The Experts below are selected from a list of 1989 Experts worldwide ranked by ideXlab platform
Pablo V Escriba - One of the best experts on this subject based on the ideXlab platform.
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Membrane Lipid Switches: How Membrane Lipid Structure Influences Protein–Lipid Interactions
2020Co-Authors: Manuel Torres, Victoria Llado, Catalina Ana Rosselló, Paula Fernández-garcía, Pablo V EscribaAbstract:Peripheral membrane proteins are required for signal propagation upon ligand-induced receptor activation at the plasma membrane. The translocation of this amphitropic peripheral proteins from or to the plasma membrane enables signal cascade propagation into the cells. This translocation greatly depends on the membrane’s Lipid composition and, consequently, regulation of the Lipid bilayer emerges as a novel therapeutic strategy. Indeed, relevant changes in membrane Lipids can induce massive translocation of peripheral signaling proteins from or to the plasma membrane, which controls how cells behave. We called these changes “Lipid switches”, as they alter the cell’s status (e.g., proliferation, differentiation, death, etc.) in response to the modulation of membrane Lipids. This discovery enables therapeutic interventions focused on modifying the bilayer’s Lipids, an approach known as membrane-Lipid Therapy (MLT) or meliTherapy.
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The Implications for Cells of the Lipid Switches Driven by Protein-Membrane Interactions and the Development of Membrane Lipid Therapy.
International Journal of Molecular Sciences, 2020Co-Authors: Manuel Torres, Victoria Llado, Catalina Ana Rosselló, Paula Fernández-garcía, Or Kakhlon, Pablo V EscribaAbstract:The cell membrane contains a variety of receptors that interact with signaling molecules. However, agonist–receptor interactions not always activate a signaling cascade. Amphitropic membrane proteins are required for signal propagation upon ligand-induced receptor activation. These proteins localize to the plasma membrane or internal compartments; however, they are only activated by ligand-receptor complexes when both come into physical contact in membranes. These interactions enable signal propagation. Thus, signals may not propagate into the cell if peripheral proteins do not co-localize with receptors even in the presence of messengers. As the translocation of an amphitropic protein greatly depends on the membrane’s Lipid composition, regulation of the Lipid bilayer emerges as a novel therapeutic strategy. Some of the signals controlled by proteins non-permanently bound to membranes produce dramatic changes in the cell’s physiology. Indeed, changes in membrane Lipids induce translocation of dozens of peripheral signaling proteins from or to the plasma membrane, which controls how cells behave. We called these changes “Lipid switches”, as they alter the cell’s status (e.g., proliferation, differentiation, death, etc.) in response to the modulation of membrane Lipids. Indeed, this discovery enables therapeutic interventions that modify the bilayer’s Lipids, an approach known as membrane-Lipid Therapy (MLT) or meliTherapy.
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Membrane-Lipid Therapy: A historical perspective of membrane-targeted therapies - From Lipid bilayer structure to the pathophysiological regulation of cells.
Biochimica et Biophysica Acta, 2017Co-Authors: Pablo V EscribaAbstract:Abstract Our current understanding of membrane Lipid composition, structure and functions has led to the investigation of their role in cell signaling, both in healthy and pathological cells. As a consequence, therapies based on the regulation of membrane Lipid composition and structure have been recently developed. This novel field, known as Membrane Lipid Therapy, is growing and evolving rapidly, providing treatments that are now in use or that are being studied for their application to oncological disorders, Alzheimer's disease, spinal cord injury, stroke, diabetes, obesity, and neuropathic pain. This field has arisen from relevant discoveries on the behavior of membranes in recent decades, and it paves the way to adopt new approaches in modern pharmacology and nutrition. This innovative area will promote further investigation into membranes and the development of new therapies with molecules that target the cell membrane. Due to the prominent roles of membranes in the cells' physiology and the paucity of therapeutic approaches based on the regulation of the Lipids they contain, it is expected that membrane Lipid Therapy will provide new treatments for numerous pathologies. The first on-purpose rationally designed molecule in this field, minerval, is currently being tested in clinical trials and it is expected to enter the market around 2020. However, it seems feasible that during the next few decades other membrane regulators will also be marketed for the treatment of human pathologies. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escriba
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g protein membrane interactions i gαi1 myristoyl and palmitoyl modifications in protein Lipid interactions and its implications in membrane microdomain localization
Biochimica et Biophysica Acta, 2015Co-Authors: Rafael Alvarez, David J Lopez, Jesus Casas, Victoria Llado, Monica Higuera, Tunde Nagy, Miquel Barcelo, Xavier Busquets, Pablo V EscribaAbstract:G proteins are fundamental elements in signal transduction involved in key cell responses, and their interactions with cell membrane Lipids are critical events whose nature is not fully understood. Here, we have studied how the presence of myristic and palmitic acid moieties affects the interaction of the Gαi1 protein with model and biological membranes. For this purpose, we quantified the binding of purified Gαi1 protein and Gαi1 protein acylation mutants to model membranes, with Lipid compositions that resemble different membrane microdomains. We observed that myristic and palmitic acids not only act as membrane anchors but also regulate Gαi1 subunit interaction with Lipids characteristics of certain membrane microdomains. Thus, when the Gαi1 subunit contains both fatty acids it prefers raft-like lamellar membranes, with a high sphingomyelin and cholesterol content and little phosphatidylserine and phosphatidylethanolamine. By contrast, the myristoylated and non-palmitoylated Gαi1 subunit prefers other types of ordered Lipid microdomains with higher phosphatidylserine content. These results in part explain the mobility of Gαi1 protein upon reversible palmitoylation to meet one or another type of signaling protein partner. These results also serve as an example of how membrane Lipid alterations can change membrane signaling or how membrane Lipid Therapy can regulate the cell's physiology.
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Membrane Lipid Therapy: Modulation of the cell membrane composition and structure as a molecular base for drug discovery and new disease treatment
Progress in Lipid Research, 2015Co-Authors: Pablo V Escriba, Xavier Busquets, Ibolya Horváth, John L. Harwood, Jin-ichi Inokuchi, Gábor Balogh, Zsolt Török, László VíghAbstract:Nowadays we understand cell membranes not as a simple double Lipid layer but as a collection of complex and dynamic protein–Lipid structures and microdomains that serve as functional platforms for interacting signaling Lipids and proteins. Membrane Lipids and Lipid structures participate directly as messengers or regulators of signal transduction. In addition, protein–Lipid interactions participate in the localization of signaling protein partners to specific membrane microdomains. Thus, Lipid alterations change cell signaling that are associated with a variety of diseases including cancer, obesity, neurodegenerative disorders, cardiovascular pathologies, etc. This article reviews the newly emerging field of membrane Lipid Therapy which involves the pharmacological regulation of membrane Lipid composition and structure for the treatment of diseases. Membrane Lipid Therapy proposes the use of new molecules specifically designed to modify membrane Lipid structures and microdomains as pharmaceutical disease-modifying agents by reversing the malfunction or altering the expression of disease-specific protein or Lipid signal cascades. Here, we provide an in-depth analysis of this emerging field, especially its molecular bases and its relevance to the development of innovative therapeutic approaches.
Xue Qiao Zhao - One of the best experts on this subject based on the ideXlab platform.
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Mortality reduction in patients treated with long-term intensive Lipid Therapy: 25-year follow-up of the Familial Atherosclerosis Treatment Study—Observational Study
Journal of Clinical Lipidology, 2016Co-Authors: Xue Qiao Zhao, Binh An P. Phan, Joseph Davis, Daniel Isquith, Moni B. Neradilek, Alice Dowdy, Suzanne Boltz, Erik A. Monick, Andrew T. Brockenbrough, Ellen E. Hus-frechetteAbstract:Background Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk factors present and length of exposure to these risk factors including hyperLipidemia. Objectives The clinical benefit of intensive Lipid Therapy over 25 years was investigated in the Familial Atherosclerosis Treatment Study—Observational Study. Methods Of 175 coronary artery disease subjects with mean low-density lipoprotein cholesterol (LDL-C) of 191 mg/dL and mean age of 50 years, who completed the randomized and placebo-controlled Familial Atherosclerosis Treatment Study, 100 chose receiving Lipid management by their physicians (usual care [UC]) and 75 elected to receive an intensive treatment [IT] for Lipid management with lovastatin (40 mg/d), niacin (2.5 g/d), and colestipol (20 g/d) from 1989 to 2004, followed by double Therapy with simvastatin (40–80 mg/d) and niacin from 2005 to 2006 and by triple Therapy of ezetimibe 10 mg and simvastatin 40 to 80 mg/d plus niacin during 2007 to 2012. Deaths from CVD, non-CVD, and any cause were compared between UC and IT using Cox proportional hazards model. Results UC and IT groups were similar in risk factors with the exception that IT had more severe coronary artery disease. Mean LDL-C levels were 167 mg/dL from 1988 to 2004, 97 from 2005 to 2006, and 96 from 2007 to 2012 in surviving subjects receiving UC. IT lowered LDL-C to 119, 97, and 83 mg/dL in the 3 periods, respectively. Compared with UC, IT significantly reduced total mortality (11.1 vs 26.3 per 1000 person years [PY], hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.26–0.77, P = .003) and CVD mortality (10.6 vs 27.7 per 1000 PY, HR = 0.34, 95% CI: 0.15–0.80, P = .009). The non-CVD mortality was also reduced but was not of statistical significance (6.8 vs 12.7 per 1000 PY, HR = 0.55, 95% CI: 0.27–1.14, P = .11). Conclusions Long-term intensive Lipid Therapy significantly reduced total and cardiovascular mortality in Familial Atherosclerosis Treatment Study—Observational Study. These results support the importance of lifetime risk management to improve long-term outcome.
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Abstract 16722: Changes in Carotid Wall Morphology and Plaque Composition in Patients With Established Vascular Disease and Treated With Intensive Lipid Therapy in the AIM-HIGH Study
Circulation, 2014Co-Authors: Xue Qiao Zhao, Thomas S. Hatsukami, Daniel S. Hippe, Daniel Isquith, Niranjan Balu, Moni B. Neradilek, Kiyofumi Yamada, Gador Canton, John R. CrouseAbstract:Objective: Changes in carotid wall morphology (MORPH) and plaque composition (COMP) over 2 years (yrs) of intensive Lipid Therapy by plaque types were investigated in AIM-HIGH. Methods: Qualified baseline and 2-yr follow-up scans were obtained in 156 AIM-HIGH subjects. MR images were analyzed by independent Core Lab reviewers using published criteria for quantifications of MORPH and COMP. MORPH included volumes of total vessel (TVV), lumen (LV), wall (WV=TVV-LV) and fibrous tissue (FTV) in mm3 and %WV was calculated using the formula: (WV/TVV) X 100% in all available slices. COMP focused on percentages of Lipid-rich necrotic core (%LRNC), FT (%FT) and calcium (%CA) calculated using the formula: (LRNC, FT or CA V/WV) x 100% using the slices containing LRNC. Of 156, 89 were in statin+placebo for extended-release niacin (ERN) and 67 in statin+ERN groups. Changes in MORPH and COMP were compared between the 2 treatment groups and between plaque types: w/o LRNC (n=76), w/ LRNC but w/o intraplaque hemorrhage (IPH) (n=62), w/ LRNC & IPH (n=18). Results: In the 76 subjects w/o LRNC, there were significant increases in TVV (24±52 mm3/yr, p Conclusions: Intensive Lipid Therapy with statin or statin plus ERN significantly associated with positive MORPH remodeling in plaques w/o LRNC. Plaques w/ LRNC experienced COMP improvement without significant MORPH changes. However, the COMP improvement was not seen in plaques w/ IPH. These results indicate that plaques in different disease stages respond to Lipid Therapy differently.
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Abstract 16783: Risk Factors Associated With Progression of Carotid Wall Volume and Plaque Lipid Content in Patients With Established Vascular Disease and Treated With Intensive Lipid Therapy in the AIM-HIGH Study
Circulation, 2014Co-Authors: Xue Qiao Zhao, Daniel S. Hippe, Daniel Isquith, Niranjan Balu, Moni B. Neradilek, Kiyofumi Yamada, Gador Canton, Kevin D. O'brien, John R. CrouseAbstract:Objective: Previous studies showed that large wall volume (WV) and Lipid-rich necrotic core (LRNC) are associated with increased risk of cardiovascular events. We examined the association between risk factors and progression of carotid WV and plaque LRNC over 2 years (yrs) in patients with established vascular disease and undergoing Lipid Therapy in AIM-HIGH. Methods: 156 AIM-HIGH subjects had qualified baseline and 2-yr follow-up scans. MR images were analyzed by Core Lab reviewers, blinded to Therapy, lab results and clinical course using published criteria for quantifications of WV and LRNC and detection of calcium (CA) and intraplaque hemorrhage (IPH). %WV was calculated using the formula: WV/total vessel volume) X 100% for all available slices. %LRNC was calculated using the formula: (LRNC volume/WV) X 100% for slices containing LRNC. Of 156, 89 were on statin+placebo for extended-release niacin (ERN) and 67 received statin+ERN. Multivariate linear regression analysis was performed to identify factor...
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Prolonged combination Lipid Therapy is associated with reduced carotid intima-media thickness: A case-control study of the 20-year Familial Atherosclerosis Treatment - Observational Study (FATS-OS)
Journal of Clinical Lipidology, 2014Co-Authors: Binh An P. Phan, Andrew B. Moore, Joseph Davis, Laura J. Pollan, Blazej Neradilek, B. Greg Brown, Xue Qiao ZhaoAbstract:Background Studies have documented the short-term vascular benefits of combination Lipid Therapy. Objective Our objective was to evaluate the long-term effects of combination Lipid Therapy on carotid intima-media thickness (CIMT) in patients with coronary artery disease. Methods We performed a case-control study in patients who had finished the Familial Atherosclerosis Treatment Study (FATS) and returned to usual care with statin Therapy alone or had elected to participate in the 20-year FATS-Observational Study (FATS-OS) and received combination Therapy with lovastatin (40 mg/day), niacin (2–3 g/day), and colestipol (20 gm/day) for 11 years, then continued with simvastatin (10–80 mg/day) or lovastatin (40–80 mg/day) plus niacin (2–4 g/day). After 17.8 ± 0.8 years with combination Therapy and 19.0 ± 0.8 years with usual care, cholesterol levels and CIMT were collected in 43 FATS-OS patients and 26 usual care patients. Results Combination Therapy group had a greater decrease in total cholesterol (−42 ± 14% vs −31 ± 17%, P = .008) and low-density lipoprotein cholesterol (LDL-C) (−57 ± 13% vs −38 ± 25%, P P = .02) as compared with usual care. CIMT (0.902 ± 0.164 vs 1.056 ± 0.169 mm, P P = .003) and on-Therapy LDL-C (0.15; 0.02 to 0.28, P = .03) were significant independent predictors of CIMT. Conclusions Prolonged combination Lipid Therapy is associated with greater improvements in LDL-C and HDL-C levels and less atherosclerotic burden as compared with statin Therapy alone.
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Utilizing imaging tools in Lipidology: examining the potential of MRI for monitoring cholesterol Therapy
Clinical Lipidology, 2012Co-Authors: Xue Qiao Zhao, William S. KerwinAbstract:Lipid abnormalities play important roles in the development of atherosclerosis. Lipid therapies result in alterations in atherosclerotic plaques including halting of progression of the plaque, Lipid transport out of the plaque and reducing inflammatory activity, which lead to plaque morphologies that are less prone to disruption, the main cause of clinical events. In order to investigate and monitor plaque morphological changes during Lipid Therapy in vivo we need an imaging method that can provide accurate assessment of plaque tissue components and activity. MRI of atherosclerosis has been validated as a reliable assessment of the size of the vessel lumen, but also the size of the plaque, its tissue composition and plaque activity, including inflammation. The purpose of this review is to summarize the state of evidence for the direct assessment of atherosclerotic plaque and its change by MRI, and to establish the proven role of MRI of atherosclerosis in pharmaceutical trials with Lipid Therapy.
David J Lopez - One of the best experts on this subject based on the ideXlab platform.
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g protein membrane interactions i gαi1 myristoyl and palmitoyl modifications in protein Lipid interactions and its implications in membrane microdomain localization
Biochimica et Biophysica Acta, 2015Co-Authors: Rafael Alvarez, David J Lopez, Jesus Casas, Victoria Llado, Monica Higuera, Tunde Nagy, Miquel Barcelo, Xavier Busquets, Pablo V EscribaAbstract:G proteins are fundamental elements in signal transduction involved in key cell responses, and their interactions with cell membrane Lipids are critical events whose nature is not fully understood. Here, we have studied how the presence of myristic and palmitic acid moieties affects the interaction of the Gαi1 protein with model and biological membranes. For this purpose, we quantified the binding of purified Gαi1 protein and Gαi1 protein acylation mutants to model membranes, with Lipid compositions that resemble different membrane microdomains. We observed that myristic and palmitic acids not only act as membrane anchors but also regulate Gαi1 subunit interaction with Lipids characteristics of certain membrane microdomains. Thus, when the Gαi1 subunit contains both fatty acids it prefers raft-like lamellar membranes, with a high sphingomyelin and cholesterol content and little phosphatidylserine and phosphatidylethanolamine. By contrast, the myristoylated and non-palmitoylated Gαi1 subunit prefers other types of ordered Lipid microdomains with higher phosphatidylserine content. These results in part explain the mobility of Gαi1 protein upon reversible palmitoylation to meet one or another type of signaling protein partner. These results also serve as an example of how membrane Lipid alterations can change membrane signaling or how membrane Lipid Therapy can regulate the cell's physiology.
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the effect of natural and synthetic fatty acids on membrane structure microdomain organization cellular functions and human health
Biochimica et Biophysica Acta, 2014Co-Authors: Maitane Ibarguren, David J Lopez, Pablo V EscribaAbstract:Abstract This review deals with the effects of synthetic and natural fatty acids on the biophysical properties of membranes, and on their implication on cell function. Natural fatty acids are constituents of more complex Lipids, like triacylglycerides or phosphoLipids, which are used by cells to store and obtain energy, as well as for structural purposes. Accordingly, natural and synthetic fatty acids may modify the structure of the Lipid membrane, altering its microdomain organization and other physical properties, and provoking changes in cell signaling. Therefore, by modulating fatty acids it is possible to regulate the structure of the membrane, influencing the cell processes that are reliant on this structure and potentially reverting pathological cell dysfunctions that may provoke cancer, diabetes, hypertension, Alzheimer's and Parkinson's disease. The so-called Membrane Lipid Therapy offers a strategy to regulate the membrane composition through drug administration, potentially reverting pathological processes by re-adapting cell membrane structure. Certain fatty acids and their synthetic derivatives are described here that may potentially be used in such therapies, where the cell membrane itself can be considered as a target to combat disease. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.
Moni B. Neradilek - One of the best experts on this subject based on the ideXlab platform.
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Mortality reduction in patients treated with long-term intensive Lipid Therapy: 25-year follow-up of the Familial Atherosclerosis Treatment Study—Observational Study
Journal of Clinical Lipidology, 2016Co-Authors: Xue Qiao Zhao, Binh An P. Phan, Joseph Davis, Daniel Isquith, Moni B. Neradilek, Alice Dowdy, Suzanne Boltz, Erik A. Monick, Andrew T. Brockenbrough, Ellen E. Hus-frechetteAbstract:Background Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk factors present and length of exposure to these risk factors including hyperLipidemia. Objectives The clinical benefit of intensive Lipid Therapy over 25 years was investigated in the Familial Atherosclerosis Treatment Study—Observational Study. Methods Of 175 coronary artery disease subjects with mean low-density lipoprotein cholesterol (LDL-C) of 191 mg/dL and mean age of 50 years, who completed the randomized and placebo-controlled Familial Atherosclerosis Treatment Study, 100 chose receiving Lipid management by their physicians (usual care [UC]) and 75 elected to receive an intensive treatment [IT] for Lipid management with lovastatin (40 mg/d), niacin (2.5 g/d), and colestipol (20 g/d) from 1989 to 2004, followed by double Therapy with simvastatin (40–80 mg/d) and niacin from 2005 to 2006 and by triple Therapy of ezetimibe 10 mg and simvastatin 40 to 80 mg/d plus niacin during 2007 to 2012. Deaths from CVD, non-CVD, and any cause were compared between UC and IT using Cox proportional hazards model. Results UC and IT groups were similar in risk factors with the exception that IT had more severe coronary artery disease. Mean LDL-C levels were 167 mg/dL from 1988 to 2004, 97 from 2005 to 2006, and 96 from 2007 to 2012 in surviving subjects receiving UC. IT lowered LDL-C to 119, 97, and 83 mg/dL in the 3 periods, respectively. Compared with UC, IT significantly reduced total mortality (11.1 vs 26.3 per 1000 person years [PY], hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.26–0.77, P = .003) and CVD mortality (10.6 vs 27.7 per 1000 PY, HR = 0.34, 95% CI: 0.15–0.80, P = .009). The non-CVD mortality was also reduced but was not of statistical significance (6.8 vs 12.7 per 1000 PY, HR = 0.55, 95% CI: 0.27–1.14, P = .11). Conclusions Long-term intensive Lipid Therapy significantly reduced total and cardiovascular mortality in Familial Atherosclerosis Treatment Study—Observational Study. These results support the importance of lifetime risk management to improve long-term outcome.
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Abstract 16722: Changes in Carotid Wall Morphology and Plaque Composition in Patients With Established Vascular Disease and Treated With Intensive Lipid Therapy in the AIM-HIGH Study
Circulation, 2014Co-Authors: Xue Qiao Zhao, Thomas S. Hatsukami, Daniel S. Hippe, Daniel Isquith, Niranjan Balu, Moni B. Neradilek, Kiyofumi Yamada, Gador Canton, John R. CrouseAbstract:Objective: Changes in carotid wall morphology (MORPH) and plaque composition (COMP) over 2 years (yrs) of intensive Lipid Therapy by plaque types were investigated in AIM-HIGH. Methods: Qualified baseline and 2-yr follow-up scans were obtained in 156 AIM-HIGH subjects. MR images were analyzed by independent Core Lab reviewers using published criteria for quantifications of MORPH and COMP. MORPH included volumes of total vessel (TVV), lumen (LV), wall (WV=TVV-LV) and fibrous tissue (FTV) in mm3 and %WV was calculated using the formula: (WV/TVV) X 100% in all available slices. COMP focused on percentages of Lipid-rich necrotic core (%LRNC), FT (%FT) and calcium (%CA) calculated using the formula: (LRNC, FT or CA V/WV) x 100% using the slices containing LRNC. Of 156, 89 were in statin+placebo for extended-release niacin (ERN) and 67 in statin+ERN groups. Changes in MORPH and COMP were compared between the 2 treatment groups and between plaque types: w/o LRNC (n=76), w/ LRNC but w/o intraplaque hemorrhage (IPH) (n=62), w/ LRNC & IPH (n=18). Results: In the 76 subjects w/o LRNC, there were significant increases in TVV (24±52 mm3/yr, p Conclusions: Intensive Lipid Therapy with statin or statin plus ERN significantly associated with positive MORPH remodeling in plaques w/o LRNC. Plaques w/ LRNC experienced COMP improvement without significant MORPH changes. However, the COMP improvement was not seen in plaques w/ IPH. These results indicate that plaques in different disease stages respond to Lipid Therapy differently.
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Abstract 16783: Risk Factors Associated With Progression of Carotid Wall Volume and Plaque Lipid Content in Patients With Established Vascular Disease and Treated With Intensive Lipid Therapy in the AIM-HIGH Study
Circulation, 2014Co-Authors: Xue Qiao Zhao, Daniel S. Hippe, Daniel Isquith, Niranjan Balu, Moni B. Neradilek, Kiyofumi Yamada, Gador Canton, Kevin D. O'brien, John R. CrouseAbstract:Objective: Previous studies showed that large wall volume (WV) and Lipid-rich necrotic core (LRNC) are associated with increased risk of cardiovascular events. We examined the association between risk factors and progression of carotid WV and plaque LRNC over 2 years (yrs) in patients with established vascular disease and undergoing Lipid Therapy in AIM-HIGH. Methods: 156 AIM-HIGH subjects had qualified baseline and 2-yr follow-up scans. MR images were analyzed by Core Lab reviewers, blinded to Therapy, lab results and clinical course using published criteria for quantifications of WV and LRNC and detection of calcium (CA) and intraplaque hemorrhage (IPH). %WV was calculated using the formula: WV/total vessel volume) X 100% for all available slices. %LRNC was calculated using the formula: (LRNC volume/WV) X 100% for slices containing LRNC. Of 156, 89 were on statin+placebo for extended-release niacin (ERN) and 67 received statin+ERN. Multivariate linear regression analysis was performed to identify factor...
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mr imaging of carotid plaque composition during Lipid lowering Therapy a prospective assessment of effect and time course
Jacc-cardiovascular Imaging, 2011Co-Authors: Xue Qiao Zhao, Binh An P. Phan, Moni B. Neradilek, Li Dong, T S Hatsukami, Andrew Moore, Trevor Lane, Nayak L Polissar, Duane Monick, Hunter R UnderhillAbstract:Objectives The purpose of this study was to test the Lipid depletion hypothesis and to establish the time course of change in carotid plaque morphology and composition during Lipid Therapy using high-resolution magnetic resonance imaging (MRI). Background Lipid Therapy is thought to improve plaque stability and reduce cardiovascular events by targeting the plaque rupture risk features such as large Lipid core, thin fibrous cap, and high level of inflammatory infiltrates. However, the plaque stabilizing process during Lipid Therapy has not been clearly demonstrated in humans and in vivo. Methods Subjects with coronary or carotid artery disease, apolipoprotein B ≥120 mg/dl, and Lipid treatment history Results After 3 years of Lipid Therapy, the 33 subjects with measurable Lipid-rich necrotic core (LRNC) at baseline had a significant reduction in plaque Lipid content: LRNC volume decreased from 60.4 ± 59.5 mm3 to 37.4 ± 69.5 mm3 (p Conclusions Intensive Lipid Therapy significantly depletes carotid plaque Lipid. Statistically significant plaque Lipid depletion is observed after 1 year of treatment and continues in the second year, and precedes plaque regression. (Using Magnetic Resonance Imaging to Evaluate Carotid Artery Plaque Composition in People Receiving Cholesterol-Lowering Medications [The CPC Study]; NCT00715273 ).
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carotid artery atherosclerosis effect of intensive Lipid Therapy on the vasa vasorum evaluation by using dynamic contrast enhanced mr imaging
Radiology, 2011Co-Authors: Li Dong, Thomas S. Hatsukami, Moni B. Neradilek, Hunter R Underhill, Williams S Kerwin, Huijun Chen, Chun Yuan, Xue Qiao ZhaoAbstract:Dynamic contrast-enhanced MR imaging may be a useful imaging method and Ktrans may prove to be an imaging marker for the assessment of the therapeutic response of the vasa vasorum in patients with atherosclerotic plaque.
Victoria Llado - One of the best experts on this subject based on the ideXlab platform.
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Membrane Lipid Switches: How Membrane Lipid Structure Influences Protein–Lipid Interactions
2020Co-Authors: Manuel Torres, Victoria Llado, Catalina Ana Rosselló, Paula Fernández-garcía, Pablo V EscribaAbstract:Peripheral membrane proteins are required for signal propagation upon ligand-induced receptor activation at the plasma membrane. The translocation of this amphitropic peripheral proteins from or to the plasma membrane enables signal cascade propagation into the cells. This translocation greatly depends on the membrane’s Lipid composition and, consequently, regulation of the Lipid bilayer emerges as a novel therapeutic strategy. Indeed, relevant changes in membrane Lipids can induce massive translocation of peripheral signaling proteins from or to the plasma membrane, which controls how cells behave. We called these changes “Lipid switches”, as they alter the cell’s status (e.g., proliferation, differentiation, death, etc.) in response to the modulation of membrane Lipids. This discovery enables therapeutic interventions focused on modifying the bilayer’s Lipids, an approach known as membrane-Lipid Therapy (MLT) or meliTherapy.
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The Implications for Cells of the Lipid Switches Driven by Protein-Membrane Interactions and the Development of Membrane Lipid Therapy.
International Journal of Molecular Sciences, 2020Co-Authors: Manuel Torres, Victoria Llado, Catalina Ana Rosselló, Paula Fernández-garcía, Or Kakhlon, Pablo V EscribaAbstract:The cell membrane contains a variety of receptors that interact with signaling molecules. However, agonist–receptor interactions not always activate a signaling cascade. Amphitropic membrane proteins are required for signal propagation upon ligand-induced receptor activation. These proteins localize to the plasma membrane or internal compartments; however, they are only activated by ligand-receptor complexes when both come into physical contact in membranes. These interactions enable signal propagation. Thus, signals may not propagate into the cell if peripheral proteins do not co-localize with receptors even in the presence of messengers. As the translocation of an amphitropic protein greatly depends on the membrane’s Lipid composition, regulation of the Lipid bilayer emerges as a novel therapeutic strategy. Some of the signals controlled by proteins non-permanently bound to membranes produce dramatic changes in the cell’s physiology. Indeed, changes in membrane Lipids induce translocation of dozens of peripheral signaling proteins from or to the plasma membrane, which controls how cells behave. We called these changes “Lipid switches”, as they alter the cell’s status (e.g., proliferation, differentiation, death, etc.) in response to the modulation of membrane Lipids. Indeed, this discovery enables therapeutic interventions that modify the bilayer’s Lipids, an approach known as membrane-Lipid Therapy (MLT) or meliTherapy.
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g protein membrane interactions i gαi1 myristoyl and palmitoyl modifications in protein Lipid interactions and its implications in membrane microdomain localization
Biochimica et Biophysica Acta, 2015Co-Authors: Rafael Alvarez, David J Lopez, Jesus Casas, Victoria Llado, Monica Higuera, Tunde Nagy, Miquel Barcelo, Xavier Busquets, Pablo V EscribaAbstract:G proteins are fundamental elements in signal transduction involved in key cell responses, and their interactions with cell membrane Lipids are critical events whose nature is not fully understood. Here, we have studied how the presence of myristic and palmitic acid moieties affects the interaction of the Gαi1 protein with model and biological membranes. For this purpose, we quantified the binding of purified Gαi1 protein and Gαi1 protein acylation mutants to model membranes, with Lipid compositions that resemble different membrane microdomains. We observed that myristic and palmitic acids not only act as membrane anchors but also regulate Gαi1 subunit interaction with Lipids characteristics of certain membrane microdomains. Thus, when the Gαi1 subunit contains both fatty acids it prefers raft-like lamellar membranes, with a high sphingomyelin and cholesterol content and little phosphatidylserine and phosphatidylethanolamine. By contrast, the myristoylated and non-palmitoylated Gαi1 subunit prefers other types of ordered Lipid microdomains with higher phosphatidylserine content. These results in part explain the mobility of Gαi1 protein upon reversible palmitoylation to meet one or another type of signaling protein partner. These results also serve as an example of how membrane Lipid alterations can change membrane signaling or how membrane Lipid Therapy can regulate the cell's physiology.