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da Rocha GHO, Müller C, Przybylski-Wartner S, Schaller H, Riemschneider S, Lehmann J. AhR-Induced Anti-Inflammatory Effects on a Caco-2/THP-1 Co-Culture Model of Intestinal Inflammation Are Mediated by PPARγ. Int J Mol Sci 2024; 25:13072. [PMID: 39684781 DOI: 10.3390/ijms252313072] [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: 11/08/2024] [Revised: 11/29/2024] [Accepted: 12/02/2024] [Indexed: 12/18/2024] Open
Abstract
The aryl hydrocarbon receptor (AhR) and the peroxisome proliferator-activated receptor γ (PPARγ) are ligand-activated transcription factors that have in recent years been investigated for their anti-inflammatory properties for treatment of inflammatory bowel diseases (IBDs). These are globally prevalent chronic maladies of the gut that lack cost-efficient therapeutical options capable of inducing long-term remission. In the present study, we used an in vitro Transwell® co-culture model composed of Caco-2 epithelial cells in the apical compartment and lipopolysaccharide-treated (LPS) THP-1 macrophages in the basolateral compartment. Secretion of cytokines, disruption of epithelial integrity, and expression of surface markers and junctional proteins were assessed in order to investigate interactions between AhR and PPARγ on the ligand-elicited effects on the control of inflammation. The results revealed that the potent AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ) attenuated LPS-induced IL-6 release by macrophages, which then stabilized Caco-2 monolayer permeability by decreasing claudin-2 expression. These effects were disrupted by GW9662 and to some extent by CH223191, inhibitors of PPARγ and AhR, respectively. Our main findings evidence PPARγ might be a downstream regulator of AhR activation essential for its ligand-based anti-inflammatory effects, suggesting it might be employed as either an auxiliary target or as a biomarker of therapeutical efficacy on AhR-based IBD pharmacotherapy.
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Affiliation(s)
| | - Claudia Müller
- Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
| | - Susanne Przybylski-Wartner
- Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
| | - Heidrun Schaller
- Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
| | - Sina Riemschneider
- Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
| | - Jörg Lehmann
- Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases [CIMD], 04103 Leipzig, Germany
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Zhaoyu L, Xiaomeng Y, Na L, Jiamin S, Guanhua D, Xiuying Y. Roles of natural products on myokine expression and secretion in skeletal muscle atrophy. Gen Comp Endocrinol 2024; 355:114550. [PMID: 38768928 DOI: 10.1016/j.ygcen.2024.114550] [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: 01/31/2024] [Revised: 05/15/2024] [Accepted: 05/15/2024] [Indexed: 05/22/2024]
Abstract
Skeletal muscles serve both in movement and as endocrine organs. Myokines secreted by skeletal muscles activate biological functions within muscles and throughout the body via autocrine, paracrine, and/or endocrine pathways. Skeletal muscle atrophy can influence myokine expression and secretion, while myokines can impact the structure and function of skeletal muscles. Regulating the expression and secretion of myokines through the pharmacological approach is a strategy for alleviating skeletal muscle atrophy. Natural products possess complex structures and chemical properties. Previous studies have demonstrated that various natural products exert beneficial effects on skeletal muscle atrophy. This article reviewed the regulatory effects of natural products on myokines and summarized the research progress on skeletal muscle atrophy associated with myokine regulation. The focus is on how small-molecule natural products affect the regulation of interleukin 6 (IL-6), irisin, myostatin, IGF-1, and FGF-21 expression. We contend that the development of small-molecule natural products targeting the regulation of myokines holds promise in combating skeletal muscle atrophy.
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Affiliation(s)
- Liu Zhaoyu
- Beijing Key Laboratory of Drug Target Identification and New Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Ye Xiaomeng
- Beijing Key Laboratory of Drug Target Identification and New Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Li Na
- Beijing Key Laboratory of Drug Target Identification and New Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Shang Jiamin
- Beijing Key Laboratory of Drug Target Identification and New Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Du Guanhua
- Beijing Key Laboratory of Drug Target Identification and New Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
| | - Yang Xiuying
- Beijing Key Laboratory of Drug Target Identification and New Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
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Hwang YJ, Jung GS, Lee KM. Alantolactone alleviates epithelial-mesenchymal transition by regulating the TGF-β/STAT3 signaling pathway in renal fibrosis. Heliyon 2024; 10:e36253. [PMID: 39253189 PMCID: PMC11382038 DOI: 10.1016/j.heliyon.2024.e36253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 08/05/2024] [Accepted: 08/13/2024] [Indexed: 09/11/2024] Open
Abstract
Objective The epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells (RTECs) plays a crucial role in renal interstitial fibrosis and inflammation, which are key components of chronic kidney disease (CKD). Alantolactone, a selective inhibitor of signal transducer and activator of transcription 3 (STAT3), is used in Chinese herbal medicine. Despite its use, the effects of alnatolactone on EMT of RTECs has not been fully elucidated. Methods In this study, we investigated the potential of alantolactone to EMT in vivo and in vitro. Our experiments were performed using a unilateral ureteral obstruction (UUO) models and HK-2 cells, RTECs, treated with transforming growth factor (TGF-β). Results Alantolactone decreased tubular injury and reduced the expression of vimentin, a key EMT marker, while increasing E-cadherin expression in UUO kidneys. Similarly, in RTECs, alantolactone inhibited TGF-β-induced EMT and its markers. Furthermore, alantolactone attenuated UUO- and TGF-β-induced STAT3 phosphorylation both in vivo and in vitro, and inhibited the expression of TWIST, an EMT transcription factor, in both models. Conclusion Alantolactone improves EMT in RTECs by inhibiting STAT3 phosphorylation and Twist expression, suggesting its potential as a therapeutic agent for kidney fibrosis.
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Affiliation(s)
- Yeo Jin Hwang
- Division of AI, Big Data and Block Chain, Daegu Gyeongbuk Institute of Science and Technology, Daegu, 42988, Republic of Korea
| | - Gwon-Soo Jung
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea
| | - Kyeong-Min Lee
- Division of Biomedical Technology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, 42988, Republic of Korea
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Kumar S, Mehan S, Khan Z, Das Gupta G, Narula AS. Guggulsterone Selectively Modulates STAT-3, mTOR, and PPAR-Gamma Signaling in a Methylmercury-Exposed Experimental Neurotoxicity: Evidence from CSF, Blood Plasma, and Brain Samples. Mol Neurobiol 2024; 61:5161-5193. [PMID: 38170440 DOI: 10.1007/s12035-023-03902-x] [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: 10/11/2023] [Accepted: 12/14/2023] [Indexed: 01/05/2024]
Abstract
Amyotrophic lateral sclerosis (ALS) is a paralytic disease that damages the brain and spinal cord motor neurons. Several clinical and preclinical studies have found that methylmercury (MeHg+) causes ALS. In ALS, MeHg+-induced neurotoxicity manifests as oligodendrocyte destruction; myelin basic protein (MBP) deficiency leads to axonal death. ALS development has been connected to an increase in signal transducer and activator of transcription-3 (STAT-3), a mammalian target of rapamycin (mTOR), and a decrease in peroxisome proliferator-activated receptor (PPAR)-gamma. Guggulsterone (GST), a plant-derived chemical produced from Commiphorawhighitii resin, has been found to protect against ALS by modulating these signaling pathways. Vitamin D3 (VitD3) deficiency has been related to oligodendrocyte precursor cells (OPC) damage, demyelination, and white matter deterioration, which results in motor neuron death. As a result, the primary goal of this work was to investigate the therapeutic potential of GST by altering STAT-3, mTOR, and PPAR-gamma levels in a MeHg+-exposed experimental model of ALS in adult rats. The GST30 and 60 mg/kg oral treatments significantly improved the behavioral, motor, and cognitive dysfunctions and increased remyelination, as proven by the Luxol Fast Blue stain (LFB), and reduced neuroinflammation as measured by histological examinations. Furthermore, the co-administration of VitD3 exhibits moderate efficacy when administered in combination with GST60. Our results show that GST protects neurons by decreasing STAT-3 and mTOR levels while increasing PPAR-gamma protein levels in ALS rats.
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Affiliation(s)
- Sumit Kumar
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy (An Autonomous College), NAAC Accredited "A" Grade College, GT Road, Ghal-Kalan, Moga, 142 001, Punjab, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India
| | - Sidharth Mehan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy (An Autonomous College), NAAC Accredited "A" Grade College, GT Road, Ghal-Kalan, Moga, 142 001, Punjab, India.
- IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India.
| | - Zuber Khan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy (An Autonomous College), NAAC Accredited "A" Grade College, GT Road, Ghal-Kalan, Moga, 142 001, Punjab, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India
| | - Ghanshyam Das Gupta
- IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, India
| | - Acharan S Narula
- Narula Research, LLC, 107 Boulder Bluff, Chapel Hill, NC, 27516, USA
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Kumar S, Mehan S, Narula AS. Therapeutic modulation of JAK-STAT, mTOR, and PPAR-γ signaling in neurological dysfunctions. J Mol Med (Berl) 2023; 101:9-49. [PMID: 36478124 DOI: 10.1007/s00109-022-02272-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 10/10/2022] [Accepted: 11/11/2022] [Indexed: 12/12/2022]
Abstract
The cytokine-activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) cascade is a pleiotropic pathway that involves receptor subunit multimerization. The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine-threonine kinase that perceives and integrates a variety of intracellular and environmental stimuli to regulate essential activities such as cell development and metabolism. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a prototypical metabolic nuclear receptor involved in neural differentiation and axon polarity. The JAK-STAT, mTOR, and PPARγ signaling pathways serve as a highly conserved signaling hub that coordinates neuronal activity and brain development. Additionally, overactivation of JAK/STAT, mTOR, and inhibition of PPARγ signaling have been linked to various neurocomplications, including neuroinflammation, apoptosis, and oxidative stress. Emerging research suggests that even minor disruptions in these cellular and molecular processes can have significant consequences manifested as neurological and neuropsychiatric diseases. Of interest, target modulators have been proven to alleviate neuronal complications associated with acute and chronic neurological deficits. This research-based review explores the therapeutic role of JAK-STAT, mTOR, and PPARγ signaling modulators in preventing neuronal dysfunctions in preclinical and clinical investigations.
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Affiliation(s)
- Sumit Kumar
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Punjab, Moga, India
| | - Sidharth Mehan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Punjab, Moga, India.
| | - Acharan S Narula
- Narula Research, LLC, 107 Boulder Bluff, Chapel Hill, NC, 27516, USA
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Xiang H, Yu H, Zhou Q, Wu Y, Ren J, Zhao Z, Tao X, Dong D. Macrophages: A rising star in immunotherapy for chronic pancreatitis. Pharmacol Res 2022; 185:106508. [DOI: 10.1016/j.phrs.2022.106508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 10/10/2022] [Indexed: 11/29/2022]
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Abstract
Acute and chronic pancreatitis, the latter associated with fibrosis, are multifactorial inflammatory disorders and leading causes of gastrointestinal disease-related hospitalization. Despite the global health burden of pancreatitis, currently, there are no effective therapeutic agents. In this regard, the protease A Disintegrin And Metalloproteinase 17 (ADAM17) mediates inflammatory responses through shedding of bioactive inflammatory cytokines and mediators, including tumor necrosis factor α (TNFα) and the soluble interleukin (IL)-6 receptor (sIL-6R), the latter of which drives proinflammatory IL-6 trans-signaling. However, the role of ADAM17 in pancreatitis is unclear. To address this, Adam17ex/ex mice-which are homozygous for the hypomorphic Adam17ex allele resulting in marked reduction in ADAM17 expression-and their wild-type (WT) littermates were exposed to the cerulein-induced acute pancreatitis model, and acute (1-wk) and chronic (20-wk) pancreatitis models induced by the cigarette smoke carcinogen nicotine-derived nitrosamine ketone (NNK). Our data reveal that ADAM17 expression was up-regulated in pancreatic tissues of animal models of pancreatitis. Moreover, the genetic (Adam17ex/ex mice) and therapeutic (ADAM17 prodomain inhibitor [A17pro]) targeting of ADAM17 ameliorated experimental pancreatitis, which was associated with a reduction in the IL-6 trans-signaling/STAT3 axis. This led to reduced inflammatory cell infiltration, including T cells and neutrophils, as well as necrosis and fibrosis in the pancreas. Furthermore, up-regulation of the ADAM17/IL-6 trans-signaling/STAT3 axis was a feature of pancreatitis patients. Collectively, our findings indicate that the ADAM17 protease plays a pivotal role in the pathogenesis of pancreatitis, which could pave the way for devising novel therapeutic options to be deployed against this disease.
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Zhang N, Guan C, Liu Z, Li C, Yang C, Xu L, Niu M, Zhao L, Zhou B, Che L, Wang Y, Xu Y. Calycosin attenuates renal ischemia/reperfusion injury by suppressing NF-κB mediated inflammation via PPARγ/EGR1 pathway. Front Pharmacol 2022; 13:970616. [PMID: 36278223 PMCID: PMC9585199 DOI: 10.3389/fphar.2022.970616] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 09/26/2022] [Indexed: 08/10/2023] Open
Abstract
Renal ischemia reperfusion injury (IRI) is a leading and common cause of acute kidney injury (AKI), and inflammation is a critical factor in ischemic AKI progression. Calycosin (CAL), a major active component of Radix astragali, has been reported to have anti-inflammatory effect in multiple organs. However, whether CAL can alleviate renal IRI and its mechanism remain uncertain. In the present study, a renal IRI model is established by bilateral renal pedicles occlusion for 35 min in male C57BL/6 mice, and the effect of CAL on renal IRI is measured by serum creatinine and pathohistological assay. Hypoxia/reoxygenation (H/R) stimulated human renal tubular epithelial cells HK-2 were applied to explore the regulatory mechanisms of CAL. Luciferase reporter assay and molecular docking were applied to identify the CAL's target protein and pathway. In the mice with renal IRI, CAL dose dependently alleviated the renal injury and decreased nuclear factor kappa B (NF-κB) mediated inflammatory response. Bioinformatics analysis and experiments showed that early growth response 1 (EGR1) increased in mice with renal IRI and promoted NF-κB mediated inflammatory processes, and CAL dose-dependably reduced EGR1. Through JASPAR database and luciferase reporter assay, peroxisome proliferator-activated receptor γ (PPARγ) was predicted to be a transcription factor of EGR1 and repressed the expression of EGR1 in renal tubular epithelial cells. CAL could increase PPARγ in a dose dependent manner in mice with renal IRI and molecular docking predicted CAL could bind stably to PPARγ. In HK-2 cells after H/R, CAL increased PPARγ, decreased EGR1, and inhibited NF-κB mediated inflammatory response. However, PPARγ knockdown by siRNA transfection abrogated the anti-inflammation therapeutic effect of CAL. CAL produced a protective effect on renal IRI by attenuating NF-κB mediated inflammatory response via PPARγ/EGR1 pathway.
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Ahn YJ, Lim JW, Kim H. Lutein inhibits IL‑6 expression by inducing PPAR‑γ activation and SOCS3 expression in cerulein‑stimulated pancreatic acinar cells. Mol Med Rep 2022; 26:302. [PMID: 35946453 PMCID: PMC9434989 DOI: 10.3892/mmr.2022.12818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/29/2022] [Indexed: 12/02/2022] Open
Abstract
Acute pancreatitis is a severe inflammatory disease of the pancreas. In experimental acute pancreatitis, cerulein induces the expression of interleukin-6 (IL-6) by activating Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 in pancreatic acinar cells. Ligands of peroxisome proliferator activated receptor-γ (PPAR-γ) and suppressor of cytokine signaling (SOCS) 3 inhibit IL-6 expression by suppressing JAK2/STAT3 in cerulein-stimulated pancreatic acinar AR42J cells. Lutein, an oxygenated carotenoid, upregulates and activates PPAR-γ to regulate inflammation in a renal injury model. The present study aimed to determine whether lutein activated PPAR-γ and induced SOCS3 expression in unstimulated AR42J cells, and whether lutein inhibited activation of JAK2/STAT3 and IL-6 expression via activation of PPAR-γ and SOCS3 expression in cerulein-stimulated AR42J cells. The anti-inflammatory mechanism of lutein was determined using reverse transcription-quantitative PCR, western blot analysis and enzyme-linked immunosorbent assay in AR42J cells stimulated with or without cerulein. In another experiment, cells were treated with lutein and the PPAR-γ antagonist GW9662 or the PPAR-γ agonist troglitazone prior to cerulein stimulation to determine the involvement of PPAR-γ activation. The results indicated that lutein increased PPAR-γ and SOCS3 levels in unstimulated cells. Cerulein increased phospho-specific forms of JAK2 and STAT3, and mRNA and protein expression of IL-6, but decreased SOCS3 levels in AR42J cells. Cerulein-induced alterations were suppressed by lutein or troglitazone. GW9662 alleviated the inhibitory effect of lutein on JAK2/STAT3 activation and IL-6 expression in cerulein-stimulated cells. In conclusion, lutein inhibited the activation of JAK2/STAT3 and reduced IL-6 levels via PPAR-γ-mediated SOCS3 expression in pancreatic acinar cells stimulated with cerulein.
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Affiliation(s)
- Yu Jin Ahn
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
| | - Joo Weon Lim
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
| | - Hyeyong Kim
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
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Lee Y, Lim JW, Kim H. α‑lipoic acid inhibits cerulein/resistin‑induced expression of interleukin‑6 by activating peroxisome proliferator‑activated receptor‑γ in pancreatic acinar cells. Mol Med Rep 2022; 26:264. [PMID: 35730599 PMCID: PMC9260878 DOI: 10.3892/mmr.2022.12780] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 06/09/2022] [Indexed: 11/06/2022] Open
Abstract
Cerulein‑induced pancreatitis resembles human acute pancreatitis in terms of pathological events, such as enzymatic activation and inflammatory cell infiltration in the pancreas. Cerulein is a cholecystokinin analog that increases levels of reactive oxygen species (ROS) and interleukin‑6 (IL‑6) expression level in pancreatic acinar cells. Serum levels of resistin, which is secreted from adipocytes, are reportedly higher in patients with acute pancreatitis than in healthy individuals. Previously, it was shown that the adipokine resistin can aggravate the cerulein‑induced increase in ROS levels and IL‑6 expression level in pancreatic acinar cells. Peroxisome proliferator‑activated receptor‑gamma (PPAR‑γ) is a key regulator of the transcription and expression of antioxidant enzymes, including heme oxygenase 1 (HO‑1) and catalase. α‑lipoic acid, a naturally occurring dithiol antioxidant, can prevent cerulein‑induced pancreatic damage in rats. In the present study, it was aimed to investigate whether α‑lipoic acid can attenuate the cerulein/resistin‑induced increase in IL‑6 expression and ROS levels via PPAR‑γ activation in pancreatic acinar AR42J cells. The anti‑inflammatory mechanism of α‑lipoic acid was determined using reverse transcription‑quantitative PCR, western blot analysis, enzyme‑linked immunosorbent assay, immunofluorescence staining and fluorometry. Treatment with cerulein and resistin increased ROS levels and IL‑6 expression level, which were inhibited by α‑lipoic acid in pancreatic acinar cells. α‑lipoic acid increased the nuclear translocation and expression level of PPAR‑γ and the expression levels of its target genes: HO‑1 and catalase. The PPAR‑γ antagonist GW9662 and HO‑1 inhibitor zinc protoporphyrin reversed the inhibitory effect of α‑lipoic acid on cerulein/resistin‑induced increase in ROS and IL‑6 levels. In conclusion, α‑lipoic acid inhibits the cerulein/resistin‑induced increase in ROS production and IL‑6 expression levels by activating PPAR‑γ and inducing the expression of HO‑1 and catalase in pancreatic acinar cells.
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Affiliation(s)
- Yujin Lee
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
| | - Joo Weon Lim
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
| | - Hyeyoung Kim
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
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Duarte I, de Souza MCM, Curinga RM, Mendonça HM, de Lacerda de Oliveira L, Milenkovic D, Hassimotto NMA, Costa AM, Malaquias JV, Dos Santos Borges TK. Effect of Passiflora setacea juice and its phenolic metabolites on insulin resistance markers in overweight individuals and on microglial cell activity. Food Funct 2022; 13:6498-6509. [PMID: 35621054 DOI: 10.1039/d1fo04334j] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Passiflora setacea (PS) is a species of wild Brazilian passion fruit, rich in bioactive compounds. Scientific evidence suggests that food rich in polyphenols can modulate inflammation, thereby playing an important role in preventing chronic non-communicable diseases, such as type 2 diabetes (DT2) and cardiovascular diseases (CVD). This study aimed to investigate the effect of PS consumption on metabolic and inflammatory biomarkers in overweight male volunteers and to identify the underlying mechanism of action using an in vitro study using phenolic metabolites isolated from the plasma of volunteers at physiologically relevant concentrations. Volunteers participated in a double-blind, placebo-controlled (PB) study with two phases: phase I (acute study) and phase II (chronic study). In phase I, 15 volunteers ingested a single dose of 50 g, 150 g of PS pulp and PB in three different interventions. In phase II, nine volunteers ingested 50 g of PS or PB for 14 days. Blood samples were collected before (T0 h) and 3 h (T3 h) (phase I) or 15 days after (phase II) ingestion of PS or PB. Blood biochemical markers, HOMA IR, and inflammatory markers were analyzed and data on BMI, waist circumference, and consumption of polyphenol-rich foods were collected. Phenolic metabolites were extracted from plasma by solid-phase separation and were used to treat BV-2 cells stimulated by LPS or anacardic acid to assess p50, p65 and PPAR-γ activation. It was observed that the consumption of a single dose of PS juice significantly reduced basal insulin levels and HOMA IR. After prolonged consumption for two weeks, PS contributed to the reduction of circulating levels of IL-6. BV-2 cells treated with PS phenolic metabolites showed increased PPAR-γ activity, which resulted in an anti-inflammatory and anti-diabetic effect of PS metabolites. In conclusion, PS juice consumption exerts beneficial effects on inflammatory markers in overweight individuals, being a possible and important tool in the prevention of T2D and CVD in risk groups.
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Affiliation(s)
- Isabella Duarte
- Postgraduate Program in Human Nutrition, Faculty of Health Sciences, Campus Universitário Darcy Ribeiro, Universidade de Brasília, Brasília, DF, 70.910-900, Brazil.
| | - Maria Carolina Miranda de Souza
- Department of Nutrition, Faculty of Health Sciences, Campus Universitário Darcy Ribeiro, Universidade de Brasília, Brasília, DF, 70.910-900, Brazil
| | - Rafaela Moura Curinga
- Laboratory of Cellular Immunology, Faculty of Medicine, University of Brasilia, Brasilia, DF, 70.910-900, Brazil
| | - Henrique Matos Mendonça
- Laboratory of Cellular Immunology, Faculty of Medicine, University of Brasilia, Brasilia, DF, 70.910-900, Brazil
| | - Livia de Lacerda de Oliveira
- Postgraduate Program in Human Nutrition, Faculty of Health Sciences, Campus Universitário Darcy Ribeiro, Universidade de Brasília, Brasília, DF, 70.910-900, Brazil.
| | - Dragan Milenkovic
- Department of Nutrition, University of California, Davis, Davis, CA, USA
| | - Neuza Mariko Aymoto Hassimotto
- Food Research Center (FoRC-CEPID) and Department of Food Science and Experimental Nutrition, School of Pharmaceutical Science, University of São Paulo, São Paulo, SP, Brazil
| | - Ana Maria Costa
- Embrapa Cerrados, BR 020, Km18, Laboratory of Food Science, Planaltina, DF, 73.310-970, Brazil
| | - Juaci Vitorio Malaquias
- Embrapa Cerrados, BR 020, Km18, Laboratory of Food Science, Planaltina, DF, 73.310-970, Brazil
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Role of JAK-STAT and PPAR-Gamma Signalling Modulators in the Prevention of Autism and Neurological Dysfunctions. Mol Neurobiol 2022; 59:3888-3912. [PMID: 35437700 DOI: 10.1007/s12035-022-02819-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 03/23/2022] [Indexed: 01/10/2023]
Abstract
The Janus-kinase (JAK) and signal transducer activator of transcription (STAT) signalling pathways regulate gene expression and control various factors involved in normal physiological functions such as cell proliferation, neuronal development, and cell survival. JAK activation phosphorylates STAT3 in astrocytes and microglia, and this phosphorylation has been linked to mitochondrial damage, apoptosis, neuroinflammation, reactive astrogliosis, and genetic mutations. As a regulator, peroxisome proliferator-activated receptor gamma (PPAR-gamma), in relation to JAK-STAT signalling, prevents this phosphorylation and aids in the treatment of the above-mentioned neurocomplications. Changes in cellular signalling may also contribute to the onset and progression of autism. Thus, PPAR-gamma agonist upregulation may be associated with JAK-STAT signal transduction downregulation. It may also be responsible for attenuating neuropathological changes by stimulating SOCS3 or involving RXR or SMRT, thereby reducing transcription of the various cytokine proteins and genes involved in neuronal damage. Along with JAK-STAT inhibitors, PPAR-gamma agonists could be used as target therapeutic interventions for autism. This research-based review explores the potential involvement and mutual regulation of JAK-STAT and PPAR-gamma signalling in controlling multiple pathological factors associated with autism.
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Yang X, Geng H, You L, Yuan L, Meng J, Ma Y, Gu X, Lei M. Rhein Protects Against Severe Acute Pancreatitis In vitro and In vivo by Regulating the JAK2/STAT3 Pathway. Front Pharmacol 2022; 13:778221. [PMID: 35370748 PMCID: PMC8969574 DOI: 10.3389/fphar.2022.778221] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 02/28/2022] [Indexed: 01/30/2023] Open
Abstract
Rhein is widely used in inflammation treatment in China, but its effects on severe acute pancreatitis (SAP) have not been studied closely. This study investigated rhein’s protective effects against SAP using in vitro and in vivo models to determine whether its protective mechanism regulated the Janus kinase two and signal transducer and activator of transcription 3 (JAK2/STAT3) signalling pathway. Thirty-six male Sprague–Dawley rats were randomised into sham operation, SAP and rhein groups. The SAP model was induced by retrograde pancreatic bile duct injection of sodium taurocholate. Serum TNF-α and interleukin (IL)-6 levels were determined by ELISA, whereas serum amylase and lipase concentrations were measured using test kits. Western blot and/or immunohistochemistry quantified JAK2 and STAT3 expression. Furthermore, histopathological pancreatic changes were detected by haematoxylin and eosin staining. AR42J cells were randomly divided into the control, cerulein and rhein groups. Amylase activity was assessed using an amylase test kit; the tumour necrosis factor-α (TNF-α) expression was determined by enzyme-linked immunosorbent assay (ELISA). JAK2 and STAT3 protein expression were evaluated by western blot. SAP was concomitant with increased JAK2 and STAT3 expressions in vivo. Pre-treatment with rhein attenuated serum TNF–α and IL-6 levels effectively, and notably reduced p-JAK2, p-STAT3, JAK2 and STAT3 protein expression. Rhein significantly alleviated pancreatic histopathology. Compared to untreated groups, rhein significantly reduced amylase activity in supernatants of AR42J cells induced by cerulein in vitro. Furthermore, rhein altered JAK2 and STAT3 protein levels in AR42J cells after cerulein induction. Overall, rhein exerted protective effect on SAP in vitro and in vivo, possibly through the JAK2/STAT3 signalling pathway.
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Affiliation(s)
- Xiaofang Yang
- Department of Critical Care Medicine, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huan Geng
- Department of Critical Care Medicine, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lijiao You
- Department of Critical Care Medicine, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lin Yuan
- Department of Critical Care Medicine, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jialei Meng
- Department of Critical Care Medicine, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuhui Ma
- Department of Critical Care Medicine, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xuelian Gu
- Department of Critical Care Medicine, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ming Lei
- Department of Critical Care Medicine, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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14
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Khera R, Mehan S, Bhalla S, Kumar S, Alshammari A, Alharbi M, Sadhu SS. Guggulsterone Mediated JAK/STAT and PPAR-Gamma Modulation Prevents Neurobehavioral and Neurochemical Abnormalities in Propionic Acid-Induced Experimental Model of Autism. Molecules 2022; 27:889. [PMID: 35164154 PMCID: PMC8839522 DOI: 10.3390/molecules27030889] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 01/21/2022] [Accepted: 01/27/2022] [Indexed: 12/11/2022] Open
Abstract
Autism spectrum disorder is a neurodevelopmental disorder marked by repetitive behaviour, challenges in verbal and non-verbal communication, poor socio-emotional health, and cognitive impairment. An increased level of signal transducer and activator of transcription 3 (STAT3) and a decreased level of peroxisome proliferator-activated receptor (PPAR) gamma have been linked to autism pathogenesis. Guggulsterone (GST) has a neuroprotective effect on autistic conditions by modulating these signalling pathways. Consequently, the primary objective of this study was to examine potential neuroprotective properties of GST by modulating JAK/STAT and PPAR-gamma levels in intracerebroventricular propionic acid (ICV PPA) induced experimental model of autism in adult rats. In this study, the first 11 days of ICV-PPA injections in rats resulted in autism-like behavioural, neurochemical, morphological, and histopathological changes. The above modifications were also observed in various biological samples, including brain homogenate, CSF, and blood plasma. GST was also observed to improve autism-like behavioural impairments in autistic rats treated with PPA, including locomotion, neuromuscular coordination, depression-like behaviour, spatial memory, cognition, and body weight. Prolonged GST treatment also restored neurochemical deficits in a dose-dependent manner. Chronic PPA administration increased STAT3 and decreased PPAR gamma in autistic rat brain, CSF, and blood plasma samples, which were reversed by GST. GST also restored the gross and histopathological alterations in PPA-treated rat brains. Our results indicate the neuroprotective effects of GST in preventing autism-related behavioural and neurochemical alterations.
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Affiliation(s)
- Rishabh Khera
- Department of Pharmacology, Neuropharmacology Division, ISF College of Pharmacy, Moga 142001, Punjab, India; (R.K.); (S.B.); (S.K.)
| | - Sidharth Mehan
- Department of Pharmacology, Neuropharmacology Division, ISF College of Pharmacy, Moga 142001, Punjab, India; (R.K.); (S.B.); (S.K.)
| | - Sonalika Bhalla
- Department of Pharmacology, Neuropharmacology Division, ISF College of Pharmacy, Moga 142001, Punjab, India; (R.K.); (S.B.); (S.K.)
| | - Sumit Kumar
- Department of Pharmacology, Neuropharmacology Division, ISF College of Pharmacy, Moga 142001, Punjab, India; (R.K.); (S.B.); (S.K.)
| | - Abdulrahman Alshammari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (A.A.); (M.A.)
| | - Metab Alharbi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (A.A.); (M.A.)
| | - Satya Sai Sadhu
- Chemistry Department, Northern Michigan University, 1401, Presque, Isle, Marquette, MI 49855, USA;
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15
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Noise-Induced Cochlear Damage Involves PPAR Down-Regulation through the Interplay between Oxidative Stress and Inflammation. Antioxidants (Basel) 2021; 10:antiox10081188. [PMID: 34439436 PMCID: PMC8388985 DOI: 10.3390/antiox10081188] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 12/14/2022] Open
Abstract
The cross-talk between oxidative stress and inflammation seems to play a key role in noise-induced hearing loss. Several studies have addressed the role of PPAR receptors in mediating antioxidant and anti-inflammatory effects and, although its protective activity has been demonstrated in several tissues, less is known about how PPARs could be involved in cochlear dysfunction induced by noise exposure. In this study, we used an in vivo model of noise-induced hearing loss to investigate how oxidative stress and inflammation participate in cochlear dysfunction through PPAR signaling pathways. Specifically, we found a progressive decrease in PPAR expression in the cochlea after acoustic trauma, paralleled by an increase in oxidative stress and inflammation. By comparing an antioxidant (Q-ter) and an anti-inflammatory (Anakinra) treatment, we demonstrated that oxidative stress is the primary element of damage in noise-induced cochlear injury and that increased inflammation can be considered a consequence of PPAR down-regulation induced by ROS production. Indeed, by decreasing oxidative stress, PPARs returned to control values, reactivating the negative control on inflammation in a feedback loop.
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16
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Tao X, Xiang H, Pan Y, Shang D, Guo J, Gao G, Xiao GG. Pancreatitis initiated pancreatic ductal adenocarcinoma: Pathophysiology explaining clinical evidence. Pharmacol Res 2021; 168:105595. [PMID: 33823219 DOI: 10.1016/j.phrs.2021.105595] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/04/2021] [Accepted: 03/31/2021] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant lethal disease due to its asymptomatic at its early lesion of the disease and drug resistance. Target therapy associated with molecular pathways so far seems not to produce reasonable outcomes. Understanding of the molecular mechanisms underlying inflammation-initiated tumorigenesis may be helpful for development of an effective therapy of the disease. A line of studies showed that pancreatic tumorigenesis was resulted from pancreatitis, which was caused synergistically by various pancreatic cells. This review focuses on those players and their possible clinic implications, such as exocrine acinar cells, ductal cells, and various stromal cells, including pancreatic stellate cells (PSCs), macrophages, lymphocytes, neutrophils, mast cells, adipocytes and endothelial cells, working together with each other in an inflammation-mediated microenvironment governed by a myriad of cellular signaling networks towards PDAC.
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Affiliation(s)
- Xufeng Tao
- Department of Pharmacology at School of Chemical Engineering, Dalian University of Technology, Dalian, China
| | - Hong Xiang
- Clinical Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yue Pan
- Department of Pharmacology at School of Chemical Engineering, Dalian University of Technology, Dalian, China
| | - Dong Shang
- Clinical Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Junchao Guo
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Ge Gao
- Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Gary Guishan Xiao
- Department of Pharmacology at School of Chemical Engineering, Dalian University of Technology, Dalian, China; The UCLA Agi Hirshberg Center for Pancreatic Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Functional Genomics and Proteomics Laboratory, Osteoporosis Research Center, Creighton University Medical Center, Omaha, NE, United States.
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17
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Zhang Y, Zhang Y, Li Y, Zhang L, Yu S. Preclinical Investigation of Alpinetin in the Treatment of Cancer-Induced Cachexia via Activating PPARγ. Front Pharmacol 2021; 12:687491. [PMID: 34093209 PMCID: PMC8176100 DOI: 10.3389/fphar.2021.687491] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 05/04/2021] [Indexed: 01/06/2023] Open
Abstract
The ongoing loss of skeletal muscle is a central event of cancer cachexia, and its consequences include adverse effects on patient’s quality of life and survival. Alpinetin (Alp), a natural plant-derived flavonoid obtained from Alpinia katsumadai Hayata, has been reported to possess potent anti-inflammatory and antitumor activities. This study aimed to explore the therapeutic effect and underlying mechanism of Alp in the prevention of cancer cachexia. We found that Alp (25–100 μM) dose-dependently attenuated Lewis lung carcinoma–conditioned medium-induced C2C12 myotube atrophy and reduced expression of the E3 ligases Atrogin-1 and MuRF1. Moreover, Alp administration markedly improved vital features of cancer cachexia in vivo with visible reduction of the loss of tumor-free body weight and wasting of multiple tissues, including skeletal muscle, epididymal fat, and decreased expression of Atrogin-1 and MuRF1 in cachectic muscle. Alp suppressed the elevated spleen weight and serum concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. Further, Alp treatment remained protective against cancer cachexia in the advanced stage of tumor growth. Molecular docking results suggested that Alp was docked into the active site of PPARγ with the docking score of –7.6 kcal/mol, forming a hydrogen bond interaction with PPARγ protein amino acid residue HIS449 with a bond length of 3.3 Å. Mechanism analysis revealed that Alp activated PPARγ, resulting in the downregulated phosphorylation of NF-κB and STAT3 in vitro and in vivo. PPARγ inhibition induced by GW9662 notably attenuated the improvement of Alp on the above cachexia phenomenon, indicating that PPARγ activation mediated the therapeutic effect of Alp. These findings suggested that Alp might be a potential therapeutic candidate against cancer cachexia.
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Affiliation(s)
- Yujie Zhang
- Department of Oncology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yuxin Zhang
- Hepatic Surgery Center, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yichen Li
- Department of Oncology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Li Zhang
- Department of Oncology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Shiying Yu
- Department of Oncology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
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18
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Kim SJ, Cho NC, Han B, Kim K, Hahn YI, Kim KP, Suh YG, Choi BY, Na HK, Surh YJ. 15-Deoxy-Δ 12,14 -prostaglandin J 2 binds and inactivates STAT3 via covalent modification of cysteine 259 in H-Ras-transformed human breast epithelial cells. FEBS Lett 2021; 595:604-622. [PMID: 33452674 DOI: 10.1002/1873-3468.14040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 01/02/2023]
Abstract
Signal transducer and activator of transcription 3 (STAT3) has been considered as a potential target for development of anticancer therapeutics. Here, we report a novel mechanism by which the cyclopentenone prostaglandin, 15-deoxy-Δ12,14 -prostaglandin J2 (15d-PGJ2 ) functions as an allosteric inhibitor of STAT3. 15d-PGJ2 inhibits phosphorylation, dimerization, nuclear translocation, and transcriptional activity of STAT3 in H-Ras-transformed human mammary epithelial cells (MCF10A-Ras) through the Michael addition reaction at cysteine 259 of STAT3. Comparative studies with 15d-PGJ2 analogues reveal that both C12-C13 and C9-C10 double bonds conjugated to the carbonyl group in the cyclopentenone ring of 15d-PGJ2 are essential for STAT3 binding. Antiproliferative and pro-apoptotic activities of 15d-PGJ2 in MCF10A-Ras cells are attributable to covalent modification of STAT3 on Cys259, and mimic the effects induced by mutation of this amino acid.
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Affiliation(s)
- Su-Jung Kim
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Korea
| | - Nam-Chul Cho
- Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Korea
| | - Bitnara Han
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, Korea
| | - Kyeojin Kim
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Korea
| | - Young-Il Hahn
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Korea
| | - Kwang Pyo Kim
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, Korea.,Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, Korea
| | - Young Ger Suh
- College of Pharmacy, CHA University, Gyeonggi-do, Korea
| | - Bu Young Choi
- Department of Pharmaceutical Science and Engineering, School of Convergence Bioscience and Technology, Seowon University, Chungbuk, Korea
| | - Hye-Kyung Na
- Department of Food Science and Biotechnology, College of Knowledge Based Services Engineering, Sungshin Women's University, Seoul, Korea
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Korea.,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Korea.,Cancer Research Institute, Seoul National University, Korea
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19
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Lyu X, Wang G, Pi Z, Wu L. Circadian clock disruption attenuated growth hormone(GH)-mediated signalling. Gen Comp Endocrinol 2021; 302:113670. [PMID: 33245935 DOI: 10.1016/j.ygcen.2020.113670] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 10/26/2020] [Accepted: 11/19/2020] [Indexed: 10/22/2022]
Abstract
The circadian molecular clock is an internal time-keeping system, which regulates various physiological processes through the generation of approximately 24-hour circadian rhythms. BMAL1 (brain and muscle arnt-like 1) is a core component of the circadian clock. Previous studies have shown that the circadian clock correlates with rhythmic secretion of endocrine hormone (such as growth hormone, GH). Currently, the effect of circadian clock on the GH-mediated biological activities is not fully understood. In this work, we used BMAL1 gene knockout mice (BMAL-/- mice) model to explore the effect of circadian clock dysfunction on GH's activities, and the results from in vivo and in vitro experiments showed that GH-induced signaling is down-regulated. In vivo, GH/GHR-mediated tyrosine phosphorylation of signaling molecules (such as the Janus kinase-signal transducer and activator of transcription, JAK-STAT) in BMAL-/- mice was significantly lower compared to control mice. In vitro, GH/GHR-mediated signaling in the hepatocytes from BMAL-/- mice is decreased compared to hepatocytes from control mice. Furthermore, we explore the mechanism by which GH/GHR-mediated signalling is down-regulated in BMAL-/- mice, and results indicated that the expression levels of negative regulators of cytokine signaling (such as the suppressor of cytokine signaling (SOCS) and protein phosphatase) were increased, which may be one of the factors that cause the GH signaling downregulation. In summary, our results show that the circadian clock affects the biological activities of GH. This finding lays the foundation for future investigations into the relationship between the circadian clock and biological activities of GH.
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Affiliation(s)
- Xintong Lyu
- Department of Pediatric Gastroenterology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Guohua Wang
- Department of Neonatology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Zhuang Pi
- Department of Pediatric Gastroenterology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Lan Wu
- Department of Pediatric Gastroenterology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China.
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20
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Li S, Xu Z, Guo J, Zheng J, Sun X, Yu J. Farnesoid X receptor activation induces antitumour activity in colorectal cancer by suppressing JAK2/STAT3 signalling via transactivation of SOCS3 gene. J Cell Mol Med 2020; 24:14549-14560. [PMID: 33164339 PMCID: PMC7754034 DOI: 10.1111/jcmm.16083] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 10/20/2020] [Accepted: 10/25/2020] [Indexed: 12/14/2022] Open
Abstract
Farnesoid X receptor (FXR, encoded by NR1H4), a bile acid‐activated nuclear receptor, is widely implicated in human tumorigenesis. The FXR agonist obeticholic acid (OCA) has preliminarily displayed tumour suppressor potential. However, the anticancer effects of this agent on colorectal cancer (CRC) remain unclear. In this study, the treatment of colon cancer cells with OCA inhibited cell proliferation and invasion in vitro, retarded tumour growth in vivo and prevented the G0/G1 to S phase transition. Moreover, the expression of active caspase‐3, p21 and E‐cadherin was up‐regulated and the expression of cyclin D1, c‐Myc, vimentin, N‐cadherin and MMP9 was down‐regulated in OCA‐treated colon cancer cells. Mechanistic studies indicated that OCA treatment suppressed the activity of JAK2/STAT3 pathway by up‐regulating SOCS3 expression. Colivelin, an agonist of JAK2/STAT3 pathway, antagonized the tumour‐suppressive effect of OCA on colon cancer cells. Dual‐luciferase reporter and quantitative chromatin immunoprecipitation (qChIP) assays further confirmed that OCA promoted SOCS3 transcription by enhancing the binding of FXR to the FXRE/IR9 of the SOCS3 promoter. In conclusion, our study demonstrates that targeting FXR and improving its function might be a promising strategy for CRC treatment.
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Affiliation(s)
- Shan Li
- Department of Reproductive Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhengshui Xu
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jing Guo
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jianbao Zheng
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xuejun Sun
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Junhui Yu
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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21
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Lyu X, Wang G, Pi Z, Wu L. Acute sleep deprivation leads to growth hormone (GH) resistance in rats. Gen Comp Endocrinol 2020; 296:113545. [PMID: 32622934 DOI: 10.1016/j.ygcen.2020.113545] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 06/04/2020] [Accepted: 06/26/2020] [Indexed: 11/21/2022]
Abstract
Sleep is an essential physiological process that is required by all higher animals. Sleep has many important physiological functions. Previous studies have focused on the relationship between sleep and growth hormone secretion patterns. However, to date, whether sleep affects the biological activities of GH remains unclear. Here, we investigated this issue by evaluating the growth hormone receptor (GHR)-mediated intracellular signalling pathway in a sleep-deprived rat model. The results showed that GH's signalling ability is decreased in an acute sleep deprivation rat model. JAK2-STAT signalling was decreased significantly compared to that in control rats. We further analysed the possible molecular mechanism of GH signal inhibition in sleep-deprived rats. The results showed that the protein expression levels of SOCS3 (suppressors of cytokine signalling 3, which functions as the negative regulatory molecule of GH's signalling) increased; however, other negative regulatory proteins, such as protein phosphatase (PTP1B), did not change. In addition, acute sleep deprivation results in a significant increase in serum FFA (free fatty acid) level, which is also one of the factors contributing to GH inhibition. These findings suggest that GH signal resistance may be caused by a combination of factors. This study could serve as an important reference for related studies on the effect of sleep deprivation on endocrine systems.
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Affiliation(s)
- Xintong Lyu
- Department of Pediatric Gastroenterology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Guohua Wang
- Department of Neonatology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Zhuang Pi
- Department of Pediatric Gastroenterology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Lan Wu
- Department of Pediatric Gastroenterology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China.
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22
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Song X, Yang W, Wu C, Han Y, Lu Y. USP9X promotes the proliferation, invasion and metastasis of liver cancer cells through regulating the JAK2/STAT3 signaling. Oncol Lett 2020; 20:2897-2905. [PMID: 32782606 PMCID: PMC7400992 DOI: 10.3892/ol.2020.11824] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Accepted: 05/27/2020] [Indexed: 12/25/2022] Open
Abstract
X-linked ubiquitin-specific peptidase 9 (USP9X) serves important roles in the development and progression of various human cancers. However, its role and molecular mechanism in liver cancer require further elucidation. In the present study, USP9X was found to be upregulated in liver cancer tissues. At the same time, overexpression of USP9X promoted the proliferation, invasiveness and migration of liver cancer cells, which were subsequently suppressed by USP9X silencing. On a molecular level, the results revealed that USP9X knockdown suppressed elements of the Janus kinase 2 (JAK2)/STAT3 signaling pathway, including JAK2, STAT3, matrix metalloproteinase-2 and c-Myc. By contrast, overexpression of USP9X had the opposite effect. In conclusion, the results of the present study suggest that USP9X is upregulated in patients with liver cancer, which may accelerate the proliferation, invasiveness and migration of liver cancer cells by regulating the JAK2/STAT3 signaling pathway.
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Affiliation(s)
- Xingchao Song
- Department of General Surgery, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China.,Department of General Surgery, Xuzhou No. 1 People's Hospital, Xuzhou, Jiangsu 221000, P.R. China
| | - Weibin Yang
- Department of General Surgery, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China.,Department of General Surgery, Xuzhou No. 1 People's Hospital, Xuzhou, Jiangsu 221000, P.R. China
| | - Chao Wu
- Department of General Surgery, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China.,Department of General Surgery, Xuzhou No. 1 People's Hospital, Xuzhou, Jiangsu 221000, P.R. China
| | - Yamin Han
- Department of General Surgery, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China.,Department of General Surgery, Xuzhou No. 1 People's Hospital, Xuzhou, Jiangsu 221000, P.R. China
| | - Yaowu Lu
- Department of General Surgery, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China.,Department of General Surgery, Xuzhou No. 1 People's Hospital, Xuzhou, Jiangsu 221000, P.R. China
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23
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d'Angelo M, Castelli V, Tupone MG, Catanesi M, Antonosante A, Dominguez-Benot R, Ippoliti R, Cimini AM, Benedetti E. Lifestyle and Food Habits Impact on Chronic Diseases: Roles of PPARs. Int J Mol Sci 2019; 20:ijms20215422. [PMID: 31683535 PMCID: PMC6862628 DOI: 10.3390/ijms20215422] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 10/28/2019] [Accepted: 10/29/2019] [Indexed: 02/07/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert important functions in mediating the pleiotropic effects of diverse exogenous factors such as physical exercise and food components. Particularly, PPARs act as transcription factors that control the expression of genes implicated in lipid and glucose metabolism, and cellular proliferation and differentiation. In this review, we aim to summarize the recent advancements reported on the effects of lifestyle and food habits on PPAR transcriptional activity in chronic disease.
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Affiliation(s)
- Michele d'Angelo
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Maria Grazia Tupone
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Mariano Catanesi
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Andrea Antonosante
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Reyes Dominguez-Benot
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Rodolfo Ippoliti
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Anna Maria Cimini
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA.
| | - Elisabetta Benedetti
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
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Uddin MS, Kabir MT, Jakaria M, Mamun AA, Niaz K, Amran MS, Barreto GE, Ashraf GM. Endothelial PPARγ Is Crucial for Averting Age-Related Vascular Dysfunction by Stalling Oxidative Stress and ROCK. Neurotox Res 2019; 36:583-601. [PMID: 31055770 DOI: 10.1007/s12640-019-00047-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 04/01/2019] [Accepted: 04/11/2019] [Indexed: 02/07/2023]
Abstract
Aging plays a significant role in the progression of vascular diseases and vascular dysfunction. Activation of the ADP-ribosylation factor 6 and small GTPases by inflammatory signals may cause vascular permeability and endothelial leakage. Pro-inflammatory molecules have a significant effect on smooth muscle cells (SMC). The migration and proliferation of SMC can be promoted by tumor necrosis factor alpha (TNF-α). TNF-α can also increase oxidative stress in SMCs, which has been identified to persuade DNA damage resulting in apoptosis and cellular senescence. Peroxisome proliferator-activated receptor (PPAR) acts as a ligand-dependent transcription factor and a member of the nuclear receptor superfamily. They play key roles in a wide range of biological processes, including cell differentiation and proliferation, bone formation, cell metabolism, tissue remodeling, insulin sensitivity, and eicosanoid signaling. The PPARγ activation regulates inflammatory responses, which can exert protective effects in the vasculature. In addition, loss of function of PPARγ enhances cardiovascular events and atherosclerosis in the vascular endothelium. This appraisal, therefore, discusses the critical linkage of PPARγ in the inflammatory process and highlights a crucial defensive role for endothelial PPARγ in vascular dysfunction and disease, as well as therapy for vascular aging.
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Affiliation(s)
- Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh.
| | | | - Md Jakaria
- Department of Applied Life Sciences, Graduate School, Konkuk University, Chungju, South Korea
| | | | - Kamal Niaz
- Department of Pharmacology and Toxicology, Faculty of Bio-Sciences, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
| | - Md Shah Amran
- Department of Pharmaceutical Chemistry, University of Dhaka, Dhaka, Bangladesh
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, DC, Colombia.,Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia. .,Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
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Ding Q, Sun J, Xie W, Zhang M, Zhang C, Xu X. Stemona alkaloids suppress the positive feedback loop between M2 polarization and fibroblast differentiation by inhibiting JAK2/STAT3 pathway in fibroblasts and CXCR4/PI 3K/AKT1 pathway in macrophages. Int Immunopharmacol 2019; 72:385-394. [PMID: 31030094 DOI: 10.1016/j.intimp.2019.04.030] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 04/08/2019] [Accepted: 04/14/2019] [Indexed: 12/24/2022]
Abstract
This study aimed to investigate the interaction between macrophages and fibroblasts in pulmonary fibrosis and the effects of total alkaloids of Stemona tuberosa (STA, 9 alkaloids with relative content of 91.2%) on them. The culture medium of LPS- or IL-4-induced macrophages was used as conditioned medium (CM) to co-culture with fibroblasts to study the effect of macrophages on the differentiation of fibroblasts. Similarly，the CM of TGF-β1-induced fibroblasts was co-culture with macrophages to study the effect of fibroblasts on the polarization of macrophages. The results showed that the TGF-β1 level in IL-4-induced (M2) rather than LPS-induced (M1) macrophages was significantly high (p < 0.001), and the SDF-1 level in TGF-β1-induced fibroblasts (MF) was significantly high (p < 0.001). The expressions of α-SMA and Col-1 in M2-CM-induced fibroblasts and Arg-1 and CXCR4 in MF-CM-induced macrophages were significantly increased (p < 0.01). STA effectively decreased the expressions of α-SMA (p < 0.05, 0.01 at 10, 100 μg/mL), Col-1 (p < 0.05, 0.05, 0.01 at 1, 10, 100 μg/mL), Arg-1 (p < 0.01 at 1, 10, 100 μg/mL) and CXCR4 (p < 0.01, 0.001 at 10, 100 μg/mL), which were consistent with the experimental results in vivo. These results suggested that there was a positive feedback loop between M2 polarization and fibroblast differentiation in pulmonary fibrosis. Further studies showed that the transcription of sdf-1 gene in MF was initiated by JAK2/STAT3 pathway and the M2 polarization was promoted by SDF-1/CXCR4/PI3K/AKT1 pathway. STA blocked the feedback loop by suppressing JAK2/STAT3 pathway in fibroblasts and CXCR4-PI3K/AKT1 pathway in macrophages.
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Affiliation(s)
- Qi Ding
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Jing Sun
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Weina Xie
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Mian Zhang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China.
| | - Chaofeng Zhang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Xianghong Xu
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China.
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Korbecki J, Bobiński R, Dutka M. Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors. Inflamm Res 2019; 68:443-458. [PMID: 30927048 PMCID: PMC6517359 DOI: 10.1007/s00011-019-01231-1] [Citation(s) in RCA: 247] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/24/2019] [Accepted: 03/22/2019] [Indexed: 12/14/2022] Open
Abstract
The peroxisome proliferator-activated receptor (PPAR) family includes three transcription factors: PPARα, PPARβ/δ, and PPARγ. PPAR are nuclear receptors activated by oxidised and nitrated fatty acid derivatives as well as by cyclopentenone prostaglandins (PGA2 and 15d-PGJ2) during the inflammatory response. This results in the modulation of the pro-inflammatory response, preventing it from being excessively activated. Other activators of these receptors are nonsteroidal anti-inflammatory drug (NSAID) and fatty acids, especially polyunsaturated fatty acid (PUFA) (arachidonic acid, ALA, EPA, and DHA). The main function of PPAR during the inflammatory reaction is to promote the inactivation of NF-κB. Possible mechanisms of inactivation include direct binding and thus inactivation of p65 NF-κB or ubiquitination leading to proteolytic degradation of p65 NF-κB. PPAR also exert indirect effects on NF-κB. They promote the expression of antioxidant enzymes, such as catalase, superoxide dismutase, or heme oxygenase-1, resulting in a reduction in the concentration of reactive oxygen species (ROS), i.e., secondary transmitters in inflammatory reactions. PPAR also cause an increase in the expression of IκBα, SIRT1, and PTEN, which interferes with the activation and function of NF-κB in inflammatory reactions.
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Affiliation(s)
- Jan Korbecki
- Department of Molecular Biology, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 Str., 40-752, Katowice, Poland. .,Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa 2 Str., 43-309, Bielsko-Biała, Poland.
| | - Rafał Bobiński
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa 2 Str., 43-309, Bielsko-Biała, Poland
| | - Mieczysław Dutka
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa 2 Str., 43-309, Bielsko-Biała, Poland
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Abstract
OBJECTIVE Chronic pancreatitis is the consequence of multiple episodes of recurrent acute pancreatitis (RAP). We hypothesized that apigenin can minimize the sequelae of RAP by limiting acinar cells' proinflammatory signaling pathways. METHODS AR42J acinar cells were treated in vitro with transforming growth factor β (TGF-β), apigenin, and other inhibitors. Dual luciferase reporter assay measured parathyroid hormone-related protein (PTHrP) promoter activity. MAPK/ERK pathway activity was assessed by immunoblotting and in vivo by immunohistochemistry with a cerulein-induced RAP mouse model. Nuclear factor κ B nuclear localization was analyzed in vitro in cells stimulated with tumor necrosis factor α. Primary acini were isolated and treated with cerulein; interleukin 6 messenger RNA was measured comparing PTHrP wild-type and knockout mice. RESULTS Apigenin and PD98059 each downregulated TGF-β stimulation of PTHrP P3 promoter activity. In a RAP mouse model, apigenin reduced pERK nuclear localization in acinar cells and preserved acinar cell architecture. Apigenin suppressed tumor necrosis factor α-mediated signaling by decreasing nuclear factor κ B nuclear localization and decreased interleukin 6 messenger RNA levels via a PTHrP-dependent mechanism. CONCLUSIONS Apigenin reduced inflammatory responses in experimental models of RAP. The mechanisms mediating the actions of apigenin, in part, are owing to attenuation of PTHrP and TGF-β proinflammatory signaling.
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Pharmacological stimulation of NQO1 decreases NADPH levels and ameliorates acute pancreatitis in mice. Cell Death Dis 2018; 10:5. [PMID: 30584237 PMCID: PMC6315021 DOI: 10.1038/s41419-018-1252-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 11/28/2018] [Accepted: 12/03/2018] [Indexed: 02/07/2023]
Abstract
Reactive oxygen species (ROS) regulates the activation of inflammatory cascades and tissue damage in acute pancreatitis. NADPH oxidase (NOX) is upregulated in pancreatitis and is one of the major enzymes involved in ROS production using NADPH as a general rate-limiting substrate. Dunnione, a well-known substrate of NAD(P)H:quinone oxidoreductase 1 (NQO1), reduces the ratio of cellular NADPH/NADP+ through the enzymatic action of NQO1. This study assessed whether a reduction in cellular NADPH/NADP+ ratio can be used to regulate caerulein-induced pancreatic damage associated with NOX-induced ROS production in animal models. Dunnione treatment significantly reduced the cellular NADPH/NADP+ ratio and NOX activity through the enzymatic action of NQO1 in the pancreas of the caerulein-injection group. Similar to these results, total ROS production and expressions of mRNA and protein for NOX subunits Nox1, p27phox, p47phox, and p67phox also decreased in the dunnione-treated group. In addition, caerulein-induced pancreatic inflammation and acinar cell injury were significantly reduced by dunnione treatment. This study is the first to demonstrate that modulation of the cellular NADPH:NADP+ ratio by enzymatic action of NQO1 protects acute pancreatitis through the regulation of NOX activity. Furthermore, these results suggest that modulation of the NADPH:NADP+ ratio in cells by NQO1 may be a novel therapeutic strategy for acute pancreatitis.
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Nie S, Cui X, Guo J, Ma X, Zhi H, Li S, Li Y. Inhibiting role of rosiglitazone in the regulation of inflammatory response and protective effects for severe acute pancreatitis in mice. J Cell Biochem 2018; 120:799-808. [PMID: 30206968 DOI: 10.1002/jcb.27440] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 07/16/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Our study aimed to probe the effects of rosiglitazone treatment on a severe acute pancreatitis (SAP) model induced by caerulein and investigate the underlying mechanism. METHODS Differentially expressed messenger RNAs (mRNAs) in the mice of a SAP group were screened out by microarray analysis. The inflammatory response pathway was obtained from the online website DAVID Bioinformatics Resources 6.8. The interactions of caerulein and its target proteins were shown by search tool for interactions of chemicals (STITCH). Functional interactions of the genes associated with pancreatitis and the target proteins of caerulein were obtained with search tool for interactions of chemicals (STRING). SAP mice were established by hourly intraperitoneal injection of caerulein. Rosiglitazone was used as treatment drug, and pancreatic inflammation was assessed. The expression of Socs3 was studied by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis. The expression of interleukin (IL)-6, IL-1b, and Egr1 were studied by RT-PCR and Western blot analysis. RESULTS The GSE77983 data were analyzed, and the results showed that Socs3 was overexpressed in SAP tissues. The inflammation response pathway in pancreas was selected by DAVID, STITCH, and STRING. After injection of rosiglitazone in mice, the serum levels of amylase and lipase were decreased. Furthermore, the mRNA and protein levels of Socs3 and inflammatory cytokines in pancreatic tissues were downregulated. CONCLUSIONS Rosiglitazone could protect mice with SAP from injury by downregulating Socs3 and inhibiting the inflammatory response pathway.
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Affiliation(s)
- Shen Nie
- Department of Emergency, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Xiaoya Cui
- Department of Emergency, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Jinping Guo
- Department of Emergency, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Xiaohua Ma
- Department of Emergency, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Haijun Zhi
- Department of Emergency, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Shilei Li
- Department of Emergency, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Yong Li
- Department of Emergency, Cangzhou Central Hospital, Cangzhou, Hebei, China
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Ji XX, Ji XJ, Li QQ, Lu XX, Luo L. Rosiglitazone Reduces Apoptosis and Inflammation in Lipopolysaccharide-Induced Human Umbilical Vein Endothelial Cells. Med Sci Monit 2018; 24:6200-6207. [PMID: 30185768 PMCID: PMC6140784 DOI: 10.12659/msm.910036] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Although the peroxisome proliferator-activated receptor-g (PPARg) agonist rosiglitazone has significant anti-inflammatory properties, no scientific studies have provided new insights in its pharmacological properties with respect to acute respiratory distress syndrome (ARDS). The present investigation aimed to evaluate whether rosiglitazone can reduce apoptosis and inflammation in a lipopolysaccharide (LPS)-induced acute respiratory distress syndrome in vitro model. MATERIAL AND METHODS Human umbilical vein endothelial cells (HUVECs) were treated with 1 µg/ml LPS in the absence or presence of 10 µM rosiglitazone for 24 h. Cell viability was measured by MTT assay. Flow cytometry was used to examine the cell apoptosis and ROS production in HUVECs response to LPS and rosiglitazone. The levels of pro-inflammatory cytokine factors, including TNF-α, IL-6, CXCL12, and CXCR4, were measured by ELISA, real-time PCR, and Western blot assay, respectively. The expression of PPARg, Bcl-2, and Bax and the activity of JAK2 and STAT3 were also investigated by Western blot assay. RESULTS We found that rosiglitazone significantly inhibited LPS-induced cell apoptosis, ROS production, and inflammation in HUVECs. Furthermore, we found a significant reduction of JAK2/STAT3 activation and the Bax/Bcl-2 ratio in LPS-induced HUVECs response to rosiglitazone treatment. CONCLUSIONS Treatment with rosiglitazone can reduce apoptosis and inflammation in HUVECs induced by LPS.
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Affiliation(s)
- Xiao-Xia Ji
- Department of Critical Care Medicine, Wuxi No.2 Hospital affiliated to Nanjing Medical University, Wuxi, Jiangsu, China (mainland)
| | - Xiao-Jing Ji
- Department of Internal Medicine, Wuxi No.2 Hospital affiliated to Nanjing Medical University, Wuxi, Jiangsu, China (mainland)
| | - Qian-Qian Li
- Department of Critical Care Medicine, Wuxi No.2 Hospital affiliated to Nanjing Medical University, Wuxi, Jiangsu, China (mainland)
| | - Xiao-Xian Lu
- Department of Critical Care Medicine, Wuxi No.2 Hospital affiliated to Nanjing Medical University, Wuxi, Jiangsu, China (mainland)
| | - Liang Luo
- Department of Critical Care Medicine, Wuxi No.2 Hospital affiliated to Nanjing Medical University, Wuxi, Jiangsu, China (mainland)
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Li M, Zhang X, Wang B, Xu X, Wu X, Guo M, Wang F. Effect of JAK2/STAT3 signaling pathway on liver injury associated with severe acute pancreatitis in rats. Exp Ther Med 2018; 16:2013-2021. [PMID: 30186433 DOI: 10.3892/etm.2018.6433] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 06/22/2018] [Indexed: 12/19/2022] Open
Abstract
Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling constitutes one of the major pathways for cytokine signal transduction. However, the role of the JAK2/STAT3 pathway in liver injury during severe acute pancreatitis (SAP) remains unclear. The aim of this study was to investigate the role of the JAK2/STAT3 signaling pathway in liver injury after SAP. In the present study 64 male Sprague-Dawley rats were randomly divided into four groups: Control, AG490 (inhibition of JAK2), SAP and SAP with AG490. SAP was induced by retrograde infusion of 4% sodium taurocholate into the biliopancreatic duct. The activities of amylase (AMY) and liver enzymes were measured in serum. Livers and pancreas were isolated for measurements of histological damage. Blood and liver samples were taken for the measurement of TNF-α, IL-6 and IL-18 concentrations. The expression levels of JAK2 and STAT3 in liver tissue were detected by immunohistochemical staining and western blotting. The results demonstrated that amylase and liver enzymes were higher in the SAP groups compared with the control, AG490 and AG490-treated groups. The serum levels of TNF-α, IL-6 and IL-18 were effectively increased in the SAP groups, whereas they were reduced by AG490. Interestingly, JAK2 and STAT3 protein expression levels were significantly increased following induction of SAP and were significantly decreased in the AG490-pretreated groups. Administration of AG490 decreased the activity of pro-inflammatory cytokines and significantly attenuated SAP associated-liver injury in the rats. These results suggested that the mechanism may relate to the inhibition of TNF-α, IL-6 and IL-18, and inhibiting excessive JAK2 and STAT3 activation, and may play a crucial role in the liver injury associated with SAP.
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Affiliation(s)
- Minli Li
- Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Xiaohua Zhang
- Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Bin Wang
- Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Xiaobing Xu
- Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Xiaowei Wu
- Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Meixia Guo
- Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Fangyu Wang
- Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
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Wang D, Tang M, Zong P, Liu H, Zhang T, Liu Y, Zhao Y. MiRNA-155 Regulates the Th17/Treg Ratio by Targeting SOCS1 in Severe Acute Pancreatitis. Front Physiol 2018; 9:686. [PMID: 29937734 PMCID: PMC6002743 DOI: 10.3389/fphys.2018.00686] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 05/17/2018] [Indexed: 12/11/2022] Open
Abstract
Acute pancreatitis (AP) is a serious condition associated with intestinal barrier disruption or inflammation of the pancreatic tissue. Specific microRNAs are involved in the pathogenesis of AP, during which IL-17-producing CD4+ T helper (Th17) cells accumulate in the pancreas. In this study, significantly increased levels of miR-155 were detected in clinical samples from patients with AP, and overexpression of miR-155 correlated with severe AP (SAP). To identify the effect of miR-155 on T cell differentiation, we isolated CD4+ T lymphocytes and in vitro experiments showed that inhibition of miR-155 significantly reversed the stress-induced increase in the Th17/Treg ratio. The results also showed that miR-155 increased the Th17-mediated inflammatory response by targeting SOCS1. The interaction between miR-155 and the 3′-UTR of SOCS1 was confirmed by a dual luciferase reporter assay and RT-PCR. Experimental AP of varying severity was induced in BALB/c mice by caerulein hyperstimulation and miR-155 expression was found to increase with disease progression. Inhibition of miR-155 expression significantly improved the pathology of the pancreas. We also observed downregulation of expression of inflammatory factors, IL-17, SOCS1 and phosphorylated STAT1 after miR-155 inhibition. In summary, miR-155 regulates the Th17/Treg ratio by targeting SOCS1, most probably via direct binding to its 3′-UTR region, indicating that this microRNA may be a potential biomarker and/or therapeutic target for AP.
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Affiliation(s)
- Dongyan Wang
- Department of Gastroenterology, Tenth People's Hospital of Tongji University, Shanghai, China
| | - Maochun Tang
- Department of Gastroenterology, Tenth People's Hospital of Tongji University, Shanghai, China
| | - Pengfei Zong
- Department of Gastroenterology, Tenth People's Hospital of Tongji University, Shanghai, China
| | - Hua Liu
- Department of Gastroenterology, Tenth People's Hospital of Tongji University, Shanghai, China
| | - Ting Zhang
- Department of Gastroenterology, Tenth People's Hospital of Tongji University, Shanghai, China
| | - Yu Liu
- The Community Health Service Center of Nanxiang Town, Shanghai, China
| | - Yan Zhao
- Department of Gastroenterology, Tenth People's Hospital of Tongji University, Shanghai, China
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PGD2/PTGDR2 Signaling Restricts the Self-Renewal and Tumorigenesis of Gastric Cancer. Stem Cells 2018; 36:990-1003. [DOI: 10.1002/stem.2821] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 02/12/2018] [Accepted: 02/27/2018] [Indexed: 12/20/2022]
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Zhang YL, Wang RB, Li WY, Xia FZ, Liu L. Pioglitazone ameliorates retinal ischemia/reperfusion injury via suppressing NLRP3 inflammasome activities. Int J Ophthalmol 2017; 10:1812-1818. [PMID: 29259897 DOI: 10.18240/ijo.2017.12.04] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Accepted: 10/25/2017] [Indexed: 01/16/2023] Open
Abstract
AIM To explore the role of Pioglitazone (Pio) on a mouse model of retinal ischemia/reperfusion (I/R) injury and to elucidate the potential mechanism. METHODS Retinal ischemia was induced in mice by increasing the intraocular pressure, and Pio was administered 4h though periocular injection before I/R. The number of cells in the ganglion cell layer (GCL) was counted 7d after retinal I/R injury. Glial fibrillary acidic protein (GFAP), nuclear factor-kappa B (NF-κB), p38, phosphorylated-p38, PPAR-γ, interleukin-1β (IL-1β), Toll-like receptor 4 (TLR4), NLRP3, cleaved caspase-1, caspase-1 were determined by real-time polymerase chain reaction and Western blotting. RESULTS Pio promoted the survival of retinal cells in GCL following retinal I/R injury (P<0.05). Besides, retinal I/R injury stimulated the expression of GFAP and TLR4, which were partially reversed by Pio treatment (P<0.05). Retinal I/R injury-upregulated expression of NLRP3, cleaved caspase-1, IL-1β was attenuated after Pio treatment (P<0.05). Moreover, I/R injury induced activation of NF-κB and p38 were inhibited by Pio treatment (P<0.05). CONCLUSION Pio promotes retinal ganglion cells survival by suppressing I/R-induced activation of TLR4/NLRP3 inflammasomes via inhibiting NF-κB and p38 phosphorylation.
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Affiliation(s)
- Yue-Lu Zhang
- Department of Ophthalmology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Ruo-Bing Wang
- Department of Ophthalmology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Wei-Yi Li
- Department of Ophthalmology, Shandong University Qilu Hospital (Qingdao), Qingdao 266035, Shandong Province, China
| | - Fang-Zhou Xia
- Department of Ophthalmology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Lin Liu
- Department of Ophthalmology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
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Tsubaki M, Takeda T, Tomonari Y, Kawashima K, Itoh T, Imano M, Satou T, Nishida S. Pioglitazone inhibits cancer cell growth through STAT3 inhibition and enhanced AIF expression via a PPARγ-independent pathway. J Cell Physiol 2017; 233:3638-3647. [PMID: 29030979 DOI: 10.1002/jcp.26225] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2017] [Accepted: 10/05/2017] [Indexed: 12/14/2022]
Abstract
Pioglitazone is an anti-diabetic agent that belongs to the thiazolidinedione class, which target peroxisome proliferator-activated receptor γ (PPARγ), a transcription factor in the nuclear receptor family. Different cancer cells expressing high levels of PPARγ and PPARγ ligands induce cell cycle arrest, cell differentiation, and apoptosis. However, the mechanisms underlying these processes remain unknown. Here, we investigated the mechanism underlying pioglitazone-induced apoptosis in human cancer cells. We showed that at similar concentrations, pioglitazone induced death in cancer cells expressing high or low levels of PPARγ. Combined treatment of pioglitazone and GW9662, a PPARγ antagonist, did not rescue this cell death phenotype. Z-VAD-fmk, a pan-caspase inhibitor, did not reverse pioglitazone-induced apoptosis in cancer cells expressing PPARγ at high or low levels. Pioglitazone suppressed the activation of signal transducers and activator of transcription 3 (STAT3) and Survivin expression, and enhanced the apoptosis-inducing factor (AIF) levels in these cells. Furthermore, pioglitazone enhanced the cytotoxic effect of cisplatin and oxaliplatin by suppressing Survivin and increasing AIF expression. These results indicated that pioglitazone induced apoptosis via a PPARγ-independent pathway, thus describing pioglitazone as a potential therapeutic agent for controlling the progression of different cancers.
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Affiliation(s)
- Masanobu Tsubaki
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashi-Osaka, Japan
| | - Tomoya Takeda
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashi-Osaka, Japan
| | - Yoshika Tomonari
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashi-Osaka, Japan
| | - Keishi Kawashima
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashi-Osaka, Japan
| | - Tatsuki Itoh
- Department of Food Science and Nutrition, Faculty of Agriculture, Kindai University, Nara, Nara, Japan
| | - Motohiro Imano
- Department of Surgery, Faculty of Medicine, Kindai University, Osakasayama, Osaka, Japan
| | - Takao Satou
- Department of Pathology, Faculty of Medicine, Kindai University, Osakasayama, Osaka, Japan
| | - Shozo Nishida
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashi-Osaka, Japan
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Ju KD, Lim JW, Kim H. Peroxisome Proliferator-activated Receptor-gamma Inhibits the Activation of STAT3 in Cerulein-stimulated Pancreatic Acinar Cells. J Cancer Prev 2017; 22:189-194. [PMID: 29018784 PMCID: PMC5624460 DOI: 10.15430/jcp.2017.22.3.189] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 08/10/2017] [Accepted: 08/12/2017] [Indexed: 12/31/2022] Open
Abstract
Cerulein-induced pancreatitis is similar to human edematous pancreatitis, characterized by the dysregulation of digestive enzyme production, edema formation, and an infiltration of inflammatory cells into the pancreas. We previously showed that the Janus kinase 2 (JAK2)/STAT3 pathway mediates inflammatory signaling in cerulein-stimulated pancreatic acinar cells. PPAR-γ has been implicated in the regulation of inflammatory responses in several cells. In the present study, we investigated the role of PPAR-γ in cerulein-induced activation of JAK2/STAT3 in pancreatic acinar cells. Treatment with cerulein induced the activation of JAK2/STAT3 and PPAR-γ expression in AR42J cells. Cerulein-induced PPAR-γ expression was inhibited by AG490, a JAK2/STAT3 inhibitor, in AR42J cells. An immunoprecipitation analysis showed that PPAR-γ binds to STAT3 in cerulein-stimulated AR42J cells. Down-regulation of PPAR-γ by siRNA increased STAT3 phosphorylation in AR42J cells stimulated with cerulein. These results show that PPAR-γ inactivates STAT3 by directly interacting with STAT3 in cerulein-stimulated pancreatic acinar cells. Overexpression of PPAR-γ may be beneficial for preventing pancreatitis by suppressing the activation of STAT3 in pancreatic acinar cells.
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Affiliation(s)
- Kyung Don Ju
- Department of Pharmacology, Yonsei University College of Medicine, Yonsei University, Seoul, Korea
| | - Joo Weon Lim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
| | - Hyeyoung Kim
- Department of Pharmacology, Yonsei University College of Medicine, Yonsei University, Seoul, Korea.,Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
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Dai JJ, Jiang MJ, Wang XP, Tian L. Inflammation-Related Pancreatic Carcinogenesis: Mechanisms and Clinical Potentials in Advances. Pancreas 2017; 46:973-985. [PMID: 28796135 DOI: 10.1097/mpa.0000000000000886] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Chronic inflammation has long been considered critical in pancreatic carcinogenesis, and recently studies showed that some anti-inflammatory agents such as aspirin could potentially be used to attenuate pancreatic carcinogenesis. Several inflammation-related critical transcription factors and pathways such as NF-κB (nuclear factor κ-light-chain enhancer of activated B cells) and reactive oxygen species have been confirmed to be involved in carcinogenesis. However, its underlying mechanisms are far from clear, which largely limits further development of potential anticarcinogenesis drugs. As a result, it is of great importance for us to better understand and gain a better perspective in inflammation-related pancreatic carcinogenesis. In this review, we systematically analyzed recent advances concerning inflammation-related pancreatic carcinogenesis and brought out the possible underlying mechanisms. Potential preventive and therapeutic strategies based on anti-inflammatory agents have also been further discussed.
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Affiliation(s)
- Juan-Juan Dai
- From the *Shanghai Key Laboratory of Pancreatic Diseases, †Institute of Translational Medicine, and ‡Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Jeong YK, Lee S, Lim JW, Kim H. Docosahexaenoic Acid Inhibits Cerulein-Induced Acute Pancreatitis in Rats. Nutrients 2017; 9:E744. [PMID: 28704954 PMCID: PMC5537858 DOI: 10.3390/nu9070744] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 07/05/2017] [Accepted: 07/06/2017] [Indexed: 12/11/2022] Open
Abstract
Oxidative stress is an important regulator in the pathogenesis of acute pancreatitis (AP). Reactive oxygen species induce activation of inflammatory cascades, inflammatory cell recruitment, and tissue damage. NF-κB regulates inflammatory cytokine gene expression, which induces an acute, edematous form of pancreatitis. Protein kinase C δ (PKCδ) activates NF-κB as shown in a mouse model of cerulein-induced AP. Docosahexaenoic acid (DHA), an ω-3 fatty acid, exerts anti-inflammatory and antioxidant effects in various cells and tissues. This study investigated whether DHA inhibits cerulein-induced AP in rats by assessing pancreatic edema, myeloperoxidase activity, levels of lipid peroxide and IL-6, activation of NF-κB and PKCδ, and by histologic observation. AP was induced by intraperitoneal injection (i.p.) of cerulein (50 μg/kg) every hour for 7 h. DHA (13 mg/kg) was administered i.p. for three days before AP induction. Pretreatment with DHA reduced cerulein-induced activation of NF-κB, PKCδ, and IL-6 in pancreatic tissues of rats. DHA suppressed pancreatic edema and decreased the abundance of lipid peroxide, myeloperoxidase activity, and inflammatory cell infiltration into the pancreatic tissues of cerulein-stimulated rats. Therefore, DHA may help prevent the development of pancreatitis by suppressing the activation of NF-κB and PKCδ, expression of IL-6, and oxidative damage to the pancreas.
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Affiliation(s)
- Yoo Kyung Jeong
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
| | - Sle Lee
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
| | - Joo Weon Lim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
| | - Hyeyoung Kim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
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Lin CC, Chen DY, Tang KT, Chao YH, Shen CH, Lui PW. Inhibitory effects of propofol on Th17 cell differentiation. Immunopharmacol Immunotoxicol 2017; 39:211-218. [PMID: 28555509 DOI: 10.1080/08923973.2017.1327962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Propofol (2,6-diisopropylphenol) is probably the most widely used intravenous anesthetic agent in daily practice. It has been reported to show immunomodulatory activity. However, the effect of propofol on the differention of T cells remains unclear. In this study, we demonstrated for the first time that propofol inhibited both interleukin (IL)-6 plus transforming growth factor-β (TGF-β)-induced Th17 cell differentiation in vitro and in LPS-challenged mice. Propofol also suppressed the IL-6-induced phosphorylation of Janus kinase-2 (JAK2)/signal transducer and activator of transcription (STAT3) pathway, a cytokine-activated essential transcription factor in Th17 cell development, which occurred concomitantly with the enhancement of suppressor of cytokine signaling-3 (SOCS3) expression involved in the downregulation of STAT3 phosphorylation. These data extend our knowledge of the immunosuppressive effects of propofol and their underlying mechanism.
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Affiliation(s)
- Chi-Chien Lin
- a Institute of Biomedical Science, National Chung Hsing University , Taichung , Taiwan.,b Department of Medical Research , China Medical University Hospital , Taichung , Taiwan.,c Department of Biotechnology , Asia University , Taichung , Taiwan
| | - Der-Yuan Chen
- d Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine , Taichung Veterans General Hospital , Taichung , Taiwan.,e School of Medicine , National Yang-Ming University , Taipei , Taiwan.,f Department of Medical Research , Taichung Veterans General Hospital , Taichung , Taiwan
| | - Kuo-Tung Tang
- a Institute of Biomedical Science, National Chung Hsing University , Taichung , Taiwan.,d Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine , Taichung Veterans General Hospital , Taichung , Taiwan
| | - Ya-Hsuan Chao
- a Institute of Biomedical Science, National Chung Hsing University , Taichung , Taiwan
| | - Ching-Hui Shen
- e School of Medicine , National Yang-Ming University , Taipei , Taiwan.,g Department of Anesthesiology , Taichung Veterans General Hospital , Taichung , Taiwan
| | - Ping-Wing Lui
- a Institute of Biomedical Science, National Chung Hsing University , Taichung , Taiwan.,e School of Medicine , National Yang-Ming University , Taipei , Taiwan.,f Department of Medical Research , Taichung Veterans General Hospital , Taichung , Taiwan.,g Department of Anesthesiology , Taichung Veterans General Hospital , Taichung , Taiwan
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Song EA, Lim JW, Kim H. Docosahexaenoic acid inhibits IL-6 expression via PPARγ-mediated expression of catalase in cerulein-stimulated pancreatic acinar cells. Int J Biochem Cell Biol 2017; 88:60-68. [PMID: 28483666 DOI: 10.1016/j.biocel.2017.05.011] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 04/28/2017] [Accepted: 05/04/2017] [Indexed: 02/07/2023]
Abstract
Cerulein pancreatitis mirrors human acute pancreatitis. In pancreatic acinar cells exposed to cerulein, reactive oxygen species (ROS) mediate inflammatory signaling by Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3, and cytokine induction. Docosahexaenoic acid (DHA) acts as an agonist of peroxisome proliferator activated receptor γ (PPARγ), which mediates the expression of some antioxidant enzymes. We hypothesized that DHA may induce PPARγ-target catalase expression and reduce ROS levels, leading to the inhibition of JAK2/STAT3 activation and IL-6 expression in cerulein-stimulated acinar cells. Pancreatic acinar AR42J cells were treated with DHA in the presence or absence of the PPARγ antagonist GW9662, or treated with the PPARγ agonist troglitazone, and then stimulated with cerulein. Expression of IL-6 and catalase, ROS levels, JAK2/STAT3 activation, and nuclear translocation of PPARγ were assessed. DHA suppressed the increase in ROS, JAK2/STAT3 activation, and IL-6 expression induced nuclear translocation of PPARγ and catalase expression in cerulein-stimulated AR42J cells. Troglitazone inhibited the cerulein-induced increase in ROS and IL-6 expression, but induced catalase expression similar to DHA in AR42J cells. GW9662 abolished the inhibitory effect of DHA on cerulein-induced increase in ROS and IL-6 expression in AR42J cells. DHA-induced expression of catalase was suppressed by GW9662 in cerulein-stimulated AR42J cells. Thus, DHA induces PPARγ activation and catalase expression, which inhibits ROS-mediated activation of JAK2/STAT3 and IL-6 expression in cerulein-stimulated pancreatic acinar cells.
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Affiliation(s)
- Eun Ah Song
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
| | - Joo Weon Lim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
| | - Hyeyoung Kim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea.
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41
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Immunopathogenesis of pancreatitis. Mucosal Immunol 2017; 10:283-298. [PMID: 27848953 DOI: 10.1038/mi.2016.101] [Citation(s) in RCA: 141] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 10/06/2016] [Indexed: 02/04/2023]
Abstract
The conventional view of the pathogenesis of acute and chronic pancreatitis is that it is due to a genetic- or environment-based abnormality of intracellular acinar trypsinogen activation and thus to the induction of acinar cell injury that, in turn, sets in motion an intra-pancreatic inflammatory process. More recent studies, reviewed here, present strong evidence that while such trypsinogen activation is likely a necessary first step in the inflammatory cascade underlying pancreatitis, sustained pancreatic inflammation is dependent on damage-associated molecular patterns-mediated cytokine activation causing the translocation of commensal (gut) organisms into the circulation and their induction of innate immune responses in acinar cells. Quite unexpectedly, these recent studies reveal that the innate responses involve activation of responses by an innate factor, nucleotide-binding oligomerization domain 1 (NOD1), and that such NOD1 responses have a critical role in the activation/production of nuclear factor-kappa B and type I interferon. In addition, they reveal that chronic inflammation and its accompanying fibrosis are dependent on the generation of IL-33 by injured acinar cells and its downstream induction of T cells producing IL-13. These recent studies thus establish that pancreatitis is quite a unique form of inflammation and one susceptible to newer, more innovative therapy.
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Fernandez MO, Sharma S, Kim S, Rickert E, Hsueh K, Hwang V, Olefsky JM, Webster NJG. Obese Neuronal PPARγ Knockout Mice Are Leptin Sensitive but Show Impaired Glucose Tolerance and Fertility. Endocrinology 2017; 158:121-133. [PMID: 27841948 PMCID: PMC5412981 DOI: 10.1210/en.2016-1818] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 11/04/2016] [Indexed: 11/19/2022]
Abstract
The peroxisome-proliferator activated receptor γ (PPARγ) is expressed in the hypothalamus in areas involved in energy homeostasis and glucose metabolism. In this study, we created a deletion of PPARγ brain-knockout (BKO) in mature neurons in female mice to investigate its involvement in metabolism and reproduction. We observed that there was no difference in age at puberty onset between female BKOs and littermate controls, but the BKOs gave smaller litters when mated and fewer oocytes when ovulated. The female BKO mice had regular cycles but showed an increase in the number of cycles with prolonged estrus. The mice also had increased luteinizing hormone (LH) levels during the LH surge and histological examination showed hemorrhagic corpora lutea. The mice were challenged with a 60% high-fat diet (HFD). Metabolically, the female BKO mice showed normal body weight, glucose and insulin tolerance, and leptin levels but were protected from obesity-induced leptin resistance. The neuronal knockout also prevented the reduction in estrous cycles due to the HFD. Examination of ovarian histology showed a decrease in the number of primary and secondary follicles in both genotypes due to the HFD, but the BKO ovaries showed an increase in the number of hemorrhagic follicles. In summary, our results show that neuronal PPARγ is required for optimal female fertility but is also involved in the adverse effects of diet-induced obesity by creating leptin resistance potentially through induction of the repressor Socs3.
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Affiliation(s)
| | | | - Sun Kim
- Department of Medicine, School of Medicine, and
| | | | | | - Vicky Hwang
- Department of Medicine, School of Medicine, and
| | | | - Nicholas J G Webster
- Department of Medicine, School of Medicine, and
- Moores Cancer Center, University of California, San Diego, La Jolla, California 92093; and
- Medical Research Service, VA San Diego Healthcare System, San Diego, California 92161
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43
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Guo F, Xu Z, Zhang Y, Jiang P, Huang G, Chen S, Lyu X, Zheng P, Zhao X, Zeng Y, Wang S, He F. FXR induces SOCS3 and suppresses hepatocellular carcinoma. Oncotarget 2016; 6:34606-16. [PMID: 26416445 PMCID: PMC4741476 DOI: 10.18632/oncotarget.5314] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 09/11/2015] [Indexed: 12/20/2022] Open
Abstract
Suppressor of cytokine signaling 3 (SOCS3) is regarded as a vital repressor in the liver carcinogenesis mainly by inhibiting signal transducer and activator of transcription 3 (STAT3) activity. Farnesoid X Receptor (FXR), highly expressed in liver, has an important role in protecting against hepatocellular carcinoma (HCC). However, it is unclear whether the tumor suppressive activity of FXR involves the regulation of SOCS3. In the present study, we found that activation of FXR by its specific agonist GW4064 in HCC cells inhibited cell growth, induced cell cycle arrest at G1 phase, elevated p21 expression and repressed STAT3 activity. The above anti-tumor effects of FXR were dramatically alleviated by knockdown of SOCS3 with siRNA. Reporter assay revealed that FXR activation enhanced the transcriptional activity of SOCS3 promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay displayed that FXR directly bound to IR9 DNA motif within SOCS3 promoter region. The in vivo study in nude mice showed that treatment with FXR ligand GW4064 could decelerate the growth of HCC xenografts, up-regulate SOCS3 and p21 expression and inhibit STAT3 phosphorylation in the xenografts. These results suggest that induction of SOCS3 may be a novel mechanism by which FXR exerts its anti-HCC effects, and the FXR-SOCS3 signaling may serve as a new potential target for the prevention/treatment of HCC.
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Affiliation(s)
- Fei Guo
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Zhizhen Xu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Yan Zhang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Peng Jiang
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Gang Huang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Shan Chen
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Xilin Lyu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Ping Zheng
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Xin Zhao
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Yijun Zeng
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Shuguang Wang
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Fengtian He
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
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Abstract
Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas frequently associated with metabolic causes, contributing factors, or consequences, including hypertriglyceridemia, obesity, and disorders of intermediary metabolism, respectively. To date, there is no specific therapy for this disease. Future optimal therapy should correct both inflammatory and metabolic components of the disease. Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that control inflammatory and metabolic pathways via ligand-dependent and ligand-independent mechanisms. There are 3 known subtypes, PPAR-α, PPAR-β/δ, and PPAR-γ, which are differentially expressed in various tissues. The PPARs interact closely with other transcription factors such as nuclear factor κB and signal tranducers and activators of transcription that have pivotal roles in the pathobiology of AP. In this comprehensive review, we summarize the role of PPARs in AP, highlighting important in vitro and in vivo experimental findings. Finally, we propose future research directions as well as potential translational use of PPAR agonists in the treatment of AP.
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Parathyroid Hormone-Related Protein Interacts With the Transforming Growth Factor-β/Bone Morphogenetic Protein-2/Gremlin Signaling Pathway to Regulate Proinflammatory and Profibrotic Mediators in Pancreatic Acinar and Stellate Cells. Pancreas 2016; 45:659-70. [PMID: 26495794 PMCID: PMC4833530 DOI: 10.1097/mpa.0000000000000522] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Transforming growth factor β (TGF-β) regulates immune and fibrotic responses of chronic pancreatitis. The bone morphogenetic protein 2 (BMP-2) antagonist gremlin is regulated by TGF-β. Parathyroid hormone-related protein (PTHrP) levels are elevated in chronic pancreatitis. Here, we investigated the cross-talk between TGF-β/BMP-2/gremlin and PTHrP signaling. METHODS Reverse transcription/real-time polymerase chain reaction, chromatin immunoprecipitation, Western blotting, and transient transfection were used to investigate PTHrP regulation by TGF-β and BMP-2 and gremlin regulation by PTHrP. The PTHrP antagonist PTHrP (7-34) and acinar cells with conditional Pthrp gene deletion (PTHrP) were used to assess PTHrP's role in the proinflammatory and profibrotic effects of TGF-β and gremlin. RESULTS Transforming growth factor β increased PTHrP levels in acinar cells and pancreatic stellate cells (PSCs) through a Smad3-dependent pathway. Transforming growth factor β's effects on levels of IL-6 and intercellular adhesion molecule 1 (ICAM-1) (acinar cells) and procollagen I and fibronectin (PSCs) were inhibited by PTHrP (7-34). PTHrP suppressed TGF-β's effects on IL-6 and ICAM-1. Parathyroid hormone-related hormone increased gremlin in acinar cells, and inhibiting gremlin action suppressed TGF-β's and PTHrP's effects on IL-6 and ICAM-1. Transforming growth factor β-mediated gremlin up-regulation was suppressed in PTHrP cells. Bone morphogenetic protein 2 suppressed PTHrP levels in PSCs. CONCLUSIONS Parathyroid hormone-related hormone functions as a novel mediator of the proinflammatory and profibrotic effects of TGF-β. Transforming growth factor β and BMP-2 regulate PTHrP expression, and PTHrP regulates gremlin levels.
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Shen J, Jia W, Yu Y, Chen J, Cao X, Du Y, Zhang X, Zhu S, Chen W, Xi J, Wei T, Wang G, Yuan D, Duan T, Jiang C, Kang J. Pwp1 is required for the differentiation potential of mouse embryonic stem cells through regulating Stat3 signaling. Stem Cells 2015; 33:661-73. [PMID: 25335925 DOI: 10.1002/stem.1876] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Revised: 08/19/2014] [Accepted: 09/04/2014] [Indexed: 11/08/2022]
Abstract
Leukemia inhibitory factor/Stat3 signaling is critical for maintaining the self-renewal and differentiation potential of mouse embryonic stem cells (mESCs). However, the upstream effectors of this pathway have not been clearly defined. Here, we show that periodic tryptophan protein 1 (Pwp1), a WD-40 repeat-containing protein associated with histone H4 modification, is required for the exit of mESCs from the pluripotent state into all lineages. Knockdown (KD) of Pwp1 does not affect mESC proliferation, self-renewal, or apoptosis. However, KD of Pwp1 impairs the differentiation potential of mESCs both in vitro and in vivo. PWP1 chromatin immunoprecipitation-seq results revealed that the PWP1-occupied regions were marked with significant levels of H4K20me3. Moreover, Pwp1 binds to sites in the upstream region of Stat3. KD of Pwp1 decreases the level of H4K20me3 in the upstream region of Stat3 gene and upregulates the expression of Stat3. Furthermore, Pwp1 KD mESCs recover their differentiation potential through suppressing the expression of Stat3 or inhibiting the tyrosine phosphorylation of STAT3. Together, our results suggest that Pwp1 plays important roles in the differentiation potential of mESCs.
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Affiliation(s)
- Junwei Shen
- Shanghai Key Laboratory of Signaling and Disease Research, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Science and Technology, Tongji University, Shanghai, People's Republic of China
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Zhou X, Liu Z, Cheng X, Zheng Y, Zeng F, He Y. Socs1 and Socs3 degrades Traf6 via polyubiquitination in LPS-induced acute necrotizing pancreatitis. Cell Death Dis 2015; 6:e2012. [PMID: 26633718 PMCID: PMC4720878 DOI: 10.1038/cddis.2015.342] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Revised: 10/20/2015] [Accepted: 10/22/2015] [Indexed: 01/01/2023]
Abstract
Mechanisms involved in inflammatory development during acute pancreatitis (AP) are largely vague, especially in the transformation of acute edematous pancreatitis (AEP) into acute necrotizing pancreatitis (ANP). This current study aims to investigate the functions of Traf6 in different AP models in vitro and in vivo, and to identify the possible regulatory mechanism in the progression of inflammation from mild to severe. Our data revealed that the level of Traf6 expression was significantly increased in the mild AP induced by caerulein, and the upregulation of Traf6 played a protective role in acinar cells against caerulein-induced apoptosis. In contrast, only Traf6 protein but not mRNA was downregulated in the severe ANP induced by combination treatment of caerulein and LPS. Mechanistic studies showed that LPS upregulated the levels of Socs1 and Socs3 expressions in acinar cells, Socs1 and Socs3 interacted Traf6 directly and degraded Traf6 protein via polyubiquitination, thereby counteracted the protective function of Traf6. In vivo study further showed that combination treatment of caerulein and LPS failed to induce an ANP model in the TLR4 knockout mice, and the level of Traf6 expression in the pancreatic tissues remained the same as that from the acute edematous pancreatitis (AEP) mouse. Taken together, our study reveals that Traf6 functioned as a protective factor in the progression of AP, and LPS-induced Socs1 and Socs3 exacerbate mild AP to severe AP, which provides evidence for developing a new therapeutic target to combat AP.
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Affiliation(s)
- X Zhou
- Department of Vascular and Thyroid, The Affiliated Hospital of Sichuan Medical University, Luzhou, Sichuan Province, P. R. China
| | - Z Liu
- Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - X Cheng
- Department of Gastroenterology, The Affiliated Hospital of Sichuan Medical University, Luzhou, Sichuan Province, P. R. China
| | - Y Zheng
- Department of Vascular and Thyroid, The Affiliated Hospital of Sichuan Medical University, Luzhou, Sichuan Province, P. R. China
| | - F Zeng
- Department of Biochemistry and Molecular Biology, Sichuan Medical University, Luzhou, Sichuan Province, P. R. China
| | - Y He
- Department of Vascular and Thyroid, The Affiliated Hospital of Sichuan Medical University, Luzhou, Sichuan Province, P. R. China
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48
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Hu S, Zhang Y, Zhang M, Guo Y, Yang P, Zhang S, Simsekyilmaz S, Xu JF, Li J, Xiang X, Yu Q, Wang CY. Aloperine Protects Mice against Ischemia-Reperfusion (IR)-Induced Renal Injury by Regulating PI3K/AKT/mTOR Signaling and AP-1 Activity. Mol Med 2015; 21:912-923. [PMID: 26552059 DOI: 10.2119/molmed.2015.00056] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 10/27/2015] [Indexed: 01/03/2023] Open
Abstract
Aloperine is a quinolizidine alkaloid extracted from the leaves of Sophora plants. It has been recognized with the potential to treat inflammatory and allergic diseases as well as tumors. In this report, we demonstrate that pretreatment with aloperine provided protection for mice against ischemia-reperfusion (IR)-induced acute renal injury as manifested by the attenuated inflammatory infiltration, reduced tubular apoptosis, and well-preserved renal function. Mechanistic studies revealed that aloperine selectively repressed IL-1β and IFN-γ expression by regulating PI3K/Akt/mTOR signaling and NF-κB transcriptional activity. However, aloperine did not show a perceptible impact on IL-6 and TGF-β expression and the related Jak2/Stat3 signaling. It was also noted that aloperine regulates AP-1 activity, through which it not only enhances SOD expression to increase reactive oxygen species (ROS) detoxification but also promotes the expression of antiapoptotic Bcl-2, thereby preventing tubular cells from IR-induced apoptosis. Collectively, our data suggest that administration of aloperine prior to IR insults, such as renal transplantation, could be a viable approach to prevent IR-induced injuries.
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Affiliation(s)
- Shuang Hu
- The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuxing Zhang
- The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meng Zhang
- The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanchao Guo
- The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ping Yang
- The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shu Zhang
- The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sakine Simsekyilmaz
- The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun-Fa Xu
- Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical College, Dongguan, China
| | - Jinxiu Li
- Department of Emergency Medicine, Institute of Emergency Medicine and Rare Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Xudong Xiang
- Department of Emergency Medicine, Institute of Emergency Medicine and Rare Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Qilin Yu
- The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cong-Yi Wang
- The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical College, Dongguan, China.,Department of Emergency Medicine, Institute of Emergency Medicine and Rare Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
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Mateu A, De Dios I, Manso MA, Ramudo L. Unsaturated but not saturated fatty acids induce transcriptional regulation of CCL2 in pancreatic acini. A potential role in acute pancreatitis. Biochim Biophys Acta Mol Basis Dis 2015; 1852:2671-7. [PMID: 26415685 DOI: 10.1016/j.bbadis.2015.09.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 09/14/2015] [Accepted: 09/21/2015] [Indexed: 01/27/2023]
Affiliation(s)
- A Mateu
- Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain
| | - I De Dios
- Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain
| | - M A Manso
- Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain
| | - L Ramudo
- Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain.
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Tyrosine 705 Phosphorylation of STAT3 Is Associated with Phenotype Severity in TGFβ1 Transgenic Mice. BIOMED RESEARCH INTERNATIONAL 2015; 2015:843743. [PMID: 26380299 PMCID: PMC4561300 DOI: 10.1155/2015/843743] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Accepted: 03/30/2015] [Indexed: 01/15/2023]
Abstract
Transforming growth factor beta 1 (TGFβ1) is a key player in skeletal muscle degenerative and regenerative processes. We previously showed that conditionally overexpressing TGFβ1 in skeletal muscles caused myofiber atrophy and endomysial fibrosis in mice. However, the disease severity varied significantly among individual mice. While 40% of mice developed severe muscle pathology and lost body weight within 2 weeks of TGFβ1 transgene induction in muscles, the rest showed milder or no phenotype. This study aims at determining whether signal transducer and activator of transcription 3 (STAT3) plays a role in the phenotypic difference and whether it can be activated by TGFβ1 directly in muscle cells. Our results show that while total STAT3 was not differentially expressed between the two groups of mice, there was significantly higher pSTAT3 (Tyr705) in the muscles of the mice with severe phenotype. Immunohistochemistry showed that pSTAT3 (Tyr705) was localized in approximately 50% of the nuclei of the muscles. We further showed that TGFβ1 induced Tyr705 phosphorylation of STAT3 in C2C12 cells within 30 minutes of treatment while total STAT3 was not affected. Our findings suggest that TGFβ1 alone can induce Tyr705 phosphorylation of STAT3 in skeletal muscle cells and contribute to disease severity in transgenic TGFβ1 mice.
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