المؤلفون: Soto-Catalán, Manuel, Opazo-Ríos, Lucas, Quiceno, Hernán, Lázaro, Iolanda, Moreno, Juan Antonio, Gómez-Guerrero, Carmen, Egido, J., Mas-Fontao, Sebastián

المصدر: Int. J. Mol. Sci., 25(5), 2961 (2024)

مصطلحات موضوعية: Diabetes, Insulin resistance, GLP1 receptor agonists, Obesity, Semaglutide, Steatosis

الوصف: Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent clinical condition associated with elevated morbidity and mortality rates. Patients with MASLD treated with semaglutide, a glucagon-like peptide-1 receptor agonist, demonstrate improvement in terms of liver damage. However, the mechanisms underlaying this beneficial effect are not yet fully elucidated. We investigated the efficacy of semaglutide in halting MASLD progression using a genetic mouse model of diabesity. Leptin-receptor-deficient mice with obesity and diabetes (BKS db/db) were either untreated or administered with semaglutide for 11 weeks. Changes in food and water intake, body weight and glycemia were monitored throughout the study. Body fat composition was assessed by dual-energy X-ray absorptiometry. Upon sacrifice, serum biochemical parameters, liver morphology, lipidomic profile and liver-lipid-related pathways were evaluated. The semaglutide-treated mice exhibited lower levels of glycemia, body weight, serum markers of liver dysfunction and total and percentage of fat mass compared to untreated db/db mice without a significant reduction in food intake. Histologically, semaglutide reduced hepatic steatosis, hepatocellular ballooning and intrahepatic triglycerides. Furthermore, the treatment ameliorated the hepatic expression of de novo lipogenesis markers and modified lipid composition by increasing the amount of polyunsaturated fatty acids. The administration of semaglutide to leptin-receptor-deficient, hyperphagic and diabetic mice resulted in the amelioration of MASLD, likely independently of daily caloric intake, suggesting a direct effect of semaglutide on the liver through modulation of the lipid profile.

وصف الملف: application/pdf

العلاقة: https://doi.org/10.3390/ijms25052961Test; Gobierno de España. Grants RTI2018-098788-B-I00; Gobierno de España. PID2021-127741OB-I00; Gobierno de España. DTS19/00093; Junta de Andalucía. 1381179-R; http://hdl.handle.net/10396/27601Test

الإتاحة: https://doi.org/10.3390/ijms25052961Test
http://hdl.handle.net/10396/27601Test

المؤلفون: Prieto, Ignacio, Kavanagh, María, Jiménez Castilla, Luna, Pardines, Marisa, Herrero del Real, Isabel, Flores Muñoz, Monica, Egido, Jesus, López Franco, Óscar, Gómez Guerrero, Carmen

المساهمون: UAM. Departamento de Medicina

مصطلحات موضوعية: © 2023 The Author(s), Medicina

الوصف: Diabetic kidney disease (DKD) is a common microvascular complication of diabetes, a global health issue. Hyperglycemia, in concert with cytokines, activates the Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) pathway to induce inflammation and oxidative stress contributing to renal damage. There is evidence of microRNA-155 (miR-155) involvement in diabetes complications, but the underlying mechanisms are unclear. In this study, gain- and loss-of-function experiments were conducted to investigate the interplay between miR-155-5p and suppressor of cytokine signaling 1 (SOCS1) in the regulation of the JAK/STAT pathway during renal inflammation and DKD. In experimental models of mesangial injury and diabetes, miR-155-5p expression correlated inversely with SOCS1 and positively with albuminuria and expression levels of cytokines and prooxidant genes. In renal cells, miR-155-5p mimic downregulated SOCS1 and promoted STAT1/3 activation, cytokine expression, and cell proliferation and migration. Conversely, both miR-155-5p antagonism and SOCS1 overexpression protected cells from inflammation and hyperglycemia damage. In vivo, SOCS1 gene delivery decreased miR-155-5p and kidney injury in diabetic mice. Moreover, therapeutic inhibition of miR-155- 5p suppressed STAT1/3 activation and alleviated albuminuria, mesangial damage, and renal expression of inflammatory and fibrotic genes. In conclusion, modulation of the miR-155/ SOCS1 axis protects kidneys against diabetic damage, thus highlighting its potential as therapeutic target for DKD ; This research was funded by grants from Spanish Ministry of Science and Innovation (RTI2018-098788-B-I00 and PID2021-127741OBI00) to C.G.-G., Instituto de Salud Carlos III (PI20/00487) to J.E, CIBERDEM (postdoctoral contract) to I.P., and Conacyt-Mexico (CB-2015-01 256639 and FOP02-2022-02 321869) to O.L.-F. The authors thank Ana Melgar and Patricia Saperas (IIS-FJD, Madrid) for technical support in mouse sample processing and histology, and Carmen Liliana Peña ...

وصف الملف: application/pdf

العلاقة: Molecular Therapy Nucleic Acids; https://doi.org/10.1016/j.omtn.2023.102041Test; Gobierno de España. RTI2018-098788-B-I00; Gobierno de España. PID2021-127741OBI00; Molecular Therapy Nucleic Acids 34 (2023): 102041; 2162-2531 (online); http://hdl.handle.net/10486/709648Test; 102041-1; 102041; 34

الإتاحة: https://doi.org/10.1016/j.omtn.2023.102041Test
http://hdl.handle.net/10486/709648Test

المؤلفون: Lázaro, Iolanda, Bobi, Joaquim, Cofán, Montserrat, Kapravelou, Garyfallia, Amor, Antonio J., Surra, Joaquin, Gómez-Guerrero, Carmen, Ortega, Emilio, Osada, Jesus, Dantas, Ana Paula, Sala-Vila, Aleix

الوصف: Introduction: The lower rates of cardiovascular disease in Southern Europe could be partially explained by the low prevalence of lipid-rich atheroma plaques. Consumption of certain foods affects the progression and severity of atherosclerosis. We investigated whether the isocaloric inclusion of walnuts within an atherogenic diet prevents phenotypes predicting unstable atheroma plaque in a mouse model of accelerated atherosclerosis. Methods: Apolipoprotein E-deficient male mice (10-week-old) were randomized to receive a control diet (9.6% of energy as fat, n = 14), a palm oil-based high-fat diet (43% of energy as fat, n = 15), or an isocaloric diet in which part of palm oil was replaced by walnuts in a dose equivalent to 30 g/day in humans (n = 14). All diets contained 0.2% cholesterol. Results: After 15 weeks of intervention, there were no differences in size and extension in aortic atherosclerosis among groups. Compared to control diet, palm oil-diet induced features predicting unstable atheroma plaque (higher lipid content, necrosis, and calcification), and more advanced lesions (Stary score). Walnut inclusion attenuated these features. Palm oil-based diet also boosted inflammatory aortic storm (increased expression of chemokines, cytokines, inflammasome components, and M1 macrophage phenotype markers) and promoted defective efferocytosis. Such response was not observed in the walnut group. The walnut group’s differential activation of nuclear factor kappa B (NF-κB; downregulated) and Nrf2 (upregulated) in the atherosclerotic lesion could explain these findings. Conclusion: The isocaloric inclusion of walnuts in an unhealthy high-fat diet promotes traits predicting stable advanced atheroma plaque in mid-life mice. This contributes novel evidence for the benefits of walnuts, even in an unhealthy dietary environment.

وصف الملف: application/pdf

العلاقة: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI15-01014; info:eu-repo/grantAgreement/ES/MICINN/PID2021-127741OB-I00; http://zaguan.unizar.es/record/125261Test

الإتاحة: https://doi.org/10.3389/fnut.2023.1079407Test
http://zaguan.unizar.es/record/125261Test

المؤلفون: Prieto, Ignacio, Kavanagh, María, Jimenez-Castilla, Luna, Pardines, Marisa, Lazaro, Iolanda, Herrero del Real, Isabel, Flores-Muñoz, Monica, Egido, Jesus, Lopez-Franco, Oscar, Gomez-Guerrero, Carmen

المصدر: Molecular Therapy - Nucleic Acids ; volume 34, page 102041 ; ISSN 2162-2531

مصطلحات موضوعية: Drug Discovery, Molecular Medicine

الإتاحة: https://doi.org/10.1016/j.omtn.2023.102041Test
https://api.elsevier.com/content/article/PII:S2162253123002597?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2162253123002597?httpAccept=text/plainTest

المؤلفون: Jiménez‐castilla, Luna, Marín‐royo, Gema, Orejudo, Macarena, Opazo‐ríos, Lucas, Caro‐ordieres, Teresa, Artaiz, Inés, Suárez‐cortés, Tatiana, Zazpe, Arturo, Hernández, Gonzalo, Gómez‐guerrero, Carmen, Egido, Jesús

المساهمون: UAM. Departamento de Medicina

مصطلحات موضوعية: Albuminuria, Diabetic nephropathy, Hidrosmin, Inflammation, Oxidative stress, Medicina

الوصف: Diabetes mellitus (DM) is a high‐impact disease commonly characterized by hyperglycemia, inflammation, and oxidative stress. Diabetic nephropathy (DN) is a common diabetic microvascular complication and the leading cause of chronic kidney disease worldwide. This study investigates the protective effects of the synthetic flavonoid hidrosmin (5‐O‐(beta-hydroxyethyl) diosmin) in experimental DN induced by streptozotocin injection in apolipoprotein E deficient mice. Oral administration of hidrosmin (300 mg/kg/day, n = 11) to diabetic mice for 7 weeks markedly reduced albuminuria (albumin‐to‐creatinine ratio: 47 ± 11% vs. control) and ameliorated renal pathological damage and expression of kidney injury markers. Kidneys of hidrosmin‐treated mice exhibited lower content of macrophages and T cells, reduced expression of cytokines and chemokines, and attenuated inflammatory signaling pathways. Hidrosmin treatment improved the redox balance by reducing prooxidant enzymes and enhancing antioxidant genes, and also decreased senescence markers in diabetic kidneys. In vitro, hidrosmin dose‐dependently reduced the expression of inflammatory and oxidative genes in tubuloepithelial cells exposed to either high‐glucose or cytokines, with no evidence of cytotoxicity at effective concentrations. In conclusion, the synthetic flavonoid hidrosmin exerts a beneficial effect against DN by reducing inflammation, oxidative stress, and senescence pathways. Hidrosmin could have a potential role as a coadjutant therapy for the chronic complications of DM. ; This work was supported by grants from the Spanish Ministry of Science and Innovation- FEDER funds (Retos Colaboración RTC2017-6089-1 and Retos Investigación RTI2018-098788-B-I00) and Instituto de Salud Carlos III (PI20/00487 and DTS 19/00093)

وصف الملف: application/pdf

العلاقة: Antioxidants; Gobierno de España. RTC2017-6089-1; Gobierno de España. RTI2018-098788-B-I00; Gobierno de España. PI20/00487; Gobierno de España. DTS19/00093; Antioxidants 10.12 (2021): 1920; http://hdl.handle.net/10486/704948Test; 1920-1; 12; 1920-17; 10

الإتاحة: https://doi.org/10.3390/antiox10121920Test
http://hdl.handle.net/10486/704948Test

المؤلفون: Cerro-Pardo, Isabel, Lindholt, Jes S., Núñez, Estefanía, Roldan-Montero, Raquel, Ortega-Villanueva, Lucia, Vegas-Dominguez, Cesar, Gomez-Guerrero, Carmen, Michel, Jean Baptiste, Blanco-Colio, Luis M., Vázquez, Jesús, Martín-Ventura, José L.

المصدر: Cerro-Pardo , I , Lindholt , J S , Núñez , E , Roldan-Montero , R , Ortega-Villanueva , L , Vegas-Dominguez , C , Gomez-Guerrero , C , Michel , J B , Blanco-Colio , L M , Vázquez , J & Martín-Ventura , J L 2022 , ' Combined Immunoglobulin Free Light Chains Are Novel Predictors of Cardiovascular Events in Patients With Abdominal Aortic Aneurysm ' , European Journal of Vascular and Endovascular Surgery , vol. 63 , no. 5 , pp. 751-758 . https://doi.org/10.1016/j.ejvs.2021.11.025Test

مصطلحات موضوعية: Abdominal aortic aneurysm, Biomarkers, Immune response, Immunoglobulins, Mortality

الوصف: Objective: Abdominal aortic aneurysm (AAA) is characterised by the presence of B cells and immunoglobulins in the aortic wall, mainly in the adventitia. Kappa (κ) and lambda (λ) free light chains (FLCs) are produced from B cells during immunoglobulin synthesis. This study investigated the presence and prognostic value of combined FLCs (cFLCs or summed κ and λ) in patients with AAA. Methods: cFLCs were analysed by a turbidimetric specific assay in tissue conditioned media from AAA samples (n = 34) compared with healthy aortas (n = 34) from France and in plasma samples from patients with AAA (n = 434) and age matched controls (n = 104) selected from the Viborg Vascular (VIVA) AAA screening trial in Denmark. t test, logistic regression, and Cox regression were used to test whether plasma cFLCs serve as a marker for AAA presence and whether cFLCs were predictive of death, major adverse cardiovascular events (MACE), or major adverse lower limb events (MALE). Results: Increased cFLC levels were detected in the AAA adventitial layer compared with the AAA medial layer and healthy media layer (13.65 ± 3.17 vs. 6.57 ± 1.01 vs. 0.49 ± 0.09 mg/L, respectively, p < .050). The upper tertile of plasma cFLCs was independently associated with AAA presence after correcting for confounders (odds ratio [OR] 7.596, 95% confidence intervals [CI] 3.117 – 18.513; p < .001). Of 434 patients with AAA, 89 (20.5%) died, 104 (24.0%) suffered MACE, and 63 (14.5%) suffered MALE, during a five year follow up. In univariable analysis, the cFLC upper tertile was associated with a higher risk of death, MACE, and MALE (p < .001 for all). After adjustment for confounders, cFLCs remained an independent predictor of all cause mortality (hazard ratio [HR] 4.310, 95% CI 2.157 – 8.609; p < .001), MACE (HR 2.153, 95% CI 1.218 – 3.804; p = .008), or MALE (HR 3.442, 95% CI 1.548 – 7.652; p = .002) for those in the upper tertile. Conclusion: Increased cFLCs are observed in adventitial tissue of patients with AAA, indicating local activation of B ...

وصف الملف: application/pdf

العلاقة: https://portal.findresearcher.sdu.dk/da/publications/4cd3e361-388d-4847-9b3d-53e4c1b0fa3fTest

الإتاحة: https://doi.org/10.1016/j.ejvs.2021.11.025Test
https://portal.findresearcher.sdu.dk/da/publications/4cd3e361-388d-4847-9b3d-53e4c1b0fa3fTest
https://findresearcher.sdu.dk/ws/files/202924291/PIIS1078588421009539.pdfTest

المؤلفون: La Manna, Sara, Lopez-Sanz, Laura, Bernal, Susana, Fortuna, Sara, Mercurio, Flavia A., Leone, Marilisa, Gomez-Guerrero, Carmen, Marasco, Daniela

المساهمون: La Manna, Sara, Lopez-Sanz, Laura, Bernal, Susana, Fortuna, Sara, Mercurio, Flavia A., Leone, Marilisa, Gomez-Guerrero, Carmen, Marasco, Daniela

مصطلحات موضوعية: Mimetic peptide, Cytokine signaling, JAK/STAT, SOCS1, Oxidative stre, Inflammation

الوصف: Herein we investigated the structural and cellular effects ensuing from the cyclization of a potent inhibitor of JAK2 as mimetic of SOCS1 protein, named PS5. The introduction of un-natural residues and a lactam internal bridge, within SOCS1-KIR motif, produced candidates that showed high affinity toward JAK2 catalytic domain. By combining CD, NMR and computational studies, we obtained valuable models of the interactions of two peptidomimetics of SOCS1 to deepen their functional behaviors. Notably, when assayed for their biological cell responses mimicking SOCS1 activity, the internal cyclic PS5 analogues demonstrated able to inhibit JAK-mediated tyrosine phosphorylation of STAT1 and to reduce cytokine-induced proinflammatory gene expression, oxidative stress generation and cell migration. The present study well inserts in the field of low-molecular-weight proteomimetics with improved longtime cellular effects and adds a new piece to the puzzled way for the conversion of bioactive peptides into drugs.

العلاقة: info:eu-repo/semantics/altIdentifier/wos/WOS:000661282500037; volume:221; firstpage:113547; lastpage:-; numberofpages:11; journal:EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; http://hdl.handle.net/11368/2990292Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85106934508

الإتاحة: https://doi.org/10.1016/j.ejmech.2021.113547Test
http://hdl.handle.net/11368/2990292Test

المؤلفون: Gómez Guerrero, Carmen

مرشدي الرسالة: Egido de los Rios, Jesús

مصطلحات موضوعية: Bioquímica

الوصف: El daño glomerular progresivo es la principal causa de insuficiencia renal y puede producirse como consecuencia del depósito en el glomerulo de componentes biológicamente activos como los inmunocomplejos. Dentro del glomerulo, el mesangio, formado por células mesangiales y matriz extracelular, ocupa una posición central en la estructura y participa en su funcionalidad. Estudios previos han demostrado que las células mesangiales poseen un receptor específico para igg y estudios en nuestro laboratorio han mostrado que la interacción entre las células mesangiales y los inmunocomplejos de iga induce la liberación de mediadores, pero hasta el momento no se han determinado las características bioquímicas, moleculares y funcionales de los posibles receptores para iga en estas células. Los resultados que se exponen en esta tesis doctoral demuestran que en la célula mesangial existe un receptor específico para iga, capaz de unir con alta afinidad esta inmunoglobulina a través de la región fc. Este receptor puede ser incluido en la familia de los receptores fc alfa, pues presenta ciertas analogías con los receptores fc alfa descritos en otros tipos de células. Los carbohidratos contenidos en la estructura de la iga participan de forma muy importante en dicha interacción. Demostramos además algunos aspectos funcionales que ocurren después de la ocupación de los receptores de la membrana celular por la iga, como los fenómenos de endocitosis y degradación de la iga, y la activación de los procesos de transducción de la señal (incremento del calcio intracelular), proliferación mesangial y liberación de citocinas (factor de necrosis tumoral e interleucina 6). Con este trabajo se aportan nuevos conocimientos sobre los mecanismos patogénicos que provocan daño tisular en algunas enfermedades, como la nefropatía iga, una de las glomerulonefritis más comunes en el mundo, caracterizada por el depósito de inmunocomplejos de iga en el mesangio. La interacción de estos inmunocomplejos con las células mesangiales provoca su activación y la consiguiente liberación de mediadores proinflamatorios, participando así activamente en la progresión del daño glomerular

الوصول الحر: http://eprints.ucm.es/2096Test/

المؤلفون: Amor, Antonio J., Gómez Guerrero, Carmen, Ortega, Emilio, Sala-Vila, Aleix, Lázaro, Iolanda

المساهمون: UAM. Departamento de Medicina, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)

مصطلحات موضوعية: Diabetic complications, Ellagic acid, Glucose metabolism, Inflammation, Oxidative stress, Type 2 diabetes, Medicina

الوصف: Oxidative stress contributes not only to the pathogenesis of type 2 diabetes (T2D) but also to diabetic vascular complications. It follows that antioxidants might contribute to limiting the diabetes burden. In this review we focus on ellagic acid (EA), a compound that can be obtained upon intestinal hydrolysis of dietary ellagitannins, a family of polyphenols naturally found in several fruits and seeds. There is increasing research on cardiometabolic effects of ellagitannins, EA, and urolithins (EA metabolites). We updated research conducted on these compounds and (I) glucose metabolism; (II) inflammation, oxidation, and glycation; and (III) diabetic complications. We included studies testing EA in isolation, extracts or preparations enriched in EA, or EA-rich foods (mostly pomegranate juice). Animal research on the topic, entirely conducted in murine models, mostly reported glucose-lowering, antioxidant, anti-inflammatory, and anti-glycation effects, along with prevention of micro-and macrovascular diabetic complications. Clinical research is incipient and mostly involved non-randomized and low-powered studies, which confirmed the antioxidant and anti-inflammatory properties of EA-rich foods, but without conclusive results on glucose control. Overall, EA-related compounds might be potential agents to limit the diabetes burden, but well-designed human randomized controlled trials are needed to fill the existing gap between experimental and clinical research. ; A.S.-V. is recipient of the Instituto de Salud Carlos III Miguel Servet fellowship (grant CP II17/00029).

وصف الملف: application/pdf

العلاقة: Antioxidants; http://doi.org/10.3390/antiox9121226Test; Antioxidants 9.12 (2020): 1226; http://hdl.handle.net/10486/695639Test; 1226-1; 12; 1226-26

الإتاحة: https://doi.org/10.3390/antiox9121226Test
http://hdl.handle.net/10486/695639Test

المؤلفون: Opazo-Ríos, Lucas, Plaza, Anita, Matus, Yenniffer Sánchez, Bernal, Susana, Lopez-Sanz, Laura, Jimenez-Castilla, Luna, Carpio, Daniel, Droguett, Alejandra, Mezzano, Sergio, Egido, Jesús, Gómez Guerrero, Carmen

المساهمون: UAM. Departamento de Medicina, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)

مصطلحات موضوعية: Albuminuria, BTBR ob/ob mice, Diabetic nephropathy, Inflammation, NF-κB pathway, Medicina

الوصف: Diabetic nephropathy (DN) is a multifactorial disease characterized by hyperglycemia and close interaction of hemodynamic, metabolic and inflammatory factors. Nuclear factor-κB (NF-κB) is a principal matchmaker linking hyperglycemia and inflammation. The present work investigates the cell-permeable peptide containing the inhibitor of kappa B kinase γ (IKKγ)/NF-κB essential modulator (NEMO)-binding domain (NBD) as therapeutic option to modulate inflammation in a preclinical model of type 2 diabetes (T2D) with DN. Black and tan, brachyuric obese/obese mice were randomized into 4 interventions groups: Active NBD peptide (10 and 6 µg/g body weight); Inactive mutant peptide (10 µg/g); and vehicle control. In vivo/ex vivo fluorescence imaging revealed efficient delivery of NBD peptide, systemic biodistribution and selective renal metabolization. In vivo administration of active NBD peptide improved albuminuria (>40% reduction on average) and kidney damage, decreased podocyte loss and basement membrane thickness, and modulated the expression of proinflammatory and oxidative stress markers. In vitro, NBD blocked IKK-mediated NF-κB induction and target gene expression in mesangial cells exposed to diabetic-like milieu. These results constitute the first nephroprotective effect of NBD peptide in a T2D mouse model that recapitulates the kidney lesions observed in DN patients. Targeting IKK-dependent NF-κB activation could be a therapeutic strategy to combat kidney inflammation in DN. ; This work was supported by grants from: Fondecyt Project No 1160465 to S.M. and PhD CONICYT Grant No 21150768 to L.O-R.; Spanish Ministry of Economy and Competitiveness (MINECO/FEDER; SAF2015-63696-R to C.G-G.), Ministry of Science and Innovation (MICINN/FEDER; RTI2018-098788-B-1I00 to C.G-G.) and Instituto de Salud Carlos III (FIS/FEDER; PI17/01495 and DTS-2017/00203 to J.E.)

وصف الملف: application/pdf

العلاقة: International Journal of Molecular Sciences; http://doi.org/10.3390/ijms21124225Test; Gobierno de España. PI17/01495; Gobierno de España. DTS-2017/00203; International Journal of Molecular Sciences 21.12 (2020): 4225; http://hdl.handle.net/10486/695184Test; 4225-1; 12; 4225-17; 21

الإتاحة: https://doi.org/10.3390/ijms21124225Test
http://hdl.handle.net/10486/695184Test