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Mohamed N, Ahmed Abukhadir SS, Syed Hashim SA, Adnan NS, Aziz MA, Muhammad N. Vitamin E Improves Cellular and Structural Bone Histomorphometry in an Alcohol-Induced Osteoporosis Rat Model. Pharmaceuticals (Basel) 2024; 17:1730. [PMID: 39770572 PMCID: PMC11677299 DOI: 10.3390/ph17121730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/06/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Alcohol-induced osteoporosis is a significant health concern, impairing bone formation and enhancing resorption, thereby weakening skeletal integrity. This study examines the effects of palm vitamin E on bone histomorphometry in a male rat model of alcohol-induced osteoporosis. Methods: Three-month-old Sprague-Dawley rats were randomized into seven groups, with one baseline control group (BC) and six experimental groups undergoing a two-phase treatment. In the first month, the control group received normal saline, while experimental groups received intraperitoneal alcohol (3 g/kg) three times weekly. For the subsequent two months, alcohol treatment continued in one group (A), while others received olive oil (C), saline (AN), alpha-tocopherol (AA), or palm vitamin E (AE) orally. Results: Femur histomorphometric analysis post-sacrifice showed that alcohol exposure significantly decreased osteoblastic activity and impaired bone microarchitecture, evidenced by reduced Ob.S/BS, OS/BS, OV/BV, Tb.Th, BV/TV, and Tb.N, alongside increased Oc.S/BS, ES/BS, and Tb.Sp. Both alpha-tocopherol and palm vitamin E improved bone parameters, with palm vitamin E showing superior efficacy except in OV/BV. Conclusions: These findings suggest that palm vitamin E may offer a therapeutic benefit for mitigating alcohol-induced bone damage.
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Affiliation(s)
- Norazlina Mohamed
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (S.S.A.A.); (S.A.S.H.); (N.S.A.); (M.A.A.); (N.M.)
| | - Seham Salem Ahmed Abukhadir
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (S.S.A.A.); (S.A.S.H.); (N.S.A.); (M.A.A.); (N.M.)
| | - Syed Alhafiz Syed Hashim
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (S.S.A.A.); (S.A.S.H.); (N.S.A.); (M.A.A.); (N.M.)
- Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK
| | - Nur Sabariah Adnan
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (S.S.A.A.); (S.A.S.H.); (N.S.A.); (M.A.A.); (N.M.)
| | - Muhamad Arizi Aziz
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (S.S.A.A.); (S.A.S.H.); (N.S.A.); (M.A.A.); (N.M.)
| | - Norliza Muhammad
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (S.S.A.A.); (S.A.S.H.); (N.S.A.); (M.A.A.); (N.M.)
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Sandoval C, Vera A, Birditt K, Godoy K, Carmine F, Caamaño J, Farías J. β-Carotene Supplementation Improves Pancreas Function during Moderate Ethanol Consumption: Initial Characterization from a Morphological Overview. Int J Mol Sci 2024; 25:1219. [PMID: 38279214 PMCID: PMC10815982 DOI: 10.3390/ijms25021219] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 01/09/2024] [Accepted: 01/11/2024] [Indexed: 01/28/2024] Open
Abstract
Alcohol is believed to harm acinar cells, pancreatic ductal epithelium, and pancreatic stellate cells. After giving ethanol and/or β-carotene to C57BL/6 mice, our goal was to evaluate their biochemistry, histology, and morpho-quantitative features. There were six groups of C57BL/6 mice: 1. Group C (control), 2. Group LA (low-dose alcohol), 3. Group MA (moderate-dose alcohol), 4. Group B (β-carotene), 5. Group LA + B (low-dose alcohol combined with β-carotene), and 6. Group MA + B (moderate-dose alcohol combined with β-carotene). After the animals were euthanized on day 28, each specimen's pancreatic tissue was taken. Lipase, uric acid, and amylase were assessed using biochemical assessment. Furthermore, the examination of the pancreatic structure was conducted using Ammann's fibrosis scoring system. Finally, the morpho-quantitative characteristics of the pancreatic islets and acinar cells were determined. In the serum of the MA + B group, there were higher amounts of total amylase (825.953 ± 193.412 U/L) and lower amounts of lipase (47.139 ± 6.099 U/L) (p < 0.05). Furthermore, Ammann's fibrosis punctuation in the pancreas revealed significant variations between the groups (p < 0.001). Finally, the stereological analysis of pancreatic islets showed that the groups were different (p < 0.001). These findings suggest that antioxidant treatments might help decrease the negative effects of ethanol exposure in animal models.
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Affiliation(s)
- Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Los Carreras 753, Osorno 5310431, Chile;
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Angeles Vera
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile;
| | - Katherine Birditt
- Physiology Development and Neuroscience Department, University of Cambridge, Cambridge CB2 1TN, UK;
| | - Karina Godoy
- Núcleo Científico y Tecnológico en Biorecursos (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile;
| | - Florencia Carmine
- Carrera de Medicina, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile;
| | - José Caamaño
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
- Laboratorio de Inmunohematología y Medicina Transfusional, Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Jorge Farías
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile
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Zhang J, Fan H, Gross M, Liu N, Carlson H, Wood A, Hoffman K, Petrosino J, Pankratz N, Thyagarajan B, Fisher W. Progressive reduction in circulating levels of carotenoids and other micronutrients in patients with chronic pancreatitis. Pancreatology 2022; 22:1126-1133. [PMID: 36198488 DOI: 10.1016/j.pan.2022.09.243] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/26/2022] [Accepted: 09/21/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND Although micronutrients modulate immunity and inflammation, it remains elusive whether they are implicated in the development and progression of chronic pancreatitis (CP). This study aimed to investigate differences in the circulating levels of selected carotenoids and vitamins between CP and controls and trends in the levels of these micronutrients across controls, early CP, and definite CP. METHODS Demographic and lifestyle data were extracted from medical records for 53 patients with CP (13 early and 38 definite) and obtained using a questionnaire for 52 controls. Plasma β-carotene, lycopene, cryptoxanthin, zeaxanthin, and α-tocopherol and serum 25(OH)D, folate, IL-6, TNF-α, and MCP-1 were measured with state-of-the-art methods. RESULTS The levels of all micronutrients (except folate) were significantly lower in CP than in controls. There was a progressive decrease in the levels of these micronutrients across controls, early CP, and definite CP (all p values for trend: ≤0.0012); e.g., plasma lycopene was 36.6, 21.5, and 14.5 μg/dL for controls, early CP, and definite CP, respectively. After adjustment for confounders, there were strong, inverse associations between the levels of all micronutrients (except folate) and CP (e.g., OR (95% CI) for ≥ median vs. <median: 0.10 (0.04, 0.27) for lycopene, 0.15 (0.05, 0.38) for α-tocopherol, and 0.24 (0.09, 0.64) for 25(OH)D). These associations became weaker after additional adjustment for inflammation markers (IL-6, TNF-α, and MCP-1). CONCLUSIONS The circulating levels of some carotenoids, α-tocopherol, and vitamin D were reduced in CP patients compared with controls and this reduction was more pronounced in definite CP than in early CP.
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Affiliation(s)
- Jianjun Zhang
- Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA.
| | - Hao Fan
- Department of Epidemiology and Biostatistics, School of Public Health, Indiana University, Bloomington, IN, USA
| | - Myron Gross
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Nianjun Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Indiana University, Bloomington, IN, USA
| | - Hannah Carlson
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Amy Wood
- Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Kristi Hoffman
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Joseph Petrosino
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Nathan Pankratz
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - William Fisher
- Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
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Zhang J, Bai J, Zhou Q, Hu Y, Wang Q, Yang L, Chen H, An H, Zhou C, Wang Y, Chen X, Li M. Glutathione prevents high glucose-induced pancreatic fibrosis by suppressing pancreatic stellate cell activation via the ROS/TGFβ/SMAD pathway. Cell Death Dis 2022; 13:440. [PMID: 35523788 PMCID: PMC9076672 DOI: 10.1038/s41419-022-04894-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 04/25/2022] [Accepted: 04/28/2022] [Indexed: 12/14/2022]
Abstract
The activation of pancreatic stellate cells (PSCs) is the key mechanism of pancreatic fibrosis, which can lead to β-cell failure. Oxidative stress is an important risk factor for PSC activation. There is no direct evidence proving if administration of glutathione can inhibit fibrosis and β-cell failure. To explore the role of glutathione in pancreatic fibrosis and β-cell failure induced by hyperglycaemia, we established a rat model of pancreatic fibrosis and β-cell failure. The model was founded through long-term oscillating glucose (LOsG) intake and the setup of a sham group and a glutathione intervention group. In vitro, rat PSCs were treated with low glucose, high glucose, or high glucose plus glutathione to explore the mechanism of high glucose-induced PSC activation and the downstream effects of glutathione. Compared with sham rats, LOsG-treated rats had higher reactive oxygen species (ROS) levels in peripheral leukocytes and pancreatic tissue while TGFβ signalling was upregulated. In addition, as the number of PSCs and pancreatic fibrosis increased, β-cell function was significantly impaired. Glutathione evidently inhibited the upregulation of TGFβ signalling and several unfavourable outcomes caused by LOsG. In vitro treatment of high glucose for 72 h resulted in higher ROS accumulation and potentiated TGFβ pathway activation in PSCs. PSCs showed myofibroblast phenotype transformation with upregulation of α-SMA expression and increased cell proliferation and migration. Treatment with either glutathione or TGFβ pathway inhibitors alleviated these changes. Together, our findings suggest that glutathione can inhibit PSC activation-induced pancreatic fibrosis via blocking ROS/TGFβ/SMAD signalling in vivo and in vitro.
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Affiliation(s)
- Jitai Zhang
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Juan Bai
- grid.268099.c0000 0001 0348 3990Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qian Zhou
- grid.268099.c0000 0001 0348 3990Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yuxin Hu
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qian Wang
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Lanting Yang
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Huamin Chen
- grid.268099.c0000 0001 0348 3990Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Hui An
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China ,grid.417384.d0000 0004 1764 2632Department of Anesthesia and Critical Care, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chuanzan Zhou
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yongyu Wang
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xiufang Chen
- grid.268099.c0000 0001 0348 3990Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ming Li
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China ,grid.417384.d0000 0004 1764 2632The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
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Xia SH. Prospect and clinical value of oxymatrine in prevention and treatment of pancreatic fibrosis. Shijie Huaren Xiaohua Zazhi 2020; 28:819-826. [DOI: 10.11569/wcjd.v28.i17.819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Studies have confirmed that pancreatic stellate cell activation is the central event in the initiation and development of pancreatic fibrosis (PF), but the specific mechanism of PF is still unknown, and there is no specific treatment for PF. Some basic studies have confirmed that oxymatrine (OMT) has a certain therapeutic effect on PF, but further research is needed. It can be predicted that OMT has a far-reaching research prospect and good clinical application value for the prevention and treatment of PF, and is also conducive to the better development and utilization of traditional Chinese herbal medicine radix sophorae flavescentis.
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Affiliation(s)
- Shi-Hai Xia
- Gastroenterology Department of Medical Center of the Chinese People's Armed Police Force (Institute of Digestive Diseases of Medical Center), Medical Center for Hepatobiliary, Pancreatic and Splenic Disease of the Chinese People's Armed Police Force, Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis and Treatment, Tianjin 300162, China
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Abstract
The discovery of vitamin E (α-tocopherol) began in 1922 as a vital component required in reproduction. Today, there are eight naturally occurring vitamin E isoforms, namely α-, β-, γ- and δ-tocopherol and α-, β-, γ- and δ-tocotrienol. Vitamin E is potent antioxidants, capable of neutralizing free radicals directly by donating hydrogen from its chromanol ring. α-Tocopherol is regarded the dominant form in vitamin E as the α-tocopherol transfer protein in the liver binds mainly α-tocopherol, thus preventing its degradation. That contributed to the oversight of tocotrienols and resulted in less than 3% of all vitamin E publications studying tocotrienols. Nevertheless, tocotrienols have been shown to possess superior antioxidant and anti-inflammatory properties over α-tocopherol. In particular, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase to lower cholesterol, attenuating inflammation via downregulation of transcription factor NF-κB activation, and potent radioprotectant against radiation damage are some properties unique to tocotrienols, not tocopherols. Aside from cancer, vitamin E has also been shown protective in bone, cardiovascular, eye, nephrological and neurological diseases. In light of the different pharmacological properties of tocopherols and tocotrienols, it becomes critical to specify which vitamin E isoform(s) are being studied in any future vitamin E publications. This review provides an update on vitamin E therapeutic potentials, protective effects and modes of action beyond cancer, with comparison of tocopherols against tocotrienols. With the concerted efforts in synthesizing novel vitamin E analogs and clinical pharmacology of vitamin E, it is likely that certain vitamin E isoform(s) will be therapeutic agents against human diseases besides cancer.
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Affiliation(s)
- Hong Yong Peh
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore
| | - W S Daniel Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore
| | - Wupeng Liao
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore
| | - W S Fred Wong
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore; Immunology Program, Life Science Institute, National University of Singapore, Singapore.
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Sunflower Oil but Not Fish Oil Resembles Positive Effects of Virgin Olive Oil on Aged Pancreas after Life-Long Coenzyme Q Addition. Int J Mol Sci 2015; 16:23425-45. [PMID: 26426013 PMCID: PMC4632707 DOI: 10.3390/ijms161023425] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Revised: 09/21/2015] [Accepted: 09/22/2015] [Indexed: 12/15/2022] Open
Abstract
An adequate pancreatic structure is necessary for optimal organ function. Structural changes are critical in the development of age-related pancreatic disorders. In this context, it has been reported that different pancreatic compartments from rats were affected according to the fat composition consumed. Since there is a close relationship between mitochondria, oxidative stress and aging, an experimental approach has been developed to gain more insight into this process in the pancreas. A low dosage of coenzyme Q was administered life-long in rats in order to try to prevent pancreatic aging-related alterations associated to some dietary fat sources. According to that, three groups of rats were fed normocaloric diets containing Coenzyme Q (CoQ) for two years, where virgin olive, sunflower, or fish oil was included as unique fat source. Pancreatic samples for microscopy and blood samples were collected at the moment of euthanasia. The main finding is that CoQ supplementation gives different results according to fat used in diet. When sunflower oil was the main fat in the diet, CoQ supplementation seems to improve endocrine pancreas structure and in particular β-cell mass resembling positive effects of virgin olive oil. Conversely, CoQ intake does not seem to improve the structural alterations of exocrine compartment previously observed in fish oil fed rats. Therefore CoQ may improve pancreatic alterations associated to the chronic intake of some dietary fat sources.
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Hou XJ, Jin ZD, Jiang F, Zhu JW, Li ZS. Expression of Smad7 and Smad ubiquitin regulatory factor 2 in a rat model of chronic pancreatitis. J Dig Dis 2015; 16:408-15. [PMID: 25943897 DOI: 10.1111/1751-2980.12253] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To quantify the expressions of Smad7 and Smad ubiquitin regulatory factor 2 (Smurf2) in the pancreas in rats with chronic pancreatitis (CP). METHODS A total of 16 male Wistar rats were randomly divided into the control group and the CP group, with 8 rats in each group. CP was induced in vivo with dibutyltin dichloride (DBTC). Four weeks after DBTC administration, histological assessment and the measurement of hydroxyproline content in the pancreatic tissues were performed to assess the inflammation and fibrosis of the pancreas. Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) for transforming growth factor (TGF)-β1 and α-smooth muscle actin (α-SMA) were applied to assess activated pancreatic stellate cells (PSC) and TGF-β1 expression. Smad7 and Smurf2 expressions in the pancreas were measured using Western blot and RT-PCR. RESULTS Typical histopathological characteristics of DBTC-induced CP in the rats with extensively activated PSC. Compared with the control group, the expressions of TGF-β1, α-SMA and hydroxyproline content in the pancreatic tissues in the CP group were significantly increased. Meanwhile, the mRNA and protein expressions of Smad7 and Smurf2 were significant increased in the fibrotic pancreas, in which the expressions of Smad7 proteins showed an obvious reduction compared with controls. CONCLUSION The dysregulation of Smad7 and Smurf2 may be associated with the pathogenesis of pancreatic fibrosis through the TGF-β signaling pathway.
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Affiliation(s)
- Xiao Jia Hou
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Zhen Dong Jin
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Fei Jiang
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Jian Wei Zhu
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Zhao Shen Li
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
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Zhang JS, Zhang SJ, Li Q, Liu YH, He N, Zhang J, Zhou PH, Li M, Guan T, Liu JR. Tocotrienol-rich fraction (TRF) suppresses the growth of human colon cancer xenografts in Balb/C nude mice by the Wnt pathway. PLoS One 2015; 10:e0122175. [PMID: 25807493 PMCID: PMC4373919 DOI: 10.1371/journal.pone.0122175] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 02/07/2015] [Indexed: 01/27/2023] Open
Abstract
Tocotrienols have been shown many biologic functions such as antioxidant, anti-cancer, maintaining fertility and regulating the immune system and so on. In this study, after feeding with tocotrienol-rich fraction from palm oil (TRF) for 2 weeks, Balb/c nude mice were inoculated human colon SW620 cancer cell and then continued to feed TRF for 4 weeks. At termination of experiments, xenografts were removed and determined the expression of Wnt-pathways related protein by immunohistochemistry or western blotting. Liver tissues were homogenated for determining the levels of antioxidative enzymes activity or malondialdehyde (MDA). The results showed that TRF significantly inhibited the growth of xenografts in nude mice. TRF also affected the activity of antioxidative enzymes in the liver tissue of mice. These changes were partly contributed to activation of wnt pathways or affecting their related protein. Thus, these finding suggested that the potent anticancer effect of TRF is associated with the regulation of Wnt signal pathways.
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Affiliation(s)
- Jing-Shu Zhang
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin, People’s Republic of China
- College of Public Health, Tianjin Medical University, Tianjin, People’s Republic of China
- * E-mail: (JSZ); (JRL)
| | - Shu-Jing Zhang
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin, People’s Republic of China
- College of Public Health, Tianjin Medical University, Tianjin, People’s Republic of China
| | - Qian Li
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin, People’s Republic of China
- College of Public Health, Tianjin Medical University, Tianjin, People’s Republic of China
| | - Ying-Hua Liu
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin, People’s Republic of China
| | - Ning He
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin, People’s Republic of China
| | - Jing Zhang
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin, People’s Republic of China
| | - Peng-Hui Zhou
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin, People’s Republic of China
- College of Public Health, Tianjin Medical University, Tianjin, People’s Republic of China
| | - Min Li
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin, People’s Republic of China
| | - Tong Guan
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin, People’s Republic of China
| | - Jia-Ren Liu
- Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail: (JSZ); (JRL)
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10
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Imam MU, Ismail M, Ooi DJ, Azmi NH, Sarega N, Chan KW, Bhanger MI. Are bioactive-rich fractions functionally richer? Crit Rev Biotechnol 2015; 36:585-93. [DOI: 10.3109/07388551.2014.995586] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- Mustapha Umar Imam
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor,
| | - Maznah Ismail
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor,
- Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, and
| | - Der Jiun Ooi
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor,
| | - Nur Hanisah Azmi
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor,
| | - Nadarajan Sarega
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor,
| | - Kim Wei Chan
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor,
| | - Muhammad Iqbal Bhanger
- International Center for Chemical and Biological Sciences, HEJ Research Institute of Chemistry, University of Karachi, Karachi, Pakistan
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11
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Wang LW, Lin H, Lu Y, Xia W, Gao J, Li ZS. Sonic hedgehog expression in a rat model of chronic pancreatitis. World J Gastroenterol 2014; 20:4712-4717. [PMID: 24782623 PMCID: PMC4000507 DOI: 10.3748/wjg.v20.i16.4712] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Accepted: 03/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the activation of sonic hedgehog (SHh) signaling pathways in a rat model of chronic pancreatitis.
METHODS: Forty Wistar rats were randomly divided into 2 groups: experimental group and control group (20 rats in each group). Dibutyltin dichloride was infused into the tail vein of the rats to induce chronic pancreatitis in the experimental group. The same volume of ethanol and glycerol mixture was infused in the control group. The expression of Ptch, Smo and Gli were analyzed using immunohistochemistry, and real-time reverse transcription polymerase chain reaction (RT-PCR).
RESULTS: Compared with the control group, significant histological changes in terms of the areas of abnormal architecture, glandular atrophy, fibrosis, pseudo tubular complexes, and edema were observed at week 4 in the experimental group. The expression of Ptch1, Smo and Gli1 in the pancreatic tissue increased significantly in the experimental group. Using RT-PCR, mRNA levels of Ptch, Smo and Gli in the experimental group increased significantly compared with the control group.
CONCLUSION: The SHh signaling pathway is aberrantly activated in rats with chronic pancreatitis. The SHh signaling pathway plays an important role in the development of chronic pancreatitis. These results may be helpful in studies focusing on the relationship between chronic pancreatitis and pancreatic cancer.
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MESH Headings
- Animals
- Atrophy
- Disease Models, Animal
- Fibrosis
- Hedgehog Proteins/metabolism
- Kruppel-Like Transcription Factors/genetics
- Kruppel-Like Transcription Factors/metabolism
- Male
- Organotin Compounds
- Pancreas/metabolism
- Pancreas/pathology
- Pancreatitis, Chronic/chemically induced
- Pancreatitis, Chronic/genetics
- Pancreatitis, Chronic/metabolism
- Pancreatitis, Chronic/pathology
- Patched Receptors
- Patched-1 Receptor
- RNA, Messenger/metabolism
- Rats, Wistar
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Signal Transduction
- Smoothened Receptor
- Time Factors
- Zinc Finger Protein GLI1
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12
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Siriwardena AK. Reappraisal of xenobiotic-induced, oxidative stress-mediated cellular injury in chronic pancreatitis: A systematic review. World J Gastroenterol 2014; 20:3033-3043. [PMID: 24659895 PMCID: PMC3961990 DOI: 10.3748/wjg.v20.i11.3033] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 10/25/2013] [Accepted: 12/04/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To reappraise the hypothesis of xenobiotic induced, cytochrome P450-mediated, micronutrient-deficient oxidative injury in chronic pancreatitis.
METHODS: Individual searches of the Medline and Embase databases were conducted for each component of the theory of oxidative-stress mediated cellular injury for the period from 1st January 1990 to 31st December 2012 using appropriate medical subject headings. Boolean operators were used. The individual components were drawn from a recent update on theory of oxidative stress-mediated cellular injury in chronic pancreatitis.
RESULTS: In relation to the association between exposure to volatile hydrocarbons and chronic pancreatitis the studies fail to adequately control for alcohol intake. Cytochrome P450 (CYP) induction occurs as a diffuse hepatic and extra-hepatic response to xenobiotic exposure rather than an acinar cell-specific process. GSH depletion is not consistently confirmed. There is good evidence of superoxide dismutase depletion in acute phases of injury but less to support a chronic intra-acinar depletion. Although the liver is the principal site of CYP induction there is no evidence to suggest that oxidative by-products are carried in bile and reflux into the pancreatic duct to cause injury.
CONCLUSION: Pancreatic acinar cell injury due to short-lived oxygen free radicals (generated by injury mediated by prematurely activated intra-acinar trypsin) is an important mechanism of cell damage in chronic pancreatitis. However, in contemporary paradigms of chronic pancreatitis this should be seen as one of a series of cell-injury mechanisms rather than a sole mediator.
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13
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Sanches LD, Santos SAA, Carvalho JR, Jeronimo GDM, Favaro WJ, Reis MDG, Felisbino SL, Justulin LA. Protective effect of γ-tocopherol-enriched diet on N-methyl-N-nitrosourea-induced epithelial dysplasia in rat ventral prostate. Int J Exp Pathol 2013; 94:362-72. [PMID: 24205794 DOI: 10.1111/iep.12042] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2013] [Revised: 06/14/2013] [Accepted: 07/02/2013] [Indexed: 12/19/2022] Open
Abstract
Despite recent advances in understanding the biological basis of prostate cancer (PCa), the management of this disease remains a challenge. Chemoprotective agents have been used to protect against or eradicate prostate malignancies. Here, we investigated the protective effect of γ-tocopherol on N-methyl-N-nitrosourea (MNU)-induced epithelial dysplasia in the rat ventral prostate (VP). Thirty-two male Wistar rats were divided into four groups (n = 8): control (CT): healthy control animals fed a standard diet; control+γ-tocopherol (CT+γT): healthy control animals without intervention fed a γ-tocopherol-enriched diet (20 mg/kg); N-methyl-N-nitrosourea (MNU): rats that received a single dose of MNU (30 mg/kg) plus testosterone propionate (100 mg/kg) and were fed a standard diet; and MNU+γ-tocopherol (MNU+γT): rats that received the same treatment of MNU plus testosterone and were fed with a γ-tocopherol-enriched diet (20 mg/kg). After 4 months, the VPs were excised to evaluate morphology, cell proliferation and apoptosis, as well as cyclooxygenase-2 (Cox-2), glutathione-S-transferase-pi (GST-pi) and androgen receptor (AR) protein expression, and matrix metalloproteinase-9 (MMP-9) activity. An increase in the incidence of epithelial dysplasias, such as stratified epithelial hyperplasia and squamous metaplasia, in the MNU group was accompanied by augmented cell proliferation, GST-pi and Cox-2 immunoexpression and pro-MMP-9 activity. Stromal thickening and inflammatory foci were also observed. The administration of a γ-tocopherol-enriched diet significantly attenuated the adverse effects of MNU in the VP. The incidence of epithelial dysplasia decreased, along with the cell proliferation index, GST-pi and Cox-2 immunoexpression. The gelatinolytic activity of pro-MMP-9 returned to the levels observed for the CT group. These results suggest that γ-tocopherol acts as a protective agent against MNU-induced prostatic disorders in the rat ventral prostate.
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Affiliation(s)
- Lucas D Sanches
- Department of Structural Biology, Institute of Biological and Natural Sciences, Federal University of Triangulo Mineiro, Uberaba, MG, Brazil
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14
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Tocotrienols reverse cardiovascular, metabolic and liver changes in high carbohydrate, high fat diet-fed rats. Nutrients 2012. [PMID: 23201770 PMCID: PMC3497010 DOI: 10.3390/nu4101527] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Tocotrienols have been reported to improve lipid profiles, reduce atherosclerotic lesions, decrease blood glucose and glycated haemoglobin concentrations, normalise blood pressure in vivo and inhibit adipogenesis in vitro, yet their role in the metabolic syndrome has not been investigated. In this study, we investigated the effects of palm tocotrienol-rich fraction (TRF) on high carbohydrate, high fat diet-induced metabolic, cardiovascular and liver dysfunction in rats. Rats fed a high carbohydrate, high fat diet for 16 weeks developed abdominal obesity, hypertension, impaired glucose and insulin tolerance with increased ventricular stiffness, lower systolic function and reduced liver function. TRF treatment improved ventricular function, attenuated cardiac stiffness and hypertension, and improved glucose and insulin tolerance, with reduced left ventricular collagen deposition and inflammatory cell infiltration. TRF improved liver structure and function with reduced plasma liver enzymes, inflammatory cell infiltration, fat vacuoles and balloon hepatocytes. TRF reduced plasma free fatty acid and triglyceride concentrations but only omental fat deposition was decreased in the abdomen. These results suggest that tocotrienols protect the heart and liver, and improve plasma glucose and lipid profiles with minimal changes in abdominal obesity in this model of human metabolic syndrome.
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15
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Abstract
PURPOSE OF REVIEW We review important new clinical observations in chronic pancreatitis reported in 2011. RECENT FINDINGS Smoking increases the risk of nongallstone acute pancreatitis and the progression of acute pancreatitis to chronic pancreatitis. Binge drinking during Oktoberfest did not associate with increased hospital admissions for acute pancreatitis. The unfolded protein response is an adaptive mechanism to maintain pancreatic health in response to noxious stimuli such as alcohol. Onset of diabetes mellitus in chronic pancreatitis is likely due to progressive disease rather than individual variables. Insufficient pancreatic enzyme dosing is common for treatment of pancreatic steatorrhea; 90 000 United States Pharmacopeia units of lipase should be given with meals. Surgical drainage provides sustained, superior pain relief compared with endoscopic treatment in patients advanced chronic pancreatitis with a dilated main duct ± pancreatic stones. The central acting gabapentoid pregabalin affords a modest 12% pain reduction in patients with chronic pancreatitis but approximately 30% of patients have significant side effects. SUMMARY Patients with nongallstone-related acute pancreatitis or chronic pancreatitis of any cause should cease smoking. Results of this year's investigations further elucidated the pancreatic pathobiology due to alcohol, onset of diabetes mellitus in chronic pancreatitis, and the mechanisms and treatment of neuropathic pain in chronic pancreatitis.
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16
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Erkan M, Hausmann S, Michalski CW, Fingerle AA, Dobritz M, Kleeff J, Friess H. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol 2012; 9:454-67. [PMID: 22710569 DOI: 10.1038/nrgastro.2012.115] [Citation(s) in RCA: 483] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the five most lethal malignancies worldwide and survival has not improved substantially in the past 30 years. Desmoplasia (abundant fibrotic stroma) is a typical feature of PDAC in humans, and stromal activation commonly starts around precancerous lesions. It is becoming clear that this stromal tissue is not a bystander in disease progression. Cancer-stroma interactions effect tumorigenesis, angiogenesis, therapy resistance and possibly the metastatic spread of tumour cells. Therefore, targeting the tumour stroma, in combination with chemotherapy, is a promising new option for the treatment of PDAC. In this Review, we focus on four issues. First, how can stromal activity be used to detect early steps of pancreatic carcinogenesis? Second, what is the effect of perpetual pancreatic stellate cell activity on angiogenesis and tissue perfusion? Third, what are the (experimental) antifibrotic therapy options in PDAC? Fourth, what lessons can be learned from Langton's Ant (a simple mathematical model) regarding the unpredictability of genetically engineered mouse models?
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Affiliation(s)
- Mert Erkan
- Department of General Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 12, 81675 Munich, Germany.
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17
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The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. J Gastrointest Cancer 2012; 40:1-9. [PMID: 22710569 DOI: 10.1007/s12029-009-9071-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2009] [Accepted: 05/27/2009] [Indexed: 12/18/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the five most lethal malignancies worldwide and survival has not improved substantially in the past 30 years. Desmoplasia (abundant fibrotic stroma) is a typical feature of PDAC in humans, and stromal activation commonly starts around precancerous lesions. It is becoming clear that this stromal tissue is not a bystander in disease progression. Cancer-stroma interactions effect tumorigenesis, angiogenesis, therapy resistance and possibly the metastatic spread of tumour cells. Therefore, targeting the tumour stroma, in combination with chemotherapy, is a promising new option for the treatment of PDAC. In this Review, we focus on four issues. First, how can stromal activity be used to detect early steps of pancreatic carcinogenesis? Second, what is the effect of perpetual pancreatic stellate cell activity on angiogenesis and tissue perfusion? Third, what are the (experimental) antifibrotic therapy options in PDAC? Fourth, what lessons can be learned from Langton's Ant (a simple mathematical model) regarding the unpredictability of genetically engineered mouse models?
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