Sesame oil downregulates the expression of ADAMTS-4 in high-fat diet-induced atherosclerosis.

Atherosclerosis is a chronic inflammatory disease forming plaques in medium and large-sized arteries. ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs-4) is an extracellular-matrix remodelling enzyme involved in the degradation of versican in the arterial wall. Recent reports indicated that increased expression of ADAMTS-4 is associated with plaque progression and vulnerability. Bioactive components of dietary oil, like sesame oil, are reported to have anti-inflammatory and antioxidant properties. Here, we studied the effect of sesame oil on regulating ADAMTS-4 in high-fat diet-induced atherosclerosis rat model. Our results indicated that sesame oil supplementation improved the anti-inflammatory and anti-oxidative status of the body. It also reduced atherosclerotic plaque formation in high-fat diet-fed rats. Our results showed that the sesame oil supplementation significantly down-regulated the expression of ADAMTS-4 in serum and aortic samples. The versican, the large proteoglycan substrate of ADAMTS-4 in the aorta, was downregulated to normal control level on sesame oil supplementation. This study, for the first time, reveals that sesame oil could down-regulate the expression of ADAMTS-4 in high-fat diet-induced atherosclerosis, imparting a new therapeutic potential for sesame oil in the management of atherosclerosis.

Chrysin downregulates the expression of ADAMTS-4 in foam cells.

BACKGROUND: Chrysin, a polyphenolic compound, possesses antioxidant and anti-inflammatory properties. In this study, we investigated the effect of chrysin on the expression of A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4), a protease enzyme involved in degrading extracellular matrix associated with atherosclerosis. METHODS AND RESULTS: We have studied the cell viability by MTT assay and foam cell formation by oil red O staining. The mRNA and protein expression of ADAMTS-4 was studied using quantitative polymerase chain reaction (qPCR) and Western blotting, respectively. Our study showed that chrysin significantly downregulates the expression of ADAMTS-4 in foam cells. CONCLUSION: Chrysin's ability to downregulate the expression of ADAMTS-4, a protease involved in degrading the extracellular matrix, bestows upon it a new therapeutic potential for managing atherosclerosis.

Effect of acute cold exposure on cardiac mitochondrial function: role of sirtuins.

Cardiac function depends mainly on mitochondrial metabolism. Cold conditions increase the risk of cardiovascular diseases by increasing blood pressure. Adaptive thermogenesis leads to increased mitochondrial biogenesis and function in skeletal muscles and adipocytes. Here, we studied the effect of acute cold exposure on cardiac mitochondrial function and its regulation by sirtuins. Significant increase in mitochondrial DNA copy number as measured by the ratio between mitochondrial-coded COX-II and nuclear-coded cyclophilin A gene expression by qRT-PCR and increase in the expression of PGC-1α, a mitochondriogenic factor and its downstream target NRF-1 were observed on cold exposure. This was associated with an increase in the activity of SIRT-1, which is known to activate PGC-1α. Mitochondrial SIRT-3 was also upregulated. Increase in sirtuin activity was reflected in total protein acetylome, which decreased in cold-exposed cardiac tissue. An increase in mitochondrial MnSOD further indicated enhanced mitochondrial function. Further evidence for this was obtained from ex vivo studies of cardiac tissue treated with norepinephrine, which caused a significant increase in mitochondrial MnSOD and SIRT-3. SIRT-3 appears to mediate the regulation of MnSOD, as treatment with AGK-7, a SIRT-3 inhibitor reversed the norepinephrine-induced upregulation of MnSOD. It, therefore, appears that SIRT-3 activation in response to SIRT-1-PGC-1α activation contributes to the regulation of cardiac mitochondrial activity during acute cold exposure.

Anti-angiogenic effect of chebulagic acid involves inhibition of the VEGFR2- and GSK-3ß-dependent signaling pathways.

Inhibition of angiogenesis is a useful strategy to prevent cancer growth by targeting new vessels that grow to nourish actively proliferating tumor cells. Endothelial cells can use a number of different pathways to cause angiogenesis, and each step in these pathways can be targeted. The use of multi-targeted drugs is gaining much importance in this scenario. Our previous results have shown that chebulagic acid (a benzopyran tannin present in the fruits of Terminalia chebula) has anti-angiogenic properties. Thus, this study was designed to examine the molecular mechanism for the anti-angiogenic effects of chebulagic acid. Results from our investigations using molecular docking studies and human umbilical vein endothelial cells in culture suggested that chebulagic acid inhibits both GSK-3ß-dependent ß-catenin phosphorylation (an important mediator of VE-cadherin-ß-catenin signaling) and VEGFR2 phosphorylation, which is an important step in VEGF signaling. Chebulagic acid inhibits angiogenesis by blocking both the VEGF-VEGFR2 complex and cell-cell contact dependent downstream signaling pathways.

Evaluating Influenza Vaccination Practices among COPD Patients.

Chronic Obstructive Pulmonary Disease (COPD) stands as a global health concern linked to considerable morbidity and mortality. In Jordan, the prevalence of COPD is substantial, but research in this area is limited. Exacerbations of COPD can lead to severe outcomes, including hospitalization and increased cardiovascular risk. Influenza is a significant trigger of exacerbations in COPD patients, and vaccination is recommended. However, studies have shown negative attitudes towards the influenza vaccine. This cross-sectional study aimed to investigate the knowledge, attitudes, practices, and intentions of COPD patients in Jordan regarding influenza vaccination. Data were collected through a custom-designed questionnaire from 300 COPD patients. The study revealed low influenza vaccination rates, with forgetfulness and lack of knowledge about vaccine effectiveness being the main barriers. Higher knowledge and positive attitudes were associated with greater intention to vaccinate. To tackle these challenges, it is recommended to implement customized health education campaigns, foster collaborations with healthcare providers, and engage in community-focused initiatives to enhance acceptance of the influenza vaccine among COPD patients in Jordan. These findings underscore the importance of addressing knowledge gaps and negative attitudes to enhance vaccine uptake and improve health outcomes for COPD patients.

EBV-positive, HHV8-negative large B-cell lymphoma with an unusual germinotropic growth pattern in an immunocompetent patient.

Clinicopathologic and cytogenetic findings of an unusual EBV+ve, HHV8-ve germinotropic lymphoma, with a nongerminal center immunophenotype occurring in an immunocompetent individual, are presented. A comprehensive literature search revealed a single report of three similar cases. These may represent a unique subset of EBV-positive large B-cell lymphomas in immunocompetent individuals.

Anti-inflammatory effect of curcumin involves downregulation of MMP-9 in blood mononuclear cells.

Curcumin (1, 7-bis (4-hydroxyl-3-methoxyphenyl)-1, 6 heptadiene-3, 5-dione) is a potent natural anti oxidant and anti-inflammatory agent, which mediates its effects mainly by inhibiting the activity of enzymes like cyclooxygenase, lipooxygenases and phospholipase A2. Here we examined the possibility of curcumin affecting the production of matrix metalloproteinases (MMPs) by peripheral blood mononuclear cells (PBMCs), which play an important role in inflammation. Zymographic analysis and ELISA showed that curcumin significantly inhibited the activity and level of MMPs produced by PBMCs isolated from human and inflammation-induced rabbit in a concentration dependent manner. The administration of curcumin to inflammation-induced rabbits also caused downregulation of MMP-9. Kinetic analysis showed that the effect of curcumin was a delayed one indicating inhibition of de novo protein synthesis. RT-PCR and immunoblot analysis showed inhibition of the production of MMP-9 mRNA and protein respectively by human PBMCs, which were activated in vitro by Artocarpus Lakoocha agglutinin (ALA) lectin. EMSA and super shift showed activation of classical NFkappaB in in vitro activated PBMCs and treatment with curcumin inhibited activation of NFkappaB. Immunoblot analysis suggested that ALA-induced activation of NFkappaB leading to the upregulation of MMP-9 was due to the degradation of IkappaB-alpha. Curcumin inhibited the degradation of IkappaB-alpha, which inhibited the ALA mediated activation of NFkappaB and upregulation of MMP-9. These results indicated that anti-inflammatory effect of curcumin also involves inhibition of the production of MMP-9 in PBMCs.

Anthropometric and body composition analysis of infertile women with polycystic ovary syndrome.

OBJECTIVES: To evaluate the body composition and anthropometric profile of infertile women who have been diagnosed with polycystic ovary syndrome (PCOS) and to investigate the incidence of PCOS and to examine body fat composition as a risk factor for this disease. METHODS: This hospital-based case controlled study was conducted on a cohort of 132 patients with and without PCOS. Bioelectrical impedance analysis was used to record body composition parameters, such as total body fat, visceral fat, subcutaneous fat, skeletal muscle composition and their distribution in the trunk, legs and arms, as well as blood pressure. Anthropometric profile parameters, including body mass index (BMI), ideal body weight (IBW), waist circumference, hip circumference and waist-to-hip ratio, were also recorded. RESULTS: The mean age of incidence of PCOS was 29.74 ± 3.32 years (OR 1.417), and most of the cohort exhibited high to very high visceral fat with significant correlation (p < 0.001). Total body fat distribution and whole, trunk, arm and leg subcutaneous fat were significantly higher in patients with PCOS (p < 0.001). The mean BMI, waist and hip circumference of the PCOS group were 28.2 ± 6.08, 97.44 ± 15.11 cm and 109.22 ± 17.39 cm, respectively. The results also indicated significant increases in DP and MAP (OR 1.528) in patients with PCOS compared to the control group (p < 0.001). CONCLUSION: This study exhibits higher levels of BMI, body fat distribution, waist and hip circumference, diastolic and mean blood pressure, visceral fat, and a disproportionate increase in the level of global fat and its distribution.

cAMP-mediated upregulation of gelatinases in primary cultures of isolated rat hepatocytes.

Matrix metalloproteinases (MMPs) play a major role in tissue remodelling and repair in pathophysiological conditions, such as liver fibrosis and regeneration. Regulation of the MMPs produced by liver cells is important in maintaining cell-matrix ratio in liver, which is a major target site for hormones that mediate their intracellular effects through cAMP. The possibility of cAMP affecting the activity of MMPs and their endogenous inhibitors, tissue inhibitor of MMPs (TIMPs) was studied using isolated rat hepatocytes in culture. Zymographic analysis showed that treatment with hormones like epinephrine, thyroxine and dexamethasone and Bt2 cAMP increased 92 kDa MMP-9 activity. Bt2 cAMP caused upregulation of MMP-9 in a dose-dependent manner. The effect of hormones was less on MMP-2. ELISA using specific antibodies showed increase in levels of MMP-9 and TIMP-1 protein. Kinetic analysis of production of MMPs and TIMPs showed that the response to Bt2 cAMP was a delayed one, indicating its effect on de novo protein synthesis. These results suggest the possibility of cAMP dependent regulation of MMP-9 in the hepatocytes.

Inhibition of Angiogenesis In Vitro by Chebulagic Acid: A COX-LOX Dual Inhibitor.

Angiogenesis is a crucial step in the growth of cancer and its metastasis. It is regulated by several endogenous factors which may stimulate or inhibit the new blood vessel growth. Besides these endogenous factors, several exogenous factors including some natural compounds are known to modulate angiogenesis. Angiogenesis being a potential target for drugs against a number of pathological conditions, search for compounds from natural sources that can affect angiogenesis is of great interest. The objective of our present study was to understand the effect of chebulagic acid, a COX-LOX dual inhibitor isolated from the fruits of Terminalia chebula Retz., on angiogenesis. The model systems used were rat aortic rings and human umbilical vein endothelial cells. The results showed that chebulagic acid exerts an antiangiogenic effect. This was evidenced from decreased sprouting in rat aortic rings and decrease in biochemical markers in endothelial cells treated with chebulagic acid. It downregulated the production of CD31, E-selectin, and vascular endothelial growth factor in human umbilical vein endothelial cells in culture (HUVEC). Further studies to understand the molecular mechanism of action of chebulagic acid revealed that CA exerts its anti angiogenic effect by modulating VE cadherin-ß catenin signalling in human umbilical vein endothelial cells.

Activation dependent expression of MMPs in peripheral blood mononuclear cells involves protein kinase A.

Monocyte/Macrophages are integral cellular components of inflammation. Matrix metalloproteinases (MMPs) produced by these cells play a crucial role in every aspect of inflammation. Results of the investigations on activation dependent upregulation of MMPs in human peripheral blood mononuclear cells in culture using different lectins as an in vitro model system to mimic inflammatory monocytes are presented. Under normal physiological conditions the monocytes produced only very low amount of MMPs in an indomethacin insensitive PG/cAMP independent manner. Zymographic analysis and ELISA showed that treatment of monocyte with lectins like concanavalin A (ConA), wheat germ agglutinin (WGA) and Artocarpus lakoocha agglutinin (ALA) caused upregulation of MMPs and the maximum effect was produced by ALA. ALA significantly upregulated MMP-9 in a concentration and time dependent manner. Immunoblot analysis and RT-PCR confirmed ALA mediated upregulation of MMP-9 production. Inhibition of ALA effect by indomethacin and reversal of the indomethacin effect by Bt(2)cAMP indicated involvement of cAMP dependent signaling pathway. Further support for the prostaglandin mediated effect was obtained by the upregulation of cyclooxygenase by ALA. H-89, an inhibitor of protein kinase A (PKA), inhibited the expression of MMP-9 indicating that ALA mediated upregulation of MMP-9 is mediated through PKA pathway. Increase in MMP production and increase in cyclooxygenase activity and inhibition of the effect of ALA on MMP production by indomethacin suggested that the ALA activated monocytes in culture can be used as an in vitro model system to study the intracellular signaling process involved in the mediation of inflammatory response.

Current surgical therapy for bronchiectasis.

The ideal classification system for bronchiectasis continues to be debated. As an alternative to the present morphologic classification, a hemodynamic-based functional classification is proposed. This study examines the rationale for and outcome of surgery based on this classification in patients with unilateral or bilateral bronchiectasis. Between July 1987 and January 1997 the morphologic and hemodynamic features in 85 bronchiectatic patients were examined: 18 with bilateral bronchiectasis and 67 with unilateral disease. A policy of unilateral lung resection of the nonperfused bronchiectasis and preservation of the perfused type was adopted in all patients. The mean age at operation was 29.4 +/- 9.7 years (range 6-55 years) with a mean follow-up period of 45.2 +/- 21.0 months (range 2-120 months). Left-sided predominance of bronchiectasis was evident in this series both in frequency and severity. In those with unilateral disease, bronchiectasis was left-sided in 49 (73.1%) patients and right-sided in 18 (26.9%). The left lung was totally bronchiectatic in 11 (16.4%) patients and the right in 3 (4.4%). Moreover, among the patients with bilateral bronchiectasis, 14 of 18 (77.7%) patients had the left lung more severely involved. Based on the morphologic and hemodynamic features in the investigated patients, two types of bronchiectasis were recognized: a perfused type with intact pulmonary artery flow and a nonperfused type with absent pulmonary artery flow. Lobectomy was performed in 55 patients, basal segmentectomy and preservation of the apical segment in 16, and pneumonectomy in 14. There was no mortality in this series. Altogether 63 patients (74.1%) achieved excellent results, 19 (22.4%) scored good results, and 3 (3.5%) patients had not benefited from surgery at last follow-up. In the face of the general criticism of the traditional morphologic classification, the proposed classification not only predicts whether the involved lung will have a measure of respiratory function with regard to gas exchange but reflects the degree of severity of the disease process. Thus the question of which side to resect and which to preserve is defined more precisely. This classification was found to be logical, physiologically sound, and of proven benefit.