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15 pages, 4433 KiB

Open AccessArticle

Hyperlipidemia Increases Nalbuphine Brain Accumulation with Multiple Dosing without Affecting Its Analgesic Response—Its Respiratory Depression Potential Should Be Investigated in Future Studies

by Marwa E. Elsherbiny, May Almukainzi, Eman Amer and Marwan Emara

Pharmaceuticals 2024, 17(3), 282; https://doi.org/10.3390/ph17030282 - 22 Feb 2024

Viewed by 2009

Abstract

Nalbuphine is associated with a significant risk of respiratory depression. Its central nervous system entry is hindered by P-glycoproteins, and lower P-glycoprotein activity is a risk factor for respiratory depression. We assessed the effect of hyperlipidemia on nalbuphine pharmacokinetics, brain and liver uptake, and analgesic response following single (2.5 mg/kg) and multiple (2.5 mg/kg/day for three days) doses in normolipidemic and hyperlipidemic rats. Trends of reduction and increase in nalbuphine C_max and Vd_ss/F were observed, respectively, in hyperlipidemic rats. Negative correlations were observed between C_max and serum lipoproteins. Serum-normalized brain and liver levels at 1 h post-dose were lower in hyperlipidemic rats, with brain and liver levels being negatively and positively correlated with TG and HDL, respectively. At steady state, marked nalbuphine accumulation was observed in hyperlipidemic rat brains (R = 1.6) compared with normolipidemic rats (R = 1.1). Nalbuphine analgesic response was not altered by hyperlipidemia at steady state. Caution should be exercised since greater brain accumulation in hyperlipidemic patients treated with nalbuphine could increase their risk of respiratory depression. Our study highlights an unexpected role of lipoproteins in drug absorption and tissue uptake. We also propose a model for reduced nalbuphine absorption based on interaction with intestinal HDL-3. Full article

(This article belongs to the Section Pharmacology)

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14 pages, 1252 KiB

Open AccessArticle

Elevated Circulating Endocan Levels Are Associated with Increased Levels of Endothelial and Inflammation Factors in Postprandial Lipemia

by Serap Ozer Yaman, Fulya Balaban Yucesan, Cihan Orem, Birgul Vanizor Kural and Asım Orem

J. Clin. Med. 2023, 12(4), 1267; https://doi.org/10.3390/jcm12041267 - 6 Feb 2023

Cited by 2 | Viewed by 2358

Abstract

Background: Postprandial lipemia (PPL) causes endothelial dysfunction by causing endothelial damage to lipoproteins that remain rich in triglycerides. Endocan is a proteoglycan with increased tissue expression, endothelial activation, and neovascularization. The aim of the study was to examine circulating endocan levels in PPL subjects by considering the degree of PPL response according to a high-fat test meal. The other aim was to determine the association between endocan levels and endothelial and inflammatory factors. Method: Fifty-four hyperlipidemic subjects and 28 normolipidemic subjects consumed the high-fat meal. Endocan, sICAM-1, sVCAM-1, and VEGFA as endothelial factors and IL-6 and LFA-1α as inflammatory factors were evaluated. Results: Fasting serum endocan, VEGFA, sICAM-1, sVCAM-1 IL-6, and LFA-1α levels were increased in the PPL group compared to the control group. The PPL group was divided into tertiles based on mean AUC levels. Endocan levels in tertile 3 were at the highest and were increased significantly compared to tertiles 1 and 2. AUC and endocan levels were positively correlated with other endothelial and inflammation factors. ROC analysis showed endocan levels to be one of the highest values. Conclusions: Circulating endocan is seen at significantly higher levels and independently associated with endothelial and inflammatory factors in postprandial lipemia and dyslipidemia. Full article

(This article belongs to the Section Cardiovascular Medicine)

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13 pages, 7833 KiB

Open AccessCommunication

Mechanism Underlying Naringenin Hypocholesterolemic Effects: Involvement of Estrogen Receptor α Subtype

by Valentina Pallottini, Marco Segatto, Filippo Acconcia, Marco Fiocchetti and Maria Marino

Int. J. Mol. Sci. 2022, 23(24), 15809; https://doi.org/10.3390/ijms232415809 - 13 Dec 2022

Cited by 3 | Viewed by 1828

Abstract

Naringenin (Nar) is one of major citrus flavonoids predominantly found in grapefruit and orange. In vivo studies have demonstrated Nar potential as a normolipidemic agent capable to reduce circulating cholesterol in hypercholesterolemic rabbits, rats, and patients, suggesting a new role for this molecule in cardiovascular disease prevention. Although Nar cholesterol-lowering effects are known, the underlying mechanisms have not yet been elucidated. Interestingly, Nar binds to the estrogen receptors (ERs), modulating both transcriptional and membrane-initiating signals. Although estrogen and ERs are deeply involved in lipid metabolism, no data are available regarding a putative role of these nuclear receptors as mediators of the hypocholesterolemic effect exerted by Nar. Thus, the aim of this work was to study the involvement of ERs in Nar-induced modulation of cholesterol metabolism. Results obtained in HepG2 cell line demonstrate that Nar can modulate the molecular network of cholesterol homeostasis. However, these effects were only partially dependent on the activity of estrogen receptor α. As a whole, our data highlight new molecular mechanisms by which Nar influences cholesterol metabolism, opening a new scenery about dietary impact on human health. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

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15 pages, 1273 KiB

Open AccessReview

Autoimmune Rheumatic Diseases: An Update on the Role of Atherogenic Electronegative LDL and Potential Therapeutic Strategies

by Der-Yuan Chen, Tatsuya Sawamura, Richard A. F. Dixon, José Luis Sánchez-Quesada and Chu-Huang Chen

J. Clin. Med. 2021, 10(9), 1992; https://doi.org/10.3390/jcm10091992 - 6 May 2021

Cited by 8 | Viewed by 3197

Abstract

Atherosclerosis has been linked with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Autoimmune rheumatic diseases (AIRDs) are associated with accelerated atherosclerosis and ASCVD. However, the mechanisms underlying the high ASCVD burden in patients with AIRDs cannot be explained only by conventional risk factors despite disease-specific factors and chronic inflammation. Nevertheless, the normal levels of plasma low-density lipoprotein (LDL) cholesterol observed in most patients with AIRDs do not exclude the possibility of increased LDL atherogenicity. By using anion-exchange chromatography, human LDL can be divided into five increasingly electronegative subfractions, L1 to L5, or into electropositive and electronegative counterparts, LDL (+) and LDL (−). Electronegative L5 and LDL (−) have similar chemical compositions and can induce adverse inflammatory reactions in vascular cells. Notably, the percentage of L5 or LDL (−) in total LDL is increased in normolipidemic patients with AIRDs. Electronegative L5 and LDL (−) are not recognized by the normal LDL receptor but instead signal through the lectin-like oxidized LDL receptor 1 (LOX-1) to activate inflammasomes involving interleukin 1β (IL-1β). Here, we describe the detailed mechanisms of AIRD-related ASCVD mediated by L5 or LDL (−) and discuss the potential targeting of LOX-1 or IL-1β signaling as new therapeutic modalities for these diseases. Full article

(This article belongs to the Special Issue Lipids, Lipoproteins, and Atherothrombotic Disease: Clinical Pharmacology Now and in the Future)

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22 pages, 4730 KiB

Open AccessArticle

Antidiabetic, Lipid Normalizing, and Nephroprotective Actions of the Strawberry: A Potent Supplementary Fruit

by Pallavi Mandave, Suresh Khadke, Manjiri Karandikar, Vijaya Pandit, Prabhakar Ranjekar, Aniket Kuvalekar and Nitin Mantri

Int. J. Mol. Sci. 2017, 18(1), 124; https://doi.org/10.3390/ijms18010124 - 11 Jan 2017

Cited by 27 | Viewed by 6879

Abstract

The study was designed to assess the effect of different strawberry extracts on glucose levels, lipid profiles, and oxidative stress in nicotinamide-streptozotocin (NIC-STZ) induced diabetic rats. The associated changes were evaluated through biochemical, molecular, and histological assays. Diabetes was induced by intraperitoneal injection of STZ to albino Wistar rats after treatment with nicotinamide. Aqueous, hydroalcoholic, and alcoholic strawberry extracts were administrated orally to diabetic rats. Treatment of strawberry extracts improved lipid profile, liver function, and serum creatinine and led to a significant increase in antioxidant status in diabetic rats. Real-time PCR expression analysis of genes from the liver of animals treated with strawberry extracts exhibited downregulation of several fatty acid synthesis genes, transcription factors, such as Sterol regulatory Element Binding Transcription factor (SREBP) and Nuclear Factor-κβ (NF-κβ), and inflammatory markers, like Interleukin 6 (IL6) and Tumor Necrosis Factor-α (TNF-α). Strawberry extracts also upregulated liver Peroxisome Proliferator Activated Receptor-γ (PPAR-γ). Histological examination confirmed the nephroprotective and β-cell regeneration/protection effects of strawberry extracts. The present study demonstrates several beneficial effects of strawberry extracts along with its probable mechanism of action. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals and Functional Food Ingredients in Fruits and Vegetables 2016)

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