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High plasma level of low-density lipoprotein (LDL) is the main driver of the initiation and progression of cardiovascular disease (CVD). Nevertheless, high-density lipoprotein (HDL) is considered an anti-atherogenic lipoprotein due to its role in reverse cholesterol transport and its ability to receive cholesterol that effluxes from macrophages in the artery wall. The scavenger receptor B class type 1 (SR-B1) was identified as the high-affinity HDL receptor, which facilitates the selective uptake of cholesterol ester (CE) into the liver via HDL and is also implicated in the plasma clearance of LDL, very low-density lipoprotein (VLDL) and lipoprotein(a) (Lp(a)). Thus, SR-B1 is a multifunctional receptor that plays a main role in the metabolism of different lipoproteins. The aim of this review is to highlight the association between SR-B1 and CVD risk through mice and human genetic studies.
Gracia-Rubio Irene; Martín César; Civeira Fernando; Cenarro Ana. SR-B1, a Key Receptor Involved in the Progression of Cardiovascular Disease: A Perspective from Mice and Human Genetic Studies. Biomedicines 2021, 9, 612 .
AMA StyleGracia-Rubio Irene, Martín César, Civeira Fernando, Cenarro Ana. SR-B1, a Key Receptor Involved in the Progression of Cardiovascular Disease: A Perspective from Mice and Human Genetic Studies. Biomedicines. 2021; 9 (6):612.
Chicago/Turabian StyleGracia-Rubio Irene; Martín César; Civeira Fernando; Cenarro Ana. 2021. "SR-B1, a Key Receptor Involved in the Progression of Cardiovascular Disease: A Perspective from Mice and Human Genetic Studies." Biomedicines 9, no. 6: 612.
Background: Mesenchymal stem cells (MSCs) are stem cells present in adult tissues. They can be cultured, have great growth capacity, and can differentiate into several cell types. The isolation of urine-derived mesenchymal stem cells (hUSCs) was recently described. hUSCs present additional benefits in the fact that they can be easily obtained noninvasively. Regarding gene delivery, nonviral vectors based on cationic niosomes have been used and are more stable and have lower immunogenicity than viral vectors. However, their transfection efficiency is low and in need of improvement. Methods: We isolated hUSCs from urine, and the cell culture was tested and characterized. Different cationic niosomes were elaborated using reverse-phase evaporation, and they were physicochemically characterized. Then, they were screened into hUSCs for transfection efficiency, and their internalization was evaluated. Results: GPxT-CQ at a lipid/DNA ratio of 5:1 (w/w) had the best transfection efficiency. Intracellular localization studies confirmed that nioplexes entered mainly via caveolae-mediated endocytosis. Conclusions: In conclusion, we established a protocol for hUSC isolation and their transfection with cationic niosomes, which could have relevant clinical applications such as in gene therapy. This methodology could also be used for creating cellular models for studying and validating pathogenic genetic variants, and even for performing functional studies. Our study increases knowledge about the internalization of tested cationic niosomes in these previously unexplored cells.
Yerai Vado; Gustavo Puras; Melania Rosique; Cesar Martin; Jose Pedraz; Shifa Jebari-Benslaiman; Marian de Pancorbo; Jon Zarate; Guiomar Perez de Nanclares. Design and Validation of a Process Based on Cationic Niosomes for Gene Delivery into Novel Urine-Derived Mesenchymal Stem Cells. Pharmaceutics 2021, 13, 696 .
AMA StyleYerai Vado, Gustavo Puras, Melania Rosique, Cesar Martin, Jose Pedraz, Shifa Jebari-Benslaiman, Marian de Pancorbo, Jon Zarate, Guiomar Perez de Nanclares. Design and Validation of a Process Based on Cationic Niosomes for Gene Delivery into Novel Urine-Derived Mesenchymal Stem Cells. Pharmaceutics. 2021; 13 (5):696.
Chicago/Turabian StyleYerai Vado; Gustavo Puras; Melania Rosique; Cesar Martin; Jose Pedraz; Shifa Jebari-Benslaiman; Marian de Pancorbo; Jon Zarate; Guiomar Perez de Nanclares. 2021. "Design and Validation of a Process Based on Cationic Niosomes for Gene Delivery into Novel Urine-Derived Mesenchymal Stem Cells." Pharmaceutics 13, no. 5: 696.
(r)HDL therapeutics has progressed a long way but has yet to produce fruitful results. Based on what has been learned and on the most innovative perspectives, a new generation of “smart” rHDL is emerging as an alternative for the management of CVD.
Kepa B. Uribe; Asier Benito-Vicente; Cesar Martin; Francisco Blanco-Vaca; Noemi Rotllan. (r)HDL in theranostics: how do we apply HDL's biology for precision medicine in atherosclerosis management? Biomaterials Science 2021, 9, 3185 -3208.
AMA StyleKepa B. Uribe, Asier Benito-Vicente, Cesar Martin, Francisco Blanco-Vaca, Noemi Rotllan. (r)HDL in theranostics: how do we apply HDL's biology for precision medicine in atherosclerosis management? Biomaterials Science. 2021; 9 (9):3185-3208.
Chicago/Turabian StyleKepa B. Uribe; Asier Benito-Vicente; Cesar Martin; Francisco Blanco-Vaca; Noemi Rotllan. 2021. "(r)HDL in theranostics: how do we apply HDL's biology for precision medicine in atherosclerosis management?" Biomaterials Science 9, no. 9: 3185-3208.
Type 2 diabetes (T2D), a heterogeneous disorder derived from metabolic dysfunctions, leads to a glucose overflow in the circulation due to both defective insulin secretion and peripheral insulin resistance. One of the critical risk factor for T2D is obesity, which represents a global epidemic that has nearly tripled since 1975. Obesity is characterized by chronically elevated free fatty acid (FFA) levels, which cause deleterious effects on glucose homeostasis referred to as lipotoxicity. Here, we review the physiological FFA roles onto glucose-stimulated insulin secretion (GSIS) and the pathological ones affecting many steps of the mechanisms and modulation of GSIS. We also describe in vitro and in vivo experimental evidences addressing lipotoxicity in β-cells and the role of saturation and chain length of FFA on the potency of GSIS stimulation. The molecular mechanisms underpinning lipotoxic-β-cell dysfunction are also reviewed. Among them, endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, inflammation, impaired autophagy and β-cell dedifferentiation. Finally therapeutic strategies for the β-cells dysfunctions such as the use of metformin, glucagon-like peptide 1, thiazolidinediones, anti-inflammatory drugs, chemical chaperones and weight are discussed.
Asier Benito-Vicente; Shifa Jebari-Benslaiman; Unai Galicia-Garcia; Asier Larrea-Sebal; Kepa B. Uribe; Cesar Martin. Molecular mechanisms of lipotoxicity-induced pancreatic β-cell dysfunction. International Review of Cell and Molecular Biology 2021, 359, 357 -402.
AMA StyleAsier Benito-Vicente, Shifa Jebari-Benslaiman, Unai Galicia-Garcia, Asier Larrea-Sebal, Kepa B. Uribe, Cesar Martin. Molecular mechanisms of lipotoxicity-induced pancreatic β-cell dysfunction. International Review of Cell and Molecular Biology. 2021; 359 ():357-402.
Chicago/Turabian StyleAsier Benito-Vicente; Shifa Jebari-Benslaiman; Unai Galicia-Garcia; Asier Larrea-Sebal; Kepa B. Uribe; Cesar Martin. 2021. "Molecular mechanisms of lipotoxicity-induced pancreatic β-cell dysfunction." International Review of Cell and Molecular Biology 359, no. : 357-402.
The developing of antibacterial resistance is becoming in crisis. In this sense, natural products play a fundamental role in the discovery of antibacterial agents with diverse mechanisms of action. Phytochemical investigation of Cissus incisa leaves led to isolation and characterization of the ceramides mixture (1): (8E)-2-(tritriacont-9-enoyl amino)-1,3,4-octadecanetriol-8-ene (1-I); (8E)-2-(2',3'-dihydroxyoctacosanoyl amino)-1,3,4-octadecanetriol-8-ene (1-II); (8E)-2-(2'-hydroxyheptacosanoyl amino)-1,3,4-octadecanetriol-8-ene (1-III); and (8E)-2-(-2'-hydroxynonacosanoyl amino)-1,3,4-octadecanetriol-8-ene (1-IV). Until now, this is the first report of the ceramides (1-I), (1-II), and (1-IV). The structures were elucidated using NMR and mass spectrometry analyses. Antibacterial activity of ceramides (1) and acetylated derivates (2) was evaluated against nine multidrug-resistant bacteria by Microdilution method. (1) showed the best results against Gram-negatives, mainly against carbapenems-resistant Acinetobacter baumannii with MIC = 50 μg/mL. Structure-activity analysis and molecular docking revealed interactions between plant ceramides with membrane proteins, and enzymes associated with biological membranes of Gram-negative bacteria, through hydrogen bonding of functional groups. Vesicular contents release assay showed the capacity of (1) to disturb membrane permeability detected by an increase of fluorescence probe over time. The membrane disruption is not caused for ceramides lytic action on cell membranes, according in vitro hemolytic activity results. Combining SAR analysis, bioinformatics and biophysical techniques, and also experimental tests, it was possible to explain the antibacterial action of these natural ceramides.
Deyani Nocedo-Mena; Sonia Arrasate; Elvira Garza-González; Verónica M. Rivas-Galindo; Antonio Romo-Mancillas; Cristian R. Munteanu; Nuria Sotomayor; Esther Lete; Iratxe Barbolla; César A. Martín; María Del Rayo Camacho-Corona. Molecular docking, SAR analysis and biophysical approaches in the study of the antibacterial activity of ceramides isolated from Cissus incisa. Bioorganic Chemistry 2021, 109, 104745 .
AMA StyleDeyani Nocedo-Mena, Sonia Arrasate, Elvira Garza-González, Verónica M. Rivas-Galindo, Antonio Romo-Mancillas, Cristian R. Munteanu, Nuria Sotomayor, Esther Lete, Iratxe Barbolla, César A. Martín, María Del Rayo Camacho-Corona. Molecular docking, SAR analysis and biophysical approaches in the study of the antibacterial activity of ceramides isolated from Cissus incisa. Bioorganic Chemistry. 2021; 109 ():104745.
Chicago/Turabian StyleDeyani Nocedo-Mena; Sonia Arrasate; Elvira Garza-González; Verónica M. Rivas-Galindo; Antonio Romo-Mancillas; Cristian R. Munteanu; Nuria Sotomayor; Esther Lete; Iratxe Barbolla; César A. Martín; María Del Rayo Camacho-Corona. 2021. "Molecular docking, SAR analysis and biophysical approaches in the study of the antibacterial activity of ceramides isolated from Cissus incisa." Bioorganic Chemistry 109, no. : 104745.
Objective: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor ( LDLR ) mutations account for >90% of cases, apolipoprotein B ( APOB ) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 ( PCSK9 ) gain of function mutations are rare (<1% of cases). We aimed to evaluate the functional impact of several novel PCSK9 variants in a cohort of patients with FH by genetic cascade screening and in vitro functionality assays. Approach and Results: Patients with clinically diagnosed FH underwent genetic analysis of LDLR , and if negative, sequential testing of APOB and PCSK9 . We analyzed cosegregation of hypercholesterolemia with novel PCSK9 variants. Gain of function status was determined by in silico analyses and validated by in vitro functionality assays. Among 1055 persons with clinical FH, we identified nonsynonymous PCSK9 variants in 27 (2.6%) patients and 7 of these carried one of the 4 previously reported gain of function variants. In the remaining 20 patients with FH, we identified 7 novel PCSK9 variants. The G516V variant (c.1547G>T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; P <0.001). In vitro studies demonstrated the pathogenicity of the G516V variant. Conclusions: In our study, 1.14% of cases with clinical FH were clearly attributable to pathogenic variants in PCSK9 . Pathogenicity is established beyond doubt for the G516V variant.
Roeland Huijgen; Dirk J. Blom; Merel L. Hartgers; Kévin Chemello; Asier Benito-Vicente; Kepa B. Uribe; Zorena Behardien; Dee M. Blackhurst; Brigitte C. Brice; Joep C. Defesche; Annemiek G. de Jong; Rosemary J. Jooste; Gabriele A.E. Solomon; Karen H. Wolmarans; G. Kees Hovingh; Cesar Martin; Gilles Lambert; A. David Marais. Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town. Arteriosclerosis, Thrombosis, and Vascular Biology 2021, 41, 934 -943.
AMA StyleRoeland Huijgen, Dirk J. Blom, Merel L. Hartgers, Kévin Chemello, Asier Benito-Vicente, Kepa B. Uribe, Zorena Behardien, Dee M. Blackhurst, Brigitte C. Brice, Joep C. Defesche, Annemiek G. de Jong, Rosemary J. Jooste, Gabriele A.E. Solomon, Karen H. Wolmarans, G. Kees Hovingh, Cesar Martin, Gilles Lambert, A. David Marais. Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town. Arteriosclerosis, Thrombosis, and Vascular Biology. 2021; 41 (2):934-943.
Chicago/Turabian StyleRoeland Huijgen; Dirk J. Blom; Merel L. Hartgers; Kévin Chemello; Asier Benito-Vicente; Kepa B. Uribe; Zorena Behardien; Dee M. Blackhurst; Brigitte C. Brice; Joep C. Defesche; Annemiek G. de Jong; Rosemary J. Jooste; Gabriele A.E. Solomon; Karen H. Wolmarans; G. Kees Hovingh; Cesar Martin; Gilles Lambert; A. David Marais. 2021. "Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town." Arteriosclerosis, Thrombosis, and Vascular Biology 41, no. 2: 934-943.
Carotid atherosclerotic plaque rupture can lead to cerebrovascular accident (CVA). By comparing RNA-Seq data from vascular smooth muscle cells (VSMC) extracted from carotid atheroma surgically excised from a group of asymptomatic and symptomatic subjects, we identified more than 700 genomic variants associated with symptomatology (p < 0.05). From these, twelve single nucleotide polymorphisms (SNPs) were selected for further validation. Comparing genotypes of a hospital-based cohort of asymptomatic with symptomatic patients, an exonic SNP in the BIRC6 (BRUCE/Apollon) gene, rs35286811, emerged as significantly associated with CVA symptomatology (p = 0.002; OR = 2.24). Moreover, BIRC6 mRNA levels were significantly higher in symptomatic than asymptomatic subjects upon measurement by qPCR in excised carotid atherosclerotic tissue (p < 0.0001), and significantly higher in carriers of the rs35286811 risk allele (p < 0.0001). rs35286811 is a proxy of a GWAS SNP reported to be associated with red cell distribution width (RDW); RDW was increased in symptomatic patients (p < 0.03), but was not influenced by the rs35286811 genotype in our cohort. BIRC6 is a negative regulator of both apoptosis and autophagy. This work introduces BIRC6 as a novel genetic risk factor for stroke, and identifies autophagy as a genetically regulated mechanism of carotid plaque vulnerability.
Iraide Alloza; Andrea Salegi; Jorge Mena; Raquel Tulloch Navarro; César Martin; Patricia Aspichueta; Lucía Martínez Salazar; Jon Uriarte Carpio; Patricia De-La-Hera Cagigal; Reyes Vega; Juan Carlos Triviño; Maria Del Mar Freijo; Koen Vandenbroeck. BIRC6 Is Associated with Vulnerability of Carotid Atherosclerotic Plaque. International Journal of Molecular Sciences 2020, 21, 9387 .
AMA StyleIraide Alloza, Andrea Salegi, Jorge Mena, Raquel Tulloch Navarro, César Martin, Patricia Aspichueta, Lucía Martínez Salazar, Jon Uriarte Carpio, Patricia De-La-Hera Cagigal, Reyes Vega, Juan Carlos Triviño, Maria Del Mar Freijo, Koen Vandenbroeck. BIRC6 Is Associated with Vulnerability of Carotid Atherosclerotic Plaque. International Journal of Molecular Sciences. 2020; 21 (24):9387.
Chicago/Turabian StyleIraide Alloza; Andrea Salegi; Jorge Mena; Raquel Tulloch Navarro; César Martin; Patricia Aspichueta; Lucía Martínez Salazar; Jon Uriarte Carpio; Patricia De-La-Hera Cagigal; Reyes Vega; Juan Carlos Triviño; Maria Del Mar Freijo; Koen Vandenbroeck. 2020. "BIRC6 Is Associated with Vulnerability of Carotid Atherosclerotic Plaque." International Journal of Molecular Sciences 21, no. 24: 9387.
Insulin resistance (IR) is one of the key contributing factors in the development of type 2 diabetes mellitus (T2DM). However, the molecular mechanisms leading to IR are still unclear. The implication of microRNAs (miRNAs) in the pathophysiology of multiple cardiometabolic pathologies, including obesity, atherosclerotic heart failure and IR, has emerged as a major focus of interest in recent years. Indeed, upregulation of several miRNAs has been associated with obesity and IR. Among them, miR-27b is overexpressed in the liver in patients with obesity, but its role in IR has not yet been thoroughly explored. In this study, we investigated the role of miR-27b in regulating insulin signaling in hepatocytes, both in vitro and in vivo. Therefore, assessment of the impact of miR-27b on insulin resistance through the hepatic tissue is of special importance due to the high expression of miR-27b in the liver together with its known role in regulating lipid metabolism. Notably, we found that miR-27b controls post-transcriptional expression of numerous components of the insulin signaling pathway including the insulin receptor (INSR) and insulin receptor substrate 1 (IRS1) in human hepatoma cells. These results were further confirmed in vivo showing that overexpression and inhibition of hepatic miR-27 enhances and suppresses hepatic INSR expression and insulin sensitivity, respectively. This study identified a novel role for miR-27 in regulating insulin signaling, and this finding suggests that elevated miR-27 levels may contribute to early development of hepatic insulin resistance.
Asier Benito-Vicente; Kepa B. Uribe; Noemi Rotllan; Cristina M. Ramírez; Shifa Jebari-Benslaiman; Leigh Goedeke; Alberto Canfrán-Duque; Unai Galicia-García; Diego Saenz De Urturi; Patricia Aspichueta; Yajaira Suárez; Carlos Fernández-Hernando; Cesar Martín. miR-27b Modulates Insulin Signaling in Hepatocytes by Regulating Insulin Receptor Expression. International Journal of Molecular Sciences 2020, 21, 8675 .
AMA StyleAsier Benito-Vicente, Kepa B. Uribe, Noemi Rotllan, Cristina M. Ramírez, Shifa Jebari-Benslaiman, Leigh Goedeke, Alberto Canfrán-Duque, Unai Galicia-García, Diego Saenz De Urturi, Patricia Aspichueta, Yajaira Suárez, Carlos Fernández-Hernando, Cesar Martín. miR-27b Modulates Insulin Signaling in Hepatocytes by Regulating Insulin Receptor Expression. International Journal of Molecular Sciences. 2020; 21 (22):8675.
Chicago/Turabian StyleAsier Benito-Vicente; Kepa B. Uribe; Noemi Rotllan; Cristina M. Ramírez; Shifa Jebari-Benslaiman; Leigh Goedeke; Alberto Canfrán-Duque; Unai Galicia-García; Diego Saenz De Urturi; Patricia Aspichueta; Yajaira Suárez; Carlos Fernández-Hernando; Cesar Martín. 2020. "miR-27b Modulates Insulin Signaling in Hepatocytes by Regulating Insulin Receptor Expression." International Journal of Molecular Sciences 21, no. 22: 8675.
Cardiovascular disease (CVD), the leading cause of mortality worldwide is primarily caused by atherosclerosis, which is promoted by the accumulation of low-density lipoproteins into the intima of large arteries. Multiple nanoparticles mimicking natural HDL (rHDL) have been designed to remove cholesterol excess in CVD therapy. The goal of this investigation was to assess the cholesterol efflux efficiency of rHDLs with different lipid compositions, mimicking different maturation stages of high-density lipoproteins (HDLs) occurring in vivo. Methods: the cholesterol efflux activity of soybean PC (Soy-PC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), DPPC:Chol:1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (LysoPC) and DPPC:18:2 cholesteryl ester (CE):LysoPC rHDLs was determined in several cell models to investigate the contribution of lipid composition to the effectiveness of cholesterol removal. Results: DPPC rHDLs are the most efficient particles, inducing cholesterol efflux in all cellular models and in all conditions the effect was potentiated when the ABCA1 transporter was upregulated. Conclusions: DPPC rHDLs, which resemble nascent HDL, are the most effective particles in inducing cholesterol efflux due to the higher physical binding affinity of cholesterol to the saturated long-chain-length phospholipids and the favored cholesterol transfer from a highly positively curved bilayer, to an accepting planar bilayer such as DPPC rHDLs. The physicochemical characteristics of rHDLs should be taken into consideration to design more efficient nanoparticles to promote cholesterol efflux.
Shifa Jebari-Benslaiman; Kepa B. Uribe; Asier Benito-Vicente; Unai Galicia-Garcia; Asier Larrea-Sebal; Iraide Alloza; Koen Vandenbroeck; Helena Ostolaza; César Martín. Cholesterol Efflux Efficiency of Reconstituted HDL Is Affected by Nanoparticle Lipid Composition. Biomedicines 2020, 8, 373 .
AMA StyleShifa Jebari-Benslaiman, Kepa B. Uribe, Asier Benito-Vicente, Unai Galicia-Garcia, Asier Larrea-Sebal, Iraide Alloza, Koen Vandenbroeck, Helena Ostolaza, César Martín. Cholesterol Efflux Efficiency of Reconstituted HDL Is Affected by Nanoparticle Lipid Composition. Biomedicines. 2020; 8 (10):373.
Chicago/Turabian StyleShifa Jebari-Benslaiman; Kepa B. Uribe; Asier Benito-Vicente; Unai Galicia-Garcia; Asier Larrea-Sebal; Iraide Alloza; Koen Vandenbroeck; Helena Ostolaza; César Martín. 2020. "Cholesterol Efflux Efficiency of Reconstituted HDL Is Affected by Nanoparticle Lipid Composition." Biomedicines 8, no. 10: 373.
Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. Because insulin release and activity are essential processes for glucose homeostasis, the molecular mechanisms involved in the synthesis and release of insulin, as well as in its detection are tightly regulated. Defects in any of the mechanisms involved in these processes can lead to a metabolic imbalance responsible for the development of the disease. This review analyzes the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism leading to T2DM and insulin resistance. For that purpose, we summarize the data gathered up until now, focusing especially on insulin synthesis, insulin release, insulin sensing and on the downstream effects on individual insulin-sensitive organs. The review also covers the pathological conditions perpetuating T2DM such as nutritional factors, physical activity, gut dysbiosis and metabolic memory. Additionally, because T2DM is associated with accelerated atherosclerosis development, we review here some of the molecular mechanisms that link T2DM and insulin resistance (IR) as well as cardiovascular risk as one of the most important complications in T2DM.
Unai Galicia-Garcia; Asier Benito-Vicente; Shifa Jebari; Asier Larrea-Sebal; Haziq Siddiqi; Kepa B. Uribe; Helena Ostolaza; César Martín. Pathophysiology of Type 2 Diabetes Mellitus. International Journal of Molecular Sciences 2020, 21, 6275 .
AMA StyleUnai Galicia-Garcia, Asier Benito-Vicente, Shifa Jebari, Asier Larrea-Sebal, Haziq Siddiqi, Kepa B. Uribe, Helena Ostolaza, César Martín. Pathophysiology of Type 2 Diabetes Mellitus. International Journal of Molecular Sciences. 2020; 21 (17):6275.
Chicago/Turabian StyleUnai Galicia-Garcia; Asier Benito-Vicente; Shifa Jebari; Asier Larrea-Sebal; Haziq Siddiqi; Kepa B. Uribe; Helena Ostolaza; César Martín. 2020. "Pathophysiology of Type 2 Diabetes Mellitus." International Journal of Molecular Sciences 21, no. 17: 6275.
Peptide hormones and neuropeptides encompass a large class of bioactive peptides that regulate physiological processes like anxiety, blood glucose, appetite, inflammation and blood pressure. Here, we execute a focused discovery strategy to provide an extensive map of O-glycans on peptide hormones. We find that almost one third of the 279 classified peptide hormones carry O-glycans. Many of the identified O-glycosites are conserved and are predicted to serve roles in proprotein processing, receptor interaction, biodistribution and biostability. We demonstrate that O-glycans positioned within the receptor binding motifs of members of the neuropeptide Y and glucagon families modulate receptor activation properties and substantially extend peptide half-lives. Our study highlights the importance of O-glycosylation in the biology of peptide hormones, and our map of O-glycosites in this large class of biomolecules serves as a discovery platform for an important class of molecules with potential opportunities for drug designs.
Thomas D. Madsen; Lasse H. Hansen; John Hintze; Zilu Ye; Shifa Jebari; Daniel Andersen; Hiren J. Joshi; Tongzhong Ju; Jens Peter Goetze; Cesar Martin; Mette M. Rosenkilde; Jens J. Holst; Rune E. Kuhre; Christoffer K. Goth; Sergey Y. Vakhrushev; Katrine T. Schjoldager. An atlas of O-linked glycosylation on peptide hormones reveals diverse biological roles. Nature Communications 2020, 11, 1 -13.
AMA StyleThomas D. Madsen, Lasse H. Hansen, John Hintze, Zilu Ye, Shifa Jebari, Daniel Andersen, Hiren J. Joshi, Tongzhong Ju, Jens Peter Goetze, Cesar Martin, Mette M. Rosenkilde, Jens J. Holst, Rune E. Kuhre, Christoffer K. Goth, Sergey Y. Vakhrushev, Katrine T. Schjoldager. An atlas of O-linked glycosylation on peptide hormones reveals diverse biological roles. Nature Communications. 2020; 11 (1):1-13.
Chicago/Turabian StyleThomas D. Madsen; Lasse H. Hansen; John Hintze; Zilu Ye; Shifa Jebari; Daniel Andersen; Hiren J. Joshi; Tongzhong Ju; Jens Peter Goetze; Cesar Martin; Mette M. Rosenkilde; Jens J. Holst; Rune E. Kuhre; Christoffer K. Goth; Sergey Y. Vakhrushev; Katrine T. Schjoldager. 2020. "An atlas of O-linked glycosylation on peptide hormones reveals diverse biological roles." Nature Communications 11, no. 1: 1-13.
Statins are the gold-standard treatment for the prevention of primary and secondary cardiovascular disease, which is the leading cause of mortality worldwide. Despite the safety and relative tolerability of statins, observational studies, clinical trials and meta-analyses indicate an increased risk of developing new-onset type 2 diabetes mellitus (T2DM) after long-term statin treatment. It has been shown that statins can impair insulin sensitivity and secretion by pancreatic β-cells and increase insulin resistance in peripheral tissues. The mechanisms involved in these processes include, among others, impaired Ca2+ signaling in pancreatic β-cells, down-regulation of GLUT-4 in adipocytes and compromised insulin signaling. In addition, it has also been described that statins’ impact on epigenetics may also contribute to statin-induced T2DM via differential expression of microRNAs. This review focuses on the evidence and mechanisms by which statin therapy is associated with the development of T2DM. This review describes the multifactorial combination of effects that most likely contributes to the diabetogenic effects of statins. Clinically, these findings should encourage clinicians to consider diabetes monitoring in patients receiving statin therapy in order to ensure early diagnosis and appropriate management.
Unai Galicia-Garcia; Shifa Jebari; Asier Larrea-Sebal; Kepa B. Uribe; Haziq Siddiqi; Helena Ostolaza; Asier Benito-Vicente; César Martín. Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights. International Journal of Molecular Sciences 2020, 21, 4725 .
AMA StyleUnai Galicia-Garcia, Shifa Jebari, Asier Larrea-Sebal, Kepa B. Uribe, Haziq Siddiqi, Helena Ostolaza, Asier Benito-Vicente, César Martín. Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights. International Journal of Molecular Sciences. 2020; 21 (13):4725.
Chicago/Turabian StyleUnai Galicia-Garcia; Shifa Jebari; Asier Larrea-Sebal; Kepa B. Uribe; Haziq Siddiqi; Helena Ostolaza; Asier Benito-Vicente; César Martín. 2020. "Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights." International Journal of Molecular Sciences 21, no. 13: 4725.
The primary genetic cause of familial hypercholesterolemia (FH) is related to mutations in the LDLR gene encoding the Low-density Lipoprotein Receptor. LDLR structure is organized in 5 different domains, including an EGF-precursor homology domain that plays a pivotal role in lipoprotein release and receptor recycling. Mutations in this domain constitute 51.7% of the total missense variants described in LDLR. The aim of the present work was to analyse how clinically significant variants in the EGF-precursor homology domain impact LDLR. The activity of sixteen LDLR variants was functionally characterized by determining LDLR expression by Western blot and LDLR expression, LDL binding capacity and uptake, and LDLR recycling activity by flow cytometry in transfected CHO-ldlA7 cells. Of the analysed variants, we found six non-pathogenic LDLR variants and ten pathogenic variants distributed as follow: three class 3 variants; four class 2 variants; and three class 5 variants. These results can be incorporated into clinical management of patients by helping guide the appropriate level of treatment intensity depending on the extent of loss of LDLR activity. This data can also contribute to cascade-screening for pathogenic FH variants.
Unai Galicia-Garcia; Asier Benito-Vicente; Kepa B. Uribe; Shifa Jebari; Asier Larrea-Sebal; Rocio Alonso-Estrada; Joseba Aguilo-Arce; Helena Ostolaza; Lourdes Palacios; Cesar Martin. Mutation type classification and pathogenicity assignment of sixteen missense variants located in the EGF-precursor homology domain of the LDLR. Scientific Reports 2020, 10, 1 -11.
AMA StyleUnai Galicia-Garcia, Asier Benito-Vicente, Kepa B. Uribe, Shifa Jebari, Asier Larrea-Sebal, Rocio Alonso-Estrada, Joseba Aguilo-Arce, Helena Ostolaza, Lourdes Palacios, Cesar Martin. Mutation type classification and pathogenicity assignment of sixteen missense variants located in the EGF-precursor homology domain of the LDLR. Scientific Reports. 2020; 10 (1):1-11.
Chicago/Turabian StyleUnai Galicia-Garcia; Asier Benito-Vicente; Kepa B. Uribe; Shifa Jebari; Asier Larrea-Sebal; Rocio Alonso-Estrada; Joseba Aguilo-Arce; Helena Ostolaza; Lourdes Palacios; Cesar Martin. 2020. "Mutation type classification and pathogenicity assignment of sixteen missense variants located in the EGF-precursor homology domain of the LDLR." Scientific Reports 10, no. 1: 1-11.
Background and aims Autosomal dominant familial hypercholesterolemia (FH) is caused by mutations in LDLR , APOB and PCSK9. Two new putative loci causing FH have been identified recently, the p.(Leu167del) mutation in APOE and new mutations in the signal transducing adaptor family member STAP1. We aimed at investigating the role of STAP1 mutations in the etiology of FH. Methods We sequenced LDLR, APOB, PCSK9, LDLRAP1, APOE, LIPA and STAP1 with the LipidInCode platform in 400 unrelated subjects from Spain with a clinical diagnosis of FH. All subjects carrying rare predicted pathogenic variants in STAP1 gene, described as pathogenic by at least three bioinformatic analysis and having an allelic frequency lower than 1% in general population, were selected for family study. Available relatives were recruited, including both hypercholesterolemic and non-hypercholesterolemic family members. Results Sequencing analysis of STAP1 gene revealed seventeen rare variants, four of them being described as pathogenic by bioinformatic analysis. We studied the cosegregation with hypercholesterolemia of four rare predicted pathogenic variants, c.-60A > G, p.(Arg12His), p.(Glu97Asp), p.(Pro176Ser) in seven families. We did not observe any cosegregation between genotype and phenotype, even carriers of rare variants in STAP1 had lower LDL cholesterol levels than non-carriers. Conclusions This study analyzes the family cosegregation of four rare predicted pathogenic variants of STAP1, p.(Arg12His), p.(Glu97Asp), p.(Pro176Ser) and c.-60A > G, in seven families, showing absence of cosegregation in all of them. These results would suggest that STAP1 gene is not involved in hypercholesterolemia of these families.
Itziar Lamiquiz-Moneo; María Alejandra Restrepo-Córdoba; Rocío Mateo-Gallego; Ana María Bea; María Del Pino Alberiche-Ruano; Pablo García-Pavía; Ana Cenarro; Cesar Martín; Fernando Civeira; Rosa María Sánchez-Hernández. Predicted pathogenic mutations in STAP1 are not associated with clinically defined familial hypercholesterolemia. Atherosclerosis 2019, 292, 143 -151.
AMA StyleItziar Lamiquiz-Moneo, María Alejandra Restrepo-Córdoba, Rocío Mateo-Gallego, Ana María Bea, María Del Pino Alberiche-Ruano, Pablo García-Pavía, Ana Cenarro, Cesar Martín, Fernando Civeira, Rosa María Sánchez-Hernández. Predicted pathogenic mutations in STAP1 are not associated with clinically defined familial hypercholesterolemia. Atherosclerosis. 2019; 292 ():143-151.
Chicago/Turabian StyleItziar Lamiquiz-Moneo; María Alejandra Restrepo-Córdoba; Rocío Mateo-Gallego; Ana María Bea; María Del Pino Alberiche-Ruano; Pablo García-Pavía; Ana Cenarro; Cesar Martín; Fernando Civeira; Rosa María Sánchez-Hernández. 2019. "Predicted pathogenic mutations in STAP1 are not associated with clinically defined familial hypercholesterolemia." Atherosclerosis 292, no. : 143-151.
Familial hypercholesterolemia (FH) is a monogenic disease characterized by high levels of low-density lipoprotein cholesterol and premature atherosclerotic cardiovascular disease. FH is caused by loss of function mutations in genes encoding LDL receptor (LDLR), and Apolipoprotein B (APOB) or gain of function (GOF) mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9). In this study, we identified a novel variant in PCSK9, p.(Arg499His), located in the C-terminal domain, in two unrelated FH patients from Spain and Italy. We studied familial segregation and determined variant activity in vitro. We determined PCSK9 expression, secretion and activity of the variant in transfected HEK293 cells; extracellular activity of the recombinant p.(Arg499His) PCSK9 variant in HEK 293 and HepG2 cells; PCSK9 affinity to the LDL receptor at neutral and acidic pH; the mechanism of action of the p.(Arg499His) PCSK9 variant by co-transfection with a soluble construct of the LDL receptor and by determining total PCSK9 intracellular accumulation when endosomal acidification is impaired and when an excess of soluble LDLr is present in the culture medium. Our results show high LDL-C concentrations and FH phenotype in p.(Arg499His) carriers. In vitro functional characterization shows that p.(Arg499His) PCSK9 variant causes a reduction in LDLr expression and LDL uptake. An intracellular activity for this variant is also shown when blocking the activity of secreted PCSK9 and by inhibiting endosomal acidification. We demonstrated that p.(Arg499His) PCSK9 variant causes a direct intracellular degradation of LDLr therefore causing FH by reducing LDLr availability.
Rosa M. Sánchez-Hernández; Maria Donata Di Taranto; Asier Benito-Vicente; Kepa B. Uribe; Itziar Lamiquiz-Moneo; Asier Larrea-Sebal; Shifa Jebari; Unai Galicia-Garcia; F. Javier Nóvoa; Mauro Boronat; Ana M. Wägner; Fernando Civeira; César Martín; Giuliana Fortunato. The Arg499His gain-of-function mutation in the C-terminal domain of PCSK9. Atherosclerosis 2019, 289, 162 -172.
AMA StyleRosa M. Sánchez-Hernández, Maria Donata Di Taranto, Asier Benito-Vicente, Kepa B. Uribe, Itziar Lamiquiz-Moneo, Asier Larrea-Sebal, Shifa Jebari, Unai Galicia-Garcia, F. Javier Nóvoa, Mauro Boronat, Ana M. Wägner, Fernando Civeira, César Martín, Giuliana Fortunato. The Arg499His gain-of-function mutation in the C-terminal domain of PCSK9. Atherosclerosis. 2019; 289 ():162-172.
Chicago/Turabian StyleRosa M. Sánchez-Hernández; Maria Donata Di Taranto; Asier Benito-Vicente; Kepa B. Uribe; Itziar Lamiquiz-Moneo; Asier Larrea-Sebal; Shifa Jebari; Unai Galicia-Garcia; F. Javier Nóvoa; Mauro Boronat; Ana M. Wägner; Fernando Civeira; César Martín; Giuliana Fortunato. 2019. "The Arg499His gain-of-function mutation in the C-terminal domain of PCSK9." Atherosclerosis 289, no. : 162-172.
Pore-forming toxins (PFTs) form nanoscale pores across target membranes causing cell death. The pore-forming cytolysins of the RTX (repeats in toxin) family belong to a steadily increasing family of proteins characterized by having in their primary sequences a number of glycine- and aspartate-rich nonapeptide repeats. They are secreted by a variety of Gram-negative bacteria and form ion-permeable pores in several cell types, such as immune cells, epithelial cells, or erythrocytes. Pore-formation by RTX-toxins leads to the dissipation of ionic gradients and membrane potential across the cytoplasmic membrane of target cells, which results in cell death. The pores formed in lipid bilayers by the RTX-toxins share some common properties such as cation selectivity and voltage-dependence. Hemolytic and cytolytic RTX-toxins are important virulence factors in the pathogenesis of the producing bacteria. And hence, understanding the function of these proteins at the molecular level is critical to elucidating their role in disease processes. In this review we summarize the current state of knowledge on pore-formation by RTX toxins, and include recent results from our own laboratory regarding the pore-forming activity of adenylate cyclase toxin (ACT or CyaA), a large protein toxin secreted by Bordetella pertussis, the bacterium causative of whooping cough.
Helena Ostolaza; David González-Bullón; Kepa B. Uribe; Cesar Martín; Jone Amuategi; Xabier Fernandez-Martínez. Membrane Permeabilization by Pore-Forming RTX Toxins: What Kind of Lesions Do These Toxins Form? Toxins 2019, 11, 354 .
AMA StyleHelena Ostolaza, David González-Bullón, Kepa B. Uribe, Cesar Martín, Jone Amuategi, Xabier Fernandez-Martínez. Membrane Permeabilization by Pore-Forming RTX Toxins: What Kind of Lesions Do These Toxins Form? Toxins. 2019; 11 (6):354.
Chicago/Turabian StyleHelena Ostolaza; David González-Bullón; Kepa B. Uribe; Cesar Martín; Jone Amuategi; Xabier Fernandez-Martínez. 2019. "Membrane Permeabilization by Pore-Forming RTX Toxins: What Kind of Lesions Do These Toxins Form?" Toxins 11, no. 6: 354.
RTX (Repeats in ToXin) pore-forming toxins constitute an expanding family of exoproteins secreted by many Gram-negative bacteria and involved in infectious diseases caused by said pathogens. Despite the relevance in the host/pathogen interactions, the structure and characteristics of the lesions formed by these toxins remain enigmatic. Here, we capture the first direct nanoscale pictures of lytic pores formed by an RTX toxin, the Adenylate cyclase (ACT), secreted by the whooping cough bacterium Bordetella pertussis. We reveal that ACT associates into growing-size oligomers of variable stoichiometry and heterogeneous architecture (lines, arcs, and rings) that pierce the membrane, and that, depending on the incubation time and the toxin concentration, evolve into large enough "holes" so as to allow the flux of large molecular mass solutes, while vesicle integrity is preserved. We also resolve ACT assemblies of similar variable stoichiometry in the cell membrane of permeabilized target macrophages, proving that our model system recapitulates the process of ACT permeabilization in natural membranes. Based on our data we propose a non-concerted monomer insertion and sequential mechanism of toroidal pore formation by ACT. A size-tunable pore adds a new regulatory element to ACT-mediated cytotoxicity, with different pore sizes being putatively involved in different physiological scenarios or cell types.
David González-Bullón; Kepa B. Uribe; Eneko Largo; Garazi Guembelzu; Aritz B. García-Arribas; César Martín; Helena Ostolaza. Membrane Permeabilization by Bordetella Adenylate Cyclase Toxin Involves Pores of Tunable Size. Biomolecules 2019, 9, 183 .
AMA StyleDavid González-Bullón, Kepa B. Uribe, Eneko Largo, Garazi Guembelzu, Aritz B. García-Arribas, César Martín, Helena Ostolaza. Membrane Permeabilization by Bordetella Adenylate Cyclase Toxin Involves Pores of Tunable Size. Biomolecules. 2019; 9 (5):183.
Chicago/Turabian StyleDavid González-Bullón; Kepa B. Uribe; Eneko Largo; Garazi Guembelzu; Aritz B. García-Arribas; César Martín; Helena Ostolaza. 2019. "Membrane Permeabilization by Bordetella Adenylate Cyclase Toxin Involves Pores of Tunable Size." Biomolecules 9, no. 5: 183.
Adenylate cyclase toxin (ACT, CyaA) is one of the important virulence factors secreted by the whooping cough bacterium Bordetella pertussis, and it is essential for the colonization of the human respiratory tract by this bacterium. Cytotoxicity by ACT results from the synergy between toxin’s two main activities, production of supraphysiological cAMP levels by its N-terminal adenylate cyclase domain (AC domain), and cell membrane permeabilization, induced by its C-terminal pore-forming domain (hemolysin domain), which debilitate the host defenses. In a previous study we discovered that purified ACT is endowed with intrinsic phospholipase A1 (PLA) activity and that Ser in position 606 of the ACT polypeptide is a catalytic site for such hydrolytic activity, as part of G-X-S-X-G catalytic motif. Recently these findings and our conclusions have been directly questioned by other authors who claim that ACT-PLA activity does not exist. Here we provide new data on ACT phospholipase A1 characteristics. Based on our results we reaffirm our previous conclusions that ACT is endowed with PLA activity; that our purified ACT preparations are devoid of any impurity with phospholipase A activity; that ACT-S606A is a PLA-inactive mutant and thus, that Ser606 is a catalytic site for the toxin hydrolytic activity on phospholipids, and that ACT-PLA activity is involved in AC translocation.
David González-Bullón; César Martín; Helena Ostolaza. Characterization of the Intrinsic Phospholipase A1 Activity of Bordetella pertussis Adenylate Cyclase Toxin. Toxins 2018, 10, 514 .
AMA StyleDavid González-Bullón, César Martín, Helena Ostolaza. Characterization of the Intrinsic Phospholipase A1 Activity of Bordetella pertussis Adenylate Cyclase Toxin. Toxins. 2018; 10 (12):514.
Chicago/Turabian StyleDavid González-Bullón; César Martín; Helena Ostolaza. 2018. "Characterization of the Intrinsic Phospholipase A1 Activity of Bordetella pertussis Adenylate Cyclase Toxin." Toxins 10, no. 12: 514.
Familial Hypercholesterolemia (FH) is a common genetic disorder caused most often by mutations in the Low Density Lipoprotein Receptor gene (LDLr) leading to high blood cholesterol levels, and ultimately to development of premature coronary heart disease. Genetic analysis and subsequent cascade screening in relatives allow diagnosis of FH at early stage, especially relevant to diagnose children. So far, more than 2300 LDLr variants have been described but only a minority of them have been functionally analysed to evaluate their pathogenicity in FH. Thus, identifying pathogenic mutations in LDLr is a long-standing challenge in the field. In this study, we investigated in vitro the activity p.(Asp47Asn) and p.(Thr62Met) LDLr variants, both in the LR1 region. We used CHO-ldlA7 transfected cells with plasmids carrying p.(Asp47Asn) or p.(Thr62Met) LDLr variants to analyse LDLr expression by FACS and immunoblotting, LDL binding and uptake was determined by FACS and analysis of mutation effects was assessed in silico. The in vitro activity assessment of p.(Asp47Asn) and p.(Thr62Met) LDLr variants shows a fully functional LDL binding and uptake activities. Therefore indicating that the three of them are non-pathogenic LDLr variants. These findings also emphasize the importance of in vitro functional LDLr activity studies to optimize the genetic diagnosis of FH avoiding the report of non-pathogenic variants and possible misdiagnose in relatives if cascade screening is carried out.
A. Benito-Vicente; H. Siddiqi; K. B. Uribe; S. Jebari; U. Galicia-Garcia; A. Larrea-Sebal; M. Stef; H. Ostolaza; L. Palacios; C. Martin. p.(Asp47Asn) and p.(Thr62Met): non deleterious LDL receptor missense variants functionally characterized in vitro. Scientific Reports 2018, 8, 16614 .
AMA StyleA. Benito-Vicente, H. Siddiqi, K. B. Uribe, S. Jebari, U. Galicia-Garcia, A. Larrea-Sebal, M. Stef, H. Ostolaza, L. Palacios, C. Martin. p.(Asp47Asn) and p.(Thr62Met): non deleterious LDL receptor missense variants functionally characterized in vitro. Scientific Reports. 2018; 8 (1):16614.
Chicago/Turabian StyleA. Benito-Vicente; H. Siddiqi; K. B. Uribe; S. Jebari; U. Galicia-Garcia; A. Larrea-Sebal; M. Stef; H. Ostolaza; L. Palacios; C. Martin. 2018. "p.(Asp47Asn) and p.(Thr62Met): non deleterious LDL receptor missense variants functionally characterized in vitro." Scientific Reports 8, no. 1: 16614.
Cholesterol is an essential component of cell barrier formation and signaling transduction involved in many essential physiologic processes. For this reason, cholesterol metabolism must be tightly controlled. Cell cholesterol is mainly acquired from two sources: Dietary cholesterol, which is absorbed in the intestine and, intracellularly synthesized cholesterol that is mainly synthesized in the liver. Once acquired, both are delivered to peripheral tissues in a lipoprotein dependent mechanism. Malfunctioning of cholesterol metabolism is caused by multiple hereditary diseases, including Familial Hypercholesterolemia, Sitosterolemia Type C and Niemann-Pick Type C1. Of these, familial hypercholesterolemia (FH) is a common inherited autosomal co-dominant disorder characterized by high plasma cholesterol levels. Its frequency is estimated to be 1:200 and, if untreated, increases the risk of premature cardiovascular disease. This review aims to summarize the current knowledge on cholesterol metabolism and the relation of FH to cholesterol homeostasis with special focus on the genetics, diagnosis and treatment.
Asier Benito-Vicente; Kepa B. Uribe; Shifa Jebari; Unai Galicia-Garcia; Helena Ostolaza; Cesar Martin. Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease. International Journal of Molecular Sciences 2018, 19, 3426 .
AMA StyleAsier Benito-Vicente, Kepa B. Uribe, Shifa Jebari, Unai Galicia-Garcia, Helena Ostolaza, Cesar Martin. Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease. International Journal of Molecular Sciences. 2018; 19 (11):3426.
Chicago/Turabian StyleAsier Benito-Vicente; Kepa B. Uribe; Shifa Jebari; Unai Galicia-Garcia; Helena Ostolaza; Cesar Martin. 2018. "Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease." International Journal of Molecular Sciences 19, no. 11: 3426.