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1
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Tian Y, Huang Q, Ren YT, Jiang X, Jiang B. Visceral adipose tissue predicts severity and prognosis of acute pancreatitis in obese patients. Hepatobiliary Pancreat Dis Int 2024; 23:458-462. [PMID: 37648552 DOI: 10.1016/j.hbpd.2023.08.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 08/21/2023] [Indexed: 09/01/2023]
Abstract
Acute pancreatitis is a common systemic inflammatory disease, manifested by a spectrum of severity, ranging from mild in the majority of patients to severe acute pancreatitis. Patients with severe acute pancreatitis suffer from severe local and systemic complications and organ failure, leading to a poor prognosis. The early recognition of the severe condition is important to improve prognosis. Obesity has risen in tandem with an increase in the severity of acute pancreatitis in recent years. Studies have revealed that adipose tissue, particularly visceral adipose tissue is associated with the prognosis of acute pancreatitis. This review discussed the role of visceral adipose tissue in obese patients with acute pancreatitis and explored the possible mechanism involved.
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Affiliation(s)
- Yuan Tian
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Qing Huang
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Yu-Tang Ren
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Xuan Jiang
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Bo Jiang
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China.
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Song Q, Li H, Yan H, Yu Z, Li Z, Yuan J, Jiang N, Ni Z, Gu L, Fang W. Inhibition of STAT3 by S3I-201 suppress peritoneal fibroblast phenotype conversion and alleviate peritoneal fibrosis. J Cell Mol Med 2024; 28:e18381. [PMID: 38780509 PMCID: PMC11114217 DOI: 10.1111/jcmm.18381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/22/2024] [Accepted: 04/27/2024] [Indexed: 05/25/2024] Open
Abstract
Peritoneal fibrosis is a common pathological response to long-term peritoneal dialysis (PD) and a major cause for PD discontinuation. Understanding the cellular and molecular mechanisms underlying the induction and progression of peritoneal fibrosis is of great interest. In our study, in vitro study revealed that signal transducer and activator of transcription 3 (STAT3) is a key factor in fibroblast activation and extracellular matrix (ECM) synthesis. Furthermore, STAT3 induced by IL-6 trans-signalling pathway mediate the fibroblasts of the peritoneal stroma contributed to peritoneal fibrosis. Inhibition of STAT3 exerts an antifibrotic effect by attenuating fibroblast activation and ECM production with an in vitro co-culture model. Moreover, STAT3 plays an important role in the peritoneal fibrosis in an animal model of peritoneal fibrosis developed in mice. Blocking STAT3 can reduce the peritoneal morphological changes induced by chlorhexidine gluconate. In conclusion, our findings suggested STAT3 signalling played an important role in peritoneal fibrosis. Therefore, blocking STAT3 might become a potential treatment strategy in peritoneal fibrosis.
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Affiliation(s)
- Qianhui Song
- Department of Nephrology, Renji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople's Republic of China
- Shanghai Center for Peritoneal Dialysis ResearchShanghaiPeople's Republic of China
| | - Han Li
- Department of Nephrology, Renji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople's Republic of China
- Shanghai Center for Peritoneal Dialysis ResearchShanghaiPeople's Republic of China
| | - Hao Yan
- Department of Nephrology, Renji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople's Republic of China
- Shanghai Center for Peritoneal Dialysis ResearchShanghaiPeople's Republic of China
| | - Zanzhe Yu
- Department of Nephrology, Renji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople's Republic of China
- Shanghai Center for Peritoneal Dialysis ResearchShanghaiPeople's Republic of China
| | - Zhenyuan Li
- Department of Nephrology, Renji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople's Republic of China
- Shanghai Center for Peritoneal Dialysis ResearchShanghaiPeople's Republic of China
| | - Jiangzi Yuan
- Department of Nephrology, Renji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople's Republic of China
- Shanghai Center for Peritoneal Dialysis ResearchShanghaiPeople's Republic of China
| | - Na Jiang
- Department of Nephrology, Renji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople's Republic of China
- Shanghai Center for Peritoneal Dialysis ResearchShanghaiPeople's Republic of China
| | - Zhaohui Ni
- Department of Nephrology, Renji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople's Republic of China
- Shanghai Center for Peritoneal Dialysis ResearchShanghaiPeople's Republic of China
| | - Leyi Gu
- Department of Nephrology, Renji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople's Republic of China
- Shanghai Center for Peritoneal Dialysis ResearchShanghaiPeople's Republic of China
| | - Wei Fang
- Department of Nephrology, Renji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople's Republic of China
- Shanghai Center for Peritoneal Dialysis ResearchShanghaiPeople's Republic of China
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3
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Wei H, Zhao H, Cheng D, Zhu Z, Xia Z, Lu D, Yu J, Dong R, Yue J. miR-148a and miR-551b-5p regulate inflammatory responses via regulating autophagy in acute pancreatitis. Int Immunopharmacol 2024; 127:111438. [PMID: 38159552 DOI: 10.1016/j.intimp.2023.111438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 12/08/2023] [Accepted: 12/21/2023] [Indexed: 01/03/2024]
Abstract
Acute pancreatitis (AP) is a common inflammatory response that occurs in the pancreas with mortality rates as high as 30 %. However, there is still no consistent and effective treatment for AP now. MicroRNA-148 was reported to be involved in AP through IL-6 signaling pathway. Therefore, we aimed to further explore the detailed mechanisms of AP, to develop more therapeutic approach for AP. Exosomes were isolated from peripheral blood mononuclear cells of 20 AP patients and 20 healthy volunteers to evaluate the abnormally expressed miRNA. Then pancreatic acinar cells (PACs) were transfected with retrovirus to overexpress miR-148a/miR-551b-5p to evaluate their function. Both miR-148a and miR-551b-5p were highly expressed in AP patients than these in healthy cases. Then overexpressing miR-551b-5p in PACs could regulate autophagy through directly binding to Baculoviral IAP Repeat Containing 6, leading to the increased secretions of interleukin-1β (IL-1β) and interleukin-18 (IL-18) through interleukin-1 (IL-1) signaling pathway. Moreover, overexpressing miR-148a in PACs could decrease the secretions of IL-1β and IL-18 to modulate autophagy. The exosomal miRNA-148a and miRNA-551b-5p derived from peripheral blood mononuclear cells of AP patients may two-way mediate autophagy damage through IL-6/STAT3 signaling pathway, which participated in the AP pathogenesis. Our findings may provide new targets for the diagnosis and treatment of AP.
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Affiliation(s)
- Huiping Wei
- Department of Emergency, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China
| | - Hui Zhao
- Department of Emergency, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China.
| | - Dongliang Cheng
- Pediatric Intensive Care Unit, Henan Provincial People's Hospital, No. 7 Weiwu Road, Jinshui District, Zhengzhou 450000, Henan Province, China
| | - Zhenni Zhu
- Pediatric Gastroenterology Department, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China
| | - Zhi Xia
- Pediatric Intensive Care Unit, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China
| | - Dan Lu
- Department of Clinical Examination, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China
| | - Jing Yu
- Department of General Surgery, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China
| | - Ran Dong
- Department of Emergency, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China
| | - Jing Yue
- Department of Emergency, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China
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Miescher I, Wolint P, Opelz C, Snedeker JG, Giovanoli P, Calcagni M, Buschmann J. Impact of High-Molecular-Weight Hyaluronic Acid on Gene Expression in Rabbit Achilles Tenocytes In Vitro. Int J Mol Sci 2022; 23:ijms23147926. [PMID: 35887273 PMCID: PMC9320370 DOI: 10.3390/ijms23147926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 11/17/2022] Open
Abstract
(1) Background: Surgical tendon repair often leads to adhesion formation, leading to joint stiffness and a reduced range of motion. Tubular implants set around sutured tendons might help to reduce peritendinous adhesions. The lubricant hyaluronic acid (HA) is a viable option for optimizing such tubes with the goal of further enhancing the anti-adhesive effect. As the implant degrades over time and diffusion is presumed, the impact of HA on tendon cells is important to know. (2) Methods: A culture medium of rabbit Achilles tenocytes was supplemented with high-molecular-weight (HMW) HA and the growth curves of the cells were assessed. Additionally, after 3, 7 and 14 days, the gene expression of several markers was analyzed for matrix assembly, tendon differentiation, fibrosis, proliferation, matrix remodeling, pro-inflammation and resolution. (3) Results: The addition of HA decreased matrix marker genes, downregulated the fibrosis marker α-SMA for a short time and slightly increased the matrix-remodeling gene MMP-2. Of the pro-inflammatory marker genes, only IL-6 was significantly upregulated. IL-6 has to be kept in check, although IL-6 is also needed for a proper initial inflammation and efficient resolution. (4) Conclusions: The observed effects in vitro support the intended anti-adhesion effect and therefore, the use of HMW HA is promising as a biodegradable implant for tendon repair.
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Affiliation(s)
- Iris Miescher
- Division of Plastic Surgery and Hand Surgery, University Hospital Zurich, Sternwartstrasse 14, 8091 Zurich, Switzerland; (I.M.); (P.W.); (C.O.); (P.G.); (M.C.)
| | - Petra Wolint
- Division of Plastic Surgery and Hand Surgery, University Hospital Zurich, Sternwartstrasse 14, 8091 Zurich, Switzerland; (I.M.); (P.W.); (C.O.); (P.G.); (M.C.)
| | - Christine Opelz
- Division of Plastic Surgery and Hand Surgery, University Hospital Zurich, Sternwartstrasse 14, 8091 Zurich, Switzerland; (I.M.); (P.W.); (C.O.); (P.G.); (M.C.)
| | - Jess G. Snedeker
- Orthopaedic Biomechanics, University Clinic Balgrist, Forchstrasse 340, 8008 Zurich, Switzerland;
| | - Pietro Giovanoli
- Division of Plastic Surgery and Hand Surgery, University Hospital Zurich, Sternwartstrasse 14, 8091 Zurich, Switzerland; (I.M.); (P.W.); (C.O.); (P.G.); (M.C.)
| | - Maurizio Calcagni
- Division of Plastic Surgery and Hand Surgery, University Hospital Zurich, Sternwartstrasse 14, 8091 Zurich, Switzerland; (I.M.); (P.W.); (C.O.); (P.G.); (M.C.)
| | - Johanna Buschmann
- Division of Plastic Surgery and Hand Surgery, University Hospital Zurich, Sternwartstrasse 14, 8091 Zurich, Switzerland; (I.M.); (P.W.); (C.O.); (P.G.); (M.C.)
- Correspondence: ; Tel.: +41-44-255-98-95
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Fasullo M, Omer E, Kaspar M. Sarcopenia in Chronic Pancreatitis - Prevalence, Diagnosis, Mechanisms and Potential Therapies. Curr Gastroenterol Rep 2022; 24:53-63. [PMID: 35167003 DOI: 10.1007/s11894-022-00837-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
PURPOSE OF REVIEW To investigate the prevalence, pathogenesis, diagnosis, clinical sequelae, and management of sarcopenia to improve mortality and quality of life in those with Chronic Pancreatitis. RECENT FINDINGS Sarcopenia is prevalent in chronic pancreatitis and can significantly affect clinical outcomes. Sarcopenia is prevalent in chronic pancreatitis. While effects on some clinical outcomes is has been shown, there is a significant gap in knowledge regarding effects on outcomes, pathophysiology, and options for management.
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Affiliation(s)
- Matthew Fasullo
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University (VCU), Richmond, VA, USA
| | - Endashaw Omer
- Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY, USA
| | - Matthew Kaspar
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University (VCU), Richmond, VA, USA.
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6
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Anandam KY, Srinivasan P, Yasujima T, Al-Juburi S, Said HM. Proinflammatory cytokines inhibit thiamin uptake by human and mouse pancreatic acinar cells: involvement of transcriptional mechanism(s). Am J Physiol Gastrointest Liver Physiol 2021; 320:G108-G116. [PMID: 33146542 PMCID: PMC8112188 DOI: 10.1152/ajpgi.00361.2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/22/2020] [Accepted: 10/27/2020] [Indexed: 01/31/2023]
Abstract
Thiamin (vitamin B1) plays critical roles in normal metabolism and function of all mammalian cells. Pancreatic acinar cells (PACs) import thiamin from circulation via specific carrier-mediated uptake that involves thiamin transporter-1 and -2 (THTR-1 and -2; products of SLC19A2 and SLC19A3, respectively). Our aim in this study was to investigate the effect(s) of proinflammatory cytokines on thiamin uptake by PACs. We used human primary (h)PACs, PAC 266-6 cells, and mice in vivo as models in the investigations. First, we examined the level of expression of THTR-1 and -2 mRNA in pancreatic tissues of patients with chronic pancreatitis and observed severe reduction in their expression compared with normal control subjects. Exposing hPACs and PAC 266-6 to proinflammatory cytokines (hyper IL-6, TNF-α, and IL-1β) was found to lead to a significant inhibition in thiamin uptake. Focusing on hyper-IL-6 (which also inhibited thiamin uptake by primary mouse PACs), the inhibition in thiamin uptake was found to be associated with significant reduction in THTR-1 and -2 proteins and mRNA expression as well as in activity of the SLC19A2 and SLC19A3 promoters; it was also associated with reduction in level of expression of the transcription factor Sp1 (which is required for activity of these promoters). Finally, blocking the intracellular Stat3 signaling pathway was found to lead to a significant reversal in the inhibitory effect of hyper IL-6 on thiamin uptake by PAC 266-6. These results show that exposure of PACs to proinflammatory cytokines negatively impacts thiamin uptake via (at least in part) transcriptional mechanism(s).NEW & NOTEWORTHY Findings of the current study demonstrate, for the first time, that exposure of pancreatic acinar cells to proinflammatory cytokines (including hyper IL-6) cause significant inhibition in vitamin B1 (thiamin; a micronutrient that is essential for normal cellular energy metabolism) and that this effect is mediated at the level of transcription of the thiamin transporter genes SLC19A2 and SLC19A3.
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Affiliation(s)
- Kasin Yadunandam Anandam
- Departments of Physiology/Biophysics, School of Medicine, University of California, Irvine, California
- Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California
| | - Padmanabhan Srinivasan
- Departments of Physiology/Biophysics, School of Medicine, University of California, Irvine, California
- Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California
| | - Tomoya Yasujima
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Japan
| | - Saleh Al-Juburi
- Departments of Physiology/Biophysics, School of Medicine, University of California, Irvine, California
| | - Hamid M Said
- Departments of Physiology/Biophysics, School of Medicine, University of California, Irvine, California
- Department of Medicine, School of Medicine, University of California, Irvine, California
- Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California
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7
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Jiang L, Liu B, Qi Y, Zhu L, Cui X, Liu Z. Antagonistic effects of activin A and TNF-α on the activation of L929 fibroblast cells via Smad3-independent signaling. Sci Rep 2020; 10:20623. [PMID: 33244088 PMCID: PMC7693280 DOI: 10.1038/s41598-020-77783-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 11/17/2020] [Indexed: 02/07/2023] Open
Abstract
Fibroblasts play an important role in inflammation and tissue fibrosis. Both activin A and TNF-α can activate immune cells, however, the roles and relationship of them in activating fibroblasts in inflammation remain unclear. Here, this study revealed that TNF-α promoted the release of NO and IL-6 by L929 fibroblast cells, but co-treatment with activin A attenuated these effects. In contrast, activin A induced cell migration and increased the production of tissue fibrosis-related TGF-β1 and fibronectin, while TNF-α inhibited these function changes of L929 cells induced by activin A. Moreover, this study revealed that activin A and TNF-α regulated the activities of L929 cells via ERK1/2/MAPK pathway, rather than Smad3-dependent signaling pathway. Taken together, these data indicate that activin A and TNF-α exert mutually antagonistic effects on regulating fibroblasts activities, and the balance between their action may determine the process and outcome of fibroblasts-mediated inflammation.
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Affiliation(s)
- Lingling Jiang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China.,Department of General Dentistry, School and Hospital of Stomatology, Jilin University, Changchun, 130021, Jilin, China
| | - Boyang Liu
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin, China.,Department of Scientific Research, Jilin Jianzhu University, Changchun, 130118, Jilin, China
| | - Yan Qi
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Linru Zhu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Xueling Cui
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin, China
| | - Zhonghui Liu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China.
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Robich M, Ryzhov S, Kacer D, Palmeri M, Peterson SM, Quinn RD, Carter D, Sheppard F, Hayes T, Sawyer DB, Rappold J, Prudovsky I, Kramer RS. Prolonged Cardiopulmonary Bypass is Associated With Endothelial Glycocalyx Degradation. J Surg Res 2020; 251:287-295. [PMID: 32199337 DOI: 10.1016/j.jss.2020.02.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/23/2020] [Accepted: 02/16/2020] [Indexed: 01/06/2023]
Abstract
BACKGROUND The endothelial glycocalyx (EG) is involved in critical regulatory mechanisms that maintain endothelial vascular integrity. We hypothesized that prolonged cardiopulmonary bypass (CPB) may be associated with EG degradation. We performed an analysis of soluble syndecan-1 levels in relation to duration of CPB, as well as factors associated with cell stress and damage, such as mitochondrial DNA (mtDNA) and inflammation. METHODS Blood samples from subjects undergoing cardiac surgery with CPB (n = 54) were obtained before and during surgery, 4-8 h and 24 h after completion of CPB, and on postoperative day 4. Flow cytometry was used to determine subpopulations of white blood cells. Plasma levels of mtDNA were determined using quantitative polymerase chain reaction and plasma content of shed syndecan-1 was measured. To determine whether syndecan-1 was signaling white blood cells, the effect of recombinant syndecan-1 on mobilization of neutrophils from bone marrow was tested in mice. RESULTS CPB is associated with increased mtDNA during surgery, increased syndecan-1 blood levels at 4-8 h, and increased white blood cell count at 4-8 h and 24 h. Correlation analysis revealed significant positive associations between time on CPB and syndecan-1 (rs = 0.488, P < 0.001) and level of syndecan-1 and neutrophil count (rs = 0.351, P = 0.038) at 4-8 h. Intravenous administration of recombinant syndecan-1 in mice resulted in a 2.5-fold increase in the number of circulating neutrophils, concurrent with decreased bone marrow neutrophil number. CONCLUSIONS Longer duration of CPB is associated with increased plasma levels of soluble syndecan-1, a signal for EG degradation, which can induce neutrophil egress from the bone marrow. Development of therapy targeting EG shedding may be beneficial in patients with prolonged CPB.
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Affiliation(s)
- Michael Robich
- Maine Medical Center Cardiovascular Institute, Portland, Maine; Maine Medical Center Research Institute, Scarborough, Maine
| | - Sergey Ryzhov
- Maine Medical Center Research Institute, Scarborough, Maine
| | - Doreen Kacer
- Maine Medical Center Research Institute, Scarborough, Maine
| | - Monica Palmeri
- Maine Medical Center Cardiovascular Institute, Portland, Maine; Maine Medical Center Research Institute, Scarborough, Maine
| | | | - Reed D Quinn
- Maine Medical Center Cardiovascular Institute, Portland, Maine
| | - Damien Carter
- Maine Medical Center Research Institute, Scarborough, Maine; Maine Medical Center, Department of Surgery, Portland, Maine
| | - Forest Sheppard
- Maine Medical Center, Department of Surgery, Portland, Maine
| | - Timothy Hayes
- Maine Medical Center, Department of Pathology, Portland, Maine
| | - Douglas B Sawyer
- Maine Medical Center Cardiovascular Institute, Portland, Maine; Maine Medical Center Research Institute, Scarborough, Maine
| | - Joseph Rappold
- Maine Medical Center Cardiovascular Institute, Portland, Maine; Maine Medical Center Research Institute, Scarborough, Maine; Maine Medical Center, Department of Surgery, Portland, Maine
| | - Igor Prudovsky
- Maine Medical Center Research Institute, Scarborough, Maine
| | - Robert S Kramer
- Maine Medical Center Cardiovascular Institute, Portland, Maine; Maine Medical Center Research Institute, Scarborough, Maine.
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9
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Srivastava S, Pandey H, Singh SK, Tripathi YB. Anti-oxidant, anti-apoptotic, anti-hypoxic and anti-inflammatory conditions induced by PTY-2 against STZ-induced stress in islets. Biosci Trends 2019; 13:382-393. [PMID: 31597821 DOI: 10.5582/bst.2019.01181] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The earlier assessment of Pueraria tuberosa (PT) has shown anti-diabetic effects through enhancing incretin action and DPP-IV (Dipeptidyl peptidase-IV) inhibition. The aim of this work was to further explore the protective role of aqueous extract of Pueraria tuberosa tuber (PTY-2) against streptozotocin (STZ) induced islet stress in rats. Diabetes was induced by STZ (65 mg/kg body weight) in charles foster male rats. After 60 days of STZ administration, animals with blood glucose levels > 200 g/dL were considered as diabetic. All the rats were later divided into three groups: Group-1 (STZ untreated normal rats), Group-2 (Diabetic control), and Group-3 (PTY-2 [50 mg/100 g bw treatment for next 10 days to diabetic rats). The rats were then sacrificed after the 10th day of treatment accordingly. STZ treatment led to an increase in expression of Matrix metalloproteinases-9 (MMP-9), Tumour necrosis factor-α (Tnf-α), Hypoxia inducible factor-α (HIF-1α), Vascular endothelial growth factor (VEGF), Interleukin-6 (IL-6), Protein kinase C-ε (PKC-ε), Nuclear factor kappa-light-chain-enhancer of activated B-cells (NFkB), and Caspase-3. Reverse Transcriptase-PCR (RT-PCR), Immunohistochemistry and Western-Blot analysis showed an increase in the expressions of Superoxide Dismutase (SOD) and Nephrin, and a decrease in the expressions of NFkB, PKC-ε, TNF-α, MMP-9, HIF-1α, VEGF, Caspase-3 and IL-6 after 10 days of PTY-2 treatment. The results showed that PTY-2 favorably changed all the expressions via anti-oxidant, anti-apoptotic, anti-hypoxic and anti-inflammatory pathways, making itself as a protective agent against STZ induced islet stress. Further evaluation of PTY-2 might be helpful in establishing its role in the management of diabetes mellitus.
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Affiliation(s)
- Shivani Srivastava
- Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Harsh Pandey
- Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Surya Kumar Singh
- Department of Endocrinology and Metabolism, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Yamini Bhusan Tripathi
- Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
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10
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Tougaard P, Martinsen LO, Zachariassen LF, Krych L, Nielsen DS, Buus TB, Pedersen AE, Hansen AK, Skov S, Hansen CHF. TL1A Aggravates Cytokine-Induced Acute Gut Inflammation and Potentiates Infiltration of Intraepithelial Natural Killer Cells in Mice. Inflamm Bowel Dis 2019; 25:510-523. [PMID: 30462201 DOI: 10.1093/ibd/izy351] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Indexed: 12/26/2022]
Abstract
BACKGROUND The tumor necrosis factor alpha (TNFα)-homologous cytokine TL1A is emerging as a major player in intestinal inflammation. From in vitro experiments on human lymphocytes, TNF-like molecule 1A (TL1A) is known to activate a highly inflammatory lymphoid response in synergy with interleukin (IL)-12 and IL-18. Carriers of specific genetic polymorphisms associated with IL-12, IL-18, or TL1A signaling have increased Crohn's disease risk, and all 3 cytokines are upregulated during active disease. The study aim was to investigate whether the type 1-polarizing cytokines IL-12 and IL-18 could directly initiate intestinal pathology in mice and how TL1A would influence the resulting inflammatory response. METHODS Conventional barrier-bred and germ-free mice were randomly allocated to different groups and injected twice with different combinations of IL-12, IL-18, and TL1A, and killed 3 days after the first injection. All treatment groups were co-housed and fed a piroxicam-supplemented chow diet. RESULTS Intestinal pathology was evident in IL-12- and IL-18-treated mice and highly exacerbated by TL1A in both the colon and ileum. The cytokine-induced intestinal inflammation was characterized by epithelial damage, increased colonic levels of TNFα, IL-1β, IFN-γ, and IL-6, and various chemokines along with gut microbiota alterations exhibiting high abundance of Enterobacteriaceae. Furthermore, the inflamed ileum and colon exhibited a TL1A-specific increased infiltration of intraepithelial natural killer cells co-expressing NKG2D and IL-18Ra and a higher frequency of unconventional T cells in the colonic epithelium. Upon cytokine injection, germ-free mice exhibited similar intraepithelial lymphoid infiltration and increased colonic levels of IFNγ and TNFα. CONCLUSIONS This study demonstrates that TL1A aggravates IL-12- and IL-18-induced intestinal inflammation in the presence and absence of microbiota.
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Affiliation(s)
- Peter Tougaard
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.,Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Louise Otterstrøm Martinsen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Line Fisker Zachariassen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Lukasz Krych
- Department of Food Science, Faculty of Science, University of Copenhagen, Denmark
| | | | - Terkild Brink Buus
- Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Anders Elm Pedersen
- Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Axel Kornerup Hansen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Søren Skov
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Camilla Hartmann Friis Hansen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
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11
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Activin in acute pancreatitis: Potential risk-stratifying marker and novel therapeutic target. Sci Rep 2017; 7:12786. [PMID: 28986573 PMCID: PMC5630611 DOI: 10.1038/s41598-017-13000-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 09/12/2017] [Indexed: 02/07/2023] Open
Abstract
Acute Pancreatitis is a substantial health care challenge with increasing incidence. Patients who develop severe disease have considerable mortality. Currently, no reliable predictive marker to identify patients at risk for severe disease exists. Treatment is limited to rehydration and supporting care suggesting an urgent need to develop novel approaches to improve standard care. Activin is a critical modulator of inflammatory responses, but has not been assessed in pancreatitis. Here, we demonstrate that serum activin is elevated and strongly correlates with disease severity in two established murine models of acute pancreatitis induced by either cerulein or IL-12 + IL-18. Furthermore, in mice, inhibition of activin conveys survival benefits in pancreatitis. In addition, serum activin levels were measured from a retrospective clinical cohort of pancreatitis patients and high activin levels in patients at admission are predictive of worse outcomes, indicated by longer overall hospital and intensive care unit stays. Taken together, activin is a novel candidate as a clinical marker to identify those acute pancreatitis patients with severe disease who would benefit from aggressive treatment and activin may be a therapeutic target in severe acute pancreatitis.
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12
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Li N, Wang B, Cai S, Liu P. The Role of Serum High Mobility Group Box 1 and Interleukin‐6 Levels in Acute Pancreatitis: A Meta‐Analysis. J Cell Biochem 2017; 119:616-624. [PMID: 28618057 DOI: 10.1002/jcb.26222] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 06/14/2017] [Indexed: 12/14/2022]
Affiliation(s)
- Nuo Li
- Department of GastroenterologyThe Fourth Affiliated Hospital of China Medical UniversityShenyang110032P.R. China
| | - Bao‐Ming Wang
- Department of InterventionThe Fourth Affiliated Hospital of China Medical UniversityShenyang110032P.R. China
| | - Shuang Cai
- Department of GastroenterologyThe Fourth Affiliated Hospital of China Medical UniversityShenyang110032P.R. China
| | - Peng‐Liang Liu
- Department of GastroenterologyThe Fourth Affiliated Hospital of China Medical UniversityShenyang110032P.R. China
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13
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Candelaria PV, Rampoldi A, Harbuzariu A, Gonzalez-Perez RR. Leptin signaling and cancer chemoresistance: Perspectives. World J Clin Oncol 2017; 8:106-119. [PMID: 28439492 PMCID: PMC5385432 DOI: 10.5306/wjco.v8.i2.106] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 12/20/2016] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
Obesity is a major health problem and currently is endemic around the world. Obesity is a risk factor for several different types of cancer, significantly promoting cancer incidence, progression, poor prognosis and resistance to anti-cancer therapies. The study of this resistance is critical as development of chemoresistance is a serious drawback for the successful and effective drug-based treatments of cancer. There is increasing evidence that augmented adiposity can impact on chemotherapeutic treatment of cancer and the development of resistance to these treatments, particularly through one of its signature mediators, the adipokine leptin. Leptin is a pro-inflammatory, pro-angiogenic and pro-tumorigenic adipokine that has been implicated in many cancers promoting processes such as angiogenesis, metastasis, tumorigenesis and survival/resistance to apoptosis. Several possible mechanisms that could potentially be developed by cancer cells to elicit drug resistance have been suggested in the literature. Here, we summarize and discuss the current state of the literature on the role of obesity and leptin on chemoresistance, particularly as it relates to breast and pancreatic cancers. We focus on the role of leptin and its significance in possibly driving these proposed chemoresistance mechanisms, and examine its effects on cancer cell survival signals and expansion of the cancer stem cell sub-populations.
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14
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Zhang C, Wang Y, Fu W, Zhang W, Wang T, Qin H. A Meta-analysis on the Effect of Ulinastatin on Serum Levels of C-Reactive Protein, Interleukin 6, and Tumor Necrosis Factor Alpha in Asian Patients with Acute Pancreatitis. Genet Test Mol Biomarkers 2016; 20:118-24. [PMID: 26780230 DOI: 10.1089/gtmb.2015.0192] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVES We aimed to investigate the influence of ulinastatin (UTI) on the serum levels of C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) in Asian patients with acute pancreatitis (AP) by performance of a meta-analysis. METHODS Two investigators independently searched 11 databases, including PUBMED, EBSCO, Ovid, SpringerLink, Wiley, Web of Science, Cochrane Library, Wanfang database, China National Knowledge Infrastructure (CNKI), Chinese Journal Full-text Database, and China Biomedicine Database. The full-text articles were screened and the data were extracted using a standardized data extraction form. All statistical analyses were conducted with Stata software, version 12.0 (Stata Corporation, College Station, TX). RESULTS A total of 94 studies were initially retrieved, and 10 studies containing 424 Asian patients with AP were ultimately enrolled in this meta-analysis. The results revealed that the serum levels of CRP, IL-6, and TNF-α in Asian AP patients significantly decreased after UTI therapy (CRP: standardized mean difference [SMD] = 3.26, 95% confidence interval [CI] = 1.69-4.83, p < 0.001; IL-6: SMD = 5.92, 95% CI = 2.09-9.75, p = 0.002; TNF-α: SMD = 4.07, 95% CI = 0.79-7.35, p = 0.015). CONCLUSION The results of this meta-analysis suggest that UTI can effectively depress the serum levels of CRP, IL-6, and TNF-α in Asian patients with AP, and thereby inhibit inflammation.
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Affiliation(s)
- Chunze Zhang
- 1 Department of Colorectal Surgery, Tianjin Union Medicine Centre , Tianjin, P.R. China
| | - Yijia Wang
- 2 Department of Pathology, Tianjin Union Medicine Centre , Tianjin, P.R. China
| | - Wenzheng Fu
- 1 Department of Colorectal Surgery, Tianjin Union Medicine Centre , Tianjin, P.R. China
| | - Weihua Zhang
- 1 Department of Colorectal Surgery, Tianjin Union Medicine Centre , Tianjin, P.R. China
| | - Tao Wang
- 1 Department of Colorectal Surgery, Tianjin Union Medicine Centre , Tianjin, P.R. China
| | - Hai Qin
- 1 Department of Colorectal Surgery, Tianjin Union Medicine Centre , Tianjin, P.R. China
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15
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Noel P, Patel K, Durgampudi C, Trivedi RN, de Oliveira C, Crowell MD, Pannala R, Lee K, Brand R, Chennat J, Slivka A, Papachristou GI, Khalid A, Whitcomb DC, DeLany JP, Cline RA, Acharya C, Jaligama D, Murad FM, Yadav D, Navina S, Singh VP. Peripancreatic fat necrosis worsens acute pancreatitis independent of pancreatic necrosis via unsaturated fatty acids increased in human pancreatic necrosis collections. Gut 2016; 65:100-11. [PMID: 25500204 PMCID: PMC4869971 DOI: 10.1136/gutjnl-2014-308043] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 11/17/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Peripancreatic fat necrosis occurs frequently in necrotising pancreatitis. Distinguishing markers from mediators of severe acute pancreatitis (SAP) is important since targeting mediators may improve outcomes. We evaluated potential agents in human pancreatic necrotic collections (NCs), pseudocysts (PCs) and pancreatic cystic neoplasms and used pancreatic acini, peripheral blood mononuclear cells (PBMC) and an acute pancreatitis (AP) model to determine SAP mediators. METHODS We measured acinar and PBMC injury induced by agents increased in NCs and PCs. Outcomes of caerulein pancreatitis were studied in lean rats coadministered interleukin (IL)-1β and keratinocyte chemoattractant/growth-regulated oncogene, triolein alone or with the lipase inhibitor orlistat. RESULTS NCs had higher fatty acids, IL-8 and IL-1β versus other fluids. Lipolysis of unsaturated triglyceride and resulting unsaturated fatty acids (UFA) oleic and linoleic acids induced necro-apoptosis at less than half the concentration in NCs but other agents did not do so at more than two times these concentrations. Cytokine coadministration resulted in higher pancreatic and lung inflammation than caerulein alone, but only triolein coadministration caused peripancreatic fat stranding, higher cytokines, UFAs, multisystem organ failure (MSOF) and mortality in 97% animals, which were prevented by orlistat. CONCLUSIONS UFAs, IL-1β and IL-8 are elevated in NCs. However, UFAs generated via peripancreatic fat lipolysis causes worse inflammation and MSOF, converting mild AP to SAP.
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Affiliation(s)
- Pawan Noel
- Departments of Medicine, Mayo Clinic, Scottsdale, Arizona, USA
| | - Krutika Patel
- Departments of Medicine, Mayo Clinic, Scottsdale, Arizona, USA
| | - Chandra Durgampudi
- Departments of Medicine, University of Pittsburgh Medical Center, Pasavant, Pennsylvania, USA
| | - Ram N Trivedi
- Departments of Medicine, Mayo Clinic, Scottsdale, Arizona, USA
| | | | | | - Rahul Pannala
- Departments of Medicine, Mayo Clinic, Scottsdale, Arizona, USA
| | - Kenneth Lee
- Departments of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Randall Brand
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jennifer Chennat
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Adam Slivka
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | | | - Asif Khalid
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - David C Whitcomb
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - James P DeLany
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Rachel A Cline
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Chathur Acharya
- Departments of Medicine, University of Pittsburgh Medical Center, Pasavant, Pennsylvania, USA
| | - Deepthi Jaligama
- Departments of Medicine, University of Pittsburgh Medical Center, Pasavant, Pennsylvania, USA
| | - Faris M Murad
- Departments of Medicine, Washington University, Saint Louis, Missouri, USA
| | - Dhiraj Yadav
- Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sarah Navina
- Departments of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Vijay P Singh
- Departments of Medicine, Mayo Clinic, Scottsdale, Arizona, USA
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16
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Amaral WZ, Krueger RF, Ryff CD, Coe CL. Genetic and environmental determinants of population variation in interleukin-6, its soluble receptor and C-reactive protein: insights from identical and fraternal twins. Brain Behav Immun 2015; 49:171-81. [PMID: 26086344 PMCID: PMC4567498 DOI: 10.1016/j.bbi.2015.05.010] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Revised: 05/19/2015] [Accepted: 05/25/2015] [Indexed: 12/26/2022] Open
Abstract
Interleukin-6 and C-reactive protein are commonly assessed biomarkers linked to illness, obesity, and stressful life events. However, relatively little is known about their heritability. By comparing Caucasian twins from the Midlife in the US project (MIDUS), we estimated the heritability of IL-6, its soluble receptor, and CRP. Based on the hypothesis that adiposity might contribute more to IL-6 than to sIL-6r, we fit heritability models quantifying the extent to which each reflected genetic and environmental factors shared with obesity. Genetic influences on IL-6 and its receptor proved to be distinct. Further, the appearance of a heritable basis for IL-6 was mediated largely via shared paths with obesity. Supporting this conclusion, we confirmed that when unrelated adult controls are carefully matched to twin participants on BMI, age, gender and socioeconomic indices, their IL-6 is similar to the corresponding twins. In contrast, the effect of BMI on CRP was split between shared genetics and environmental influences. In conclusion, IL-6 is strongly affected by factors associated with obesity accounting for its lability and responsiveness to diet, life style and contemporaneous events.
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Affiliation(s)
- Wellington Z Amaral
- Department of Psychology, University of Wisconsin-Madison, Madison, WI 53715, USA
| | - Robert F Krueger
- Department of Psychology, University of Minnesota, Minneapolis, MN 55455, USA.
| | - Carol D Ryff
- Department of Psychology, University of Wisconsin-Madison, Madison, WI 53715, USA.
| | - Christopher L Coe
- Department of Psychology, University of Wisconsin-Madison, Madison, WI 53715, USA.
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17
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Chen XY, Yang YS, Chen K, Chen LS, Xie WR, Wang H. JAK-STAT signaling pathway and acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2015; 23:932-937. [DOI: 10.11569/wcjd.v23.i6.932] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The pathogenesis of acute pancreatitis has long been an important research topic. In acute pancreatitis, cytokines and growth factors bind to Janus kinase (JAK) related receptors, and activate JAKs. The activated JAKs phosphorylate the tyrosine residues of the receptor. The downstream signal transducers and activators of transcription (STAT) then bind to the specific site of the phosphorylated JAK receptor complexes, leading to the activation of STATs. The activated STATs detach from the receptor complexes and translocate to the nucleus to regulate the expression of Bcl-2, Bcl-X(L), Mcl-1 and other genes, thereby participating in the pathogenesis of pancreatitis. Such signal transduction can be terminated by the dephosphorylation of STATs. At present, more and more clinical experiments and animal studies have shown that the JAK-STAT pathway is closely related with acute pancreatitis. In this article, we will review the structure, distribution, and function of JAK-STAT signaling pathway as well as the role of JAK-STAT signaling pathway in the pathogenesis of acute pancreatitis.
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18
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Ryan RE, Martin B, Mellor L, Jacob RB, Tawara K, McDougal OM, Oxford JT, Jorcyk CL. Oncostatin M binds to extracellular matrix in a bioactive conformation: implications for inflammation and metastasis. Cytokine 2015; 72:71-85. [PMID: 25622278 DOI: 10.1016/j.cyto.2014.11.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 09/25/2014] [Accepted: 11/06/2014] [Indexed: 12/18/2022]
Abstract
Oncostatin M (OSM) is an interleukin-6-like inflammatory cytokine reported to play a role in a number of pathological processes including cancer. Full-length OSM is expressed as a 26 kDa protein that can be proteolytically processed into 24 kDa and 22 kDa forms via removal of C-terminal peptides. In this study, we examined both the ability of OSM to bind to the extracellular matrix (ECM) and the activity of immobilized OSM on human breast carcinoma cells. OSM was observed to bind to ECM proteins collagen types I and XI, laminin, and fibronectin in a pH-dependent fashion, suggesting a role for electrostatic bonds that involves charged amino acids of both the ECM and OSM. The C-terminal extensions of 24 kDa and 26 kDa OSM, which contains six and thirteen basic amino acids, respectively, enhanced electrostatic binding to ECM at pH 6.5-7.5 when compared to 22 kDa OSM. The highest levels of OSM binding to ECM, though, were observed at acidic pH 5.5, where all forms of OSM bound to ECM proteins to a similar extent. This indicates additional electrostatic binding properties independent of the OSM C-terminal extensions. The reducing agent dithiothreitol also inhibited the binding of OSM to ECM suggesting a role for disulfide bonds in OSM immobilization. OSM immobilized to ECM was protected from cleavage by tumor-associated proteases and maintained activity following incubation at acidic pH for extended periods of time. Importantly, immobilized OSM remained biologically active and was able to induce and sustain the phosphorylation of STAT3 in T47D and ZR-75-1 human breast cancer cells over prolonged periods, as well as increase levels of STAT1 and STAT3 protein expression. Immobilized OSM also induced epithelial-mesenchymal transition-associated morphological changes in T47D cells. Taken together, these data indicate that OSM binds to ECM in a bioactive state that may have important implications for the development of chronic inflammation and tumor metastasis.
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Affiliation(s)
- Randall E Ryan
- Department of Biological Sciences, 1910 University Drive, Boise, ID 83725, United States; Biomolecular Research Center, 1910 University Drive, Boise, ID 83725, United States
| | - Bryan Martin
- Biomolecular Research Center, 1910 University Drive, Boise, ID 83725, United States; Department of Chemistry and Biochemistry, 1910 University Drive, Boise, ID 83725, United States
| | - Liliana Mellor
- Biomolecular Research Center, 1910 University Drive, Boise, ID 83725, United States
| | - Reed B Jacob
- Department of Chemistry and Biochemistry, 1910 University Drive, Boise, ID 83725, United States
| | - Ken Tawara
- Department of Biological Sciences, 1910 University Drive, Boise, ID 83725, United States; Biomolecular Research Center, 1910 University Drive, Boise, ID 83725, United States
| | - Owen M McDougal
- Biomolecular Research Center, 1910 University Drive, Boise, ID 83725, United States; Department of Chemistry and Biochemistry, 1910 University Drive, Boise, ID 83725, United States
| | - Julia Thom Oxford
- Department of Biological Sciences, 1910 University Drive, Boise, ID 83725, United States; Biomolecular Research Center, 1910 University Drive, Boise, ID 83725, United States
| | - Cheryl L Jorcyk
- Department of Biological Sciences, 1910 University Drive, Boise, ID 83725, United States; Biomolecular Research Center, 1910 University Drive, Boise, ID 83725, United States.
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19
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Patel K, Trivedi RN, Durgampudi C, Noel P, Cline RA, DeLany JP, Navina S, Singh VP. Lipolysis of visceral adipocyte triglyceride by pancreatic lipases converts mild acute pancreatitis to severe pancreatitis independent of necrosis and inflammation. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:808-19. [PMID: 25579844 DOI: 10.1016/j.ajpath.2014.11.019] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 11/13/2014] [Accepted: 11/20/2014] [Indexed: 02/06/2023]
Abstract
Visceral fat necrosis has been associated with severe acute pancreatitis (SAP) for over 100 years; however, its pathogenesis and role in SAP outcomes are poorly understood. Based on recent work suggesting that pancreatic fat lipolysis plays an important role in SAP, we evaluated the role of pancreatic lipases in SAP-associated visceral fat necrosis, the inflammatory response, local injury, and outcomes of acute pancreatitis (AP). For this, cerulein pancreatitis was induced in lean and obese mice, alone or with the lipase inhibitor orlistat and parameters of AP induction (serum amylase and lipase), fat necrosis, pancreatic necrosis, and multisystem organ failure, and inflammatory response were assessed. Pancreatic lipases were measured in fat necrosis and were overexpressed in 3T3-L1 cells. We noted obesity to convert mild cerulein AP to SAP with greater cytokines, unsaturated fatty acids (UFAs), and multisystem organ failure, and 100% mortality without affecting AP induction or pancreatic necrosis. Increased pancreatic lipase amounts and activity were noted in the extensive visceral fat necrosis of dying obese mice. Lipase inhibition reduced fat necrosis, UFAs, organ failure, and mortality but not the parameters of AP induction. Pancreatic lipase expression increased lipolysis in 3T3-L1 cells. We conclude that UFAs generated via lipolysis of visceral fat by pancreatic lipases convert mild AP to SAP independent of pancreatic necrosis and the inflammatory response.
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Affiliation(s)
- Krutika Patel
- Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania; Mayo Clinic, Scottsdale, Arizona
| | - Ram N Trivedi
- Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania; Mayo Clinic, Scottsdale, Arizona
| | - Chandra Durgampudi
- Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Pawan Noel
- Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania; Mayo Clinic, Scottsdale, Arizona
| | - Rachel A Cline
- Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania
| | - James P DeLany
- Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Sarah Navina
- Department of Pathology, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Vijay P Singh
- Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania; Mayo Clinic, Scottsdale, Arizona.
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20
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York JM, Castellanos KJ, Cabay RJ, Fantuzzi G. Inhibition of the nucleotide-binding domain, leucine-rich containing family, pyrin-domain containing 3 inflammasome reduces the severity of experimentally induced acute pancreatitis in obese mice. Transl Res 2014; 164:259-69. [PMID: 25152324 PMCID: PMC4180798 DOI: 10.1016/j.trsl.2014.06.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 06/06/2014] [Accepted: 06/23/2014] [Indexed: 12/24/2022]
Abstract
Acute pancreatitis (AP), although most often a mild and self-limiting inflammatory disease, worsens to a characteristically necrotic severe acute pancreatitis (SAP) in about 20% of cases. Obesity, affecting more than one-third of American adults, is a risk factor for the development of SAP, but the exact mechanism of this association has not been identified. Coincidental with chronic low-grade inflammation, activation of the nucleotide-binding domain, leucine-rich containing family, pyrin-domain containing 3 (NLRP3) inflammasome increases with obesity. Lean mice genetically deficient in specific components of the NLRP3 inflammasome are protected from experimentally induced AP, indicating a direct involvement of this pathway in AP pathophysiology. We hypothesized that inhibition of the NLRP3 inflammasome with the sulfonylurea drug glyburide would reduce disease severity in obese mice with cerulein-induced SAP. Treatment with glyburide led to significantly reduced relative pancreatic mass and water content and less pancreatic damage and cell death in genetically obese ob/ob mice with SAP compared with vehicle-treated obese SAP mice. Glyburide administration in ob/ob mice with cerulein-induced SAP also resulted in significantly reduced serum levels of interleukin 6, lipase, and amylase and led to lower production of lipopolysaccharide-stimulated interleukin 1β release in cultured peritoneal cells, compared with vehicle-treated ob/ob mice with SAP. Together, these data indicate involvement of the NLRP3 inflammasome in obesity-associated SAP and expose the possible utility of its inhibition in prevention or treatment of SAP in obese individuals.
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Affiliation(s)
- Jason M York
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Ill.
| | - Karla J Castellanos
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Ill
| | - Robert J Cabay
- Department of Pathology, University of Illinois at Chicago, Chicago, Ill
| | - Giamila Fantuzzi
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Ill
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21
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Therapeutic administration of orlistat, rosiglitazone, or the chemokine receptor antagonist RS102895 fails to improve the severity of acute pancreatitis in obese mice. Pancreas 2014; 43:903-8. [PMID: 24632545 PMCID: PMC4151050 DOI: 10.1097/mpa.0000000000000115] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Currently, there is no therapy for severe acute pancreatitis (AP) except for supportive care. The lipase inhibitor orlistat, the peroxisome proliferator-activated receptor γ agonist rosiglitazone, and the chemokine receptor 2 antagonists attenuate the severity of AP in rodents if administered before or at the time of induction of pancreatitis. However, it is unknown whether these treatments are effective if administered therapeutically after induction of pancreatitis. METHODS Male C57BL6 mice with diet-induced obesity received 2 injections of mrIL-12 (150 ng per mouse) and mrIL-18 (750 ng per mouse) intraperitoneally at 24-hour intervals. The mice were injected 2, 24, and 48 hours after the second injection of IL-12 + IL-18 with orlistat (2 mg per mouse), rosiglitazone (0.4 mg per mouse), RS102895 (0.3 mg per mouse), or vehicle (20 μL of DMSO and 80 μL of canola oil) and euthanized after 72 hours. RESULTS Orlistat decreased intra-abdominal fat necrosis compared with vehicle (P < 0.05). However, none of the drug treatments produced significant decreases in pancreatic edema, acinar necrosis, or intrapancreatic fat necrosis. CONCLUSIONS Drugs previously shown to improve the severity of AP when given before or at the time of induction of pancreatitis failed to do so when administered therapeutically in the IL-12 + IL-18 model.
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22
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Acharya C, Navina S, Singh VP. Role of pancreatic fat in the outcomes of pancreatitis. Pancreatology 2014; 14:403-8. [PMID: 25278311 PMCID: PMC4185152 DOI: 10.1016/j.pan.2014.06.004] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 06/19/2014] [Accepted: 06/19/2014] [Indexed: 12/11/2022]
Abstract
The role of obesity in relation to various disease processes is being increasingly studied, with reports over the last several years increasingly mentioning its association with worse outcomes in acute disease. Obesity has also gained recognition as a risk factor for severe acute pancreatitis (SAP).The mortality in SAP may be as high as 30% and is usually attributable to multi system organ failure (MSOF) earlier in the disease, and complications of necrotizing pancreatitis later [9-11]. To date there is no specific treatment for acute pancreatitis (AP) and the management is largely expectant and supportive. Obesity in general has also been associated with poor outcomes in sepsis and other pathological states including trauma and burns. With the role of unsaturated fatty acids (UFA) as propagators in SAP having recently come to light and with the recognition of acute lipotoxicity, there is now an opportunity to explore different strategies to reduce the mortality and morbidity in SAP and potentially other disease states associated with such a pathophysiology. In this review we will discuss the role of fat and implications of the consequent acute lipotoxicity on the outcomes of acute pancreatitis in lean and obese states and during acute on chronic pancreatitis.
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Affiliation(s)
- Chathur Acharya
- Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA
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23
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Zhao JB, Liao DH, Nissen TD. Animal models of pancreatitis: Can it be translated to human pain study? World J Gastroenterol 2013; 19:7222-7230. [PMID: 24259952 PMCID: PMC3831203 DOI: 10.3748/wjg.v19.i42.7222] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 08/12/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
Abstract
Chronic pancreatitis affects many individuals around the world, and the study of the underlying mechanisms leading to better treatment possibilities are important tasks. Therefore, animal models are needed to illustrate the basic study of pancreatitis. Recently, animal models of acute and chronic pancreatitis have been thoroughly reviewed, but few reviews address the important aspect on the translation of animal studies to human studies. It is well known that pancreatitis is associated with epigastric pain, but the understanding regarding to mechanisms and appropriate treatment of this pain is still unclear. Using animal models to study pancreatitis associated visceral pain is difficult, however, these types of models are a unique way to reveal the mechanisms behind pancreatitis associated visceral pain. In this review, the animal models of acute, chronic and un-common pancreatitis are briefly outlined and animal models related to pancreatitis associated visceral pain are also addressed.
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Shao R. YKL-40 acts as an angiogenic factor to promote tumor angiogenesis. Front Physiol 2013; 4:122. [PMID: 23755018 PMCID: PMC3664773 DOI: 10.3389/fphys.2013.00122] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Accepted: 05/10/2013] [Indexed: 01/28/2023] Open
Abstract
A secreted glycoprotein YKL-40 also named chitinase-3-like-1 is normally expressed by multiple cell types such as macrophages, chondrocytes, and vascular smooth muscle cells. However, a prominently high level of YKL-40 was found in a wide spectrum of human diseases including cancers and chronic inflammatory diseases where it was strongly expressed by cancerous cells and infiltrating macrophages. Here, we summarized recent important findings of YKL-40 derived from cancerous cells and smooth muscle cells during tumor angiogenesis and development. YKL-40 is a potent angiogenic factor capable of stimulating tumor vascularization mediated by endothelial cells and maintaining vascular integrity supported by smooth muscle cells. In addition, YKL-40 induces FAK-MAPK signaling and up-regulates VEGF receptor 2 in endothelial cells; but a neutralizing antibody (mAY) against YKL-40 inhibits its angiogenic activity. While YKL-40 is essential for angiogenesis, little is known about its functional role in tumor-associated macrophage (TAM)-mediated tumor development. Therefore, significant efforts are urgently needed to identify pathophysiological function of YKL-40 in the dynamic interaction between tumor cells and TAMs in the tumor microenvironment, which may offer substantial mechanistic insights into tumor angiogenesis and metastasis, and also point to a therapeutic target for treatment of cancers and other diseases.
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Affiliation(s)
- Rong Shao
- Molecular and Cellular Biology Program, Morrill Science Center, University of Massachusetts Amherst, MA, USA ; Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, MA, USA
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Pang J, Rhodes DH, Pini M, Akasheh RT, Castellanos KJ, Cabay RJ, Cooper D, Perretti M, Fantuzzi G. Increased adiposity, dysregulated glucose metabolism and systemic inflammation in Galectin-3 KO mice. PLoS One 2013; 8:e57915. [PMID: 23451284 PMCID: PMC3579848 DOI: 10.1371/journal.pone.0057915] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 01/27/2013] [Indexed: 12/14/2022] Open
Abstract
Obesity and type 2 diabetes are associated with increased production of Galectin-3 (Gal-3), a protein that modulates inflammation and clearance of glucose adducts. We used Lean and Diet-induced Obese (DIO) WT and Gal-3 KO mice to investigate the role of Gal-3 in modulation of adiposity, glucose metabolism and inflammation. Deficiency of Gal-3 lead to age-dependent development of excess adiposity and systemic inflammation, as indicated by elevated production of acute-phase proteins, number of circulating pro-inflammatory Ly6Chigh monocytes and development of neutrophilia, microcytic anemia and thrombocytosis in 20-week-old Lean and DIO male Gal-3 KO mice. This was associated with impaired fasting glucose, heightened response to a glucose tolerance test and reduced adipose tissue expression of adiponectin, Gal-12, ATGL and PPARγ, in the presence of maintained insulin sensitivity and hepatic expression of gluconeogenic enzymes in 20-week-old Gal-3 KO mice compared to their diet-matched WT controls. Expression of PGC-1α and FGF-21 in the liver of Lean Gal-3 KO mice was comparable to that observed in DIO animals. Impaired fasting glucose and altered responsiveness to a glucose load preceded development of excess adiposity and systemic inflammation, as demonstrated in 12-week-old Gal-3 KO mice. Finally, a role for the microflora in mediating the fasting hyperglycemia, but not the excessive response to a glucose load, of 12-week-old Gal-3 KO mice was demonstrated by administration of antibiotics. In conclusion, Gal-3 is an important modulator of glucose metabolism, adiposity and inflammation.
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Affiliation(s)
- Jingbo Pang
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Davina H. Rhodes
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Maria Pini
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Rand T. Akasheh
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Karla J. Castellanos
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Robert J. Cabay
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Dianne Cooper
- The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Mauro Perretti
- The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Giamila Fantuzzi
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
- * E-mail:
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Momi N, Kaur S, Krishn SR, Batra SK. Discovering the route from inflammation to pancreatic cancer. MINERVA GASTROENTERO 2012; 58:283-297. [PMID: 23207606 PMCID: PMC3556910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Pancreatic cancer (PC) remains a complex malignancy with the worst prognosis, lack of early diagnostic symptoms and resistance to conventional chemo- and radiotherapies. A better understanding of the etiology and early developmental events of PC requires profound attention. The evolution of fully blown PC from initial pancreatic injury is a multi-factorial phenomenon with a series of sequential events. The initial acute infection or tissue damage triggers inflammation that, in conjunction with innate immunity, establishes a state of homeostasis to limit harm to the body. Recurrent pancreatic injuries due to genetic susceptibility, smoking, unhealthy diet, and alcohol abuse induces a pro-inflammatory milieu, consisting of various types of immune cells, cytokines, chemokines, growth factors and restructured extracellular matrix, leading to prolonged inflammatory/chronic conditions. Cells having sustained DNA damage and/or mutagenic assault take advantage of this prolonged inflammatory response and aid in the initiation and development of neoplastic/fibrotic events. Eventually, many tumor-stromal interactions result in a chaotic environment accompanied by a loss of immune surveillance and repair response, thereby leading to PC. A better understanding of the inflammatory markers defining this "injury-inflammation-cancer" pathway would help to identify novel molecular targets for early screening and therapeutic intervention for this lethal malignancy.
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Affiliation(s)
- N Momi
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
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Pini M, Castellanos KJ, Rhodes DH, Fantuzzi G. Obesity and IL-6 interact in modulating the response to endotoxemia in mice. Cytokine 2012; 61:71-7. [PMID: 23010503 DOI: 10.1016/j.cyto.2012.08.027] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 08/27/2012] [Indexed: 01/07/2023]
Abstract
Obesity is associated with elevated levels of IL-6. High IL-6 is prognostic of mortality in sepsis, while controversial data link obesity to sepsis outcome. We used Lean and diet-induced obese (DIO) WT and IL-6 KO mice to investigate the interaction between obesity and IL-6 in endotoxemia. Circulating levels of IL-6 were significantly higher in WT DIO versus WT Lean mice receiving LPS (2.5 μg/mouse, ip). Obesity lead to greater weight loss in response to LPS, with IL-6 deficiency being partially protective. Plasma TNFα, IFNγ, Galectin-3 and leptin were significantly elevated in response to LPS and were each differentially affected by obesity and/or IL-6 deficiency. Plasma Galectin-1 and adiponectin were significantly suppressed by LPS, with obesity and IL-6 deficiency modulating the response. However, LPS comparably increased IL-10 levels in each group. Leukopenia with relative neutrophilia and thrombocytopenia developed in each group after injection of LPS, with obesity and genotype affecting the kinetics, but not the magnitude, of the response. Hepatic induction of the acute-phase protein SAA by LPS was not affected by obesity or IL-6 deficiency, although baseline levels were highest in WT DIO mice. Injection of LPS significantly increased hepatic mRNA expression of PAI-1 in Lean WT and Lean KO mice, while it suppressed the high baseline levels observed in the liver of DIO WT and DIO KO mice. Thus, both IL-6 and obesity modulate the response to endotoxemia, suggesting a complex interaction that needs to be considered when evaluating the effect of obesity on the outcome of septic patients.
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Affiliation(s)
- Maria Pini
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, United States
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Involvement of inflammatory factors in pancreatic carcinogenesis and preventive effects of anti-inflammatory agents. Semin Immunopathol 2012; 35:203-27. [PMID: 22955327 DOI: 10.1007/s00281-012-0340-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Accepted: 08/23/2012] [Indexed: 12/13/2022]
Abstract
Chronic inflammation is known to be a risk for many cancers, including pancreatic cancer. Heavy alcohol drinking and cigarette smoking are major causes of pancreatitis, and epidemiological studies have shown that smoking and chronic pancreatitis are risk factors for pancreatic cancer. Meanwhile, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are elevated in pancreatitis and pancreatic cancer tissues in humans and in animal models. Selective inhibitors of iNOS and COX-2 suppress pancreatic cancer development in a chemical carcinogenesis model of hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). In addition, hyperlipidemia, obesity, and type II diabetes are also suggested to be associated with chronic inflammation in the pancreas and involved in pancreatic cancer development. We have shown that a high-fat diet increased pancreatic cancer development in BOP-treated hamsters, along with aggravation of hyperlipidemia, severe fatty infiltration, and increased expression of adipokines and inflammatory factors in the pancreas. Of note, fatty pancreas has been observed in obese and/or diabetic cases in humans. Preventive effects of anti-hyperlipidemic/anti-diabetic agents on pancreatic cancer have also been shown in humans and animals. Taking this evidence into consideration, modulation of inflammatory factors by anti-inflammatory agents will provide useful data for prevention of pancreatic cancer.
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Pini M, Rhodes DH, Castellanos KJ, Cabay RJ, Grady EF, Fantuzzi G. Rosiglitazone improves survival and hastens recovery from pancreatic inflammation in obese mice. PLoS One 2012; 7:e40944. [PMID: 22815875 PMCID: PMC3397967 DOI: 10.1371/journal.pone.0040944] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2012] [Accepted: 06/15/2012] [Indexed: 02/06/2023] Open
Abstract
Obesity increases severity of acute pancreatitis (AP) by unclear mechanisms. We investigated the effect of the PPAR-gamma agonist rosiglitazone (RGZ, 0.01% in the diet) on severity of AP induced by administration of IL-12+ IL-18 in male C57BL6 mice fed a low fat (LFD) or high fat diet (HFD), under the hypothesis that RGZ would reduce disease severity in HFD-fed obese animals. In both LFD and HFD mice without AP, RGZ significantly increased body weight and % fat mass, with significant upregulation of adiponectin and suppression of erythropoiesis. In HFD mice with AP, RGZ significantly increased survival and hastened recovery from pancreatic inflammation, as evaluated by significantly improved pancreatic histology, reduced saponification of visceral adipose tissue and less severe suppression of erythropoiesis at Day 7 post-AP. This was associated with significantly lower circulating and pancreas-associated levels of IL-6, Galectin-3, osteopontin and TIMP-1 in HFD + RGZ mice, particularly at Day 7 post-AP. In LFD mice with AP, RGZ significantly worsened the degree of intrapancreatic acinar and fat necrosis as well as visceral fat saponification, without affecting other parameters of disease severity or inflammation. Induction of AP lead to major suppression of adiponectin levels at Day 7 in both HFD and HFD + RGZ mice. In conclusion, RGZ prevents development of severe AP in obese mice even though it significantly increases adiposity, indicating that obesity can be dissociated from AP severity by improving the metabolic and inflammatory milieu. However, RGZ worsens selective parameters of AP severity in LFD mice.
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Affiliation(s)
- Maria Pini
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Davina H. Rhodes
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Karla J. Castellanos
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Robert J. Cabay
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Eileen F. Grady
- Department of Surgery, University of California San Francisco, San Francisco, California, United States of America
| | - Giamila Fantuzzi
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
- * E-mail:
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