129 results on '"Gorelick, F"'
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2. 200 TOBACCO TOXIN NNK MEDIATES ACUTE PANCREATITIS RESPONSES
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Alexandre, M., Akinbiyi, E., Uduman, A. K., Shugrue, C., Kolodecik, T., Picciotto, M. R., Gorelick, F., and Thrower, E.
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- 2013
3. Effect of ligands that increase cAMP on caerulein-induced zymogen activation in pancreatic acini
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Lu, Z., Kolodecik, T.R., Karne, S., Nyce, M., and Gorelick, F.
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Chymotrypsin -- Research ,Biological sciences - Abstract
Lu, Z., T. R. Kolodecik, S. Karne, M. Nyce, and F. Gorelick. Effect of ligands that increase cAMP on caeruleininduced zymogen activation in pancreatic acini. Am J Physiol Gastrointest Liver Physiol 285: G822-G828, 2003. First published July 24, 2003; 10.1152/ajpgi.00213.2003.--The pathological activation of proteases within the pancreatic acinar cell is critical to initiating pancreatitis. Stimulation of acinar cells with supraphysiological concentrations of the CCK analog caerulein (CER) leads to protease activation and pancreatitis. Agents that sensitize the acinar cell to the effects of CCK might contribute to disease. The effects of physiological ligands that increase acinar cell cAMP [secretin, VIP, and pituitary adenylate cyclase activating peptide (PACAP)] on CER-induced responses were examined in isolated rat pancreatic acini. Each ligand sensitized the acinar cell to zymogen activation by physiological concentrations of CER (0.1 nM). VIP and PACAP but not secretin also enhanced activation by supraphysiological concentrations of CER (0.1 [micro]M). A cell-permeable cAMP analog also sensitized the acinar cell to CER-induced activation. The cAMP antagonist Rp-8-BrcAMP inhibited these sensitizing effects. These findings suggest that ligands that increase acinar cell cAMP levels can sensitize the acinar cell to the effects of CCK-induced zymogen activation. caerulein; chymotrypsin; secretin; trypsin
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- 2003
4. Effect of buprenorphine on pancreatic enzyme synthesis and secretion in normal rats and rats with acute edematous pancreatitis
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Ogden, J. M., Modlin, I. M., Gorelick, F. S., and Marks, I. N.
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- 1994
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5. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes
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Holman, Rr, Bethel, Ma, Mentz, Rj, Thompson, Vp, Lokhnygina, Y, Buse, Jb, Chan, Jc, Choi, J, Gustavson, Sm, Iqbal, N, Maggioni, Ap, Marso, Sp, Öhman, P, Pagidipati, Nj, Poulter, N, Ramachandran, A, Zinman, B, Hernandez, Af, EXSCEL Study Group, : Califf RM, Patel, R, George, J, Sourij, H, Wong, Yw, Hannan, K, Sellers, Ma, Gottlieb, P, Lavender, P, Leloudis, D, Meadows, Y, Larson, D, Anderson, H, Elkins, M, Stone, A, Tisch, A, Perkins, L, Sanders, K, Campbell, C, Kennedy, I, Heal, P, Masterson, M, Darbyshire, J, Mumtaz, L, Athwal, R, Ferch, A, Batra, P, Durborow, L, Vincent, J, Woodall, A, Flanagan, T, Katona, B, Reicher, B, Pozzi, E, Oulhaj, A, Coleman, R, Rouleau, Jl, Pocock, Sj, Gorelick, F, Mcmurray, J, Riddle, M, Gagel, R, Collier, T, Markovic, T, Kong, Aps, Hian, Sk, Scott, R, Panelo, A, Yoon, Kh, Sheu, W, Sritara, P, Linong, J, Pan, C, Yong, H, Schernthaner, G, Mathieu, C, Tankova, T, Widimsky, P, Hanefeld, M, Keltai, M, Wainstein, J, del Prato, S, Pirags, V, Jakuboniene, N, Kooy, A, Dziemidok, P, Veresiu, Ia, Dreval, Av, Murin, J, Torello, Al, Sattar, N, Parkhomenko, O, Omar, M, Diaz, R, Lopes, R, Lanas, F, Urina Triana, M, Leiva-Pons, Jl, Aguliera, D, Bergenstal, R, Goodman, S, Yale, Jf, Caterson, I, Weng, J, Hu, D, Junbo, G, Zannad, F, Anoop, M, Ambrish, M, Gallegos, Ja, Green, Jb, Akerblom, A, Alexander, K, Al-Khatib, S, Armaganijan, L, Barros, P, Batit, M, Bernacki, G, Bernandez, S, Bloomfield, G, Clausen, E, De Souza Brito, F, Devore, A, Dombrowski, K, Eapen, Z, Gellad, Z, George, D, Guimaraes, P, Halim, S, Harrison, R, Hawes, J, Hess, C, Hyland, K, Jackson, L, Jones, S, Jordan, D, Katz, M, Kong, D, Koshizaka, M, Lakey, W, Leblanc, T, Leonardi, S, Luo, N, Mahaffey, K, Mandawat, A, Mehta, R, Melloni, C, Morse, M, Pagidpati, N, Patel, C, Patel, K, Pokorney, S, Posvic, T, Rao, M, Roe, M, Shah, B, Tillmann, H, Truffa, A, Zazula, A, Zeitler, E, Sicer, M, Ulla, Mr, Maffei, L, Klyver, Mi, Calella, P, Alvarisqueta, A, De La Fuente RL, Aizenberg, D, Roque, F, Cruciani, A, Frechtel, G, Gelersztein, E, Villarino, A, Mallagray, M, Nardone, L, Zaidman, C, Novaretto, L, Bartolacci, I, de Salvo, M, Delcourt, C, Crimmins, D, Jackson, R, O’Neal, D, Colman, P, Jeffries, W, Mah, Pm, Wittert, G, Proietto, J, Amerena, J, Marks, S, Tan, R, Colquhoun, D, Pieber, T, Drexel, H, Prager, R, Schnack, C, Hoppichler, F, Fasching, P, Francesconi, C, Luger, A, Schoenherr, Hr, Ebenbichler, C, Paulweber, B, Shernthaner, G, Verhaegen, A, Vanuytsel, J, Thissen, Jp, e Silva P, Barros, Gonzaga, C, Borges, J, Hissa, M, Rea, R, Rossi, P, Chacra, A, Eliaschewitz, F, Garbelini, B, Felicio, J, Rassi, N, Rossi, F, Nunes dos Santos, M, e Farias F, Bandeira, Lisboa, H, e Forti A, Costa, Saraiva, Jk, Kovacheva, S, Levterov, G, Sheinkova, G, Ilieva, E, Lyubenova, L, Damyanova, V, Gushterova, V, Mincheva, L, Illiev, D, Ivanov, V, Bobeva, R, Nikitov, Z, Shumkova, R, Lefterov, In, Zaharieva, S, Videva, V, Yakov, A, Cheung, S, Elliott, T, Mehta, P, Ross, S, Sigal, R, Woo, V, Jaffer, S, Kuritsky, R, Bell, A, Dumas, R, Gosselin, G, Robitaille, Y, Greenspoon, A, Lochnan, H, Tytus, R, Leiter, L, Pandey, A, Punthakee, Z, Dube, F, Sigalas, J, Pearce, M, Woodford, T, Paul, P, Bourgeois, R, Conway, R, Mazza, G, Hatheway, R, Misterski, J, Raffo, C, Olivares, C, Godoy, J, Potthoff, S, Santibañez, C, Larenas Yanez GJ, Gu, W, Shen, F, Ma, J, Guo, X, Li, Q, Du, Y, Hu, J, Ji, L, Li, Y, Deng, H, Feng, Y, Liu, L, Mu, Y, Ma, C, Qu, S, Wang, J, Wang, Y, Yuan, Z, Zhang, L, Zhou, S, Yang, T, Dong, Y, Liu, D, Coronel Arroyo, J, Perez Amador, G, Botero Lopes, R, Jaramilo, C, Orozco Linares, A, Cure Cure CA, Hernandez Triana, E, Molina de Salazar DI, Marin, Cr, Jaramilo Gomez CJ, Kellinerova, I, Adamkova, V, Krami, P, Brychta, T, Havelkova, J, Pantikova, K, Schoper, F, Pohl, W, Schumm-Draeger, Pm, Julius, U, Tschöpe, D, Hamann, A, Seissler, J, Schellong, S, Rose, L, Becker, B, Linn, T, Oerter, Em, Strotmann, Hj, Mölle, A, Pfutzner, A, Forst, T, Schäufele, T, Mugge, A, Lehrke, M, Meyer-Pannwitt, U, Mehling, H, Simon-Wagner, I, Schenkenberger, I, Busch, K, Hermes, S, Milek, K, Landers, B, Grueneberg, M, Braun, M, Nothroff, J, Kamke, W, Hergdt, G, Duengen, Hd, Kleinertz, K, Kuesters, D, Boenninghoff, Ah, Appel, Kf, Schaefer, A, Bieler, T, Ozaki, R, Luk, Aoy, Chu, Dw, Cheung-Wong, Mm, Siu, Dc, Yan, Bpy, Kung, K, Wong, Sys, Tsang, Cc, Yeung, Vt, Cheung, Bm, Tse, Hf, Hodi, G, Nagy, K, Lippai, J, Takacs, J, Fulop, T, Gaal, Z, Pauker, Z, Foldesi, I, Simon, J, Oroszan, T, Futo, L, Bezzegh, K, Nagy, A, Vandorfi, G, Kiss, J, Kesmarki, N, Kis, E, Papp, A, Kovacs, A, Szakal, I, Palinkas, A, Czegany, Z, Voros, P, Reiber, I, Kerenyi, Z, Dezso, E, Wittman, I, Penzes, J, Ples, Z, Taller, A, Farago, K, Kis, Jt, Zilahi, Z, Molnar, M, Barkai, L, Mileder, M, Szentpeteri, I, Peterfai, E, Lovasz, O, Mosenzon, O, Minuchin, O, Jaffe, A, Vishlitsky, V, Shimon, I, Bashkin, A, Stern, N, Elias, N, Bental, T, Butnaru, A, Lewis, B, Adawi, F, Nseir, W, Klainman, E, Herskovits, T, Cignarelli, M, Rotella, Cm, Ambrosio, G, Pozzilli, P, Genovese, S, Cavarape, A, Salvioni, A, Sokolova, J, Strautina, I, Teterovska, D, Stalte, V, Pastare, S, Leitane, I, Lagzdina, L, Andersone, I, Eglite, R, Stelmane, I, Levinger, A, Barsiene, L, Sulskiene, M, Varanauskiene, E, Danyte, E, Urbanaviciene, E, Urbanavicius, V, Zabuliene, L, Juskiene, R, Velaviciene, A, Kakariekiene, V, Augusteniene, A, Velickiene, D, Lasiene, J, Dauksiene, D, Caponis, J, Tan, At, Ramanathan, L, Hassan, Mra, Tan, F, Ong, Tk, Foo, Sh, Ghani, Ra, Cheah, Wk, Sanchez Mijangos JH, Cabrera Jardines, R, Barrientos Perez, M, Sauque Reyna, L, Alcocer Gamba MA, Villeda Espinosa, E, Tamez Perez HE, De La Garza Hernandez NE, Lopes, Sm, Ramirez Diaz SP, Reyes Sanchez, R, Márquez-Rodriguez, E, Köse, V, Voors-Pette, C, Oldenburg-Ligtenberg, Pc, van Kempen WW, Cox, K, Hoogendyk, J, Swinkels-Diepenmaat, L, Rojas-Lingan, G, Kentgens, S, Schipperen, S, de Valk HW, Swart, H, van Bemmel, B, Hoogslag, Pam, Diamant, M, Serné, Eh, Hamer, A, Wilson, S, Fisher, N, Dixon, P, Chaudhri, O, Crawford, V, Quinn, D, Nirmalaraj, K, Dunn, P, Gillies, J, Cutfield, R, Krebs, J, Helm, C, Kerr, J, Pryke, J, Ebo, G, Denopol, M, Ang, E, Uy, N, Jimeno, C, Mirasoi, R, Paz Pacheco, E, Custodio, M, Nicodemus, N Jr, Catindig, Ea, Magno, M, Tirador, L, Cylkowska, B, Stasinksa, T, Silwinska, T, Sroka, M, Piepiorka, M, Korzeniak, R, Mirecka, H, Zaluska, R, Pupek-Musialik, D, Homenda, W, Grabowska, A, Okopien, B, Niegowska, J, Pogorzelska, H, Mikolajczyk-Swatko, A, Sikorski, M, Sowinski, D, Tahk, Sj, Kim, Yn, Nam, Cw, Rim, Sj, Kim, Cj, Choi, Km, Lee, Ik, Kim, Ij, Namgung, J, Moon, Kw, Kim, Ks, Oh, Bh, Lee, Wy, Choi, Sh, Kim, Es, Moon, S, Mindrescu, Nm, Aron, G, Graur, M, Hancu, N, Mlitaru, C, Nafornita, V, Szilagyi, I, Popa, Ar, Angelescu, Lm, Negrisanu, Gd, Zaharie, Dg, Culman, Mi, Vacaru, G, Munteanu, M, Constantinescu, S, Tivadar, S, Dreval, A, Barbarash, O, Strongin, L, Dogadin, S, Suplotova, L, Izmozherova, N, Marasaev, V, Khokhlov, A, Repin, A, Turova, E, Bondar, I, Samoylova, Y, Sherenkov, A, Smolenskaya, O, Zrahevskiy, K, Koshelskaya, O, Obrezan, A, Dzupina, A, Stevlik, J, Buganova, I, Pella, D, Vinanska, D, Jascur, J, Micko, K, Sosovec, D, Philippiova, A, Olexa, P, Fedacko, J, Selecky, J, Nicolau, J, Mediavilla Garcia, J, Botella Serrano, M, Lecube, A, Arguelles, I, Sabán, J, Gómez Cerezo, F, Soto, A, Bellido, D, Sucunza Alfonso, N, Vendrell Ortega, J, Alvarez, L, Garcia Puig, J, Angustias Quesada, M, Contreras Gilbert, J, Almeida, Ca, Tinahones, Fj, Garcia Ortiz, L, Gómez Marcos MA, Aomar, I, Fernández Balsells, M, Distiller, L, Padayachee, T, Badat, A, Ebrahim, I, Naiker, P, Ranjith, N, Kelfkens, Y, Makan, H, Mogashoa, S, Fulat, M, Carim-Ganey, N, Coetzee, K, Govender, T, Nortje, H, Wilhase, A, Seedat, S, Gani, M, Ellis, G, Rheeder, P, Wing, J, Blignaut, S, Kaplan, H, Lottering, H, Pillai, P, Louw, C, Coetzer, T, Sheu, Whh, Chen, Jf, Yang, Cy, Tseng, St, Wang, Cy, Lai, Wt, Hung, Yj, Hsieh, Ic, Su, Sl, Pei, D, Benjasuratwong, Y, Purewal, T, Milward, A, Dimitropoulos, I, Kumar, S, Barber, T, Wiles, P, Dang, C, Adler, A, Philip, S, Bellary, S, Price, D, Oelbaum, R, Heller, S, Sathayapalan, T, Clark, J, Leese, G, Simpson, H, Kilvert, A, Dawson, A, Hall, T, Takhar, A, Bundy, C, Harvey, P, Maxwell, S, Asamoah-Owusu, Nj, Mcknight, J, Chatterjee, S, Calvert, J, Wright, A, Macrury, S, Macfarlane, D, Johnson, A, Litchfield, J, Field, B, Koval, O, Larin, O, Levchenko, O, Martynyuk, L, Maslyanko, V, Rudyk, I, Suprun, Y, Tseluyko, V, Botsyurko, V, Vatutin, M, Fushtey, I, Grishyna, O, Kuskalo, P, Panina, S, Pererva, L, Prysupa, L, Teliatnikova, Z, Sokolova, L, Vlasenko, M, Berenfus, V, Gyrina, O, Kopytsya, M, Vizir, V, Vayda, M, Shanik, M, Headapohl, D, Pahl, J, Aronoff, S, Bartkowiak, A Jr, Chang, A, Gaudiani, L, Kayne, D, Look, M, Patel, N, Moran, J, Stout, E, Tsao, J, Struble, R, Fishman, N, Rodbard, H, Lucas, K, Dugano-Daphnis, P, Merrick, B, Nadar, V, Severa, L, Sorli, C, Chang, M, Reed, J III, Grunberger, G, Bain, C, Bestermann, W Jr, Morawski, E, White, J, Azizad, M, Ukwade, P, Anekwe, A, Jimenez, A, Weiss, D, Green, S, Overcash, J, Eaton, C, Roseman, H, Soler, N, Mikell, F, Manos, P, Levinson, L, Claxton, E Jr, Weiss, R, Argoud, G, Bickel, L, Wilson, J, Short, B, Webster, B, Mcneill, R, Schnall, A, Force, R, Phillips, L, Bybee, K, Forker, A, Denham, D, Vonderhaar, T, Pullman, J, Kruger, D, Whitehouse, F, Wysham, C, Baron, M, Kravitz, A, Dushkin, H, Manning, Mb, Wine, A, Jaffrani, N, Chadha, C, Sperl-Hillen, J, Busch, R, Estevez, R, Robbins, D, Rassouli, N, Garvey, T, Oparil, S, Eckel, R, Mcdermott, M, Rasouli, N, Mcgill, J, Corder, C, Klonoff, D, Mills, R, Earl, J, Kessel, J, Cuddihy, R, Zimmerman, R, Dayamani, P, Oral, E, Zimering, M, Marks, J, Farnsworth, K, Sugimoto, D, Toth, P, Bhargava, A, Mcguire, D, Rohatgi, A, Davies, M, Peden, E, Wyne, K, Alfonso, L, Seyoum, B, Akpunonu, B, Feinglos, M, Reaven, P, Soule, J, Luttrell, L, Schactman, B, Canadas, R, Boggs, B, Abbott, L, Herring, C, Roberts, L, Hage-Korban, E, Schubart, U, Taylon, A, Tannenbaum, A, Kingsley, J, Lenhard, J, Biscoveanu, M, Cohen, J, Donovan, D, Laferrere, B, Thompson, N, Wade, T, Detweiler, R, Henson, B, White, A, Cavale, A, Ravi, C, Thomas, A, Goodman, H, Kalen, V, Fox, D, Dauber, I, Rizvi, S, Marcus, A, Mulford, M, Higgins, A, Chane, M, Bland, V, Osunkoya, A, Suresh, D, Khan, S, Anastasi, L, Bajaj, M, Eisen, H, Mudaliar, Sr, Powell, S, Carr, K, Tripathy, D, Azad, N, Wakefield, P, Acheatel, R, Bressler, P, Dean, J, El Shahawy, M, Gilbert, J, Haque, I, Humiston, D, Ison, R, Karounos, D, Lillestol, M, Ferrier, N, Labroo, A, Vo, A, D’Agostino, R, Dulin, M, Mcwilliams, A, Hargrove, J, Blumberg, E, Jackson, B, Staniloae, C, Salacata, A, Hidalgo, H Jr, Nicol, P, Digiovanna, M, Soufer, J, Mahabadi, V, Akinboboye, O, Arauz-Pacheco, C, Neutel, J, Dungan, K, Benson, M, Powell, T, Gandy, W, Rovner, S, Berk, M, Khan, A, Ledesma, G, Madu, I, Erickson, B, Radbill, M, Graves, M, Kaczmarek, G, Giep, S, Baldauf, C, Golden, G, Lesh, K, Davis, C, Godbole, N, Kirby, W, Razzaque, N, Bhatt, B, Wilson, M., Internal medicine, ACS - Diabetes & metabolism, and ACS - Microcirculation
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Male ,medicine.medical_specialty ,EXSCEL Study Group ,Injections, Subcutaneous ,030209 endocrinology & metabolism ,Type 2 diabetes ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,Placebo ,Article ,Drug Administration Schedule ,GLP1-agonists ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Interquartile range ,Internal medicine ,Diabetes mellitus ,General & Internal Medicine ,medicine ,Humans ,Hypoglycemic Agents ,Least-Squares Analysis ,Aged ,Glycated Hemoglobin ,business.industry ,Venoms ,Semaglutide ,Incidence ,Type 2 diabetes, GLP1-agonists, exenatide, cardiovascular effects ,General Medicine ,11 Medical And Health Sciences ,Middle Aged ,medicine.disease ,Surgery ,Albiglutide ,Editorial ,Diabetes Mellitus, Type 2 ,Cardiovascular Diseases ,Exenatide ,Dulaglutide ,Female ,business ,Peptides ,cardiovascular effects ,medicine.drug - Abstract
BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P
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- 2017
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6. Cigarette toxin 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces experimental pancreatitis through α7 nicotinic acetylcholine receptors (nAChRs) in mice.
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Alahmari, A. A., Sreekumar, B., Patel, V., Ashat, M., Alexandre, M., Uduman, A. K., Akinbiyi, E. O., Ceplenski, A., Shugrue, C. A., Kolodecik, T. R., Tashkandi, N., Messenger, S. W., Groblewski, G. E., Gorelick, F. S., and Thrower, E. C.
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SMOKING ,PANCREATITIS ,NICOTINE ,ZYMOGENS ,CHOLINERGIC receptors - Abstract
Clinical studies have shown that cigarette smoking is a dose-dependent and independent risk factor for acute pancreatitis. Cigarette smoke contains nicotine which can be converted to the potent receptor ligand and toxin, NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]. Previously, we have shown that NNK induces premature activation of pancreatic zymogens in rats, an initiating event in pancreatitis, and this activation is prevented by pharmacologic inhibition of nicotinic acetylcholine receptors (nAChR). In this study, we determined whether NNK mediates pancreatitis through the α7 isoform of nAChR using α7nAChR knockout mice. PCR analysis confirmed expression of non-neuronal α7nAChR in C57BL/6 (WT) mouse and human acinar cells. NNK treatment stimulated trypsinogen activation in acini from WT but not α7nAChR
-/- mice. NNK also stimulated trypsinogen activation in human acini. To further confirm these findings, WT and α7nAChR-/- mice were treated with NNK in vivo and markers of pancreatitis were measured. As observed in acini NNK treatment induced trypsinogen activation in WT but not α7nAChR-/- mice. NNK also induced other markers of pancreatitis including pancreatic edema, vacuolization and pyknotic nuclei in WT but not α7nAChR-/- animals. NNK treatment led to increased neutrophil infiltration, a marker of inflammation, in WT mice and to a significantly lesser extent in α7nAChR-/- mice. We also examined downstream targets of α7nAChR activation and found that calcium and PKC activation are involved down stream of NNK stimulation of α7nAChR. In this study we used genetic deletion of the α7nAChR to confirm our previous inhibitor studies that demonstrated NNK stimulates pancreatitis by activating this receptor. Lastly, we demonstrate that NNK can also stimulate zymogen activation in human acinar cells and thus may play a role in human disease. [ABSTRACT FROM AUTHOR]- Published
- 2018
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7. Incretin-Based Therapies for the Treatment of Type 2 Diabetes: Evaluation of the Risks and Benefits
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Sherman, S. I., Drucker, D. J., Gorelick, F. S., Buse, J. B., Bergenstal, R. M., and Sherwin, R. S.
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Limited evidence suggests that GLP-I may also preserve ventricular function and improve outcomes in human subjects with heart failure or myocardial infarction (11,12). [...] both exenatide and liraglutide reduce blood pressure, body weight, and plasma lipid profiles in subjects with type 2 diabetes (13), raising the hope that longterm treatment with these agents may reduce the incidence of cardiovascular events.\n However, two safety issues have been raised - pancreatitis and medullary carcinoma of the thyroid.
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- 2010
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8. Synaptic vesicle-associated Ca2+/calmodulin-dependent protein kinase II is a binding protein for synapsin I
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Benfenati, Fabio, Valtorta, F., Rubenstein, J. L., Gorelick, F. S., Greengard, P., and Czernik, A. J.
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- 1992
9. Tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone initiates and enhances pancreatitis responses.
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Alexandre, M., Uduman, A. K., Minervini, S., Raoof, A., Shugrue, C. A., Akinbiyi, E. O., Patel, V., Shitia, M., Kolodecik, T. R., Patton, R., Gorelick, F. S., and Thrower, E. C.
- Abstract
Clinical studies indicate that cigarette smoking increases the risk for developing acute pancreatitis. The nicotine metabolite 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone (NNK) is a major cigarette smoke toxin. We hypothesized that NNK could sensitize to pancreatitis and examined its effects in isolated rat pancreatic acini and in vivo. In acini, 100 nM NNK caused three- and fivefold activation of trypsinogen and chymotrypsinogen, respectively, above control. Furthermore, NNK pretreatment in acini enhanced zymogen activation in a cerulein pancreatitis model. The long-term effects of NNK were examined in vivo after intraperitoneal injection of NNK (100 mg/kg body wt) three times weekly for 2 wk. NNK alone caused zymogen activation (6-fold for trypsinogen and 2-fold for chymotrypsinogen vs. control), vacuolization, pyknotic nuclei, and edema. This NNK pretreatment followed by treatment with cerulein (40 μg/kg) for 1 h to induce early pancreatitis responses enhanced trypsinogen and chymotrypsinogen activation, as well as other parameters of pancreatitis, compared with cerulein alone. Potential targets of NNK include nicotinic acetylcholine receptors and β-adrenergic receptors; mRNA for both receptor types was detected in acinar cell preparations. Studies with pharmacological inhibitors of these receptors indicate that NNK can mediate acinar cell responses through an nonneuronal α
7 -nicotinic acetylcholine receptor (α7 -nAChR). These studies suggest that prolonged exposure to this tobacco toxin can cause pancreatitis and sensitize to disease. Therapies targeting NNK-mediated pathways may prove useful in treatment of smoking-related pancreatitis. [ABSTRACT FROM AUTHOR]- Published
- 2012
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10. Molecular basis for pancreatitis.
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Thrower E, Husain S, Gorelick F, Owyang C, Thrower, Edwin, Husain, Sohail, and Gorelick, Fred
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- 2008
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11. Second messenger systems and adaptation.
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Gorelick, F S
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- 1987
12. Distribution of calcium/calmodulin-dependent protein kinase II in rat ileal enterocytes.
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MATOVCIK, L. M., HAIMOWITZ, B., GOLDENRING, J. R., CZERNIK, A. J., and GORELICK, F. S.
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- 1993
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13. Somatostatin decreases diarrhea in patients with the short-bowel syndrome.
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Dharmsathaphorn, K, Gorelick, F S, Sherwin, R S, Cataland, S, and Dobbins, J W
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- 1982
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14. Serologic assay for secretory component distinguishes mechanical from hepatocellular cholestasis in humans.
- Author
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Versland, Mark, Wu, George, Gorelick, Fred, Larkin, Janet, Versland, M R, Wu, G Y, Gorelick, F S, and Larkin, J M
- Abstract
In rats, serum secretory component (SC) is elevated in mechanical but not hepatocellular cholestasis. To determine if serum SC might distinguish cholestatic syndromes in humans, serum samples were obtained from control subjects and patients with mechanical and hepatocellular cholestasis. Equal volumes of serum were assayed for SC by immunoblotting with an antibody specific for human SC. Quantitative densitometry of these immunoblots showed that in mechanically obstructed patients serum SC was reversibly elevated to a level approximately 10-fold higher than that of patients with hepatocellular cholestasis (P < 0.001). When comparing the two cholestatic groups, levels of serum alkaline phosphatase, but not bilirubin and alanine aminotransferase, were significantly higher in the group with mechanical cholestasis (P < 0.01). When comparing individual patients, serum SC was more reliable than alkaline phosphatase in distinguishing the two cholestatic syndromes (P < 0.05). Thus, serum SC may distinguish mechanical from hepatocellular cholestasis in humans. [ABSTRACT FROM AUTHOR]
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- 1997
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15. New Perspectives on Acute Pancreatitis.
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Leach, S. D., Gorelick, F. S., and Modlin, I. M.
- Published
- 1992
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16. Development of Secretagogue Responsiveness in the Pancreas.
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Jamieson, J. D., Gorelick, F. S., and Chang, A.
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- 1988
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17. Diabetes mellitus and the exocrine pancreas
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Gorelick, F. S.
- Subjects
Blood Glucose ,Pancreatitis ,Diabetes Mellitus ,Humans ,Glucagon ,Pancreas ,Research Article - Abstract
Diabetes and carbohydrate intolerance can occur in pancreatitis. Although one-half of patients with acute pancreatitis will have some evidence of glucose intolerance during their acute illness, few will require insulin administration on either a short- or long-term basis. The diabetes seen in acute pancreatitis is likely due to a combination of factors, including alerted insulin secretion, increased glucagon release, and decreased glucose utilization by the liver and peripheral tissue. Chronic pancreatitis is often associated with diabetes mellitus, with the incidence as high as 70 percent when pancreatic calcification is present. These patients tend to be very sensitive to the effects of insulin and hypoglycemia. This is probably secondary to concurrent hepatic disease, malnutrition, and a relative decrease in glucagon reserves. The diabetes seen in chronic pancreatitis is associated with decreased insulin production. Finally, although the endocrine pancreas may influence the exocrine gland through a portal system, primary diabetes mellitus probably does not result in clinically significant alterations in pancreatic exocrine function.
- Published
- 1983
18. O0093 THE RYANODINE RECEPTOR MODULATES SECRETAGOGUE STIMULATED PANCREATIC ZYMOGEN ACTIVATION.
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Husain, S. Z., Prasad, P., Kolodecik, T. R., Nathanson, M. H., and Gorelick, F. S.
- Published
- 2004
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19. Cachectin, tumor-necrosis factor, and anorexia.
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Swedlund, Anne P., Gorelick, Fred S., Swedlund, A P, and Gorelick, F S
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- 1987
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20. AGE-DEPENDENT POLYPLOIDIZATION IN MOUSE EXOCRINE PANCREAS.
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Xanthopoulos, J. M., Gorelick, F. S., and Swenson, E. S.
- Published
- 2008
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21. DIFFERENTIAL ROLES OF PROTEIN KINASE C ISOFORMS IN ACUTE PANCREATITIS.
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Osgood, S., Kolodecik, T. R., Reeve, J., Pandol, S. J., Gorelick, F. S., and Thrower, E. C.
- Published
- 2007
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22. PRE-CHYLOMICRON TRANSPORT VESICLE (PCTV) UTILIZES A NOVEL SNARE-COMPLEX TO FUSE WITH INTESTINAL GOLGI.
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Mansbach, C, Mahan, J, Gorelick, F, and Siddiqi, S
- Published
- 2004
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23. Regulated phosphorylation of secretory granule membrane proteins of the rat parotid gland
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Gorelick, F [Yale Univ. School of Medicine, New Haven, CT (USA)]
- Published
- 1990
24. Renalase peptides reduce pancreatitis severity in mice.
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Kolodecik TR, Guo X, Shugrue CA, Guo X, Desir GV, Wen L, and Gorelick F
- Subjects
- Animals, Male, Mice, Female, Disease Models, Animal, Severity of Illness Index, Peptides pharmacology, Pancreas pathology, Pancreas drug effects, Pancreas metabolism, Anti-Inflammatory Agents pharmacology, Chymases metabolism, Monoamine Oxidase, Pancreatitis prevention & control, Pancreatitis pathology, Ceruletide, Mice, Inbred C57BL
- Abstract
Acute pancreatitis, an acute inflammatory injury of the pancreas, lacks a specific treatment. The circulatory protein renalase is produced by the kidney and other tissues and has potent anti-inflammatory and prosurvival properties. Recombinant renalase can reduce the severity of mild cerulein pancreatitis; the activity is contained in a conserved 20 aa renalase site (RP220). Here, we investigated the therapeutic effects of renalase on pancreatitis using two clinically relevant models of acute pancreatitis. The ability of peptides containing the RP220 site to reduce injury in a 1-day post-endoscopic retrograde cholangiopancreatography (ERCP) and a 2-day severe cerulein induced in mice was examined. The initial dose of renalase peptides was given either prophylactically (before) or therapeutically (after) the initiation of the disease. Samples were collected to determine early pancreatitis responses (tissue edema, plasma amylase, active zymogens) and later histologic tissue injury and inflammatory changes. In both preclinical models, renalase peptides significantly reduced histologic damage associated with pancreatitis, especially inflammation, necrosis, and overall injury. Quantifying inflammation using specific immunohistochemical markers demonstrated that renalase peptides significantly reduced overall bone marrow-derived inflammation and neutrophils and macrophage populations in both models. In the severe cerulein model, administering a renalase peptide with or without pretreatment significantly reduced injury. Pancreatitis and renalase peptide effects appeared to be the same in female and male mice. These studies suggest renalase peptides that retain the anti-inflammatory and prosurvival properties of recombinant renalase can reduce the severity of acute pancreatitis and might be attractive candidates for therapeutic development. NEW & NOTEWORTHY Renalase is a secretory protein. The prosurvival and anti-inflammatory effects of the whole molecule are contained in a 20 aa renalase site (RP220). Systemic treatment with peptides containing this renalase site reduced the severity of post-endoscopic retrograde cholangiopancreatography (ERCP) and severe cerulein pancreatitis in mouse models.
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- 2024
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25. Acute pancreatitis: pathogenesis and emerging therapies.
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Zaman S and Gorelick F
- Abstract
Acute pancreatitis is a severe inflammatory disorder with limited treatment options. Improved understanding of disease mechanisms has led to new and potential therapies. Here we summarize what we view as some of the most promising new therapies for treating acute pancreatitis, emphasizing the rationale of specific treatments based on disease mechanisms. Targeted pharmacologic interventions are highlighted. We explore potential treatment benefits and risks concerning reducing acute injury, minimizing complications, and improving long-term outcomes. Mechanisms associated with acute pancreatitis initiation, perpetuation, and reconstitution are highlighted, along with potential therapeutic targets and how these relate to new treatments., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Chinese Medical Association, Published by Wolters Kluwer Health, Inc.)
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- 2024
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26. Ovariectomy Affects Acute Pancreatitis in Mice.
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Wang M and Gorelick F
- Subjects
- Acute Disease, Animals, Estradiol pharmacology, Female, Mice, Mice, Inbred C57BL, Ovariectomy, Pancreatitis chemically induced
- Abstract
Background: Serum estradiol levels in severe acute injury are correlated with in hospital mortality. In acute pancreatitis, serum estradiol levels are strong predictors of disease severity. Studies of whether changes in estradiol levels play a causative role in acute pancreatitis severity are limited. The ovariectomized mouse model has been used to study the effects of estradiol in health and disease., Aims: We assessed whether the ovariectomized mouse model could be used to assess the effects of estradiol on pancreatitis severity., Methods: C57BL/6 mice with their ovaries removed were used to simulate low circulating estradiol conditions. Ovariectomized mice were treated with six hourly injections of cerulein to induce mild acute pancreatitis and compared to ovariectomized mice pre-treated with subcutaneous estradiol injections., Results: Findings suggest ovariectomized model is a problematic preparation to study pancreatitis. At baseline, ovariectomy leads to prominent acinar cell ultrastructure changes as well as changes in other select morphologic and biomarkers of pancreatitis. In addition, ovariectomy changed select acute pancreatitis responses that were only partially rescued by estradiol pre-treatment., Conclusions: These findings suggest that the ovariectomized mouse as a model of estradiol depletion should be used with caution in pancreatic studies. Future studies should explore whether derangements in other female hormones produced by the ovaries can lead to changes in pancreatic studies., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
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27. Renalase and its receptor, PMCA4b, are expressed in the placenta throughout the human gestation.
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Wang M, Silva T, Toothaker JM, McCourt BT, Shugrue C, Desir G, Gorelick F, and Konnikova L
- Subjects
- Chorionic Villi metabolism, Decidua metabolism, Female, Humans, Monoamine Oxidase, Placentation, Plasma Membrane Calcium-Transporting ATPases, Pregnancy, Placenta metabolism, Trophoblasts metabolism
- Abstract
Placental function requires organized growth, transmission of nutrients, and an anti-inflammatory milieu between the maternal and fetal interface, but placental factors important for its function remain unclear. Renalase is a pro-survival, anti-inflammatory flavoprotein found to be critical in other tissues. We examined the potential role of renalase in placental development. PCR, bulk RNA sequencing, immunohistochemistry, and immunofluorescence for renalase and its binding partners, PMCA4b and PZP, were performed on human placental tissue from second-trimester and full-term placentas separated into decidua, placental villi and chorionic plates. Quantification of immunohistochemistry was used to localize renalase across time course from 17 weeks to term. Endogenous production of renalase was examined in placental tissue and organoids. Renalase and its receptor PMCA4b transcripts and proteins were present in all layers of the placenta. Estimated RNLS protein levels did not change with gestation in the decidual samples. However, placental villi contained more renalase immunoreactive cells in fetal than full-term placental samples. RNLS co-labeled with markers for Hofbauer cells and trophoblasts within the placental villi. Endogenous production of RNLS, PMCA4b, and PZP by trophoblasts was validated in placental organoids. Renalase is endogenously expressed throughout placental tissue and specifically within Hofbauer cells and trophoblasts, suggesting a potential role for renalase in placental development and function. Future studies should assess renalase's role in normal and diseased human placenta., (© 2022. The Author(s).)
- Published
- 2022
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28. Association of renalase with clinical outcomes in hospitalized patients with COVID-19.
- Author
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Safdar B, Wang M, Guo X, Cha C, Chun HJ, Deng Y, Dziura J, El-Khoury JM, Gorelick F, Ko AI, Lee AI, Safirstein R, Simonov M, Zhou B, and Desir GV
- Subjects
- Adult, Aged, COVID-19 mortality, COVID-19 virology, Endothelium metabolism, Endothelium pathology, Female, Hospitalization, Humans, Intensive Care Units, Interleukin-6 blood, Kaplan-Meier Estimate, Male, Middle Aged, Proportional Hazards Models, Respiration, Artificial, Retrospective Studies, Risk Factors, SARS-CoV-2 isolation & purification, Severity of Illness Index, COVID-19 pathology, Monoamine Oxidase blood
- Abstract
Renalase is a secreted flavoprotein with anti-inflammatory and pro-cell survival properties. COVID-19 is associated with disordered inflammation and apoptosis. We hypothesized that blood renalase levels would correspond to severe COVID-19 and survival. In this retrospective cohort study, clinicopathologic data and blood samples were collected from hospitalized COVID-19 subjects (March-June 2020) at a single institution tertiary hospital. Plasma renalase and cytokine levels were measured and clinical data abstracted from health records. Of 3,450 COVID-19 patients, 458 patients were enrolled. Patients were excluded if <18 years, or opted out of research. The primary composite outcome was intubation or death within 180 days. Secondary outcomes included mortality alone, intensive care unit admission, use of vasopressors, and CPR. Enrolled patients had mean age 64 years (SD±17), were 53% males, and 48% non-whites. Mean renalase levels was 14,108·4 ng/ml (SD±8,137 ng/ml). Compared to patients with high renalase, those with low renalase (< 8,922 ng/ml) were more likely to present with hypoxia, increased ICU admission (54% vs. 33%, p < 0.001), and cardiopulmonary resuscitation (10% vs. 4%, p = 0·023). In Cox proportional hazard model, every 1000 ng/ml increase in renalase decreased the risk of death or intubation by 5% (HR 0·95; 95% CI 0·91-0·98) and increased survival alone by 6% (HR 0·95; CI 0·90-0·98), after adjusting for socio-demographics, initial disease severity, comorbidities and inflammation. Patients with high renalase-low IL-6 levels had the best survival compared to other groups (p = 0·04). Renalase was independently associated with reduced intubation and mortality in hospitalized COVID-19 patients. Future studies should assess the pathophysiological relevance of renalase in COVID-19 disease., Competing Interests: Dr. Desir reports grants and other from Bessor Pharma, other from Personal Therapeutics, outside the submitted work; In addition, Dr. Desir has a patent US 7,700,095 licensed to Bessor Pharma, a patent US 7,858,084 licensed to Bessor Pharma, a patent US 10,066,025 B2 licensed to Bessor Pharma, a patent US 10,273,311 licensed to Bessor Pharma, a patent US 10,618,975 licensed to Bessor Pharma, and a patent US 10,941,212 licensed to Bessor Pharma. Dr. Gorelick reports grants from Veterans Administration, grants from Bessor Pharma/NIH NIDDK SBIR2, from null, during the conduct of the study. Dr. Ko reports grants from Bristol Myer Squib, grants from Regeneron, grants from Serimmune, grants and personal fees from Tata Medical Devices, outside the submitted work. Dr. Safdar reports institutional grants from NHLBI, and Comprehensive Research Associates, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2022
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29. Sex Differences in the Exocrine Pancreas and Associated Diseases.
- Author
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Wang M, Gorelick F, and Bhargava A
- Subjects
- COVID-19 pathology, Female, Hormones metabolism, Humans, Male, Pregnancy, Pancreas, Exocrine pathology, Pancreatic Diseases pathology, Sex Characteristics
- Abstract
Differences in pancreatic anatomy, size, and function exist in men and women. The anatomical differences could contribute to the increase in complications associated with pancreatic surgery in women. Although diagnostic criteria for pancreatitis are the same in men and women, major sex differences in etiology are reported. Alcohol and tobacco predominate in men, whereas idiopathic and obstructive etiologies predominate in women. Circulating levels of estrogens, progesterone, and androgens contribute significantly to overall health outcomes; premenopausal women have lower prevalence of cardiovascular and pancreatic diseases suggesting protective effects of estrogens, whereas androgens promote growth of normal and cancerous cells. Sex chromosomes and gonadal and nongonadal hormones together determine an individual's sex, which is distinct from gender or gender identity. Human pancreatic disease etiology, outcomes, and sex-specific mechanisms are largely unknown. In rodents of both sexes, glucocorticoids and estrogens from the adrenal glands influence pancreatic secretion and acinar cell zymogen granule numbers. Lack of corticotropin-releasing factor receptor 2 function, a G protein-coupled receptor whose expression is regulated by both estrogens and glucocorticoids, causes sex-specific changes in pancreatic histopathology, zymogen granule numbers, and endoplasmic reticulum ultrastructure changes in acute pancreatitis model. Here, we review existing literature on sex differences in the normal exocrine pancreas and mechanisms that operate at homeostasis and diseased states in both sexes. Finally, we review pregnancy-related pancreatic diseases and discuss the effects of sex differences on proposed treatments in pancreatic disease., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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30. Zinc: Roles in pancreatic physiology and disease.
- Author
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Wang M, Phadke M, Packard D, Yadav D, and Gorelick F
- Subjects
- Animals, Humans, Inflammation etiology, Inflammation metabolism, Pancreas physiopathology, Zinc physiology, Pancreas metabolism, Pancreas physiology, Pancreatic Diseases metabolism, Pancreatic Diseases physiopathology, Zinc deficiency, Zinc metabolism
- Abstract
Zinc is an essential trace element. Deficiencies are frequently seen with gastrointestinal diseases, including chronic pancreatitis, nutritional deficiency, and reduced intestinal absorption. Additionally, reduced zinc levels have been linked to cellular changes associated with acute pancreatitis such as enhanced inflammation with increased macrophage activation and production of inflammatory cytokines such as IL-1β, impaired autophagy, and modulation of calcium homeostasis. Preliminary data suggest that zinc deficiency may lead to pancreatic injury in animal models. The purpose of this review is to explore the biologic effects of zinc deficiency that could impact pancreatic disease. MESH KEYWORDS: Malnutrition, inflammation, trace element., Competing Interests: Declaration of competing interest The authors have no financial disclosures or conflicts of interest for this review., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
31. Decreased plasma levels of the survival factor renalase are associated with worse outcomes in COVID-19.
- Author
-
Wang M, Guo X, Chun HJ, Lee AI, Cha C, Gorelick F, and Desir GV
- Abstract
Introduction: Renalase (RNLS), a novel secreted plasma flavoprotein, has anti-inflammatory effects in a variety of disease processes. Severe COVID-19 disease is associated with disordered inflammatory responses. We hypothesized that reduced plasma RNLS levels could be a marker of COVID-19 disease severity., Methods: Plasma was collected from 51 hospitalized COVID-19 patients and 15 uninfected non-hospitalized controls. Plasma RNLS and cytokine levels were measured and sociodemographic and clinical data were collected from chart review. Data were analyzed using nonparametric analyses and Kaplan Meir curve log rank analysis., Results: Plasma RNLs levels were negatively correlated with inflammatory markers, including IL-1b, IL-6, and TNFa (p = 0.04, p = 0.03, p = 0.01, respectively). Patients with COVID-19 disease had lower levels of RNLS than controls. Lower levels of RNLS were associated with more severe disease among COVID-19 patients. Low RNLS was also associated with worse survival among COVID-19 patients (HR = 4.54; 95% CI: 1.06-19.43; p = 0.005)., Conclusion: Low plasma RNLS levels are associated with severe COVID-19 disease and may be a useful additional biomarker when identifying patients with severe COVID-19 disease. Given RNLS anti-inflammatory properties and negative correlation with inflammatory markers, these findings also suggest evidence of a potential pathophysiological mechanism for severe COVID-19 disease.
- Published
- 2020
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- View/download PDF
32. TRPV4 helps Piezo1 put the squeeze on pancreatic acinar cells.
- Author
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Gorelick F and Nathanson MH
- Subjects
- Acinar Cells metabolism, Calcium metabolism, Cholecystokinin genetics, Cholecystokinin metabolism, Humans, Ion Channels, Pancreas metabolism, TRPV Cation Channels genetics, Pancreas, Exocrine metabolism, Pancreatitis genetics, Transient Receptor Potential Channels
- Abstract
Alterations in calcium signaling in pancreatic acinar cells can result in pancreatitis. Although pressure changes in the pancreas can elevate cytosolic calcium (Ca2+) levels, it is not known how transient pressure-activated elevations in calcium can cause prolonged calcium changes and consequent pancreatitis. In this issue of the JCI, Swain et al. describe roles for the mechanically activated plasma membrane calcium channels Piezo1 and transient receptor potential vanilloid subfamily 4 (TRPV4) in acinar cells. The authors used genetic deletion models and cell culture systems to investigate calcium signaling. Notably, activation of the Piezo1-dependent TRPV4 pathway was independent of the cholecystokinin (CCK) stimulation pathway. These results elegantly resolve an apparent discrepancy in calcium signaling and the pathogenesis of pancreatitis in pancreatic acinar cells.
- Published
- 2020
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33. Identification of Two Forms of Human Plasma Renalase, and Their Association With All-Cause Mortality.
- Author
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Chang J, Guo X, Rao V, Gromisch ES, Chung S, Kluger HM, Cha C, Gorelick F, Testani J, Safirstein R, Crowley S, Peixoto AJ, and Desir GV
- Published
- 2019
- Full Text
- View/download PDF
34. Presentation of the Julius M. Friedenwald Medal to Loren A. Laine.
- Author
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Fennerty MB, McQuaid K, and Gorelick F
- Subjects
- History, 20th Century, History, 21st Century, Societies, Medical history, United States, Awards and Prizes, Gastroenterology history
- Published
- 2018
- Full Text
- View/download PDF
35. Academic Pancreas Centers of Excellence: Guidance from a multidisciplinary chronic pancreatitis working group at PancreasFest.
- Author
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Sheth SG, Conwell DL, Whitcomb DC, Alsante M, Anderson MA, Barkin J, Brand R, Cote GA, Freedman SD, Gelrud A, Gorelick F, Lee LS, Morgan K, Pandol S, Singh VK, Yadav D, Wilcox CM, and Hart PA
- Subjects
- Guidelines as Topic, Humans, Pancreatic Function Tests, Pancreatitis, Chronic diagnosis, Patient Care Team, Pancreas, Pancreatitis, Chronic therapy
- Abstract
Chronic pancreatitis (CP) is a progressive inflammatory disease, which leads to loss of pancreatic function and other disease-related morbidities. A group of academic physicians and scientists developed comprehensive guidance statements regarding the management of CP that include its epidemiology, diagnosis, medical treatment, surgical treatment, and screening. The statements were developed through literature review, deliberation, and consensus opinion. These statements were ultimately used to develop a conceptual framework for the multidisciplinary management of chronic pancreatitis referred to as an academic pancreas center of excellence (APCOE)., (Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.)
- Published
- 2017
- Full Text
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36. Inhibition of renalase expression and signaling has antitumor activity in pancreatic cancer.
- Author
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Guo X, Hollander L, MacPherson D, Wang L, Velazquez H, Chang J, Safirstein R, Cha C, Gorelick F, and Desir GV
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Antibodies pharmacology, Apoptosis drug effects, Apoptosis genetics, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal metabolism, Cell Cycle Checkpoints drug effects, Cell Cycle Checkpoints genetics, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Male, Mice, Nude, Middle Aged, Monoamine Oxidase immunology, Monoamine Oxidase metabolism, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, Xenograft Model Antitumor Assays methods, Carcinoma, Pancreatic Ductal genetics, Monoamine Oxidase genetics, Pancreatic Neoplasms genetics, RNA Interference
- Abstract
An essential feature of cancer is dysregulation of cell senescence and death. Renalase, a recently discovered secreted flavoprotein, provides cytoprotection against ischemic and toxic cellular injury by signaling through the PI3K-AKT and MAPK pathways. Here we show that renalase expression is increased in pancreatic cancer tissue and that it functions as a growth factor. In a cohort of patients with pancreatic ductal adenocarcinoma, overall survival was inversely correlated with renalase expression in the tumor mass, suggesting a pathogenic role for renalase. Inhibition of renalase signaling using siRNA or inhibitory anti-renalase antibodies decreased the viability of cultured pancreatic ductal adenocarcinoma cells. In two xenograft mouse models, either the renalase monoclonal antibody m28-RNLS or shRNA knockdown of renalase inhibited pancreatic ductal adenocarcinoma growth. Inhibition of renalase caused tumor cell apoptosis and cell cycle arrest. These results reveal a previously unrecognized role for the renalase in cancer: its expression may serve as a prognostic maker and its inhibition may provide an attractive therapeutic target in pancreatic cancer.
- Published
- 2016
- Full Text
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37. Acute Pancreatitis-Progress and Challenges: A Report on an International Symposium.
- Author
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Afghani E, Pandol SJ, Shimosegawa T, Sutton R, Wu BU, Vege SS, Gorelick F, Hirota M, Windsor J, Lo SK, Freeman ML, Lerch MM, Tsuji Y, Melmed GY, Wassef W, and Mayerle J
- Subjects
- Acute Disease, American Medical Association, Biomarkers analysis, Disease Progression, Humans, Japan, Prognosis, Severity of Illness Index, Societies, Medical, United States, Pancreas, Pancreatitis diagnosis, Pancreatitis therapy
- Abstract
An international symposium entitled "Acute pancreatitis: progress and challenges" was held on November 5, 2014 at the Hapuna Beach Hotel, Big Island, Hawaii, as part of the 45th Anniversary Meeting of the American Pancreatic Association and the Japanese Pancreas Society. The course was organized and directed by Drs. Stephen Pandol, Tooru Shimosegawa, Robert Sutton, Bechien Wu, and Santhi Swaroop Vege. The symposium objectives were to: (1) highlight current issues in management of acute pancreatitis, (2) discuss promising treatments, (3) consider development of quality indicators and improved measures of disease activity, and (4) present a framework for international collaboration for development of new therapies. This article represents a compilation and adaptation of brief summaries prepared by speakers at the symposium with the purpose of broadly disseminating information and initiatives.
- Published
- 2015
- Full Text
- View/download PDF
38. Abdominal Paracentesis Drainage: Which Patients With Severe Acute Pancreatitis Will Benefit?
- Author
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Foglio EJ and Gorelick F
- Subjects
- Acute Disease, Humans, Pancreatitis classification, Pancreatitis physiopathology, Severity of Illness Index, Pancreatitis therapy, Paracentesis methods, Practice Guidelines as Topic
- Published
- 2015
- Full Text
- View/download PDF
39. Adenylyl cyclases in the digestive system.
- Author
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Sabbatini ME, Gorelick F, and Glaser S
- Subjects
- Adenylyl Cyclases chemistry, Animals, Catalytic Domain, Digestive System Physiological Phenomena physiology, Humans, Isoenzymes physiology, Pancreatitis enzymology, Signal Transduction, Adenylyl Cyclases physiology, Digestive System enzymology
- Abstract
Adenylyl cyclases (ACs) are a group of widely distributed enzymes whose functions are very diverse. There are nine known transmembrane AC isoforms activated by Gαs. Each has its own pattern of expression in the digestive system and differential regulation of function by Ca(2+) and other intracellular signals. In addition to the transmembrane isoforms, one AC is soluble and exhibits distinct regulation. In this review, the basic structure, regulation and physiological roles of ACs in the digestive system are discussed., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
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40. Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity.
- Author
-
Hoque R, Farooq A, Ghani A, Gorelick F, and Mehal WZ
- Subjects
- Animals, Anti-Inflammatory Agents administration & dosage, Arrestins metabolism, Carrier Proteins metabolism, Cell Line, Ceruletide, Chemical and Drug Induced Liver Injury etiology, Chemical and Drug Induced Liver Injury genetics, Chemical and Drug Induced Liver Injury immunology, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury pathology, Cytoprotection, Disease Models, Animal, Dose-Response Relationship, Drug, Down-Regulation, Galactosamine, Humans, Inflammasomes immunology, Inflammasomes metabolism, Injections, Intraperitoneal, Interleukin-1beta metabolism, Lipopolysaccharides, Liver immunology, Liver metabolism, Liver pathology, Macrophages drug effects, Macrophages immunology, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Monocytes drug effects, Monocytes immunology, Monocytes metabolism, NF-kappa B metabolism, NLR Family, Pyrin Domain-Containing 3 Protein, Pancreas immunology, Pancreas metabolism, Pancreas pathology, Pancreatitis chemically induced, Pancreatitis genetics, Pancreatitis immunology, Pancreatitis metabolism, Pancreatitis pathology, RNA Interference, RNA, Small Interfering metabolism, Receptors, G-Protein-Coupled genetics, Signal Transduction drug effects, Sodium Lactate administration & dosage, Toll-Like Receptor 4 drug effects, Toll-Like Receptor 4 metabolism, Toll-Like Receptors metabolism, Transfection, beta-Arrestin 2, beta-Arrestins, Anti-Inflammatory Agents pharmacology, Chemical and Drug Induced Liver Injury prevention & control, Immunity, Innate drug effects, Inflammasomes drug effects, Liver drug effects, Pancreas drug effects, Pancreatitis prevention & control, Receptors, G-Protein-Coupled metabolism, Sodium Lactate pharmacology, Toll-Like Receptors drug effects
- Abstract
Background & Aims: The NACHT, LRR, and pyrin domain-containing protein 3 (NLRP3) inflammasome induces inflammation in response to organ injury, but little is known about its regulation. Toll-like receptors (TLRs) provide the first signal required for activation of the inflammasome and stimulate aerobic glycolysis to generate lactate. We examined whether lactate and the lactate receptor, Gi-protein-coupled receptor 81 (GPR81), regulate TLR induction of signal 1 and limit inflammasome activation and organ injury., Methods: Primary mouse macrophages and human monocytes were incubated with TLR4 agonists and lactate and assayed for levels of pro-interleukin (IL)1β, NLRP3, and caspase-1 (CASP1); release of IL1β; and activation of nuclear factor-κB (NF-κB) and caspase-1. Small interfering RNAs were used to reduce levels of GPR81 and arrestin β-2 (ARRB2), and an NF-κB luciferase reporter transgene was transfected in RAW 264.7 cells. Cell lysates were analyzed by immunoprecipitation with an antibody against GPR81. Acute hepatitis was induced in C56BL/6N mice by administration of lipopolysaccharide and D-galactosamine. Acute pancreatitis was induced by administration of lipopolysaccharide and cerulein. Some mice were given intraperitoneal injections of sodium lactate or small interfering RNA against Gpr81. Activation of NF-κB in tissue macrophages was assessed in mice that expressed a reporter transgene., Results: In macrophages and monocytes, increasing concentrations of lactate reduced TLR4-mediated induction of Il1B, Nlrp3, and Casp1; activation of NF-κB; release of IL1β; and cleavage of CASP1. GPR81 and ARRB2 physically interacted and were required for these effects. The administration of lactate reduced inflammation and organ injury in mice with immune hepatitis; this reduction required Gpr81 dependence in vivo. Lactate also prevented activation of NF-κB in macrophages of mice, and, when given after injury, reduced the severity of acute pancreatitis and acute liver injury., Conclusions: Lactate negatively regulates TLR induction of the NLRP3 inflammasome and production of IL1β, via ARRB2 and GPR81. Lactate could be a promising immunomodulatory therapy for patients with acute organ injury., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
41. Sterile inflammatory response in acute pancreatitis.
- Author
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Hoque R, Malik AF, Gorelick F, and Mehal WZ
- Subjects
- Acute Disease, Animals, Humans, Inflammation genetics, Inflammation immunology, Inflammation pathology, Inflammation therapy, Pancreas pathology, Pancreatitis genetics, Pancreatitis immunology, Pancreatitis pathology, Pancreatitis therapy, Inflammation etiology, Inflammation Mediators metabolism, Pancreas immunology, Pancreatitis complications, Signal Transduction genetics
- Abstract
The initial injury in acute pancreatitis is characteristically sterile and results in acinar cells necrosis. Intracellular contents released from damaged cells into the extracellular space serve as damage-associated molecular patterns (DAMPs) that trigger inflammation. There is increasing evidence that this sterile inflammatory response mediated through DAMPs released from necrotic acinar cells is a key determinant of further pancreatic injury, remote organ injury, and disease resolution in experimental models. A number of DAMPS, including high-mobility group box protein 1, DNA, adenosine triphosphate and heat shock protein 70, have been shown to have a role in experimental pancreatitis. Many of these DAMPs are also detectable in the human pancreatitis. Genetic deletion and pharmacologic antagonism demonstrate that specific DAMP receptors, including Toll-like receptor (TLR) 4, TLR9, and P2X7, are also required for inflammation in experimental acute pancreatitis. Downstream DAMP-sensing components include nod-like receptor protein 3, caspase 1, interleukin-1β (IL-1), IL-18, and IL-1 receptor, and also are required for full experimental pancreatitis. These DAMP-mediated pathways provide novel therapeutic targets using antagonists of TLRs and other receptors.
- Published
- 2012
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42. TLR9 and the NLRP3 inflammasome link acinar cell death with inflammation in acute pancreatitis.
- Author
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Hoque R, Sohail M, Malik A, Sarwar S, Luo Y, Shah A, Barrat F, Flavell R, Gorelick F, Husain S, and Mehal W
- Subjects
- Acute Disease, Animals, Anti-Inflammatory Agents pharmacology, Apoptosis, Apoptosis Regulatory Proteins, CARD Signaling Adaptor Proteins, Carrier Proteins genetics, Caspase 1 genetics, Caspase 1 metabolism, Ceruletide, Cytoskeletal Proteins genetics, Cytoskeletal Proteins metabolism, DNA pharmacology, Disease Models, Animal, Inflammasomes deficiency, Inflammasomes genetics, Interleukin-1 metabolism, Macrophages immunology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NLR Family, Pyrin Domain-Containing 3 Protein, Necrosis, Neutrophil Infiltration, Pancreas drug effects, Pancreas pathology, Pancreatitis chemically induced, Pancreatitis genetics, Pancreatitis pathology, Pancreatitis prevention & control, Pneumonia immunology, Pneumonia prevention & control, Protein Precursors metabolism, Purinergic P2X Receptor Antagonists pharmacology, RNA, Messenger metabolism, Receptors, Purinergic P2X7 genetics, Receptors, Purinergic P2X7 metabolism, Severity of Illness Index, Taurolithocholic Acid analogs & derivatives, Toll-Like Receptor 9 antagonists & inhibitors, Toll-Like Receptor 9 deficiency, Toll-Like Receptor 9 genetics, Carrier Proteins metabolism, Inflammasomes metabolism, Pancreas immunology, Pancreatitis immunology, Signal Transduction drug effects, Toll-Like Receptor 9 metabolism
- Abstract
Background & Aims: Acute pancreatitis is characterized by early activation of intracellular proteases followed by acinar cell death and inflammation. Activation of damage-associated molecular pattern (DAMP) receptors and a cytosolic complex termed the inflammasome initiate forms of inflammation. In this study, we examined whether DAMP-receptors and the inflammasome provide the link between cell death and the initiation of inflammation in pancreatitis., Methods: Acute pancreatitis was induced by caerulein stimulation in wild-type mice and mice deficient in components of the inflammasome (apoptosis-associated speck-like protein containing a caspase recruitment domain [ASC], NLRP3, caspase-1), Toll-like receptor 9 (TLR9), or the purinergic receptor P2X(7). Resident and infiltrating immune cell populations and pro-interleukin-1β expression were characterized in control and caerulein-treated adult murine pancreas. TLR9 expression was quantified in pancreatic cell populations. Additionally, wild-type mice were pretreated with a TLR9 antagonist before induction of acute pancreatitis by caerulein or retrograde bile duct infusion of taurolithocholic acid 3-sulfate., Results: Caspase-1, ASC, and NLRP3 were required for inflammation in acute pancreatitis. Genetic deletion of Tlr9 reduced pancreatic edema, inflammation, and pro-IL-1β expression in pancreatitis. TLR9 was expressed in resident immune cells of the pancreas, which are predominantly macrophages. Pretreatment with the TLR9 antagonist IRS954 reduced pancreatic edema, inflammatory infiltrate, and apoptosis. Pretreatment with IRS954 reduced pancreatic necrosis and lung inflammation in taurolithocholic acid 3-sulfate-induced acute pancreatitis., Conclusions: Components of the inflammasome, ASC, caspase-1, and NLRP3, are required for the development of inflammation in acute pancreatitis. TLR9 and P2X(7) are important DAMP receptors upstream of inflammasome activation, and their antagonism could provide a new therapeutic strategy for treating acute pancreatitis., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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43. The vacuolar-ATPase modulates matrix metalloproteinase isoforms in human pancreatic cancer.
- Author
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Chung C, Mader CC, Schmitz JC, Atladottir J, Fitchev P, Cornwell ML, Koleske AJ, Crawford SE, and Gorelick F
- Subjects
- Cell Line, Tumor, Enzyme Activation, Gene Knockdown Techniques, Humans, Immunohistochemistry, Neoplasm Invasiveness, Pancreatic Neoplasms pathology, Vacuolar Proton-Translocating ATPases antagonists & inhibitors, Vacuolar Proton-Translocating ATPases genetics, Isoenzymes metabolism, Matrix Metalloproteinases metabolism, Pancreatic Neoplasms enzymology, Vacuolar Proton-Translocating ATPases metabolism
- Abstract
The vacuolar-ATPase (v-ATPase) is a proton transporter found on many intracellular organelles and the plasma membrane (PM). The v-ATPase on PMs of cancer cells may contribute to their invasive properties in vitro. Its relevance to human cancer tissues remains unclear. We investigated whether the expression and cellular localization of v-ATPase corresponded to the stage of human pancreatic cancer, and its effect on matrix metalloproteinase (MMP) activation in vitro. The intensity of v-ATPase staining increased significantly across the range of pancreatic histology from normal ducts to pancreatic intraepithelial neoplasms (PanIN), and finally pancreatic ductal adenocarcinoma (PDAC). Low-grade PanIN lesions displayed polarized staining confined to the basal aspect of the cell in the majority (86%) of fields examined. High-grade PanIN lesions and PDAC showed intense and diffuse v-ATPase localization. In pancreatic cancer cells, PM-associated v-ATPase colocalized with cortactin, a component of the leading edge that helps direct MMP release. Blockade of the v-ATPase with concanamycin or short-hairpin RNA targeting the V₁E subunit reduced MMP-9 activity; this effect was greatest in cells with prominent PM-associated v-ATPase. In cells with detectable MMP-2 activities, however, treatment with concanamycin markedly increased MMP-2's most activated forms. V-ATPase blockade inhibited functional migration and invasion in those cells with predominantly MMP-9 activity. These results indicate that human PDAC specimens show loss of v-ATPase polarity and increased expression that correlates with increasing invasive potential. Thus, v-ATPase selectively modulates specific MMPs that may be linked to an invasive cancer phenotype.
- Published
- 2011
- Full Text
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44. Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease.
- Author
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He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, and Greengard P
- Subjects
- Amyloid Precursor Protein Secretases chemistry, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor chemistry, Amyloid beta-Protein Precursor metabolism, Animals, Benzamides, Cell Line, Disease Models, Animal, Gene Knockdown Techniques, Humans, Imatinib Mesylate, Mice, Peptide Fragments metabolism, Piperazines pharmacology, Proteins genetics, Pyrimidines pharmacology, RNA Interference, Receptor, Notch1 metabolism, Alzheimer Disease metabolism, Proteins antagonists & inhibitors, Proteins metabolism
- Abstract
Accumulation of neurotoxic amyloid-beta is a major hallmark of Alzheimer's disease. Formation of amyloid-beta is catalysed by gamma-secretase, a protease with numerous substrates. Little is known about the molecular mechanisms that confer substrate specificity on this potentially promiscuous enzyme. Knowledge of the mechanisms underlying its selectivity is critical for the development of clinically effective gamma-secretase inhibitors that can reduce amyloid-beta formation without impairing cleavage of other gamma-secretase substrates, especially Notch, which is essential for normal biological functions. Here we report the discovery of a novel gamma-secretase activating protein (GSAP) that drastically and selectively increases amyloid-beta production through a mechanism involving its interactions with both gamma-secretase and its substrate, the amyloid precursor protein carboxy-terminal fragment (APP-CTF). GSAP does not interact with Notch, nor does it affect its cleavage. Recombinant GSAP stimulates amyloid-beta production in vitro. Reducing GSAP concentrations in cell lines decreases amyloid-beta concentrations. Knockdown of GSAP in a mouse model of Alzheimer's disease reduces levels of amyloid-beta and plaque development. GSAP represents a type of gamma-secretase regulator that directs enzyme specificity by interacting with a specific substrate. We demonstrate that imatinib, an anticancer drug previously found to inhibit amyloid-beta formation without affecting Notch cleavage, achieves its amyloid-beta-lowering effect by preventing GSAP interaction with the gamma-secretase substrate, APP-CTF. Thus, GSAP can serve as an amyloid-beta-lowering therapeutic target without affecting other key functions of gamma-secretase.
- Published
- 2010
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45. GENETIC AND PHARMACOLOGIC MANIPULATION OF VACUOLAR ATPASE; EFFECTS ON ZYMOGEN ACTIVATION IN PANCREATIC ACINI.
- Author
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Kolodecik T, Gorelick F, and Thrower E
- Abstract
Premature activation of inactive digestive enzymes (or zymogens) within the pancreatic acinar cell is an initiating event in acute pancreatitis (AP). We have found that this response depends on the assembly and activation of an ATP-dependent proton pump, the vacuolar ATPase (vATPase). Previously, we have shown that the classic vATPase inhibitors concanamycin and bafilomycin can inhibit zymogen activation induced experimentally by high doses of the cholecystokinin orthologue, cerulein (CER) in isolated acinar cells. Recent studies have questioned the specificity of these inhibitors. In the current study we examine the role of the vATPase in pancreatitis using the newly developed novel vATPase inhibitors lobatomide-B and salicylihalamide-A as well as a genetic approach using siRNA. Both lobatomide-B and salicylihalamide-A inhibited CER stimulated zymogen (trypsinogen and chymotrypsinogen) activation but had no effect on amylase secretion. Lobatomide-B (0.1μM) was more potent, reducing activation to baseline levels. Treatment of cells with siRNA specific for the vATPase E-subunit (V1E) significantly decreased V1E expression. V1E siRNA also significantly decreased chymotrypsinogen activation, but not amylase secretion. These studies confirm a role for the vATPase in zymogen activation and demonstrate that the novel and specific inhibitors lobatomide-B and salicylihalamide-A reduce early pancreatitis responses.
- Published
- 2009
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46. Ethanol exposure depletes hepatic pigment epithelium-derived factor, a novel lipid regulator.
- Author
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Chung C, Shugrue C, Nagar A, Doll JA, Cornwell M, Gattu A, Kolodecik T, Pandol SJ, and Gorelick F
- Subjects
- Animals, Eye Proteins physiology, Fatty Liver chemically induced, Fatty Liver metabolism, Gelatinases metabolism, Hepatic Stellate Cells enzymology, Hepatic Stellate Cells physiology, Humans, Lipid Metabolism, Liver chemistry, Male, Matrix Metalloproteinase 2 physiology, Matrix Metalloproteinase 9 physiology, Nerve Growth Factors physiology, Rats, Rats, Wistar, Serpins physiology, Triglycerides analysis, Ethanol toxicity, Eye Proteins analysis, Liver drug effects, Nerve Growth Factors analysis, Serpins analysis
- Abstract
Background & Aims: Ethanol abuse can lead to hepatic steatosis and evolve into cirrhosis and hepatocellular carcinoma. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein that is expressed by hepatocytes. Proteomic, experimental, and clinical studies implicate PEDF's role in lipid regulation. Because matrix metalloproteinase (MMP)-2/9 activity regulates PEDF levels, we investigated whether PEDF degradation by MMPs has a permissive role in ethanol-induced hepatic steatosis., Methods: PEDF levels were examined in liver biopsy specimens from patients with ethanol-induced steatosis. Hepatic PEDF levels and MMP activity were assessed in 2 animal models of ethanol feeding (rats on an alcohol-containing liquid diet and mice given intragastric infusion of ethanol). The consequences of PEDF depletion in the liver were examined in PEDF-null mice., Results: Liver biopsy samples from patients with ethanol-induced steatosis had reduced PEDF levels, compared with normal liver samples. Ethanol-fed animals had histologic steatosis and increased liver triglyceride content (P< .05), as well as reduced levels of hepatic PEDF and increased MMP-2/9 activity. Ethanol-exposed hepatic lysates degraded PEDF in a MMP-2/9-dependent manner, and liver sections demonstrated abundant MMP-2/9 activity in situ. Addition of recombinant PEDF to PEDF-null hepatocytes, reduced their triglyceride content., Conclusions: Ethanol exposure leads to marked loss of hepatic PEDF in human livers and in 2 animal models of ethanol feeding. Loss of PEDF contributes to the accumulation of lipids in ethanol-induced hepatic steatosis.
- Published
- 2009
- Full Text
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47. Prevention of post-ERCP pancreatitis: a little antacid might go a long way.
- Author
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Nagar AB and Gorelick F
- Subjects
- Contrast Media adverse effects, Female, Humans, Hydrogen-Ion Concentration, Male, Pancreatic Ducts injuries, Risk Factors, Antacids therapeutic use, Cholangiopancreatography, Endoscopic Retrograde adverse effects, Pancreatitis prevention & control
- Published
- 2008
- Full Text
- View/download PDF
48. Protein kinase C in the pancreatic acinar cell.
- Author
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Gorelick F, Pandol S, and Thrower E
- Subjects
- Protein Isoforms, Signal Transduction, Glucagon-Secreting Cells physiology, Protein Kinase C physiology
- Abstract
Pathological activation of selective signaling molecules within the pancreatic acinar cell mediates the development of acute pancreatitis. Some of the key early acinar cell events include activation of proteases, inhibition of apical secretion, and elaboration of inflammatory mediators. Previous studies have shown that supraphysiological concentrations of cholecystokinin (CCK) that can cause pancreatitis in vivo, also initiate these pathological responses in dispersed groups of acinar cells (acini). Protein kinase C (PKC) regulates many cellular events and a role for this family of signaling molecules has been described in some of the pathological responses of pancreatitis. Notably, ethanol can activate specific PKC isoforms and sensitize the acinar cells to the pathological effects of CCK. Our preliminary studies in isolated pancreatic acini and a cell-free reconstitution system suggest that PKC can mediate protease activation in the acinar cell. These findings may be relevant to the pathogenesis of pancreatitis from alcohol and other etiologies.
- Published
- 2008
- Full Text
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49. Regulation of insulin secretion and GLUT4 trafficking by the calcium sensor synaptotagmin VII.
- Author
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Li Y, Wang P, Xu J, Gorelick F, Yamazaki H, Andrews N, and Desir GV
- Subjects
- Adipose Tissue metabolism, Animals, Crosses, Genetic, Glucose Tolerance Test, Insulin Secretion, Islets of Langerhans metabolism, Male, Mice, Mice, Inbred C57BL, Models, Biological, Muscle, Skeletal metabolism, Calcium metabolism, Gene Expression Regulation, Glucose Transporter Type 4 metabolism, Insulin metabolism, Synaptotagmins metabolism
- Abstract
Insulin regulates blood glucose by promoting uptake by fat and muscle, and inhibiting production by liver. Insulin-stimulated glucose uptake is mediated by GLUT4, which translocates from an intracellular compartment to the plasma membrane. GLUT4 traffic and insulin secretion both rely on calcium-dependent, regulated exocytosis. Deletion of the voltage-gated potassium channel Kv1.3 results in constitutive expression of GLUT4 at the plasma membrane. Inhibition of channel activity stimulated GLUT4 translocation through a calcium dependent mechanism. The synaptotagmins (Syt) are calcium sensors for vesicular traffic, and Syt VII mediates lysosomal and secretory granule exocytosis. We asked if Syt VII regulates insulin secretion by pancreatic beta cells, and GLUT4 translocation in insulin-sensitive tissues mouse model. Syt VII deletion (Syt VII -/-) results in glucose intolerance and a marked decrease in glucose-stimulated insulin secretion in vivo. Pancreatic islet cells isolated from Syt VII -/- cells secreted significantly less insulin than islets of littermate controls. Syt VII deletion disrupted GLUT4 traffic as evidenced by constitutive expression of GLUT4 present at the plasma membrane of fat and skeletal muscle cells and unresponsiveness to insulin. These data document a key role for Syt VII in peripheral glucose homeostasis through its action on both insulin secretion and GLUT4 traffic.
- Published
- 2007
- Full Text
- View/download PDF
50. Development and physiological regulation of intestinal lipid absorption. II. Dietary lipid absorption, complex lipid synthesis, and the intracellular packaging and secretion of chylomicrons.
- Author
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Mansbach CM 2nd and Gorelick F
- Subjects
- Animals, Chylomicrons metabolism, Endoplasmic Reticulum metabolism, Humans, Triglycerides biosynthesis, Chylomicrons physiology, Dietary Fats metabolism, Intestinal Absorption physiology, Lipid Metabolism
- Abstract
Research in dietary fat absorption has developed urgency because of the widely recognized epidemic of obesity in the United States. Despite its clinical importance, many controversies exist over some of the basic aspects of this process from the mechanisms of fatty acid uptake to the control of triacylglycerol export in chylomicrons. Recent advances have included the identification of a number of fatty acid transporters, the discovery of families of acyl-CoA synthetase long chains and acyltransferases, a physiological function for liver-fatty acid binding protein, and the characterization of the prechylomicron transport vesicle transporting chylomicrons from the endoplasmic reticulum to the Golgi.
- Published
- 2007
- Full Text
- View/download PDF
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