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6 results on '"Michael D. McHugh"'

1. Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin

Author

Michael D McHugh, Tarek M. Fahmy, Sean Bickerton, Jung Seok Lee, Ragy Ragheb, Rabib Chaudhury, David A. Horwitz, Shihan N. Khan, Alyssa Siefert, Robert M. Samstein, Karlo Perica, José M. Carballido, Gerald Rea, Dongin Kim, Hyun Bong Park, Jason M. Criscione, and Patrick Han

Subjects
Type 1 diabetes, Chemistry, Insulin, medicine.medical_treatment, Biomedical Engineering, Medicine (miscellaneous), Bioengineering, Inflammation, Pharmacology, medicine.disease, G protein-coupled bile acid receptor, Ursodeoxycholic acid, Intestinal absorption, Computer Science Applications, Diabetes mellitus, medicine, Nanocarriers, medicine.symptom, Biotechnology, medicine.drug
Abstract

Oral formulations of insulin are typically designed to improve its intestinal absorption and increase its blood bioavailability. Here we show that polymerized ursodeoxycholic acid, selected from a panel of bile-acid polymers and formulated into nanoparticles for the oral delivery of insulin, restored blood-glucose levels in mice and pigs with established type 1 diabetes. The nanoparticles functioned as a protective insulin carrier and as a high-avidity bile-acid-receptor agonist, increased the intestinal absorption of insulin, polarized intestinal macrophages towards the M2 phenotype, and preferentially accumulated in the pancreas of the mice, binding to the islet-cell bile-acid membrane receptor TGR5 with high avidity and activating the secretion of glucagon-like peptide and of endogenous insulin. In the mice, the nanoparticles also reversed inflammation, restored metabolic functions and extended animal survival. When encapsulating rapamycin, they delayed the onset of diabetes in mice with chemically induced pancreatic inflammation. The metabolic and immunomodulatory functions of ingestible bile-acid-polymer nanocarriers may offer translational opportunities for the prevention and treatment of type 1 diabetes.

Published
2021
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2. Author Correction: Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin

Author

Sean Bickerton, Robert M. Samstein, Hyun Bong Park, José M. Carballido, Jung Seok Lee, Gerald Rea, Dongin Kim, Ragy Ragheb, Michael D McHugh, Alyssa Siefert, Patrick Han, Rabib Chaudhury, Jason M. Criscione, Tarek M. Fahmy, David A. Horwitz, Shihan N. Khan, and Karlo Perica

Subjects
Type 1 diabetes, Bile acid, medicine.drug_class, business.industry, Insulin, medicine.medical_treatment, Biomedical Engineering, Medicine (miscellaneous), Bioengineering, Pharmacology, medicine.disease, Computer Science Applications, medicine, Nanocarriers, business, Biotechnology
Published
2021
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3. Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin

Author

Jung Seok, Lee, Patrick, Han, Rabib, Chaudhury, Shihan, Khan, Sean, Bickerton, Michael D, McHugh, Hyun Bong, Park, Alyssa L, Siefert, Gerald, Rea, José M, Carballido, David A, Horwitz, Jason, Criscione, Karlo, Perica, Robert, Samstein, Ragy, Ragheb, Dongin, Kim, and Tarek M, Fahmy

Subjects
Bile Acids and Salts, Sirolimus, Mice, Diabetes Mellitus, Type 1, Glucagon-Like Peptide 1, Polymers, Swine, Animals, Bile, Insulin, Receptors, G-Protein-Coupled
Abstract

Oral formulations of insulin are typically designed to improve its intestinal absorption and increase its blood bioavailability. Here we show that polymerized ursodeoxycholic acid, selected from a panel of bile-acid polymers and formulated into nanoparticles for the oral delivery of insulin, restored blood-glucose levels in mice and pigs with established type 1 diabetes. The nanoparticles functioned as a protective insulin carrier and as a high-avidity bile-acid-receptor agonist, increased the intestinal absorption of insulin, polarized intestinal macrophages towards the M2 phenotype, and preferentially accumulated in the pancreas of the mice, binding to the islet-cell bile-acid membrane receptor TGR5 with high avidity and activating the secretion of glucagon-like peptide and of endogenous insulin. In the mice, the nanoparticles also reversed inflammation, restored metabolic functions and extended animal survival. When encapsulating rapamycin, they delayed the onset of diabetes in mice with chemically induced pancreatic inflammation. The metabolic and immunomodulatory functions of ingestible bile-acid-polymer nanocarriers may offer translational opportunities for the prevention and treatment of type 1 diabetes.

Published
2019

4. Paracrine co-delivery of TGF-β and IL-2 using CD4-targeted nanoparticles for induction and maintenance of regulatory T cells

Author

Tarek M. Fahmy, Michael D McHugh, David A. Horwitz, Ross Uhrich, Wenda Gao, and Jason Park

Subjects
Interleukin 2, Regulatory T cell, T cell, Biophysics, Bioengineering, Inflammation, medicine.disease_cause, T-Lymphocytes, Regulatory, Article, Autoimmunity, Proinflammatory cytokine, Cell Line, Biomaterials, Paracrine signalling, Mice, Transforming Growth Factor beta, medicine, Animals, Mice, Inbred BALB C, biology, Transforming growth factor beta, Mice, Inbred C57BL, medicine.anatomical_structure, Mechanics of Materials, Immunology, CD4 Antigens, Ceramics and Composites, biology.protein, Interleukin-2, Nanoparticles, Female, medicine.symptom, medicine.drug
Abstract

The cytokine milieu is critical for orchestration of lineage development towards effector T cell (Teff) or regulatory T cell (Treg) subsets implicated in the progression of cancer and autoimmune disease. Importantly, the fitness and survival of the Treg subset is dependent on the cytokines Interleukin-2 (IL-2) and transforming growth factor beta (TGF-β). The production of these cytokines is impaired in autoimmunity increasing the probability of Treg conversion to aggressive effector cells in a proinflammatory microenvironment. Therapy using soluble TGF-β and IL-2 administration is hindered by the cytokines' toxic pleiotropic effects and hence bioavailability to CD4(+) T cell targets. Thus, there is a clear need for a strategy that rectifies the cytokine milieu in autoimmunity and inflammation leading to enhanced Treg stability, frequency and number. Here we show that inert biodegradable nanoparticles (NP) loaded with TGF-β and IL-2 and targeted to CD4(+) cells can induce CD4(+) Tregs in-vitro and expand their number in-vivo. The stability of induced Tregs with cytokine-loaded NP was enhanced leading to retention of their suppressive phenotype even in the presence of proinflammatory cytokines. Our results highlight the importance of a nanocarrier-based approach for stabilizing and expanding Tregs essential for cell-immunotherapy of inflammation and autoimmune disease.

Published
2015

5. Acute exposure to ZnO nanoparticles induces autophagic immune cell death

Author

Donald T. Gracias, Joseph A. Fraietta, Jennifer L. Hope, Michael D McHugh, Christopher J Stairiker, Brandon M. Johnson, Lauren J. Jablonowski, Peter D. Katsikis, Margaret A. Wheatley, Prachi R. Patel, Yvonne M. Mueller, and Immunology

Subjects
inorganic chemicals, Programmed cell death, Materials science, Cell Survival, Surface Properties, T-Lymphocytes, Necroptosis, Biomedical Engineering, Toxicology, Jurkat Cells, Immune system, Autophagy, Animals, Humans, Particle Size, Dose-Response Relationship, Drug, Pyroptosis, Flow Cytometry, Cell biology, Mice, Inbred C57BL, Apoptosis, Nanotoxicology, Immunology, Nanoparticles, Female, Zinc Oxide, Reactive Oxygen Species, Spleen, Intracellular
Abstract

The increasing risk of incidental exposure to nanomaterials has led to mounting concerns regarding nanotoxicity. Zinc oxide nanoparticles (ZnO NPs) are produced in large quantities and have come under scrutiny due to their capacity to cause cytotoxicity in vitro and potential to cause harm in vivo. Recent evidence has indicated that ZnO NPs promote autophagy in cells; however, the signaling pathways and the role of ion release inducing toxicity remain unclear. In this study, we report that ZnO NPs are immunotoxic to primary and immortalized immune cells. Importantly, such immunotoxicity is observed in mice in vivo, since death of splenocytes is seen after intranasal exposure to ZnO NPs. We determined that ZnO NPs release free Zn(2+) that can be taken up by immune cells, resulting in cell death. Inhibiting free Zn(2+) ions in solution with EDTA or their uptake with CaCl2 abrogates ZnO NP-induced cell death. ZnO NP-mediated immune cell death was associated with increased levels of intracellular reactive oxygen species (ROS). ZnO NP death was not due to apoptosis, necroptosis or pyroptosis. Exposure of immune cells to ZnO NPs resulted in autophagic death and increased levels of LC3A, an essential component of autophagic vacuoles. Accordingly, ZnO NP-mediated upregulation of LC3A and induction of immune cell death were inhibited by blocking autophagy and ROS production. We conclude that release of Zn(2+) from ZnO NPs triggers the production of excessive intracellular ROS, resulting in autophagic death of immune cells. Our findings suggest that exposure to ZnO NPs has the potential to impact host immunity.

Published
2015

6. Abstracts

Author

W. A. C. Mutch, I. W. C. White, N. Donen, I. R. Thomson, M. Rosenbloom, M. Cheang, M. West, Greg Bryson, Christina Mundi, Jean-Yves Dupuis, Michael Bourke, Paul McDonagh, Michael Curran, John Kitts, J. Earl Wynands, Alison S. Carr, Elizabeth J. Hartley, Helen M. Holtby, Peter Cox, Bruce A. Macpherson, James E. Baker, Andrew J. Baker, C. David Mazer, C. Peniston, T. David, D. C. H. Cheng, J. Karski, B. Asokumar, J. Carroll, H. Nierenberg, S. Roger, A. N. Sandier, J. Tong, C. M. Feindel, J. F. Boylan, S. J. Teasdale, J. Boylan, P. Harley, Jennifer E. Froelich, David P. Archer, Alastair Ewen, Naaznin Samanani, Sheldon H. Roth, Richard I. Hall, Michael Neumeister, Gwen Dawe, Cathy Cody, Randy O’Brien, Jan Shields-Thomson, Kenneth M. LeDez, Catherine Penney, Walter Snedden, John Tucker, Nicolas Fauvel, Mladen Glavinovic, François Donati, S. B. Backman, R. D. Stein, C. Polosa, C. Abdallah, S. Gal, A. John Clark, George A. Doig, Tunde Gondocz, E. A. Peter, A. Lopez, A. Mathieu, Pierre Couture, Daniel Boudreault, Marc Derouin, Martin Allard, Gilbert Blaise, Dominique Girard, Richard L. Knill, Teresa Novick, Margaret K. Vandervoort, Frances Chung, Shantha Paramanathar, Smita Parikh, Charles Cruise, Christina Michaloliakou, Brenda Dusek, D. K. Rose, M. M. Cohen, D. DeBoer, George Shorten, Earnest Cutz, Jerrold Lerman, Myrna Dolovich, Edward T. Crosby, Robert Cirone, Dennis Reid, Joanne Lind, Melanie Armstrong, Wanda Doyle, S. Halpern, P. Glanc, T. Myhr, M -L. Ryan, K. Fong, K. Amankwah, A. Ohlsson, R. Preston, Andor Petras, Michael J. Jacka, Brian Milne, Kanji Nakatsu, S. Pancham, Graeme Smith, Kush N. Duggal, M. Joanne Douglas, Pamela M. Merrick, Philip Blew, Donald Miller, Raymond Martineau, Kathryn Hull, C. M. Baron, S. Kowalskl, R. Greengrass, T. Horan, H. Unruh, C. L. Baron, Patricia M. Cruchley, K. Nakajima, Y. Sugiura, Y. Goto, K. Takakura, J. Harada, Robert M. K. W. Lee, Angelica M. Fargas-Babjak, Jin Ni, Eva S. Werstiuk, Joseph Woo, David H. Morison, Michael D. McHugh, Hanna M. Pappius, Hironori Ishihara, Yuki Shimodate, Hiroaki Koh, Akitomo Matsuki, John W. R. Mclntyre, Pierre Bergeron, Lulz G. R. DeLima, Jean-Yves Dupuls, James Enns, J. M. Murkin, F. N. McKenzie, S. White, N. A. Shannon, Wojciech B. Dobkowski, Judy L. Kutt, Bernard J. Mezon, David R. Grant, William J. Wall, Dennis D. Doblar, Yong C. Lim, Luc Frenette, Jaime R. Ronderos, Steve Poplawski, Dinesh Ranjan, L. Dubé, L. Van Obbergh, M. Francoeur, C. Blouin, R. Carrier, D. Doblar, J. Ronderos, D. Singer, J. Cox, B. Gosdin, M. Boatwright, Charles E. Smith, Aleksandr Rovner, Carlos Botero, Curt Holbrook, Nileshkumar Patel, Alfred Pinchak, Alfred C. Pinchak, Yin James Kao, Andrew Thio, Steven J. Barker, Patrick Sullivan, Matthew Posner, C. William Cole, Patty Lindsay, Paul B. Langevin, Paul A. Gulig, N. Gravenstein, David T. Wong, Manuel Gomez, Glenn P. McGuire, Robert J. Byrick, Shared K. Sharma, Frederick J. Carmicheal, Walter J. Montanera, Sharad Sharma, D. A. Yee, Basem I. Naser, G. L. Bryson, J. B. Kitts, D. R. Miller, R. J. Martineau, M. J. Curran, P. R. Bragg, Jacek M. Karski, Davy Cheng, Kevin Bailey, S. Levytam, R. Arellano, J. Katz, J. Doyle, Mitchel B. Sosis, William Blazek, G. Plourde, A. Malik, Tammy Peddle, James Au, Jeffrey Sloan, Mark Cleland, Donald E. Hancock, Nilesh Patel, Frank Costello, Louise Patterson, Masao Yamashita, Tsukasa Kondo, M. R. Graham, D. Thiessen, David F. Vener, Thomas Long, S. Marion, D. J. Steward, Berton Braverman, Mark Levine, Steve Yentis, Catherine R. Bachman, Murray Kopelow, Ann McNeill, R. Graham, Norbert Froese, Leena Patel, Heinz Reimer, Jo Swartz, Suzanne Ullyot, Harley Wong, Maria A. Markakis, Nancy Siklch, Blair D. Goranson, Scott A. Lang, Martin J. Stockwell, Bibiana Cujec, Raymond W. Yip, Lucy C. Southeriand, Tanya Duke B. Vet, Jeisane M. Gollagher, Lesley-Ann Crone, James G. Ferguson, Demetrius Litwin, Maria Bertlik, Beverley A. Orser, Lu-Wang Yang, John F. MacDonald, Gary F. Morris, Wendy L. Gore-Hickman, J. E. Zamora, O. P. Rosaeg, M. P. Lindsay, M. L. Crossan, Carol Pattee, Michael Adams, John P. Koller, Guy J. Lavoie, Wynn M. Rigal, Dylan A. Taylor, Michael G. Grace, Barry A. Flnegan, Christopher Hawkes, Harry Hopkins, Michael Tierney, David R. Drover, Gordon Whatley, J. W. Donald Knox, Jarmila Rausa, Hossam El-Beheiry, Ronald Seegobin, Georgia C. Hirst, William N. Dust, J. David Cassidy, D. Boisvert, H. Braden, M. L. Halperin, S. Cheema-Dhadli, D. J. McKnight, W. Singer, Thomas Elwood, Shirley Huchcroft, Charles MacAdams, R. Peter Farran, Gerald Goresky, Phillip LaLande, Gilles Lacroix, Martin Lessard, Claude Trépanier, Janet M. van Vlymen, Joel L. Parlow, Chikwendu Ibebunjo, Arnold H. Morscher, Gregory J. Gordon, H. P. Grocott, Susan E. Belo, Georgios Koutsoukos, Susan Belo, David Smith, Sarah Henderson, Adriene Gelb, G. Kantor, N. H. Badner, W. E. Komar, R. Bhandari, D. Cuillerier, W. Dobkowski, M. H. Smith, A. N. Vannelli, Sean Wharton, Mike Tierney, E. Redmond, E. Reddy, A. Gray, J. Flynn, R. B. Bourne, C. H. Rorabeck, S. J. MacDonald, J. A. Doyle, Peter T. Newton, Carol A. Moote, R. Joiner, M. F. X. Glynn, Vytas Zulys, M. Hennessy, T. Winton, W. Demajo, William P. S. McKay, Peter H. Gregson, Benjamin W. S. McKay, Julio Militzer, Eric Hollebone, Raymond Yee, George Klein, R. L. Garnett, J. Conway, F. E. Ralley, G. R. Robbins, James E. Brown, J. V. Frei, Edward Podufal, Norman J. Snow, Altagracia M. Chavez, Richard P. Kramer, D. Mickle, William A. Tweed, Bisharad M. Shrestha, Narendra B. Basnyat, Bhawan D. Lekhak, Susan D. O’Leary, J. K. Maryniak, John H. Tucker, Cameron B. Guest, J. Brendan Mullen, J. Colin Kay, Dan F. Wigglesworth, Mashallah Goodarzi, Nicte Ha Shier, John A. Ogden, O. R. Hung, S. Pytka, M. F. Murphy, B. Martin, and R. D. Stewart

Subjects
Anesthesiology and Pain Medicine, General Medicine
Published
1994
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