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Vu HT, Nguyen VD, Ikenaga H, Matsubara T. Application of PPAR Ligands and Nanoparticle Technology in Metabolic Steatohepatitis Treatment. Biomedicines 2024; 12:1876. [PMID: 39200340 PMCID: PMC11351628 DOI: 10.3390/biomedicines12081876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/10/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH) is a major disease worldwide whose effective treatment is challenging. Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and function as ligand-activated transcription factors. To date, three distinct subtypes of PPARs have been characterized: PPARα, PPARβ/δ, and PPARγ. PPARα and PPARγ are crucial regulators of lipid metabolism that modulate the transcription of genes involved in fatty acid (FA), bile acid, and cholesterol metabolism. Many PPAR agonists, including natural (FAs, eicosanoids, and phospholipids) and synthetic (fibrate, thiazolidinedione, glitazar, and elafibranor) agonists, have been developed. Furthermore, recent advancements in nanoparticles (NPs) have led to the development of new strategies for MASLD/MASH therapy. This review discusses the applications of specific cell-targeted NPs and highlights the potential of PPARα- and PPARγ-targeted NP drug delivery systems for MASLD/MASH treatment.
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Affiliation(s)
- Hung Thai Vu
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan; (H.T.V.); (V.D.N.)
| | - Vien Duc Nguyen
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan; (H.T.V.); (V.D.N.)
| | - Hiroko Ikenaga
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan; (H.T.V.); (V.D.N.)
- Research Institute for Light-induced Acceleration System (RILACS), Osaka Metropolitan University, Sakai 599-8570, Osaka, Japan
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Hassani B, Attar Z, Firouzabadi N. The renin-angiotensin-aldosterone system (RAAS) signaling pathways and cancer: foes versus allies. Cancer Cell Int 2023; 23:254. [PMID: 37891636 PMCID: PMC10604988 DOI: 10.1186/s12935-023-03080-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 09/20/2023] [Indexed: 10/29/2023] Open
Abstract
The renin-angiotensin-aldosterone system (RAAS), is an old system with new fundamental roles in cancer biology which influences cell growth, migration, death, and metastasis. RAAS signaling enhances cell proliferation in malignancy directly and indirectly by affecting tumor cells and modulating angiogenesis. Cancer development may be influenced by the balance between the ACE/Ang II/AT1R and the ACE2/Ang 1-7/Mas receptor pathways. The interactions between Ang II/AT1R and Ang I/AT2R as well as Ang1-7/Mas and alamandine/MrgD receptors in the RAAS pathway can significantly impact the development of cancer. Ang I/AT2R, Ang1-7/Mas, and alamandine/MrgD interactions can have anticancer effects while Ang II/AT1R interactions can be involved in the development of cancer. Evidence suggests that inhibitors of the RAAS, which are conventionally used to treat cardiovascular diseases, may be beneficial in cancer therapies.Herein, we aim to provide a thorough description of the elements of RAAS and their molecular play in cancer. Alongside this, the role of RAAS components in sex-dependent cancers as well as GI cancers will be discussed with the hope of enlightening new venues for adjuvant cancer treatment.
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Affiliation(s)
- Bahareh Hassani
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zeinab Attar
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Negar Firouzabadi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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Chen H, Tan H, Wan J, Zeng Y, Wang J, Wang H, Lu X. PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets. Pharmacol Ther 2023; 245:108391. [PMID: 36963510 DOI: 10.1016/j.pharmthera.2023.108391] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/20/2023] [Accepted: 03/20/2023] [Indexed: 03/26/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD), currently the leading cause of global chronic liver disease, has emerged as a major public health problem, more efficient therapeutics of which are thus urgently needed. Peroxisome proliferator-activated receptor γ (PPAR-γ), ligand-activated transcription factors of the nuclear hormone receptor superfamily, is considered a crucial metabolic regulator of hepatic lipid metabolism and inflammation. The role of PPAR-γ in the pathogenesis of NAFLD is gradually being recognized. Here, we outline the involvement of PPAR-γ in the pathogenesis of NAFLD through adipogenesis, insulin resistance, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In addition, the evidence for PPAR-γ- targeted therapy for NAFLD are summarized. Altogether, PPAR-γ is a promising therapeutic target for NAFLD, and the development of drugs that can balance the beneficial and undesirable effects of PPAR-γ will bring new light to NAFLD patients.
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Affiliation(s)
- Hao Chen
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Huabing Tan
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Juan Wan
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine / West China School of Nursing, Sichuan University, Chengdu, China
| | - Yong Zeng
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jincheng Wang
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haichuan Wang
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
| | - Xiaojie Lu
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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Devan AR, Nair B, Kumar AR, Nath LR. An insight into the role of telmisartan as PPAR-γ/α dual activator in the management of nonalcoholic fatty liver disease. Biotechnol Appl Biochem 2022; 69:461-468. [PMID: 33578449 DOI: 10.1002/bab.2123] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 02/07/2021] [Indexed: 02/05/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease. It is rapidly emerging as the frequent cause for liver transplantation with the risk of disease recurrence, even after transplantation. Clinical evidence showed an abnormally altered expression of different peroxisome proliferator-activated receptor (PPAR) isotypes (PPAR-α/γ/δ) in NAFLD with an involvement in the induction of insulin resistance, hepatic steatosis, reactive oxygen species (ROS) formation, and hepatic inflammation. Recently, several dual PPAR-γ/α agonists were developed to simultaneously achieve the insulin-sensitizing effect of PPAR-γ as well as lipid catabolizing effect of PPAR-α. PPAR-α activation could counterbalance the steatogenic and adipogenic effects of PPAR-γ. But most of the drugs were ended in the initial level itself due to harmful adverse effects. In the present review, we discuss the possible mechanism of telmisartan, a typical angiotensin receptor blocker with excellent safety and pharmacokinetic profile, as a PPAR-γ/α dual agonist in the treatment of NAFLD.
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Affiliation(s)
- Aswathy R Devan
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, India
| | - Bhagyalakshmi Nair
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, India
| | - Ayana R Kumar
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, India
| | - Lekshmi R Nath
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, India
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Pryymachuk G, El-Awaad E, Piekarek N, Drebber U, Maul AC, Hescheler J, Wodarz A, Pfitzer G, Neiss WF, Pietsch M, Schroeter MM. Angiotensin II type 1 receptor localizes at the blood-bile barrier in humans and pigs. Histochem Cell Biol 2022; 157:513-524. [PMID: 35229169 PMCID: PMC9114028 DOI: 10.1007/s00418-022-02087-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/07/2022] [Indexed: 12/24/2022]
Abstract
Animal models and clinical studies suggest an influence of angiotensin II (AngII) on the pathogenesis of liver diseases via the renin–angiotensin system. AngII application increases portal blood pressure, reduces bile flow, and increases permeability of liver tight junctions. Establishing the subcellular localization of angiotensin II receptor type 1 (AT1R), the main AngII receptor, helps to understand the effects of AngII on the liver. We localized AT1R in situ in human and porcine liver and porcine gallbladder by immunohistochemistry. In order to do so, we characterized commercial anti-AT1R antibodies regarding their capability to recognize heterologous human AT1R in immunocytochemistry and on western blots, and to detect AT1R using overlap studies and AT1R-specific blocking peptides. In hepatocytes and canals of Hering, AT1R displayed a tram-track-like distribution, while in cholangiocytes AT1R appeared in a honeycomb-like pattern; i.e., in liver epithelia, AT1R showed an equivalent distribution to that in the apical junctional network, which seals bile canaliculi and bile ducts along the blood–bile barrier. In intrahepatic blood vessels, AT1R was most prominent in the tunica media. We confirmed AT1R localization in situ to the plasma membrane domain, particularly between tight and adherens junctions in both human and porcine hepatocytes, cholangiocytes, and gallbladder epithelial cells using different anti-AT1R antibodies. Localization of AT1R at the junctional complex could explain previously reported AngII effects and predestines AT1R as a transmitter of tight junction permeability.
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Affiliation(s)
- Galyna Pryymachuk
- Department of Anatomy I, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
| | - Ehab El-Awaad
- Institute II of Pharmacology, Center of Pharmacology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Gleueler Str. 24, 50931, Cologne, Germany
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Nadin Piekarek
- Department of Anatomy I, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany
| | - Uta Drebber
- Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany
| | - Alexandra C Maul
- Experimental Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Ostmerheimer Str. 200, 51109, Cologne, Germany
| | - Juergen Hescheler
- Institute for Neurophysiology, Center for Physiology and Pathophysiology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Robert-Koch-Str. 39, 50931, Cologne, Germany
| | - Andreas Wodarz
- Department of Anatomy I, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany
- Cologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Str. 21, 50931, Cologne, Germany
| | - Gabriele Pfitzer
- Institute of Vegetative Physiology, Center for Physiology and Pathophysiology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Robert-Koch-Str. 39, 50931, Cologne, Germany
| | - Wolfram F Neiss
- Department of Anatomy I, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany
| | - Markus Pietsch
- Institute II of Pharmacology, Center of Pharmacology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Gleueler Str. 24, 50931, Cologne, Germany
| | - Mechthild M Schroeter
- Institute for Neurophysiology, Center for Physiology and Pathophysiology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Robert-Koch-Str. 39, 50931, Cologne, Germany
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Ommati MM, Mohammadi H, Mousavi K, Azarpira N, Farshad O, Dehghani R, Najibi A, Kamran S, Niknahad H, Heidari R. Metformin alleviates cholestasis-associated nephropathy through regulating oxidative stress and mitochondrial function. LIVER RESEARCH 2021; 5:171-180. [PMID: 39957842 PMCID: PMC11791814 DOI: 10.1016/j.livres.2020.12.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 10/01/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022]
Abstract
Background and aim Cholestasis-associated renal injury or cholemic nephropathy (CN) is a serious clinical problem. Previous studies mentioned that oxidative stress and mitochondrial impairment play a role in CN. There is no specific pharmacological intervention for CN. Metformin is an anti-diabetic drug administered for decades. On the other hand, novel pharmacological properties have emerged for this drug. The effect of metformin on oxidative stress parameters has been well-recognized in different experimental models. It has also been found that metformin positively affected mitochondrial function. The current study aimed to evaluate the effects of metformin in an animal model of CN. Methods Rats underwent bile duct ligation (BDL) and were treated with metformin (250 and 500 mg/kg) for 14 consecutive days. Two weeks after the BDL operations, urine, serum, and kidney samples were collected and analyzed. Results Markers of oxidative stress, including reactive oxygen species (ROS) formation, lipid peroxidation, protein carbonylation, depleted antioxidant capacity, and decreased glutathione (GSH) levels were detected in BDL animals. Moreover, mitochondrial indices, including adenosine triphosphate (ATP) level, dehydrogenase activity, mitochondrial membrane potential, and mitochondrial permeability, were impaired in the kidney of cholestatic rats. Renal histopathological alterations in cholestatic animals included tubular degeneration and interstitial inflammation, cast formation, and fibrosis. It was found that metformin significantly alleviated oxidative stress and improved mitochondrial indices in the kidney of cholestatic rats. Tissue histopathological alterations were also mitigated in metformin-treated groups. Conclusions Metformin could be a candidate for managing CN. The nephroprotective role of metformin is primarily associated with its effects on oxidative stress parameters and mitochondrial function.
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Affiliation(s)
| | - Hamidreza Mohammadi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Khadijeh Mousavi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omid Farshad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reyhaneh Dehghani
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Asma Najibi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Chemistry, Payame Noor University, Tehran, Iran
| | - Sedigheh Kamran
- Department of Chemistry, Payame Noor University, Tehran, Iran
| | - Hossein Niknahad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Dong XH, Dai D, Yang ZD, Yu XO, Li H, Kang H. S100 calcium binding protein A6 and associated long noncoding ribonucleic acids as biomarkers in the diagnosis and staging of primary biliary cholangitis. World J Gastroenterol 2021; 27:1973-1992. [PMID: 34007134 PMCID: PMC8108032 DOI: 10.3748/wjg.v27.i17.1973] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/23/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a chronic and slowly progressing cholestatic disease, which causes damage to the small intrahepatic bile duct by immuno-regulation, and may lead to cholestasis, liver fibrosis, cirrhosis and, eventually, liver failure.
AIM To explore the potential diagnosis and staging value of plasma S100 calcium binding protein A6 (S100A6) messenger ribonucleic acid (mRNA), LINC00312, LINC00472, and LINC01257 in primary biliary cholangitis.
METHODS A total of 145 PBC patients and 110 healthy controls (HCs) were enrolled. Among them, 80 PBC patients and 60 HCs were used as the training set, and 65 PBC patients and 50 HCs were used as the validation set. The relative expression levels of plasma S100A6 mRNA, long noncoding ribonucleic acids LINC00312, LINC00472 and LINC01257 were analyzed using quantitative reverse transcription-polymerase chain reaction. The bile duct ligation (BDL) mouse model was used to simulate PBC. Then double immunofluorescence was conducted to verify the overexpression of S100A6 protein in intrahepatic bile duct cells of BDL mice. Human intrahepatic biliary epithelial cells were treated with glycochenodeoxycholate to simulate the cholestatic environment of intrahepatic biliary epithelial cells in PBC.
RESULTS The expression of S100A6 protein in intrahepatic bile duct cells was up-regulated in the BDL mouse model compared with sham mice. The relative expression levels of plasma S100A6 mRNA, log10 LINC00472 and LINC01257 were up-regulated while LINC00312 was down-regulated in plasma of PBC patients compared with HCs (3.01 ± 1.04 vs 2.09 ± 0.87, P < 0.0001; 2.46 ± 1.03 vs 1.77 ± 0.84, P < 0.0001; 3.49 ± 1.64 vs 2.37 ± 0.96, P < 0.0001; 1.70 ± 0.33 vs 2.07 ± 0.53, P < 0.0001, respectively). The relative expression levels of S100A6 mRNA, LINC00472 and LINC01257 were up-regulated and LINC00312 was down-regulated in human intrahepatic biliary epithelial cells treated with glycochenodeoxycholate compared with control (2.97 ± 0.43 vs 1.09 ± 0.08, P = 0.0018; 2.70 ± 0.26 vs 1.10 ± 0.10, P = 0.0006; 2.23 ± 0.21 vs 1.10 ± 0.10, P = 0.0011; 1.20 ± 0.04 vs 3.03 ± 0.15, P < 0.0001, respectively). The mean expression of S100A6 in the advanced stage (III and IV) of PBC was up-regulated compared to that in HCs and the early stage (II) (3.38 ± 0.71 vs 2.09 ± 0.87, P < 0.0001; 3.38 ± 0.71 vs 2.57 ± 1.21, P = 0.0003, respectively); and in the early stage (II), it was higher than that in HCs (2.57 ± 1.21 vs 2.09 ± 0.87, P = 0.03). The mean expression of LINC00312 in the advanced stage was lower than that in the early stage and HCs (1.39 ± 0.29 vs 1.56 ± 0.33, P = 0.01; 1.39 ± 0.29 vs 2.07 ± 0.53, P < 0.0001, respectively); in addition, the mean expression of LINC00312 in the early stage was lower than that in HCs (1.56 ± 0.33 vs 2.07 ± 0.53, P < 0.0001). The mean expression of log10 LINC00472 in the advanced stage was higher than those in the early stage and HCs (2.99 ± 0.87 vs 1.81 ± 0.83, P < 0.0001; 2.99 ± 0.87 vs 1.77 ± 0.84, P < 0.0001, respectively). The mean expression of LINC01257 in both the early stage and advanced stage were up-regulated compared with HCs (3.88 ± 1.55 vs 2.37 ± 0.96, P < 0.0001; 3.57 ± 1.79 vs 2.37 ± 0.96, P < 0.0001, respectively). The areas under the curves (AUC) for S100A6, LINC00312, log10 LINC00472 and LINC01257 in PBC diagnosis were 0.759, 0.7292, 0.6942 and 0.7158, respectively. Furthermore, the AUC for these four genes in PBC staging were 0.666, 0.661, 0.839 and 0.5549, respectively. The expression levels of S100A6 mRNA, log10 LINC00472, and LINC01257 in plasma of PBC patients were decreased (2.35 ± 1.02 vs 3.06 ± 1.04, P = 0.0018; 1.99 ± 0.83 vs 2.33 ± 0.96, P = 0.036; 2.84 ± 0.92 vs 3.69 ± 1.54, P = 0.0006), and the expression level of LINC00312 was increased (1.95 ± 0.35 vs 1.73 ± 0.32, P = 0.0007) after treatment compared with before treatment using the paired t-test. Relative expression of S100A6 mRNA was positively correlated with log10 LINC00472 (r = 0.683, P < 0.0001); serum level of collagen type IV was positively correlated with the relative expression of log10 LINC00472 (r = 0.482, P < 0.0001); relative expression of S100A6 mRNA was positively correlated with the serum level of collagen type IV (r = 0.732, P < 0.0001). The AUC for the four biomarkers obtained in the validation set were close to the training set.
CONCLUSION These four genes may potentially act as novel biomarkers for the diagnosis of PBC. Moreover, LINC00472 acts as a potential biomarker for staging in PBC.
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Affiliation(s)
- Xi-Hua Dong
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Di Dai
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Zhi-Dong Yang
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xiao-Ou Yu
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Hua Li
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Hui Kang
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Ommati MM, Farshad O, Azarpira N, Ghazanfari E, Niknahad H, Heidari R. Silymarin mitigates bile duct obstruction-induced cholemic nephropathy. Naunyn Schmiedebergs Arch Pharmacol 2021; 394:1301-1314. [PMID: 33538845 DOI: 10.1007/s00210-020-02040-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 12/09/2020] [Indexed: 12/14/2022]
Abstract
Bile duct obstruction or cholestasis can occur by several diseases or xenobiotics. Cholestasis and the accumulation of the bile constituents in the liver primarily damage this organ. On the other hand, extrahepatic organs are also affected by cholestasis. The kidney is the most affected tissue during cholestatic liver injury. Cholestasis-associated renal injury is known as cholemic nephropathy (CN). Several lines of evidence specify the involvement of oxidative stress and mitochondrial impairment in the pathogenesis of CN. The current study aimed to assess the role of silymarin as a potent antioxidant on CN-induced oxidative stress and mitochondrial dysfunction in the kidney. Bile duct ligated (BDL) rats were treated with silymarin (10 and 100 mg/kg, oral) for seven consecutive days. A significant increase in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and oxidized glutathione (GSSG) levels were evident in the kidney of BDL animals. Moreover, reduced glutathione (GSH) content and total antioxidant capacity were significantly decreased in the kidney of cholestatic rats. Mitochondrial depolarization, decreased mitochondrial dehydrogenases activity, mitochondrial permeabilization, and depleted ATP stores were detected in the kidney mitochondria isolated from BDL animals. Kidney histopathological alterations, as well as serum and urine levels of renal injury biomarkers, were also significantly different in the BDL group. It was found that silymarin treatment significantly ameliorated CN-induced renal injury. The antioxidant effects of silymarin and its positive impact on mitochondrial indices seem to play a significant role in its renoprotective effects during cholestasis.
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Affiliation(s)
- Mohammad Mehdi Ommati
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Omid Farshad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St., Shiraz, Fars, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elmira Ghazanfari
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St., Shiraz, Fars, Iran
| | - Hossein Niknahad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. .,Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St., Shiraz, Fars, Iran.
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Fougerat A, Montagner A, Loiseau N, Guillou H, Wahli W. Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease. Cells 2020; 9:E1638. [PMID: 32650421 PMCID: PMC7408116 DOI: 10.3390/cells9071638] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/26/2020] [Accepted: 07/04/2020] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. Thus, they represent relevant clinical targets for NAFLD. In this review, we describe the determinants and mechanisms underlying the pathogenesis of NAFLD, its progression and complications, as well as the current therapeutic strategies that are employed. We also focus on the complementary and distinct roles of PPAR isotypes in many biological processes and on the effects of first-generation PPAR agonists. Finally, we review novel and safe PPAR agonists with improved efficacy and their potential use in the treatment of NAFLD.
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Affiliation(s)
- Anne Fougerat
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Alexandra Montagner
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
- Institut National de la Santé et de la Recherche Médicale (Inserm), Institute of Metabolic and Cardiovascular Diseases, UMR1048 Toulouse, France
- Institute of Metabolic and Cardiovascular Diseases, University of Toulouse, UMR1048 Toulouse, France
| | - Nicolas Loiseau
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Hervé Guillou
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Walter Wahli
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road, Singapore 308232, Singapore
- Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland
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10
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The Role of High Fat Diets and Liver Peptidase Activity in the Development of Obesity and Insulin Resistance in Wistar Rats. Nutrients 2020; 12:nu12030636. [PMID: 32121057 PMCID: PMC7146256 DOI: 10.3390/nu12030636] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 02/23/2020] [Accepted: 02/25/2020] [Indexed: 12/13/2022] Open
Abstract
High-fat diets (HFD) have been widely associated with an increased risk of metabolic disorders and overweight. However, a high intake of sources that are rich in monounsaturated fatty acids has been suggested as a dietary agent that is able to positively influence energy metabolism and vascular function. The main objective of this study was to analyze the role of dietary fats on hepatic peptidases activities and metabolic disorders. Three diets: standard (S), HFD supplemented with virgin olive oil (VOO), and HFD supplemented with butter plus cholesterol (Bch), were administered over six months to male Wistar rats. Plasma and liver samples were collected for clinical biochemistry and aminopeptidase activities (AP) analysis. The expression of inducible nitric oxide synthase (iNOS) was also determined by Western blot in liver samples. The diet supplement with VOO did not induce obesity, in contrast to the Bch group. Though the VOO diet increased the time that was needed to return to the basal levels of plasma glucose, the fasting insulin/glucose ratio and HOMA2-%B index (a homeostasis model index of insulin secretion and valuation of β-cell usefulness (% β-cell secretion)) were improved. An increase of hepatic membrane-bound dipeptidyl-peptidase 4 (DPP4) activity was found only in VOO rats, even if no differences in fasting plasma glucagon-like peptide 1 (GLP-1) were obtained. Both HFDs induced changes in hepatic pyroglutamyl-AP in the soluble fraction, but only the Bch diet increased the soluble tyrosyl-AP. Angiotensinase activities that are implicated in the metabolism of angiotensin II (AngII) to AngIV increased in the VOO diet, which was in agreement with the higher activity of insulin-regulated-AP (IRAP) in this group. Otherwise, the diet that was enriched with butter increased soluble gamma-glutamyl transferase (GGT) and Leucyl-AP, iNOS expression in the liver, and plasma NO. In summary, VOO increased the hepatic activity of AP that were related to glucose metabolism (DPP4, angiotensinases, and IRAP). However, the Bch diet increased activities that are implicated in the control of food intake (Tyrosine-AP), the index of hepatic damage (Leucine-AP and GGT), and the expression of hepatic iNOS and plasma NO. Taken together, these results support that the source of fat in the diet affects several peptidases activities in the liver, which could be related to alterations in feeding behavior and glucose metabolism.
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11
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Blockade of the renin-angiotensin system suppresses hydroxyl radical production in the rat striatum during carbon monoxide poisoning. Sci Rep 2020; 10:2602. [PMID: 32054947 PMCID: PMC7018774 DOI: 10.1038/s41598-020-59377-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 01/28/2020] [Indexed: 02/01/2023] Open
Abstract
Oxidative stress has been suggested to play a role in brain damage during carbon monoxide (CO) poisoning. Severe poisoning induced by CO at 3000 ppm, but not 1000 ppm, enhances hydroxyl radical (˙OH) production in the rat striatum, which might be mediated by NADPH oxidase (NOX) activation associated with Ras-related C3 botulinum toxin substrate (Rac) via cAMP signaling pathway activation. CO-induced ˙OH production was suppressed by antagonists of angiotensin II (AngII) type 1 receptor (AT1R) and type 2 receptor (AT2R) but not an antagonist of the Mas receptor. Suppression by an AT1R antagonist was unrelated to peroxisome proliferator-activated receptor γ. Angiotensin-converting enzyme inhibitors also suppressed CO-induced ˙OH production. Intrastriatal AngII at high concentrations enhanced ˙OH production. However, the enhancement of ˙OH production was resistant to inhibitors selective for NOX and Rac and to AT1R and AT2R antagonists. This indicates a different mechanism for ˙OH production induced by AngII than for that induced by CO poisoning. AT1R and AT2R antagonists had no significant effects on CO-induced cAMP production or ˙OH production induced by forskolin, which stimulates cAMP production. These findings suggest that the renin-angiotensin system might be involved in CO-induced ˙OH production in a manner independent of cAMP signaling pathways.
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12
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Abstract
Liver fibrosis (LF) is known as a result of the progressive accumulation of extracellular matrix (ECM), and always ascribed to chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, portal hypertension, and even multi-organ dysfunction and will bring up a health care burden worldwide. Cyclic AMP response-element binding protein (CREB), as a critical transcriptional factor, binds with conserved cAMP response-element (CRE), which is located in the promoter of targeted genes, to regulate the transcription. In the past decades, numerous studies have contributed to improved understanding of the links between CREB and liver fibrosis. In this review, we will summarize molecular mechanisms of CREB pathways and discuss contributions of CREB to liver fibrosis, focusing on activation and proliferation of hepatic stellate cells (HSCs), proliferation of cholangiocytes, deposition of extracellular matrix (ECM) and inflammation, for the development of antifibrotic therapies.
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Affiliation(s)
- Guixin Li
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qianqian Jiang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Keshu Xu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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13
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Hepatotoxicity effect of short-term Bradykinin potentiating factor in cholestatic rats. Toxicol Lett 2019; 301:73-78. [DOI: 10.1016/j.toxlet.2018.11.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 10/16/2018] [Accepted: 11/14/2018] [Indexed: 02/06/2023]
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14
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Ehrlich L, Scrushy M, Meng F, Lairmore TC, Alpini G, Glaser S. Biliary epithelium: A neuroendocrine compartment in cholestatic liver disease. Clin Res Hepatol Gastroenterol 2018; 42:296-305. [PMID: 29678444 PMCID: PMC6129425 DOI: 10.1016/j.clinre.2018.03.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 03/04/2018] [Accepted: 03/13/2018] [Indexed: 02/07/2023]
Abstract
Hepatic fibrosis is characterized by abnormal accumulation of extracellular matrix (ECM) that can lead to ductopenia, cirrhosis, and even malignant transformation. In this review, we examine cholestatic liver diseases characterized by extensive biliary fibrosis such as primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), polycystic liver disease (PLD), and MDR2-/- and BDL mouse models. Following biliary injury, cholangiocytes, the epithelial cells that line the bile ducts, become reactive and adopt a neuroendocrine phenotype in which they secrete and respond to neurohormones and neuropeptides in an autocrine and paracrine fashion. Emerging evidence indicates that cholangiocytes influence and respond to changes in the ECM and stromal cells in the microenvironment. For example, activated myofibroblasts and hepatic stellate cells are major drivers of collagen deposition and biliary fibrosis. Additionally, the liver is richly innervated with adrenergic, cholinergic, and peptidergic fibers that release neurohormones and peptides to maintain homeostasis and can be deranged in disease states. This review summarizes how cholangiocytes interact with their surrounding environment, with particular focus on how autonomic and sensory regulation affects fibrotic pathophysiology.
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Affiliation(s)
- Laurent Ehrlich
- Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, TX 76504, United States
| | - Marinda Scrushy
- Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, TX 76504, United States
| | - Fanyin Meng
- Research, Central Texas Veterans Health Care System, College of Medicine, Temple, TX 76504, United States; Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White, Baylor Scott & White Health, Temple, TX 76504, United States
| | - Terry C Lairmore
- Department of Surgery, Baylor Scott & White Health and Texas A&M University, College of Medicine, Temple, TX 76504, United States
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, College of Medicine, Temple, TX 76504, United States; Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White, Baylor Scott & White Health, Temple, TX 76504, United States; Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, TX 76504, United States
| | - Shannon Glaser
- Research, Central Texas Veterans Health Care System, College of Medicine, Temple, TX 76504, United States; Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White, Baylor Scott & White Health, Temple, TX 76504, United States; Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, TX 76504, United States.
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15
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Sato K, Meng F, Giang T, Glaser S, Alpini G. Mechanisms of cholangiocyte responses to injury. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1262-1269. [PMID: 28648950 PMCID: PMC5742086 DOI: 10.1016/j.bbadis.2017.06.017] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 06/06/2017] [Accepted: 06/19/2017] [Indexed: 12/12/2022]
Abstract
Cholangiocytes, epithelial cells that line the biliary epithelium, are the primary target cells for cholangiopathies including primary sclerosing cholangitis and primary biliary cholangitis. Quiescent cholangiocytes respond to biliary damage and acquire an activated neuroendocrine phenotype to maintain the homeostasis of the liver. The typical response of cholangiocytes is proliferation leading to bile duct hyperplasia, which is a characteristic of cholestatic liver diseases. Current studies have identified various signaling pathways that are associated with cholangiocyte proliferation/loss and liver fibrosis in cholangiopathies using human samples and rodent models. Although recent studies have demonstrated that extracellular vesicles and microRNAs could be mediators that regulate these messenger/receptor axes, further studies are required to confirm their roles. This review summarizes current studies of biliary response and cholangiocyte proliferation during cholestatic liver injury with particular emphasis on the secretin/secretin receptor axis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Affiliation(s)
- Keisaku Sato
- Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
| | - Fanyin Meng
- Research, Central Texas Veterans Health Care System, Temple, TX, United States; Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, United States; Academic Research Integration, Baylor Scott & White Health, Temple, TX, United States; Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
| | - Thao Giang
- Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
| | - Shannon Glaser
- Research, Central Texas Veterans Health Care System, Temple, TX, United States; Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, United States; Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Temple, TX, United States; Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, United States; Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, United States.
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16
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Pantho AF, Price M, Ashraf AZ, Wajid U, Khansari ME, Jahan A, Afroze SH, Rhaman MM, Johnson CR, Kuehl TJ, Hossain MA, Uddin MN. Synthetic Receptors Induce Anti Angiogenic and Stress Signaling on Human First Trimester Cytotrophoblast Cells. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2017; 14:E517. [PMID: 28492503 PMCID: PMC5451968 DOI: 10.3390/ijerph14050517] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 04/28/2017] [Accepted: 04/28/2017] [Indexed: 01/08/2023]
Abstract
The cytotrophoblast (CTB) cells of the human placenta have membrane receptors that bind certain cardiotonic steroids (CTS) found in blood plasma. One of these, marinobufagenin, is a key factor in the etiology of preeclampsia. Herein, we used synthetic receptors (SR) to study their effectiveness on the angiogenic profile of human first trimester CTB cells. The humanextravillous CTB cells (Sw.71) used in this study were derived from first trimester chorionic villus tissue. Culture media of CTB cells treated with ≥1 nM SR level revealed sFlt-1 (Soluble fms-like tyrosine kinase-1) was significantly increased while VEGF (vascular endothelial growth factor) was significantly decreased in the culture media (* p < 0.05 for each) The AT₂ receptor (Angiotensin II receptor type 2) expression was significantly upregulated in ≥1 nM SR-treated CTB cells as compared to basal; however, the AT₁ (Angiotensin II receptor, type 1) and VEGFR-1 (vascular endothelial growth factor receptor 1) receptor expression was significantly downregulated (* p < 0.05 for each). Our results show that the anti-proliferative and anti-angiogenic effects of SR on CTB cells are similar to the effects of CTS. The observed anti angiogenic activity of SR on CTB cells demonstrates that the functionalized-urea/thiourea molecules may be useful as potent inhibitors to prevent CTS-induced impairment of CTB cells.
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Affiliation(s)
- Ahmed F Pantho
- Department of Biochemistry, University of Texas at Austin, Austin, TX 78712, USA.
| | - Mason Price
- Department of Biology, Angelo State University, San Angelo, TX 76904, USA.
| | - Ahm Zuberi Ashraf
- Department of Obstetrics & Gynecology, Baylor Scott & White Health, Temple/Texas A&M Health Science Center College of Medicine, Temple, TX 76508, USA.
| | - Umaima Wajid
- Department of Obstetrics & Gynecology, Baylor Scott & White Health, Temple/Texas A&M Health Science Center College of Medicine, Temple, TX 76508, USA.
| | - Maryam Emami Khansari
- Department of Chemistry & Biochemistry, Jackson State University, Jackson, MS 39217, USA.
| | - Afsana Jahan
- Department of Chemistry & Biochemistry, Jackson State University, Jackson, MS 39217, USA.
| | - Syeda H Afroze
- Medical Physiology, Texas A&M Health Science Center College of Medicine, Temple, TX 76504, USA.
| | - Md Mhahabubur Rhaman
- Department of Chemistry & Biochemistry, Jackson State University, Jackson, MS 39217, USA.
| | - Corey R Johnson
- Department of Chemistry & Biochemistry, Jackson State University, Jackson, MS 39217, USA.
| | - Thomas J Kuehl
- Department of Obstetrics & Gynecology, Baylor Scott & White Health, Temple/Texas A&M Health Science Center College of Medicine, Temple, TX 76508, USA.
- Department of Pediatrics, Baylor Scott & White Health, Temple/Texas A&M Health Science Center College of Medicine, Temple, TX 76508, USA.
| | - Md Alamgir Hossain
- Department of Chemistry & Biochemistry, Jackson State University, Jackson, MS 39217, USA.
| | - Mohammad Nasir Uddin
- Department of Obstetrics & Gynecology, Baylor Scott & White Health, Temple/Texas A&M Health Science Center College of Medicine, Temple, TX 76508, USA.
- Department of Pediatrics, Baylor Scott & White Health, Temple/Texas A&M Health Science Center College of Medicine, Temple, TX 76508, USA.
- Internal Medicine, Baylor Scott & White Health, Temple/Texas A&M Health Science Center College of Medicine, Temple, TX 76508, USA.
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17
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Schwabl P, Laleman W. Novel treatment options for portal hypertension. Gastroenterol Rep (Oxf) 2017; 5:90-103. [PMID: 28533907 PMCID: PMC5421460 DOI: 10.1093/gastro/gox011] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 03/12/2017] [Indexed: 12/13/2022] Open
Abstract
Portal hypertension is most frequently associated with cirrhosis and is a major driver for associated complications, such as variceal bleeding, ascites or hepatic encephalopathy. As such, clinically significant portal hypertension forms the prelude to decompensation and impacts significantly on the prognosis of patients with liver cirrhosis. At present, non-selective β-blockers, vasopressin analogues and somatostatin analogues are the mainstay of treatment but these strategies are far from satisfactory and only target splanchnic hyperemia. In contrast, safe and reliable strategies to reduce the increased intrahepatic resistance in cirrhotic patients still represent a pending issue. In recent years, several preclinical and clinical trials have focused on this latter component and other therapeutic avenues. In this review, we highlight novel data in this context and address potentially interesting therapeutic options for the future.
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Affiliation(s)
- Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Wim Laleman
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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18
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Martínez AK, Jensen K, Hall C, O'Brien A, Ehrlich L, White T, Meng F, Zhou T, Greene J, Bernuzzi F, Invernizzi P, Dostal DE, Lairmore T, Alpini G, Glaser SS. Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:1093-1105. [PMID: 28315314 DOI: 10.1016/j.ajpath.2017.01.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 12/29/2016] [Accepted: 01/17/2017] [Indexed: 12/20/2022]
Abstract
Nicotine, the main addictive substance in tobacco, is known to play a role in the development and/or progression of a number of malignant tumors. However, nicotine's involvement in the pathogenesis of cholangiocarcinoma is controversial. Therefore, we studied the effects of nicotine on the growth of cholangiocarcinoma cells in vitro and the progression of cholangiocarcinoma in a mouse xenograft model. The predominant subunit responsible for nicotine-mediated proliferation in normal and cancer cells, the α7 nicotinic acetylcholine receptor (α7-nAChR), was more highly expressed in human cholangiocarcinoma cell lines compared with normal human cholangiocytes. Nicotine also stimulated the proliferation of cholangiocarcinoma cell lines and promoted α7-nAChR-dependent activation of proliferation and phosphorylation of extracellular-regulated kinase in Mz-ChA-1 cells. In addition, nicotine and PNU282987 (α7-nAChR agonist) accelerated the growth of the cholangiocarcinoma tumors in our xenograft mouse model and increased fibrosis, proliferation of the tumor cells, and phosphorylation of extracellular-regulated kinase activation. Finally, α7-nAChR was expressed at significantly higher levels in human cholangiocarcinoma compared with normal human control liver samples. Taken together, results of this study suggest that nicotine acts through α7-nAChR and plays a novel role in the pathogenesis of cholangiocarcinoma. Furthermore, nicotine may act as a mitogen in cholestatic liver disease processes, thereby facilitating malignant transformation.
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Affiliation(s)
- Allyson K Martínez
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Kendal Jensen
- Department of Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Chad Hall
- Department of Surgery, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - April O'Brien
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Laurent Ehrlich
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Tori White
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Fanyin Meng
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas; Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
| | - Tianhao Zhou
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - John Greene
- Department of Pathology, Baylor Scott & White Health, Temple, Texas
| | - Francesca Bernuzzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Pietro Invernizzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - David E Dostal
- Department of Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas
| | - Terry Lairmore
- Department of Surgery, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Gianfranco Alpini
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Department of Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas; Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
| | - Shannon S Glaser
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas; Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas.
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19
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McMillin M, Frampton G, Grant S, DeMorrow S. The Neuropeptide Galanin Is Up-Regulated during Cholestasis and Contributes to Cholangiocyte Proliferation. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:819-830. [PMID: 28196718 DOI: 10.1016/j.ajpath.2016.12.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 12/07/2016] [Accepted: 12/22/2016] [Indexed: 12/18/2022]
Abstract
During the course of cholestatic liver diseases, mitotically dormant cholangiocytes proliferate and subsequently acquire a neuroendocrine phenotype. Galanin is a neuroendocrine factor responsible for regulation of physiological responses, such as feeding behavior and mood, and has been implicated in the development of fatty liver disease, although its role in biliary hyperplasia is unknown. Biliary hyperplasia was induced in rats via bile duct ligation (BDL) surgery, and galanin was increased in serum and liver homogenates from BDL rats. Treatment of sham and BDL rats with recombinant galanin increased cholangiocyte proliferation and intrahepatic biliary mass, liver damage, and inflammation, whereas blocking galanin expression with specific vivo-morpholino sequences inhibited hyperplastic cholangiocyte proliferation, liver damage, inflammation, and subsequent fibrosis. The proliferative effects of galanin were via activation of galanin receptor 1 expressed specifically on cholangiocytes and were associated with an activation of extracellular signal-regulated kinase 1/2, and ribosomal S6 kinase 1 signal transduction pathways and subsequent increase in cAMP responsive element binding protein DNA-binding activity and induction of Yes-associated protein expression. Strategies to inhibit extracellular signal-regulated kinase 1/2, ribosomal S6 kinase 1, or cAMP responsive element binding protein DNA-binding activity prevented the proliferative effects of galanin. Taken together, these data suggest that targeting galanin signaling may be effective for the maintenance of biliary mass during cholestatic liver diseases.
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Affiliation(s)
- Matthew McMillin
- Central Texas Veterans Health Care System, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Gabriel Frampton
- Central Texas Veterans Health Care System, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Stephanie Grant
- Central Texas Veterans Health Care System, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Sharon DeMorrow
- Central Texas Veterans Health Care System, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas.
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20
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Hall C, Sato K, Wu N, Zhou T, Kyritsi K, Meng F, Glaser S, Alpini G. Regulators of Cholangiocyte Proliferation. Gene Expr 2017; 17:155-171. [PMID: 27412505 PMCID: PMC5494439 DOI: 10.3727/105221616x692568] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cholangiocytes, a small population of cells within the normal liver, have been the focus of a significant amount of research over the past two decades because of their involvement in cholangiopathies such as primary sclerosing cholangitis and primary biliary cholangitis. This article summarizes landmark studies in the field of cholangiocyte physiology and aims to provide an updated review of biliary pathogenesis. The historical approach of rodent extrahepatic bile duct ligation and the relatively recent utilization of transgenic mice have led to significant discoveries in cholangiocyte pathophysiology. Cholangiocyte physiology is a complex system based on heterogeneity within the biliary tree and a number of signaling pathways that serve to regulate bile composition. Studies have expanded the list of neuropeptides, neurotransmitters, and hormones that have been shown to be key regulators of proliferation and biliary damage. The peptide histamine and hormones, such as melatonin and angiotensin, angiotensin, as well as numerous sex hormones, have been implicated in cholangiocyte proliferation during cholestasis. Numerous pathways promote cholangiocyte proliferation during cholestasis, and there is growing evidence to suggest that cholangiocyte proliferation may promote hepatic fibrosis. These pathways may represent significant therapeutic potential for a subset of cholestatic liver diseases that currently lack effective therapies.
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Affiliation(s)
- Chad Hall
- *Research, Central Texas Veterans Health Care System, Temple, TX, USA
- †Baylor Scott & White Digestive Disease Research Center, Temple, TX, USA
- ‡Department of Surgery, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
| | - Keisaku Sato
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
| | - Nan Wu
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
| | - Tianhao Zhou
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
| | | | - Fanyin Meng
- *Research, Central Texas Veterans Health Care System, Temple, TX, USA
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
- ¶Department of Medicine, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
| | - Shannon Glaser
- *Research, Central Texas Veterans Health Care System, Temple, TX, USA
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
- ¶Department of Medicine, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
| | - Gianfranco Alpini
- ‡Department of Surgery, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
- ¶Department of Medicine, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
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Karin D, Koyama Y, Brenner D, Kisseleva T. The characteristics of activated portal fibroblasts/myofibroblasts in liver fibrosis. Differentiation 2016; 92:84-92. [PMID: 27591095 PMCID: PMC5079826 DOI: 10.1016/j.diff.2016.07.001] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 06/08/2016] [Accepted: 07/11/2016] [Indexed: 12/12/2022]
Abstract
Liver fibrosis results from chronic injury of hepatocytes and activation of Collagen Type I producing myofibroblasts that produce fibrous scar in liver fibrosis. Myofibroblasts are not present in the normal liver but rapidly appear early in experimental and clinical liver injury. The origin of the myofibroblast in liver fibrosis is still unresolved. The possibilities include activation of liver resident cells including portal fibroblasts, hepatic stellate cells, mesenchymal progenitor cells, and fibrocytes recruited from the bone marrow. It is considered that hepatic stellate cells and portal fibroblasts are the major source of hepatic myofibroblasts. In fact, the origin of myofibroblasts differs significantly for chronic liver diseases of different etiologies, such as cholestatic liver disease or hepatotoxic liver disease. Depending on etiology of hepatic injury, the fibrogenic foci might initiate within the hepatic lobule as seen in chronic hepatitis, or primarily affect the portal areas as in most biliary diseases. It has been suggested that activated portal fibroblasts/myofibroblasts work as "myofibroblasts for cholangiocytes" while hepatic stellate cells work as "myofibroblast for hepatocytes". This review will focus on our current understanding of the activated portal fibroblasts/myofibroblasts in cholestatic liver fibrosis.
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Affiliation(s)
- Daniel Karin
- Department of Surgery, University of California, San Diego, La Jolla CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla CA 92093, USA
| | - Yukinori Koyama
- Department of Surgery, University of California, San Diego, La Jolla CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla CA 92093, USA; Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Pediatrics, University of California, San Diego, La Jolla CA 92093, USA
| | - David Brenner
- Department of Medicine, University of California, San Diego, La Jolla CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla CA 92093, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla CA 92093, USA.
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