Expression Of Monocyte Chemoattractant Research Articles

Berberine Exhibits Anti‐atherosclerotic Effects in a Mouse Model by Targeting the JAK/STAT Pathway

AbstractAtherosclerosis, a serious and commonly diagnosed pathological condition is the main cause of coronary and cerebrovascular disorder which has a high rate of morbidity and mortality globally. In the present study effect of berberine on damage to the aorta wall induced by atherosclerosis in mice model was investigated. The results demonstrated that berberine treatment significantly (P<0.05) reverses the atherosclerosis‐induced increase in the area of the lesions in the mice aortas. Berberine treatment at 0.5, 1.0 and 2.0 mg/kg doses reduced lesion area in the aorta of atherosclerosis mice to 53.5±3.69, 39.4±3.69 and 13.8±2.12 %, respectively. Atherosclerosis‐induced up‐regulation of interleukin (IL)‐1β and IL‐6 production was down‐regulated in mice aortas on treatment with berberine. Treatment with berberine downregulated the atherosclerosis‐induced increase in expression of monocyte chemoattractant protein‐1 (MCP‐1), tumor necrosis factor (TNF)‐α, angiotensin II (AngII), Alveolar type 2 progenitor cells (AT1), and AT2 in mice aorta tissues. Moreover, berberine treatment of atherosclerosis mice led to a marked reduction in the activation of signal transducer and activator of transcription 3 (STAT3), p65, and p38 proteins. In summary, berberine treatment reverses damage associated with atherosclerosis in mice aorta walls by inhibiting the inflammatory response. It targets activation of Janus kinase (JAK)/STAT pathway and downregulated RAAS expression in atherosclerotic mice. Therefore, berberine may be developed as a potential chemotherapeutic agent for atherosclerosis treatment.

Preeclamptic Fetal Programming Alters Neuroinflammatory and Cardiovascular Consequences of Endotoxemia in Sex Specific Manners

Preeclampsia (PE)‐induced fetal programming predisposes offspring to health hazards in adult life. Here, we tested the hypothesis that preeclamptic fetal programming elicits sexually dimorphic inflammatory and cardiovascular complications to endotoxemia in adult rat offspring. Preeclampsia was induced by oral administration of of L‐NAME (50 mg/kg/day for 7 consecutive days) starting from day 14 of conception. Cardiovascular studies were performed in conscious adult male and female offspring pre‐instrumented with femoral indwelling catheters. Compared with non‐PE male counterparts, i.v. administration of lipopolysaccharide (LPS, 5 mg/kg) to PE male offspring caused significantly greater (i) falls in blood pressure, (ii) rises in heart rate and left ventricular contractility (dP/dtmax), and (iii) decreases in time‐ and frequency‐domain indices of heart rate variability. By contrast, the hypotensive and tachycardic actions of LPS in female offspring were independent of the preeclamptic state and no clear changes in heart rate variability or left ventricular function were noted. Measurement of arterial baroreflex activity by the vasoactive method revealed no sex specificity in baroreflex dysfunction induced by LPS. Immunohistochemical studies showed increased protein expression of toll‐like receptor 4 in the heart as well as in brainstem neuronal pools of the nucleus of the solitary tract and rostralventrolateral medulla in endotoxic PE male, but not female, offspring. Enhanced myocardial, but not neuronal, expression of monocyte chemoattractant protein‐1 was also demonstrated in LPS‐treated male offspring. Together, preeclamptic fetal programming aggravates endotoxic manifestations of hypotension and autonomic dysfunction in male offspring via exacerbating myocardial and neuromedullary inflammatory pathways.Support or Funding InformationSupported by the Science and Technology Development Fund, Egypt (STDF Grants No. 14895)

Interleukin-17-induced expression of monocyte chemoattractant protein-1 in cardiac myocytes requires nuclear factor κB through the phosphorylation of p65.

IL-17 plays a key role in a variety of autoimmune diseases. MCP-1 is involved in the infiltration of mononuclear cells of myocardium in VMC. However, the relationship between IL-17 and MCP-1 in myocardial injury remains unclear. In this study, expression of MCP-1 mRNA and protein in cardiac myocytes was detected with qRT-PCR and ELISA, respectively. It was found that IL-17A induced MCP-1 expression in a dose- and time-dependent manner in cardiac myocytes, which could be blocked by IL-17A and IL-17RA neutralizing antibodies. NF-κB p65 and p-p65 protein expression in cardiac myocytes was studied with western blotting. Rates of p-p65 in whole lysates and in nuclear lysates all increased in the first 15 min. Meanwhile, the amount of NF-κB p65 in whole lysates did not change, but the amount of NF-κB p65 in nuclear lysates increased in the first 15 min. Then the optimal sequence and concentration of NF-κB p65 siRNAs was selected. After transfection of 10 nM siRNA-2 of NF-κB p65 into cardiac myocytes before stimulation by IL-17A, expression of MCP-1 mRNA and protein obviously decreased. In conclusion, expression of MCP-1 induced by IL-17 requires NF-κB through the phosphorylation of p65 in cardiac myocytes, which is meaningful to study the onset of chronic viral myocarditis and will provide a new target for the treatment of viral myocarditis.

A Reduction in Selenoprotein S Amplifies the Inflammatory Profile of Fast-Twitch Skeletal Muscle in the mdx Dystrophic Mouse.

Excessive inflammation is a hallmark of muscle myopathies, including Duchenne muscular dystrophy (DMD). There is interest in characterising novel genes that regulate inflammation due to their potential to modify disease progression. Gene polymorphisms in Selenoprotein S (Seps1) are associated with elevated proinflammatory cytokines, and in vitro SEPS1 is protective against inflammatory stress. Given that SEPS1 is highly expressed in skeletal muscle, we investigated whether the genetic reduction of Seps1 exacerbated inflammation in the mdx mouse. F1 male mdx mice with a heterozygous Seps1 deletion (mdx:Seps1−/+) were generated. The mdx:Seps1−/+ mice had a 50% reduction in SEPS1 protein expression in hindlimb muscles. In the extensor digitorum longus (EDL) muscles, mRNA expression of monocyte chemoattractant protein 1 (Mcp-1) (P = 0.034), macrophage marker F4/80 (P = 0.030), and transforming growth factor-β1 (Tgf-β1) (P = 0.056) were increased in mdx:Seps1−/+ mice. This was associated with a reduction in muscle fibre size; however, ex vivo EDL muscle strength and endurance were unaltered. In dystrophic slow twitch soleus muscles, SEPS1 reduction had no effect on the inflammatory profile nor function. In conclusion, the genetic reduction of Seps1 appears to specifically exacerbate the inflammatory profile of fast-twitch muscle fibres, which are typically more vulnerable to degeneration in dystrophy.

Identification of a Novel Heart-Liver Axis: Matrix Metalloproteinase-2 Negatively Regulates Cardiac Secreted Phospholipase A2 to Modulate Lipid Metabolism and Inflammation in the Liver.

BackgroundEndocrine functions of the heart have been well established. We investigated the hypothesis that cardiac secretion of a unique phospholipase A2 recently identified by our laboratory (cardiac secreted phospholipase A2 [sPLA 2]) establishes a heart–liver endocrine axis that is negatively regulated by matrix metalloproteinase‐2 (MMP‐2).Methods and ResultsIn Mmp2 −/− mice, cardiac (but not hepatic) sPLA 2 was elevated, leading to hepatic inflammation, immune cell infiltration, dysregulation of the sterol regulatory element binding protein‐2 and liver X receptor‐α pathways, abnormal transcriptional responses to dietary cholesterol, and elevated triglycerides in very low‐density lipoprotein and in the liver. Expression of monocyte chemoattractant protein‐3, a known MMP‐2 substrate, was elevated at both mRNA and protein levels in the heart. Functional studies including in vivo antibody neutralization identified cardiac monocyte chemoattractant protein 3 as a possible agonist of cardiac sPLA 2 secretion. Conversely, systemic sPLA 2 inhibition almost fully normalized the cardiohepatic phenotype without affecting monocyte chemoattractant protein‐3. Finally, wild‐type mice that received high‐performance liquid chromatography–isolated cardiac sPLA 2 from Mmp2 −/− donors developed a cardiohepatic gene expression profile similar to that of Mmp2 −/− mice.ConclusionsThese findings identified the novel MMP‐2/cardiac sPLA 2 pathway that endows the heart with important endocrine functions, including regulation of inflammation and lipid metabolism in the liver. Our findings could also help explain how MMP2 deficiency leads to cardiac problems, inflammation, and metabolic dysregulation in patients.

Expression of monocyte chemoattractant protein-1 in brain tissue of patients with intractable epilepsy

To investigate the expression ofmonocyte chemoattractant protein-1 (MCP-1) in the brain tissue of patients with intractable epilepsy (IE) and to explore its role in the pathogenesis of IE. Patients with IE were collected from the Department of Neurosurgery of several Chinese hospitals between 2002 and 2005. The average age of these 40 patients was 23.65 +/- 10.14 (X +/- SD) years (11 - 58 years), with 19 males and 21 females. In addition to the typical symptoms and distinct EEG features of epilepsy, all recruited patients met the requirements of intractable epilepsy. On the basis of positive results obtained from gene chip analysis, the expression of MCP-1 was first investigated in the brain tissue of IE patients (40 cases) using Western Blotting and immunohistochemistry and then compared with the controls. Gene chip scanning demonstrated that expression of MCP-1 mRNA was upregulated in the brain tissue of patients with IE. Western Blotting and immunohistochemical experiments further confirmed that, as compared with that in the control group, expression of MCP-1 protein was significantly increased in the IE patients (p < 0.05). These results suggest that MCP-1 are involved in the pathogenesis of IE.

Expression of monocyte chemoattractant protein-1 and interleukin-8 receptors on subsets of T cells: correlation with transendothelial chemotactic potential.

The differential expression of chemokine receptors may be an important mechanism for the regulation of T cell migration. To test this, we examined the expression and function of the monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8 receptors on various population of T cells. Using a simple and reliable transendothelial chemotaxis assay, both MCP-1 and IL-8 were shown to be chemotactic for subsets of blood T cells, although the relative response varied from donor to donor. To examine receptor expression and correlate it with chemotaxis of T cell subsets, monoclonal antibodies (mAb) to the receptors were produced by immunizing mice either with synthetic peptides (MCP-1 receptor), or with receptor transfectants (IL-8 receptors A and B). A flow cytometric analysis of blood T cells with an anti-MCP-1 receptor mAb revealed low expression on the CD26hi subset and undetectable expression on other T cells. Staining of T cells with anti-Il-8RA and anti-IL-8RB showed much higher levels of expression, but only on a subset of CD3+ cells which were CD8+ and CD56+. That IL-8 and MCP-1 attracted distinct subsets of T cells was best illustrated using the CD26 marker, since IL-8R+ T cells were CD26-, whereas T cells expressing detectable MCP-1R or which responded to MCP-1 in chemotaxis assays were CD26hi. T cells activated in vitro with anti-CD3 up-regulated expression of the MCP-1 receptor, but not the IL-8 receptors, and were attracted to MCP-1 much more efficiently than resting T cells. These results show that there is a clear distinction between the IL-8 and MCP-1-responsive T cell populations and that chemokine receptor expression on T cells may be regulated with respect to linkage as well as cellular activation.