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Khaled SS, Soliman HA, Abdel-Gabbar M, Ahmed NA, El-Nahass ES, Ahmed OM. Naringin and naringenin counteract taxol-induced liver injury in Wistar rats via suppression of oxidative stress, apoptosis and inflammation. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:90892-90905. [PMID: 37466839 PMCID: PMC10439847 DOI: 10.1007/s11356-023-28454-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 06/22/2023] [Indexed: 07/20/2023]
Abstract
This research aimed to evaluate the preventing effects of naringin, naringenin, and their combination on liver injury induced by Taxol (paclitaxel) in Wistar rats. Male Wistar rats received 2 mg/kg Taxol intraperitoneal injections twice weekly on the second and fifth days of each week for 6 weeks. During the same period as Taxol administration, rats were given naringin, naringenin, or a combination of the two (10 mg/kg b.wt) every other day. Treatment with naringin and/or naringenin reduced the abnormally high serum levels of total bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and gamma-glutamyl transferase in Taxol-treated rats. It also significantly increased the level of serum albumin, indicating an improvement in the liver. The perturbed histological liver changes were markedly improved due to the naringin and/or naringenin treatment in Taxol-administered rats. Additionally, the treatments reduced high hepatic lipid peroxidation and increased liver glutathione content as well as the activities of superoxide dismutase and glutathione peroxidase. Furthermore, the treatments reduced the levels of alpha-fetoprotein and caspase-3, a pro-apoptotic mediator. The naringin and naringenin mixture appeared more effective in improving organ function and structural integrity. In conclusion, naringin and naringenin are suggested to employ their hepatoprotective benefits via boosting the body's antioxidant defense system, reducing inflammation, and suppressing apoptosis.
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Affiliation(s)
- Shimaa S. Khaled
- Biochemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Hanan A. Soliman
- Biochemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Mohammed Abdel-Gabbar
- Biochemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Noha A. Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - El-Shaymaa El-Nahass
- Department of Pathology, Faculty of Veterinary Medicine, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Osama M. Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
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Matboli M, ElGwad AA, Hasanin AH, El-Tawdi A, Habib EK, Elmansy RA, Ibrahim D, Shehata H, Tash F. Pantoprazole attenuates tumorigenesis via inhibition of exosomal secretion in a rat model of hepatic precancerous lesion induced by diethylnitrosamine and 2-acetamidofluorene. J Cell Biochem 2019; 120:14946-14959. [PMID: 31009125 DOI: 10.1002/jcb.28757] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/21/2018] [Accepted: 01/07/2019] [Indexed: 02/06/2023]
Abstract
The present study aimed to evaluate the potential therapeutic effect of pantoprazole, a proton-pump inhibitor, on precancerous lesion (PCL) in rats. diethylnitrosamine and 2-acetylaminofluorene were used to induce PCL in rats, in vivo. The rats were treated with three doses of pantoprazole (100, 50, and 25 mg/kg; three times weekly) during the last 4 weeks of the total 10 weeks of the experiment. Blood and liver tissue samples were collected for measurement of the exosomal abundance and exosomal competing endogenous RNA markers. Results revealed that pantoprazole administration had an ameliorating effect on liver function tests and microscopic features of the liver; and decreased exosome abundance in the liver tissue samples and sera of the rats. Meanwhile, the treatment also resulted in a dose-dependent decrease in exosomal RAB11A mRNA and long noncoding RNA RP11-513I15.6, which is an important participant in th exosomal secretion process with an increase in exosomal miRNA-1262. Based on these results, we postulated that pantoprazole has the potential to attenuate liver tumorigenesis in this rat model.
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Affiliation(s)
- Marwa Matboli
- Department of Medical Biochemistry and Molecular biology, Faculty of Medicine, Ain Shams University, Abbassia, Cairo, Egypt
| | - Asmaa Abd ElGwad
- Department of Medical Biochemistry and Molecular biology, Faculty of Medicine, Ain Shams University, Abbassia, Cairo, Egypt
| | - Amany H Hasanin
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ahmed El-Tawdi
- Department of General surgery, Military Medical Academy, Cairo, Egypt
| | - Eman K Habib
- Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Rasha Ahmed Elmansy
- Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.,Department of Anatomy and Embryology, Faculty of Medicine, Unaizah College of Medicine, AlQassim University, AlQassim, KSA
| | - Doaa Ibrahim
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Hanan Shehata
- Department of Medical Biochemistry and Molecular biology, Faculty of Medicine, Ain Shams University, Abbassia, Cairo, Egypt
| | - Fathy Tash
- Department of Medical Biochemistry and Molecular biology, Faculty of Medicine, Ain Shams University, Abbassia, Cairo, Egypt
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Uslu S, Alaca N, Kilic KD, Uysal A, Kurtel H. The effects of aerobic exercise frequencies on liver fibrosis, α-fetoprotein and cytokeratin 19 in experimental type 2 diabetes-induced rats: an immunohistochemistry study. Biotech Histochem 2018; 93:615-622. [DOI: 10.1080/10520295.2018.1517898] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Affiliation(s)
- S. Uslu
- Department of Histology and Embryology, Medeniyet University School of Medicine, Istanbul, Turkey
| | - N. Alaca
- Department of Physiotherapy, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - K. D. Kilic
- Department of Histology and Embryology, Ege University School of Medicine, Izmir, Turkey
| | - A. Uysal
- Department of Histology and Embryology, Ege University School of Medicine, Izmir, Turkey
| | - H. Kurtel
- Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
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Tissue-specific transplantation antigen P35B (TSTA3) immune response-mediated metabolism coupling cell cycle to postreplication repair network in no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) by biocomputation. Immunol Res 2012; 52:258-68. [PMID: 22528125 DOI: 10.1007/s12026-012-8337-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
We constructed the low-expression tissue-specific transplantation antigen P35B (TSTA3) immune response-mediated metabolism coupling cell cycle to postreplication repair network in no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) compared with high-expression (fold change ≥ 2) human hepatocellular carcinoma in GEO data set, by using integration of gene regulatory network inference method with gene ontology analysis of TSTA3-activated up- and downstream networks. Our results showed TSTA3 upstream-activated CCNB2, CKS1B, ELAVL3, GAS7, NQO1, NTN1, OCRL, PLA2G1B, REG3A, SSTR5, etc. and TSTA3 downstream-activated BAP1, BRCA1, CCL20, MCM2, MS4A2, NTN1, REG1A, TP53I11, VCAN, SLC16A3, etc. in no-tumor hepatitis/cirrhotic tissues. TSTA3-activated network enhanced the regulation of apoptosis, cyclin-dependent protein kinase activity, cell migration, insulin secretion, transcription, cell division, cell proliferation, DNA replication, postreplication repair, cell differentiation, T-cell homeostasis, neutrophil-mediated immunity, neutrophil chemotaxis, interleukin-8 production, inflammatory response, immune response, B-cell activation, humoral immune response, actin filament organization, xenobiotic metabolism, lipid metabolism, phospholipid metabolism, leukotriene biosynthesis, organismal lipid catabolism, phosphatidylcholine metabolism, arachidonic acid secretion, activation of phospholipase A2, deoxyribonucleotide biosynthesis, heterophilic cell adhesion, activation of MAPK activity, signal transduction by p53 class mediator resulting in transcription of p21 class mediator, G-protein-coupled receptor protein signaling pathway, response to toxin, acute-phase response, DNA damage response, intercellular junction assembly, cell communication, and cell recognition, as a result of inducing immune response-mediated metabolism coupling cell cycle to postreplication repair in no-tumor hepatitis/cirrhotic tissues.
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Assimakopoulos SF, Tsamandas AC, Alexandris IH, Georgiou C, Vagianos CE, Scopa CD. Stimulation of oval cell and hepatocyte proliferation by exogenous bombesin and neurotensin in partially hepatectomized rats. World J Gastrointest Pathophysiol 2011; 2:146-54. [PMID: 22180848 PMCID: PMC3240906 DOI: 10.4291/wjgp.v2.i6.146] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Revised: 11/07/2011] [Accepted: 11/14/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of the neuropeptides bombesin (BBS) and neurotensin (NT) on oval cell proliferation in partially hepatectomized rats not pretreated with a known hepatocyte inhibitor.
METHODS: Seventy male Wistar rats were randomly divided into five groups: I = controls, II = sham operated, III = partial hepatectomy 70% (PHx), IV = PHx + BBS (30 μg/kg per day), V = PHx + NT (300 μg/kg per day). Forty eight hours after liver resection, portal endotoxin levels and hepatic glutathione redox state were determined. α-fetoprotein (AFP) mRNA (in situ hybridisation), cytokeratin-19 and Ki67 antigen expression (immunohistochemistry) and apoptosis (TUNEL) were evaluated on liver tissue samples. Cells with morphological features of oval cells that were cytokeratin-19 (+) and AFP mRNA (+) were scored in morphometric analysis and their proliferation was recorded. In addition, the proliferation and apoptotic rates of hepatocytes were determined.
RESULTS: In the control and sham operated groups, oval cells were significantly less compared to groups III, IV and V (P < 0.001). The neuropeptides BBS and NT significantly increased the proliferation of oval cells compared to group III (P < 0.001). In addition, BBS and NT induced a significant increase of hepatocyte proliferation (P < 0.001), whereas it decreased their apoptotic activity (P < 0.001) compared to group III. BBS and NT significantly decreased portal endotoxemia (P < 0.001) and increased the hepatic GSH: GSSG ratio (P < 0.05 and P < 0.001, respectively) compared to group III.
CONCLUSION: BBS and NT stimulated oval cell proliferation in a model of liver regeneration, without use of concomitant suppression of hepatocyte proliferation as oval cell activation stimuli, and improved the hepatocyte regenerative response. This peptides-induced combined stimulation of oval cell and hepatocyte proliferation might serve as a possible treatment modality for several liver diseases.
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Crema A, Ledda M, De Carlo F, Fioretti D, Rinaldi M, Marchese R, Sanchez M, Giuliani M, Arena V, Durrbach A, Brunetti E, Haas C, Ponzetto A, Lisi A, Carloni G. Cord blood CD133 cells define an OV6-positive population that can be differentiated in vitro into engraftable bipotent hepatic progenitors. Stem Cells Dev 2011; 20:2009-21. [PMID: 21291316 DOI: 10.1089/scd.2010.0545] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Cell therapy represents the most promising alternative strategy for end-stage liver diseases and hepatic progenitors are the best candidates. We have identified a reservoir of immature hepatic precursors within human cord blood, which can derive engraftable bipotent progenitors. We isolated a stem cell subset CD133+/CD34+/OV6(low) expressing a surface-marker profile consistent with that of fetal liver cells. Upon induction of hepatic commitment by a medium containing cytokines and factors involved in vivo oval-cell activation, a heterogeneous cell population displaying characteristics of functional oval-cell-like bipotent hepatic progenitors was obtained. The cells expressed markers of hepatocytes and cholangiocytes and were highly enriched in OV6, c-Met, c-Kit, and Thy-1. They also displayed liver functional activity as glycogen storage, urea production, albumin secretion, and inducible CyP2B6 activity. When injected into liver-damaged severe-combined immunodeficient mice, induced bipotent hepatic progenitors appropriately engrafted livers of recipient animals, where they formed clusters of human-derived cells expressing human leucocyte antigen-class I, Hep-Par1, and OV6 antigens. Human-specific albumin, alpha-fetoprotein, and cytokeratin 19 were also expressed. In transplanted animals, AST serum levels showed a significative reduction with regard to controls. This human model for in vitro progenitor-cell activation may provide a powerful tool for elucidating the pathways and synergies that regulate this complex process and can represent a valuable source, exploitable for liver cell-based therapies and regenerative medicine.
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Affiliation(s)
- Annalisa Crema
- Institute of Translational Pharmacology, Department of Medicine, National Research Council (CNR), Rome, Italy.
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Assimakopoulos SF, Tsamandas AC, Georgiou CD, Vagianos CE, Scopa CD. Bombesin and neurotensin exert antiproliferative effects on oval cells and augment the regenerative response of the cholestatic rat liver. Peptides 2010; 31:2294-303. [PMID: 20833216 DOI: 10.1016/j.peptides.2010.09.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Revised: 09/02/2010] [Accepted: 09/02/2010] [Indexed: 12/30/2022]
Abstract
The regenerative capacity of the cholestatic liver is significantly attenuated. Oval cells are hepatic stem cells involved in liver's regeneration following diverse types of injury. The present study investigated the effect of the neuropeptides bombesin (BBS) and neurotensin (NT) on oval cell proliferation as well as on hepatocyte and cholangiocyte proliferation and apoptosis in the cholestatic rat liver. Seventy male Wistar rats were randomly divided into five groups: controls, sham operated, bile duct ligated (BDL), BDL+BBS (30 μg/kg/d), BDL+NT (300 μg/kg/d). Ten days later, alpha-fetoprotein (AFP) mRNA (in situ hybridization), cytokeratin-19 and Ki67 antigen expression (immunohistochemistry) and apoptosis (TUNEL) were evaluated on liver tissue samples. Cells with morphologic features of oval cells that were cytokeratin-19(+) and AFP mRNA(+) were scored in morphometric analysis and their proliferation was recorded. In addition, the proliferation and apoptotic rates of hepatocytes and cholangiocytes were determined. Alanine aminotransferase (ALT) levels and hepatic oxidative stress (lipid peroxidation and glutathione redox state) were also estimated. The neuropeptides BBS and NT significantly reduced ALT levels and hepatic oxidative stress. Both agents exerted similar and cell type-specific effects on oval cells, hepatocytes and cholangiocytes: (a) oval cell proliferation and accumulation in the cholestatic liver was attenuated, (b) hepatocyte proliferation was increased along with a decreased rate of their apoptosis and (c) cholangiocyte proliferation was attenuated and their apoptosis was increased. These observations might be of potential value in patients with extrahepatic cholestasis.
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Kanmura S, Uto H, Sato Y, Kumagai K, Sasaki F, Moriuchi A, Oketani M, Ido A, Nagata K, Hayashi K, Stuver SO, Tsubouchi H. The complement component C3a fragment is a potential biomarker for hepatitis C virus-related hepatocellular carcinoma. J Gastroenterol 2010; 45:459-67. [PMID: 20012107 DOI: 10.1007/s00535-009-0160-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2009] [Accepted: 10/28/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) has a high mortality rate, and early detection of HCC improves patient survival. However, the molecular diagnostic markers for early HCC have not been fully elucidated. The aim of this study was to identify novel diagnostic markers for HCC. METHODS Serum protein profiles of 45 hepatitis C virus infection (HCV)-related HCC patients (HCV-HCC) were compared to 42 HCV-related chronic liver disease patients without HCC (HCV-CLD) and 21 healthy volunteers using the ProteinChip SELDI system. One of the identified proteins was evaluated as a diagnostic marker for HCC in patients with HCV. RESULTS Five protein peaks (4067, 4470, 7564, 7929, and 8130 m/z) had p-values less than 1 x 10(-7) and were significantly increased in the sera of HCV-HCC patients compared to HCV-CLD patients and healthy volunteers. Among these proteins, an 8130 m/z peak was the most differentially expressed and identified as the complement component 3a (C3a) fragment. For HCV-HCC and HCV-CLD, the relative intensity of this C3a fragment had the best area under the ROC curve [0.70], followed by des-gamma-carboxy prothrombin (DCP) [0.68], lectin-bound alpha fetoprotein (AFP-L3) [0.58] and AFP [0.53] for HCC. A combined analysis of the C3a fragment, AFP and DCP led to a 98% positive identification rate. In addition, the measurable C3a fragment in some HCC patients was not only significantly higher in the year of HCC onset compared to the pre-onset year, but also decreased after treatment. CONCLUSIONS The 8130 m/z C3a fragment is a potential marker for the early detection of HCV-related HCC.
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Affiliation(s)
- Shuji Kanmura
- Digestive Disease and Life-style Related Disease Health Research, Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
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Antonacopoulou AG, Tsamandas AC, Petsas T, Liava A, Scopa CD, Papavassiliou AG, Kalofonos HP. EGFR, HER-2 and COX-2 levels in colorectal cancer. Histopathology 2009; 53:698-706. [PMID: 19102009 DOI: 10.1111/j.1365-2559.2008.03165.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
AIMS Receptor tyrosine kinases epidermal growth factor receptor (EGFR) and HER-2 and cyclooxygenase-2 (COX-2) are promising molecular targets for cancer therapy and/or prevention. The aim was to evaluate EGFR, HER-2 and COX-2 mRNA and protein expression in colorectal cancer patients. METHODS AND RESULTS EGFR, HER-2 and COX-2 protein levels were evaluated by immunohistochemistry in malignant tissue, dysplastic tissue and normal mucosa samples from 124 cases with primary colorectal carcinoma. Moreover, the corresponding mRNA levels were assessed by quantitative reverse transcriptase-polymerase chain reaction in 46 colorectal carcinomas. There was strong correlation between mRNA and protein expression for EGFR (P < 0.001), HER-2 (P < 0.004) and COX-2 (P < 0.007). EGFR levels did not correlate with stage of the disease or tumour differentiation. HER-2 and COX-2 levels increased in advanced stages and in differentiated carcinomas. Furthermore, a correlation between HER-2 and COX-2 expression was revealed in neoplastic tissue. CONCLUSIONS EGFR as well as HER-2 and COX-2 overexpression represent important alterations that are related to the molecular pathways underpinning colorectal carcinogenesis. Further investigation is required to evaluate the impact of these markers on the management of patients with colorectal cancer.
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Affiliation(s)
- A G Antonacopoulou
- Clinical Oncology Laboratory, School of Medicine, University of Patras, Rion, Patras, Greece
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Abstract
The liver diseases remain major causes of death all over the world. Although orthotopic liver transplantation is an effective treatment for end-stage liver diseases. However, shortage of healthy livers for transplantation worldwide have urgently limited the use of liver transplantation for acute and chronic liver diseases. Stem cells play an important role in the concert of liver regeneration. Hepatic stem cells have been shown experimentally to participate in liver proliferation. Furthermore, it has been postulated that hepatic stem cells are able to transdifferentiate into both hepatocytes and bole duct cells. These data indicate a possible role and therapeutic potential of hepatic stem cells in liver diseases. In this paper, we reviewed the application of stem cells in liver diseases.
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