CONTADOR MARTINEZ, DAVID ERNESTO
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CONTADOR MARTINEZ, DAVID ERNESTO
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dcontador@udd.cl
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8251610900

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Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice

2020 , DE GREGORIO CONCHA, CRISTIAN ALEJANDRO , CONTADOR MARTINEZ, DAVID ERNESTO , Cristian Acosta , Diego Díaz , Constanza Cárcamo , Daniela Santapau , Lorena Lobos-Gonzalez , Mario Campero , Daniel Carpio , Caterina Gabriele , Marco Gaspari , Victor Aliaga-Tobar , Vinicius Maracaja-Coutinho , EZQUER, EDUARDO MARCELO , EZQUER, EDUARDO FERNANDO

Abstract Background Diabetic polyneuropathy (DPN) is the most common and early developing complication of diabetes mellitus, and the key contributor for foot ulcers development, with no specific therapies available. Different studies have shown that mesenchymal stem cell (MSC) administration is able to ameliorate DPN; however, limited cell survival and safety reasons hinder its transfer from bench to bedside. MSCs secrete a broad range of antioxidant, neuroprotective, angiogenic, and immunomodulatory factors (known as conditioned medium), which are all decreased in the peripheral nerves of diabetic patients. Furthermore, the abundance of these factors can be boosted in vitro by incubating MSCs with a preconditioning stimulus, enhancing their therapeutic efficacy. We hypothesize that systemic administration of conditioned medium derived from preconditioned MSCs could reverse DPN and prevent foot ulcer formation in a mouse model of type II diabetes mellitus. Methods Diabetic BKS db/db mice were treated with systemic administration of conditioned medium derived from preconditioned human MSCs; conditioned medium derived from non-preconditioned MSCs or vehicle after behavioral signs of DPN was already present. Conditioned medium or vehicle administration was repeated every 2 weeks for a total of four administrations, and several functional and structural parameters characteristic of DPN were evaluated. Finally, a wound was made in the dorsal surface of both feet, and the kinetics of wound closure, re-epithelialization, angiogenesis, and cell proliferation were evaluated. Results Our molecular, electrophysiological, and histological analysis demonstrated that the administration of conditioned medium derived from non-preconditioned MSCs or from preconditioned MSCs to diabetic BKS db/db mice strongly reverts the established DPN, improving thermal and mechanical sensitivity, restoring intraepidermal nerve fiber density, reducing neuron and Schwann cell apoptosis, improving angiogenesis, and reducing chronic inflammation of peripheral nerves. Furthermore, DPN reversion induced by conditioned medium administration enhances the wound healing process by accelerating wound closure, improving the re-epithelialization of the injured skin and increasing blood vessels in the wound bed in a skin injury model that mimics a foot ulcer. Conclusions Studies conducted indicate that MSC-conditioned medium administration could be a novel cell-free therapeutic approach to reverse the initial stages of DPN, avoiding the risk of lower limb amputation triggered by foot ulcer formation and accelerating the wound healing process in case it occurs.

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Status and Trends of Physical Activity Surveillance, Policy, and Research in 164 Countries: Findings From the Global Observatory for Physical Activity—GoPA! 2015 and 2020 Surveys

2023 , Andrea Ramírez Varela , Pedro C. Hallal , Juliana Mejía Grueso , Željko Pedišić , Deborah Salvo , Anita Nguyen , Bojana Klepac , Adrian Bauman , Katja Siefken , Erica Hinckson , Adewale L. Oyeyemi , Justin Richards , Elena Daniela Salih Khidir , Shigeru Inoue , Shiho Amagasa , Alejandra Jauregui , Marcelo Cozzensa da Silva , I-Min Lee , Melody Ding , Harold W. Kohl , Ulf Ekelund , Gregory W. Heath , Kenneth E. Powell , Charlie Foster , Aamir Raoof Memon , Abdoulaye Doumbia , Abdul Roof Rather , Abdur Razzaque , Adama Diouf , Adriano Akira Hino , Albertino Damasceno , Alem Deksisa Abebe , Alex Antonio Florindo , Alice Mannocci , Altyn Aringazina , Andrea Backović Juričan , Andrea Poffet , Andrew Decelis , Angela Carlin , Angelica Enescu , Angélica María Ochoa Avilés , Anna Kontsevaya , Annamaria Somhegyi , Anne Vuillemin , Asmaa El Hamdouchi , Asse Amangoua Théodore , Bojan Masanovic , Brigid M. Lynch , Catalina Medina , Cecilia del Campo , Chalchisa Abdeta , Changa Moreways , Chathuranga Ranasinghe , Christina Howitt , Christine Cameron , Danijel Jurakić , CONTADOR MARTINEZ, DAVID ERNESTO , Dawn Tladi , Debrework Tesfaye Diro , Deepti Adlakha , Dušan Mitić , Duško Bjelica , Elżbieta Biernat , Enock M. Chisati , Estelle Victoria Lambert , Ester Cerin , Eun-Young Lee , Eva-Maria Riso , Felicia Cañete Villalba , Felix Assah , Franjo Lovrić , Gerardo A. Araya-Vargas , Giuseppe La Torre , Gloria Isabel Niño Cruz , Gul Baltaci , Haleama Al Sabbah , Hanna Nalecz , Hilde Liisa Nashandi , Hyuntae Park , Inés Revuelta-Sánchez , Jackline Jema Nusurupia , LEPPE ZAMORA, JAIME ESTEBAN , Jaroslava Kopcakova , Javier Brazo-Sayavera , Jean-Michel Oppert , Jinlei Nie , John C. Spence , John Stewart Bradley , Jorge Mota , Josef Mitáš , Junshi Chen , Kamilah S Hylton , Karel Fromel , Karen Milton , Katja Borodulin , Keita Amadou Moustapha , Kevin Martinez-Folgar , Lara Nasreddine , Lars Breum Christiansen , Laurent Malisoux , Leapetswe Malete , Lorelie C. Grepo-Jalao , Luciana Zaranza Monteiro , Lyutha K. Al Subhi , Maja Dakskobler , Majed Alnaji , Margarita Claramunt Garro , Maria Hagströmer , Marie H. Murphy , Matthew  Mclaughlin , Mercedes Rivera-Morales , Mickey Scheinowitz , Mimoza Shkodra , Monika Piątkowska , Moushumi Chaudhury , Naif Ziyad Alrashdi , Nanette Mutrie , Niamh Murphy , Norhayati Haji Ahmad , Nour A. Obeidat , Nubia Yaneth Ruiz Gómez , Nucharapon Liangruenrom , Oscar Díaz Arnesto , Oscar Flores-Flores , Oscar Incarbone , Oyun Chimeddamba , Pascal Bovet , Pedro Magalhães , Pekka Jousilahti , Piyawat Katewongsa , Rafael Alexander Leandro Gómez , Rawan Awni Shihab , Reginald Ocansey , Réka Veress , Richard Marine , Rolando Carrizales-Ramos , Saad Younis Saeed , Said El-Ashker , Samuel Green , Sandra Kasoma , Santiago Beretervide , Se-Sergio Baldew , Selby Nichols , Selina Khoo , Seyed Ali Hosseini , Shifalika Goenka , Shima Gholamalishahi , Soewarta Kosen , Sofie Compernolle , Stefan Paul Enescu , Stevo Popovic , Susan Paudel , Susana Andrade , Sylvia Titze , Tamu Davidson , Theogene Dusingizimana , Thomas E. Dorner , Tracy L. Kolbe-Alexander , Tran Thanh Huong , Vanphanom Sychareun , Vera Jarevska-Simovska , Viliami Kulikefu Puloka , Vincent Onywera , Wanda Wendel-Vos , Yannis Dionyssiotis , Michael Pratt

Background: Physical activity (PA) surveillance, policy, and research efforts need to be periodically appraised to gain insight into national and global capacities for PA promotion. The aim of this paper was to assess the status and trends in PA surveillance, policy, and research in 164 countries. Methods: We used data from the Global Observatory for Physical Activity (GoPA!) 2015 and 2020 surveys. Comprehensive searches were performed for each country to determine the level of development of their PA surveillance, policy, and research, and the findings were verified by the GoPA! Country Contacts. Trends were analyzed based on the data available for both survey years. Results: The global 5-year progress in all 3 indicators was modest, with most countries either improving or staying at the same level. PA surveillance, policy, and research improved or remained at a high level in 48.1%, 40.6%, and 42.1% of the countries, respectively. PA surveillance, policy, and research scores decreased or remained at a low level in 8.3%, 15.8%, and 28.6% of the countries, respectively. The highest capacity for PA promotion was found in Europe, the lowest in Africa and low- and lower-middle-income countries. Although a large percentage of the world’s population benefit from at least some PA policy, surveillance, and research efforts in their countries, 49.6 million people are without PA surveillance, 629.4 million people are without PA policy, and 108.7 million live in countries without any PA research output. A total of 6.3 billion people or 88.2% of the world’s population live in countries where PA promotion capacity should be significantly improved. Conclusion: Despite PA is essential for health, there are large inequalities between countries and world regions in their capacity to promote PA. Coordinated efforts are needed to reduce the inequalities and improve the global capacity for PA promotion.

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The Antidiabetic Effect of Mesenchymal Stem Cells Is Unrelated to Their Transdifferentiation Potential But to Their Capability to Restore Th1/Th2 Balance and to Modify the Pancreatic Microenvironment

2012 , EZQUER, EDUARDO FERNANDO , EZQUER, EDUARDO MARCELO , CONTADOR MARTINEZ, DAVID ERNESTO , Ricca, Micaela , Simon, Valeska , CONGET MOLINA, PAULETTE ANDREA

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Administration of secretome derived from human mesenchymal stem cells prevents diabetic neuropathy progression in an animal model of type 2 diabetes

2019 , EZQUER, EDUARDO FERNANDO , DE GREGORIO CONCHA, CRISTIAN ALEJANDRO , CONTADOR MARTINEZ, DAVID ERNESTO , Campero, M. , Santapau, D , EZQUER, EDUARDO MARCELO

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Characterization of diabetic neuropathy progression in a mouse model of type 2 diabetes mellitus

2018 , DE GREGORIO CONCHA, CRISTIAN ALEJANDRO , CONTADOR MARTINEZ, DAVID ERNESTO , Mario Campero , EZQUER, EDUARDO MARCELO , EZQUER, EDUARDO FERNANDO

Diabetes mellitus (DM) is one of most frequent chronic diseases with an increasing incidence in most countries. Diabetic neuropathy (DN) is one of the earliest and main complications of diabetic patients, which is characterized by progressive, distal-to-proximal degeneration of peripheral nerves. The cellular and molecular mechanisms that trigger DN are highly complex, heterogeneous and not completely known. Animal models have constituted a valuable tool for understanding diabetes pathophysiology; however, the temporal course of DN progression in animal models of type 2 diabetes (T2DM) is not completely understood. In this work, we characterized the onset and progression of DN in BKS db/db mice, including the main functional and histological features observed in the human disease. We demonstrated that diabetic animals display a progressive sensory loss and electrophysiological impairments in early-to-mid phases of disease. Furthermore, we detected an early decrease in intraepidermal nerve fibers (IENF) density in 18-week-old diabetic mice, which is highly associated with sensory loss and constitutes a reliable marker of DN. Other common histological parameters of DN, like Schwann cells apoptosis and infiltration of CD3+ cells in the sciatic nerve, were altered in mid-to-late phases of disease. Our results support the general consensus that DN evolves from initial functional to late structural changes. This work aimed to characterize the progression of DN in a reliable animal model sharing the main human disease features, which is necessary to assess new therapies for this complex disease. Finally, we also aimed to identify an effective temporal window where these potential treatments could be successfully applied.

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Human renal adipose tissue induces the invasion and progression of renal cell carcinoma

2017 , Peng Liu , Zhipeng Wang , Sarah Brown , Vinodh Kannappan , Patricia Erebi Tawari , Wenguo Jiang , Juan M. Irache , James Z. Tang , Stephen Britland , Angel L. Armesilla , John L. Darling , Xing Tang , Weiguang Wang , CONTADOR MARTINEZ, DAVID ERNESTO

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Renal peritumoral adipose tissue undergoes a browning process and stimulates the expression of epithelial-mesenchymal transition markers in human renal cells

2022 , Matías Ferrando , Flavia Alejandra Bruna , Leonardo Rafael Romeo , CONTADOR MARTINEZ, DAVID ERNESTO , Daiana Lorena Moya-Morales , Flavia Santiano , Leila Zyla , Silvina Gomez , Constanza Matilde Lopez-Fontana , Juan Carlos Calvo , Rubén Walter Carón , Judith Toneatto , Virginia Pistone-Creydt

AbstractTumor cells can interact with neighboring adipose cells and adipocyte dedifferentiation appears to be an important aspect of tumorigenesis. We evaluated the size of adipocytes in human adipose explants from normal (hRAN) and kidney cancer (hRAT); changes in the expression of WAT and BAT/beige markers in hRAN and hRAT; the expression of epithelial-mesenchymal transition (EMT) cell markers in human kidney tumor (786-O, ACHN and Caki-1); and non-tumor (HK-2) epithelial cell lines incubated with the conditioned media (CMs) of hRAN and hRAT. We observed that hRAT adipocytes showed a significantly minor size compared to hRAN adipocytes. Also, we observed that both Prdm16 and Tbx1 mRNA and the expression of UCP1, TBX1, PPARγ, PCG1α, c/EBPα LAP and c/EBPα LIP was significantly higher in hRAT than hRAN. Finally, we found an increase in vimentin and N-cadherin expression in HK-2 cells incubated for 24 h with hRAT-CMs compared to hRAN- and control-CMs. Furthermore, desmin and N-cadherin expression also increased significantly in 786-O when these cells were incubated with hRAT-CMs compared to the value observed with hRAN- and control-CMs. We observed a significant decrease in E-cadherin expression in the ACHN cell line incubated with hRAT-CMs versus hRAN- and control-CMs. However, we did not observe changes in E-cadherin expression in HK-2, 786-O or Caki-1. The results obtained, together with the results previously published by our group, allow us to conclude that perirenal white adipose tissue browning contributes to tumor development in kidney cancer. In addition, hRAT-CMs increases the expression of mesenchymal markers in renal epithelial cells, which could indicate a regulation of EMT due to this adipose tissue.

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Human renal adipose tissue from normal and tumor kidney: its influence on renal cell carcinoma

2019 , Stephanie L. Smith-Roe , Jun Nakamura , Darcy Holley , Paul D. Chastain , Gary B. Rosson , Dennis A. Simpson , John R. Ridpath , David G. Kaufman , William K. Kaufmann , Scott J. Bultman , CONTADOR MARTINEZ, DAVID ERNESTO

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Dexamethasone and rosiglitazone are sufficient and necessary for producing functional adipocytes from mesenchymal stem cells

2015 , CONTADOR MARTINEZ, DAVID ERNESTO , EZQUER, EDUARDO FERNANDO , Maximiliano Espinosa , Martha Arango-Rodriguez , Carlos Puebla , Luis Sobrevia , CONGET MOLINA, PAULETTE ANDREA

The final product of adipogenesis is a functional adipocyte. This mature cell acquires the necessary machinery for lipid metabolism, loses its proliferation potential, increases its insulin sensitivity, and secretes adipokines. Multipotent mesechymal stromal cells have been recognized as a source of adipocytes both in vivo and in vitro. The in vitro adipogenic differentiation of human MSC (hMSC) has been induced up to now by using a complex stimulus which includes dexamethasone, 3-isobutyl-1-methylxanthine, indomethacin, and insulin (a classical cocktail) and evaluated according to morphological changes. The present work was aimed at demonstrating that the simultaneous activation of dexamethasone’s canonical signaling pathways, through the glucocorticoid receptor and CCAAT-enhancer-binding proteins ( C/EBPs) and rosiglitazone through peroxisome proliferator-activated receptor gamma ( PPAR-gamma) is sufficient yet necessary for inducing hMSC adipogenic differentiation. It was also ascertained that hMSC exposed just to dexamethasone and rosiglitazone (D&R) differentiated into cells which accumulated neutral lipid droplets, expressed C/EBP-alpha, PPAR-gamma, aP2, lipoprotein lipase, acyl-CoA synthetase, phosphoenolpyruvate carboxykinase, adiponectin, and leptin genes but did not proliferate. Glucose uptake was dose dependent on insulin stimulus and high levels of adipokines were secreted (i.e. displaying not only the morphology but also expressing mature adipocytes’ specific genes and functional characteristics). This work has demonstrated that (i) the activating C/EBPs and PPAR-gamma signaling pathways were sufficient to induce adipogenic differentiation from hMSC, (ii) D&R producing functional adipocytes from hMSC, (iii) D&R induce adipogenic differentiation from mammalian MSC (including those which are refractory to classical adipogenic differentiation stimuli). D&R would thus seem to be a useful tool for MSC characterization, studying adipogenesis pathways and producing functional adipocytes.

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Characterisation of an animal model of type 2 diabetes with potential application in the evaluation of new therapies for diabetic neuropathy

2018 , EZQUER, EDUARDO MARCELO , DE GREGORIO CONCHA, CRISTIAN ALEJANDRO , CONTADOR MARTINEZ, DAVID ERNESTO , Daniela Santapau , Campero, M

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