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Malinauskas M, Paskeviciene D, Steponaitienė R, Gudaityte R, Kupčinskas L, Casselbrant A, Maleckas A. Role of DPP-4 and NPY Family Peptides in Gastrointestinal Symptoms Associated with Obesity and Type 2 Diabetes Mellitus. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:504. [PMID: 40142315 PMCID: PMC11944138 DOI: 10.3390/medicina61030504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 03/03/2025] [Accepted: 03/12/2025] [Indexed: 03/28/2025]
Abstract
Background and Objectives: Neuropeptide Y (NPY) family peptides and dipeptidyl peptidase-4 (DPP-4) are involved in gastrointestinal regulation and may contribute to obesity and type 2 diabetes mellitus (T2DM) pathophysiology. This study investigates their expression in jejunal muscular tissue and associations with gastrointestinal symptoms in patients with obesity, with (OB+/DM+) and without T2DM (OB+/DM-). Materials and Methods: This cross-sectional study includes forty-four patients undergoing laparoscopic Roux-en-Y gastric bypass divided based on T2DM status. Gastrointestinal symptoms were assessed using the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire, and jejunal tissue samples were analyzed for DPP-4, NPY, peptide YY (PYY), and pancreatic polypeptide (PP) mRNA and protein levels. Results: DPP-4, NPY, PYY, and PP gene expression in jejunal muscular tissue was similar between groups. In the OB+/DM+ group, PP protein was higher, while DPP-4 and PYY were lower compared to the OB+/DM- group. Significant positive correlations between DPP-4 and NPY, PYY, and PP were found in the OB+/DM- group, while only DPP-4 and PYY correlated in the OB+/DM+ group. Gastrointestinal symptoms in the OB+/DM- group showed positive correlations with PP (abdominal pain), DPP-4 (indigestion), and NPY (constipation). Conclusions: The study demonstrates significant differences in DPP-4, PYY, and PP protein expression between patients with obesity, with or without T2DM. Peptide correlations with gastrointestinal symptoms in non-diabetic patients suggest distinct regulatory mechanisms, warranting further research.
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Affiliation(s)
- Mantas Malinauskas
- Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
| | - Deimante Paskeviciene
- Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania
| | - Rūta Steponaitienė
- Institute for Digestive Research, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania
| | - Rita Gudaityte
- Department of Surgery, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania (A.M.)
| | - Limas Kupčinskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania
| | - Anna Casselbrant
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 413 45 Goteborg, Sweden
| | - Almantas Maleckas
- Department of Surgery, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania (A.M.)
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Ahmadzadeh AM, Aliabadi MM, Mirheidari SB, Hamedi-Asil M, Garousi S, Mottahedi M, Sahebkar A. Beneficial effects of resveratrol on diabetes mellitus and its complications: focus on mechanisms of action. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:2407-2442. [PMID: 39446148 DOI: 10.1007/s00210-024-03527-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 10/07/2024] [Indexed: 10/25/2024]
Abstract
Diabetes mellitus (DM) is a significant global health issue, associated with various microvascular and macrovascular complications that significantly impair patients' quality of life as well as healthspan and lifespan. Despite the availability of several anti-diabetic medications with different mechanisms of action, there remains no definite curative treatment. Hence, discovering new efficient complementary therapies is essential. Natural products have received significant attention due to their advantages in various pathological conditions. Resveratrol is a natural polyphenol that possesses antioxidant and anti-inflammatory properties, and its efficacy has been previously investigated in several diseases, including DM. Herein, we aimed to provide a holistic view of the signaling pathways and mechanisms of action through which resveratrol exerts its effects against DM and its complications.
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Affiliation(s)
- Amir Mahmoud Ahmadzadeh
- Department of Radiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | | | - Mahdie Hamedi-Asil
- School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Setareh Garousi
- Department of Surgical and Interventional Sciences, McGill University, Montreal, Quebec, Canada
| | - Mehran Mottahedi
- Department of Surgical and Interventional Sciences, McGill University, Montreal, Quebec, Canada
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Cao Y, Yang Z, Tang Q. The association between oxidative balance score with constipation and diarrhea in US adults: a cross-sectional analysis of NHANES 2007-2010. BMC Gastroenterol 2025; 25:29. [PMID: 39844079 PMCID: PMC11752723 DOI: 10.1186/s12876-025-03597-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 01/07/2025] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND Oxidative stress is associated with functional bowel disorders. The Oxidative Balance Score (OBS) is used to represent the overall level of oxidative stress experienced by an individual. Sex differences are exhibited in the occurrence of constipation and diarrhea. This population-based study aimed to examine the association between the OBS, constipation, and diarrhea, among adults in the United States (US), stratified by sex. METHODS Using data from the National Health and Nutrition Examination Survey (NHANES) database spanning from 2007 to 2010, a cross-sectional study including 4,462 participants (2,386 males and 2,076 females) was performed to assess the relationship between the OBS, constipation, and diarrhea, among adult men and women in the US. Constipation and diarrhea were identified according to bowel frequency and stool type, as outlined in the Bowel Health Questionnaire. The independent variable was the OBS based on 20 types of dietary and lifestyle components. We conducted a binary logistic regression subgroup analysis by sex, and a univariate subgroup analysis; and used a restricted cubic spline (RCS) to illustrate the relationship between the OBS and abnormal bowel health. RESULTS After adjusting for all covariates, a multivariate binary logistic regression analysis revealed that the OBS was negatively correlated with constipation in males [odds ratios (OR) (95% confidence intervals (CI)): 0.937 (0.888, 0.988), P = 0.017], and diarrhea in females [OR (95%CI): 0.951 (0.916, 0.987), P = 0.009]. RCS analysis identified a negative linear trend between OBS and constipation in males (P for non-linearity = 0.63), as well as between OBS and diarrhea in females (P for non-linearity > 0.05). CONCLUSION The current study found a negative correlation between the OBS and the risk of constipation in males, along with diarrhea in females. Oxidative stress, gut microbiota, and sex differences may be associated with intestinal dysfunction. These findings suggest that antioxidant-rich dietary modifications may be an effective strategy for preventing constipation in males and diarrhea in females.
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Affiliation(s)
- Yaoling Cao
- Department of General Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Zhihao Yang
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Qinqing Tang
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
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Cheng CK, Ye L, Wang Y, Wang YL, Xia Y, Wong SHS, Chen S, Huang Y. Exercised gut microbiota improves vascular and metabolic abnormalities in sedentary diabetic mice through gut‒vascular connection. JOURNAL OF SPORT AND HEALTH SCIENCE 2025; 14:101026. [PMID: 39827989 PMCID: PMC11937666 DOI: 10.1016/j.jshs.2025.101026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 12/05/2024] [Accepted: 12/13/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND Exercise elicits cardiometabolic benefits, reducing the risks of cardiovascular diseases and type 2 diabetes. This study aimed to investigate the vascular and metabolic effects of gut microbiota from exercise-trained donors on sedentary mice with type 2 diabetes and the potential mechanism. METHODS Leptin receptor-deficient diabetic (db/db) and nondiabetic (db/m+) mice underwent running treadmill exercise for 8 weeks, during which fecal microbiota transplantation (FMT) was parallelly performed from exercise-trained to sedentary diabetic (db/db) mice. Endothelial function, glucose homeostasis, physical performance, and vascular signaling of recipient mice were assessed. Vascular and intestinal stresses, including inflammation, oxidative stress, and endoplasmic reticulum (ER) stress, were investigated. RNA sequencing analysis on mouse aortic and intestinal tissues was performed. Gut microbiota profiles of recipient mice were evaluated by metagenomic sequencing. RESULTS Chronic exercise improved vascular and metabolic abnormalities in donor mice. Likewise, FMT from exercised donors retarded body weight gain and slightly improved grip strength and rotarod performance in recipient mice. Exercise-associated FMT enhanced endothelial function in different arteries, suppressed vascular and intestinal stresses, and improved glucose homeostasis in recipient mice, with noted microRNA-181b upregulation in aortas and intestines. Altered gut microbiota profiles and gut-derived factors (e.g., short-chain fatty acids and glucagon-like peptide-1) as well as improved intestinal integrity shall contribute to the cardiometabolic benefits, implying a gut‒vascular connection. CONCLUSION This proof-of-concept study indicates that exercised microbiota confers cardiometabolic benefits on sedentary db/db mice, extending the beneficial mechanism of exercise through gut‒vascular communication. The findings open up new therapeutic opportunities for cardiometabolic diseases and shed light on the development of exercise mimetics by targeting the gut microbiota.
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Affiliation(s)
- Chak Kwong Cheng
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR 999077, China; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
| | - Lianwei Ye
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong SAR 999077, China
| | - Yu Wang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China; Department of Endocrinology and Metabolism, Shenzhen University General Hospital, Shenzhen 518071, China
| | - Ya-Ling Wang
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong SAR 999077, China
| | - Yin Xia
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
| | - Stephen Heung-Sang Wong
- Department of Sports Science and Physical Education, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
| | - Sheng Chen
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong SAR 999077, China.
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR 999077, China; Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR 999077, China.
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Song HJ, Seol A, Park J, Kim JE, Kim TR, Park KH, Park ES, Lim SJ, Wang SH, Sung JE, Choi Y, Lee H, Hwang DY. Antioxidant and Laxative Effects of Methanol Extracts of Green Pine Cones ( Pinus densiflora) in Sprague-Dawley Rats with Loperamide-Induced Constipation. Antioxidants (Basel) 2024; 14:37. [PMID: 39857371 PMCID: PMC11762744 DOI: 10.3390/antiox14010037] [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: 09/20/2024] [Revised: 12/22/2024] [Accepted: 12/26/2024] [Indexed: 01/27/2025] Open
Abstract
Oxidative stress is the key cause of the etiopathogenesis of several diseases associated with constipation. This study examined whether the green pine cone can improve the symptoms of constipation based on the antioxidant activities. The changes in the key parameters for the antioxidant activity and laxative effects were examined in the loperamide (Lop)-induced constipation of Sprague-Dawley (SD) rats after being treated with the methanol extracts of green pine cone (MPC, unripe fruits of Pinus densiflora). MPC contained several bioactive compounds, including diterpenoid compounds such as dehydroabietic acid, taxodone, and ferruginol. In addition, it exhibited high scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals. These effects of MPC successfully reflected the improvement in nicotinamide adenine dinucleotide phosphate oxidase (NADP) H oxidase transcription, superoxide dismutase (SOD) levels, and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation levels in the mid colon of Lop+MPC-treated SD rats. Furthermore, significant improvements in the stool parameters, gastrointestinal (GI) transit, intestine length, and histopathological structure of the mid colon were detected in the Lop-induced constipation rats after MPC treatment. The other parameters, including the regulators for the adherens junction (AJ) and tight junction (TJ), and GI hormone secretion for laxative effects, were improved significantly in Lop+MPC-treated SD rats. These effects were also verified in Lop+MPC-treated primary rat intestine smooth muscle cells (pRISMCs) through analyses for antioxidant defense mechanisms. Overall, the finding of this study offers novel scientific evidence that MPC could be considered as a significant laxative for chronic constipation based on its antioxidant activity.
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Affiliation(s)
- Hee-Jin Song
- Department of Biomaterials Science (BK 21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (H.-J.S.); (A.S.); (J.-E.K.); (T.-R.K.); (K.-H.P.); (E.-S.P.); (S.-J.L.); (S.-H.W.); (J.-E.S.); (Y.C.)
| | - Ayun Seol
- Department of Biomaterials Science (BK 21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (H.-J.S.); (A.S.); (J.-E.K.); (T.-R.K.); (K.-H.P.); (E.-S.P.); (S.-J.L.); (S.-H.W.); (J.-E.S.); (Y.C.)
| | - Jumin Park
- Department of Food Science and Nutrition, College of Human Ecology, Pusan National University, Busan 46241, Republic of Korea; (J.P.); (H.L.)
| | - Ji-Eun Kim
- Department of Biomaterials Science (BK 21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (H.-J.S.); (A.S.); (J.-E.K.); (T.-R.K.); (K.-H.P.); (E.-S.P.); (S.-J.L.); (S.-H.W.); (J.-E.S.); (Y.C.)
| | - Tae-Ryeol Kim
- Department of Biomaterials Science (BK 21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (H.-J.S.); (A.S.); (J.-E.K.); (T.-R.K.); (K.-H.P.); (E.-S.P.); (S.-J.L.); (S.-H.W.); (J.-E.S.); (Y.C.)
| | - Ki-Ho Park
- Department of Biomaterials Science (BK 21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (H.-J.S.); (A.S.); (J.-E.K.); (T.-R.K.); (K.-H.P.); (E.-S.P.); (S.-J.L.); (S.-H.W.); (J.-E.S.); (Y.C.)
| | - Eun-Seo Park
- Department of Biomaterials Science (BK 21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (H.-J.S.); (A.S.); (J.-E.K.); (T.-R.K.); (K.-H.P.); (E.-S.P.); (S.-J.L.); (S.-H.W.); (J.-E.S.); (Y.C.)
| | - Su-Jeong Lim
- Department of Biomaterials Science (BK 21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (H.-J.S.); (A.S.); (J.-E.K.); (T.-R.K.); (K.-H.P.); (E.-S.P.); (S.-J.L.); (S.-H.W.); (J.-E.S.); (Y.C.)
| | - Su-Ha Wang
- Department of Biomaterials Science (BK 21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (H.-J.S.); (A.S.); (J.-E.K.); (T.-R.K.); (K.-H.P.); (E.-S.P.); (S.-J.L.); (S.-H.W.); (J.-E.S.); (Y.C.)
| | - Ji-Eun Sung
- Department of Biomaterials Science (BK 21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (H.-J.S.); (A.S.); (J.-E.K.); (T.-R.K.); (K.-H.P.); (E.-S.P.); (S.-J.L.); (S.-H.W.); (J.-E.S.); (Y.C.)
| | - Youngwoo Choi
- Department of Biomaterials Science (BK 21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (H.-J.S.); (A.S.); (J.-E.K.); (T.-R.K.); (K.-H.P.); (E.-S.P.); (S.-J.L.); (S.-H.W.); (J.-E.S.); (Y.C.)
| | - Heeseob Lee
- Department of Food Science and Nutrition, College of Human Ecology, Pusan National University, Busan 46241, Republic of Korea; (J.P.); (H.L.)
| | - Dae-Youn Hwang
- Department of Biomaterials Science (BK 21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (H.-J.S.); (A.S.); (J.-E.K.); (T.-R.K.); (K.-H.P.); (E.-S.P.); (S.-J.L.); (S.-H.W.); (J.-E.S.); (Y.C.)
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Jiang Y, Xu L, Zhu X, Zhu X, Xu X, Li J. Hyperglycemic stress induces oxidative damage of enteric glial cells by triggering redoxosomes/p66SHC activation. Redox Rep 2024; 29:2324234. [PMID: 38444386 PMCID: PMC10919305 DOI: 10.1080/13510002.2024.2324234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2024] Open
Abstract
OBJECTIVES Diabetic gastrointestinal dysfunction (DGD) is a serious complication of diabetic mellitus (DM), affecting the enteric nervous system (ENS), particular enteric glial cells (EGCs). This study aimed to elucidate the effects and underlying molecular mechanisms of hyperglycemic stress on EGCs in in vitro and in vivo models of DM. METHODS In in vitro studies, enteric glial cell line CRL-2690 was exposed to hyperglycemia stress, and cell viability, cell apoptosis and oxidative damage were assessed. In in vivo studies, STZ-induced diabetic mice were constructed, and cell apoptosis and oxidative damage of EGCs in the duodenum of DM mice were assessed. RESULTS The results showed that hyperglycemic stress markedly induced oxidative damage of EGCs in in vitro and in vivo models of DM. This damage was found to be dependent on the activation of redoxosomes, which involved the phosphorylation of SRC and Vav2, the up-regulation of active RAC1-GTP, and the activation of NADPH oxidase (NOX). Moreover, inhibitors of redoxosomes, such as the RAC1 inhibitor NSC23766 and the NOX inhibitor VAS2870, effectively mitigated the hyperglycemic stress-induced oxidative damage of EGCs. Additionally, inhibition of p66SHC, a downstream target of redoxosomes, attenuated oxidative damage of EGCs under hyperglycemic stress. DISCUSSION Our findings suggest that the redoxosomes/p66SHC signaling is involved in the oxidative damage of EGCs during the pathological process of DGD. This signaling cascade may represent a potential therapeutic target for the treatment of DGD.
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Affiliation(s)
- Yanmin Jiang
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
- Department of Endocrinology, Wuxi Medical Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Nanjing Medical University, Wuxi, People’s Republic of China
| | - Lan Xu
- Department of Endocrinology, Wuxi Medical Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Nanjing Medical University, Wuxi, People’s Republic of China
| | - Xue Zhu
- National Health Commission (NHC) Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, People’s Republic of China
| | - Xiaowei Zhu
- Department of Endocrinology, Wuxi Medical Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Nanjing Medical University, Wuxi, People’s Republic of China
| | - Xiang Xu
- Department of Endocrinology, Wuxi Medical Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Nanjing Medical University, Wuxi, People’s Republic of China
| | - Jianbo Li
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
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Esteves-Monteiro M, Ferreira-Duarte M, Vitorino-Oliveira C, Costa-Pires J, Oliveira S, Matafome P, Morato M, Dias-Pereira P, Costa VM, Duarte-Araújo M. Oxidative Stress and Histomorphometric Remodeling: Two Key Intestinal Features of Type 2 Diabetes in Goto-Kakizaki Rats. Int J Mol Sci 2024; 25:12115. [PMID: 39596183 PMCID: PMC11594829 DOI: 10.3390/ijms252212115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/30/2024] [Accepted: 11/01/2024] [Indexed: 11/28/2024] Open
Abstract
Gastrointestinal complications of diabetes are often overlooked, despite affecting up to 75% of patients. This study innovatively explores local glutathione levels and morphometric changes in the gut of Goto-Kakizaki (GK) rats, a type 2 diabetes animal model. Segments of the intestine, cecum, and colon were collected for histopathological analysis and glutathione quantification. A significant increase in the total thickness of the intestinal wall of GK rats was observed, particularly in the duodenum (1089.02 ± 39.19 vs. 864.19 ± 37.17 µm), ileum (726.29 ± 24.75 vs. 498.76 ± 16.86 µm), cecum (642.24 ± 34.15 vs. 500.97 ± 28.81 µm), and distal colon (1211.81 ± 51.32 vs. 831.71 ± 53.2 µm). Additionally, diabetic rats exhibited thickening of the muscular layers in all segments, except for the duodenum, which was also the only portion where the number of smooth muscle cells did not decrease. Moreover, myenteric neuronal density was lower in GK rats, suggesting neurological loss. Total glutathione levels were lower in all intestinal segments of diabetic rats (except duodenum), and the reduced/oxidized glutathione ratio (GSH/GSSG) was significantly decreased in GK rats, indicating increased oxidative stress. These findings strongly indicate that GK rats undergo significant intestinal remodeling, notable shifts in neuronal populations, and heightened oxidative stress-factors that likely contribute to the functional gastrointestinal alterations seen in diabetic patients.
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Affiliation(s)
- Marisa Esteves-Monteiro
- Associated Laboratory for Green Chemistry (LAQV) Network of Chemistry and Technology (REQUIMTE), University of Porto, 4050-313 Porto, Portugal (M.M.)
- Department of Immuno-Physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto (FFUP), 4050-313 Porto, Portugal
| | - Mariana Ferreira-Duarte
- Associated Laboratory for Green Chemistry (LAQV) Network of Chemistry and Technology (REQUIMTE), University of Porto, 4050-313 Porto, Portugal (M.M.)
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto (FFUP), 4050-313 Porto, Portugal
| | - Cláudia Vitorino-Oliveira
- Institute for Health and Bioeconomy (i4HB), Laboratory of Toxicology, Department of Biological Sciences, FFUP, 4050-313 Porto, Portugal (V.M.C.)
- Research Unit on Applied Molecular Biosciences (UCIBIO), FFUP, Laboratory of Toxicology, Department of Biological Sciences, FFUP, 4050-313 Porto, Portugal
| | - José Costa-Pires
- Department of Immuno-Physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
| | - Sara Oliveira
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Institute of Physiology, Faculty of Medicine, University of Coimbra (UC), 3000-548 Coimbra, Portugal; (S.O.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), UC, 3000-548 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-548 Coimbra, Portugal
| | - Paulo Matafome
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Institute of Physiology, Faculty of Medicine, University of Coimbra (UC), 3000-548 Coimbra, Portugal; (S.O.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), UC, 3000-548 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-548 Coimbra, Portugal
- Coimbra Health School (ESTeSC), Polytechnic University of Coimbra, 3046-854 Coimbra, Portugal
| | - Manuela Morato
- Associated Laboratory for Green Chemistry (LAQV) Network of Chemistry and Technology (REQUIMTE), University of Porto, 4050-313 Porto, Portugal (M.M.)
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto (FFUP), 4050-313 Porto, Portugal
| | - Patrícia Dias-Pereira
- Department of Pathology and Molecular Immunology, ICBAS-UP, 4050-313 Porto, Portugal;
| | - Vera Marisa Costa
- Institute for Health and Bioeconomy (i4HB), Laboratory of Toxicology, Department of Biological Sciences, FFUP, 4050-313 Porto, Portugal (V.M.C.)
- Research Unit on Applied Molecular Biosciences (UCIBIO), FFUP, Laboratory of Toxicology, Department of Biological Sciences, FFUP, 4050-313 Porto, Portugal
| | - Margarida Duarte-Araújo
- Associated Laboratory for Green Chemistry (LAQV) Network of Chemistry and Technology (REQUIMTE), University of Porto, 4050-313 Porto, Portugal (M.M.)
- Department of Immuno-Physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
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Abolfazli S, Foroumand S, Mohammadi E, Ahangar N, Kheirandish A, Fathi H, Mohammadi H. Brain mitochondrial damage attenuation by quercetin and N-acetyl cysteine: peripheral and central antiemetic effects. Toxicol Res (Camb) 2024; 13:tfae139. [PMID: 39246710 PMCID: PMC11374534 DOI: 10.1093/toxres/tfae139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 08/12/2024] [Accepted: 08/27/2024] [Indexed: 09/10/2024] Open
Abstract
Nausea serves as a protective mechanism in organisms to prevent excessive consumption of toxic substances. Due to the adverse effects of chemical anti-nausea drugs, there is a growing interest in using herbal remedies and natural antioxidants. In this study, we evaluated the neuroprotective effects of quercetin (QU) and N-acetylcysteine (NAC) against oxidative damage induced by nausea. Emesis was induced in chickens using ipecac and copper sulfate (600 and 60 mg/kg, orally, respectively). QU and NAC (with doses of 50, 100, 200 mg/kg), and their combination were administered, along with a standard therapy (metoclopramide; MET 2 mg/kg) for one-time. Mitochondrial function, lipid peroxidation (LPO), protein carbonyl (PC), glutathione level (GSH), and reactive oxygen species (ROS) as oxidative damage biomarkers were evaluated in the chicken's brain mitochondria. QU and NAC significantly reduced emesis induced by copper sulfate and ipecac compared to the control group (P < 0.001). Significant differences in oxidative damage were observed in the groups received of copper sulfate and ipecac compared with control group. Levels of LPO, ROS, and PC were significantly decreased after the administration of QU and NAC in emesis induced by copper sulfate and ipecac. While, mitochondrial function and GSH levels were increased after the administration of QU and NAC. Combination therapy with QU and NAC yielded the most effective results. This study suggests that QU and NAC possess antiemetic effects through both peripheral and central mechanisms and exhibit neuroprotective effects against oxidative brain damage induced by emesis by increasing plasma antioxidants or scavenging free radicals.
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Affiliation(s)
- Sajad Abolfazli
- Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Mazandaran Province, Farah Abad Road, P3MV+78R. PO Box- 48175/861, Sari, Iran
| | - Sarvenaz Foroumand
- Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Mazandaran Province, Farah Abad Road, P3MV+78R. PO Box- 48175/861, Ramsar, Iran
| | - Elham Mohammadi
- Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Mazandaran Province, Farah Abad Road, P3MV+78R. PO Box- 48175/861, Ramsar, Iran
| | - Nematollah Ahangar
- Department of Pharmacology, school of medicine, Gilan University of Medical Sciences, Mazandaran Province, Farah Abad Road, P3MV+78R. PO Box- 48175/861, Rasht, Iran
| | - Ali Kheirandish
- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Mazandaran Province, Farah Abad Road, P3MV+78R. PO Box- 48175/861, Tehran, Iran
| | - Hamed Fathi
- Pharmacutical Sciences Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Mazandaran Province, Farah Abad Road, P3MV+78R. PO Box- 48175/861, Sari, Iran
| | - Hamidreza Mohammadi
- Pharmacutical Sciences Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Mazandaran Province, Farah Abad Road, P3MV+78R. PO Box- 48175/861, Sari, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Mazandaran Province, Farah Abad Road, P3MV+78R. PO Box- 48175/861, Sari, Iran
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9
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Szczupak M, Jankowska M, Jankowski B, Wierzchowska J, Kobak J, Szczupak P, Kosydar-Bochenek J, Krupa-Nurcek S. Prokinetic effect of erythromycin in the management of gastroparesis in critically ill patients-our experience and literature review. Front Med (Lausanne) 2024; 11:1440992. [PMID: 39314225 PMCID: PMC11416996 DOI: 10.3389/fmed.2024.1440992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/26/2024] [Indexed: 09/25/2024] Open
Abstract
Introduction Gastroparesis is a disorder characterized by impaired gastric emptying and the accumulation of food in the intestines without any clear mechanical cause. Gastroparesis in critical care patients is a prevalent issue in the intensive care unit. The disruption of normal gastrointestinal motility in critically ill patients is linked to a significant risk of intolerance to enteral feeding, colonization of the gastrointestinal tract with pathogenic bacterial strains, increased permeability of the intestinal wall, translocation of the intestinal microbiota, leading to progressive malnutrition, and potential development of bacterial infection. Materials and methods The literature was reviewed to assess the benefits and risks associated with the use of this medication. Aim The aim of the study was to treat the symptoms of gastroparesis and stimulate gastrointestinal motility. Consequently, the aim was to reduce the amount of backed-up food content in the stomach, accelerate gastrointestinal motility, and return to intestinal feeding. Results Gastroparesis is a frequent issue among patients in the intensive care unit. Critical illness can lead to gastrointestinal motility disorders, causing slowed gastric emptying. This increases the risk of problems such as intolerance to enteral feeding, regurgitation, and aspiration of gastrointestinal contents into the respiratory tract, as well as colonization of the gastrointestinal tract by pathogens. Over time, impaired intestinal absorption can result in malnutrition, necessitating the initiation of parenteral nutrition. Conclusion After analysis of the literature and published scientific reports, as well as considering their own research, it is evident that erythromycin, as a prokinetic drug, effectively enhances gastrointestinal motility. This contributes to stimulating gastric emptying in critically ill patients with gastroparesis who are hospitalized in an intensive care unit. The use of erythromycin in combination with metoclopramide and/or itopride hydrochloride allows for a synergistic effect, leading to the quickest possible return to enteral feeding.
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Affiliation(s)
- Mateusz Szczupak
- Department of Anesthesiology and Intensive Care, Copernicus Hospital, Gdansk, Poland
| | - Magdalena Jankowska
- Department of Anesthesiology and Intensive Care, Copernicus Hospital, Gdansk, Poland
| | - Bartłomiej Jankowski
- Department of Anesthesiology and Intensive Care, Copernicus Hospital, Gdansk, Poland
| | - Jolanta Wierzchowska
- Department of Anesthesiology and Intensive Care, Copernicus Hospital, Gdansk, Poland
| | - Jacek Kobak
- Department of Otolaryngology, Medical University of Gdansk, Gdansk, Poland
| | - Paweł Szczupak
- Department of Electrical Engineering and Computer Science, Rzeszow University of Technology, Rzeszow, Poland
| | - Justyna Kosydar-Bochenek
- Institute of Health Sciences, College of Medical Sciences of the University of Rzeszow, Rzeszow, Poland
| | - Sabina Krupa-Nurcek
- Department of Surgery, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland
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10
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Gong K, Chen J, Yin X, Wu M, Zheng H, Jiang L. Untargeted metabolomics analysis reveals spatial metabolic heterogeneity in different intestinal segments of type 1 diabetic mice. Mol Omics 2024; 20:128-137. [PMID: 37997452 DOI: 10.1039/d3mo00163f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2023]
Abstract
Type 1 diabetes (T1D) has been reported to cause systematic metabolic disorders, but metabolic changes in different intestinal segments of T1D remain unclear. In this study, we analyzed metabolic profiles in the jejunum, ileum, cecum and colon of streptozocin-induced T1D and age-matched control (CON) mice by an LC-MS-based metabolomics method. The results show that segment-specific metabolic disorders occurred in the gut of T1D mice. In the jejunum, we found that T1D mainly led to disordered amino acid metabolism and most amino acids were significantly lower relative to CON mice. Moreover, fatty acid metabolism was disrupted mainly in the ileum, cecum and colon of T1D mice, such as arachidonic acid, alpha-linolenic acid and linoleic acid metabolism. Thus, our study reveals spatial metabolic heterogeneity in the gut of T1D mice and provides a metabolic view on diabetes-associated intestinal diseases.
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Affiliation(s)
- Kaiyan Gong
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Junli Chen
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Xiaoli Yin
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Mengjun Wu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Hong Zheng
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Lingling Jiang
- College of Science and Technology, Wenzhou-Kean University, Wenzhou 325060, China.
- Wenzhou Municipal Key Laboratory for Applied Biomedical and Biopharmaceutical Informatics, Wenzhou-Kean University, Wenzhou 325060, China
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11
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Blagov AV, Orekhova VA, Sukhorukov VN, Melnichenko AA, Orekhov AN. Potential Use of Antioxidant Compounds for the Treatment of Inflammatory Bowel Disease. Pharmaceuticals (Basel) 2023; 16:1150. [PMID: 37631065 PMCID: PMC10458684 DOI: 10.3390/ph16081150] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 07/29/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Since inflammatory bowel diseases (IBDs) are chronic, the development of new effective therapeutics to combat them does not lose relevance. Oxidative stress is one of the main pathological processes that determines the progression of IBD. In this regard, antioxidant therapy seems to be a promising approach. The role of oxidative stress in the development and progression of IBD is considered in detail in this review. The main cause of oxidative stress in IBD is an inadequate response of leukocytes to dysbiosis and food components in the intestine. Passage of immune cells through the intestinal barrier leads to increased ROS concentration and the pathological consequences of exposure to oxidative stress based on the development of inflammation and impaired intestinal permeability. To combat oxidative stress in IBD, several promising natural (curcumin, resveratrol, quercetin, and melatonin) and artificial antioxidants (N-acetylcysteine (NAC) and artificial superoxide dismutase (aSOD)) that had been shown to be effective in a number of clinical trials have been proposed. Their mechanisms of action on pathological events in IBD and clinical manifestations from their impact have been determined. The prospects for the use of other antioxidants that have not yet been tested in the treatment of IBD, but have the properties of potential therapeutic candidates, have been also considered.
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Affiliation(s)
- Alexander V. Blagov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, Moscow 125315, Russia; (V.A.O.); (V.N.S.); (A.A.M.)
| | - Varvara A. Orekhova
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, Moscow 125315, Russia; (V.A.O.); (V.N.S.); (A.A.M.)
- Institute for Atherosclerosis Research, Osennyaya Street 4-1-207, Moscow 121609, Russia
| | - Vasily N. Sukhorukov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, Moscow 125315, Russia; (V.A.O.); (V.N.S.); (A.A.M.)
- Institute for Atherosclerosis Research, Osennyaya Street 4-1-207, Moscow 121609, Russia
| | - Alexandra A. Melnichenko
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, Moscow 125315, Russia; (V.A.O.); (V.N.S.); (A.A.M.)
| | - Alexander N. Orekhov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, Moscow 125315, Russia; (V.A.O.); (V.N.S.); (A.A.M.)
- Institute for Atherosclerosis Research, Osennyaya Street 4-1-207, Moscow 121609, Russia
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12
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Zarezadeh M, Mahmoudinezhad M, Hosseini B, Khorraminezhad L, Razaghi M, Alvandi E, Saedisomeolia A. Dietary pattern in autism increases the need for probiotic supplementation: A comprehensive narrative and systematic review on oxidative stress hypothesis. Clin Nutr 2023; 42:1330-1358. [PMID: 37418842 DOI: 10.1016/j.clnu.2023.06.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/15/2023] [Accepted: 06/11/2023] [Indexed: 07/09/2023]
Abstract
Autism spectrum disorders (ASDs) are associated with specific dietary habits, including limited food selection and gastrointestinal problems, resulting in an altered gut microbiota. Autistic patients have an elevated abundance of certain gut bacteria associated with increased oxidative stress in the gastrointestinal tract. Probiotic supplementation has been shown to decrease oxidative stress in a simulated gut model, but the antioxidant effects of probiotics on the oxidative stress of the gut in autistic patients have not been directly studied. However, it is speculated that probiotic supplementation may help decrease oxidative stress in the gastrointestinal tract of autistic patients due to their specific dietary habits altering the microbiota. PubMed, Scopus and Web of Science databases and Google Scholar were searched up to May 2023. This systematic-narrative review aims to present the latest evidence regarding the changes in eating habits of autistic children which may further increase the gut microbiota induced oxidative stress. Additionally, this review will assess the available literature on the effects of probiotic supplementation on oxidative stress parameters.
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Affiliation(s)
- Meysam Zarezadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Banafshe Hosseini
- Clinical Research and Knowledge Transfer Unit on Childhood Asthma, Research Centre, Sainte-Justine University Health Centre, Montreal, QC H3T 1C5, Canada
| | - Leila Khorraminezhad
- School of Human Nutrition, McGill University, Ste-Anne-de-Bellevue, Québec, Canada
| | - Maryam Razaghi
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Ehsan Alvandi
- School of Medicine, Western Sydney University, NSW, Australia
| | - Ahmad Saedisomeolia
- School of Human Nutrition, McGill University, Ste-Anne-de-Bellevue, Québec, Canada.
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13
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Yao Q, Yu Z, Meng Q, Chen J, Liu Y, Song W, Ren X, Zhou J, Chen X. The Role of Small Intestinal Bacterial Overgrowth in Obesity and Its Related Diseases. Biochem Pharmacol 2023; 212:115546. [PMID: 37044299 DOI: 10.1016/j.bcp.2023.115546] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/31/2023] [Accepted: 04/04/2023] [Indexed: 04/14/2023]
Abstract
Obesity has become a major public health problem worldwide and its occurrence is increasing globally. Obesity has also been shown to be involved in the occurrence and development of many diseases and pathological conditions, such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), insulin resistance (IR). In recent years, gut microbiota has received extensive attention as an important regulatory part involved in host diseases and health status. A growing body of evidence suggests that gut microbiota dysbiosis has a significant adverse effect on the host. Small intestinal bacterial overgrowth (SIBO), a type of intestinal microbial dysbiosis, has been gradually revealed to be associated with obesity and its related diseases. The presence of SIBO may lead to the destruction of intestinal barrier integrity, increased intestinal permeability, increased endotoxin levels, activation of inflammatory responses, and translocation of bacteria from the colon to the small intestine. However, the causal relationship between SIBO and obesity and the specific mechanisms have not been well elucidated. This review discusses the cross-talk between SIBO and obesity and its related diseases, and expounds its potential mechanisms and interventions, which may help to discover new therapeutic targets for obesity and its related diseases and develop treatment options.
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Affiliation(s)
- Qinyan Yao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Zihan Yu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Qingguo Meng
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Jihua Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Yaxin Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Wenxuan Song
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Xiangfeng Ren
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Jinjie Zhou
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Xin Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China.
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14
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Sprouse J, Sampath C, Gangula P. 17β-Estradiol Suppresses Gastric Inflammatory and Apoptotic Stress Responses and Restores nNOS-Mediated Gastric Emptying in Streptozotocin (STZ)-Induced Diabetic Female Mice. Antioxidants (Basel) 2023; 12:758. [PMID: 36979006 PMCID: PMC10045314 DOI: 10.3390/antiox12030758] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/09/2023] [Accepted: 03/12/2023] [Indexed: 03/30/2023] Open
Abstract
Gastroparesis (Gp) is a severe complication of diabetes mellitus (DM) observed predominantly in women. It is characterized by abnormal gastric emptying (GE) without mechanical obstruction in the stomach. Nitric oxide (NO) is an inhibitory neurotransmitter produced by neuronal nitric oxide synthase (nNOS). It plays a critical role in gastrointestinal (GI) motility and stomach emptying. Here, we wanted to demonstrate the protective effects of supplemental 17β-estradiol (E2) on NO-mediated gastric function. We showed E2 supplementation to alleviate oxidative and inflammatory stress in streptozotocin (STZ)-induced diabetic female mice. Our findings suggest that daily administration of E2 at therapeutic doses is beneficial for metabolic homeostasis. This restoration occurs via regulating and modulating the expression/function of glycogen synthase kinase-3β (GSK-3β), nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), Phase II enzymes, MAPK- and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB)-mediated inflammatory cytokines (IL-1β, IL-6, TNFα, IGF-1), and gastric apoptotic regulators. We also showed E2 supplementation to elevate GCH-1 protein levels in female diabetic mice. Since GCH-1 facilitates the production of tetrahydrobiopterin (BH4, cofactor for nNOS), an increase in GCH-1 protein levels in diabetic mice may improve their GE and nitrergic function. Our findings provide new insights into the impact of estrogen on gastric oxidative stress and intracellular inflammatory cascades in the context of Gp.
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Affiliation(s)
- Jeremy Sprouse
- Department of Oral Diagnostic Sciences and Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA
- Department of Endodontics, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA
| | - Chethan Sampath
- Department of Oral Diagnostic Sciences and Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA
| | - Pandu Gangula
- Department of Oral Diagnostic Sciences and Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA
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15
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de Oliveira K, Severo J, da Silva A, dos Santos B, Mendes P, Sabino J, Filho A, Correia-de-Sá P, dos Santos A, da Silva M. P2X7 receptor antagonist improves gastrointestinal disorders in spontaneously hypertensive rats. Braz J Med Biol Res 2023; 56:e12569. [PMID: 36856255 PMCID: PMC9974071 DOI: 10.1590/1414-431x2023e12569] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 01/05/2023] [Indexed: 03/02/2023] Open
Abstract
The purinergic system participates in the control of blood pressure. Hypertension promotes the occurrence of gastrointestinal disorders such as intestinal inflammation and gastric emptying delay. This study aimed i) to investigate the participation of the P2X7 receptor blocker Brilliant Blue G (BBG) on gastric emptying of solids and changes in oxidative stress in the gastric fundus, duodenum, and colon of spontaneously hypertensive rats (SHR) and ii) to study the putative relationship of this effect with the renin-angiotensin system. Rats were divided into five groups: Control, SHR, SHR+BBG, SHR+BBG+ATP, and SHR+BBG+ANG II. In the gastrointestinal tract, we assessed gastric emptying (GE) and oxidative stress markers (NOx, MPO, GSH, SOD). We observed a decrease in the GE rate (P<0.05) in SHR vs control rats (21.8±2.0% vs 42.8±3.5%). The decrease in GE was returned (P<0.05) to control levels by BBG in SHR rats (21.8±2.0% vs 41.6±3.2%). Co-administration of ATP or ANG II together with BBG bypassed the effect of the P2X7 antagonist on GE in SHR (P<0.05) (21.9±5.0% vs 25.6±3.0% vs 41.6±3.2%). The MPO activity increased (P<0.05) in the gastric fundus of SHR compared to control rats (6.12±2.26 vs 0.077±0.02 UMPO/mg tissue); this effect was prevented (P<0.05) by BBG (0.55±0.15 vs 6.12±2.26 UMPO/mg tissue). Data demonstrated that blockage of P2X7 receptors with BBG can improve the GE delay and oxidative stress biomarkers in SHR animals. This preventive effect of BBG on GE delay was abrogated by ANG II and ATP, thus prompting crosstalk between renin-angiotensin and the purinergic signaling systems underlying this phenomenon.
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Affiliation(s)
- K.B.V. de Oliveira
- Programa de Pós-Graduação em Farmacologia, Universidade Federal do Piauí, Teresina, PI, Brasil,Departamento de Educação Física, Laboratório de Exercício e Trato Gastrointestinal, Universidade Federal do Piauí, Teresina, PI, Brasil
| | - J.S. Severo
- Programa de Pós-Graduação em Alimentação e Nutrição, Universidade Federal do Piauí, Teresina, PI, Brasil,Departamento de Educação Física, Laboratório de Exercício e Trato Gastrointestinal, Universidade Federal do Piauí, Teresina, PI, Brasil
| | - A.C.A. da Silva
- Programa de Pós-Graduação em Farmacologia, Universidade Federal do Piauí, Teresina, PI, Brasil,Departamento de Educação Física, Laboratório de Exercício e Trato Gastrointestinal, Universidade Federal do Piauí, Teresina, PI, Brasil
| | - B.L.B. dos Santos
- Departamento de Educação Física, Laboratório de Exercício e Trato Gastrointestinal, Universidade Federal do Piauí, Teresina, PI, Brasil,Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Piauí, Teresina, PI, Brasil
| | - P.H.M. Mendes
- Departamento de Educação Física, Laboratório de Exercício e Trato Gastrointestinal, Universidade Federal do Piauí, Teresina, PI, Brasil
| | - J.P.J. Sabino
- Departamento de Biofísica e Fisiologia, Universidade Federal do Piauí, Teresina, PI, Brasil,Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Piauí, Teresina, PI, Brasil
| | - A.L.M.M. Filho
- Centro de Ciências da Saúde, Universidade Estadual do Piauí, Teresina, PI, Brasil
| | - P. Correia-de-Sá
- Departamento de Imuno-Fisiologia e Farmacologia, Laboratório de Farmacologia e Neurobiologia, Centro de Descoberta de Fármacos e Medicamentos Inovadores, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - A.A. dos Santos
- Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - M.T.B. da Silva
- Programa de Pós-Graduação em Farmacologia, Universidade Federal do Piauí, Teresina, PI, Brasil,Programa de Pós-Graduação em Alimentação e Nutrição, Universidade Federal do Piauí, Teresina, PI, Brasil,Departamento de Educação Física, Laboratório de Exercício e Trato Gastrointestinal, Universidade Federal do Piauí, Teresina, PI, Brasil,Departamento de Imuno-Fisiologia e Farmacologia, Laboratório de Fisiologia, Centro de Descoberta de Fármacos e Medicamentos Inovadores, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
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16
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Was H, Borkowska A, Bagues A, Tu L, Liu JYH, Lu Z, Rudd JA, Nurgali K, Abalo R. Mechanisms of Chemotherapy-Induced Neurotoxicity. Front Pharmacol 2022; 13:750507. [PMID: 35418856 PMCID: PMC8996259 DOI: 10.3389/fphar.2022.750507] [Citation(s) in RCA: 103] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 03/02/2022] [Indexed: 12/15/2022] Open
Abstract
Since the first clinical trials conducted after World War II, chemotherapeutic drugs have been extensively used in the clinic as the main cancer treatment either alone or as an adjuvant therapy before and after surgery. Although the use of chemotherapeutic drugs improved the survival of cancer patients, these drugs are notorious for causing many severe side effects that significantly reduce the efficacy of anti-cancer treatment and patients’ quality of life. Many widely used chemotherapy drugs including platinum-based agents, taxanes, vinca alkaloids, proteasome inhibitors, and thalidomide analogs may cause direct and indirect neurotoxicity. In this review we discuss the main effects of chemotherapy on the peripheral and central nervous systems, including neuropathic pain, chemobrain, enteric neuropathy, as well as nausea and emesis. Understanding mechanisms involved in chemotherapy-induced neurotoxicity is crucial for the development of drugs that can protect the nervous system, reduce symptoms experienced by millions of patients, and improve the outcome of the treatment and patients’ quality of life.
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Affiliation(s)
- Halina Was
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Warsaw, Poland
| | - Agata Borkowska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Warsaw, Poland.,Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Ana Bagues
- Área de Farmacología y Nutrición, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), Alcorcón, Spain.,High Performance Research Group in Experimental Pharmacology (PHARMAKOM-URJC), URJC, Alcorcón, Spain.,Unidad Asociada I+D+i del Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Longlong Tu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Julia Y H Liu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Zengbing Lu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - John A Rudd
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.,The Laboratory Animal Services Centre, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia.,Department of Medicine Western Health, University of Melbourne, Melbourne, VIC, Australia.,Regenerative Medicine and Stem Cells Program, Australian Institute for Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia
| | - Raquel Abalo
- Área de Farmacología y Nutrición, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), Alcorcón, Spain.,Unidad Asociada I+D+i del Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.,High Performance Research Group in Physiopathology and Pharmacology of the Digestive System (NeuGut-URJC), URJC, Alcorcón, Spain.,Grupo de Trabajo de Ciencias Básicas en Dolor y Analgesia de la Sociedad Española del Dolor, Madrid, Spain
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17
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Busa P, Kuthati Y, Huang N, Wong CS. New Advances on Pathophysiology of Diabetes Neuropathy and Pain Management: Potential Role of Melatonin and DPP-4 Inhibitors. Front Pharmacol 2022; 13:864088. [PMID: 35496279 PMCID: PMC9039240 DOI: 10.3389/fphar.2022.864088] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/14/2022] [Indexed: 12/14/2022] Open
Abstract
Pre-diabetes and diabetes are growing threats to the modern world. Diabetes mellitus (DM) is associated with comorbidities such as hypertension (83.40%), obesity (90.49%), and dyslipidemia (93.43%), creating a substantial burden on patients and society. Reductive and oxidative (Redox) stress level imbalance and inflammation play an important role in DM progression. Various therapeutics have been investigated to treat these neuronal complications. Melatonin and dipeptidyl peptidase IV inhibitors (DPP-4i) are known to possess powerful antioxidant and anti-inflammatory properties and have garnered significant attention in the recent years. In this present review article, we have reviewed the recently published reports on the therapeutic efficiency of melatonin and DPP-4i in the treatment of DM. We summarized the efficacy of melatonin and DPP-4i in DM and associated complications of diabetic neuropathy (DNP) and neuropathic pain. Furthermore, we discussed the mechanisms of action and their efficacy in the alleviation of oxidative stress in DM.
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Affiliation(s)
- Prabhakar Busa
- Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan
| | - Yaswanth Kuthati
- Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan
| | - Niancih Huang
- Department of Anesthesiology, Tri-Service General Hospital, Taipei, Taiwan
- Grauate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Shung Wong
- Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan
- Department of Anesthesiology, Tri-Service General Hospital, Taipei, Taiwan
- Grauate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
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18
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Feng X, Li XQ. The prevalence of small intestinal bacterial overgrowth in diabetes mellitus: a systematic review and meta-analysis. Aging (Albany NY) 2022; 14:975-988. [PMID: 35086065 PMCID: PMC8833117 DOI: 10.18632/aging.203854] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 01/21/2022] [Indexed: 11/25/2022]
Abstract
OBJECTIVE We conducted this systematic review and meta-analysis to estimate the prevalence of SIBO in diabetic patients and to determine the association between SIBO and diabetes. METHODS A comprehensive literature search of the PubMed, Cochrane Library and EMBASE databases from inception to June 2021 was conducted for studies correlating SIBO with diabetes. Studies were screened, and relevant data were extracted and analysed. The pooled prevalence of SIBO among diabetic patients and the odds ratio of SIBO among diabetic patients compared with controls were calculated. RESULTS Fourteen studies including 1417 diabetic patients and 649 controls met the inclusion criteria. The pooled prevalence of SIBO in diabetes was 29% (95% CI 20-39%). The odds ratio of SIBO in diabetic patients was 2.91 (95% CI 0.82-10.32, p=0.1) compared with controls. Subgroup analyses showed that the prevalence of SIBO in diabetes was higher in studies using jejunal aspirate culture for diagnosis (39%, 95% CI 12-66%) than in those using the lactulose breath test (31%, 95% CI 18-43%) or glucose breath test (29%, 95% CI 14-43%). The prevalence of SIBO in diabetes was higher in studies conducted in Western countries (35%, 95% CI 21-49%) than in those conducted in Eastern countries (24%, 95% CI 14-34%), and the prevalence of SIBO in type 1 diabetes (25%, 95% CI 14%-36%) was not significantly different from that in type 2 diabetes (30%, 95% CI 13%-47%). CONCLUSIONS Twenty-nine percent of diabetic patients tested positive for SIBO, and the risk of SIBO in diabetic patients was 2.91 times higher than that in patients without diabetes. Diabetes could be a predisposing factor for the development of SIBO, especially among patients diagnosed by jejunal aspirate culture or those in Western populations.
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Affiliation(s)
- Xin Feng
- Department of Gastroenterology, The People's Hospital of Yubei District of Chongqing City, Chongqing 401120, China
| | - Xiao-Qing Li
- Department of Gastroenterology, Chongqing University Cancer Hospital, Shapingba, Chongqing 400030, China
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19
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Oraebosi MI, Olurishe TO, Anafi SB, Bisalla M. Diurnal efficacy of alpha-lipoic acid/nifedipine/glimepiride combination mitigates diabetic neuropathies in rats. ANNALES PHARMACEUTIQUES FRANÇAISES 2021; 80:291-300. [PMID: 34599891 DOI: 10.1016/j.pharma.2021.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 09/17/2021] [Accepted: 09/22/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVES Time-dependent effects of alpha-lipoic acid/nifedipine/glimepiride combination on diabetic neuropathies were investigated in rats. 7 groups (N=9) of rats were used. MATERIALS AND METHODS First and second groups were apparently normal and diabetic rats respectively, and were administered 1 mL/kg distilled water. The rest of the groups were diabetic and administered 10 mg/kg glimepiride at night-time (8:00 pm). Groups 4-7 were administered additional 20 mg/kg nifedipine at morning-time (8:00 am), while groups 5-7 were also administered 100 mg/kg alpha-lipoic acid (ALA) in the morning, afternoon and night-time respectively (8:00 am, 2:00 pm and 8:00 pm). During the 28 days of oral treatment, paw pressure, tail immersion and motor coordination tests were conducted. The rats were euthanized on the 29th day after a charcoal meal. The small intestines were excised to determine intestinal transit while the brain was collected, homogenised and used to determine levels of oxidative stress. RESULTS Data show that treatment with ALA at 8:00 am or 2:00 pm significantly (p ≤ 0.01) produced a delay in the onset and improved prognosis of neuropathies. Treatment with ALA at 8:00 pm prevented manifestation of neuropathies throughout the study with positive antioxidant effects. CONCLUSION Time-dependent ALA treatment in combination with nifedipine and glimepiride should be studied in humans with an approximately similar circadian timing. This may provide additional clinical therapeutic options for diabetic neuropathies.
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Affiliation(s)
| | | | - Sherifat Bola Anafi
- Department of Pharmacology and Therapeutics, Ahmadu Bello University, Zaria, Nigeria
| | - Mohammed Bisalla
- Department of Veterinary Pathology and Microbiology, Ahmadu Bello University, Zaria, Nigeria
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20
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Sharma A, Kaur R, Kaur J, Garg S, Bhatti R, Kaur A. An endophytic Schizophyllum commune Fr. exhibits in-vitro and in-vivo antidiabetic activity in streptozotocin induced diabetic rats. AMB Express 2021; 11:58. [PMID: 33881650 PMCID: PMC8060376 DOI: 10.1186/s13568-021-01219-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 04/09/2021] [Indexed: 03/06/2023] Open
Abstract
The present study aimed at isolation of endophytic basidiomycetous fungi and evaluation of their in-vitro and in-vivo antidiabetic potential. Preliminary screening for in-vitro activity was carried out using α-glucosidase inhibition assay. An endophytic isolate Sch1 (isolated from Aloe vera), identified to be Schizophyllum commune Fr. on molecular basis, exhibiting more than 90% α-glucosidase inhibitiory activity was selected for further studies. Detailed in-vivo investigations for antidiabetic potential of ethyl acetate extract of S. commune (Sch1), at two different doses, were carried out in streptozotocin induced diabetic Wistar rats. Treatment of diabetic rats with S. commune extract caused significant decrease in blood glucose level and increase in body weight after 14 days experimental period. It significantly restored renal parameters including creatinine, blood urea nitrogen, fractional excretion of sodium, and potassium level in diabetic rats. Improvement in lipid profile and level of antioxidant parameters viz. reduced glutathione, thiobarbituric acid reactive species, and superoxide anion generation was also observed after treatment. Liver enzymes (serum glutamic pyruvic transaminase, serum glutamic-oxaloacetic transaminases, and alkaline phosphatase) homeostasis was found to be markedly improved in diabetic rats administered with S. commune extract. The effects were more pronounced at higher concentration and comparable to acarbose which was used as positive control. Phytochemical analysis revealed the presence of phenolics and terpenoids in the ethyl acetate extract. This is the first report highlighting the therapeutic potential of an endophytic S. commune in the management of diabetes.
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21
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Medeńska W, Dratwa-Chałupnik A, Ożgo M. Cow’s whey proteins involvement in the development of the immunological system and gastrointestinal tract in calves. A review. JOURNAL OF ANIMAL AND FEED SCIENCES 2021. [DOI: 10.22358/jafs/134176/2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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22
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Protective effects of quercetin-loaded microcapsules on the enteric nervous system of diabetic rats. Auton Neurosci 2021; 230:102759. [DOI: 10.1016/j.autneu.2020.102759] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 11/27/2020] [Accepted: 12/02/2020] [Indexed: 02/06/2023]
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23
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Sampath C, Srinivasan S, Freeman ML, Gangula PR. Inhibition of GSK-3β restores delayed gastric emptying in obesity-induced diabetic female mice. Am J Physiol Gastrointest Liver Physiol 2020; 319:G481-G493. [PMID: 32812777 PMCID: PMC7654647 DOI: 10.1152/ajpgi.00227.2020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Diabetic gastroparesis (DG) is a clinical syndrome characterized by delayed gastric emptying (DGE). Loss of nuclear factor erythroid 2-related factor 2 (Nrf2) is associated with reduced neuronal nitric oxide synthase-α (nNOSα)-mediated gastric motility and DGE. Previous studies have shown that nuclear exclusion and inactivation of Nrf2 is partly regulated by glycogen synthase kinase 3β (GSK-3β). In the current study, the molecular signaling of GSK-3β-mediated Nrf2 activation and its mechanistic role on DG were investigated in high-fat diet (HFD)-induced obese/Type 2 diabetes (T2D) female mice. Adult female C57BL/6J mice were fed with HFD or normal diet (ND) with or without GSK-3β inhibitor (SB 216763, 10 mg/kg body wt ip) start from the 14th wk and continued feeding mice for an additional 3-wk time period. Our results show that treatment with GSK-3β inhibitor SB attenuated DGE in obese/T2D mice. Treatment with SB restored impaired gastric 1) Nrf2 and phase II antioxidant enzymes through PI3K/ERK/AKT-mediated pathway, 2) tetrahydrobiopterin (BH4, cofactor of nNOS) biosynthesis enzyme dihydrofolate reductase, and 3) nNOSα dimerization in obese/T2 diabetic female mice. SB treatment normalized caspase 3 activity and downstream GSK-3β signaling in the gastric tissues of the obese/T2 diabetic female mice. In addition, GSK-3β inhibitor restored impaired nitrergic relaxation in hyperglycemic conditions. Finally, SB treatment reduced GSK3 marker, pTau in adult primary enteric neuronal cells. These findings emphasize the importance of GSK-3β on regulating gastric Nrf2 and nitrergic mediated gastric emptying in obese/diabetic rodents.NEW & NOTEWORTHY Inhibition of glycogen synthase kinase 3β (GSK-3β) with SB 216763 attenuates delayed gastric emptying through gastric nuclear factor erythroid 2-related factor 2 (Nrf2)-phase II enzymes in high-fat diet-fed female mice. SB 216763 restored impaired gastric PI3K/AKT/ β-catenin/caspase 3 expression. Inhibition of GSK-3β normalized gastric dihydrofolate reductase, neuronal nitric oxide synthase-α expression, dimerization and nitrergic relaxation. SB 216763 normalized both serum estrogen and nitrate levels in female obese/Type 2 diabetes mice. SB 216763 reduced downstream signaling of GSK-3β in enteric neuronal cells in vitro.
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Affiliation(s)
- Chethan Sampath
- 1Department of Oral Diagnostic Sciences and Research, School of Dentistry, Meharry Medical College, Nashville, Tennessee
| | - Shanthi Srinivasan
- 2Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia and Atlanta Veterans Affairs Health Care System, Decatur, Atlanta, Georgia
| | - Michael L. Freeman
- 3Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Pandu R. Gangula
- 1Department of Oral Diagnostic Sciences and Research, School of Dentistry, Meharry Medical College, Nashville, Tennessee
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24
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Sprouse JC, Sampath C, Gangula PR. Supplementation of 17β-Estradiol Normalizes Rapid Gastric Emptying by Restoring Impaired Nrf2 and nNOS Function in Obesity-Induced Diabetic Ovariectomized Mice. Antioxidants (Basel) 2020; 9:E582. [PMID: 32635208 PMCID: PMC7402187 DOI: 10.3390/antiox9070582] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 06/25/2020] [Accepted: 07/01/2020] [Indexed: 12/13/2022] Open
Abstract
Gastroparesis (Gp) is a multifactorial condition commonly observed in females and is characterized by delayed or rapid gastric emptying (GE). The role of ovarian hormones on GE in the pathogenesis of obesity induced type 2 diabetes mellitus (T2DM) is completely unknown. The aims of our study are to investigate whether supplementation of 17β-estradiol (E2) or progesterone (P4) restores impaired nuclear factor erythroid 2-related factor 2 (Nrf2, an oxidative stress-responsive transcription factor) and nitric oxide (NO)-mediated gastric motility in ovariectomized (OVX) mice consuming a high-fat diet (HFD, a model of T2DM). Groups of OVX+HFD mice were administered daily subcutaneous doses of either E2 or P4 for 12 weeks. The effects of E2 and P4 on body weight, metabolic homeostasis, solid GE, gastric antrum NO-mediated relaxation, total nitrite levels, neuronal nitric oxide synthase (nNOSα), and its cofactor expression levels were assessed in OVX+HFD mice. HFD exacerbated hyperglycemia and insulinemia while accelerating GE (p < 0.05) in OVX mice. Exogenous E2, but not P4, attenuated rapid gastric emptying and restored gastric nitrergic relaxation, total nitrite levels, nNOSα, and cofactor expression via normalizing Nrf2-Phase II enzymes, inflammatory response, and mitogen-activated protein kinase (MAPK) protein expression in OVX+HFD mice. We conclude that E2 is beneficial in normalizing metabolic homeostasis and gastric emptying in obese, diabetic OVX mice consuming a fat-rich diet.
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Affiliation(s)
- Jeremy C. Sprouse
- School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USA;
| | - Chethan Sampath
- Department of ODS & Research, School of Dentistry, Nashville, TN 37208, USA;
| | - Pandu R. Gangula
- Department of ODS & Research, School of Dentistry, Nashville, TN 37208, USA;
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25
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Malik A, Morya RK, Saha S, Singh PK, Bhadada SK, Rana SV. Oxidative stress and inflammatory markers in type 2 diabetic patients. Eur J Clin Invest 2020; 50:e13238. [PMID: 32298466 DOI: 10.1111/eci.13238] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 03/16/2020] [Accepted: 03/31/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is most demanding public health problem of 21st century. Uncontrolled diabetes may cause complications affecting any part of gut from mouth to rectum presenting as vomiting, nausea, bloating, abdominal pain, constipation and diarrhoea. The aim of this study was to compare levels of oxidative stress and inflammatory markers in small intestinal bacterial overgrowth (SIBO)-positive and negative diabetic patients. SUBJECTS AND METHODS An observational analytical study was conducted on 300 T2DM (>5 years' duration) attending Diabetic Clinic. A total of 200 age- and sex-matched healthy individuals were enrolled as controls. Noninvasive glucose hydrogen breath test was used to diagnose SIBO. A total of 5 mL blood was taken. Plasma was used for measurement of inflammatory cytokines (TNF-α, IL-6 and IL-10) by ELISA. Hemolysate was used for measurement of lipid peroxidation, reduced GSH, superoxide dismutase and catalase. RESULTS It was observed that constipation was present in 59.6% T2DM patients. SIBO was observed significantly higher (P < .0001) in T2DM patients than controls. Inflammatory and oxidative stress markers were significantly (P < .001) higher in diabetic and SIBO-positive patients than controls and SIBO negative. Reduced GSH was significantly (P < .05) lower whereas superoxide dismutase (SOD) and catalase antioxidant enzymes were significantly (<.05) higher in diabetic and SIBO-positive patients than controls and SIBO-negative patients. CONCLUSION From this study, it could be concluded that SIBO in T2DM patients can cause oxidative stress and inflammation. Therefore, SIBO should be taken care to prevent further damage to intestine.
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Affiliation(s)
- Aastha Malik
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rajesh Kumar Morya
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sarama Saha
- Department of Biochemistry, All India Institute of Medical Sciences Rishikesh, Rishikesh, India
| | - Praveen Kumar Singh
- Department of Biochemistry, All India Institute of Medical Sciences Rishikesh, Rishikesh, India
| | - Sanjay Kumar Bhadada
- Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Satya Vati Rana
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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26
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Han X, Song C, Feng X, Wang Y, Meng T, Li S, Bai Y, Du B, Sun Q. Isolation and hypoglycemic effects of water extracts from mulberry leaves in Northeast China. Food Funct 2020; 11:3112-3125. [DOI: 10.1039/d0fo00012d] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Diabetes is the main chronic disease that greatly affects human life.
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Affiliation(s)
- Xiaoyun Han
- Engineering Research Center of Agricultural Microbiology Technology
- Ministry of Education
- Heilongjiang University
- Harbin 150500
- China
| | - Chunyue Song
- Engineering Research Center of Agricultural Microbiology Technology
- Ministry of Education
- Heilongjiang University
- Harbin 150500
- China
| | - Xiaoxin Feng
- Engineering Research Center of Agricultural Microbiology Technology
- Ministry of Education
- Heilongjiang University
- Harbin 150500
- China
| | - Yanan Wang
- Engineering Research Center of Agricultural Microbiology Technology
- Ministry of Education
- Heilongjiang University
- Harbin 150500
- China
| | - Tingting Meng
- Engineering Research Center of Agricultural Microbiology Technology
- Ministry of Education
- Heilongjiang University
- Harbin 150500
- China
| | - Shichao Li
- Engineering Research Center of Agricultural Microbiology Technology
- Ministry of Education
- Heilongjiang University
- Harbin 150500
- China
| | - Yunlong Bai
- Engineering Research Center of Agricultural Microbiology Technology
- Ministry of Education
- Heilongjiang University
- Harbin 150500
- China
| | | | - Qingshen Sun
- Engineering Research Center of Agricultural Microbiology Technology
- Ministry of Education
- Heilongjiang University
- Harbin 150500
- China
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27
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Ikee R, Yano K, Tsuru T. Constipation in chronic kidney disease: it is time to reconsider. RENAL REPLACEMENT THERAPY 2019. [DOI: 10.1186/s41100-019-0246-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
AbstractConstipation is highly prevalent in patients with chronic kidney disease (CKD) and is primarily characterized by decreased intestinal motility. This chronic disorder affects the quality of life of patients. However, nephrologist and dialysis clinicians have long had a disproportionately limited understanding of constipation. Accumulating evidence has revealed a relationship between constipation and cardiovascular disease and CKD. The pathogenesis of constipation in CKD patients is multifactorial: decreased physical activity, comorbidities affecting bowel movement, such as diabetes mellitus, cerebrovascular disease, and hyperparathyroidism, a restricted dietary intake of plant-based fiber-rich foods, and multiple medications, including phosphate binders and potassium-binding resins, have all been implicated. CKD is associated with alterations in the composition and function of the gut microbiota, so-called gut dysbiosis. Recent studies showed that CKD-related gut dysbiosis decreased intestinal motility via intestinal inflammation or the increased generation of gut-derived uremic toxins, such as indoxyl sulfate and p-cresyl sulfate. Furthermore, the gastrointestinal secretion of mucin was found to be decreased in CKD animal models, which may delay colonic transit by diminished lubrication in the alimentary tract. Thus, CKD-related gut dysbiosis may play a role in constipation, but limited information is currently available. Since constipation is often intractable, particularly in CKD patients, every available means needs to be employed in its treatment. The effects of probiotics, prebiotics, and synbiotics on the composition of the gut microbiota and gut-derived uremic toxins have been increasingly reported. However, their effects on stool consistency or frequency in CKD patients remain unclear. Some laxatives may be beneficial for improving not only bowel habits but also gut dysbiosis. Further studies are required to elucidate the CKD-specific pathogenesis of constipation and develop novel effective treatment options.
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28
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Redenšek S, Flisar D, Kojović M, Kramberger MG, Georgiev D, Pirtošek Z, Trošt M, Dolžan V. Genetic variability of inflammation and oxidative stress genes does not play a major role in the occurrence of adverse events of dopaminergic treatment in Parkinson's disease. J Neuroinflammation 2019; 16:50. [PMID: 30813952 PMCID: PMC6393982 DOI: 10.1186/s12974-019-1439-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 02/18/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Inflammation and oxidative stress are recognized as important contributors to Parkinson's disease pathogenesis. As such, genetic variability in these pathways could have a role in susceptibility for the disease as well as in the treatment outcome. Dopaminergic treatment is effective in management of motor symptoms, but poses a risk for motor and non-motor adverse events. Our aim was to evaluate the impact of selected single-nucleotide polymorphisms in genes involved in inflammation and oxidative stress on Parkinson's disease susceptibility and the occurrence of adverse events of dopaminergic treatment. METHODS In total, 224 patients were enrolled, and their demographic and clinical data on the disease course were collected. Furthermore, a control group of 146 healthy Slovenian blood donors were included for Parkinson's disease' risk evaluation. Peripheral blood was obtained for DNA isolation. Genotyping was performed for NLRP3 rs35829419, CARD8 rs2043211, IL1β rs16944, IL1β rs1143623, IL6 rs1800795, CAT rs1001179, CAT rs10836235, SOD2 rs4880, NOS1 rs2293054, NOS1 rs2682826, TNF-α rs1800629, and GPX1 rs1050450. Logistic regression was used for analysis of possible associations. RESULTS We observed a nominally significant association of the IL1β rs1143623 C allele with the risk for Parkinson's disease (OR = 0.59; 95%CI = 0.38-0.92, p = 0.021). CAT rs1001179 A allele was significantly associated with peripheral edema (OR = 0.32; 95%CI = 0.15-0.68; p = 0.003). Other associations observed were only nominally significant after adjustments: NOS1 rs2682826 A allele and excessive daytime sleepiness and sleep attacks (OR = 1.75; 95%CI = 1.00-3.06, p = 0.048), SOD2 rs4880 T allele and nausea/vomiting (OR = 0.49, 95%CI = 0.25-0.94; p = 0.031), IL1β rs1143623 C allele and orthostatic hypotension (OR = 0.57, 95%CI = 0.32-1.00, p = 0.050), and NOS1 rs2682826 A allele and impulse control disorders (OR = 2.59; 95%CI = 1.09-6.19; p = 0.032). We did not find any associations between selected polymorphisms and motor adverse events. CONCLUSIONS Apart from some nominally significant associations, one significant association between CAT genetic variability and peripheral edema was observed as well. Therefore, the results of our study suggest some links between genetic variability in inflammation- and oxidative stress-related pathways and non-motor adverse events of dopaminergic treatment. However, the investigated polymorphisms do not play a major role in the occurrence of the disease and the adverse events of dopaminergic treatment.
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Affiliation(s)
- Sara Redenšek
- Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
| | - Dušan Flisar
- Department of Neurology, University Medical Centre Ljubljana, Zaloška cesta 2, 1000 Ljubljana, Slovenia
| | - Maja Kojović
- Department of Neurology, University Medical Centre Ljubljana, Zaloška cesta 2, 1000 Ljubljana, Slovenia
| | | | - Dejan Georgiev
- Department of Neurology, University Medical Centre Ljubljana, Zaloška cesta 2, 1000 Ljubljana, Slovenia
| | - Zvezdan Pirtošek
- Department of Neurology, University Medical Centre Ljubljana, Zaloška cesta 2, 1000 Ljubljana, Slovenia
| | - Maja Trošt
- Department of Neurology, University Medical Centre Ljubljana, Zaloška cesta 2, 1000 Ljubljana, Slovenia
| | - Vita Dolžan
- Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
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Salehi M, Purnell JQ. The Role of Glucagon-Like Peptide-1 in Energy Homeostasis. Metab Syndr Relat Disord 2019; 17:183-191. [PMID: 30720393 DOI: 10.1089/met.2018.0088] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Energy homeostasis is coordinated by bidirectional communication pathways between the brain and peripheral organs, including adipose tissue, muscle, the pancreas, liver, and gut. Disruption of the integrated chemical, hormonal, and neuronal signals that constitute the gut-brain axis significantly contributes to disorders of metabolism and body weight. Initial studies of glucagon-like peptide-1 (GLP-1), a gut hormone released in response to the ingestion of nutrients, focused on its incretin actions to improve postprandial glucose homeostasis by enhancing meal-induced insulin secretion. However, GLP-1 is also a key player in the gut-brain regulatory axis with multiple effects on appetite and energy metabolism outside of its peripheral glucoregulatory actions. In this review, we explore the function of GLP-1 as a component of the gut-brain axis in the regulation of energy homeostasis, and consider the implications of this role for the development of therapeutic treatment options for obesity.
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Affiliation(s)
- Marzieh Salehi
- 1 Division of Diabetes, Department of Internal Medicine, University of Texas Health at San Antonio, San Antonio, Texas.,2 Bartter Research Unit, Audie Murphy Hospital, South Texas Veteran Health Care System, San Antonio, Texas
| | - Jonathan Q Purnell
- 3 The Knight Cardiovascular Institute, Mailcode MDYMI, Oregon Health and Science University, Portland, Oregon
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Avalos DJ, Sarosiek I, Loganathan P, McCallum RW. Diabetic gastroparesis: current challenges and future prospects. Clin Exp Gastroenterol 2018; 11:347-363. [PMID: 30310300 PMCID: PMC6165730 DOI: 10.2147/ceg.s131650] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Diabetic gastroparesis (DMGP) is a condition of delayed gastric emptying after gastric outlet obstruction has been excluded. Symptoms of nausea, vomiting, early satiety, bloating, and abdominal pain are associated with DMGP. Uncontrolled symptoms can lead to overall poor quality of life and financial burdens on the healthcare system. A combination of antiemetics and prokinetics is used in symptom control; metoclopramide is the main prokinetic available for clinical use and is the only U.S. Food and Drug Administration-approved agent in the United States. However, a black box warning in 2009 reporting its association with tardive dyskinesia and recommending caution in chronically using this agent beyond 3 months has decreased its role in clinical practice. There is an unmet need for new prokinetics with good efficacy and safety profiles. Currently, there are several new drugs with different mechanisms of action in the pipeline that are under investigation and show promising preliminary results. Surgically combining gastric electrical stimulation with pyloroplasty is considered "gold" standard. Advances in therapeutic endoscopic intervention with gastric per-oral endoscopic pyloromyotomy have also been shown to improve gastric emptying and gastroparesis (GP) symptoms. In this review, we will comment on the challenges encountered when managing patients with DMGP and provide an update on advances in drug development and endoscopic and surgical interventions.
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Affiliation(s)
- Danny J Avalos
- Division of Gastroenterology, Center for Neurogastroenterology and GI Motility, Texas Tech University Health Sciences Center, El Paso, TX, USA,
| | - Irene Sarosiek
- Division of Gastroenterology, Center for Neurogastroenterology and GI Motility, Texas Tech University Health Sciences Center, El Paso, TX, USA,
| | - Priyadarshini Loganathan
- Department of Internal Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Richard W McCallum
- Division of Gastroenterology, Center for Neurogastroenterology and GI Motility, Texas Tech University Health Sciences Center, El Paso, TX, USA,
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31
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Mulberry leaf tea alleviates diabetic nephropathy by inhibiting PKC signaling and modulating intestinal flora. J Funct Foods 2018. [DOI: 10.1016/j.jff.2018.04.040] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
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Tian D, Mo F, Cai X, Miao Z, Xiao F, Chang Y, Wu L, Tang Y, Wang X, Ye C, Qian X, Gu W, Li M. Acupuncture relieves motion sickness via the IRβ-ERK1/2-dependent insulin receptor signalling pathway. Acupunct Med 2018; 36:153-161. [PMID: 29436382 DOI: 10.1136/acupmed-2016-011202] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/03/2017] [Indexed: 01/07/2023]
Abstract
OBJECTIVE Acupuncture has been widely used for the treatment of motion sickness (MS), but the underlying mechanisms are unclear. The aim of this research was to study the mechanism of acupuncture in the treatment of MS. METHODS To observe the effects of acupuncture in the treatment of MS, 80 rats were randomised into five groups that were subjected to acceleration and either remained untreated (CTRL), or received restraint (REST), scopolamine (SCOP) or acupuncture at SP4 (sham) or PC6+ST36 (verum) acupuncture points. To study the mechanism underlying the effects of acupuncture in the treatment of MS, 48 rats were randomised into three groups: acupuncture+extracellular regulated protein kinases (ERK) 1/2 inhibitor (ERKinh), acupuncture+insulin receptor (IR) antagonist (IRant), and acupuncture+vehicle (VEH). After acceleration, the MS index (MSI) and spontaneous activity (SA) of the rats were recorded. Serum stress hormones, Fos-positive cells, c-fos mRNA in the vestibular nucleus, and IRβ-, p-IRβ-, ERK1/2- and p-ERK1/2-positive cells in the dorsal motor nucleus of the vagus nerve (DMV) were detected. RESULTS After acceleration, MS symptoms in the PC6+ST36 and SCOP groups were reduced compared with the CTRL, REST, and SP4 groups. The number of p-IRβ- and p-ERK1/2-positive cells and insulin levels were higher in the PC6+ST36 group than in the CTRL, REST, and SP4 groups. After ERK1/2 inhibitor and IR antagonist treatment, MS symptoms in the VEH group were lower than in the ERKinh and IRant groups. CONCLUSIONS Our study demonstrates that acupuncture significantly alleviates MS through the IRβ-ERK1/2-dependent insulin receptor signalling pathway in the DMV.
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Affiliation(s)
- Dawei Tian
- Department of Aerospace Medicine Aerospace Biodynamics, Fourth Military Medical University, Xi'an, China
| | - Fengfeng Mo
- Department of Ship Hygiene, Faculty of Navy Medicine, Second Military Medical University, Shanghai, China
| | - Xingjian Cai
- Department of Ship Hygiene, Faculty of Navy Medicine, Second Military Medical University, Shanghai, China
| | - Zhiyuan Miao
- Faculty of Traditional Chinese Medicine, Second Military Medical University, Shanghai, China
| | - Feng Xiao
- Department of Ship Hygiene, Faculty of Navy Medicine, Second Military Medical University, Shanghai, China
| | - Yifang Chang
- Department of Urology, Changhai Hospital, Shanghai, China
| | - Lusha Wu
- Department of Ship Hygiene, Faculty of Navy Medicine, Second Military Medical University, Shanghai, China
| | - Yuxiao Tang
- Department of Ship Hygiene, Faculty of Navy Medicine, Second Military Medical University, Shanghai, China
| | - Xin Wang
- Department of Ship Hygiene, Faculty of Navy Medicine, Second Military Medical University, Shanghai, China
| | - Chen Ye
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaolu Qian
- Faculty of Traditional Chinese Medicine, Second Military Medical University, Shanghai, China
| | - Wei Gu
- Faculty of Traditional Chinese Medicine, Second Military Medical University, Shanghai, China
| | - Min Li
- Department of Ship Hygiene, Faculty of Navy Medicine, Second Military Medical University, Shanghai, China
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Veličkov A, Radenković G, Petrović V, Veličkov A. DIABETIC ALTERATIONS OF INTERSTITIAL CELLS OF CAJAL. ACTA MEDICA MEDIANAE 2017. [DOI: 10.5633/amm.2017.0416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Yanaka A. Daily intake of broccoli sprouts normalizes bowel habits in human healthy subjects. J Clin Biochem Nutr 2017; 62:75-82. [PMID: 29371757 PMCID: PMC5773831 DOI: 10.3164/jcbn.17-42] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 08/01/2017] [Indexed: 12/12/2022] Open
Abstract
Chronic oxidative stress impairs regular defecation. Sulforaphane (SFN) enhances anti-oxidant systems, ameliorating oxidative injury. SFN inhibits overgrowth of anaerobic microflora and protects small intestine from oxidative injury. We assessed whether daily intake of SFN-rich broccoli sprouts (BS) improves defecation in humans. Forty-eight subjects, with a constipation scoring system (CSS) >2 points, were assigned to either the BS group (n = 24) or the alfalfa sprouts (AS) group (n = 24), and were requested to eat 20 g daily of raw BS or AS, respectively, for 4 weeks. BS contains 4.4 mg/g sulforaphane glucosinolates (SGS), while AS contains no SGS. CSS-based questionnaires were performed to evaluate bowel habit. Stool samples were collected to evaluate intestinal microflora using a terminal restriction fragment length polymorphism flora analysis. Intervention with BS, but not AS, caused a significant decrease in the duration of attempted defecation and the total CSS score. Intervention with BS decreased the percentage of Bifidobacterium in the stool. These results suggest that daily intake of BS improves bowel habit in human subjects. Since BS treatment enhance antioxidant enzyme activities, these effects of BS appear to relate with the SFN-mediated modulation of the intestinal motility during exposure to oxidative stress. (UMIN Clinical Trial Registration Number: UMIN-000021207).
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Affiliation(s)
- Akinori Yanaka
- Hitachi Medical Education and Research Center, University of Tsukuba Hospital, Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
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Da Silva LM, da Silva RDCMVDAF, Maria-Ferreira D, Beltrame OC, da Silva-Santos JE, Werner MFDP. Vitamin C Improves Gastroparesis in Diabetic Rats: Effects on Gastric Contractile Responses and Oxidative Stress. Dig Dis Sci 2017. [PMID: 28639130 DOI: 10.1007/s10620-017-4632-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Diabetic gastroparesis is a common complication of diabetes mellitus, which mainly affects women. Previous studies have demonstrated that oxidative stress is involved in its onset and development. AIMS This study evaluated the role of vitamin C on diabetes-associated gastric dysmotility. METHODS Female rats with streptozotocin-induced diabetes were treated with vehicle (water, 1 mL/kg, p.o.), vitamin C (300 mg/kg/day, p.o.), or insulin (6 IU/day, s.c.). Gastric emptying, in vitro gastric contractility, and biochemistry parameters were analyzed at the end of the treatment (i.e. 8 weeks after the diabetes induction). RESULTS Vitamin C reversed the delayed gastric emptying of diabetic rats to normal levels, and avoided the changes in the contractile responses to acetylcholine (0.1 nM-1 µM), but not to 5-hydroxytryptamine (0.1 nM-1 µM), in the pylorus and fundus from diabetic rats. Moreover, the contraction evoked by KCl (40 mM) in the fundus, but not in the pylorus, was intensely increased in diabetic rats treated with vitamin C. Notably, the vitamin C reestablished the reduced glutathione levels by 77% and decreased the reactive oxygen species content by 60% in the gastric tissue from diabetic rats. Despite the effects on gastric motility, vitamin C treatment did not change the fasting glycaemia or the glycated hemoglobin of diabetic rats. Unsurprisingly, insulin treatment normalized all parameters evaluated. CONCLUSIONS Vitamin C exhibited a remarkable beneficial effect on gastric emptying dysfunction in diabetic rats, which was mediated by attenuation of oxidative stress and maintenance of the cholinergic contractile responses in fundus and pylorus.
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Affiliation(s)
- Luisa Mota Da Silva
- Departamento de Farmacologia, Setor de Ciências Biológicas, Universidade Federal do Paraná, Curitiba, PR, Brazil. .,Programa de Pós-Graduação em Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade do Vale do Itajaí, Itajaí, SC, Brazil.
| | | | - Daniele Maria-Ferreira
- Departamento de Farmacologia, Setor de Ciências Biológicas, Universidade Federal do Paraná, Curitiba, PR, Brazil
| | - Olair Carlos Beltrame
- Departamento de Medicina Veterinária, Hospital Veterinário, Universidade Federal do Paraná, Curitiba, PR, Brazil
| | - José Eduardo da Silva-Santos
- Laboratory of Cardiovascular Biology, Department of Pharmacology, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
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Gyuraszova M, Kovalcikova A, Gardlik R. Association between oxidative status and the composition of intestinal microbiota along the gastrointestinal tract. Med Hypotheses 2017; 103:81-85. [DOI: 10.1016/j.mehy.2017.04.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 04/19/2017] [Indexed: 02/08/2023]
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Donald EL, Stojanovska L, Apostolopoulos V, Nurgali K. Resveratrol alleviates oxidative damage in enteric neurons and associated gastrointestinal dysfunction caused by chemotherapeutic agent oxaliplatin. Maturitas 2017; 105:100-106. [PMID: 28545905 DOI: 10.1016/j.maturitas.2017.05.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2017] [Revised: 05/07/2017] [Accepted: 05/08/2017] [Indexed: 02/08/2023]
Abstract
Oxaliplatin is a first-line chemotherapeutic agent used for the treatment of colorectal cancer. Its use is associated with severe gastrointestinal (GI) side-effects, associated with oxidative damage and neurotoxicity to the enteric neurons. Resveratrol is a potent anti-oxidant that has been shown to protect against oxidative damage and neurotoxicity in other neurons and could therefore prevent oxaliplatin-induced damage to enteric neurons. We determined whether co-administration of resveratrol with oxaliplatin alleviates enteric neuron toxicity and GI dysfunction in mice. Colons were collected for immunohistochemical analysis of myenteric neurons and assessment of motor activity in organ-bath experiments. Morphological damage to the colonic mucosa and muscles was analysed. Oxaliplatin treatment induced translocation of nitrated proteins into the nuclei of myenteric neurons and significant damage to the mucosal lining, vacuolisation and a decrease in muscle thickness. This damage is linked to motor dysfunction due to inhibition of the amplitude of colonic contractions, leading to chronic constipation. Co-treatment with resveratrol prevented oxaliplatin-induced neurotoxicity, alleviated damage to GI mucosa, crypts and muscle layer, resulting in improved contractility and a decrease in constipation. Resveratrol could be integrated as part of a therapeutic regimen to help alleviate oxaliplatin-induced GI dysfunction.
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Affiliation(s)
- Elizabeth L Donald
- College of Health and Biomedicine, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, St Albans, VIC 3021, Australia
| | - Lily Stojanovska
- College of Health and Biomedicine, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, St Albans, VIC 3021, Australia
| | - Vasso Apostolopoulos
- College of Health and Biomedicine, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, St Albans, VIC 3021, Australia
| | - Kulmira Nurgali
- College of Health and Biomedicine, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, St Albans, VIC 3021, Australia.
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Bharucha AE, Daley SL, Low PA, Gibbons SJ, Choi KM, Camilleri M, Saw EJ, Farrugia G, Zinsmeister AR. Effects of hemin on heme oxygenase-1, gastric emptying, and symptoms in diabetic gastroparesis. Neurogastroenterol Motil 2016; 28:1731-1740. [PMID: 27283929 PMCID: PMC5083191 DOI: 10.1111/nmo.12874] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 05/09/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND Therapeutic options for management of diabetic gastroparesis are limited. Failure to maintain upregulation of heme oxygenase (HO1) leads to loss of interstitial cells of Cajal and delayed gastric emptying (GE) in non-obese diabetic mice. Our hypothesis was that hemin upregulation of HO1 would restore normal GE in humans with gastroparesis. AIMS To compare effects of hemin and placebo infusions on HO1 activity and protein, GE, autonomic function, and gastrointestinal symptoms in diabetic gastroparesis. METHODS In a single-center, double-blind, placebo-controlled, randomized clinical trial, we compared intravenous hemin, prepared in albumin, or albumin alone (placebo) in 20 patients, aged 41 ± 5 (SEM) years with diabetic gastroparesis. After infusions on days 1, 3, and 7, weekly infusions were administered for 7 additional weeks. Assessments included blood tests for HO1 protein and enzyme activity levels, GE with 13 C-spirulina breath test, autonomic functions (baseline and end), and gastrointestinal symptoms every 2 weeks. KEY RESULTS Nine of 11 patients randomized to hemin completed all study procedures. Compared to placebo, hemin increased HO1 protein on days 3 (p = 0.0002) and 7 (p = 0.008) and HO1 activity on day 3 (p = 0.0003) but not after. Gastric emptying, autonomic functions, and symptoms did not differ significantly in the hemin group relative to placebo. CONCLUSIONS & INFERENCES Hemin failed to sustain increased HO1 levels beyond a week and did not improve GE or symptoms in diabetic gastroparesis. Further studies are necessary to ascertain whether more frequent hemin infusions or other drugs would have a more sustained effect on HO1 and improve GE.
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Affiliation(s)
| | - Shannon L. Daley
- Enteric Neurosciences Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Simon J. Gibbons
- Department of Physiology and Biomedical Engineering, Mayo Clinic Center for Biomedical Discovery, Rochester, MN
| | - Kyoung Moo Choi
- Department of Physiology and Biomedical Engineering, Mayo Clinic Center for Biomedical Discovery, Rochester, MN
| | - Michael Camilleri
- Enteric Neurosciences Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - essica J. Saw
- Mayo Medical School, Mayo Clinic College of Medicine, Rochester, MN
| | - Gianrico Farrugia
- Enteric Neurosciences Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Alan R Zinsmeister
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN
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Bowel movement frequency and cardiovascular mortality, a matter of fibers and oxidative stress? Atherosclerosis 2016; 253:278-280. [PMID: 27594542 DOI: 10.1016/j.atherosclerosis.2016.08.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Accepted: 08/18/2016] [Indexed: 11/22/2022]
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40
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Vermorken AJM, Andrès E, Cui Y. Bowel movement frequency, oxidative stress and disease prevention. Mol Clin Oncol 2016; 5:339-342. [PMID: 27703675 DOI: 10.3892/mco.2016.987] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 06/27/2016] [Indexed: 12/13/2022] Open
Abstract
The significance of diet for disease prevention has long been recognised. Dietary recommendations have therefore been integrated in health promotion messages. Gastrointestinal functioning is essential for the digestion of nutrients. Oxidative stress has been observed in patients with constipation, as well as in those with colorectal cancer, cardiovascular disease and other chronic illnesses associated with constipation. The coexistence of colorectal neoplasia and coronary artery disease has been incriminated for exposure to common risk factors associated with increased oxidative stress. It was recently demonstrated that bowel movement frequency is inversely associated with cardiovascular mortality. The aim of the present study was to review the relevant literature in light of these findings. It was concluded that suboptimal functioning of the large bowel may contribute to oxidative stress and, therefore, to increased mortality. Bowel movement frequency may represent a simple quantifiable indicator of adequate colonic function and it is dependent on diet, exercise and other lifestyle factors, but also on individual characteristics, including colonic microbiota. Future health promotion actions may improve the prevention of a number of diseases by advocating lifestyle personalisation for assuring optimal intestinal functioning.
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Affiliation(s)
- Alphons J M Vermorken
- College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, P.R. China; National Engineering Research Center for Miniaturized Detection Systems, Xi'an, Shaanxi 710069, P.R. China
| | - Emmanuel Andrès
- Department of Internal Medicine, Diabetes and Metabolic Disorders, University Hospital of Strasbourg, 67091 Strasbourg, France
| | - Yali Cui
- College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, P.R. China; National Engineering Research Center for Miniaturized Detection Systems, Xi'an, Shaanxi 710069, P.R. China
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Bhattarai Y, Fried D, Gulbransen B, Kadrofske M, Fernandes R, Xu H, Galligan J. High-fat diet-induced obesity alters nitric oxide-mediated neuromuscular transmission and smooth muscle excitability in the mouse distal colon. Am J Physiol Gastrointest Liver Physiol 2016; 311:G210-20. [PMID: 27288421 PMCID: PMC5007291 DOI: 10.1152/ajpgi.00085.2016] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 06/06/2016] [Indexed: 02/08/2023]
Abstract
We tested the hypothesis that colonic enteric neurotransmission and smooth muscle cell (SMC) function are altered in mice fed a high-fat diet (HFD). We used wild-type (WT) mice and mice lacking the β1-subunit of the BK channel (BKβ1 (-/-)). WT mice fed a HFD had increased myenteric plexus oxidative stress, a 28% decrease in nitrergic neurons, and a 20% decrease in basal nitric oxide (NO) levels. Circular muscle inhibitory junction potentials (IJPs) were reduced in HFD WT mice. The NO synthase inhibitor nitro-l-arginine (NLA) was less effective at inhibiting relaxations in HFD compared with control diet (CD) WT mice (11 vs. 37%, P < 0.05). SMCs from HFD WT mice had depolarized membrane potentials (-47 ± 2 mV) and continuous action potential firing compared with CD WT mice (-53 ± 2 mV, P < 0.05), which showed rhythmic firing. SMCs from HFD or CD fed BKβ1 (-/-) mice fired action potentials continuously. NLA depolarized membrane potential and caused continuous firing only in SMCs from CD WT mice. Sodium nitroprusside (NO donor) hyperpolarized membrane potential and changed continuous to rhythmic action potential firing in SMCs from HFD WT and BKβ1 (-/-) mice. Migrating motor complexes were disrupted in colons from BKβ1 (-/-) mice and HFD WT mice. BK channel α-subunit protein and β1-subunit mRNA expression were similar in CD and HFD WT mice. We conclude that HFD-induced obesity disrupts inhibitory neuromuscular transmission, SMC excitability, and colonic motility by promoting oxidative stress, loss of nitrergic neurons, and SMC BK channel dysfunction.
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Affiliation(s)
- Yogesh Bhattarai
- 1The Neuroscience Program, Michigan State University, East Lansing, Michigan;
| | - David Fried
- 3Department of Physiology, Michigan State University, East Lansing, Michigan; and
| | - Brian Gulbransen
- 1The Neuroscience Program, Michigan State University, East Lansing, Michigan; ,3Department of Physiology, Michigan State University, East Lansing, Michigan; and
| | - Mark Kadrofske
- 4Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan
| | - Roxanne Fernandes
- 2Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan;
| | - Hui Xu
- 1The Neuroscience Program, Michigan State University, East Lansing, Michigan; ,2Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan;
| | - James Galligan
- The Neuroscience Program, Michigan State University, East Lansing, Michigan; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan;
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PEREIRA RENATAV, LINDEN DAVIDR, MIRANDA-NETO MARCÍLIOH, ZANONI JACQUELINEN. Differential effects in CGRPergic, nitrergic, and VIPergic myenteric innervation in diabetic rats supplemented with 2% L-glutamine. ACTA ACUST UNITED AC 2016; 88 Suppl 1:609-22. [DOI: 10.1590/0001-3765201620150228] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 06/03/2015] [Indexed: 12/29/2022]
Abstract
ABSTRACT The objective of this study was to investigate the effects of 2% L-glutamine supplementation on myenteric innervation in the ileum of diabetic rats, grouped as follows: normoglycemic (N); normoglycemic supplemented with L-glutamine (NG); diabetic (D); and diabetic supplemented with L-glutamine (DG). The ileums were subjected to immunohistochemical techniques to localize neurons immunoreactive to HuC/D protein (HuC/D-IR) and neuronal nitric oxide synthase enzyme (nNOS-IR) and to analyze varicosities immunoreactive to vasoactive intestinal polypeptide (VIP-IR) and calcitonin gene-related peptide (CGRP-IR). L-Glutamine in the DG group (i) prevented the increase in the cell body area of nNOS-IR neurons, (ii) prevented the increase in the area of VIP-IR varicosities, (iii) did not prevent the loss of HuC/D-IR and nNOS-IR neurons per ganglion, and (iv) reduced the size of CGRP-IR varicosities. L-Glutamine in the NG group reduced (i) the number of HuC/D-IR and nNOS-IR neurons per ganglion, (ii) the cell body area of nNOS-IR neurons, and (iii) the size of VIP-IR and CGRP-IR varicosities. 2% L-glutamine supplementation exerted differential neuroprotective effects in experimental diabetes neuropathy that depended on the type of neurotransmitter analyzed. However, the effects of this dose of L-glutamine on normoglycemic animals suggests there are additional actions of this beyond its antioxidant capacity.
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Wilczak J, Błaszczyk K, Kamola D, Gajewska M, Harasym JP, Jałosińska M, Gudej S, Suchecka D, Oczkowski M, Gromadzka-Ostrowska J. The effect of low or high molecular weight oat beta-glucans on the inflammatory and oxidative stress status in the colon of rats with LPS-induced enteritis. Food Funct 2016; 6:590-603. [PMID: 25520199 DOI: 10.1039/c4fo00638k] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
PURPOSE The aim of the study was to investigate the protective effect of low and high molecular weight beta-glucans on the chosen immunological parameters, markers of antioxidative potential in rats' colon tissue, the number of lactic acid bacteria (LAB) and the concentration of short-chain fatty acids (SCFA) in rats' faeces. METHODS The experiment was carried out on 72 8-week old male Sprague-Dawley rats: control (n = 36) and experimental (n = 36). In half of the animals from each group enteritis was induced by LPS (10 mg kg(-1)). Rats from the experimental group were divided into two groups receiving high (GI) or low (GII) molecular weight beta-glucans for 6 consecutive weeks. RESULTS LPS evoked enteritis in all the treated animals, manifested by changes in the levels of IL-10, IL-12 and TNF-alpha, as well as in the number of intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) in the colon tissue. Dietary supplementation with beta-glucans following LPS treatment partially reversed this effect. The changes in SCFA concentration were noted, indicating an improvement of the fermentation process in the colon. This effect coincided with an increased number of LAB, pointing at the prebiotic properties of beta-glucans. The positive influence of beta-glucans was also manifested by the improved values of antioxidative potential markers (TAS, SOD, GR and GPx activity, TBARS concentration), noted especially in rats with LPS-induced enteritis. This influence was more pronounced in the case of low molecular weight oat beta-glucan (GII). CONCLUSIONS The present study showed a positive effect of beta-glucans, especially the low molecular weight form, on the colon tissue of healthy rats, as well as animals with LPS-induced enteritis.
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Affiliation(s)
- Jacek Wilczak
- Division of Dietetics, Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences (SGGW), Nowoursynowska 159, 02-776 Warsaw, Poland.
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Marathe CS, Rayner CK, Jones KL, Horowitz M. Novel insights into the effects of diabetes on gastric motility. Expert Rev Gastroenterol Hepatol 2016; 10:581-593. [PMID: 26647088 DOI: 10.1586/17474124.2016.1129898] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Recent data from the Diabetes Control and Complications Trial/Epidemiology of Diabetic Interventions and Complications cohort indicate that the disease burden of gastroparesis in diabetes remains high, consistent with the outcome of cross-sectional studies in type 1 and 2 diabetes. An improved understanding of the pathogenesis of diabetic gastroparesis at the cellular level has emerged in the last decade, particularly as a result of initiatives such as the National Institute of Health funded Gastroparesis Clinical Research Consortium in the US. Management of diabetic gastroparesis involves dietary and psychological support, attention to glycaemic control, and the use of prokinetic agents. Given that the relationship between upper gastrointestinal symptoms and the rate of gastric emptying is weak, therapies targeted specifically at symptoms, such as nausea or pain, are important. The relationship between gastric emptying and postprandial glycaemia is complex and inter-dependent. Short-acting glucagon-like peptide-1 agonists, that slow gastric emptying, can be used to reduce postprandial glycaemic excursions and, in combination with basal insulin, result in substantial reductions in glycated haemoglobin in type 2 patients.
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Affiliation(s)
- Chinmay S Marathe
- a Discipline of Medicine , The University of Adelaide, Royal Adelaide Hospital , Adelaide , Australia
- b Centre of Research Excellence in Translating Nutritional Science to Good Health , The University of Adelaide , Adelaide , Australia
| | - Christopher K Rayner
- a Discipline of Medicine , The University of Adelaide, Royal Adelaide Hospital , Adelaide , Australia
- b Centre of Research Excellence in Translating Nutritional Science to Good Health , The University of Adelaide , Adelaide , Australia
| | - Karen L Jones
- a Discipline of Medicine , The University of Adelaide, Royal Adelaide Hospital , Adelaide , Australia
- b Centre of Research Excellence in Translating Nutritional Science to Good Health , The University of Adelaide , Adelaide , Australia
| | - Michael Horowitz
- a Discipline of Medicine , The University of Adelaide, Royal Adelaide Hospital , Adelaide , Australia
- b Centre of Research Excellence in Translating Nutritional Science to Good Health , The University of Adelaide , Adelaide , Australia
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Trivedi MS, Hodgson NW, Walker SJ, Trooskens G, Nair V, Deth RC. Epigenetic effects of casein-derived opioid peptides in SH-SY5Y human neuroblastoma cells. Nutr Metab (Lond) 2015; 12:54. [PMID: 26664459 PMCID: PMC4673759 DOI: 10.1186/s12986-015-0050-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Accepted: 12/03/2015] [Indexed: 12/18/2022] Open
Abstract
Background Casein-free, gluten-free diets have been reported to mitigate some of the inflammatory gastrointestinal and behavioral traits associated with autism, but the mechanism for this palliative effect has not been elucidated. We recently showed that the opioid peptide beta-casomorphin-7, derived from bovine (bBCM7) milk, decreases cysteine uptake, lowers levels of the antioxidant glutathione (GSH) and decreases the methyl donor S-adenosylmethionine (SAM) in both Caco-2 human GI epithelial cells and SH-SY5Y human neuroblastoma cells. While human breast milk can also release a similar peptide (hBCM-7), the bBCM7 and hBCM-7 vary greatly in potency; as the bBCM-7 is highly potent and similar to morphine in it's effects. Since SAM is required for DNA methylation, we wanted to further investigate the epigenetic effects of these food-derived opioid peptides. In the current study the main objective was to characterize functional pathways and key genes responding to DNA methylation effects of food-derived opioid peptides. Methods SH-SY5Y neuroblastoma cells were treated with 1 μM hBCM7 and bBCM7 and RNA and DNA were isolated after 4 h with or without treatment. Transcriptional changes were assessed using a microarray approach and CpG methylation status was analyzed at 450,000 CpG sites. Functional implications from both endpoints were evaluated via Ingenuity Pathway Analysis 4.0 and KEGG pathway analysis was performed to identify biological interactions between transcripts that were significantly altered at DNA methylation or transcriptional levels (p < 0.05, FDR <0.1). Results Here we show that hBCM7 and bBCM7, as well as morphine, cause epigenetic changes affecting gene pathways related to gastrointestinal disease and inflammation. These epigenetic consequences exhibited the same potency order as opiate inhibition of cysteine uptake insofar as hBCM7 was less potent than bBCM7, which was less potent than morphine. Conclusion Our findings indicate that epigenetic effects of milk-derived opiate peptides may contribute to GI dysfunction and inflammation in sensitive individuals. While the current study was performed using SH-SY5Y neuronal cellular models, similar actions on other cells types might combine to cause symptoms of intolerance. These actions may provide a potential contributing mechanism for the beneficial effects of a casein-free diet in alleviating gastrointestinal symptoms in neurological conditions including autism and other conditions. Lastly, our study also contributes to the evolving awareness of a “gut-brain connection”. Electronic supplementary material The online version of this article (doi:10.1186/s12986-015-0050-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Malav S Trivedi
- Department of Pharmaceutical Sciences, Nova Southeastern University, Rm # 3103, HPD building, Fort Lauderdale, FL USA
| | - Nathaniel W Hodgson
- Department of Molecular and Cellular Biology, Harvard Medical School, Boston, MA USA
| | - Stephen J Walker
- Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston Salem, NC USA
| | - Geert Trooskens
- Department of Mathematical Modelling, Statistics and Bioinformatics, University of Ghent, Ghent, Belgium
| | - Vineeth Nair
- Department of Pharmaceutical Sciences, Nova Southeastern University, Rm # 3103, HPD building, Fort Lauderdale, FL USA
| | - Richard C Deth
- Department of Pharmaceutical Sciences, Nova Southeastern University, Rm # 3103, HPD building, Fort Lauderdale, FL USA
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Abstract
Gastroparesis is a highly prevalent chronic disorder of the stomach, which is characterized by delayed gastric emptying and accompanied by a series of upper gastrointestinal symptoms. Diabetic gastroparesis (DGP) is one of the severe complications of diabetes, seriously affecting the patient's quality of life. At present, the pathogenesis of DGP is still unclear. The majority of DGP patients are women, and women's symptoms change with the fluctuation of the level of estrogen. Therefore, we speculate that estrogen may play an vital role in the stomach motility. Gastric emptying is an objective index for the diagnosis of gastroparesis. This article reviews the role of estrogen in DGP and the possible mechanisms.
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Tian JX, Li M, Zhen Z, Li JL, Cao Y, Yan SH, Tong XL. Establishment and evaluation of animal models of diabetic gastroparesis. Shijie Huaren Xiaohua Zazhi 2015; 23:2091-2097. [DOI: 10.11569/wcjd.v23.i13.2091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The incidence of diabetic gastrointestinal disease, one of the most common complication of diabetes, is growing in recent years. Establishing an adequate animal model of diabetic gastrointestinal disease could effectively lay a solid foundation for the exploration of its mechanism and treatment. The rate of gastric emptying in diabetic gastrointestinal disease varies from acceleration to deceleration in different stages, and there is a lack of objective indicators to evaluate it. The establishment and evaluation of animals with diabetic gastrointestinal disease is still in the exploration stage. In this paper we summarize the establishment and evaluation of animal models of diabetic gastrointestinal disease. We compare the advantages and disadvantages of these animal models, in order to provide a reference for further study and treatment of this disease.
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Cosyns SMR, Huyghe L, Thoonen R, Stasch JP, Brouckaert P, Lefebvre RA. Influence of cinaciguat on gastrointestinal motility in apo-sGC mice. Neurogastroenterol Motil 2014; 26:1573-85. [PMID: 25200007 DOI: 10.1111/nmo.12424] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 08/12/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND Cinaciguat (BAY 58-2667), an NO- and heme-independent sGC activator, was shown to be more effective when the heme-group of sGC is oxidized in vascular tissue. In apo-sGC mice (sGCβ1 (His105Phe) knockin) both sGC isoforms (sGCα1 β1 and sGCα2 β1 ) are heme-deficient and can no longer be activated by NO; these mice, showing decreased gastrointestinal nitrergic relaxation and decreased gastric emptying, can be considered as a model to study the consequence of heme-oxidation in sGC. Our aim was to compare the influence of cinaciguat, on in vitro muscle tone of gastrointestinal tissues, and on gastric emptying in WT and apo-sGC mice. METHODS Gastrointestinal smooth muscle strips were mounted in organ baths for isometric force recording and cGMP levels were determined by enzyme immunoassay. Protein levels of sGC subunits were assessed by immunoblotting. Gastric emptying was determined by phenol red recovery. KEY RESULTS Although protein levels of the sGC subunits were lower in gastrointestinal tissues of apo-sGC mice, cinaciguat induced concentration-dependent relaxations and increased cGMP levels in apo-sGC fundus and colon to a similar or greater extent than in WT mice. The sGC inhibitor ODQ increased cinaciguat-induced relaxations and cGMP levels in WT fundus and colon. In apo-sGC antrum, pylorus and jejunum, cinaciguat was not able to induce relaxations. Cinaciguat did not improve delayed gastric emptying in apo-sGC mice. CONCLUSIONS & INFERENCES Cinaciguat relaxes the fundus and colon efficiently when sGC is in the heme-free condition; the non-effect of cinaciguat in pylorus explains its inability to improve the delayed gastric emptying in apo-sGC mice.
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Affiliation(s)
- Sarah M R Cosyns
- Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium
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Yarandi SS, Srinivasan S. Diabetic gastrointestinal motility disorders and the role of enteric nervous system: current status and future directions. Neurogastroenterol Motil 2014; 26:611-24. [PMID: 24661628 PMCID: PMC4104990 DOI: 10.1111/nmo.12330] [Citation(s) in RCA: 137] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 02/18/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Gastrointestinal manifestations of diabetes are common and a source of significant discomfort and disability. Diabetes affects almost every part of gastrointestinal tract from the esophagus to the rectum and causes a variety of symptoms including heartburn, nausea, vomiting, abdominal pain, diarrhea and constipation. Understanding the underlying mechanisms of diabetic gastroenteropathy is important to guide development of therapies for this common problem. Over recent years, the data regarding the pathophysiology of diabetic gastroenteropathy is expanding. In addition to autonomic neuropathy causing gastrointestinal disturbances the role of enteric nervous system is becoming more evident. PURPOSE In this review, we summarize the reported alterations in enteric nervous system including enteric neurons, interstitial cells of Cajal and neurotransmission in diabetic animal models and patients. We also review the possible underlying mechanisms of these alterations, with focus on oxidative stress, growth factors and diabetes induced changes in gastrointestinal smooth muscle. Finally, we will discuss recent advances and potential areas for future research related to diabetes and the ENS such as gut microbiota, micro-RNAs and changes in the microvasculature and endothelial dysfunction.
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Affiliation(s)
- S. S. Yarandi
- Division of Digestive Diseases; Emory University; Atlanta GA
- Atlanta VA Medical Center; Decatur Georgia USA
| | - S. Srinivasan
- Division of Digestive Diseases; Emory University; Atlanta GA
- Atlanta VA Medical Center; Decatur Georgia USA
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Moreno-Indias I, Cardona F, Tinahones FJ, Queipo-Ortuño MI. Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus. Front Microbiol 2014; 5:190. [PMID: 24808896 PMCID: PMC4010744 DOI: 10.3389/fmicb.2014.00190] [Citation(s) in RCA: 216] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Accepted: 04/08/2014] [Indexed: 12/21/2022] Open
Abstract
Obesity and its associated disorders are a major public health concern. Although obesity has been mainly related with perturbations of the balance between food intake and energy expenditure, other factors must nevertheless be considered. Recent insight suggests that an altered composition and diversity of gut microbiota could play an important role in the development of metabolic disorders. This review discusses research aimed at understanding the role of gut microbiota in the pathogenesis of obesity and type 2 diabetes mellitus (TDM2). The establishment of gut microbiota is dependent on the type of birth. With effect from this point, gut microbiota remain quite stable, although changes take place between birth and adulthood due to external influences, such as diet, disease and environment. Understand these changes is important to predict diseases and develop therapies. A new theory suggests that gut microbiota contribute to the regulation of energy homeostasis, provoking the development of an impairment in energy homeostasis and causing metabolic diseases, such as insulin resistance or TDM2. The metabolic endotoxemia, modifications in the secretion of incretins and butyrate production might explain the influence of the microbiota in these diseases.
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Affiliation(s)
- Isabel Moreno-Indias
- Unidad de Gestion Clínica de Endocrinología y Nutrición, Laboratorio del Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario de Málaga (Virgen de la Victoria) Málaga, Spain ; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición Madrid, Spain
| | - Fernando Cardona
- Unidad de Gestion Clínica de Endocrinología y Nutrición, Laboratorio del Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario de Málaga (Virgen de la Victoria) Málaga, Spain ; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición Madrid, Spain
| | - Francisco J Tinahones
- Unidad de Gestion Clínica de Endocrinología y Nutrición, Laboratorio del Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario de Málaga (Virgen de la Victoria) Málaga, Spain ; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición Madrid, Spain
| | - María Isabel Queipo-Ortuño
- Unidad de Gestion Clínica de Endocrinología y Nutrición, Laboratorio del Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario de Málaga (Virgen de la Victoria) Málaga, Spain ; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición Madrid, Spain
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