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Funayama T, Nozu T, Ishioh M, Sumi C, Saito T, Hatayama M, Yamamoto M, Shindo M, Takahashi S, Okumura T. Brain AMPK signaling improves intestinal barrier function through brain orexin and the vagal pathway in rats. Neurosci Lett 2025; 854:138208. [PMID: 40158792 DOI: 10.1016/j.neulet.2025.138208] [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: 10/29/2024] [Revised: 02/25/2025] [Accepted: 03/19/2025] [Indexed: 04/02/2025]
Abstract
Leaky gut, an increased intestinal permeability, has been described in many diseases. We have recently demonstrated that neuropeptides such as orexin in the brain improved leaky gut, suggesting that the brain is involved in maintaining intestinal barrier function. It has been suggested that AMPK in the hypothalamus play a role in food intake. Because the hypothalamus is involved in the regulation of not only feeding behavior but also gut function, the present study was performed to clarify a hypothesis that AMPK in the brain regulate gut barrier function. Colonic permeability was determined by quantifying the absorbed Evans blue within the colonic tissue in rats. Intracisternal AICAR, an AMPK activator, could reduce LPS-induced colonic hyperpermeability while peripherally administered AICAR failed to change it. The improvement of colonic hyperpermeability by intracisternal AICAR was blocked by intracisternal but not subcutaneous compound C, AMPK inhibitor, atropine or vagotomy. The improvement of colonic hyperpermeability by intracisternal AICAR was blocked by intracisternal orexin receptor antagonist but not oxytocin or GLP-1 receptor antagonist. Intracisternal compound C prevented brain oxytocin or GLP-1 but not orexin-induced improvement of colonic hyperpermeability. These results suggest that activation of brain AMPK is capable of reducing colonic hyperpermeability through brain orexin signaling and the vagus nerve. In addition, endogenous AMPK in the brain may mediate the oxytocin or GLP-induced improvement of colonic hyperpermeability. We would suggest that improvement of leaky gut by activation of brain AMPK may play a role in leaky gut-related diseases.
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Affiliation(s)
- Takuya Funayama
- Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Japan; Department of General Medicine, Asahikawa Medical University, Japan
| | - Masatomo Ishioh
- Department of General Medicine, Asahikawa Medical University, Japan
| | - Chihiro Sumi
- Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan
| | - Takeshi Saito
- Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan
| | - Mayumi Hatayama
- Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan
| | - Masayo Yamamoto
- Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan
| | - Motohiro Shindo
- Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan
| | - Shuichiro Takahashi
- Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan
| | - Toshikatsu Okumura
- Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan; Division of Gastroenterology, Department of Medicine, Asahikawa Medical University, Japan.
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Funayama T, Nozu T, Ishioh M, Igarashi S, Tanaka H, Sumi C, Saito T, Toki Y, Hatayama M, Yamamoto M, Shindo M, Takahashi S, Okumura T. Splenectomy prevents brain orexin, ghrelin, or oxytocin but not GLP-1-induced improvement of intestinal barrier function in rats. Neurogastroenterol Motil 2025; 37:e14949. [PMID: 39450642 DOI: 10.1111/nmo.14949] [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: 05/21/2024] [Revised: 09/30/2024] [Accepted: 10/15/2024] [Indexed: 10/26/2024]
Abstract
BACKGROUND Accumulating evidence has suggested that neuropeptides such as orexin, ghrelin, or oxytocin act centrally in the brain to regulate intestinal barrier function through the vagus nerve. It has been reported that the vagal cholinergic anti-inflammatory pathway was blocked by splenectomy. In the present study, we therefore examined the effect of splenectomy on neuropeptides-induced improvement of increased intestinal permeability. METHODS Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15 min spectrophotometrically in rats. RESULTS Splenectomy increased colonic permeability. The increased permeability by splenectomy was significantly blocked by vagal activation induced by carbachol or 2-deoxy-d-glucose which was prevented by atropine, suggesting vagal activation could prevent colonic hyperpermeability in splenectomized rats. In the splenectomized rats, intracisternal injection of orexin, ghrelin, oxytocin, or butyrate failed to inhibit increased colonic permeability while intracisternal glucagon-like peptide-1 (GLP-1) analogue, liraglutide, potently blocked the increased colonic permeability in a dose-dependent manner. The liraglutide-induced improvement of increased colonic permeability was blocked by atropine in splenectomized rats. Intracisternal injection of GLP-1 receptor antagonist attenuated 2-deoxy-d-glucose-induced improvement of colonic hyperpermeability in splenectomized rats. CONCLUSION The present results suggested that the spleen is important in the improvement of intestinal barrier function by brain orexin, ghrelin or oxytocin, and butyrate. On the other hand, GLP-1 acts centrally in the brain to improve colonic hyperpermeability in a spleen-independent manner. All these results suggest that dual mechanisms (spleen dependent or independent) may exist for the brain-gut regulation in intestinal barrier function.
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Affiliation(s)
- Takuya Funayama
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Tsukasa Nozu
- Department of General Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Masatomo Ishioh
- Department of General Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Sho Igarashi
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Hiroki Tanaka
- Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Chihiro Sumi
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Takeshi Saito
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Yasumichi Toki
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Mayumi Hatayama
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Masayo Yamamoto
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Motohiro Shindo
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
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Nasser S, El-Abhar HS, El-Maraghy N, Abdallah DM, Wadie W, Mansour S. Neuroprotective role of mirabegron: Targeting beta-3 adrenergic receptors to alleviate ulcerative colitis-associated cognitive impairment. Biomed Pharmacother 2025; 183:117816. [PMID: 39809125 DOI: 10.1016/j.biopha.2025.117816] [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: 10/18/2024] [Revised: 12/30/2024] [Accepted: 01/09/2025] [Indexed: 01/16/2025] Open
Abstract
While cognitive impairment has been documented in ulcerative colitic patients, the possible influence of central β3-adrenergic receptor (β3-AR) signaling on this extraintestinal manifestation remains unclear. Previously, we identified an imperative role for mirabegron (MA) as an agonist of β3-AR, in decreasing the BACE-1/beta-amyloid (Aβ) cue in the colons of UC rats. Consequently, we investigated its therapeutic potential for alleviating cognitive impairment associated with UC. To fulfil our aim, rats administered iodoacetamide were treated with the β3-AR agonist (MA) alone, with the antagonist (SR59230A) for 8 days, or kept untreated. The animals' behavior (MWM and NOR tests) and hippocampal structure were assessed. Mechanistically, necroptosis, ER stress (ERS), Aβ-amyloidosis, inflammation/oxidative burden, and gut/BBB dysfunction were analyzed. Post-administration of MA improved weight gain, colon/hippocampal structures, and memory. Additionally, it inhibited serum levels of lipopolysaccharide and Annexin-1, indicating recovered gut and BBB integrity. MA turned off the pathogenic BACE-1/Aβ axis in the hippocampus, necroptosis trajectory (TNFR-1/RIPK1/RIPK3/MLKL), and the IRE-1α/JNK signal. Moreover, MA enhanced the transcription factor PPAR-γ, decreased NF-κΒ/TNF-α inflammatory hub, and modulated the redox imbalance by decreasing malondialdehyde and increasing catalase. Notably, MA's behavioral, structural, and molecular beneficial actions were hindered by the pre-administration of SR59230A. From a novel standpoint, we recognized the β3-AR as a therapeutic target for UC-associated cognitive impairment in the hippocampus. In this context, the aptitude of MA to inhibit UC-induced hippocampal amyloidogenesis, alongside its anti-necroptotic, anti-ERS, anti-inflammatory, and antioxidant effects, contribute to these central enhancements, while also regulating permeability in both gut and BBB barriers.
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MESH Headings
- Animals
- Cognitive Dysfunction/drug therapy
- Cognitive Dysfunction/etiology
- Cognitive Dysfunction/metabolism
- Cognitive Dysfunction/prevention & control
- Acetanilides/pharmacology
- Acetanilides/therapeutic use
- Male
- Neuroprotective Agents/pharmacology
- Thiazoles/pharmacology
- Thiazoles/therapeutic use
- Rats
- Hippocampus/drug effects
- Hippocampus/metabolism
- Hippocampus/pathology
- Adrenergic beta-3 Receptor Agonists/pharmacology
- Colitis, Ulcerative/complications
- Colitis, Ulcerative/drug therapy
- Colitis, Ulcerative/metabolism
- Amyloid beta-Peptides/metabolism
- Receptors, Adrenergic, beta-3/metabolism
- Receptors, Adrenergic, beta-3/drug effects
- Rats, Wistar
- Disease Models, Animal
- Behavior, Animal/drug effects
- Endoplasmic Reticulum Stress/drug effects
- Oxidative Stress/drug effects
- Amyloid Precursor Protein Secretases/metabolism
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Affiliation(s)
- Salma Nasser
- Pharmacology, Toxicology and Biochemistry Department, Faculty of Pharmacy, Future University in Egypt (FUE), Cairo, Egypt.
| | - Hanan S El-Abhar
- Pharmacology, Toxicology and Biochemistry Department, Faculty of Pharmacy, Future University in Egypt (FUE), Cairo, Egypt
| | - Nabila El-Maraghy
- Pharmacology, Toxicology and Biochemistry Department, Faculty of Pharmacy, Future University in Egypt (FUE), Cairo, Egypt
| | - Dalaal M Abdallah
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Walaa Wadie
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Suzan Mansour
- Pharmacology, Toxicology and Biochemistry Department, Faculty of Pharmacy, Future University in Egypt (FUE), Cairo, Egypt; Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Shrestha P, Duwa R, Lee S, Kwon TK, Jeong JH, Yook S. ROS-responsive thioketal nanoparticles delivering system for targeted ulcerative colitis therapy with potent HDAC6 inhibitor, tubastatin A. Eur J Pharm Sci 2024; 201:106856. [PMID: 39032536 DOI: 10.1016/j.ejps.2024.106856] [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: 03/05/2024] [Revised: 07/16/2024] [Accepted: 07/16/2024] [Indexed: 07/23/2024]
Abstract
Ulcerative colitis (UC) is a common gastrointestinal problem characterized by the mucosal injury primarily affecting the large intestine. Currently available therapies are not satisfactory as evidenced by high relapse rate and adverse effects. In this study we aimed to develop an effective drug delivery system using reactive oxygen species (ROS)-responsive thioketal nanoparticles (TKNP), to deliver tubastatin A, a potent HDAC6 inhibitor, to the inflamed colon in mice with ulcerative colitis (UC). TKNPs were synthesized by step-growth polymerization from an acetal exchange reaction while TUBA-TKNP was prepared using the single emulsion solvent evaporation technique. Our developed nanoparticle showed release of tubastatin A only in presence of ROS which is found to be highly present at the site of inflamed colon. Oral administration of TUBA-TKNP resulted in the higher accumulation of tubastatin A at the inflamed colon site and decreased the inflammation as evidenced by reduced infiltration of immune cells and decreased level of pro-inflammatory cytokines in TUBA-TKNP treated mice. In summary, our results show the successful localization of tubastatin A at the site of colon inflammation through TUBA-TKNP delivery, as well as resolution of clinical features of UC in mice.
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Affiliation(s)
- Prabhat Shrestha
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Ramesh Duwa
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea; Department of Radiology, Molecular Imaging Program at Standford (MIPS), School of Medicine, Standford University, Standford, California 94305, USA
| | - Sooyeun Lee
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
| | - Taeg Kyu Kwon
- Department of Immunology, School of Medicine, Keimyung University, Daegu, 42601, Republic of Korea
| | - Jee-Heon Jeong
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea.
| | - Simmyung Yook
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea; School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
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Ashiqueali SA, Chaudhari D, Zhu X, Noureddine S, Siddiqi S, Garcia DN, Gostynska A, Stawny M, Rubis B, Zanini BM, Mansoor MAM, Schneider A, Naser SA, Yadav H, Masternak MM. Fisetin modulates the gut microbiota alongside biomarkers of senescence and inflammation in a DSS-induced murine model of colitis. GeroScience 2024; 46:3085-3103. [PMID: 38191834 PMCID: PMC11009197 DOI: 10.1007/s11357-024-01060-z] [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: 12/11/2023] [Accepted: 01/01/2024] [Indexed: 01/10/2024] Open
Abstract
Colitis, a subtype of inflammatory bowel disease (IBD), is a multifactorial disorder characterized by chronic inflammation of the colon. Among various experimental models used in the study of IBD, the chemical colitogenic dextran sulfate sodium (DSS) is most commonly employed to induce colitis in vivo. In the search for new therapeutic strategies, Fisetin, a flavonoid found in many fruits and vegetables, has recently garnered attention for its senolytic properties. Female mice were administered 2.5% DSS in sterile drinking water and were subsequently treated with Fisetin or vehicle by oral gavage. DSS significantly upregulated beta-galactosidase activity in colonic proteins, while Fisetin remarkably inhibited its activity to baseline levels. Particularly, qPCR revealed that the senescence and inflammation markers Vimentin and Ptgs2 were elevated by DSS exposure with Fisetin treatment inhibiting the expression of p53, Bcl2, Cxcl1, and Mcp1, indicating that the treatment reduced senescent cell burden in the DSS targeted intestine. Alongside, senescence and inflammation associated miRNAs miR-149-5p, miR-96-5p, miR-34a-5p, and miR-30e-5p were significantly inhibited by DSS exposure and restored by Fisetin treatment, revealing novel targets for the treatment of IBDs. Metagenomics was implemented to assess impacts on the microbiota, with DSS increasing the prevalence of bacteria in the phyla Bacteroidetes. Meanwhile, Fisetin restored gut health through increased abundance of Akkermansia muciniphila, which is negatively correlated with senescence and inflammation. Our study suggests that Fisetin mitigates DSS-induced colitis by targeting senescence and inflammation and restoring beneficial bacteria in the gut indicating its potential as a therapeutic intervention for IBDs.
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Affiliation(s)
- Sarah A Ashiqueali
- University of Central Florida College of Medicine, Burnett School of Biomedical Sciences, Orlando, FL, USA
| | - Diptaraj Chaudhari
- University of South Florida Morsani College of Medicine, Neurosurgery & Brain Repair, Tampa, FL, USA
| | - Xiang Zhu
- University of Central Florida College of Medicine, Burnett School of Biomedical Sciences, Orlando, FL, USA
| | - Sarah Noureddine
- University of Central Florida College of Medicine, Burnett School of Biomedical Sciences, Orlando, FL, USA
| | - Sarah Siddiqi
- University of Central Florida College of Medicine, Burnett School of Biomedical Sciences, Orlando, FL, USA
| | - Driele N Garcia
- Faculdade de Nutricao, Universidade Federal de Pelotas, Pelotas, Rio Grande Do Sul, Brazil
| | - Aleksandra Gostynska
- Poznan University of Medical Sciences, Department of Pharmaceutical Chemistry, Poznan, Poland
| | - Maciej Stawny
- Poznan University of Medical Sciences, Department of Pharmaceutical Chemistry, Poznan, Poland
| | - Blazej Rubis
- Poznan University of Medical Sciences, Department of Pharmaceutical Chemistry, Poznan, Poland
| | - Bianka M Zanini
- Faculdade de Nutricao, Universidade Federal de Pelotas, Pelotas, Rio Grande Do Sul, Brazil
| | - Mishfak A M Mansoor
- University of Central Florida College of Medicine, Burnett School of Biomedical Sciences, Orlando, FL, USA
| | - Augusto Schneider
- Faculdade de Nutricao, Universidade Federal de Pelotas, Pelotas, Rio Grande Do Sul, Brazil
| | - Saleh A Naser
- University of Central Florida College of Medicine, Burnett School of Biomedical Sciences, Orlando, FL, USA
| | - Hariom Yadav
- University of South Florida Morsani College of Medicine, Neurosurgery & Brain Repair, Tampa, FL, USA
| | - Michal M Masternak
- University of Central Florida College of Medicine, Burnett School of Biomedical Sciences, Orlando, FL, USA.
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, Poznan, Poland.
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6
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Böhringer AC, Deters L, Windfelder AG, Merzendorfer H. Dextran sulfate sodium and uracil induce inflammatory effects and disrupt the chitinous peritrophic matrix in the midgut of Tribolium castaneum. INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY 2023; 163:104029. [PMID: 37907139 DOI: 10.1016/j.ibmb.2023.104029] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/25/2023] [Accepted: 10/26/2023] [Indexed: 11/02/2023]
Abstract
Dextran sulfate sodium is used in inflammatory bowel disease (IBD) mice models to trigger chronic intestinal inflammation. In this study, we have analyzed DSS effects in the genetic model and pest beetle, Tribolium castaneum, which can be easily and cost-effectively cultivated and examined in very large quantities compensating for individual variations. We fed the larvae with DSS and uracil, which is known to induce the production of reactive oxygen species by activating DUOX, a member of the NADPH oxidase family. Both chemicals induced IBD-like phenotypes, including impaired growth and development, midgut thickening, epithelial swelling, and a loss of epithelial barrier function. RNAi mediated knockdown of DUOX expression enhanced the effects of DSS and uracil on mortality. Finally, we showed that both treatments result in an altered activity of the intestinal microbiome, similar as observed in IBD patients. Our findings suggest that both chemicals impair the epithelial barrier by increasing the permeability of the peritrophic matrix. The loss of the barrier function may facilitate the entry of midgut bacteria triggering innate immune responses that also affect the intestinal microbiome. As the observed effects resemble those induced by DSS treatment in mice, T. castaneum might be suitable high-throughput invertebrate model for IBD research and preclinical studies.
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Affiliation(s)
| | - Lara Deters
- University of Siegen, Department of Chemistry-Biology, 57068, Siegen, Germany
| | - Anton George Windfelder
- Department of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, 35392, Gießen, Germany; Experimental Radiology, Department of Medicine, Justus Liebig University, 35392, Gießen, Germany
| | - Hans Merzendorfer
- University of Siegen, Department of Chemistry-Biology, 57068, Siegen, Germany.
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Bifidobacterium breve Bif11 supplementation improves depression-related neurobehavioural and neuroinflammatory changes in the mouse. Neuropharmacology 2023; 229:109480. [PMID: 36868402 DOI: 10.1016/j.neuropharm.2023.109480] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 02/13/2023] [Accepted: 02/23/2023] [Indexed: 03/05/2023]
Abstract
Gut dysbiosis has been closely linked to the onset and progression of several brain-related disorders such as depression. The administration of microbiota-based formulations such as probiotics helps restore healthy gut flora and plays a role in preventing and treating depression-like behavior. Therefore, we evaluated the efficacy of probiotic supplementation using our recently isolated putative probiotic Bifidobacterium breve Bif11 in ameliorating lipopolysaccharide (LPS)-induced depression-like behavior in male Swiss albino mice. Mice were fed orally with B. breve Bif11 (1 × 1010 CFU and 2 × 1010 CFU) for 21 days before being challenged with a single intraperitoneal LPS injection (0.83 mg/kg). Behavioral, biochemical, histological and molecular analysis were done with an emphasis on inflammatory pathways linked to depression-like behavior. Daily supplementation with B. breve Bif11 for 21 days prevented the onset of depression-like behavior induced by LPS injection, besides reducing the levels of inflammatory cytokines such as matrix metalloproteinase-2, c-reactive protein, interleukin-6, tumor necrosis factor-alpha and nuclear factor kappa-light-chain-enhancer of activated B cells. It also prevented the decrease of the brain-derived neurotrophic factor levels and neuronal cell viability in the prefrontal cortex of LPS-treated mice. Furthermore, we observed that gut permeability was reduced, there was an improved short-chain fatty acid profile and reduced gut dysbiosis in the LPS mice fed with B. breve Bif11. Similarly, we observed a decrease in behavioural deficits and restoration of gut permeability in chronic mild stress. Together, these results would help in deciphering the role of probiotics in the management of neurological disorders where depression, anxiety and inflammation are prominent clinical features.
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Igarashi S, Nozu T, Ishioh M, Funayama T, Sumi C, Saito T, Toki Y, Hatayama M, Yamamoto M, Shindo M, Tanabe H, Okumura T. Ghrelin prevents lethality in a rat endotoxemic model through central effects on the vagal pathway and adenosine A2B signaling : Brain ghrelin and anti-septic action. J Physiol Biochem 2023:10.1007/s13105-023-00962-4. [PMID: 37099079 DOI: 10.1007/s13105-023-00962-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 04/17/2023] [Indexed: 04/27/2023]
Abstract
Accumulating evidence suggest that ghrelin plays a role as an antiseptic peptide. The present study aimed to clarify whether the brain may be implicated ghrelin's antiseptic action. We examined the effect of brain ghrelin on survival in a novel endotoxemic model achieved by treating rats with lipopolysaccharide (LPS) and colchicine. The observation of survival stopped three days after chemicals' injection or at death. Intracisternal ghrelin dose-dependently reduced lethality in the endotoxemic model; meanwhile, neither intraperitoneal injection of ghrelin nor intracisternal des-acyl-ghrelin injection affected the mortality rate. The brain ghrelin-induced lethality reduction was significantly blocked by surgical vagotomy. Moreover, intracisternal injection of a ghrelin receptor antagonist blocked the improved survival achieved by intracisternal ghrelin injection or intravenous 2-deoxy-d-glucose administration. Intracisternal injection of an adenosine A2B receptor agonist reduced the lethality and the ghrelin-induced improvement of survival was blocked by adenosine A2B receptor antagonist. I addition, intracisternal ghrelin significantly blocked the colonic hyperpermeability produced by LPS and colchicine. These results suggest that ghrelin acts centrally to reduce endotoxemic lethality. Accordingly, activation of the vagal pathway and adenosine A2B receptors in the brain may be implicated in the ghrelin-induced increased survival. Since the efferent vagus nerve mediates anti-inflammatory mechanisms, we speculate that the vagal cholinergic anti-inflammatory pathway is implicated in the decreased septic lethality caused by brain ghrelin.
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Affiliation(s)
- Sho Igarashi
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Japan
| | - Masatomo Ishioh
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Takuya Funayama
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Chihiro Sumi
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Takeshi Saito
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Yasumichi Toki
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Mayumi Hatayama
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Masayo Yamamoto
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Motohiro Shindo
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Hiroki Tanabe
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Toshikatsu Okumura
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
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Funayama T, Nozu T, Ishioh M, Igarashi S, Sumi C, Saito T, Toki Y, Hatayama M, Yamamoto M, Shindo M, Tanabe H, Okumura T. Centrally administered GLP-1 analogue improves intestinal barrier function through the brain orexin and the vagal pathway in rats. Brain Res 2023; 1809:148371. [PMID: 37076092 DOI: 10.1016/j.brainres.2023.148371] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/11/2023] [Accepted: 04/13/2023] [Indexed: 04/21/2023]
Abstract
Leaky gut, an altered intestinal barrier function, has been described in many diseases such as irritable bowel syndrome (IBS). We have recently demonstrated that orexin in the brain blocked leaky gut in rats, suggesting that the brain plays a role in regulation of intestinal barrier function. In the present study, we tried to clarify whether GLP-1 acts centrally in the brain to regulate intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of GLP-1 analogue, liraglutide dose-dependently abolished increased colonic permeability in response to lipopolysaccharide. Either atropine or surgical vagotomy blocked the central GLP-1-induced improvement of colonic hyperpermeability. Intracisternal GLP-1 receptor antagonist, exendin (9-39) prevented the central GLP-1-induced blockade of colonic hyperpermeability. In addition, intracisternal injection of orexin receptor antagonist, SB-334867 blocked the GLP-1-induced improvement of intestinal barrier function. On the other hand, subcutaneous liraglutide also improved leaky gut but larger doses of liraglutide were needed to block it. In addition, neither atropine nor vagotomy blocked subcutaneous liraglutide-induced improvement of leaky gut, suggesting that central or peripheral GLP-1 system works separately to improve leaky gut in a vagal-dependent or independent manner, respectively. These results suggest that GLP-1 acts centrally in the brain to reduce colonic hyperpermeability. Brain orexin signaling and the vagal cholinergic pathway play a vital role in the process. We would therefore suggest that activation of central GLP-1 signaling may be useful for leaky gut-related diseases such as IBS.
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Affiliation(s)
- Takuya Funayama
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Japan
| | - Masatomo Ishioh
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Sho Igarashi
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Chihiro Sumi
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Takeshi Saito
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Yasumichi Toki
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Mayumi Hatayama
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Masayo Yamamoto
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Motohiro Shindo
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Hiroki Tanabe
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Toshikatsu Okumura
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan.
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10
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Zhong P, Wu H, Ma Y, Xu X, Jiang Y, Jin C, Zhu Q, Liu X, Suo Z, Wang J. P2X4 receptor modulates gut inflammation and favours microbial homeostasis in colitis. Clin Transl Med 2023; 13:e1227. [PMID: 37085966 PMCID: PMC10122071 DOI: 10.1002/ctm2.1227] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 03/02/2023] [Accepted: 03/08/2023] [Indexed: 04/23/2023] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a non-specific chronic inflammatory disease of the intestine. In addition to genetic susceptibility, environmental factors and dysregulated host immunity, the gut microbiota is implicated in the pathogenesis of Crohn's disease (CD) or ulcerative colitis (UC), the two primary types of IBD. The P2X4 receptor has been demonstrated to have a crucial role in preventing infection, inflammation, and organ damage. However, it remains unclear whether the P2X4 receptor affects IBD and the underlying mechanisms. METHODS Colitis was induced in mice administrated with dextran sodium sulphate (DSS). 16S rDNA sequencing was used to analyze the gut microbiota in knockout and wild-type mice. Clinical and histopathological parameters were monitored throughout the disease progression. RESULTS Gene Expression Omnibus analysis showed the downregulation of P2RX4 (P2rx4) expression in colonic tissues from patients or mice with IBD. However, its expression at the protein levels was upregulated on day 4 or 6 and then downregulated on day 7 in C57BL/6 mice treated with DSS. Gene ablation of P2rx4 aggravated DSS-induced colitis accompanying gut microbiota dysbiosis in mice. Moreover, P2X4 receptor-positive modulator ivermectin alleviated colitis and corrected dysregulated microbiota in wild-type C57BL/6 mice. Further antibiotic-treated gut microbiota depletion, cohousing experiment, and fecal microbiota transplantation proved that gut microbiota dysbiosis was associated with the aggravation of colitis in the mouse model initiated by P2rx4. CONCLUSIONS Our findings elaborate on an unrevealed etiopathophysiological mechanism by which microbiota dysbiosis induced by the P2X4 receptor influences the development of colitis, indicating that the P2X4 receptor represents a promising target for treating patients with CD and UC.
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Affiliation(s)
- Peijie Zhong
- Infection and Immunity Institute and Translational Medical Center, Huaihe HospitalHenan UniversityKaifengChina
| | - Hang Wu
- Infection and Immunity Institute and Translational Medical Center, Huaihe HospitalHenan UniversityKaifengChina
| | - Yuanqiao Ma
- Infection and Immunity Institute and Translational Medical Center, Huaihe HospitalHenan UniversityKaifengChina
| | - Xiaoxiao Xu
- Infection and Immunity Institute and Translational Medical Center, Huaihe HospitalHenan UniversityKaifengChina
| | - Yizhuo Jiang
- Infection and Immunity Institute and Translational Medical Center, Huaihe HospitalHenan UniversityKaifengChina
| | - Chaolei Jin
- Infection and Immunity Institute and Translational Medical Center, Huaihe HospitalHenan UniversityKaifengChina
| | - Qiaozhen Zhu
- Infection and Immunity Institute and Translational Medical Center, Huaihe HospitalHenan UniversityKaifengChina
| | - Xinlei Liu
- Infection and Immunity Institute and Translational Medical Center, Huaihe HospitalHenan UniversityKaifengChina
| | - Zhimin Suo
- Infection and Immunity Institute and Translational Medical Center, Huaihe HospitalHenan UniversityKaifengChina
| | - Junpeng Wang
- Infection and Immunity Institute and Translational Medical Center, Huaihe HospitalHenan UniversityKaifengChina
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11
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Li Z, Dong S, Huang S, Sun Y, Sun Y, Zhao B, Qi Q, Xiong L, Hong F, Jiang Y. Role of CD34 in inflammatory bowel disease. Front Physiol 2023; 14:1144980. [PMID: 37051017 PMCID: PMC10083274 DOI: 10.3389/fphys.2023.1144980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 03/15/2023] [Indexed: 03/29/2023] Open
Abstract
Inflammatory bowel disease (IBD) is caused by a variety of pathogenic factors, including chronic recurrent inflammation of the ileum, rectum, and colon. Immune cells and adhesion molecules play an important role in the course of the disease, which is actually an autoimmune disease. During IBD, CD34 is involved in mediating the migration of a variety of immune cells (neutrophils, eosinophils, and mast cells) to the inflammatory site, and its interaction with various adhesion molecules is involved in the occurrence and development of IBD. Although the function of CD34 as a partial cell marker is well known, little is known on its role in IBD. Therefore, this article describes the structure and biological function of CD34, as well as on its potential mechanism in the development of IBD.
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Affiliation(s)
- Zhiyuan Li
- Jiaxing Key Laboratory of Virus-Related Infectious Diseases, The Affiliated Hospital of Jiaxing University, Jiaxing University College of Medicine, Jiaxing, Zhejiang, China
- School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China
| | - Shuyan Dong
- Jiaxing Key Laboratory of Virus-Related Infectious Diseases, The Affiliated Hospital of Jiaxing University, Jiaxing University College of Medicine, Jiaxing, Zhejiang, China
| | - Shichen Huang
- School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China
| | - Yuhan Sun
- School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China
| | - Yingzhi Sun
- Jiaxing Key Laboratory of Virus-Related Infectious Diseases, The Affiliated Hospital of Jiaxing University, Jiaxing University College of Medicine, Jiaxing, Zhejiang, China
| | - Beibei Zhao
- School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China
| | - Qiulan Qi
- Jiaxing Key Laboratory of Virus-Related Infectious Diseases, The Affiliated Hospital of Jiaxing University, Jiaxing University College of Medicine, Jiaxing, Zhejiang, China
| | - Lei Xiong
- Department of Biochemistry and Molecular Biology, Wannan Medical College, Wuhu, Anhui, China
- *Correspondence: Yuxin Jiang, ; Feng Hong, ; Lei Xiong,
| | - Feng Hong
- The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
- *Correspondence: Yuxin Jiang, ; Feng Hong, ; Lei Xiong,
| | - Yuxin Jiang
- Jiaxing Key Laboratory of Virus-Related Infectious Diseases, The Affiliated Hospital of Jiaxing University, Jiaxing University College of Medicine, Jiaxing, Zhejiang, China
- *Correspondence: Yuxin Jiang, ; Feng Hong, ; Lei Xiong,
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12
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Lebrun LJ, Dusuel A, Xolin M, Le Guern N, Grober J. Activation of TLRs Triggers GLP-1 Secretion in Mice. Int J Mol Sci 2023; 24:5333. [PMID: 36982420 PMCID: PMC10049702 DOI: 10.3390/ijms24065333] [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: 02/01/2023] [Revised: 03/03/2023] [Accepted: 03/05/2023] [Indexed: 03/14/2023] Open
Abstract
The gastrointestinal tract constitutes a large interface with the inner body and is a crucial barrier against gut microbiota and other pathogens. As soon as this barrier is damaged, pathogen-associated molecular patterns (PAMPs) are recognized by immune system receptors, including toll-like receptors (TLRs). Glucagon-like peptide 1 (GLP-1) is an incretin that was originally involved in glucose metabolism and recently shown to be rapidly and strongly induced by luminal lipopolysaccharides (LPS) through TLR4 activation. In order to investigate whether the activation of TLRs other than TLR4 also increases GLP-1 secretion, we used a polymicrobial infection model through cecal ligation puncture (CLP) in wild-type and TLR4-deficient mice. TLR pathways were assessed by intraperitoneal injection of specific TLR agonists in mice. Our results show that CLP induces GLP-1 secretion both in wild-type and TLR4-deficient mice. CLP and TLR agonists increase gut and systemic inflammation. Thus, the activation of different TLRs increases GLP-1 secretion. This study highlights for the first time that, in addition to an increased inflammatory status, CLP and TLR agonists also strongly induce total GLP-1 secretion. Microbial-induced GLP-1 secretion is therefore not only a TLR4/LPS-cascade.
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Affiliation(s)
- Lorène J. Lebrun
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
- Institut Agro Dijon, 21000 Dijon, France
| | - Alois Dusuel
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
| | - Marion Xolin
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
| | - Naig Le Guern
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
| | - Jacques Grober
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
- Institut Agro Dijon, 21000 Dijon, France
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13
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Zhang J, Zeng S, Wang P, Chen Y, Zeng C. NLRP3: A Promising Therapeutic Target for Inflammatory Bowel Disease. Curr Drug Targets 2023; 24:1106-1116. [PMID: 37946354 DOI: 10.2174/0113894501255960231101105113] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 08/06/2023] [Accepted: 10/06/2023] [Indexed: 11/12/2023]
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is an intestinal disease with complicated pathological mechanisms. The incidence of IBD has been increasing in recent years, which has a significant negative impact on the lives of patients. Therefore, it is particularly important to find new therapeutic targets and innovative drugs for the development of IBD. Recent studies have revealed that NLRP3 inflammatory vesicles can play an important role in maintaining intestinal homeostasis and sustaining the intestinal immune response in IBD. On the one hand, aberrant activation of NLRP3 inflammatory vesicles may cause excessive immune response by converting caspase-1, proIL-18, and proIL-1β to their active forms and releasing pro-inflammatory cytokines to stimulate the development and progression of IBD, and we can improve IBD by targeting blockade of NLRP3 activation. On the other hand, NLRP3 may also play an enter protective role by maintaining the homeostasis of the intestinal immune system. In this paper, we reviewed the activation mechanism of NLRP3 inflammasome, and the effects of NLRP3 inflammasome activation on IBD are discussed from two different perspectives: pathology and protection. At the same time, we listed the effects of direct inhibitors, indirect inhibitors, and natural inhibitors of NLRP3 inflammasome on IBD in combination with cutting-edge advances and clinical practice results, providing new targets and new ideas for the clinical treatment of IBD.
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Affiliation(s)
- Jiayu Zhang
- Department of Gastroenterology, Digestive Disease Hospital, the First Affiliated Hospital of Nanchang University, Nanchang, China
- Huankui Academy of Nanchang University, Nanchang, China
| | - Shuyan Zeng
- Department of Gastroenterology, Digestive Disease Hospital, the First Affiliated Hospital of Nanchang University, Nanchang, China
- Huankui Academy of Nanchang University, Nanchang, China
| | - Peng Wang
- Department of Gastroenterology, Digestive Disease Hospital, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Youxiang Chen
- Department of Gastroenterology, Digestive Disease Hospital, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chunyan Zeng
- Department of Gastroenterology, Digestive Disease Hospital, the First Affiliated Hospital of Nanchang University, Nanchang, China
- Huankui Academy of Nanchang University, Nanchang, China
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14
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Ishioh M, Nozu T, Miyagishi S, Igarashi S, Funayama T, Ohhira M, Okumura T. Activation of basal forebrain cholinergic neurons improves colonic hyperpermeability through the vagus nerve and adenosine A2B receptors in rats. Biochem Pharmacol 2022; 206:115331. [PMID: 36330948 DOI: 10.1016/j.bcp.2022.115331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 10/20/2022] [Accepted: 10/24/2022] [Indexed: 12/14/2022]
Abstract
Intestinal barrier dysfunction, a leaky gut, contributes to the pathophysiology of various diseases such as dementia and irritable bowel syndrome (IBS). We recently clarified that orexin, ghrelin, or adenosine A2B signaling in the brain improved leaky gut through the vagus nerve. The present study was performed to clarify whether basal forebrain cholinergic neurons (BFCNs) are implicated in the central regulation of intestinal barrier function. We activated BFCNs using benzyl quinolone carboxylic acid (BQCA), a positive muscarinic M1 allosteric modulator, and evaluated colonic permeability by quantifying the absorbed Evans blue in rat colonic tissue. Intracisternal (not intraperitoneal) injection of BQCA blocked the increased colonic permeability in response to lipopolysaccharide. Vagotomy blocked BQCA-induced improvement of colonic hyperpermeability. Intracisternally administered pirenzepine, a muscarinic M1 selective antagonist, prevented intestinal barrier function improvement by intravenously administered 2-deoxy-d-glucose, central vagal stimulant. Adenosine A2B receptor antagonist but not dopamine or opioid receptor antagonist prevented BQCA-induced blockade of colonic hyperpermeability. Additionally, intracisternal injection of pirenzepine blocked orexin- or butyrate-induced intestinal barrier function improvement. These results suggest that BFCNs improve leaky gut through adenosine A2B signaling and the vagal pathway. Furthermore, BFCNs mediate orexin- or butyrate-induced intestinal barrier function improvement. Since BFCNs play a role in cognitive function and a leaky gut is associated with dementia, the present finding may lead us to speculate that BFCNs are involved in the development of dementia by regulating intestinal barrier function.
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Affiliation(s)
- Masatomo Ishioh
- Division of Metabolism, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan; Department of General Medicine, Asahikawa Medical University, Japan.
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Japan
| | - Saori Miyagishi
- Department of General Medicine, Asahikawa Medical University, Japan
| | - Sho Igarashi
- Division of Metabolism, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Takuya Funayama
- Division of Metabolism, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Masumi Ohhira
- Department of General Medicine, Asahikawa Medical University, Japan
| | - Toshikatsu Okumura
- Division of Metabolism, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan; Department of General Medicine, Asahikawa Medical University, Japan; Center for Medical Education, Asahikawa Medical University, Japan
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15
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Okumura T, Nozu T, Ishioh M, Igarashi S, Funayama T, Kumei S, Ohhira M. Oxytocin acts centrally in the brain to improve leaky gut through the vagus nerve and a cannabinoid signaling in rats. Physiol Behav 2022; 254:113914. [PMID: 35839845 DOI: 10.1016/j.physbeh.2022.113914] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 07/07/2022] [Accepted: 07/11/2022] [Indexed: 10/17/2022]
Abstract
Brain oxytocin plays a role in gastrointestinal functions. Among them, oxytocin acts centrally to modulate gastrointestinal motility and visceral sensation. Intestinal barrier function, one of important gut functions, is also regulated by the central nervous system. Little is, however, known about a role of central oxytocin in the regulation of intestinal barrier function. The present study was performed to clarify whether brain oxytocin is also involved in regulation of intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of oxytocin dose-dependently abolished increased colonic permeability in response to lipopolysaccharide while intraperitoneal injection of oxytocin at the same dose failed to block it. Either atropine or surgical vagotomy blocked the central oxytocin-induced improvement of colonic hyperpermeability. Cannabinoid 1 receptor antagonist but not adenosine or opioid receptor antagonist prevented the central oxytocin-induced blockade of colonic hyperpermeability. In addition, intracisternal injection of oxytocin receptor antagonist blocked the ghrelin- or orexin-induced improvement of intestinal barrier function. These results suggest that oxytocin acts centrally in the brain to reduce colonic hyperpermeability. The vagal cholinergic pathway or cannabinoid 1 receptor signaling plays a vital role in the process. The oxytocin-induced improvement of colonic hyperpermeability mediates the central ghrelin- or orexin-induced improvement of intestinal barrier function. We would therefore suggest that activation of central oxytocin signaling may be useful for leaky gut-related diseases such as irritable bowel syndrome and autism.
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Affiliation(s)
- Toshikatsu Okumura
- Division of Metabolism, Asahikawa Medical University, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan; Department of General Medicine, Asahikawa Medical University, Japan.
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Japan
| | - Masatomo Ishioh
- Division of Metabolism, Asahikawa Medical University, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Sho Igarashi
- Division of Metabolism, Asahikawa Medical University, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Takuya Funayama
- Division of Metabolism, Asahikawa Medical University, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Shima Kumei
- Department of General Medicine, Asahikawa Medical University, Japan
| | - Masumi Ohhira
- Department of General Medicine, Asahikawa Medical University, Japan
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16
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Gao J, Li L, Zhao D, Wang X, Xia Y, Li B, Liu C, Zuo X. Tilapia skin peptides, a by-product of fish processing, ameliorate DSS-induced colitis by regulating inflammation and inhibiting apoptosis. Front Nutr 2022; 9:988758. [PMID: 36185687 PMCID: PMC9525210 DOI: 10.3389/fnut.2022.988758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
Intestinal bowel disease (IBD) has always been tough to treat, therefore researchers are struggle to look for treatments that are safe, low cost, and effective. Food-derived peptides are thought to have anti-inflammatory and antioxidant properties, but they have not been studied in depth in the treatment of IBD. Based on this, we explored the effect of tilapia skin peptides (TSPs) on the remission of colitis in the present study. Colonic epithelial cell lines CT-26 and HT-29 were co-treated with lipopolysaccharide (LPS) and TSPs for 12 h. Cell viability was assessed by CCK8 assay. Dextran sulfate sodium (DSS)-induced colitis model was established and 100 mg/kg TSPs were oral administered at the same time as DSS intervention. Colonic mucosal barrier function was assessed by western blotting. The inflammatory responses were evaluated by quantitative real-time PCR along with ELISA, respectively. Apoptosis was investigated by TUNEL and flow cytometry. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to characterize peptides composition of TSPs. It was found that TSPs significantly inhibit LPS-induced inflammation and apoptosis in vitro without affecting cell viability. Moreover, the upregulation and activation of Caspase-3 and Caspase-8 were also reversed by TSPs. Subsequently, in vivo experiments demonstrated that TSPs can attenuate DSS induced colitis, manifested by a decrease in weight loss and colon shortening. The expression of ZO-1 and occluding were significantly increased, and the pro-inflammatory cytokines were down-regulated. Meanwhile, TSPs alleviated DSS-induced apoptosis and reduced the expressions of Caspase-3 and Caspase-8. Finally, we found that TSPs were composed of 51 short peptides, and 12 of them were predicted to have significant biological activity. Collectively, this study suggested that TSPs can alleviate colon damage caused by foreign stimuli via inhibiting inflammation and apoptosis which indicated that it has great potential value for the treatment of IBD.
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Affiliation(s)
- Jiahui Gao
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Lixiang Li
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Dong Zhao
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Medical Integration and Practice Center, Shandong University, Jinan, China
| | - Xia Wang
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Yanan Xia
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Bing Li
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Chang Liu
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Xiuli Zuo
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital, Shandong University, Jinan, China
- *Correspondence: Xiuli Zuo,
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17
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Zhu L, Wu Z, Zhu C, Yin J, Huang Y, Feng J, Zhang Q. The Deletion of IL-17A Enhances Helicobacter hepaticus Colonization and Triggers Colitis. J Inflamm Res 2022; 15:2761-2773. [PMID: 35518840 PMCID: PMC9064063 DOI: 10.2147/jir.s359100] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/19/2022] [Indexed: 01/14/2023] Open
Abstract
Objective IL-17 is a key regulator of the inflammatory response, and as such, it is involved in the constraint and clearance of pathogens. The mechanism of IL-17 in the pathogenesis of inflammatory bowel disease (IBD) caused by microbial infection is still unclear. Helicobacter hepaticus infection can induce colitis in many mouse strains, and thus, it has been widely used in the study of IBD pathogenesis. Methods In this study, male C57BL/6, BALB/c, Il-10−/−, and Il-17a−/− mice were infected with H. hepaticus for several weeks. Histopathology, H. hepaticus colonization and distribution, expression of inflammatory cytokines and lysozyme, and distribution of mucus in proximal colon were examined. Results The colonic colonization of H. hepaticus was abnormally high in Il-17a−/− mice. H. hepaticus infection caused only mild to moderate colitis symptoms in Il-17a−/− mice, including low levels of lymphocyte infiltration, epithelial cell defects, goblet cell reduction, and crypt atrophy without obvious hyperplasia in the later stage of infection. Furthermore, many inflammatory genes were significantly increased in the proximal colon of H. hepaticus-infected Il-17a−/− mice compared with C57BL/6 mice. In addition, the reduction of colonic mucus and the down-regulation of ZO-1, Claudin-1, and IL-22 were observed in Il-17a−/− mice compared with C57BL/6 mice post H. hepaticus infection. Conclusion These results demonstrated that the deletion of IL-17A impaired the integrity of the intestinal epithelium, weakened the secretion of mucus, attenuated colonic mucosal regeneration, reduced the ability to resist microbial infection, and finally led to colitis caused by H. hepaticus.
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Affiliation(s)
- Liqi Zhu
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
| | - Zhihao Wu
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
| | - Chen Zhu
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
| | - Jun Yin
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
| | - Yuzheng Huang
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu Province, 214064, People's Republic of China.,Public Health Research Center, Jiangnan University, Wuxi, Jiangsu Province, 214122, People's Republic of China
| | - Jie Feng
- Shanghai Laboratory Animal Research Center, Shanghai Quality Monitoring Center of Laboratory Animals, Shanghai, 201203, People's Republic of China
| | - Quan Zhang
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
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18
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Barrier effect and wound healing activity of the medical device REF-FTP78 in the treatment of gastroesophageal reflux disease. Sci Rep 2022; 12:6136. [PMID: 35414705 PMCID: PMC9005723 DOI: 10.1038/s41598-022-10171-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 04/04/2022] [Indexed: 12/16/2022] Open
Abstract
REF-FTP78 is a class IIb medical device present on the market with different trade names and developed for the treatment of gastroesophageal reflux disease (GERD). This medical device is based on polysaccharides from Aloe Barbadensis and fucoidans from brown seaweeds, such as Undaria pinnatifida and Fucus vesiculosus, and aims to exert a protective effect on the esophageal mucosa against the noxious components of refluxate. The present study reports on the efficacy of REF-FTP78 devoting a particular attention to the barrier effect and wound healing properties, combined with antioxidant and anti-inflammatory activities. Film-forming properties and barrier effect were investigated on in vitro reconstructed human esophageal epithelium, through TEER measurement and evaluation of caffeine and Lucifer yellow permeability, and in an ex vivo swine model of esophageal mucosa damage. Antioxidant and anti-inflammatory properties were evaluated in terms of scavenging activity towards DPPH, ABTS and NO radicals and a wound healing assay was carried out to study the influence of the product on cell migration. The obtained results highlighted a significant barrier effect, with a reduction in caffeine penetration equal to 65.3%, the ability to both repair and prevent the damage caused by an acid insult, confirmed by a good transepithelial resistance for the tissue treated with the tested item, and the capacity to promote wound healing. Furthermore, the tested product showed good antioxidant and anti-inflammatory properties in the performed radical scavenging assays. These findings support the use of REF-FTP78 in the treatment of GERD.
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19
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Prakash T, Janadri S. Anti-inflammatory effect of wedelolactone on DSS induced colitis in rats: IL-6/STAT3 signaling pathway. J Ayurveda Integr Med 2022:100544. [DOI: 10.1016/j.jaim.2022.100544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 12/05/2021] [Accepted: 01/11/2022] [Indexed: 11/29/2022] Open
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20
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Kang S, You HJ, Ju Y, Kim HJ, Jeong YJ, Johnston TV, Ji GE, Ku S, Park MS. Butyl-fructooligosaccharides modulate gut microbiota in healthy mice and ameliorate ulcerative colitis in a DSS-induced model. Food Funct 2022; 13:1834-1845. [DOI: 10.1039/d1fo03337a] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Butyl-fructooligosaccharides (B-FOSs) are newly synthesized prebiotics composed of short-chain FOS (GF2, 1-kestose; GF3, nystose; GF4, fructofuranosyl-nystose; GF5, 1-F-(1-b-D-fructofuranosyl)-2-nystose) bound with one or two butyric groups by ester bonds. Previous in...
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21
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Cheng N, Zhang L, Liu L. Understanding the Role of Purinergic P2X7 Receptors in the Gastrointestinal System: A Systematic Review. Front Pharmacol 2021; 12:786579. [PMID: 34987401 PMCID: PMC8721002 DOI: 10.3389/fphar.2021.786579] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/17/2021] [Indexed: 11/24/2022] Open
Abstract
Background: The role of purinergic P2X7 receptor (P2X7R) is of interest due to its involvement in inflammation and mediating immune cell responses. P2X7R is particularly implicated in the development of inflammatory bowel disease (IBD). However, the extent of the actions of P2X7R in the gastrointestinal (GI) system under physiological and pathophysiological conditions remains to be elucidated. This systematic review aimed to identify, summarize and evaluate the evidence for a critical role of P2X7R in the GI system. Methods: We searched PubMed, Embase and Scopus with search terms pertained to P2X7R in the GI system in disease or physiological state, including "P2X7 or P2X7 receptor or purinergic signaling" in combination with any of the terms "intestine or colon or gut or gastrointestinal," "pathology or inflammation or disease or disorder," and "physiology or expression." Titles and abstracts were screened for potentially eligible full texts, and animal and human studies published in English were included in this study. Data were extracted from papers meeting inclusion criteria. Meta-analysis was not feasible given the study diversity. Results: There were 48 papers included in this review. We identified 14 experimental colitis models, three sepsis models and one ischemia-reperfusion injury model. Among them, 11 studies examined P2X7R in GI infections, six studies on immune cell regulation, four studies on GI inflammation, two studies on GI malignancies, three studies involving intestinal injury due to various causes, two studies on ATP-activated P2X7R in the GI system and two studies on metabolic regulation. Conclusion: Evidence supports P2X7R mediating inflammation and immune cell responses in GI inflammation, infections and injury due to IBD and other challenges to the intestinal wall. P2X7R inhibition by gene knockout or by application of P2X7R antagonists can reduce tissue damage by suppressing inflammation. P2X7R is also implicated in GI malignancies and glucose and lipid homeostasis. P2X7R blockade, however, did not always lead to beneficial outcomes in the various pathological models of study.
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Affiliation(s)
- Nathalie Cheng
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia
| | - Li Zhang
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, NSW, Australia
| | - Lu Liu
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia
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22
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Shao J, Li Z, Gao Y, Zhao K, Lin M, Li Y, Wang S, Liu Y, Chen L. Construction of a "Bacteria-Metabolites" Co-Expression Network to Clarify the Anti-Ulcerative Colitis Effect of Flavonoids of Sophora flavescens Aiton by Regulating the "Host-Microbe" Interaction. Front Pharmacol 2021; 12:710052. [PMID: 34721011 PMCID: PMC8553221 DOI: 10.3389/fphar.2021.710052] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 09/09/2021] [Indexed: 12/30/2022] Open
Abstract
Ulcerative colitis (UC) is considered an immune disease, which is related to the dysbiosis of intestinal microbiota and disorders of the host immune system and metabolism. Sophora flavescens Aiton has been used for the clinical treatment of UC in China and East Asia for thousands of years. It has many traditional prescriptions and modern preparations, and its curative effects are definite. We are the first to report that the flavonoids in Sophora flavescens (S. flavescens) Aiton EtOAc extract (SFE) could potentially attenuate the dextran sodium sulfate–induced UC in mice, which changed the current understanding of considering alkaloids as the only anti-UC pharmacological substances of S. flavescens Aiton. Based on the 16S rRNA gene sequencing and metabolomic analysis, it was found that the anti-UC effects of SFE were due to the regulation of gut microbiota, reversing the abnormal metabolisms, and regulation of the short-chain fatty acids synthesis. Notably, according to the interaction networks of specific bacteria and “bacteria and metabolites” co-expression network, the SFE could enrich the abundance of the commensal bacterium Lactobacillus, Roseburia, norank_f__Muribaculaceae, Anaerotruncus, Candidatus_Saccharimona, and Parasutterella, which are proposed as potentially beneficial bacteria, thereby playing vital roles in the treatment of UC.
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Affiliation(s)
- Jing Shao
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhaocheng Li
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yanping Gao
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Kairui Zhao
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Minling Lin
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yadi Li
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Shumei Wang
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yi Liu
- The Fifth Affiliated Hospital of Southern Medical University, Guangzhou, China.,School of Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Lei Chen
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chinese Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
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23
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Ho SW, El-Nezami H, Corke H, Ho CS, Shah NP. L-citrulline enriched fermented milk with Lactobacillus helveticus attenuates dextran sulfate sodium (DSS) induced colitis in mice. J Nutr Biochem 2021; 99:108858. [PMID: 34587540 DOI: 10.1016/j.jnutbio.2021.108858] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 05/28/2021] [Accepted: 07/25/2021] [Indexed: 11/30/2022]
Abstract
Inflammatory bowel disease (IBD) is a group of chronic inflammatory gastrointestinal diseases that causes worldwide suffering. L. helveticus is a probiotic that can enhance intestinal barrier function via alleviation of excessive inflammatory response. Citrulline, a functional amino acid, has been reported to stimulate muscle synthesis and to function with a prebiotic-like action with certain Lactobacillus strains. The aim of this study was to investigate the potential synergistic effect of combining L. helveticus and citrulline on protection against damage induced by dextran sulfate sodium (DSS) in a mouse model. 6-week-old male C57BL/6J mice were fed with DSS water and randomly divided for administering with different milk treatments: 1) plain milk (control or DSS control), 2) 1% (w/v) citrulline enriched milk (Cit_milk), 3) milk fermented with L. helveticus (LHFM) and 4) DSS+milk fermented with L. helveticus with 1% (w/v) citrulline (Cit_LHFM). The treatment effects on the survival and macroscopic and microscopic signs were examined. All treatments presented different degrees of protective effects on attenuating the damages induced by DSS. All treatments reduced the body weight loss, disease activity index (DAI), histological scores, pro-inflammatory cytokine expression (IL-6, TNF-α and IFN-γ) and production (IL-4) (all P <0.05) and the tight junction (TJ) protein (zonula occluden-1 (ZO-1) expression. LHFM and Cit_LHFM improved survival rate (both at P<0.05). Particularly, Cit_LHFM showed greater effects on protecting the damages induced by DSS, especially in ameliorating colonic permeability, TJ protein (ZO-1, occludin and claudin-1) expression and distribution as well as in reducing IL-4 and IL-17 expression (all P <0.05). Our findings suggested that the combination of and citrulline had significant synergistic effect on protecting against injury from DSS-induced colitis. Therefore, citrulline enriched L. helveticus fermented milk is suggested to be a potential therapy for treating IBD.
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Affiliation(s)
- Sze Wing Ho
- Food and Nutritional Science, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Hani El-Nezami
- Food and Nutritional Science, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Harold Corke
- Biotechnology and Food Engineering Program, Guangdong Technion-Israel Institute of Technology, Shantou, Guangdong, China; Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel
| | - Chun Sing Ho
- Department of Pathology, Tuen Mun Hospital, Tuen Mun, Hong Kong
| | - Nagendra P Shah
- Food and Nutritional Science, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong.
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24
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Chen LZ, Zhang XX, Liu MM, Wu J, Ma D, Diao LZ, Li Q, Huang YS, Zhang R, Ruan BF, Liu XH. Discovery of Novel Pterostilbene-Based Derivatives as Potent and Orally Active NLRP3 Inflammasome Inhibitors with Inflammatory Activity for Colitis. J Med Chem 2021; 64:13633-13657. [PMID: 34506712 DOI: 10.1021/acs.jmedchem.1c01007] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Studies have shown that the abnormal activation of the NLRP3 inflammasome is involved in a variety of inflammatory-based diseases. In this study, a high content screening model targeting the activation of inflammasome was first established and pterostilbene was discovered as the active scaffold. Based on this finding, total of 50 pterostilbene derivatives were then designed and synthesized. Among them, compound 47 was found to be the best one for inhibiting cell pyroptosis [inhibitory rate (IR) = 73.09% at 10 μM], showing low toxicity and high efficiency [against interleukin-1β (IL-1β): half-maximal inhibitory concentration (IC50) = 0.56 μM]. Further studies showed that compound 47 affected the assembly of the NLRP3 inflammasomes by targeting NLRP3. The in vivo biological activity showed that this compound significantly alleviated dextran sodium sulfate (DSS)-induced colitis in mice. In general, our study provided a novel lead compound directly targeting the NLRP3 protein, which is worthy of further research and structural optimization.
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Affiliation(s)
- Liu Zeng Chen
- School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, P.R. China
- Key Lab of Biofabrication of Anhui Higher Education, Hefei University, Hefei 230601, P.R. China
| | - Xing Xing Zhang
- School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, P.R. China
| | - Ming Ming Liu
- School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, P.R. China
| | - Jing Wu
- School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, P.R. China
| | - Duo Ma
- School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, P.R. China
| | - Liang Zhuo Diao
- School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, P.R. China
| | - Qingshan Li
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230059, P.R. China
| | - Yan Shuang Huang
- School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, P.R. China
| | - Rui Zhang
- School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, P.R. China
| | - Ban Feng Ruan
- Key Lab of Biofabrication of Anhui Higher Education, Hefei University, Hefei 230601, P.R. China
| | - Xin Hua Liu
- School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, P.R. China
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25
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Colonic Epithelial PHLPP2 Deficiency Promotes Colonic Epithelial Pyroptosis by Activating the NF- κB Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5570731. [PMID: 34394827 PMCID: PMC8363454 DOI: 10.1155/2021/5570731] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 07/17/2021] [Indexed: 02/06/2023]
Abstract
Background Ulcerative colitis (UC) is a chronic inflammatory disease with increasing prevalence worldwide. Barrier defect in intestinal epithelial cells (IECs) is one of the main pathogeneses in UC. Pyroptosis is a programmed lytic cell death and is triggered by inflammatory caspases, while little is known about its role in UC. Methods Differentially expressed genes (DEGs) were identified by comparing UC patients with healthy controls from the GEO datasets. The candidate genes involved in pyroptosis were obtained, and the underlying molecular mechanism in the progression of UC was explored in vivo and in vitro. Results Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2), a protein phosphatase, was downregulated and involved in regulating inflammation-induced IEC pyroptosis by modulating the NF-κB signaling in UC through bioinformatics analysis. Moreover, we demonstrated that PHLPP2 was downregulated in UC patients and UC mice. Besides, we found that PHLPP2 depletion activated the NF-κB signaling and increased the expressions of caspase-1 P20, Gasdermin N, IL-18, and IL-1β contributing to IEC pyroptosis and inflammation in UC mice. Furthermore, we found that PHLPP2−/− mice developed hypersensitivity to dextran sulfate sodium (DSS) treatment toward colitis showing activated NF-κB signaling and dramatically induced expressions of caspase-1 P20, Gasdermin N, IL-18, and IL-1β. Mechanically, this inflammation-induced downregulation of PHLPP2 was alleviated by an NF-κB signaling inhibitor in intestinal organoids of PHLPP2−/− mice and fetal colonic cells. Conclusions PHLPP2 downexpression activated the NF-κB signaling and promoted the IEC pyroptosis, leading to UC progression. Therefore, PHLPP2 might be an attractive candidate therapeutic target for UC.
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26
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Lajczak-McGinley NK, Porru E, Fallon CM, Smyth J, Curley C, McCarron PA, Tambuwala MM, Roda A, Keely SJ. The secondary bile acids, ursodeoxycholic acid and lithocholic acid, protect against intestinal inflammation by inhibition of epithelial apoptosis. Physiol Rep 2021; 8:e14456. [PMID: 32562381 PMCID: PMC7305237 DOI: 10.14814/phy2.14456] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 04/08/2020] [Accepted: 04/09/2020] [Indexed: 12/17/2022] Open
Abstract
Increased epithelial permeability is a key feature of IBD pathogenesis and it has been proposed that agents which promote barrier function may be of therapeutic benefit. We have previously reported the secondary bile acid, ursodeoxycholic acid (UDCA), to be protective in a mouse model of colonic inflammation and that its bacterial metabolism is required for its beneficial effects. The current study aimed to compare the effects of UDCA, LCA, and a non‐metabolizable analog of UDCA, 6‐methyl‐UDCA (6‐MUDCA), on colonic barrier function and mucosal inflammation in a mouse model of colonic inflammation. Bile acids were administered daily to C57Bl6 mice by intraperitoneal injection. Colonic inflammation, induced by addition of DSS (2.5%) to the drinking water, was measured as disease activity index (DAI) and histological score. Epithelial permeability and apoptosis were assessed by measuring FITC‐dextran uptake and caspase‐3 cleavage, respectively. Cecal bile acids were measured by HPLC‐MS/MS. UDCA and LCA, but not 6‐MUDCA, were protective against DSS‐induced increases in epithelial permeability and colonic inflammation. Furthermore, UDCA and LCA inhibited colonic epithelial caspase‐3 cleavage both in DSS‐treated mice and in an in vitro model of cytokine‐induced epithelial injury. HPLC‐MS/MS analysis revealed UDCA administration to increase colonic LCA levels, whereas LCA administration did not alter UDCA levels. UDCA, and its primary metabolite, LCA, protect against intestinal inflammation in vivo, at least in part, by inhibition of epithelial apoptosis and promotion of barrier function. These data suggest that clinical trials of UDCA in IBD patients are warranted.
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Affiliation(s)
- Natalia K Lajczak-McGinley
- Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland
| | - Emanule Porru
- Department of Chemistry, University of Bologna, Bologna, Italy
| | - Ciara M Fallon
- Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland
| | - Jessica Smyth
- Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland
| | - Caitriona Curley
- Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland
| | - Paul A McCarron
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, Northern Ireland
| | - Murtaza M Tambuwala
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, Northern Ireland
| | - Aldo Roda
- Department of Chemistry, University of Bologna, Bologna, Italy.,INBB, National Institute of Bio structures and Biosystems, Rome, Italy
| | - Stephen J Keely
- Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland
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27
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Tian WJ, Wang QN, Wang XF, Dong DF. Clophosome alleviate dextran sulphate sodium-induced colitis by regulating gut immune responses and maintaining intestinal integrity in mice. Clin Exp Pharmacol Physiol 2021; 48:902-910. [PMID: 33527445 DOI: 10.1111/1440-1681.13468] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/12/2021] [Indexed: 01/08/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic progressive disorder characterized by complicated gastrointestinal inflammation. Research on therapeutic agents is still urgent due to the lack of satisfactory treatments. Gut macrophages are considered to be predominant in excessive inflammatory responses. Thus, we aimed to investigate whether depletion of macrophages would have a beneficial effect on IBD and could be a potential therapeutic strategy. In this study, we established a 12-day Dextran sodium sulphate (DSS)-induced colitis mouse model and determined the effect of the macrophage depletion agent Clophosome (neutral clodronate liposomes; CNC). The results showed that CNC significantly alleviated the symptoms of colitis, as demonstrated by greater weight gain, decreased disease activity index (DAI) scores, and lower histopathological damage scores, as well was reduced levels of the proinflammatory cytokines interleukin (IL)-6 and tumour necrosis factor (TNF)-α. To investigate T cell subsets, cells were isolated from the lamina propria and cultured to analyse the expression of IL-17A, interferon (IFN)-γ and Foxp3 in CD4+ cells by flow cytometry. The data showed that during the process of colitis, the frequencies of CD4+ IL-17A+ T cells were significantly increased. Notably, CNC treatment markedly reduced the population of CD4+ IL-17A+ T cells, especially CD4+ IL-17A+ IFN-γ+ T cells. Furthermore, intestinal barrier integrity, as assessed by immunostaining of mucin and tight junction proteins, was severely disrupted in colitis. CNC improved the intestinal barrier by enhancing the expression of muc-2 and occludin. In summary, our findings demonstrated that CNC successfully ameliorated DSS-induced colitis and that its effect may be associated with inhibiting inflammatory responses and maintaining intestinal integrity.
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Affiliation(s)
- Wen-Jie Tian
- Faculty of Medical Laboratory Science, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qian-Nan Wang
- Department of Pathology and Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Xue-Feng Wang
- Faculty of Medical Laboratory Science, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Dan-Feng Dong
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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28
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Ishioh M, Nozu T, Igarashi S, Tanabe H, Kumei S, Ohhira M, Takakusaki K, Okumura T. Activation of central adenosine A2B receptors mediate brain ghrelin-induced improvement of intestinal barrier function through the vagus nerve in rats. Exp Neurol 2021; 341:113708. [PMID: 33771554 DOI: 10.1016/j.expneurol.2021.113708] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/15/2021] [Accepted: 03/21/2021] [Indexed: 11/16/2022]
Abstract
Leaky gut that is a condition reflecting intestinal barrier dysfunction has been attracting attention for its relations with many diseases such as irritable bowel syndrome or Alzheimer dementia. We have recently demonstrated that ghrelin acts in the brain to improve leaky gut via the vagus nerve. In the present study, we tried to clarify the precise central mechanisms by which ghrelin improves intestinal barrier function through the vagus nerve. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), blocked the intracisternal ghrelin-induced improvement of intestinal hyperpermeability while dopamine, cannabinoid or opioid receptor antagonist failed to prevent it. Since DPCPX can block adenosine A1 and adenosine A2B receptors, we examined which subtype is involved in the mechanism. Intracisternal injection of adenosine A2B agonist but not adenosine A1 agonist improved colonic hyperpermeability, while peripheral injection of adenosine A2B agonist failed to improve it. Intracisternal adenosine A2B agonist-induced improvement of colonic hyperpermeability was blocked by vagotomy. Adenosine A2B specific antagonist, alloxazine blocked the ghrelin- or central vagal stimulation by 2-deoxy-d-glucose-induced improvement of intestinal hyperpermeability. These results suggest that activation of adenosine A2B receptors in the central nervous system is capable of improving intestinal barrier function through the vagal pathway, and the adenosine A2B receptors may mediate the ghrelin-induced improvement of leaky gut in a vagal dependent fashion. These findings may help us understand the pathophysiology in not only gastrointestinal diseases but also non-gastrointestinal diseases associated with the altered intestinal permeability.
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Affiliation(s)
- Masatomo Ishioh
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan; Department of General Medicine, Asahikawa Medical University, Japan
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Japan
| | - Sho Igarashi
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Hiroki Tanabe
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Shima Kumei
- Department of General Medicine, Asahikawa Medical University, Japan
| | - Masumi Ohhira
- Department of General Medicine, Asahikawa Medical University, Japan
| | - Kaoru Takakusaki
- Division of Neuroscience, Department of Physiology, Asahikawa Medical University, Japan
| | - Toshikatsu Okumura
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan; Department of General Medicine, Asahikawa Medical University, Japan.
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El-Mahdy NA, El-Sayad MES, El-Kadem AH, Abu-Risha SES. Metformin alleviates inflammation in oxazolone induced ulcerative colitis in rats: plausible role of sphingosine kinase 1/sphingosine 1 phosphate signaling pathway. Immunopharmacol Immunotoxicol 2021; 43:192-202. [PMID: 33504231 DOI: 10.1080/08923973.2021.1878214] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is associated with high sphingosine kinase 1(SPHK1) expression in the colon, however its role in pathogenesis of UC is not clearly understood so, the aim of the present study was to clarify the role of SPHK1 and investigate whether the anti-inflammatory effects of metformin in UC is mediated by Sphingosine kinase 1/sphingosine 1 phosphate (S1P) signaling pathway. MATERIAL AND METHODS Colitis was induced in adult male wistar rats by intra rectal administration of oxazolone in the fifth and seventh days from initial presensitization. Oxazolone treated rats were divided into untreated oxazolone group, metformin and mesalazine treated groups both in a dose of 100 mg/kg/day orally for 21 days. Along with these groups normal control and saline groups were used .Colitis was assessed by colon length, disease activity index (DAI) and histological examination of colontissue. Plasma samples were used to measure S1P.SPHK1 activity, signal transducer and activator of transcription -3(STAT-3), interleukin-6 (IL-6), nitric oxide (NO), myeloperoxidase activity (MPO), reduced glutathione (GSH) and tissue expression of intracellular cell adhesion molecule -1(ICAM-1) and caspase-3 genes were measured in tissue. RESULTS Metformin successfully attenuated oxazolone colitis by increasing colon length, decreasing DAI and improved colon histologic picture. Metformin also induced a significant decrease in Plasma SIP, SPHK1 activity, inflammatory, oxidative stress markers, ICAM-1 and Caspase-3 genes expression compared to oxazolone group. CONCLUSION It is revealed that metformin alleviated inflammation and underlying mechanism may result from inhibition of SPHK1/S1P signaling pathway.
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Affiliation(s)
- Nageh Ahmed El-Mahdy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Magda El-Sayed El-Sayad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Aya Hassan El-Kadem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
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30
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Dai Z, Chen XY, An LY, Li CC, Zhao N, Yang F, You ST, Hou CZ, Li K, Jiang C, You QD, Di B, Xu LL. Development of Novel Tetrahydroquinoline Inhibitors of NLRP3 Inflammasome for Potential Treatment of DSS-Induced Mouse Colitis. J Med Chem 2020; 64:871-889. [PMID: 33332136 DOI: 10.1021/acs.jmedchem.0c01924] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The NLRP3 inflammasome is a critical component of innate immunity, which defends internal and external threats. However, inappropriate activation of the NLRP3 inflammasome induces various human diseases. In this study, we discovered and synthesized a series of tetrahydroquinoline inhibitors of NLRP3 inflammasome. Among these analogues, compound 6 exhibited optimal NLRP3 inhibitory activity. In vitro studies indicated that compound 6 directly bound to the NACHT domain of NLRP3 but not to protein pyrin domain (PYD) or LRR domain, inhibited NLRP3 ATPase activity, and blocked ASC oligomerization, thereby inhibiting NLRP3 inflammasome assembly and activation. Compound 6 specifically inhibited the NLRP3 inflammasome activation, but had no effect on the activation of NLRC4 or AIM2 inflammasomes. Furthermore, in the dextran sulfate sodium (DSS)-induced colitis mouse model, compound 6 exhibited significant anti-inflammatory activity through inhibiting NLRP3 inflammasome in vivo. Therefore, our study provides a potent NLRP3 inflammasome inhibitor, which deserves further structural optimization as a novel therapeutic candidate for NLRP3-driven diseases.
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Affiliation(s)
- Zhen Dai
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Xiao-Yi Chen
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Lu-Yan An
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Cui-Cui Li
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Ni Zhao
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Fan Yang
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Song-Tao You
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Chen-Zhi Hou
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Kan Li
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Cheng Jiang
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Qi-Dong You
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
| | - Bin Di
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Li-Li Xu
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
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31
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Li C, Hu Y, Nie Q, Chen S, Li G, Li L, Chen S, Tang B, Zhang J. A reactive oxygen species-responsive antioxidant nanotherapy for the treatment of drug-induced tissue and organ injury. Biomater Sci 2020; 8:7117-7131. [PMID: 33211787 DOI: 10.1039/d0bm01660h] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Drug-induced tissue injury has become a growing public health problem. Gastrointestinal injury and liver dysfunction are the most common side effects related to drug therapies, resulting in high morbidity and mortality in recent years. The overproduction of reactive oxygen species (ROS) is critically involved in the pathogenesis of drug-induced tissue injury. Consequently, antioxidant therapy represents a very promising strategy for the treatment of drug-induced tissue injury. Herein, a multifunctional antioxidant nanotherapy (TON) is engineered from a cyclodextrin-derived ROS-responsive material and a radical scavenger tempol, and is capable of eliminating a broad spectrum of ROS. After oral administration, TON can passively accumulate in the inflamed gastrointestinal tissues in mice with indomethacin-induced gastrointestinal injury. Correspondingly, TON shows superior efficacy in two representative murine models of indomethacin-induced gastrointestinal injury and acetaminophen-induced hepatic injury via attenuating oxidative stress and mitigating inflammatory responses. Additionally, preliminary in vitro and in vivo experiments demonstrate the good safety profile of TON. Consequently, the ROS-responsive antioxidant nanotherapy TON is promising for the treatment of drug-induced tissue and organ injury.
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Affiliation(s)
- Chenwen Li
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China.
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32
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Igarashi S, Nozu T, Ishioh M, Kumei S, Saito T, Toki Y, Hatayama M, Yamamoto M, Shindo M, Tanabe H, Okumura T. Centrally administered orexin prevents lipopolysaccharide and colchicine induced lethality via the vagal cholinergic pathway in a sepsis model in rats. Biochem Pharmacol 2020; 182:114262. [DOI: 10.1016/j.bcp.2020.114262] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/02/2020] [Accepted: 10/02/2020] [Indexed: 12/15/2022]
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33
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Kotani T, Setiawan J, Konno T, Ihara N, Okamoto S, Saito Y, Murata Y, Noda T, Matozaki T. Regulation of colonic epithelial cell homeostasis by mTORC1. Sci Rep 2020; 10:13810. [PMID: 32796887 PMCID: PMC7427982 DOI: 10.1038/s41598-020-70655-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 07/30/2020] [Indexed: 12/29/2022] Open
Abstract
Cell signaling important for homeostatic regulation of colonic epithelial cells (CECs) remains poorly understood. Mammalian target of rapamycin complex 1 (mTORC1), a protein complex that contains the serine-threonine kinase mTOR, mediates signaling that underlies the control of cellular functions such as proliferation and autophagy by various external stimuli. We here show that ablation of tuberous sclerosis complex 2 (Tsc2), a negative regulator of mTORC1, specifically in intestinal epithelial cells of mice resulted in increased activity of mTORC1 of, as well as increased proliferative activity of, CECs. Such Tsc2 ablation also reduced the population of Lgr5-positive colonic stem cells and the expression of Wnt target genes in CECs. The stimulatory phosphorylation of the kinase Akt and inhibitory phosphorylation of glycogen synthase kinase 3β were both markedly decreased in the colon of the Tsc2 conditional knockout (CKO) mice. Development of colonic organoids with cryptlike structures was enhanced for Tsc2 CKO mice compared with control mice. Finally, Tsc2 CKO mice manifested increased susceptibility to dextran sulfate sodium-induced colitis. Our results thus suggest that mTORC1 activity promotes the proliferation of, as well as the expression of Wnt target genes in, CECs and thereby contributes to colonic organogenesis and homeostasis.
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Affiliation(s)
- Takenori Kotani
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Jajar Setiawan
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.,Department of Physiology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Tasuku Konno
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Noriko Ihara
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Saki Okamoto
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yasuyuki Saito
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoji Murata
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tetsuo Noda
- Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takashi Matozaki
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
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Jin J, Wu S, Xie Y, Liu H, Gao X, Zhang H. Live and heat-killed cells of Lactobacillus plantarum Zhang-LL ease symptoms of chronic ulcerative colitis induced by dextran sulfate sodium in rats. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.103994] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
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35
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Preventive effects of Korean red ginseng on experimentally induced colitis and colon carcinogenesis. J Tradit Complement Med 2020; 10:198-206. [PMID: 32670814 PMCID: PMC7340975 DOI: 10.1016/j.jtcme.2020.04.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 04/10/2020] [Accepted: 04/20/2020] [Indexed: 01/05/2023] Open
Abstract
Korean Red Ginseng (KRG) exerts chemopreventive effects on experimentally induced carcinogenesis through multiple mechanisms. In this study, we investigated effects of KRG on dextran sulfate sodium (DSS)-induced colitis and azoxymethane (AOM) plus DSS-induced colon carcinogenesis in mice. Male C57BL/6J mice were fed diet containing 1% KRG or a standard diet throughout the experiment. The mouse colitis was induced by administration of 3% DSS in drinking water for 1 week. DSS caused body weight loss, diarrhea, rectal bleeding and colon length shortening, and all these symptoms were ameliorated by KRG treatment. KRG inhibited DSS-induced expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) by suppressing activation of nuclear factor-kappa B (NF-κB) and signal transducer and activation of transcription 3 (STAT3). In another experiment, colon carcinogenesis was initiated by single intraperitoneal injection of AOM (10 mg/kg) and promoted by 2% DSS in drinking water. KRG administration relieved the symptoms of colitis and reduced the incidence, the multiplicity and the size of colon tumor. The up-regulation of COX-2, iNOS, c-Myc and Cyclin D1 by AOM plus DSS was attenuated in KRG fed mice which was associated with suppression of NF-κB and STAT3 activation. These results suggest that KRG is a potential candidate for chemoprevention of inflammation-associated cancer in the colon.
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36
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The deubiquitinase USP25 supports colonic inflammation and bacterial infection and promotes colorectal cancer. ACTA ACUST UNITED AC 2020; 1:811-825. [DOI: 10.1038/s43018-020-0089-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 05/28/2020] [Indexed: 12/19/2022]
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37
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Ishioh M, Nozu T, Igarashi S, Tanabe H, Kumei S, Ohhira M, Okumura T. Ghrelin acts in the brain to block colonic hyperpermeability in response to lipopolysaccharide through the vagus nerve. Neuropharmacology 2020; 173:108116. [PMID: 32442542 DOI: 10.1016/j.neuropharm.2020.108116] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 04/23/2020] [Accepted: 04/26/2020] [Indexed: 12/31/2022]
Abstract
Brain ghrelin plays a role in gastrointestinal functions. Among them, ghrelin acts centrally to stimulate gastrointestinal motility and induce visceral antinociception. Intestinal barrier function, one of important gastrointestinal functions, is also controlled by the central nervous system. Little is, however, known about a role of central ghrelin in regulation of intestinal permeability. The present study was performed to clarify whether brain ghrelin is also involved in regulation of intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of ghrelin dose-dependently abolished increased colonic permeability in response to LPS while intraperitoneal injection of ghrelin at the same dose or intracisternal injection of des-acyl-ghrelin failed to block it. Carbachol potently attenuated LPS-induced intestinal hyperpermeability, and atropine or bilateral subdiaphragmatic vagotomy prevented the improvement of intestinal hyperpermeability by central ghrelin. Intracisternal (D-Lys3)-GHRP-6, a selective ghrelin receptor antagonist, significantly blocked improvement of intestinal barrier function by intravenously administered 2-deoxy-d-glucose, central vagal stimulant. Intracisternal injection of orexin 1 receptor antagonist, SB-334867 blocked intracisternal ghrelin-induced improvement of colonic hyperpermeability. These results suggest that exogenously administered or endogenously released ghrelin acts centrally to improve a disturbed intestinal barrier function through orexinergic signaling and the vagal cholinergic pathway. Central ghrelin may be involved in the pathophysiology and be a novel therapeutic option in not only gastrointestinal diseases such as irritable bowel syndrome but also non-gastrointestinal diseases associated with the altered intestinal permeability.
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Affiliation(s)
- Masatomo Ishioh
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan; Department of General Medicine, Asahikawa Medical University, Japan
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Japan
| | - Sho Igarashi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Hiroki Tanabe
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Shima Kumei
- Department of General Medicine, Asahikawa Medical University, Japan
| | - Masumi Ohhira
- Department of General Medicine, Asahikawa Medical University, Japan
| | - Toshikatsu Okumura
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan; Department of General Medicine, Asahikawa Medical University, Japan.
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Araiza-Calahorra A, Wang Y, Boesch C, Zhao Y, Sarkar A. Pickering emulsions stabilized by colloidal gel particles complexed or conjugated with biopolymers to enhance bioaccessibility and cellular uptake of curcumin. Curr Res Food Sci 2020; 3:178-188. [PMID: 32914133 PMCID: PMC7473359 DOI: 10.1016/j.crfs.2020.05.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The aim of this study was to investigate the fate of curcumin (CUR)-loaded Pickering emulsions with complex interfaces during in vitro gastrointestinal transit and test the efficacy of such emulsions on improving the bioaccessibility and cellular uptake of CUR. CUR-loaded Pickering emulsions tested were whey protein nanogel particle-stabilized Pickering emulsions (CUR-EWPN) and emulsions displaying complex interfaces included 1) layer-by-layer dextran sulphate-coated nanogel-stabilized Pickering emulsions (CUR-DxS+EWPN) and 2) protein+dextran-conjugated microgel-stabilized Pickering emulsions (CUR-EWPDxM). The hypothesis was that the presence of complex interfacial material at the droplet surface would provide better protection to the droplets against physiological degradation, particularly under gastric conditions and thus, improve the delivery of CUR to Caco-2 intestinal cells. The emulsions were characterized using droplet sizing, apparent viscosity, confocal and cryo-scanning electron microscopy, zeta-potential, lipid digestion kinetics, bioaccessibility of CUR as well as cell viability and uptake by Caco-2 cells. Emulsion droplets with modified to complex interfacial composition (i.e. CUR-DxS+EWPN and CUR-EWPDxM) provided enhanced kinetic stability to the Pickering emulsion droplets against coalescence in the gastric regime as compared to droplets having unmodified interface (i.e. CUR-EWPN), whereas droplet coalescence occurred in intestinal conditions irrespective of the initial interfacial materials. A similar rate and extent of free fatty acid release occurred in all the emulsions during intestinal digestion (p > 0.05), which correlated with the bioaccessibility of CUR. Striking, CUR-DxS+EWPN and CUR-EWPDxM significantly improved cellular CUR uptake as compared to CUR-EWPN (p < 0.05). These results highlight a promising new strategy of designing gastric-stable Pickering emulsions with complex interfaces to improve the delivery of lipophilic bioactive compounds to the cells for the future design of functional foods.
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Affiliation(s)
- Andrea Araiza-Calahorra
- Food Colloids and Bioprocessing Group, School of Food Science and Nutrition, University of Leeds, Leeds, LS2 9JT, UK
| | - Yunqing Wang
- Nutritional Sciences and Epidemiology Group, School of Food Science and Nutrition, University of Leeds, Leeds, LS2 9JT, UK
| | - Christine Boesch
- Nutritional Sciences and Epidemiology Group, School of Food Science and Nutrition, University of Leeds, Leeds, LS2 9JT, UK
| | - Yansheng Zhao
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, 212013, China
| | - Anwesha Sarkar
- Food Colloids and Bioprocessing Group, School of Food Science and Nutrition, University of Leeds, Leeds, LS2 9JT, UK
- Corresponding author.
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Phung HT, Nagashima H, Kobayashi S, Asano N, Machiyama T, Sakurai T, Tayama S, Asao A, Imatani A, Kawabe T, Okuyama Y, Ishii N, So T. TRAF5 Deficiency Ameliorates the Severity of Dextran Sulfate Sodium Colitis by Decreasing TRAF2 Expression in Nonhematopoietic Cells. Immunohorizons 2020; 4:129-139. [PMID: 32156688 DOI: 10.4049/immunohorizons.2000007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 02/20/2020] [Indexed: 11/19/2022] Open
Abstract
TNFR-associated factor 5 (TRAF5) is a cytosolic adaptor protein and functions as an inflammatory regulator. However, the in vivo function of TRAF5 remains unclear, and how TRAF5 controls inflammatory responses in the intestine is not well understood. In this study, we found that intestinal epithelial cells from Traf5-/- mice expressed a significantly lower level of NF-κB-regulated proinflammatory genes, such as Tnf, Il6, and Cxcl1, as early as day 3 after dextran sulfate sodium (DSS) exposure when compared with wild-type mice. The intestinal barrier integrity of DSS-treated Traf5-/- mice remained intact at this early time point, and Traf5-/- mice showed decreased body weight loss and longer colon length at later time points. Surprisingly, the protein level of TRAF2, but not TRAF3, was reduced in colon tissues of Traf5-/- mice after DSS, indicating the requirement of TRAF5 for TRAF2 protein stability in the inflamed colon. Experiments with bone marrow chimeras confirmed that TRAF5 deficiency in nonhematopoietic cells caused the attenuated colitis. Our in vitro experiments demonstrated that proinflammatory cytokines significantly promoted the degradation of TRAF2 protein in Traf5-/- nonhematopoietic cells in a proteasome-dependent manner. Collectively, our data suggest a novel regulatory function of TRAF5 in supporting the proinflammatory function of TRAF2 in nonhematopoietic cells, which may be important for acute inflammatory responses in the intestine.
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Affiliation(s)
- Hai The Phung
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Hiroyuki Nagashima
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Shuhei Kobayashi
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Naoki Asano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Tomoaki Machiyama
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
- Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan; and
| | - Tsuyoshi Sakurai
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Shunichi Tayama
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Atsuko Asao
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Akira Imatani
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Takeshi Kawabe
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Yuko Okuyama
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Naoto Ishii
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Takanori So
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
- Laboratory of Molecular Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
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NUDT7 Loss Promotes KrasG12D CRC Development. Cancers (Basel) 2020; 12:cancers12030576. [PMID: 32131398 PMCID: PMC7139971 DOI: 10.3390/cancers12030576] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 01/02/2020] [Accepted: 02/27/2020] [Indexed: 12/21/2022] Open
Abstract
Studies have suggested that dysregulation of peroxisomal lipid metabolism might play an important role in colorectal cancer (CRC) development. Here, we found that KrasG12D-driven CRC tumors demonstrate dysfunctional peroxisomal β-oxidation and identified Nudt7 (peroxisomal coenzyme A diphosphatase NUDT7) as one of responsible peroxisomal genes. In KrasG12D-driven CRC tumors, the expression level of Nudt7 was significantly decreased. Treatment of azoxymethane/dextran sulfate sodium (AOM/DSS) into Nudt7 knockout (Nudt7−/−) mice significantly induced lipid accumulation and the expression levels of CRC-related genes whereas xenografting of Nudt7-overexpressed LS-174T cells into mice significantly reduced lipid accumulation and the expression levels of CRC-related genes. Ingenuity pathway analysis of microarray using the colon of Nudt7−/− and Nudt7+/+ mice treated with AOM/DSS suggested Wnt signaling as one of activated signaling pathways in Nudt7−/− colons. Upregulated levels of β-catenin were observed in the colons of KrasG12D and AOM/DSS-treated Nudt7−/− mice and downstream targets of β-catenin such as Myc, Ccdn1, and Nos2, were also significantly increased in the colon of Nudt7−/− mice. We observed an increased level of palmitic acid in the colon of Nudt7−/− mice and attachment of palmitic acid-conjugated chitosan patch into the colon of mice induced the expression levels of β-catenin and CRC-related genes. Overall, our data reveal a novel role for peroxisomal NUDT7 in KrasG12D-driven CRC development.
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Yuan J, Cheng W, Zhang G, Ma Q, Li X, Zhang B, Hu T, Song G. Protective effects of iridoid glycosides on acute colitis via inhibition of the inflammatory response mediated by the STAT3/NF-кB pathway. Int Immunopharmacol 2020; 81:106240. [PMID: 32044657 DOI: 10.1016/j.intimp.2020.106240] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 12/24/2019] [Accepted: 01/20/2020] [Indexed: 02/08/2023]
Abstract
Morroniside and loganin are iridoid glycosides extracted from Cornus officinalis, a plant species widely used in traditional Chinese medicine. However, the anti-inflammatory effects of morroniside and loganin in colitis are barely understood. The aim of the present study was to explore the effects of morroniside and loganin on the dextran sodium sulfate (DSS)-induced murine model of colitis and an LPS-induced colorectal cancer (CRC) cell inflammation model, and to clarify the underlying mechanisms. We found that morroniside and loganin were able to ameliorate clinical features, including disease activity index (DAI), histological inflammation score and periodic acid-Schiff staining (PAS). In the mouse model, morroniside and loganin treatment increased expression of tight junction proteins (TJs) and decreased pro-inflammatory cytokine production. Moreover, our findings showed that the expression of p-STAT3 and p-p65 were suppressed compared to the disease group. In in vitro experiments, treatment with morroniside and loganin had no obvious effects on proliferative activity in HCT116 cells and HIEC-6 cells. Expression of pro-inflammatory cytokines was inhibited by morroniside and loganin treatment in comparison with the LPS-treated group. Taken together, morroniside and loganin have beneficial effects on colitis in vivo and are anti-inflammatory in vitro. Possible mechanisms of the anti-inflammatory response may include blockade of the STAT3/NF-κB pathway.
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Affiliation(s)
- Jiahui Yuan
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Weipeng Cheng
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Gongye Zhang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Qiujuan Ma
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Xiaomei Li
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Bing Zhang
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Tianhui Hu
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Gang Song
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China.
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Choi EK, Aring L, Das NK, Solanki S, Inohara N, Iwase S, Samuelson LC, Shah YM, Seo YA. Impact of dietary manganese on experimental colitis in mice. FASEB J 2020; 34:2929-2943. [PMID: 31908045 PMCID: PMC8103308 DOI: 10.1096/fj.201902396r] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 12/04/2019] [Accepted: 12/15/2019] [Indexed: 12/18/2022]
Abstract
Diet plays a significant role in the pathogenesis of inflammatory bowel disease (IBD). A recent epidemiological study has shown an inverse relationship between nutritional manganese (Mn) status and IBD patients. Mn is an essential micronutrient required for normal cell function and physiological processes. To date, the roles of Mn in intestinal homeostasis remain unknown and the contribution of Mn to IBD has yet to be explored. Here, we provide evidence that Mn is critical for the maintenance of the intestinal barrier and that Mn deficiency exacerbates dextran sulfate sodium (DSS)-induced colitis in mice. Specifically, when treated with DSS, Mn-deficient mice showed increased morbidity, weight loss, and colon injury, with a concomitant increase in inflammatory cytokine levels and oxidative and DNA damage. Even without DSS treatment, dietary Mn deficiency alone increased intestinal permeability by impairing intestinal tight junctions. In contrast, mice fed a Mn-supplemented diet showed slightly increased tolerance to DSS-induced experimental colitis, as judged by the colon length. Despite the well-appreciated roles of intestinal microbiota in driving inflammation in IBD, the gut microbiome composition was not altered by changes in dietary Mn. We conclude that Mn is necessary for proper maintenance of the intestinal barrier and provides protection against DSS-induced colon injury.
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Affiliation(s)
- Eun-Kyung Choi
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Luisa Aring
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Nupur K. Das
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Sumeet Solanki
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Naohiro Inohara
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Shigeki Iwase
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
| | - Linda C. Samuelson
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Yatrik M. Shah
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Young Ah Seo
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
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Red lentil supplementation reduces the severity of dextran sodium sulfate-induced colitis in C57BL/6 male mice. J Funct Foods 2020. [DOI: 10.1016/j.jff.2019.103625] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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Aggeletopoulou I, Konstantakis C, Assimakopoulos SF, Triantos C. The role of the gut microbiota in the treatment of inflammatory bowel diseases. Microb Pathog 2019; 137:103774. [PMID: 31586663 DOI: 10.1016/j.micpath.2019.103774] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 09/30/2019] [Accepted: 10/02/2019] [Indexed: 02/07/2023]
Abstract
The human intestinal microbiota coevolves with its host through a symbiotic relationship and exerts great influence on substantial functions including aspects of physiology, metabolism, nutrition and regulation of immune responses leading to physiological homeostasis. Over the last years, several studies have been conducted toward the assessment of the host-gut microbiota interaction, aiming to elucidate the mechanisms underlying the pathogenesis of several diseases. A defect on the microbiota-host crosstalk and the concomitant dysregulation of immune responses combined with genetic and environmental factors have been implicated in the pathogenesis of inflammatory bowel diseases (IBD). To this end, novel therapeutic options based on the gut microbiota modulation have been an area of extensive research interest. In this review we present the recent findings on the association of dysbiosis with IBD pathogenesis, we focus on the role of gut microbiota on the treatment of IBD and discuss the novel and currently available therapeutic strategies in manipulating the composition and function of gut microbiota in IBD patients. Applicable and emerging microbiota treatment modalities, such as the use of antibiotics, prebiotics, probiotics, postbiotics, synbiotics and fecal microbiota transplantation (FMT) constitute promising therapeutic options. However, the therapeutic potential of the aforementioned approaches is a topic of investigation and further studies are needed to elucidate their position in the present treatment algorithms of IBD.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, 26504, Greece.
| | - Christos Konstantakis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, 26504, Greece.
| | | | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, 26504, Greece.
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Liu F, Lee SA, Riordan SM, Zhang L, Zhu L. Effects of Anti-Cytokine Antibodies on Gut Barrier Function. Mediators Inflamm 2019; 2019:7028253. [PMID: 31780866 PMCID: PMC6875247 DOI: 10.1155/2019/7028253] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 10/10/2019] [Indexed: 12/14/2022] Open
Abstract
Anti-cytokine antibodies are used in treating chronic inflammatory diseases and autoimmune diseases such as inflammatory bowel disease and rheumatic diseases. Patients with these diseases often have a compromised gut barrier function, suggesting that anti-cytokine antibodies may contribute to the re-establishment of gut barrier integrity, in addition to their immunomodulatory effects. This paper reviews the effects of anti-cytokine antibodies on gut barrier function and their mechanisms.
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Affiliation(s)
- Fang Liu
- Department of General Surgery and Central Lab, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Seul A. Lee
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Stephen M. Riordan
- Gastrointestinal and Liver Unit, Prince of Wales Hospital, University of New South Wales, Sydney, NSW, Australia
| | - Li Zhang
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Lixin Zhu
- Department of General Surgery and Central Lab, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
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Wu Y, Sun M, Wang D, Li G, Huang J, Tan S, Bao L, Li Q, Li G, Si L. A PepT1 mediated medicinal nano-system for targeted delivery of cyclosporine A to alleviate acute severe ulcerative colitis. Biomater Sci 2019; 7:4299-4309. [PMID: 31408067 DOI: 10.1039/c9bm00925f] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/11/2023]
Abstract
To effectively alleviate acute severe ulcerative colitis (ASUC), we developed a colon-specific delivery system-PLGA-KPV/MMT/CS multifunctional medicinal nanoparticles loaded with cyclosporine A (CyA). The lysine-proline-valine (KPV) tripeptide, which possesses anti-inflammatory properties and high affinity to peptide transporter 1 (PepT1), can target therapy-related cells (colonic epithelial cells and macrophages) via overexpression of PepT1. Montmorillonite (MMT)/chitosan (CS) coating can reduce CyA leakage in the upper gastrointestinal tract (GIT) and enhance nanoparticle adhesion to the inflamed colon. The bio-distribution demonstrated that nanoparticles can specifically accumulate in the inflamed tissues and can be retained for up to 36 h. After being treated with the CyA-PLGA-KPV/MMT/CS nanoparticles (PKMCN), the mice with DSS-induced ulcerative colitis exhibited significant improvements in body weight, colon length, and disease activity index. Moreover, biochemistry and immunohistochemical analysis showed that the PKMCN treatment group performed as well as the healthy group. Intriguingly, PKMCN without CyA also presented marked therapeutic effects. Our results suggested that PKMCN could be a promising drug delivery system for ASUC therapy by targeting inflamed cells, prolonging curative time, and mitigating colitis.
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Affiliation(s)
- Ya Wu
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Minghui Sun
- Department of Pharmacy, Affiliated Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, PR China
| | - Dan Wang
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Genyun Li
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Jiangeng Huang
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Songwei Tan
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Lin Bao
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Qian Li
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Gao Li
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Luqin Si
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
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Li C, Zhao Y, Cheng J, Guo J, Zhang Q, Zhang X, Ren J, Wang F, Huang J, Hu H, Wang R, Zhang J. A Proresolving Peptide Nanotherapy for Site-Specific Treatment of Inflammatory Bowel Disease by Regulating Proinflammatory Microenvironment and Gut Microbiota. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2019; 6:1900610. [PMID: 31559126 PMCID: PMC6755521 DOI: 10.1002/advs.201900610] [Citation(s) in RCA: 131] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 06/12/2019] [Indexed: 05/04/2023]
Abstract
The incidence and prevalence of inflammatory bowel disease (IBD) increases steadily worldwide. There is an urgent need for effective and safe IBD therapies. Accelerated resolution of inflammation is a new strategy for the management of inflammatory diseases. For effective and safe IBD treatment, herein a smart nanotherapy (i.e. oxidation-responsive nanoparticles containing a proresolving annexin A1-mimetic peptide Ac2-26, defined as AON) is developed, which can release packaged Ac2-26, in response to highly expressed reactive oxygen species (ROS) at diseased sites. AON effectively protects Ac2-26 from degradation in the enzyme-rich environment of the gastrointestinal tract. By delivering this nanotherapy to the inflamed colons of mice with IBD, site-specific release and accumulation of Ac2-26 in response to high levels of ROS at the inflammatory sites are achieved. Mechanistically, the Ac2-26-containing, oxidation-labile nanotherapy AON effectively decreases the expression of proinflammatory mediators, attenuates trafficking and infiltration of inflammatory cells, promotes efferocytosis of apoptotic neutrophils, and increases phenotypic switching of macrophages. Therapeutically, AON reduces symptoms of inflammation, accelerates intestinal mucosal wound healing, reshapes the gut microbiota composition, and increases short-chain fatty acid production. Additionally, oral delivery of this nanomedicine shows excellent safety profile in a mouse model, conferring the confidence for further development of a targeted precision therapy for IBD and other inflammatory diseases.
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Affiliation(s)
- Chenwen Li
- Department of PharmaceuticsCollege of PharmacyThird Military Medical UniversityChongqing400038China
| | - Yang Zhao
- Department of PharmaceuticsCollege of PharmacyThird Military Medical UniversityChongqing400038China
| | - Juan Cheng
- Department of PharmaceuticsCollege of PharmacyThird Military Medical UniversityChongqing400038China
| | - Jiawei Guo
- Department of PharmaceuticsCollege of PharmacyThird Military Medical UniversityChongqing400038China
| | - Qixiong Zhang
- Department of PharmaceuticsCollege of PharmacyThird Military Medical UniversityChongqing400038China
| | - Xiangjun Zhang
- State Key Laboratory of Quality Research in Chinese MedicineInstitute of Chinese Medical SciencesUniversity of MacauTaipaMacau999078China
| | - Jiong Ren
- State Key Laboratory of TraumaBurns and Combined InjuryInstitute of Combined InjuryCollege of Preventive MedicineThird Military Medical UniversityChongqing400038China
| | - Fengchao Wang
- State Key Laboratory of TraumaBurns and Combined InjuryInstitute of Combined InjuryCollege of Preventive MedicineThird Military Medical UniversityChongqing400038China
| | - Jun Huang
- Institute for Molecular EngineeringUniversity of ChicagoChicagoIL60637USA
| | - Houyuan Hu
- Department of CardiologySouthwest HospitalThird Military Medical UniversityChongqing400038China
| | - Ruibing Wang
- State Key Laboratory of Quality Research in Chinese MedicineInstitute of Chinese Medical SciencesUniversity of MacauTaipaMacau999078China
| | - Jianxiang Zhang
- Department of PharmaceuticsCollege of PharmacyThird Military Medical UniversityChongqing400038China
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Iacob S, Iacob DG. Infectious Threats, the Intestinal Barrier, and Its Trojan Horse: Dysbiosis. Front Microbiol 2019; 10:1676. [PMID: 31447793 PMCID: PMC6692454 DOI: 10.3389/fmicb.2019.01676] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 07/08/2019] [Indexed: 02/06/2023] Open
Abstract
The ecosystem of the gut microbiota consists of diverse intestinal species with multiple metabolic and immunologic activities and it is closely connected with the intestinal epithelia and mucosal immune response, with which it builds a complex barrier against intestinal pathogenic bacteria. The microbiota ensures the integrity of the gut barrier through multiple mechanisms, either by releasing antibacterial molecules (bacteriocins) and anti-inflammatory short-chain fatty acids or by activating essential cell receptors for the immune response. Experimental studies have confirmed the role of the intestinal microbiota in the epigenetic modulation of the gut barrier through posttranslational histone modifications and regulatory mechanisms induced by epithelial miRNA in the epithelial lumen. Any quantitative or functional changes of the intestinal microbiota, referred to as dysbiosis, alter the immune response, decrease epithelial permeability and destabilize intestinal homeostasis. Consequently, the overgrowth of pathobionts (Staphylococcus, Pseudomonas, and Escherichia coli) favors intestinal translocations with Gram negative bacteria or their endotoxins and could trigger sepsis, septic shock, secondary peritonitis, or various intestinal infections. Intestinal infections also induce epithelial lesions and perpetuate the risk of bacterial translocation and dysbiosis through epithelial ischemia and pro-inflammatory cytokines. Furthermore, the decline of protective anaerobic bacteria (Bifidobacterium and Lactobacillus) and inadequate release of immune modulators (such as butyrate) affects the release of antimicrobial peptides, de-represses microbial virulence factors and alters the innate immune response. As a result, intestinal germs modulate liver pathology and represent a common etiology of infections in HIV immunosuppressed patients. Antibiotic and antiretroviral treatments also promote intestinal dysbiosis, followed by the selection of resistant germs which could later become a source of infections. The current article addresses the strong correlations between the intestinal barrier and the microbiota and discusses the role of dysbiosis in destabilizing the intestinal barrier and promoting infectious diseases.
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Affiliation(s)
- Simona Iacob
- Infectious Diseases Department, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.,National Institute of Infectious Diseases "Prof. Dr. Matei Balş", Bucharest, Romania
| | - Diana Gabriela Iacob
- Infectious Diseases Department, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
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Che L, Li Y, Song R, Qin C, Hao W, Wang B, Yang L, Peng P, Xu F. Anti-inflammatory and anti-apoptosis activity of taraxasterol in ulcerative colitis in vitro and in vivo. Exp Ther Med 2019; 18:1745-1751. [PMID: 31410133 PMCID: PMC6676081 DOI: 10.3892/etm.2019.7736] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 05/03/2019] [Indexed: 12/27/2022] Open
Abstract
Ulcerative colitis is closely associated with colorectal cancer, the long-standing chronic inflammation being the key etiology of ulcerative colitis. The aim of the present study was to identify the anti-inflammatory and anti-apoptosis activity of taraxasterol in ulcerative colitis. MTT assay was used to obtain the optimal concentrations of lipopolysaccharide (LPS) and taraxasterol for cell treatments in vitro. A mouse model of colitis was established via dextran sodium sulphate (DSS) administration. Levels of IL-6 and TNF-α were detected through ELISA. Flow cytometry and western blotting were used to detect apoptosis and related protein expression levels, respectively. Hematoxylin and eosin staining was performed to detect the pathological damage. The results from the MTT assay identified the optimal concentration of LPS and taraxasterol, and ELISA results demonstrated that taraxasterol treatment decreased the expression levels of IL-6 and TNF-α in vitro and in vivo, in a dose-dependent manner. Taraxasterol treatment inhibited apoptosis, and reduced the protein levels of p53, Bcl-2 associated X (BAX) and caspase-3. Finally, pathological damages were reduced in colonic tissues of mice treated with taraxasterol. Taken together, taraxasterol treatment markedly inhibited inflammation and apoptosis in ulcerative colitis. Therefore, taraxasterol may be a promising agent for decreasing the inflammatory response in ulcerative colitis and other inflammation-related diseases.
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Affiliation(s)
- Lu Che
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Ya Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Ruifeng Song
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Cuihong Qin
- Department of General ICU, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Weiwei Hao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Bingxue Wang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Lei Yang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Puji Peng
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Feng Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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50
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Feng G, Zeng M, Huang M, Zhu S, Guo W, Wu H. Protective effect of biogenic polyphosphate nanoparticles from Synechococcus sp. PCC 7002 on dextran sodium sulphate-induced colitis in mice. Food Funct 2019; 10:1007-1016. [PMID: 30706920 DOI: 10.1039/c8fo01861h] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Biogenic polyphosphate nanoparticles (BPNPs) from Synechococcus sp. PCC 7002 have been found to exhibit intestinal protective potential in vitro and ex vivo. The aim of this study was to evaluate the in vivo intestinal protective effect of BPNPs in experimental colitis. BPNPs were intragastrically administered to C57BL/6 mice daily for 9 d during and after 5 d dextran sodium sulfate (DSS) exposure. Based on the body weight, disease activity index, colon length and colon histology, BPNPs effectively ameliorated DSS-induced colitis in mice. According to colonic myeloperoxidase activity, colonic and peripheral proinflammatory cytokines, and hematological parameters, BPNPs alleviated the DSS-induced colonic and systemic inflammation. BPNPs enhanced the intestinal barrier function by upregulating the colonic expressions of heat shock protein 25 and tight junction proteins. By high-throughput sequencing of fecal 16S rRNA, BPNPs were found to maintain gut microbial homeostasis in colitis mice. Overall, BPNPs have a considerable in vivo efficacy to maintain gut health.
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Affiliation(s)
- Guangxin Feng
- College of Food Science and Engineering, Ocean University of China, 5 Yushan Road, Qingdao, Shandong Province 266003, China.
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