Therapeutic Potential Of Ocimum Tenuiflorum As Mpo Inhibitor With Implications For Atherosclerosis Prevention

Current experimental studies show that Ocimum tenuiflorum (commonly known as basil or Tulsi) possesses many health benefits. Ocimum is suggested to be antioxidative and anti-inflammatory. Eugenol, an orthomethoxyphenol, and ursolic acid have been identified as important components of basil. Myeloperoxidase (MPO), an oxidative enzyme, has been implicated in the pathogenesis of atherosclerosis. MPO-dependent oxidation of lipoproteins has been implicated in foam cell formation, dysfunctional HDL, and abnormalities in reverse cholesterol transport. Whole leaf extract of O. tenuiflorum and its major components, eugenol and ursolic acid, inhibit the oxidation of lipoproteins by myeloperoxidase/copper as measured by conjugated diene formation as well as by the thiobarbituric acid reactive substance (TBARS) assay. Whole basil leaf extract is able to attenuate the lipopolysaccharide-induced inflammation in RAW 264.7 cells compared with its components. In addition, whole basil leaf extract and eugenol inhibited MPO enzyme activity against synthetic substrates. Based on these results, we conclude that basil extract could act as an inhibitor of MPO and may serve as a nonpharmacological therapeutic agent for atherosclerosis

BMP-7 Attenuates Sarcopenia and Adverse Muscle Remodeling in Diabetic Mice via Alleviation of Lipids, Inflammation, HMGB1, and Pyroptosis

Diabetic myopathy involves hyperglycemia, oxidative stress, and inflammation. However, the role of hypercholesterolemia-induced inflammation-mediated pathological mechanisms leading to fibrosis, sarcopenia, deterioration of muscle, and muscle dysfunction in diabetes is not well understood. In this study, we investigated the novel role of bone morphogenetic protein-7 (BMP-7) in ameliorating metabolic alterations, inflammation, pyroptosis, TGF-β/SMAD cell signaling mechanisms, and progression of diabetic myopathy. C57BL/6J mice were treated with saline, streptozotocin (STZ), or STZ+BMP-7. Diabetes was confirmed by increased fasting glucose levels and a glucose tolerance test. Gastrocnemius muscle and blood samples were collected for lipid and tissue analysis using various methods. A significant increase in hyperglycemia resulted in an increase in lipid accumulation, monocyte infiltration, and inflammation, as well as an increase in pyroptotic markers and signaling markers in diabetic muscle myocytes. A structural analysis showed significant muscle loss, and increased muscle deterioration and fibrosis leading to muscle dysfunction. BMP-7 attenuated pathological processes that resulted in significantly improved muscle function. We report, for the first time, that increased hyperlipidemia aggravates inflammation-induced pyroptosis, resulting in significant muscle loss, sarcopenia, and adverse skeletal muscle remodeling in diabetic muscle myopathy. Interventional treatment with BMP-7 attenuates hypercholesterolemia-induced inflammation-mediated sarcopenia and adverse muscle remodeling, suggesting BMP-7 could be a potential treatment option for diabetic muscle myopathy

BMP-7 Attenuates Sarcopenia and Adverse Muscle Remodeling in Diabetic Mice via Alleviation of Lipids, Inflammation, HMGB1, and Pyroptosis

Diabetic myopathy involves hyperglycemia, oxidative stress, and inflammation. However, the role of hypercholesterolemia-induced inflammation-mediated pathological mechanisms leading to fibrosis, sarcopenia, deterioration of muscle, and muscle dysfunction in diabetes is not well understood. In this study, we investigated the novel role of bone morphogenetic protein-7 (BMP-7) in ameliorating metabolic alterations, inflammation, pyroptosis, TGF-β/SMAD cell signaling mechanisms, and progression of diabetic myopathy. C57BL/6J mice were treated with saline, streptozotocin (STZ), or STZ+BMP-7. Diabetes was confirmed by increased fasting glucose levels and a glucose tolerance test. Gastrocnemius muscle and blood samples were collected for lipid and tissue analysis using various methods. A significant increase in hyperglycemia resulted in an increase in lipid accumulation, monocyte infiltration, and inflammation, as well as an increase in pyroptotic markers and signaling markers in diabetic muscle myocytes. A structural analysis showed significant muscle loss, and increased muscle deterioration and fibrosis leading to muscle dysfunction. BMP-7 attenuated pathological processes that resulted in significantly improved muscle function. We report, for the first time, that increased hyperlipidemia aggravates inflammation-induced pyroptosis, resulting in significant muscle loss, sarcopenia, and adverse skeletal muscle remodeling in diabetic muscle myopathy. Interventional treatment with BMP-7 attenuates hypercholesterolemia-induced inflammation-mediated sarcopenia and adverse muscle remodeling, suggesting BMP-7 could be a potential treatment option for diabetic muscle myopathy

Adrenergic Hormones Induce Extrapituitary Prolactin Gene Expression In Leukocytes-Potential Implications In Obesity

The pituitary hormone prolactin (PRL), originally described for its role in lactation, has been implemented in over 300 functions and is produced by multiple cell types outside of the pituitary. Monocyte/macrophages in particular show robust expression of extra-pituitary prolactin (ePRL). While ePRL protein is identical to pituitary PRL and translated from the same gene, tissues outside the pituitary engage an alternative promoter to regulate expression. Many of the factors regulating this expression, however, remain unknown. Here we show that the adrenergic hormones epinephrine and norepinephrine induce PRL expression in the human monocytic cell line THP-1 at physiological concentrations. Furthermore, our experiments show the polarization state of differentiated macrophages can influence their response in vitro, with inflammatory M 1 macrophages - common in obese adipose - showing the highest levels of PRL expression compared to other macrophage types. Adrenergic hormones have a clearly defined role in adipocyte lipid metabolism, stimulating lipolysis through hormone sensitive lipase (HSL) induction. Meanwhile, PRL has been shown to stimulate lipogenesis. This highlights ePRL production as a possible factor in obesity. The overall balance of these two signals could play a critical role in determining overall lipid turnover/accumulation in adipose depots where large numbers of adipose tissue macrophages (ATMs) reside

Doxorubicin Induced Apoptosis Enhances Monocyte Infiltration and Adverse Cardiac Remodeling in Diabetic Animals

Diabetic cancer patients treated with Doxorubicin (DOX), a potent chemotherapeutic drug induces cardiac toxicity. However, molecular mechanisms of cardiac toxicity in this specific disease progression in patients and animal models are completely unknown. Therefore, we designed a study to understand the effects of doxorubicin induced cardiac toxicity in diabetic animals and involved pathophysiological mechanisms. C57BL/6J mice were divided into DOX and diabetic (STZ) treated four groups; control, STZ, DOX and DOX+STZ. At Day 14, animals were sacrificed, echocardiography was used to examine heart function, heart and blood samples were collected to investigate apoptotic mechanisms (Caspase 3, BAX, Bcl2), inflammation and cardiac remodeling. Our data shows a significant (pThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Novel technique for generating macrophage foam cells for in vitro reverse cholesterol transport studies

Generation of foam cells, an essential step for reverse cholesterol transport studies, uses the technique of receptor-dependent macrophage loading with radiolabeled acetylated LDL. In this study, we used the ability of a biologically relevant detergent molecule, lysophosphatidylcholine (lyso-PtdCho), to form mixed micelles with cholesterol or cholesteryl ester (CE) to generate macrophage foam cells. Fluorescent or radiolabeled cholesterol/lyso-PtdCho mixed micelles were prepared and incubated with RAW 264.7 or mouse peritoneal macrophages. Results showed that such micelles were quite stable at 4 degrees C and retained the solubilized cholesterol during one month of storage. Macrophages incubated with cholesterol or CE (unlabeled, fluorescently labeled, or radiolabeled)/lyso-PtdCho mixed micelles accumulated CE as documented by microscopy, lipid staining, labeled oleate incorporation, and by TLC. Such foam cells unloaded cholesterol when incubated with HDL but not with oxidized HDL. We propose that stable cholesterol or CE/lyso-PtdCho micelles would offer advantages over existing methods

Identification And Evaluation Of Anti-Inflammatory Properties Of Aqueous Components Extracted From Sesame (Sesamum Indicum) Oil

We previously reported that sesame oil (SO) has anti-inflammatory, anti-atherosclerotic and lipid lowering properties in vivo. Our recent studies have shown that, an aqueous extract of sesame oil (SOAE) has also anti-inflammatory and anti-atherosclerotic properties but with no lipid lowering effects. The extent of reduction in atherosclerosis led us to identify components of SOAE and evaluate their anti-inflammatory properties in vitro. Liquid chromatography mass spectrometric method was used to detect and identify components of SOAE. Methoxyphenol derivatives, short and long chain carboxylic acids, dicarboxylic acids, hydroxy and oxo- carboxylic acids were detected. To our surprise, sesamol and its derivatives (lignans), were not present in the SOAE. Among the identified, a combination of methoxy phenol compounds were selected and tested their ability to reduce LPS induced inflammatory gene expression. Monocyte derived macrophages/RAW 264.7 macrophages were pre-treated with these compounds for 2 h, followed by LPS stimulation for 24 h and pro-inflammatory gene expressions were analyzed. These methoxyphenol derivatives showed potent anti-inflammatory properties. In conclusion, the anti-inflammatory molecules associated with SO may contribute the anti-inflammatory and anti-atherosclerotic properties. Also, our results shed light for the development of SOAE based non-pharmacological therapeutics, nutritional supplements and health products for various inflammatory diseases in the future

Sesame Oil And An Aqueous Extract Derived From Sesame Oil Enhance Regression Of Preexisting Atherosclerotic Lesions In Low-Density Lipoprotein Receptor Knockout Mice

Diet and exercise are recommended both as a prophylactic and as a therapeutic approach for patients with established coronary artery disease. We previously reported that sesame oil (SESO) and its aqueous extract (SOAE) showed antiatherosclerotic and anti-inflammatory properties. We also observed that genes involved in reverse cholesterol transport (RCT) might be activated. In this study, we tested whether post-treatment with SESO or SOAE would reduce preexisting atherosclerosis by enhancing RCT. Female low-density lipoprotein receptor knockout (LDL-R-/-) mice were fed an atherogenic diet for 3 months, followed by post-treatment with either control or SESO or SOAE for 1 month. Plasma lipids and atherosclerotic lesions were quantified at the end of the study. RNA was extracted from the aortic tissues and used for real-time polymerase chain reaction analysis. SESO and SOAE post-treatment significantly reduced atherosclerotic lesions in LDL-R-/- mice compared to controls. No significant change in plasma cholesterol, triglyceride, or LDL cholesterol levels was observed. Aortic gene analysis showed that the SESO/SOAE post-treatment reduced inflammatory gene expression and induced genes involved in cholesterol metabolism and RCT. This is the first study that demonstrates that post-treatment with SESO and SOAE could be an effective treatment for preexisting atherosclerosis and inflammation. The study also may suggest that reducing inflammation might be conducive to an accelerated regression of lesions

Adrenergic hormones induce extrapituitary prolactin gene expression in leukocytes-potential implications in obesity

Abstract The pituitary hormone prolactin (PRL), originally described for its role in lactation, has been implemented in over 300 functions and is produced by multiple cell types outside of the pituitary. Monocyte/macrophages in particular show robust expression of extra-pituitary prolactin (ePRL). While ePRL protein is identical to pituitary PRL and translated from the same gene, tissues outside the pituitary engage an alternative promoter to regulate expression. Many of the factors regulating this expression, however, remain unknown. Here we show that the adrenergic hormones epinephrine and norepinephrine induce PRL expression in the human monocytic cell line THP-1 at physiological concentrations. Furthermore, our experiments show the polarization state of differentiated macrophages can influence their response in vitro, with inflammatory M1 macrophages—common in obese adipose—showing the highest levels of PRL expression compared to other macrophage types. Adrenergic hormones have a clearly defined role in adipocyte lipid metabolism, stimulating lipolysis through hormone sensitive lipase (HSL) induction. Meanwhile, PRL has been shown to stimulate lipogenesis. This highlights ePRL production as a possible factor in obesity. The overall balance of these two signals could play a critical role in determining overall lipid turnover/accumulation in adipose depots where large numbers of adipose tissue macrophages (ATMs) reside

Inflammatory Cells in Atherosclerosis

Atherosclerosis is a chronic progressive disease that involves damage to the intima, inflammatory cell recruitment and the accumulation of lipids followed by calcification and plaque rupture. Inflammation is considered a key mediator of many events during the development and progression of the disease. Various types of inflammatory cells are reported to be involved in atherosclerosis. In the present paper, we discuss the involved inflammatory cells, their characteristic and functional significance in the development and progression of atherosclerosis. The detailed understanding of the role of all these cells in disease progression at different stages sheds more light on the subject and provides valuable insights as to where and when therapy should be targeted