Sara Santa-Cruz Calvo

University of Kentucky

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Barbara S. Nikolajczyk

University of Kentucky

Plácido Navas

Universidad Pablo de Olavide

Guillermo López‐Lluch

Centro Andaluz de Biología del Desarrollo

Leena P. Bharath

Merrimack College

Josephine M. Egan

National Institute on Aging

Isabel González‐Mariscal

Instituto de Salud Carlos III

Philip A. Kern

University of Kentucky

Emelia Zukowski

Merrimack College

Xiaohua Douglas Zhang

University of Kentucky

Hatice Hastürk

Harvard University

Cooperative Institutions

National Institutes of Health

National Institute on Aging

University of Kentucky

Institute on Aging

Universidad Pablo de Olavide

Merrimack College

Hospital Comarcal de Inca

Consejo Superior de Investigaciones Científicas

University of Pisa

Instituto de Salud Carlos III

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The biological mechanisms of metformin effects on aging-associated inflammation in obesity

The Journal of Immunology (2022)

Sara Santa-Cruz Calvo Leena P. Bharath Barbara S. Nikolajczyk

Abstract Obesity prevalence within the 60+ years-old (yrs) population is drastically increasing. This alarmingly high rate of obesity compels comparative studies to identify common players involved in aging-derived and obesity-associated inflammation. Blood CD4+ T cells from lean older humans show an upregulated Th17 signature accompanied by a defective redox system. Treatment of these cells with the anti-diabetic drug metformin (100μM) promoted a more young-like anti-inflammatory/antioxidant phenotype. Here, we investigate whether the protective effects of metformin observed in CD4+ T cells from lean aging adults persist in obesity. Blood CD4+ T cells from obese older (60+ yrs) donors secrete twice the amount of the Th17 cytokines IL-17F and IL-21 when compared to their younger counterparts (25–35 yrs). Glutamate production, which supports Th17 cytokines secretion, is 1.5-times higher in cells from older compared to younger subjects. Mitochondrial superoxide production in these cells was 25% higher than in younger cells, with no changes in total peroxide. Contrary to findings from cells of lean subjects, metformin failed to reduce Th17 cytokines in cells from obese older subjects, perhaps due to metformin’s inability to reduce glutamate production. However, metformin reduced hydrogen peroxide production 1.75-fold, with no effect on superoxide, in cells from obese older subjects. These results collectively indicate that 1) obesity-associated upregulation of Th17 cytokines is mechanistically linked to glutamine metabolism and mitochondrial superoxide production and 2) metformin’s action targets peroxide production rather than superoxide, which is insufficient for reducing age-associated inflammation in obesity. The Biological mechanisms of Metformin Effects on Aging-Associated Inflammation 1R56AG069685-01

10.4049/jimmunol.208.supp.165.24

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Fasting and Glucose Metabolism Differentially Impact Peripheral Inflammation in Human Type 2 Diabetes

Nutrients (2024)

Gabriella H. Kalantar S. Saraswat Sara Santa-Cruz Calvo Fatemeh Gholamrezaeinejad Aida Javidan

Cytokines produced by peripheral T-helper 1/17 cells disproportionately contribute to the inflammation (i.e., metaflammation) that fuels type 2 diabetes (T2D) pathogenesis. Shifts in the nutrient milieu could influence inflammation through changes in T-cell metabolism. We aimed to determine whether changes in glucose utilization alter cytokine profiles in T2D. Peripheral blood mononuclear cells (PBMCs), CD4

Carbohydrate Metabolism

10.3390/nu16101404

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397 Oral Iodine Supplementation and Thyroid Function in Premature Babies Born Less Than 1500 Gr of Weight

Pediatric Research (2010)

Susana Ares Segura Juan Arnáez Sara Santa-Cruz Calvo J Quero Morreale G De Escobar

10.1203/00006450-201011001-00397

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Membrane-Bound CYB5R3 Is a Common Effector of Nutritional and Oxidative Stress Response Through FOXO3a and Nrf2

Antioxidants and Redox Signaling (2014)

Emilio Siendones Sara Santa-Cruz Calvo Alejandro Martín‐Montalvo María V. Cascajo Julia Ariza

Aims: Membrane-bound CYB5R3 deficiency in humans causes recessive hereditary methaemoglobinaemia (RHM), an incurable disease that is characterized by severe neurological disorders. CYB5R3 encodes for NADH-dependent redox enzyme that contributes to metabolic homeostasis and stress protection; however, how it is involved in the neurological pathology of RHM remains unknown. Here, the role and transcriptional regulation of CYB5R3 was studied under nutritional and oxidative stress. Results:CYB5R3-deficient cells exhibited a decrease of the NAD+/NADH ratio, mitochondrial respiration rate, ATP production, and mitochondrial electron transport chain activities, which were associated with higher sensitivity to oxidative stress, and an increase in senescence-associated β-galactosidase activity. Overexpression of either forkhead box class O 3a (FOXO3a) or nuclear factor (erythroid-derived 2)-like2 (Nrf2) was associated with increased CYB5R3 levels, and genetic ablation of Nrf2 resulted in lower CYB5R3 expression. The presence of two antioxidant response element sequences in the CYB5R3 promoter led to chromatin immunoprecipitation studies, which showed that cellular stressors enhanced the binding of Nrf2 and FOXO3a to the CYB5R3 promoter. Innovation: Our findings demonstrate that CYB5R3 contributes to regulate redox homeostasis, aerobic metabolism, and cellular senescence, suggesting that CYB5R3 might be a key effector of oxidative and nutritional stress pathways. The expression of CYB5R3 is regulated by the cooperation of Nrf2 and FOXO3a. Conclusion:CYB5R3 is an essential gene that appears as a final effector for both nutritional and oxidative stress responses through FOXO3a and Nrf2, respectively, and their interaction promotes CYB5R3 expression. These results unveil a potential mechanism of action by which CYB5R3 deficiency contributes to the pathophysiological underpinnings of neurological disorders in RHM patients. Antioxid. Redox Signal. 21, 1708–1725.

10.1089/ars.2013.5479

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Human CB1 Receptor Isoforms, present in Hepatocytes and β-cells, are Involved in Regulating Metabolism

Scientific Reports (2016)

Isabel González‐Mariscal Susan M. Krzysik-Walker Maı̀re E. Doyle Qing‐Rong Liu Raffaello Cimbro

Abstract Therapeutics aimed at blocking the cannabinoid 1 (CB1) receptor for treatment of obesity resulted in significant improvements in liver function, glucose uptake and pancreatic β-cell function independent of weight loss or CB1 receptor blockade in the brain, suggesting that peripherally-acting only CB1 receptor blockers may be useful therapeutic agents. Neuropsychiatric side effects and lack of tissue specificity precluded clinical use of first-generation, centrally acting CB1 receptor blockers. In this study we specifically analyzed the potential relevance to diabetes of human CB1 receptor isoforms in extraneural tissues involved in glucose metabolism. We identified an isoform of the human CB1 receptor (CB1b) that is highly expressed in β-cells and hepatocytes but not in the brain. Importantly, CB1b shows stronger affinity for the inverse agonist JD-5037 than for rimonabant compared to CB1 full length. Most relevant to the field, CB1b is a potent regulator of adenylyl cyclase activity in peripheral metabolic tissues. CB1b blockade by JD-5037 results in stronger adenylyl cyclase activation compared to rimonabant and it is a better enhancer of insulin secretion in β-cells. We propose this isoform as a principal pharmacological target for the treatment of metabolic disorders involving glucose metabolism.

Rimonabant

10.1038/srep33302

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Resveratrol as a cell cycle & metabolic modifier in tumoral cell lines. Implications for p53 stabilization

Sara Santa-Cruz Calvo

El resveratrol (RSV) es un polifenol conocido por su capacidad antitumoral y antioxidante, entre otras. En las ultimas decadas se ha descrito su capacidad para reducir la viabilidad celular induciendo bien, parada en la progresion del ciclo celular o apoptosis dependiendo del tipo celular y de las condiciones de tratamiento. Nosotros hemos centrado nuestro estudio en definir las vias de senalizacion directamente afectadas por tratamientos con bajas dosis de RSV (1 O, 30 y 90 ?M) durante diferentes tiempos de incubacion (12, 24 y 48h mayoritariamente). Bajo estas condiciones, el RSV induce posiblemente un dano en el ADN que (i) activa la acumulacion de la forina wt de p53 atraves de la inhibicion de su degradacion y del favorecimiento de su acetilacion y fosforilacion (ii) aumenta la expresion de p21 (iii) induce un retraso en la progresion del ciclo celular (iiii) incrementa el numero de celulas en fase S. Ademas el tratamiento con este polifenol durante incubaciones largas ( 48h), genera un cambio metabolico posterior a la parada en ciclo, caracterizado mayoritariamente por un incremento de la masa mitocondrial y de los niveles de coenzima Q, asi como de la capacidad de utilizcion de otras fuentes de energia. Sugiriendo todo ello una activacion del sistema OXPHOS, de la P-oxidacion de acidos grasos y una reduccion del ratio NADH/NAD+. Ademas, los niveles de lactato disminuyen tras el tratamiento pudiendose ser la activacion de forma dependiente de p53 de la proteina TIGAR, el mecanismo responsable. El RSV a bajas dosis solo es efectivo retrasando el ciclo celular en celulas tumorales y no en celulas normales, indicando un dependencia directa del efecto del tratameinto con el tipo de metablismo celular, haciendo de este compuesto un uimioterapico prometedor.

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Insulin Is Transcribed and Translated in Mammalian Taste Bud Cells

Endocrinology (2018)

Maı̀re E. Doyle Jennifer L. Fiori Isabel González‐Mariscal Qing‐Rong Liu Erin Goodstein

Abstract We and others have reported that taste cells in taste buds express many peptides in common with cells in the gut and islets of Langerhans in the pancreas. Islets and taste bud cells express the hormones glucagon and ghrelin, the same ATP-sensitive potassium channel responsible for depolarizing the insulin-secreting β cell during glucose-induced insulin secretion, as well as the propeptide-processing enzymes PC1/3 and PC2. Given the common expression of functionally specific proteins in taste buds and islets, it is surprising that no one has investigated whether insulin is synthesized in taste bud cells. Using immunofluorescence, we demonstrated the presence of insulin in mouse, rat, and human taste bud cells. By detecting the postprocessing insulin molecule C-peptide and green fluorescence protein (GFP) in taste cells of both insulin 1-GFP and insulin 2-GFP mice and the presence of the mouse insulin transcript by in situ hybridization, we further proved that insulin is synthesized in individual taste buds and not taken up from the parenchyma. In addition to our cytology data, we measured the level of insulin transcript by quantitative RT-PCR in the anterior and posterior lingual epithelia. These analyses showed that insulin is translated in the circumvallate and foliate papillae in the posterior, but only insulin transcript was detected in the anterior fungiform papillae of the rodent tongue. Thus, some taste cells are insulin-synthesizing cells generated from a continually replenished source of precursor cells in the adult mammalian lingual epithelium.

Taste bud

Lingual papilla

Pancreatic Islets

10.1210/en.2018-00534

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Tomografía digital y COVID-19: un avance en la valoración de opacidades pulmonares./ Tomografía digital y COVID-19: un avance en la valoración de opacidades pulmonares./ Digital Tomosynthesis and COVID-19: An Improvement in the Assessment of Pulmonary Opacities.

Archivos de Bronconeumología (2020)

Inmaculada Calvo Sara Santa-Cruz Calvo María Gracia Aranzana Patricia Mármol Jorge Ángel Luque

2019-20 coronavirus outbreak

Betacoronavirus

Tomosynthesis

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T cells dominate peripheral inflammation in a cross‐sectional analysis of obesity‐associated diabetes

Obesity (2022)

Gabriella H. Pugh Sajjad Fouladvand Sara Santa-Cruz Calvo Madhur Agrawal Xiaohua Douglas Zhang

Myeloid cells dominate metabolic disease-associated inflammation (metaflammation) in mouse obesity, but the contributions of myeloid cells to the peripheral inflammation that fuels sequelae of human obesity are untested. This study used unbiased approaches to rank contributions of myeloid and T cells to peripheral inflammation in people with obesity across the spectrum of metabolic health.

Prediabetes

10.1002/oby.23528

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Resveratrol: an ergogenic compound

Revista Portuguesa de Pneumologia (2009)

Elisabet Rodríguez-Bies Sara Santa-Cruz Calvo Plácido Navas Guillermo López‐Lluch

Sedentary lifestyle

Calorie Restriction

Elderly people

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