Periodontitis-Diabetes Comorbidity-Related Complications: Killing Two Birds With One Stone

2021 ◽  
Vol 12 ◽  
Author(s):  
Luxi Yang ◽  
Qing Ge ◽  
Zhitong Ye ◽  
Lijing Wang ◽  
Liping Wang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Host Immune System ◽  
Bone Homeostasis ◽  
Vascular Growth ◽  
Beneficial Effects ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Oral Hypoglycemic Drugs ◽  
Sulfonylurea Drugs

Periodontitis is one of the most prevalent oral inflammatory diseases leading to teeth loss and oral health problems in adults. Periodontitis mainly affects periodontal tissue by affecting the host immune system and bone homeostasis. Moreover, periodontitis is associated with various systemic diseases. Diabetes is a metabolic disease with systemic effects. Both periodontitis and diabetes are common inflammatory diseases, and comorbidity of two diseases is linked to exacerbation of the pathophysiology of both diseases. Since bacterial dysbiosis is mainly responsible for periodontitis, antibiotics are widely used drugs to treat periodontitis in clinics. However, the outcomes of antibiotic treatments in periodontitis are not satisfactory. Therefore, the application of anti-inflammatory drugs in combination with antibiotics could be a treatment option for periodontitis-diabetes comorbidity. Anti-diabetic drugs usually have anti-inflammatory properties and have shown beneficial effects on periodontitis. Sulfonylureas, insulin secretagogues, are the earliest and most widely used oral hypoglycemic drugs used for type-2 diabetes. Studies have found that sulfonylurea drugs can play a certain role in the mitigation of periodontitis and inflammation. This article reviews the effects of sulfonylurea drugs on the mitigation of periodontitis-diabetes comorbidity-related inflammation, bone loss, and vascular growth as well as the involved molecular mechanisms. We discuss the possibility of a new application of sulfonylureas (old drug) to treat periodontitis-diabetes comorbidity.

scholarly journals Acute Drug-Induced Vascular Injury in Beagle Dogs: Pathology and Correlating Genomic Expression

2006 ◽  
Vol 34 (1) ◽  
pp. 27-32 ◽  
Author(s):  
Bradley E. Enerson ◽  
Aiping Lin ◽  
Bin Lu ◽  
Hongyu Zhao ◽  
Michael P. Lawton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vascular Injury ◽  
Molecular Mechanisms ◽  
Vascular Inflammation ◽  
Toxicity Testing ◽  
Vascular Damage ◽  
Common Finding ◽  
Drug Induced ◽  
Genomic Expression ◽  
Adenosine Receptor Agonist

Acute vascular injury that leads to vascular inflammation is a common finding in the preclinical toxicity testing of drugs in rats and dogs. However, the relevance of this finding for risk to humans is unclear. Concern about the safety of these drugs is heightened by the current lack of noninvasive clinical methods to predict the onset of vascular damage in animals or humans. Determining the relevance of this poorly understood preclinical outcome for humans requires a better understanding of the molecular mechanisms of injury in addition to the development of sensitive and specific leading biomarkers for the clinical diagnosis of acute vascular damage. Most molecular research on this toxicity has been performed in rats, but recent development of canine gene expression microarrays makes transcriptomic studies now possible in the dog. In this study, we investigated the molecular mechanisms of drug-induced vascular injury in dogs using gene arrays. After treating Beagles with toxic doses of CI-947, an adenosine receptor agonist, we profiled gene expression in the coronary arteries and correlated those changes with histopathology at 16 and 24 hours after dosing. The results demonstrated that pathobiological processes such as stimulation of the innate immune response, increased extracellular matrix turnover and oxidative stress were active at times of very early injury.

Sorghum Fermented by Aspergillus oryzae NK Enhances Inhibition of Vascular Inflammation in TNF-α-stimulated Human Aortic Smooth Muscle Cells

2018 ◽  
Vol 88 (5-6) ◽  
pp. 309-318
Author(s):  
Hae Seong Song ◽  
Jung-Eun Kwon ◽  
Hyun Jin Baek ◽  
Chang Won Kim ◽  
Hyelin Jeon ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Inflammatory Response ◽  
Smooth Muscle Cells ◽  
Adhesion Molecule ◽  
Vascular Inflammation ◽  
Muscle Cells ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle ◽  
Tnf Α ◽  
Cox 2

Abstract. Sorghum bicolor L. Moench is widely grown all over the world for food and feed. The effects of sorghum extracts on general inflammation have been previously studied, but its anti-vascular inflammatory effects are unknown. Therefore, this study investigated the anti-vascular inflammation effects of sorghum extract (SBE) and fermented extract of sorghum (fSBE) on human aortic smooth muscle cells (HASMCs). After the cytotoxicity test of the sorghum extract, a series of experiments were conducted. The inhibition effects of SBE and fSBE on the inflammatory response and adhesion molecule expression were measured using treatment with tumor necrosis factor-α (TNF-α), a crucial promoter for the development of atherosclerotic lesions, on HASMCs. After TNF-α (10 ng/mL) treatment for 2 h, then SBE and fSBE (100 and 200 μg/mL) were applied for 12h. Western blotting analysis showed that the expression of vascular cell adhesion molecule-1 (VCAM-1) (2.4-fold) and cyclooxygenase-2 (COX-2) (6.7-fold) decreased, and heme oxygenase-1 (HO-1) (3.5-fold) increased compared to the TNF-α control when treated with 200 μg/mL fSBE (P<0.05). In addition, the fSBE significantly increased the expression of HO-1 and significantly decreased the expression of VCAM-1 and COX-2 compared to the TNF-α control in mRNA level (P<0.05). These reasons of results might be due to the increased concentrations of procyanidin B1 (about 6-fold) and C1 (about 30-fold) produced through fermentation with Aspergillus oryzae NK for 48 h, at 37 °C. Overall, the results demonstrated that fSBE enhanced the inhibition of the inflammatory response and adherent molecule expression in HASMCs.

Natural Products for Regulating Macrophages M2 Polarization

2020 ◽  
Vol 15 (7) ◽  
pp. 559-569 ◽  
Author(s):  
Zhen Chang ◽  
Youhan Wang ◽  
Chang Liu ◽  
Wanli Smith ◽  
Lingbo Kong
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Therapeutic Strategies ◽  
Research Progress ◽  
Cellular Mechanisms ◽  
Pharmacological Activities ◽  
Current Review ◽  
M2 Polarization ◽  
Macrophages Polarization ◽  
Herbal Plants

Macrophages M2 polarization have been taken as an anti-inflammatory progression during inflammation. Natural plant-derived products, with potential therapeutic and preventive activities against inflammatory diseases, have received increasing attention in recent years because of their whole regulative effects and specific pharmacological activities. However, the molecular mechanisms about how different kinds of natural compounds regulate macrophages polarization still unclear. Therefore, in the current review, we summarized the detailed research progress on the active compounds derived from herbal plants with regulating effects on macrophages, especially M2 polarization. These natural occurring compounds including flavonoids, terpenoids, glycosides, lignans, coumarins, alkaloids, polyphenols and quinones. In addition, we extensively discussed the cellular mechanisms underlying the M2 polarization for each compound, which could provide potential therapeutic strategies aiming macrophages M2 polarization.

scholarly journals Sterilization regret in India: Is quality of care a matter of concern?

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Anjali Bansal ◽  
Laxmi Kant Dwivedi
Keyword(s):  
Quality Of Care ◽  
Family Planning ◽  
Health Facility ◽  
Fold Increase ◽  
Well Being ◽  
Poor Quality ◽  
Public Health Facility ◽  
The Family ◽  
Planning Methods

Abstract Background According to United Nations, 19% of females in the world relied only on the permanent method of family planning, with 37% in India according to NFHS-4. Limited studies tried to measure the sterilization regret, and its correlated factors. The study tried to explore the trend of sterilization regret in India from 1992 to 2015 and to elicit the determining effects of various factors on sterilization regret, especially in context to perceived quality of care in the sterilization operations and type of providers. Data and methods The pooled data from NFHS-1, NFHS-3 and NFHS-4 was used to explore the regret by creating interaction between time and all the predictors. Predicted probabilities were calculated to show the trend of sterilization regret amounting to quality of care, type of health provider at the three time periods. Results The sterilization regret was increased from 5 % in NFHS-1 to 7 % in NFHS-4. According to NFHS-4, for those whose sterilization was performed in private health facility the regret was found to be less (OR-0.937; 95% CI- (0.882–0.996)) compared to public health facility. Also, the results show a two-fold increase in regret when women reported bad quality of care. The results from predicted probabilities provide enough evidence that the regret due to bad quality of care in sterilization operation had increased with each subsequent round of NFHS. Conclusion Many socio-economic and demographic factors have influenced the regret, but the poor quality of care contributed maximum to the regret from 1992 to 2015. The health facilities have seriously strayed from improving the health and well-being of women in providing the family planning methods. In addition, to public facilities, the regret amounting to private facilities have also increased from NFHS-1 to 4. The quality of care provided in the family planning operation should be standardized in every hospital to strengthen the health systems in the country. The couple should be motivated to adopt more of spacing methods.

scholarly journals Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Ruijuan Du ◽  
Chuntian Huang ◽  
Kangdong Liu ◽  
Xiang Li ◽  
Zigang Dong
Keyword(s):  
Cancer Therapy ◽  
Molecular Mechanisms ◽  
Aurora Kinase ◽  
Interacting Proteins ◽  
Multiple Tumor ◽  
Oncogenic Pathways ◽  
Wide Range ◽  
The Family ◽  
Tumor Types ◽  
Cancer Tissues

AbstractAurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.

scholarly journals Molecular Mechanisms of ZC3H12C/Reg-3 Biological Activity and Its Involvement in Psoriasis Pathology

2021 ◽  
Vol 22 (14) ◽  
pp. 7311
Author(s):  
Mateusz Wawro ◽  
Jakub Kochan ◽  
Weronika Sowinska ◽  
Aleksandra Solecka ◽  
Karolina Wawro ◽  
...  
Keyword(s):  
Family Member ◽  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Association Studies ◽  
Psoriasis Patient ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Transcript Levels

The members of the ZC3H12/MCPIP/Regnase family of RNases have emerged as important regulators of inflammation. In contrast to Regnase-1, -2 and -4, a thorough characterization of Regnase-3 (Reg-3) has not yet been explored. Here we demonstrate that Reg-3 differs from other family members in terms of NYN/PIN domain features, cellular localization pattern and substrate specificity. Together with Reg-1, the most comprehensively characterized family member, Reg-3 shared IL-6, IER-3 and Reg-1 mRNAs, but not IL-1β mRNA, as substrates. In addition, Reg-3 was found to be the only family member which regulates transcript levels of TNF, a cytokine implicated in chronic inflammatory diseases including psoriasis. Previous meta-analysis of genome-wide association studies revealed Reg-3 to be among new psoriasis susceptibility loci. Here we demonstrate that Reg-3 transcript levels are increased in psoriasis patient skin tissue and in an experimental model of psoriasis, supporting the immunomodulatory role of Reg-3 in psoriasis, possibly through degradation of mRNA for TNF and other factors such as Reg-1. On the other hand, Reg-1 was found to destabilize Reg-3 transcripts, suggesting reciprocal regulation between Reg-3 and Reg-1 in the skin. We found that either Reg-1 or Reg-3 were expressed in human keratinocytes in vitro. However, in contrast to robustly upregulated Reg-1 mRNA levels, Reg-3 expression was not affected in the epidermis of psoriasis patients. Taken together, these data suggest that epidermal levels of Reg-3 are negatively regulated by Reg-1 in psoriasis, and that Reg-1 and Reg-3 are both involved in psoriasis pathophysiology through controlling, at least in part different transcripts.

scholarly journals Multimarker method in the study of laboratory predictors of vascular wall elasticity as the basis for the development of a personalized approach to the treatment of socially significant diseases

2021 ◽  
Vol 28 (Supplement_1) ◽  
Author(s):  
T Petelina ◽  
K Avdeeva ◽  
N Musikhina ◽  
L Gapon ◽  
S Bykova ◽  
...  
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Postmenopausal Women ◽  
Ldl Cholesterol ◽  
Blood Pressure Monitoring ◽  
Vascular Inflammation ◽  
Fold Increase ◽  
Endothelin 1 ◽  
T Score ◽  
Markers Of Inflammation

Abstract Funding Acknowledgements Type of funding sources: None. Aim To investigate the role of markers of vascular inflammation, vitamin D, parathyroid hormone as predictors of increased pulse-wave velocity (PWV) and degenerative bone changes in postmenopausal women with arterial hypertension (AH). Methods 164 females were examined. Gr.1 included 42 healthy individuals, Gr.2 - 58 patients with AH and Gr.3 - 64 postmenopausal women with AH and osteoporosis. Parameters of blood pressure monitoring; PWV, osteodensitometry (T-Score); inflammatory markers: hsCRP, TNFα, homocysteine, IL-1β, 6, 8, endothelin-1; lipid profile parameters; sex and parathyroid hormones, vitamin D  were measured. Results In Gr.3 excess levels of PWV, hsCRP, homocysteine, IL8, total cholesterol, LDL cholesterol, endothelin-1 and parathyroid hormone was detected with decrease in the level of sex hormones and vitamin D. Besides, negative correlations of T-Score with age, PWV, duration of menopause, IL-6, hsCRP were registered; positive correlations between PWV with IL6, LDL cholesterol, hsCRP, endothelin-1, DBP variability were found. The logistic regression method revealed the main markers that affect increase of PWV, such as hsCRP and endothelin-1.Rise of each marker by unit of measurement leads to increase in PWV by 1.3 times and 2.4%, respectively. In Gr.2 increase in PWV level of more than 12.05 m/s was associated with 3.8-fold increase in the risk of osteoporosis. In Gr.3 increase in PWV level on 1 m/s was associated with 6 fold increase in the risk of osteoporosis. Conclusions Elevated levels of PWV are associated with markers of inflammation, levels of parathyroid hormone, vitamin D, T-Score and may be part of the pathogenesis of the cardiovascular continuum in postmenopausal women, which will require an individual approach to the treatment of AH with comorbid metabolic disorders.

scholarly journals Expression and function of Smad7 in autoimmune and inflammatory diseases

2021 ◽  
Author(s):  
Yiping Hu ◽  
Juan He ◽  
Lianhua He ◽  
Bihua Xu ◽  
Qingwen Wang
Keyword(s):  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Signaling Mechanism ◽  
And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

scholarly journals A systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathway

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yu Zhang ◽  
Christopher D. Kontos ◽  
Brian H. Annex ◽  
Aleksander S. Popel
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Reaction Network ◽  
Vascular Growth ◽  
Downstream Signaling ◽  
Signaling Axis ◽  
Agonistic Activity ◽  
Molecular Regulatory Mechanisms

AbstractThe Ang–Tie signaling pathway is an important vascular signaling pathway regulating vascular growth and stability. Dysregulation in the pathway is associated with vascular dysfunction and numerous diseases that involve abnormal vascular permeability and endothelial cell inflammation. The understanding of the molecular mechanisms of the Ang–Tie pathway has been limited due to the complex reaction network formed by the ligands, receptors, and molecular regulatory mechanisms. In this study, we developed a mechanistic computational model of the Ang–Tie signaling pathway validated against experimental data. The model captures and reproduces the experimentally observed junctional localization and downstream signaling of the Ang–Tie signaling axis, as well as the time-dependent role of receptor Tie1. The model predicts that Tie1 modulates Tie2’s response to the context-dependent agonist Ang2 by junctional interactions. Furthermore, modulation of Tie1’s junctional localization, inhibition of Tie2 extracellular domain cleavage, and inhibition of VE-PTP are identified as potential molecular strategies for potentiating Ang2’s agonistic activity and rescuing Tie2 signaling in inflammatory endothelial cells.

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