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Popova A, Slisere B, Racenis K, Kuzema V, Karklins R, Saulite M, Seilis J, Saulite AJ, Vasilvolfa A, Vaivode K, Pjanova D, Kroica J, Cernevskis H, Lejnieks A, Petersons A, Oleinika K. IgA class-switched CD27-CD21+ B cells in IgA nephropathy. Nephrol Dial Transplant 2025; 40:505-515. [PMID: 39020236 PMCID: PMC11879059 DOI: 10.1093/ndt/gfae173] [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: 11/01/2023] [Indexed: 07/19/2024] Open
Abstract
BACKGROUND Immunoglobulin A nephropathy (IgAN) is characterized by the production of galactose-deficient IgA1 (GdIgA1) antibodies. As the source of pathogenic antibodies, B cells are central to IgAN pathogenesis, but the B cell activation pathways as well as the potential B cell source of dysregulated IgA secretion remain unknown. METHODS We carried out flow cytometry analysis of peripheral blood B cells in patients with IgAN and control subjects with a focus on IgA-expressing B cells to uncover the pathways of B cell activation in IgAN and how these could give rise to pathogenic GdIgA1 antibodies. RESULTS In addition to global changes in the B cell landscape-expansion of naïve and reduction in memory B cells-IgAN patients present with an increased frequency of IgA-expressing B cells that lack the classical memory marker CD27, but are CD21+. IgAN patients furthermore have an expanded population of IgA+ antibody-secreting cells, which correlate with serum IgA levels. Both IgA+ plasmabalsts and CD27- B cells co-express GdIgA1. Implicating dysregulation at mucosal surfaces as the driver of such B cell differentiation, we found a correlation between lipopolysaccharide in the serum and IgA+CD27- B cell frequency. CONCLUSION We propose that dysregulated immunity in the mucosa may drive de novo B cell activation within germinal centres, giving rise to IgA+CD27- B cells and subsequently IgA-producing plasmablasts. These data integrate B cells into the paradigm of IgAN pathogenesis and allow further investigation of this pathway to uncover biomarkers and develop therapeutic interventions.
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Affiliation(s)
- Anna Popova
- Department of Nephrology, Pauls Stradins Clinical University Hospital, Riga, Latvia
- Department of Biology and Microbiology, Riga Stradins University, Riga, Latvia
- Department of Internal Medicine, University of Latvia, Riga, Latvia
| | - Baiba Slisere
- Joint Laboratory, Pauls Stradins Clinical University Hospital, Riga, Latvia
- Department of Doctoral Studies, Riga Stradins University, Riga, Latvia
| | - Karlis Racenis
- Department of Nephrology, Pauls Stradins Clinical University Hospital, Riga, Latvia
- Department of Biology and Microbiology, Riga Stradins University, Riga, Latvia
- Department of Internal Diseases, Riga Stradins University, Riga, Latvia
| | - Viktorija Kuzema
- Department of Nephrology, Pauls Stradins Clinical University Hospital, Riga, Latvia
- Department of Internal Diseases, Riga Stradins University, Riga, Latvia
| | - Roberts Karklins
- Department of Internal Diseases, Riga Stradins University, Riga, Latvia
| | - Mikus Saulite
- Department of Nephrology, Pauls Stradins Clinical University Hospital, Riga, Latvia
- Department of Internal Diseases, Riga Stradins University, Riga, Latvia
| | - Janis Seilis
- Department of Nephrology, Pauls Stradins Clinical University Hospital, Riga, Latvia
| | - Anna Jana Saulite
- Department of Nephrology, Pauls Stradins Clinical University Hospital, Riga, Latvia
| | - Aiga Vasilvolfa
- Department of Nephrology, Pauls Stradins Clinical University Hospital, Riga, Latvia
- Department of Internal Medicine, University of Latvia, Riga, Latvia
- Department of Internal Diseases, Riga Stradins University, Riga, Latvia
| | - Kristine Vaivode
- Institute of Microbiology and Virology, Riga Stradins University, Riga, Latvia
| | - Dace Pjanova
- Institute of Microbiology and Virology, Riga Stradins University, Riga, Latvia
| | - Juta Kroica
- Department of Biology and Microbiology, Riga Stradins University, Riga, Latvia
| | - Harijs Cernevskis
- Department of Nephrology, Pauls Stradins Clinical University Hospital, Riga, Latvia
- Department of Internal Diseases, Riga Stradins University, Riga, Latvia
| | - Aivars Lejnieks
- Department of Internal Diseases, Riga Stradins University, Riga, Latvia
- Riga East Clinical University Hospital, Riga, Latvia
| | - Aivars Petersons
- Department of Nephrology, Pauls Stradins Clinical University Hospital, Riga, Latvia
- Department of Internal Diseases, Riga Stradins University, Riga, Latvia
| | - Kristine Oleinika
- Department of Internal Diseases, Riga Stradins University, Riga, Latvia
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical, School, Boston, MA, USA
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Lee H, Lee YH, Hong DK, Mo SJ, Jeon S, Park SD, Shim JJ, Lee JL, Lee JH. Targeting Inflammation and Skin Aging via the Gut-Skin Axis: The Role of Lactiplantibacillus plantarum HY7714-Derived Extracellular Vesicles. Microorganisms 2024; 12:2466. [PMID: 39770669 PMCID: PMC11676968 DOI: 10.3390/microorganisms12122466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/23/2024] [Accepted: 11/28/2024] [Indexed: 01/11/2025] Open
Abstract
Intestinal mucosal tissues are prone to infections, often leading to inflammation. Lactic acid bacteria in the gut can modulate these inflammatory responses, but the interaction between host cells and lactic acid bacteria remains unclear. This study examines how Lactiplantibacillus plantarum HY7714 alleviates intestinal inflammation using gut-on-a-chip technology and in vitro models. Inflammation was induced using a gut-on-a-chip, and changes in cell morphology and barrier function were analyzed. Extracellular vesicles (EVs) derived from HY7714-improved intestinal cell structure repaired damage and restored tight junction integrity. Additionally, they attenuated inflammatory cytokines by regulating the MyD88/mTOR/NF-κB signaling pathway. RNA sequencing revealed downregulation of vicinal oxygen chelate (VOC) family proteins and proline aminopeptidase, both linked to inflammation and extracellular matrix interactions in skin health. Therefore, we explored the effects of HY7714 EVs on skin cells. The findings showed that HY7714 EVs reduced cytotoxicity and downregulated metalloproteinase expression in skin cells exposed to UVB radiation, indicating their potential anti-aging and anti-photoaging properties. These findings suggest that HY7714-derived EVs enhance both intestinal and skin health by reducing inflammation and improving barrier function, with potential benefits for the gut-skin axis.
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Affiliation(s)
| | | | | | | | | | - Soo-Dong Park
- R&BD Center, hy Co., Ltd., 22, Giheungdanji-ro 24beon-gil, Giheung-gu, Yongin-si 17086, Republic of Korea; (H.L.); (Y.-H.L.); (D.-K.H.); (S.-J.M.); (S.J.); (J.-J.S.); (J.-L.L.); (J.-H.L.)
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D’Orazio G, La Ferla B. Synthesis of a Small Library of Glycoderivative Putative Ligands of SGLT1 and Preliminary Biological Evaluation. Molecules 2024; 29:5067. [PMID: 39519708 PMCID: PMC11547630 DOI: 10.3390/molecules29215067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 10/19/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
Sodium-glucose co-transporter 1 (SGLT1) is primarily expressed on the membrane of enterocytes, a type of epithelial cell found in the intestines, where it mediates the unidirectional absorption of glucose and galactose. Beyond its well-established role in nutrient absorption, SGLT1 also plays a protective role in maintaining the integrity of the intestinal barrier. Specifically, the natural ligand of SGLT1 (d-glucose) and a synthetic C-glucoside developed by our group can induce a protective anti-inflammatory effect on the intestinal epithelium. In this paper, we report the creation of a small library of C-glycoside, putative ligands for SGLT1, to gain further insights into its unclear mechanism of action. Preliminary biological experiments performed on an in vitro model of doxorubicin-induced mucositis, a severe intestinal inflammatory condition, indicate that the aromatic moiety present in all the compounds of the library is crucial for biological activity, while the sugar component appears to have less influence. These findings will be exploited to develop new, more potent anti-inflammatory compounds and to better understand and rationalize the protective mechanism of action.
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Affiliation(s)
- Giuseppe D’Orazio
- Department of Chemistry, Università degli Studi di Milano, Via C. Golgi 19, 20133 Milan, Italy
| | - Barbara La Ferla
- Department of Earth and Environmental Sciences DISAT, Università degli Studi di Milano-Bicocca, Piazza della Scienza 1, 20126 Milan, Italy
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Kapitan M, Niemiec MJ, Millet N, Brandt P, Chowdhury MEK, Czapka A, Abdissa K, Hoffmann F, Lange A, Veleba M, Nietzsche S, Mosig AS, Löffler B, Marquet M, Makarewicz O, Kline KA, Vylkova S, Swidergall M, Jacobsen ID. Synergistic cross-kingdom host cell damage between Candida albicans and Enterococcus faecalis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.11.612452. [PMID: 39314435 PMCID: PMC11419042 DOI: 10.1101/2024.09.11.612452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
The fungus Candida albicans and the Gram-positive bacterium Enterococcus faecalis share mucosal niches in the human body. As opportunistic pathogens, both are found to expand population size during dysbiosis, and can cause severe systemic infections in susceptible individuals. Here, we show that the presence of C. albicans results in increased host cell damage by E. faecalis . Furthermore, E. faecalis aggravates oropharyngeal candidiasis in mice. Increased damage is mediated by enterococcal cytolysin, and involves both physical interaction and altered glucose availability. Physical interaction promotes accumulation of bacteria on host cells, facilitating contact of cytolysin with host cells. Glucose depletion by the metabolic activity of the fungus sensitized host cells to cytolysin. This work illustrates how a complex interplay between fungi and bacteria can result in detrimental consequences for the host.
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DeMichele E, Buret AG, Taylor CT. Hypoxia-inducible factor-driven glycolytic adaptations in host-microbe interactions. Pflugers Arch 2024; 476:1353-1368. [PMID: 38570355 PMCID: PMC11310250 DOI: 10.1007/s00424-024-02953-w] [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: 02/06/2024] [Revised: 02/07/2024] [Accepted: 03/22/2024] [Indexed: 04/05/2024]
Abstract
Mammalian cells utilize glucose as a primary carbon source to produce energy for most cellular functions. However, the bioenergetic homeostasis of cells can be perturbed by environmental alterations, such as changes in oxygen levels which can be associated with bacterial infection. Reduction in oxygen availability leads to a state of hypoxia, inducing numerous cellular responses that aim to combat this stress. Importantly, hypoxia strongly augments cellular glycolysis in most cell types to compensate for the loss of aerobic respiration. Understanding how this host cell metabolic adaptation to hypoxia impacts the course of bacterial infection will identify new anti-microbial targets. This review will highlight developments in our understanding of glycolytic substrate channeling and spatiotemporal enzymatic organization in response to hypoxia, shedding light on the integral role of the hypoxia-inducible factor (HIF) during host-pathogen interactions. Furthermore, the ability of intracellular and extracellular bacteria (pathogens and commensals alike) to modulate host cellular glucose metabolism will be discussed.
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Affiliation(s)
- Emily DeMichele
- School of Medicine and Systems Biology Ireland, The Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
- Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
| | - Andre G Buret
- Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
| | - Cormac T Taylor
- School of Medicine and Systems Biology Ireland, The Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
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Scrivin R, Slater G, Mika A, Rauch C, Young P, Martinez I, Costa RJS. The impact of 48 h high carbohydrate diets with high and low FODMAP content on gastrointestinal status and symptoms in response to endurance exercise, and subsequent endurance performance. Appl Physiol Nutr Metab 2024; 49:773-791. [PMID: 38359412 DOI: 10.1139/apnm-2023-0508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
This study investigated the effects of a high carbohydrate diet, with varied fermentable oligo-, di-, and mono-saccharide and polyol (FODMAP) content, before endurance exercise on gastrointestinal integrity, motility, and symptoms; and subsequent exercise performance. Twelve endurance athletes were provided with a 48 h high carbohydrate (mean ± SD: 12.1 ± 1.8 g kg day-1) diet on two separate occasions, composed of high (54.8 ± 10.5 g day-1) and low FODMAP (3.0 ± 0.2 g day-1) content. Thereafter, participants completed a 2 h steady-state running exercise at 60% of V ˙ O 2 max (22.9 ± 1.2 °C, 46.4 ± 7.9% RH), followed by a 1 h distance performance test. Pre-exercise and every 20 min during steady-state exercise, 100 mL maltodextrin (10% w/v) solution was consumed. A 150 mL lactulose (20 g) solution was consumed 30 min into the distance performance test to determine orocecal transit time (OCTT) during exercise. Blood was collected pre- and post exercise to determine gastrointestinal integrity biomarkers (i.e., I-FABP, sCD14, and CRP). Breath hydrogen (H2) and gastrointestinal symptoms (GIS) were determined pre-exercise, every 15 min, during and throughout recovery. No differences in gastrointestinal integrity biomarkers, OCTT, or distance completed were observed between trials. Pre-exercise total-GIS (1.3 ± 2.9 vs. 4.3 ± 4.4), gut discomfort (9.9 ± 8.1 vs. 15.8 ± 9.0), and upper-GIS (2.8 ± 2.6 vs. 5.7 ± 4.8) during exercise were less severe on high carbohydrate low FODMAP (HC-LFOD) versus high carbohydrate high FODMAP (HC-HFOD) (p < 0.05). Gut discomfort (3.4 ± 4.4 vs. 0.2 ± 0.6) and total-GIS (4.9 ± 6.8 vs. 0.2 ± 0.6) were higher during recovery on HC-LFOD versus HC-HFOD (p < 0.05). The FODMAP content of a 48 h high carbohydrate diet does not impact gastrointestinal integrity or motility in response to endurance exercise. However, a high FODMAP content exacerbates GIS before and during exercise, but this does not impact performance outcomes.
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Affiliation(s)
- Rachel Scrivin
- School of Health and Behavioural Sciences, University of the Sunshine Coast, Sippy Downs, QLD, Australia
- Faculty of Health, Education and Environment, Toi Ohomai Institute of Technology, Tauranga, New Zealand
| | - Gary Slater
- School of Health and Behavioural Sciences, University of the Sunshine Coast, Sippy Downs, QLD, Australia
| | - Alice Mika
- Faculty of Medicine Nursing & Health Sciences, Department of Nutrition Dietetics and Food, Monash University, Melbourne, VIC, Australia
| | - Christopher Rauch
- Faculty of Medicine Nursing & Health Sciences, Department of Nutrition Dietetics and Food, Monash University, Melbourne, VIC, Australia
| | - Pascale Young
- Faculty of Medicine Nursing & Health Sciences, Department of Nutrition Dietetics and Food, Monash University, Melbourne, VIC, Australia
| | - Isabel Martinez
- Faculty of Medicine Nursing & Health Sciences, Department of Nutrition Dietetics and Food, Monash University, Melbourne, VIC, Australia
| | - Ricardo J S Costa
- Faculty of Medicine Nursing & Health Sciences, Department of Nutrition Dietetics and Food, Monash University, Melbourne, VIC, Australia
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Lu ZJ, Shi WJ, Ma DD, Zhang JG, Long XB, Li SY, Gao FZ, Zhang QQ, Ying GG. The azole biocide climbazole induces oxidative stress, inflammation, and apoptosis in fish gut. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 923:171475. [PMID: 38453063 DOI: 10.1016/j.scitotenv.2024.171475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/29/2024] [Accepted: 03/02/2024] [Indexed: 03/09/2024]
Abstract
Climbazole is an azole biocide that has been widely used in formulations of personal care products. Climbazole can cause developmental toxicity and endocrine disruption as well as gut disturbance in aquatic organisms. However, the mechanisms behind gut toxicity induced by climbazole still remain largely unclear in fish. Here, we evaluate the gut effects by exposing grass carp (Ctenopharyngodon idella) to climbazole at levels ranging from 0.2 to 20 μg/L for 42 days by evaluating gene transcription and expression, biochemical analyses, correlation network analysis, and molecular docking. Results showed that climbazole exposure increased cyp1a mRNA expression and ROS level in the three treatment groups. Climbazole also inhibited Nrf2 and Keap1 transcripts as well as proteins, and suppressed the transcript levels of their subordinate antioxidant molecules (cat, sod, and ho-1), increasing oxidative stress. Additionally, climbazole enhanced NF-κB and iκBα transcripts and proteins, and the transcripts of NF-κB downstream pro-inflammatory factors (tnfα, and il-1β/6/8), leading to inflammation. Climbazole increased pro-apoptosis-related genes (fadd, bad1, and caspase3), and decreased anti-apoptosis-associated genes (bcl2, and bcl-xl), suggesting a direct reaction to apoptosis. The molecular docking data showed that climbazole could form stable hydrogen bonds with CYP1A. Mechanistically, our findings suggested that climbazole can induce inflammation and oxidative stress through CYP450s/ROS/Nrf2/NF-κB pathways, resulting in cell apoptosis in the gut of grass carp.
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Affiliation(s)
- Zhi-Jie Lu
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Wen-Jun Shi
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Dong-Dong Ma
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Jin-Ge Zhang
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Xiao-Bing Long
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Si-Ying Li
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Fang-Zhou Gao
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Qian-Qian Zhang
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Guang-Guo Ying
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China.
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K VK, Bhat RG, Rao BK, R AP. The Gut Microbiota: a Novel Player in the Pathogenesis of Uterine Fibroids. Reprod Sci 2023; 30:3443-3455. [PMID: 37418220 PMCID: PMC10691976 DOI: 10.1007/s43032-023-01289-7] [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: 03/07/2023] [Accepted: 06/25/2023] [Indexed: 07/08/2023]
Abstract
Uterine fibroid is a common gynecological disorder that affects women of reproductive age and has emerged as a major public health concern. The symptoms have a negative influence on both their physical health and quality of life. The cost of treatment has a significant impact on the disease's burden. Even though its origin is uncertain, estrogen is thought to be a key player in fibroid pathophysiology. Many theories, including those based on genetic and environmental factors, explain what causes hyper-estrogenic condition in fibroid patients. One such possibility that is currently being explored is the hypothesis that an altered gut microbiome can contribute to the development of diseases characterized by estrogen dominance. Gut dysbiosis is often a "hot area" in the health sciences. According to a recent study, uterine fibroid patients have altered gut microbiome. A variety of risk factors influence both fibroid development and gut homeostasis. Diet, lifestyle, physical activity, and environmental contaminants have an impact on estrogen and the gut flora. A better understanding of uterine fibroids' pathophysiology is required to develop effective preventative and treatment options. A few ways by which the gut microbiota contributes to UF include estrogen, impaired immune function, inflammation, and altered gut metabolites. Therefore, in the future, while treating fibroid patients, various strategies to deal with changes in the gut flora may be advantageous. For developing suggestions for clinical diagnosis and therapy, we reviewed the literature on the relationship between uterine fibroids and the gut microbiota.
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Affiliation(s)
- Vineetha K K
- Department of Obstetrics and Gynecology, Melaka Manipal Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Rajeshwari G Bhat
- Department of Obstetrics and Gynecology, Melaka Manipal Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Bhamini Krishna Rao
- Department of Physiotherapy, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Archana P R
- Department of Basic Medical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India.
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Yu J, Hu G, Guo X, Cao H, Zhang C. Quercetin Alleviates Inflammation and Energy Deficiency Induced by Lipopolysaccharide in Chicken Embryos. Animals (Basel) 2023; 13:2051. [PMID: 37443849 DOI: 10.3390/ani13132051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 06/13/2023] [Accepted: 06/15/2023] [Indexed: 07/15/2023] Open
Abstract
Energy deficiency causes multiple organ dysfunctions after LPS induction. Quercetin is a phenolic compound found in herbal medicines. However, the effects of quercetin in alleviating LPS-induced energy deficiency remain unclear. In the present study, an in vivo LPS-induced inflammation model was established in chicken embryos. Specific pathogen-free chicken embryos (n = 120) were allocated to control, PBS with or without ethanol, quercetin (10, 20, or 40 nmol, respectively), and LPS (125 ng/egg) with or without quercetin groups. Fifteen day old embryonated eggs were injected with the abovementioned solutions via the allantoic cavity. On embryonic day 19, the tissues of the embryos were collected for histopathological examination using frozen oil red O staining, RNA extraction, real-time quantitative polymerase chain reaction, and immunohistochemical investigations. The glycogen and lipid contents in the liver increased after LPS stimulation as compared with the PBS group, whereas quercetin decreased the accumulation as compared with the LPS group. The mRNA expressions of AMPKα1 and AMPKα2 in the duodena, ceca, and livers were upregulated after LPS induction as compared with the PBS group, while quercetin could downregulate these expressions as compared with the LPS group. The immunopositivity of AMPKα2 in the villus, crypt, lamina propria, tunica muscularis, and myenteric plexus in the duodena and in the cytoplasms of hepatocytes significantly increased after LPS induction when compared with the PBS group (p < 0.01), whereas the immunopositivity to AMPKα2 in the quercetin treatment group significantly decreased when compared with the LPS group (p < 0.01 or p < 0.05). The LPS-induced high expressions of transcription factor PPARα and glucose transporter (SGLT1) were blocked by quercetin in the duodena, ceca, and livers. Quercetin treatment improved the LPS-induced decrease in APOA4 in the duodena, ceca, and livers. The mRNA expression of PEPT1 in the duodena and ceca increased after LPS challenge, whereas quercetin could downregulate PEPT1 gene expression. These data demonstrate that quercetin improved the energy deficiency induced by LPS in chicken embryos. The LPS-induced inflammation model was established to avoid the effect of LPS exposure from the environment and intestinal flora. The results form the basis the administration of quercetin pretreatment (in ovo infection) to improve the energy state of chicken embryos and improve the inflammation response.
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Affiliation(s)
- Jinhai Yu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Guoliang Hu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Xiaoquan Guo
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Huabin Cao
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Caiying Zhang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
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Wei CX, Wu JH, Huang YH, Wang XZ, Li JY. Lactobacillus plantarum improves LPS-induced Caco2 cell line intestinal barrier damage via cyclic AMP-PKA signaling. PLoS One 2022; 17:e0267831. [PMID: 35639684 PMCID: PMC9154120 DOI: 10.1371/journal.pone.0267831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 04/17/2022] [Indexed: 11/18/2022] Open
Abstract
Lactobacillus plantarum (LP) has been shown to exhibit protective effects on intestinal barrier function in septic rats, although the regulatory mechanism has not been established. We determined whether LP imparts such protective effects in a lipopolysaccharide (LPS)-induced Caco2 cell monolayer model and whether cAMP-PKA signaling is the underlying mechanism of action. The cyclic adenosine monophosphate (cAMP) agonist, forskolin (FSK), and the protein kinase A (PKA) inhibitor, HT89, were used to study the protective effect of LP on the destruction of the tight junction (TJ) structure of cells treated with LPS and the corresponding changes in cAMP-PKA signaling. Our experimental results demonstrated that LP promoted the expression of TJ proteins between Caco2 cells after LPS treatment, and increased the electrical barrier detection (TEER) between Caco2 cells. Moreover, transmission electron microscopy (TEM) revealed that the TJ structural integrity of cells treated with LPS + LP was improved compared to cells treated with LPS alone. In addition, our findings were consistent between the FSK and LP intervention group, while HT89 inhibited LP influence. Taken together, our results indicate that LP has an improved protective effect on LPS-induced damage to the monolayer membrane barrier function of Caco2 cells and is regulated by the cAMP-PKA pathway.
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Affiliation(s)
- Chen-Xiang Wei
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, P.R. China
| | - Ju-Hua Wu
- Digestive Endoscopy Center, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian Province, P.R. China
| | - Yue-Hong Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, P.R. China
| | - Xiao-Zhong Wang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, P.R. China
- * E-mail: (XZW); (JYL)
| | - Jian-Ying Li
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, P.R. China
- * E-mail: (XZW); (JYL)
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Mohr AE, Crawford M, Jasbi P, Fessler S, Sweazea KL. Lipopolysaccharide and the gut microbiota: Considering structural variation. FEBS Lett 2022; 596:849-875. [PMID: 35262962 DOI: 10.1002/1873-3468.14328] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 02/16/2022] [Accepted: 02/17/2022] [Indexed: 11/10/2022]
Abstract
Systemic inflammation is associated with chronic disease and is purported to be a main pathogenic mechanism underlying metabolic conditions. Microbes harbored in the host gastrointestinal tract release signaling byproducts from their cell wall, such as lipopolysaccharides (LPS), which can act locally and, after crossing the gut barrier and entering circulation, also systemically. Defined as metabolic endotoxemia, elevated concentrations of LPS in circulation are associated with metabolic conditions and chronic disease. As such, measurement of LPS is highly prevalent in animal and human research investigating these states. Indeed, LPS can be a potent stimulant of host immunity but this response depends on the microbial species' origin, a parameter often overlooked in both preclinical and clinical investigations. Indeed, the lipid A portion of LPS is mutable and comprises the main virulence and endotoxic component, thus contributing to the structural and functional diversity among LPSs from microbial species. In this review, we discuss how such structural differences in LPS can induce differential immunological responses in the host.
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Affiliation(s)
- Alex E Mohr
- College of Health Solutions, Arizona State University, Phoenix, Arizona, United States of America
| | - Meli'sa Crawford
- Biomedical Sciences, University of Riverside, California, Riverside, California, United States of America
| | - Paniz Jasbi
- College of Health Solutions, Arizona State University, Phoenix, Arizona, United States of America
| | - Samantha Fessler
- College of Health Solutions, Arizona State University, Phoenix, Arizona, United States of America
| | - Karen L Sweazea
- College of Health Solutions, Arizona State University, Phoenix, Arizona, United States of America.,School of Life Sciences, Arizona State University, Tempe, Arizona, United States of America
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12
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Ren Y, Li L, Wang M, Yang Z, Sun Z, Zhang W, Cao L, Nie S. Knockdown of circRNA Paralemmin 2 Ameliorates Lipopolysaccharide-induced Murine Lung Epithelial Cell Injury by Sponging miR-330-5p to Reduce ROCK2 Expression. Immunol Invest 2022; 51:1707-1724. [PMID: 35171050 DOI: 10.1080/08820139.2022.2027961] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Previous data have reported the high expression of circRNA paralemmin 2 (circPALM2) in mice with acute lung injury (ALI). However, the role of circPALM2 in ALI pathogenesis remains unclear. The study aims to reveal the function of circPALM2 in ALI and the underlying mechanism. C57BL/6 J mice and murine lung epithelial-12 (MLE-12) cells were treated with lipopolysaccharide (LPS) to simulate ALI mouse and ALI cell models, respectively. Lung injury score and lung wet-to-dry ratio assays were used to evaluate the ALI mouse model. Quantitative real-time polymerase chain reaction and Western blot assays were implemented to analyze the expressions of circPALM2, microRNA-330-5p (miR-330-5p), rho-associated coiled-coil containing protein kinase 2 (ROCK2), and apoptosis-related markers. Cell viability, apoptosis, and the production of inflammatory cytokines were investigated by cell counting kit-8, flow cytometry, and enzyme-linked immunosorbent assays. The expressions of circPALM2 and ROCK2 were significantly increased, while miR-330-5p was decreased in ALI mice and LPS-induced MLE-12 cells compared with controls. LPS treatment inhibited cell viability but induced apoptosis, inflammatory cytokine production, and oxidative stress; however, these effects were attenuated after the combination of circPALM2 knockdown and LPS. CircPALM2 regulated LPS-caused MLE-12 cell damage by targeting miR-330-5p. Additionally, ROCK2, a target gene of miR-330-5p, participated in LPS-induced MLE-12 cell injury. Further, circPALM2 activated ROCK2 by associating with miR-330-5p. CircPALM2 modulated LPS-caused murine lung epithelial cell injury by the miR-330-5p/ROCK2 pathway, providing a therapeutic target for ALI.
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Affiliation(s)
- Yi Ren
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Liang Li
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Mengmeng Wang
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Zhizhou Yang
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Zhaorui Sun
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Wei Zhang
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Liping Cao
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Shinan Nie
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
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13
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Lu JW, Sun Y, Fong PSA, Lin LI, Liu D, Gong Z. Lipopolysaccharides Enhance Epithelial Hyperplasia and Tubular Adenoma in Intestine-Specific Expression of krasV12 in Transgenic Zebrafish. Biomedicines 2021; 9:biomedicines9080974. [PMID: 34440178 PMCID: PMC8393945 DOI: 10.3390/biomedicines9080974] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/03/2021] [Accepted: 08/04/2021] [Indexed: 02/06/2023] Open
Abstract
Intestinal carcinogenesis is a multistep process that begins with epithelial hyperplasia, followed by a transition to an adenoma and then to a carcinoma. Many etiological factors, including KRAS mutations and inflammation, have been implicated in oncogenesis. However, the potential synergistic effects between KRAS mutations and inflammation as well as the potential mechanisms by which they promote intestinal carcinogenesis remain unclear. Thus, the objective of this study was to investigate the synergistic effects of krasV12, lipopolysaccharides (LPS), and/or dextran sulfate sodium (DSS) on inflammation, tumor progression, and intestinal disorders using transgenic adults and larvae of zebrafish. Histopathology and pathological staining were used to examine the intestines of krasV12 transgenic zebrafish treated with LPS and/or DSS. LPS and/or DSS treatment enhanced intestinal inflammation in krasV12 transgenic larvae with concomitant increases in the number of neutrophils and macrophages in the intestines. The expression of krasV12, combined with LPS treatment, also enhanced epithelial hyperplasia and tubular adenoma, demonstrated by histopathological examinations and by increases in cell apoptosis, cell proliferation, and downstream signaling of phosphorylated AKT serine/threonine kinase 1 (AKT), extracellular-signal-regulated kinase (ERK), and histone. We also found that krasV12 expression, combined with LPS treatment, significantly enhanced changes in intestinal morphology, specifically (1) decreases in goblet cell number, goblet cell size, villi height, and intervilli space, as well as (2) increases in villi width and smooth muscle thickness. Moreover, krasV12 transgenic larvae cotreated with DSS and LPS exhibited exacerbated intestinal inflammation. Cotreatment with DSS and LPS in krasV12-expressing transgenic adult zebrafish also enhanced epithelial hyperplasia and tubular adenoma, compared with wild-type fish that received the same cotreatment. In conclusion, our data suggest that krasV12 expression, combined with LPS and/or DSS treatment, can enhance intestinal tumor progression by activating the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway and may provide a valuable in vivo platform to investigate tumor initiation and antitumor drugs for gastrointestinal cancers.
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Affiliation(s)
- Jeng-Wei Lu
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (Y.S.); (P.-S.A.F.)
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 10048, Taiwan;
- Correspondence: (J.-W.L.); (Z.G.); Tel.: +65-6516-2860 (Z.G.)
| | - Yuxi Sun
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (Y.S.); (P.-S.A.F.)
- Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China;
| | - Pei-Shi Angelina Fong
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (Y.S.); (P.-S.A.F.)
| | - Liang-In Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 10048, Taiwan;
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 10048, Taiwan
| | - Dong Liu
- Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China;
| | - Zhiyuan Gong
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (Y.S.); (P.-S.A.F.)
- Correspondence: (J.-W.L.); (Z.G.); Tel.: +65-6516-2860 (Z.G.)
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14
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Pochard C, Gonzales J, Bessard A, Mahe MM, Bourreille A, Cenac N, Jarry A, Coron E, Podevin J, Meurette G, Neunlist M, Rolli-Derkinderen M. PGI 2 Inhibits Intestinal Epithelial Permeability and Apoptosis to Alleviate Colitis. Cell Mol Gastroenterol Hepatol 2021; 12:1037-1060. [PMID: 33971327 PMCID: PMC8342971 DOI: 10.1016/j.jcmgh.2021.05.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 05/01/2021] [Accepted: 05/03/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Inflammatory bowel diseases (IBDs) that encompass both ulcerative colitis and Crohn's disease are a major public health problem with an etiology that has not been fully elucidated. There is a need to improve disease outcomes and preventive measures by developing new effective and lasting treatments. Although polyunsaturated fatty acid metabolites play an important role in the pathogenesis of several disorders, their contribution to IBD is yet to be understood. METHODS Polyunsaturated fatty acids metabolite profiles were established from biopsy samples obtained from Crohn's disease, ulcerative colitis, or control patients. The impact of a prostaglandin I2 (PGI2) analog on intestinal epithelial permeability was tested in vitro using Caco-2 cells and ex vivo using human or mouse explants. In addition, mice were treated with PGI2 to observe dextran sulfate sodium (DSS)-induced colitis. Tight junction protein expression, subcellular location, and apoptosis were measured in the different models by immunohistochemistry and Western blotting. RESULTS A significant reduction of PGI2 in IBD patient biopsies was identified. PGI2 treatment reduced colonic inflammation, increased occludin expression, decreased caspase-3 cleavage and intestinal permeability, and prevented colitis development in DSS-induced mice. Using colonic explants from mouse and human control subjects, the staurosporine-induced increase in paracellular permeability was prevented by PGI2. PGI2 also induced the membrane location of occludin and reduced the permeability observed in colonic biopsies from IBD patients. CONCLUSIONS The present study identified a PGI2 defect in the intestinal mucosa of IBD patients and demonstrated its protective role during colitis.
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Affiliation(s)
- Camille Pochard
- Université de Nantes, Inserm, TENS, The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes, France
| | - Jacques Gonzales
- Université de Nantes, Inserm, TENS, The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes, France
| | - Anne Bessard
- Université de Nantes, Inserm, TENS, The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes, France
| | - Maxime M Mahe
- Université de Nantes, Inserm, TENS, The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes, France; Department of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Arnaud Bourreille
- Université de Nantes, Inserm, TENS, The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes, France; CHU de Nantes, Hôpital Hôtel-Dieu, Nantes, France; CIC 1413, Nantes, France
| | - Nicolas Cenac
- UMR1220, IRSD, INSERM, INRA, INP-ENVT, Université de Toulouse, Toulouse, France
| | - Anne Jarry
- Université de Nantes, Inserm, CRCINA, Nantes, France
| | - Emmanuel Coron
- Université de Nantes, Inserm, TENS, The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes, France; CHU de Nantes, Hôpital Hôtel-Dieu, Nantes, France
| | | | - Guillaume Meurette
- Université de Nantes, Inserm, TENS, The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes, France; CHU de Nantes, Hôpital Hôtel-Dieu, Nantes, France
| | - Michel Neunlist
- Université de Nantes, Inserm, TENS, The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes, France
| | - Malvyne Rolli-Derkinderen
- Université de Nantes, Inserm, TENS, The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes, France.
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15
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Aslam MN, McClintock SD, Attili D, Pandya S, Rehman H, Nadeem DM, Jawad-Makki MAH, Rizvi AH, Berner MM, Dame MK, Turgeon DK, Varani J. Ulcerative Colitis-Derived Colonoid Culture: A Multi-Mineral-Approach to Improve Barrier Protein Expression. Front Cell Dev Biol 2020; 8:577221. [PMID: 33330453 PMCID: PMC7719760 DOI: 10.3389/fcell.2020.577221] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 10/23/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Recent studies demonstrated that Aquamin®, a calcium-, magnesium-rich, multi-mineral natural product, improves barrier structure and function in colonoids obtained from the tissue of healthy subjects. The goal of the present study was to determine if the colonic barrier could be improved in tissue from subjects with ulcerative colitis (UC). METHODS Colonoid cultures were established with colon biopsies from 9 individuals with UC. The colonoids were then incubated for a 2-week period under control conditions (in culture medium with a final calcium concentration of 0.25 mM) or in the same medium supplemented with Aquamin® to provide 1.5 - 4.5 mM calcium. Effects on differentiation and barrier protein expression were determined using several approaches: phase-contrast and scanning electron microscopy, quantitative histology and immunohistology, mass spectrometry-based proteome assessment and transmission electron microscopy. RESULTS Although there were no gross changes in colonoid appearance, there was an increase in lumen diameter and wall thickness on histology and greater expression of cytokeratin 20 (CK20) along with reduced expression of Ki67 by quantitative immunohistology observed with intervention. In parallel, upregulation of several differentiation-related proteins was seen in a proteomic screen with the intervention. Aquamin®-treated colonoids demonstrated a modest up-regulation of tight junctional proteins but stronger induction of adherens junction and desmosomal proteins. Increased desmosomes were seen at the ultrastructural level. Proteomic analysis demonstrated increased expression of several basement membrane proteins and hemidesmosomal components. Proteins expressed at the apical surface (mucins and trefoils) were also increased as were several additional proteins with anti-microbial activity or that modulate inflammation. Finally, several transporter proteins that affect electrolyte balance (and, thereby affect water resorption) were increased. At the same time, growth and cell cycle regulatory proteins (Ki67, nucleophosmin, and stathmin) were significantly down-regulated. Laminin interactions, matrix formation and extracellular matrix organization were the top three up-regulated pathways with the intervention. CONCLUSION A majority of individuals including patients with UC do not reach the recommended daily intake for calcium and other minerals. To the extent that such deficiencies might contribute to the weakening of the colonic barrier, the findings employing UC tissue-derived colonoids here suggest that adequate mineral intake might improve the colonic barrier.
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Affiliation(s)
- Muhammad N. Aslam
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, United States
| | - Shannon D. McClintock
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, United States
| | - Durga Attili
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, United States
| | - Shailja Pandya
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, United States
| | - Humza Rehman
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, United States
| | - Daniyal M. Nadeem
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, United States
| | | | - Areeba H. Rizvi
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, United States
| | - Maliha M. Berner
- Department of Internal Medicine (The Division of Gastroenterology), The University of Michigan Medical School, Ann Arbor, MI, United States
| | - Michael K. Dame
- Department of Internal Medicine (The Division of Gastroenterology), The University of Michigan Medical School, Ann Arbor, MI, United States
| | - Danielle Kim Turgeon
- Department of Internal Medicine (The Division of Gastroenterology), The University of Michigan Medical School, Ann Arbor, MI, United States
| | - James Varani
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, United States
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16
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Jeon JW, Choi N, Lee SH, Sung JH. Three-tissue microphysiological system for studying inflammatory responses in gut-liver Axis. Biomed Microdevices 2020; 22:65. [PMID: 32915326 DOI: 10.1007/s10544-020-00519-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The interaction between the gut and the liver, often known as the gut-liver axis, play crucial roles in modulating the body's responses to the xenobiotics as well as progression of diseases. Dysfunction of the axis can cause metabolic disorders as well as obesity, diabetes, and fatty liver disease. During the progression of such diseases, inflammatory responses involving the immune system also play an important part. In this study, we developed a three-tissue microphysiological system (MPS) that can accommodate three different cell types in separated compartments connected via fluidic channels in a microfluidic device. Using computational fluid dynamics, geometry of fluidic channels and flow conditions were optimized for seeding and culturing different cell types in the three-tissue MPS. Caco-2 (gut), RAW264.7 (immune), and HepG2 (liver) cells were seeded and cultured in the chip. Stimulation of the gut cells in the MPS with lipopolysaccharide (LPS) resulted in induction of inflammatory response and production of nitric oxide (NO) in all connected chambers. The anti-inflammatory effect of luteolin was demonstrated. Our study demonstrates that the three-tissue MPS can recapitulate the inflammatory responses involving the gut, liver and immune cells.
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Affiliation(s)
- Joong-Won Jeon
- Department of Chemical Engineering, Hongik University, Seoul, 04066, Republic of Korea
| | - Nakwon Choi
- Center for BioMicrosystems, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
| | - Seung Hwan Lee
- Department of Bionano Engineering, Hanyang University, Ansan, 15588, Republic of Korea.
| | - Jong Hwan Sung
- Department of Chemical Engineering, Hongik University, Seoul, 04066, Republic of Korea.
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17
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Koepsell H. Glucose transporters in the small intestine in health and disease. Pflugers Arch 2020; 472:1207-1248. [PMID: 32829466 PMCID: PMC7462918 DOI: 10.1007/s00424-020-02439-5] [Citation(s) in RCA: 148] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 07/11/2020] [Accepted: 07/17/2020] [Indexed: 12/23/2022]
Abstract
Absorption of monosaccharides is mainly mediated by Na+-D-glucose cotransporter SGLT1 and the facititative transporters GLUT2 and GLUT5. SGLT1 and GLUT2 are relevant for absorption of D-glucose and D-galactose while GLUT5 is relevant for D-fructose absorption. SGLT1 and GLUT5 are constantly localized in the brush border membrane (BBM) of enterocytes, whereas GLUT2 is localized in the basolateral membrane (BLM) or the BBM plus BLM at low and high luminal D-glucose concentrations, respectively. At high luminal D-glucose, the abundance SGLT1 in the BBM is increased. Hence, D-glucose absorption at low luminal glucose is mediated via SGLT1 in the BBM and GLUT2 in the BLM whereas high-capacity D-glucose absorption at high luminal glucose is mediated by SGLT1 plus GLUT2 in the BBM and GLUT2 in the BLM. The review describes functions and regulations of SGLT1, GLUT2, and GLUT5 in the small intestine including diurnal variations and carbohydrate-dependent regulations. Also, the roles of SGLT1 and GLUT2 for secretion of enterohormones are discussed. Furthermore, diseases are described that are caused by malfunctions of small intestinal monosaccharide transporters, such as glucose-galactose malabsorption, Fanconi syndrome, and fructose intolerance. Moreover, it is reported how diabetes, small intestinal inflammation, parental nutrition, bariatric surgery, and metformin treatment affect expression of monosaccharide transporters in the small intestine. Finally, food components that decrease D-glucose absorption and drugs in development that inhibit or downregulate SGLT1 in the small intestine are compiled. Models for regulations and combined functions of glucose transporters, and for interplay between D-fructose transport and metabolism, are discussed.
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Affiliation(s)
- Hermann Koepsell
- Institute for Anatomy and Cell Biology, University of Würzburg, Koellikerstr 6, 97070, Würzburg, Germany.
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18
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Interleukin-4 suppresses the proliferation and alters the gene expression in enteroids. Cytotechnology 2020; 72:479-488. [PMID: 32328837 DOI: 10.1007/s10616-020-00395-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 04/14/2020] [Indexed: 12/19/2022] Open
Abstract
Interleukin (IL)-4 is known as a cytokine mainly involved in allergy and inflammation, but recent studies have suggested that IL-4 plays a part in the differentiation process of various cells. Since the effect of IL-4 on intestinal epithelial cells, particularly cryptic cells including stem cells, is poorly understood, we investigated IL-4-induced changes in intestinal epithelial cells using mouse jejunal organoids called enteroids. IL-4 treatment decreased cell proliferation, the expression of the stem cell markers leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) and olfactomedin 4 (Olfm4), and Lgr5-positive cells in enteroids. Among the differentiation markers, IL-4 significantly decreased the gene expression levels of the Paneth cell markers lysozyme 1 (Lyz1) and regenerating islet-derived protein 3 gamma (Reg3γ). A fluorescent immunostaining showed that IL-4 attenuated the emission and fluorescence intensity derived from lysozyme, which is enriched in Paneth cells. These results suggest that functional changes in Paneth cells caused by IL-4 may contribute to the reduction in Lgr5-positive cells and proliferative activity. IL-4 may affects gut function by altering the proliferation and the gene expression in enteroids.
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19
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Huang CY, Yu LCH. Distinct patterns of interleukin-12/23 and tumor necrosis factor α synthesis by activated macrophages are modulated by glucose and colon cancer metabolites. CHINESE J PHYSIOL 2020; 63:7-14. [PMID: 32056981 DOI: 10.4103/cjp.cjp_75_19] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Chronic inflammation is a major risk factor for colitis-associated colorectal carcinoma (CRC). Macrophages play a key role in altering the tumor microenvironment by producing pro-inflammatory and anti-inflammatory cytokines. Our previous studies showed that glucose metabolism conferred death resistance for tumor progression and exerted anti-inflammatory effects in ischemic gut mucosa. However, the effect of glucose and cancer metabolites in modulating macrophage cytokine profiles remains poorly defined. We used an in vitro system to mimic intestinal microenvironment and to investigate the roles of glucose and cancer metabolites in the cross-talk between carcinoma cells and macrophages. Human monocyte-derived THP-1 macrophages were stimulated with bacterial lipopolysaccharide (LPS) in the presence of conditioned media (CM) collected from human CRC Caco-2 cells incubated in either glucose-free or glucose-containing media. Our results demonstrated that glucose modulated the macrophage cytokine production, including decreased LPS-induced pro-inflammatory cytokines (i.e., tumor necrosis factor [TNF]α and interleukin [IL]-6) and increased anti-inflammatory cytokine (i.e., IL-10), at resting state. Moreover, glucose-containing CM reduced the macrophage secretion of TNFα and IL-8 but elevated the IL-12 and IL-23 levels, showing an opposite pattern of distinct pro-inflammatory cytokines modulated by cancer glucose metabolites. In contrast, LPS-induced production of macrophage inflammatory protein-1 (a macrophage-derived chemoattractant for granulocytes) was not altered by glucose or CM, indicating that resident macrophages may play a more dominant role than infiltrating granulocytes for responding to cancer metabolites. In conclusion, glucose metabolites from CRC triggered distinct changes in the cytokine profiles in macrophages. The downregulation of death-inducing TNFα and upregulation of Th1/17-polarizing IL-12/IL-23 axis in macrophages caused by exposure to cancer-derived glucose metabolites may contribute to tumor progression.
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Affiliation(s)
- Ching-Ying Huang
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei; Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan
| | - Linda Chia-Hui Yu
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan
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20
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Vojdani A, Vojdani E, Herbert M, Kharrazian D. Correlation between Antibodies to Bacterial Lipopolysaccharides and Barrier Proteins in Sera Positive for ASCA and ANCA. Int J Mol Sci 2020; 21:ijms21041381. [PMID: 32085663 PMCID: PMC7073094 DOI: 10.3390/ijms21041381] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 02/10/2020] [Accepted: 02/16/2020] [Indexed: 12/17/2022] Open
Abstract
Individuals with intestinal barrier dysfunction are more prone to autoimmunity. Lipopolysaccharides (LPS) from gut bacteria have been shown to play a role in systemic inflammation, leading to the opening of the gut and blood-brain barrier (BBB). This study aims to measure antibodies against LPS and barrier proteins in samples positive for anti-Saccharomyces cerevisiae antibodies (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA) and compare them with these same antibodies in controls to determine whether a correlation between LPS and barrier proteins could be found. We obtained 94 ASCA- and 94 ANCA-positive blood samples, as well as 188 blood samples from healthy controls. Samples were assessed for antibodies to LPS, zonulin+occludin, S100B, and aquaporin-4 (AQP4). Results show significant elevation in antibodies in about 30% of ASCA- and ANCA-positive sera and demonstrate positive linear relationships between these antibodies. The findings suggest that individuals positive for ASCA and ANCA have increased odds of developing intestinal and BBB permeability compared to healthy subjects. The levels of LPS antibodies in both ASCA- and ANCA-positive and negative specimens showed from low and moderate to high correlation with antibodies to barrier proteins. This study shows that LPS, by damaging the gut and BBBs, contribute to the extra-intestinal manifestation of IBD. We conclude that IBD patients should be screened for LPS antibodies in an effort to detect or prevent possible barrier damage at the earliest stage possible to abrogate disease symptoms in IBS and associated disorders.
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Affiliation(s)
- Aristo Vojdani
- Immunosciences Lab, Inc. 822 S. Robertson Blvd, Ste 312, Los Angeles, CA 90035, USA
- Department of Preventive Medicine, Loma Linda University, Loma Linda, CA 92350, USA;
- Correspondence: ; Tel.: +1-310-657-1077
| | - Elroy Vojdani
- Regenera Medical, 11860 Wilshire Blvd., Ste. 301, Los Angeles, CA 90025, USA;
| | - Martha Herbert
- Martha Herbert, Pediatric Neurology, Massachusetts General Hospital, Rm CNY149-2nd Floor, Boston, MA 02114, USA;
| | - Datis Kharrazian
- Department of Preventive Medicine, Loma Linda University, Loma Linda, CA 92350, USA;
- Department of Neurology, Harvard Medical, Boston, MA 02115, USA
- Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA
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21
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Buret AG. Acceptance of the 2019 Stoll-Stunkard Memorial Lectureship Award: The Study of Host-Parasite Interactions to Better Understand Fundamental Host Physiology: The Model of Giardiasis. J Parasitol 2020. [DOI: 10.1645/19-134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- André G. Buret
- Department of Biological Sciences, Host-Parasite Interactions Program, Inflammation Research Network, University of Calgary, 2500 University Drive N.W., Calgary (Alberta), T2N 1N4, Canada
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22
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Yang LT, Ma F, Zeng HT, Zhao M, Zeng XH, Liu ZQ, Yang PC. Restoration of Mal overcomes the defects of apoptosis in lung cancer cells. PLoS One 2020; 15:e0227634. [PMID: 31978067 PMCID: PMC6980397 DOI: 10.1371/journal.pone.0227634] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 12/23/2019] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND AND AIMS Cancer is one of the life-threatening diseases of human beings; the pathogenesis of cancer remains to be further investigated. Toll like receptor (TLR) activities are involved in the apoptosis regulation. This study aims to elucidate the role of Mal (MyD88-adapter-like) molecule in the apoptosis regulation of lung cancer (LC) cells. METHODS The LC tissues were collected from LC patients. LC cells and normal control (NC) cells were isolated from the tissues and analyzed by pertinent biochemical and immunological approaches. RESULTS We found that fewer apoptotic LC cells were induced by cisplatin in the culture as compared to NC cells. The expression of Fas ligand (FasL) was lower in LC cells than that in NC cells. FasL mRNA levels declined spontaneously in LC cells. A complex of FasL/TDP-43 was detected in LC cells. LC cells expressed less Mal than NC cells. Activation of Mal by lipopolysaccharide (LPS) increased TDP-43 expression in LC cells. TDP-43 formed a complex with FasL mRNA to prevent FasL mRNA from decay. Reconstitution of Mal or TDP-43 restored the sensitiveness of LC cells to apoptotic inducers. CONCLUSIONS LC cells express low Mal levels that contributes to FasL mRNA decay through impairing TDP-43 expression. Reconstitution of Mal restores sensitiveness of LC cells to apoptosis inducers that may be a novel therapeutic approach for LC treatment.
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Affiliation(s)
- Li-Tao Yang
- ENT Institute, Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen, China
| | - Fei Ma
- ENT Institute, Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen, China
| | - Hao-Tao Zeng
- ENT Institute, Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen, China
| | - Miao Zhao
- ENT Institute, Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen, China
| | - Xian-Hai Zeng
- ENT Institute, Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen, China
| | - Zhi-Qiang Liu
- ENT Institute, Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen, China
| | - Ping-Chang Yang
- ENT Institute, Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen, China
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23
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Zhang H, Xu CN, Mine Y. Synthetic phosphoserine dimer attenuates lipopolysaccharide‐induced inflammatory response in human intestinal epithelial cells via activation of NF‐κB and MAPKs cell signalling pathways. Int J Food Sci Technol 2020. [DOI: 10.1111/ijfs.14246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Hua Zhang
- Department of Food Science University of Guelph Guelph Ontario N1G 2W1 Canada
| | - Cai Na Xu
- Department of Food Science University of Guelph Guelph Ontario N1G 2W1 Canada
| | - Yoshinori Mine
- Department of Food Science University of Guelph Guelph Ontario N1G 2W1 Canada
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24
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Allain T, Buret AG. Pathogenesis and post-infectious complications in giardiasis. ADVANCES IN PARASITOLOGY 2019; 107:173-199. [PMID: 32122529 DOI: 10.1016/bs.apar.2019.12.001] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Giardia is an important cause of diarrhoea, and results in post-infectious and extra-intestinal complications. This chapter presents a state-of-the art of our understanding of how this parasite may cause such abnormalities, which appear to develop at least in part in Assemblage-dependent manner. Findings from prospective longitudinal cohort studies indicate that Giardia is one of the four most prevalent enteropathogens in early life, and represents a risk factor for stunting at 2 years of age. This may occur independently of diarrheal disease, in strong support of the pathophysiological significance of the intestinal abnormalities induced by this parasite. These include epithelial malabsorption and maldigestion, increased transit, mucus depletion, and disruptions of the commensal microbiota. Giardia increases epithelial permeability and facilitates the invasion of gut bacteria. Loss of intestinal barrier function is at the core of the acute and post-infectious complications associated with this infection. Recent findings demonstrate that the majority of the pathophysiological responses triggered by this parasite can be recapitulated by the effects of its membrane-bound and secreted cysteine proteases.
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Affiliation(s)
- Thibault Allain
- University of Calgary, Host-Parasite Interactions Program, Inflammation Research Network, Department of Biological Sciences, Calgary, Canada
| | - André G Buret
- University of Calgary, Host-Parasite Interactions Program, Inflammation Research Network, Department of Biological Sciences, Calgary, Canada.
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25
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Huang CY, Huang CY, Pai YC, Lin BR, Lee TC, Liang PH, Yu LCH. Glucose Metabolites Exert Opposing Roles in Tumor Chemoresistance. Front Oncol 2019; 9:1282. [PMID: 31824857 PMCID: PMC6881467 DOI: 10.3389/fonc.2019.01282] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 11/05/2019] [Indexed: 01/01/2023] Open
Abstract
Reprogrammed glucose metabolism and increased glycolysis have been implicated in tumor chemoresistance. The aim was to investigate the distinct roles of the glucose metabolites pyruvate and ATP in chemoresistance mechanisms, including cell death and proliferation. Our data showed higher glucose transporters in colorectal cancer (CRC) from non-responsive patients than those responsive to chemotherapy. Human CRC cell lines exposed to 5-fluorouracil (5-FU) displayed elevated cell viability and larger tumors in xenograft mouse models if cultured in high-glucose medium. Glucose conferred resistance to 5-FU-induced necroptosis via pyruvate scavenging of mitochondrial free radicals, whereas ATP replenishment had no effect on cell death. Glucose attenuated the 5-FU-induced G0/G1 shift but not the S phase arrest. Opposing effects were observed by glucose metabolites; ATP increased while pyruvate decreased the G0/G1 shift. Lastly, 5-FU-induced tumor spheroid destruction was prevented by glucose and pyruvate, but not by ATP. Our finding argues against ATP as the main effector for glucose-mediated chemoresistance and supports a key role of glycolytic pyruvate as an antioxidant for dual modes of action: necroptosis reduction and a cell cycle shift to a quiescent state.
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Affiliation(s)
- Chung-Yen Huang
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.,School of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ching-Ying Huang
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Food Science and Biotechnology, National Chung-Hsing University, Taichung City, Taiwan
| | - Yu-Chen Pai
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Been-Ren Lin
- Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Tsung-Chun Lee
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Pi-Hui Liang
- School of Pharmacy, National Taiwan University, Taipei, Taiwan
| | - Linda Chia-Hui Yu
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan
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26
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Kalra J, Mangali SB, Dasari D, Bhat A, Goyal S, Dhar I, Sriram D, Dhar A. SGLT1 inhibition boon or bane for diabetes-associated cardiomyopathy. Fundam Clin Pharmacol 2019; 34:173-188. [PMID: 31698522 DOI: 10.1111/fcp.12516] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 09/18/2019] [Accepted: 10/14/2019] [Indexed: 12/29/2022]
Abstract
Chronic hyperglycaemia is a peculiar feature of diabetes mellitus (DM). Sequential metabolic abnormalities accompanying glucotoxicity are some of its implications. Glucotoxicity most likely corresponds to the vascular intricacy and metabolic alterations, such as increased oxidation of free fatty acids and reduced glucose oxidation. More than half of those with diabetes also develop cardiac abnormalities due to unknown causes, posing a major threat to the currently available marketed preparations which are being used for treating these cardiac complications. Even though impairment in cardiac functioning is the principal cause of death in individuals with type 2 diabetes (T2D), reducing plasma glucose levels has little effect on cardiovascular disease (CVD) risk. In vitro and in vivo studies have demonstrated that inhibitors of sodium glucose transporter (SGLT) represent a putative therapeutic intervention for these pathological conditions. Several clinical trials have reported the efficacy of SGLT inhibitors as a novel and potent antidiabetic agent which along with its antihyperglycaemic activity possesses the potential of effectively treating its associated cardiac abnormalities. Thus, hereby, the present review highlights the role of SGLT inhibitors as a successful drug candidate for correcting the shifts in deregulation of cardiac energy substrate metabolism together with its role in treating diabetes-related cardiac perturbations.
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Affiliation(s)
- Jaspreet Kalra
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Suresh Babu Mangali
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Deepika Dasari
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Audesh Bhat
- Centre for Molecular Biology, Central University of Jammu, Jammu, 181143, India
| | - Srashti Goyal
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Indu Dhar
- Department of Clinical Science, University of Bergen, Bergen, 5009, Norway
| | - Dharamrajan Sriram
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Arti Dhar
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
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27
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Cell line-dependent increase in cellular quercetin accumulation upon stress induced by valinomycin and lipopolysaccharide, but not by TNF-α. Food Res Int 2019; 125:108596. [DOI: 10.1016/j.foodres.2019.108596] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 07/09/2019] [Accepted: 07/28/2019] [Indexed: 11/21/2022]
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28
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Xie K, Xie H, Su G, Chen D, Yu B, Mao X, Huang Z, Yu J, Luo J, Zheng P, Luo Y, He J. β-Defensin 129 Attenuates Bacterial Endotoxin-Induced Inflammation and Intestinal Epithelial Cell Apoptosis. Front Immunol 2019; 10:2333. [PMID: 31636641 PMCID: PMC6787771 DOI: 10.3389/fimmu.2019.02333] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 09/16/2019] [Indexed: 12/25/2022] Open
Abstract
Defensins have attracted considerable research interest worldwide because of their potential to serve as a substitute for antibiotics. In this study, we characterized a novel porcine β-defensin (pBD129) and explored its role in alleviating bacterial endotoxin-induced inflammation and intestinal epithelium atrophy. The pBD129 gene was cloned and expressed in Escherichia coli. A recombinant pBD129 protein was also purified. To explore its role in alleviating the endotoxin-induced inflammation, mice, with or without lipopolysaccharide (LPS) challenge were treated by pBD129 at different doses. The recombinant pBD129 showed significant antimicrobial activities against the E. coli and Streptococcus with a minimal inhibitory concentration (MICs) of 32 μg/mL. Hemolytic assays showed that the pBD129 had no detrimental impact on cell viabilities. Interestingly, we found that pBD129 attenuated LPS-induced inflammatory responses by decreasing serum concentrations of inflammatory cytokines, such as the IL-1β, IL-6, and TNF-α (P < 0.05). Moreover, pBD129 elevated the intestinal villus height (P < 0.05) and enhanced the expression and localization of the major tight junction-associated protein ZO-1 in LPS-challenged mice. Additionally, pDB129 at a high dose significantly decreased serum diamine oxidase (DAO) concentration (P < 0.05) and reduced intestinal epithelium cell apoptosis (P < 0.05) in LPS-challenged mice. Importantly, pBD129 elevated the expression level of Bcl-2-associated death promoter (Bcl-2), but down-regulated the expression levels of apoptosis-related genes such as the B-cell lymphoma-2-associated X protein (Bax), BH3-interacting domain death agonist (Bid), cysteinyl aspartate-specific proteinase-3 (Caspase-3), and caspase-9 in the intestinal mucosa (P < 0.05). These results suggested a novel function of the mammalian defensins, and the anti-bacterial and anti-inflammatory properties of pBD129 may allow it a potential substitute for conventionally used antibiotics or drugs.
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Affiliation(s)
- Kunhong Xie
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, China
| | - Hongmei Xie
- Shandong Vocational Animal Science and Veterinary College, Weifang, China
| | - Guoqi Su
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, China
| | - Daiwen Chen
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, China
| | - Bing Yu
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, China
| | - Xiangbing Mao
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, China
| | - Zhiqing Huang
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, China
| | - Jie Yu
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, China
| | - Junqiu Luo
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, China
| | - Ping Zheng
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, China
| | - Yuheng Luo
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, China
| | - Jun He
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-resistant Nutrition, Chengdu, China
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29
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Barekatain R, Nattrass G, Tilbrook AJ, Chousalkar K, Gilani S. Reduced protein diet and amino acid concentration alter intestinal barrier function and performance of broiler chickens with or without synthetic glucocorticoid. Poult Sci 2019; 98:3662-3675. [DOI: 10.3382/ps/pey563] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Accepted: 11/23/2018] [Indexed: 12/13/2022] Open
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30
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Sun J, Liang W, Yang X, Li Q, Zhang G. Cytoprotective effects of galacto-oligosaccharides on colon epithelial cells via up-regulating miR-19b. Life Sci 2019; 231:116589. [DOI: 10.1016/j.lfs.2019.116589] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 06/17/2019] [Accepted: 06/18/2019] [Indexed: 02/07/2023]
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31
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Li Y, Zeng Y, Meng T, Gao X, Huang B, He D, Ran X, Du J, Zhang Y, Fu S, Hu G. Farrerol protects dopaminergic neurons in a rat model of lipopolysaccharide-induced Parkinson's disease by suppressing the activation of the AKT and NF-κB signaling pathways. Int Immunopharmacol 2019; 75:105739. [PMID: 31351366 DOI: 10.1016/j.intimp.2019.105739] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 06/30/2019] [Accepted: 07/02/2019] [Indexed: 12/26/2022]
Abstract
Neuroinflammation, characterized by the activation of microglia, is one of the major pathologic processes of Parkinson's disease (PD). Overactivated microglia can release many pro-inflammatory cytokines, which cause an excessive inflammatory response and eventually damage dopaminergic neurons. Therefore, the inhibition of neuroinflammation that results from the overactivation of microglia may be an method for the treatment of PD. Farrerol is a 2,3-dihydro-flavonoid obtained from Rhododendron, and it possesses various biological functions, including anti-inflammatory, antibacterial and antioxidant activities. However, the effect of farrerol on neuroinflammation has not been investigated. The present study uncovered a neuroprotective role for farrerol. In vitro, farrerol markedly decreased the production of inflammatory mediators, including interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), cyclooxygenase 2 (COX-2) and induced nitric oxide synthase (iNOS), induced by lipopolysaccharide (LPS) in BV-2 cells. This anti-inflammatory effect was regulated via inhibiting NF-κB p65 and AKT phosphorylation. Furthermore, we found that farrerol alleviated microglial activation and dopaminergic neuronal death in rats with LPS-induced PD. Pretreatment with farrerol markedly improved motor deficits in rats with LPS-induced PD. Taken together, our results indicate that the neuroprotective effect of the farrerol, which prevents microglial overactivation in rats with LPS-induced PD, may provide a potential therapy for patients suffering from PD.
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Affiliation(s)
- Yuhang Li
- College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062, China.
| | - Yalong Zeng
- College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Tianyu Meng
- College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062, China.
| | - Xiyu Gao
- College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062, China.
| | - Bingxu Huang
- College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062, China.
| | - Dewei He
- College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062, China.
| | - Xin Ran
- College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062, China.
| | - Jian Du
- College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062, China.
| | - Yufei Zhang
- College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062, China.
| | - Shoupeng Fu
- College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062, China.
| | - Guiqiu Hu
- College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062, China.
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32
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Bercier P, Gottschalk M, Grenier D. Effects of Actinobacillus pleuropneumoniae on barrier function and inflammatory response of pig tracheal epithelial cells. Pathog Dis 2019; 77:5159464. [PMID: 30395241 DOI: 10.1093/femspd/fty079] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 11/01/2018] [Indexed: 12/11/2022] Open
Abstract
Actinobacillus pleuropneumoniae is a respiratory pathogen that causes porcine pleuropneumonia, a fatal respiratory disease responsible for high economic losses in the swine industry worldwide. With the objective to better understand the interactions between A. pleuropneumoniae and the porcine respiratory epithelium, we investigated the capacity of this pathogen to damage the epithelial barrier and induce an inflammatory response. We showed that A. pleuropneumoniae, even at a multiplicity of infection of 10, is able to break the tracheal epithelial barrier integrity as determined by monitoring the transepithelial electrical resistance and fluorescein-isothiocyanate-dextran transport. Immunofluorescence staining analysis suggested that A. pleuropneumoniae is affecting two important tight junction proteins (occludin, zonula occludens-1). As a consequence of the breakdown of the epithelial barrier integrity, A. pleuropneumoniae can translocate across a cell monolayer. We also showed that tracheal epithelial cells secrete pro-inflammatory cytokines (IL-8, IL-6, TNF-α) in response to a stimulation with this pathogen. In summary, A. pleuropneumoniae is able to induce damage to the porcine respiratory epithelial barrier. Challenging the epithelial cells with A. pleuropneumoniae was also associated with the secretion of pro-inflammatory cytokines. This better knowledge of the interactions between A. pleuropneumoniae and the epithelial cells may help to design novel strategies to prevent epithelium invasion by this bacterium along with other swine respiratory pathogens.
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Affiliation(s)
- Philippe Bercier
- Groupe de Recherche en Écologie Buccale (GREB), Faculté de médecine dentaire, Université Laval, Quebec City, Quebec, GIV 0A6, Canada
| | - Marcelo Gottschalk
- Groupe de Recherche sur les Maladies Infectieuses en Production Animale (GREMIP), Faculté de médecine vétérinaire, Université de Montréal, Saint-Hyacinthe, Quebec, J2S 2M2, Canada.,Centre de Recherche en Infectiologie Porcine et Avicole (CRIPA), Fonds de Recherche du Québec - Nature et Technologies (FRQNT), Saint-Hyacinthe, Quebec, J2S 2M2, Canada
| | - Daniel Grenier
- Groupe de Recherche en Écologie Buccale (GREB), Faculté de médecine dentaire, Université Laval, Quebec City, Quebec, GIV 0A6, Canada.,Centre de Recherche en Infectiologie Porcine et Avicole (CRIPA), Fonds de Recherche du Québec - Nature et Technologies (FRQNT), Saint-Hyacinthe, Quebec, J2S 2M2, Canada
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33
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Nighot M, Rawat M, Al-Sadi R, Castillo EF, Nighot P, Ma TY. Lipopolysaccharide-Induced Increase in Intestinal Permeability Is Mediated by TAK-1 Activation of IKK and MLCK/MYLK Gene. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:797-812. [PMID: 30711488 DOI: 10.1016/j.ajpath.2018.12.016] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 12/11/2018] [Accepted: 12/20/2018] [Indexed: 01/13/2023]
Abstract
Lipopolysaccharides (LPSs) are a major component of Gram-negative bacterial cell wall and play an important role in promoting intestinal inflammatory responses. Recent studies have shown that physiologically relevant concentrations of LPS (0 to 2000 pg/mL) cause an increase in intestinal epithelial tight junction (TJ) permeability without causing cell death. However, the intracellular pathways and the mechanisms that mediate LPS-induced increase in intestinal TJ permeability remain unclear. The aim was to delineate the intracellular pathways that mediate the LPS-induced increase in intestinal permeability using in vitro and in vivo intestinal epithelial models. LPS-induced increase in intestinal epithelial TJ permeability was preceded by an activation of transforming growth factor-β-activating kinase-1 (TAK-1) and canonical NF-κB (p50/p65) pathways. The siRNA silencing of TAK-1 inhibited the activation of NF-κB p50/p65. The siRNA silencing of TAK-1 and p65/p50 subunit inhibited the LPS-induced increase in intestinal TJ permeability and the increase in myosin light chain kinase (MLCK) expression, confirming the regulatory role of TAK-1 and NF-κB p65/p50 in up-regulating MLCK expression and the subsequent increase in TJ permeability. The data also showed that toll-like receptor (TLR)-4/myeloid differentiation primary response (MyD)88 pathway was crucial upstream regulator of TAK-1 and NF-κB p50/p65 activation. In conclusion, activation of TAK-1 by the TLR-4/MyD88 signal transduction pathway and MLCK by NF-κB p65/p50 regulates the LPS-induced increase in intestinal epithelial TJ permeability.
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Affiliation(s)
- Meghali Nighot
- Department of Medicine, Pennsylvania State University, School of Medicine, Hershey, Pennsylvania
| | - Manmeet Rawat
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico
| | - Rana Al-Sadi
- Department of Medicine, Pennsylvania State University, School of Medicine, Hershey, Pennsylvania
| | - Eliseo F Castillo
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico
| | - Prashant Nighot
- Department of Medicine, Pennsylvania State University, School of Medicine, Hershey, Pennsylvania
| | - Thomas Y Ma
- Department of Medicine, Pennsylvania State University, School of Medicine, Hershey, Pennsylvania; Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
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34
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Ding YH, Song YD, Wu YX, He HQ, Yu TH, Hu YD, Zhang DP, Jiang HC, Yu KK, Li XZ, Sun L, Qian F. Isoalantolactone suppresses LPS-induced inflammation by inhibiting TRAF6 ubiquitination and alleviates acute lung injury. Acta Pharmacol Sin 2019; 40:64-74. [PMID: 30013035 DOI: 10.1038/s41401-018-0061-3] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 06/05/2018] [Indexed: 12/11/2022]
Abstract
Isoalantolactone (IAL) is a sesquiterpene lactone extracted from roots of Inula helenium L and has shown anti-inflammatory effects. In this study we investigated the therapeutic effects of IAL on acute lung injury (ALI) and elucidated the mechanisms underlying its anti-inflammation potential in vitro and in vivo. Treatment with lipopolysaccharide (LPS, 100 ng/mL) drastically stimulated production of inflammatory mediators such as NO, TNF-α, IL-1β, and IL-6 in mouse bone marrow-derived macrophages (BMDMs), which was dose-dependently suppressed by pretreatment with IAL (2.5, 5, 10, 20 μM). We further revealed that IAL suppressed LPS-induced NF-κB, ERK, and Akt activation. Moreover, the downregulation of non-degradable K63-linked polyubiquitination of TRAF6, an upstream transcription factor of NF-κB, contributed to the anti-inflammatory effects of IAL. ALI was induced in mice by intratracheal injection of LPS (5 mg/kg). Administration of IAL (20 mg/kg, i.p.) significantly suppressed pulmonary pathological changes, neutrophil infiltration, pulmonary permeability, and pro-inflammatory cytokine expression. Our results demonstrate that IAL is a potential therapeutic reagent against inflammation and ALI.
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35
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Shin W, Kim HJ. Intestinal barrier dysfunction orchestrates the onset of inflammatory host-microbiome cross-talk in a human gut inflammation-on-a-chip. Proc Natl Acad Sci U S A 2018; 115:E10539-E10547. [PMID: 30348765 PMCID: PMC6233106 DOI: 10.1073/pnas.1810819115] [Citation(s) in RCA: 214] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The initiation of intestinal inflammation involves complex intercellular cross-talk of inflammatory cells, including the epithelial and immune cells, and the gut microbiome. This multicellular complexity has hampered the identification of the trigger that orchestrates the onset of intestinal inflammation. To identify the initiator of inflammatory host-microbiome cross-talk, we leveraged a pathomimetic "gut inflammation-on-a-chip" undergoing physiological flow and motions that recapitulates the pathophysiology of dextran sodium sulfate (DSS)-induced inflammation in murine models. DSS treatment significantly impaired, without cytotoxic damage, epithelial barrier integrity, villous microarchitecture, and mucus production, which were rapidly recovered after cessation of DSS treatment. We found that the direct contact of DSS-sensitized epithelium and immune cells elevates oxidative stress, in which the luminal microbial stimulation elicited the production of inflammatory cytokines and immune cell recruitment. In contrast, an intact intestinal barrier successfully suppressed oxidative stress and inflammatory cytokine production against the physiological level of lipopolysaccharide or nonpathogenic Escherichia coli in the presence of immune elements. Probiotic treatment effectively reduced the oxidative stress, but it failed to ameliorate the epithelial barrier dysfunction and proinflammatory response when the probiotic administration happened after the DSS-induced barrier disruption. Maintenance of epithelial barrier function was necessary and sufficient to control the physiological oxidative stress and proinflammatory cascades, suggesting that "good fences make good neighbors." Thus, the modular gut inflammation-on-a-chip identifies the mechanistic contribution of barrier dysfunction mediated by intercellular host-microbiome cross-talk to the onset of intestinal inflammation.
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Affiliation(s)
- Woojung Shin
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712
| | - Hyun Jung Kim
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712;
- Department of Medical Engineering, Yonsei University College of Medicine, 03722 Seoul, Republic of Korea
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Lu YY, Liang J, Chen SX, Wang BX, Yuan H, Li CT, Wu YY, Wu YF, Shi XG, Gao J, Hou SZ. Phloridzin alleviate colitis in mice by protecting the intestinal brush border and improving the expression of sodium glycogen transporter 1. J Funct Foods 2018. [DOI: 10.1016/j.jff.2018.02.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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Helminth infection in mice improves insulin sensitivity via modulation of gut microbiota and fatty acid metabolism. Pharmacol Res 2018; 132:33-46. [PMID: 29653264 DOI: 10.1016/j.phrs.2018.04.008] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 03/14/2018] [Accepted: 04/09/2018] [Indexed: 12/19/2022]
Abstract
Intestinal helminths are prevalent in individuals who live in rural areas of developing countries, where obesity, type 2 diabetes, and metabolic syndrome are rare. In the present study, we analyzed the modulation of the gut microbiota in mice infected with the helminth Strongyloides venezuelensis, and fed either a standard rodent chow diet or high-fat diet (HFD). To investigate the effects of the microbiota modulation on the metabolism, we analyzed the expression of tight-junction proteins present in the gut epithelium, inflammatory markers in the serum and tissue and quantified glucose tolerance and insulin sensitivity and resistance. Additionally, the levels of lipids related to inflammation were evaluated in the feces and serum. Our results show that infection with Strongyloides venezuelensis results in a modification of the gut microbiota, most notably by increasing Lactobacillus spp. These modifications in the microbiota alter the host metabolism by increasing the levels of anti-inflammatory cytokines, switching macrophages from a M1 to M2 pattern in the adipose tissue, increasing the expression of tight junction proteins in the intestinal cells (thereby reducing the permeability) and decreasing LPS in the serum. Taken together, these changes correlate with improved insulin signaling and sensitivity, which could also be achieved with HFD mice treated with probiotics. Additionally, helminth infected mice produce higher levels of oleic acid, which participates in anti-inflammatory pathways. These results suggest that modulation of the microbiota by helminth infection or probiotic treatment causes a reduction in subclinical inflammation, which has a positive effect on the glucose metabolism of the host.
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Wu P, Zheng X, Zhou XQ, Jiang WD, Liu Y, Jiang J, Kuang SY, Tang L, Zhang YA, Feng L. Deficiency of dietary pyridoxine disturbed the intestinal physical barrier function of young grass carp (Ctenopharyngodon idella). FISH & SHELLFISH IMMUNOLOGY 2018; 74:459-473. [PMID: 29339045 DOI: 10.1016/j.fsi.2018.01.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 01/03/2018] [Accepted: 01/11/2018] [Indexed: 06/07/2023]
Abstract
The aim of this study was to assess the effects of dietary pyridoxine (PN) deficiency on intestinal antioxidant capacity, cell apoptosis and intercellular tight junction in young grass carp (Ctenopharyngodon idella). A total of 540 young grass carp (231.85 ± 0.63 g) were fed six diets containing graded levels of PN (0.12-7.48 mg/kg diet) for 10 weeks. At the end of the feeding trial, the fish were challenged with Aeromonas hydrophila for 2 weeks. The results showed that compared with the optimal PN level, PN deficiency (1) increased the contents of reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl (PC), decreased the activities and mRNA levels of antioxidant enzymes such as copper, zinc superoxide dismutase (CuZnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR) (P < .05); (2) up-regulated the mRNA levels of cysteinyl aspartic acid-protease-3 (caspase-3), caspase-7, caspase-8, caspase-9, Bcl-2 associated X protein (Bax), apoptotic protease activating factor-1 (Apaf-1) and Fas ligand (FasL), and down-regulated the mRNA levels of inhibitor of apoptosis proteins (IAP), B-cell lymphoma protein-2 (Bcl-2) and myeloid cell leukaemia-1 (Mcl-1) (P < .05); (3) down-regulated the mRNA levels of ZO-1, occludin [only in middle intestine (MI)], claudin-b, claudin-c, claudin-f, claudin-3c, claudin-7a, claudin-7b and claudin-11, and up-regulated the mRNA levels of claudin-12 and claudin-15a (P < .05), which might be partly linked to Kelch-like-ECH-associated protein 1a (Keap1a)/NF-E2-related factor 2 (Nrf2), p38 mitogen-activated protein kinase (p38MAPK) and myosin light chain kinase (MLCK) signalling in the intestines of fish. However, the activities and mRNA levels of MnSOD, the mRNA levels of Keap1b, c-Jun N-terminal protein kinase (JNK) and claudin-15b in three intestinal segments, and the mRNA levels of occludin in the proximal intestine (PI) and distal intestine (DI) were not affected by graded levels of PN. These data indicate that PN deficiency could disturb the intestinal physical barrier function of fish. Additionally, based on the quadratic regression analysis for MDA content and GST activity, the dietary PN requirements for young grass carp were estimated as 4.85 and 5.02 mg/kg diet, respectively.
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Affiliation(s)
- Pei Wu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Xin Zheng
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Xiao-Qiu Zhou
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Wei-Dan Jiang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Yang Liu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Jun Jiang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Sheng-Yao Kuang
- Animal Nutrition Institute, Sichuan Academy of Animal Science, Chengdu, 610066, China
| | - Ling Tang
- Animal Nutrition Institute, Sichuan Academy of Animal Science, Chengdu, 610066, China
| | - Yong-An Zhang
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China
| | - Lin Feng
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China.
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Merigo F, Brandolese A, Facchin S, Missaggia S, Bernardi P, Boschi F, D’Incà R, Savarino EV, Sbarbati A, Sturniolo GC. Glucose transporter expression in the human colon. World J Gastroenterol 2018; 24:775-793. [PMID: 29467549 PMCID: PMC5807937 DOI: 10.3748/wjg.v24.i7.775] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 12/13/2017] [Accepted: 12/20/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate by immunostaining glucose transporter expression in human colorectal mucosa in controls and patients with inflammatory bowel disease (IBD).
METHODS Colorectal samples were obtained from patients undergoing lower endoscopic colonoscopy or recto-sigmoidoscopy. Patients diagnosed with ulcerative colitis (n = 18) or Crohn’s disease (n = 10) and scheduled for diagnostic colonoscopy were enrolled. Patients who underwent colonoscopy for prevention screening of colorectal cancer or were followed-up after polypectomy or had a history of lower gastrointestinal symptoms were designated as the control group (CTRL, n = 16). Inflammatory status of the mucosa at the sampling site was evaluated histologically and/or endoscopically. A total of 147 biopsies of colorectal mucosa were collected and processed for immunohistochemistry analysis. The expression of GLUT2, SGLT1, and GLUT5 glucose transporters was investigated using immunoperoxidase labeling. To compare immunoreactivity of GLUT5 and LYVE-1, which is a marker for lymphatic vessel endothelium, double-labeled confocal microscopy was used.
RESULTS Immunohistochemical analysis revealed that GLUT2, SGLT1, and GLUT5 were expressed only in short epithelial portions of the large intestinal mucosa. No important differences were observed in glucose transporter expression between the samples obtained from the different portions of the colorectal tract and between the different patient groups. Unexpectedly, GLUT5 expression was also identified in vessels, mainly concentrated in specific areas where the vessels were clustered. Immunostaining with LYVE-1 and GLUT5 antibodies revealed that GLUT5-immunoreactive (-IR) clusters of vessels were concentrated in areas internal to those that were LYVE-1 positive. GLUT5 and LYVE-1 did not appear to be colocalized but rather showed a close topographical relationship on the endothelium. Based on their LYVE-1 expression, GLUT5-IR vessels were identified as lymphatic. Both inflamed and non-inflamed mucosal colorectal tissue biopsies from the IBD and CTRL patients showed GLUT5-IR clusters of lymphatic vessels.
CONCLUSION Glucose transporter immunoreactivity is present in colorectal mucosa in controls and IBD patients. GLUT5 expression is also associated with lymphatic vessels. This novel finding aids in the characterization of lymphatic vasculature in IBD patients.
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Affiliation(s)
- Flavia Merigo
- Department of Neuroscience, Biomedicine and Movement, Human Anatomy and Histology Section, University of Verona, Verona I-37134, Italy
| | - Alessandro Brandolese
- Department of Medicine, Gastroenterology Section, University of Verona, Verona I-37134, Italy
| | - Sonia Facchin
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology Section, University Hospital of Padua, Padua I-35128, Italy
| | - Silvia Missaggia
- Department of Neuroscience, Biomedicine and Movement, Human Anatomy and Histology Section, University of Verona, Verona I-37134, Italy
| | - Paolo Bernardi
- Department of Neuroscience, Biomedicine and Movement, Human Anatomy and Histology Section, University of Verona, Verona I-37134, Italy
| | - Federico Boschi
- Department of Computer Science, University of Verona, Verona I-37134, Italy
| | - Renata D’Incà
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology Section, University Hospital of Padua, Padua I-35128, Italy
| | - Edoardo Vincenzo Savarino
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology Section, University Hospital of Padua, Padua I-35128, Italy
| | - Andrea Sbarbati
- Department of Neuroscience, Biomedicine and Movement, Human Anatomy and Histology Section, University of Verona, Verona I-37134, Italy
| | - Giacomo Carlo Sturniolo
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology Section, University Hospital of Padua, Padua I-35128, Italy
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Chen G, Xu Y. Biosynthesis of cerium oxide nanoparticles and their effect on lipopolysaccharide (LPS) induced sepsis mortality and associated hepatic dysfunction in male Sprague Dawley rats. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2018; 83:148-153. [DOI: 10.1016/j.msec.2017.11.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 10/25/2017] [Accepted: 11/17/2017] [Indexed: 01/12/2023]
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Nighot M, Al-Sadi R, Guo S, Rawat M, Nighot P, Watterson MD, Ma TY. Lipopolysaccharide-Induced Increase in Intestinal Epithelial Tight Permeability Is Mediated by Toll-Like Receptor 4/Myeloid Differentiation Primary Response 88 (MyD88) Activation of Myosin Light Chain Kinase Expression. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:2698-2710. [PMID: 29157665 DOI: 10.1016/j.ajpath.2017.08.005] [Citation(s) in RCA: 152] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 08/07/2017] [Accepted: 08/22/2017] [Indexed: 12/15/2022]
Abstract
Lipopolysaccharides (LPSs) are a major component of the Gram-negative bacterial cell wall and play an important role in mediating intestinal inflammatory responses in inflammatory bowel disease. Although recent studies suggested that physiologically relevant concentrations of LPS (0 to 1 ng/mL) cause an increase in intestinal epithelial tight junction (TJ) permeability, the mechanisms that mediate an LPS-induced increase in intestinal TJ permeability remain unclear. Herein, we show that myosin light chain kinase (MLCK) plays a central role in the LPS-induced increase in TJ permeability. Filter-grown Caco-2 intestinal epithelial monolayers and C57BL/6 mice were used as an in vitro and in vivo intestinal epithelial model system, respectively. LPS caused a dose- and time-dependent increase in MLCK expression and kinase activity in Caco-2 monolayers. The pharmacologic MLCK inhibition and siRNA-induced knock-down of MLCK inhibited the LPS-induced increase in Caco-2 TJ permeability. The LPS increase in TJ permeability was mediated by toll-like receptor 4 (TLR-4)/MyD88 signal-transduction pathway up-regulation of MLCK expression. The LPS-induced increase in mouse intestinal permeability also required an increase in MLCK expression. The LPS-induced increase in intestinal permeability was inhibited in MLCK-/- and TLR-4-/- mice. These data show, for the first time, that the LPS-induced increase in intestinal permeability was mediated by TLR-4/MyD88 signal-transduction pathway up-regulation of MLCK. Therapeutic targeting of these pathways can prevent an LPS-induced increase in intestinal permeability.
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Affiliation(s)
- Meghali Nighot
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Albuquerque Veterans Affairs Medical Center, Albuquerque, New Mexico
| | - Rana Al-Sadi
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico
| | - Shuhong Guo
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico
| | - Manmeet Rawat
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Albuquerque Veterans Affairs Medical Center, Albuquerque, New Mexico
| | - Prashant Nighot
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico
| | | | - Thomas Y Ma
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Albuquerque Veterans Affairs Medical Center, Albuquerque, New Mexico.
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Gilani S, Howarth GS, Nattrass G, Kitessa SM, Barekatain R, Forder REA, Tran CD, Hughes RJ. Gene expression and morphological changes in the intestinal mucosa associated with increased permeability induced by short-term fasting in chickens. J Anim Physiol Anim Nutr (Berl) 2017; 102:e653-e661. [PMID: 29034530 DOI: 10.1111/jpn.12808] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 08/02/2017] [Indexed: 01/23/2023]
Abstract
Short-term fasting for 4.5 and 9 hr has been demonstrated to increase intestinal permeability (IP) in chickens. This study aimed to investigate the effects of 0, 4.5, 9 and 19.5 hr fasting on intestinal gene expression and villus-crypt architecture of enterocytes in jejunal and ileal samples. On day 38, Ross-308 male birds were fasted according to their group and then euthanised. Two separate intestinal sections (each 2 cm long, jejunum and ileum) were collected. One section was utilised for villus height and crypt depth measurements. The second section was snap-frozen in liquid nitrogen for quantitative polymerase chain reaction (qPCR) analysis of tight junction proteins (TJP) including claudin-1, claudin-3, occludin, zonula occludens (ZO-1, ZO-2), junctional adhesion molecules (JAM) and E-cadherin. Additionally genes involved in enterocyte protection including glucagon-like peptide (GLP-2), heat-shock protein (HSP-70), intestinal alkaline phosphatase (IAP), mammalian target of rapamycin (mTOR), toll-like receptors (TLR-4), mucin (MUC-2), cluster differentiation (CD-36) and fatty acid-binding protein (FABP-6) were also analysed. Normally distributed data were analysed using one-way analysis of variance ANOVA. Other data were analysed by non-parametric one-way ANOVA. Villus height and crypt depth were increased (p < .05) only in the ileum after fasting for 4.5 and 9 hr compared with non-fasting group. mRNA expression of claudin-3 was significantly reduced in the ileum of birds fasted for 9 and 19.5 hr, suggesting a role in IP modulation. However, all other TJP genes examined were not statistically different from control. Nevertheless, ileal FABP-6 of all fasted groups was significantly reduced, which could possibly be due to reduced bile acid production during fasting.
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Affiliation(s)
- S Gilani
- School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, SA, Australia.,Poultry CRC, University of New England, Armidale, NSW, Australia
| | - G S Howarth
- School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, SA, Australia
| | - G Nattrass
- South Australian Research and Development Institute, University of Adelaide, Roseworthy, SA, Australia
| | - S M Kitessa
- South Australian Research and Development Institute, University of Adelaide, Roseworthy, SA, Australia
| | - R Barekatain
- School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, SA, Australia.,South Australian Research and Development Institute, University of Adelaide, Roseworthy, SA, Australia
| | - R E A Forder
- School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, SA, Australia
| | - C D Tran
- Health and Biosecurity, Commonwealth Scientific and Industrial Research Organisation, Adelaide, SA, Australia.,Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide, SA, Australia
| | - R J Hughes
- School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, SA, Australia.,South Australian Research and Development Institute, University of Adelaide, Roseworthy, SA, Australia
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Kraft MR, Klotz C, Bücker R, Schulzke JD, Aebischer T. Giardia's Epithelial Cell Interaction In Vitro: Mimicking Asymptomatic Infection? Front Cell Infect Microbiol 2017; 7:421. [PMID: 29018775 PMCID: PMC5622925 DOI: 10.3389/fcimb.2017.00421] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 09/12/2017] [Indexed: 12/13/2022] Open
Abstract
The protozoan parasite Giardia duodenalis is responsible for more than 280 million cases of gastrointestinal complaints ("giardiasis") every year, worldwide. Infections are acquired orally, mostly via uptake of cysts in contaminated drinking water. After transformation into the trophozoite stage, parasites start to colonize the duodenum and upper jejunum where they attach to the intestinal epithelium and replicate vegetatively. Outcome of Giardia infections vary between individuals, from self-limiting to chronic, and asymptomatic to severely symptomatic infection, with unspecific gastrointestinal complaints. One proposed mechanism for pathogenesis is the breakdown of intestinal barrier function. This has been studied by analyzing trans-epithelial electric resistances (TEER) or by indicators of epithelial permeability using labeled sugar compounds in in vitro cell culture systems, mouse models or human biopsies and epidemiological studies. Here, we discuss the results obtained mainly with epithelial cell models to highlight contradictory findings. We relate published studies to our own findings that suggest a lack of barrier compromising activities of recent G. duodenalis isolates of assemblage A, B, and E in a Caco-2 model system. We propose that this epithelial cell model be viewed as mimicking asymptomatic infection. This view will likely lead to a more informative use of the model if emphasis is shifted from aiming to identify Giardia virulence factors to defining non-parasite factors that arguably appear to be more decisive for disease.
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Affiliation(s)
- Martin R Kraft
- Unit 16 Mycotic and Parasitic Agents and Mycobacteria, Robert Koch-Institute, Berlin, Germany.,Institute of Clinical Physiology, Charité Campus Benjamin Franklin, Berlin, Germany
| | - Christian Klotz
- Unit 16 Mycotic and Parasitic Agents and Mycobacteria, Robert Koch-Institute, Berlin, Germany
| | - Roland Bücker
- Institute of Clinical Physiology, Charité Campus Benjamin Franklin, Berlin, Germany
| | - Jörg-Dieter Schulzke
- Institute of Clinical Physiology, Charité Campus Benjamin Franklin, Berlin, Germany
| | - Toni Aebischer
- Unit 16 Mycotic and Parasitic Agents and Mycobacteria, Robert Koch-Institute, Berlin, Germany
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Jiang K, Zhang T, Yin N, Ma X, Zhao G, Wu H, Qiu C, Deng G. Geraniol alleviates LPS-induced acute lung injury in mice via inhibiting inflammation and apoptosis. Oncotarget 2017; 8:71038-71053. [PMID: 29050341 PMCID: PMC5642616 DOI: 10.18632/oncotarget.20298] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2017] [Accepted: 07/19/2017] [Indexed: 12/28/2022] Open
Abstract
Geraniol (GOH), a special type of acyclic monoterpene alcohol, has been widely used to treat many diseases associated with inflammation and apoptosis. Acute lung injury (ALI) is a common clinical disease in humans characterized by pulmonary inflammation and apoptosis. In the present study, we investigated the protective effects of GOH in a mouse model of ALI induced by the intranasal administration of lipopolysaccharide (LPS) and elucidated the underlying molecular mechanisms in RAW 264.7 cells. In vivo, GOH treatment markedly ameliorated pathological injury and pulmonary cell apoptosis and reduced the wet/dry (W/D) weight ratio of lungs, myeloperoxidase (MPO) activity and the production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α). In vitro, the levels of pro-inflammatory cytokines, iNOS and COX-2 were significantly increased in LPS-stimulated RAW 264.7 cells, an effect that was decreased by GOH treatment. Moreover, GOH treatment dramatically reduced the expression of Toll-like receptor 4 (TLR4) and then prevented the nuclear factor-κB (NF-κB) activation. GOH treatment also promoted anti-apoptotic Bcl-2 expression and inhibited pro-apoptotic Bax and Caspase-3 expression. Furthermore, knockdown of TLR4 expression exerted a similar effect and inhibited the phosphorylation of p65, as well as the Bax and Caspase-3 expression. Taken together, these results suggest that GOH treatment alleviates LPS-induced ALI via inhibiting pulmonary inflammation and apoptosis, a finding that might be associated with the inhibition of TLR4-mediated NF-κB and Bcl-2/Bax signalling pathways.
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Affiliation(s)
- Kangfeng Jiang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Tao Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Nannan Yin
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Xiaofei Ma
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Gan Zhao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Haichong Wu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Changwei Qiu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Ganzhen Deng
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
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Chiappisi E, Ringseis R, Eder K, Gessner DK. Effect of endoplasmic reticulum stress on metabolic and stress signaling and kidney-specific functions in Madin-Darby bovine kidney cells. J Dairy Sci 2017. [PMID: 28624282 DOI: 10.3168/jds.2016-12406] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Recent studies demonstrated induction of endoplasmic reticulum (ER) stress in tissues of cows after parturition, but knowledge about the effect of ER stress on important cellular processes, such as critical signaling and metabolic pathways, in cattle is scarce. Thus, the present study aimed to investigate the effect of ER stress induction on nuclear factor-κB (NF-κB), nuclear factor E2-related factor 2 (Nrf2), and sterol regulatory element-binding protein (SREBF1) pathway in Madin-Darby bovine kidney (MDBK) cells, a widely used in vitro model in ruminant research. To consider the kidney origin of MDBK cells, the effect on renal distal tubular cell-specific functions, such as transport processes and regulation of 1,25(OH)2D3 levels, was also studied. Treatment of MDBK cells with 2 different ER stress inducers, thapsigargin (TG) and tunicamycin (TM), strongly induced ER stress as evident from induction of ER stress target genes, increased phosphorylation of PKR-like ER kinase, and enhanced splicing of X-box binding protein 1. The TM decreased the protein concentration of NF-κB p50 and the mRNA levels of the NF-κB target genes. Likewise, TG decreased the mRNA concentration of tumor necrosis factor and tended to decrease NF-κB p50 protein and mRNA levels of NF-κB target genes. The mRNA levels of most of the Nrf2 target genes investigated were reduced by TG and TM in MDBK cells. Both ER stress inducers reduced the mRNA levels of SREBF1 and its target genes in MDBK cells. Interestingly, TG decreased, but TM increased the mRNA level of the Ca2+ binding protein calbindin 1, whereas the mRNA level of the plasma membrane Ca2+-transporting ATPase 1 remained unchained. The mRNA level of the cytochrome P450 component 24A1 involved in 1α-hydroxylation of 25(OH)D3 was strongly elevated, whereas the mRNA level of the cytochrome P450 component 27A1 catalyzing the breakdown of 1,25(OH)2D3 was markedly reduced by both ER stress inducers. The concentration of 1,25(OH)2D3 in the supernatant of MDBK cells was increased by approximately 15% by both TG and TM. The present study indicates that under conditions of ER stress, critical signaling pathways, such as NF-κB, Nrf2, and SREBF1, are inhibited, whereas the formation of 1,25(OH)2D3 is stimulated in bovine MDBK cells. Future studies are necessary to clarify the physiological relevance of these findings.
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Affiliation(s)
- E Chiappisi
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany
| | - R Ringseis
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany
| | - K Eder
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany
| | - D K Gessner
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany.
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Effects of Dexmedetomidine on Intestinal Microcirculation and Intestinal Epithelial Barrier in Endotoxemic Rats. Anesthesiology 2017; 125:355-67. [PMID: 27111533 DOI: 10.1097/aln.0000000000001135] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Dexmedetomidine reduces cytokine production in septic patients and reduces inflammation and mortality in experimental models of endotoxemia and sepsis. This study investigated whether dexmedetomidine attenuates endothelial dysfunction, intestinal microcirculatory dysfunction, and intestinal epithelial barrier disruption in endotoxemic rats. METHODS Ninety-two male Wistar rats were randomly assigned to the following four groups: (1) Sham; (2) lipopolysaccharide, received IV lipopolysaccharide 15 and 10 mg/kg at 0 and 120 min; (3) dexmedetomidine, received IV dexmedetomidine for 240 min; and (4) lipopolysaccharide + dexmedetomidine, received both lipopolysaccharide and dexmedetomidine. Sidestream dark-field videomicroscope, tissue oxygen monitor, and full-field laser perfusion image were used to investigate the microcirculation of the terminal ileum. Serum endocan level was measured. The Ussing chamber permeability assay, lumen-to-blood gadodiamide passage by magnetic resonance imaging, and bacterial translocation were conducted to determine epithelial barrier function. Mucosal apoptotic levels and tight junctional integrity were also examined. RESULTS The density of perfused small vessels in mucosa, serosal muscular layer, and Peyer patch in the lipopolysaccharide + dexmedetomidine group was higher than that of the lipopolysaccharide group. Serum endocan level was lower in the lipopolysaccharide + dexmedetomidine group than in the lipopolysaccharide group. Mucosal ratio of cleaved to full-length occludin and spleen bacterial counts were significantly lower in the lipopolysaccharide + dexmedetomidine group than in the lipopolysaccharide group. CONCLUSION The study finding suggests that dexmedetomidine protects against intestinal epithelial barrier disruption in endotoxemic rats by attenuating intestinal microcirculatory dysfunction and reducing mucosal cell death and tight junctional damage. (Anesthesiology 2016; 125:355-67).
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Effects of isoleucine on glucose uptake through the enhancement of muscular membrane concentrations of GLUT1 and GLUT4 and intestinal membrane concentrations of Na+/glucose co-transporter 1 (SGLT-1) and GLUT2. Br J Nutr 2017; 116:593-602. [PMID: 27464458 DOI: 10.1017/s0007114516002439] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Knowledge of regulation of glucose transport contributes to our understanding of whole-body glucose homoeostasis and human metabolic diseases. Isoleucine has been reported to participate in regulation of glucose levels in many studies; therefore, this study was designed to examine the effect of isoleucine on intestinal and muscular GLUT expressions. In an animal experiment, muscular GLUT and intestinal GLUT were determined in weaning pigs fed control or isoleucine-supplemented diets. Supplementation of isoleucine in the diet significantly increased piglet average daily gain, enhanced GLUT1 expression in red muscle and GLUT4 expression in red muscle, white muscle and intermediate muscle (P<0·05). In additional, expressions of Na+/glucose co-transporter 1 and GLUT2 were up-regulated in the small intestine when pigs were fed isoleucine-supplemented diets (P<0·05). C2C12 cells were used to examine the expressions of muscular GLUT and glucose uptake in vitro. In C2C12 cells supplemented with isoleucine in the medium, cellular 2-deoxyglucose uptake was increased (P<0·05) through enhancement of the expressions of GLUT4 and GLUT1 (P<0·05). The effect of isoleucine was greater than that of leucine on glucose uptake (P<0·05). Compared with newborn piglets, 35-d-old piglets have comparatively higher GLUT4, GLUT2 and GLUT5 expressions. The results of this study demonstrated that isoleucine supplementation enhanced the intestinal and muscular GLUT expressions, which have important implications that suggest that isoleucine could potentially increase muscle growth and intestinal development by enhancing local glucose uptake in animals and human beings.
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Strategies to promote abundance of Akkermansia muciniphila, an emerging probiotics in the gut, evidence from dietary intervention studies. J Funct Foods 2017; 33:194-201. [PMID: 30416539 DOI: 10.1016/j.jff.2017.03.045] [Citation(s) in RCA: 207] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Akkermansia muciniphila is a mucin-degrading bacterium commonly found in human gut. A. muciniphila has been inversely associated with obesity, diabetes, inflammation, and metabolic disorders. Due to its highly promising probiotic activities against obesity and diabetes, A. muciniphila has drawn intensive interest for research and development in recent years. A number of human and animal studies have shown that the abundance of A. muciniphila in the gut can be enhanced through dietary interventions. The present review focuses on evidence-based dietary strategies of improving A. muciniphila abundance in the gut by critically appraising up-to-date available human and animal intervention studies on A. muciniphila growth and their impact on risk factors of obesity and diabetes. Their potential mechanisms in promoting A. muciniphila are also discussed along with the discussions of mechanism of action for A. muciniphila to exert probiotic functions.
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Beatty JK, Akierman SV, Motta JP, Muise S, Workentine ML, Harrison JJ, Bhargava A, Beck PL, Rioux KP, McKnight GW, Wallace JL, Buret AG. Giardia duodenalis induces pathogenic dysbiosis of human intestinal microbiota biofilms. Int J Parasitol 2017; 47:311-326. [PMID: 28237889 DOI: 10.1016/j.ijpara.2016.11.010] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 11/12/2016] [Accepted: 11/17/2016] [Indexed: 02/07/2023]
Abstract
Giardia duodenalis is a prevalent cause of acute diarrheal disease worldwide. However, recent outbreaks in Italy and Norway have revealed a link between giardiasis and the subsequent development of chronic post-infectious irritable bowel syndrome. While the mechanisms underlying the causation of post-infectious irritable bowel syndrome remain obscure, recent findings suggest that alterations in gut microbiota communities are linked to the pathophysiology of irritable bowel syndrome. In the present study, we use a laboratory biofilm system to culture and enrich mucosal microbiota from human intestinal biopsies. Subsequently, we show that co-culture with Giardia induces disturbances in biofilm species composition and biofilm structure resulting in microbiota communities that are intrinsically dysbiotic - even after the clearance of Giardia. These microbiota abnormalities were mediated in part by secretory-excretory Giardia cysteine proteases. Using in vitro cell culture and germ-free murine infection models, we show that Giardia-induced disruptions of microbiota promote bacterial invasion, resulting in epithelial apoptosis, tight junctional disruption, and bacterial translocation across an intestinal epithelial barrier. Additionally, these dysbiotic microbiota communities resulted in increased activation of the Toll-like receptor 4 signalling pathway, and overproduction of the pro-inflammatory cytokine IL-1beta in humanized germ-free mice. Previous studies that have sought explanations and risk factors for the development of post-infectious irritable bowel syndrome have focused on features of enteropathogens and attributes of the infected host. We propose that polymicrobial interactions involving Giardia and gut microbiota may cause persistent dysbiosis, offering a new interpretation of the reasons why those afflicted with giardiasis are predisposed to gastrointestinal disorders post-infection.
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Affiliation(s)
- Jennifer K Beatty
- Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Sarah V Akierman
- Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Jean-Paul Motta
- Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 4N1, Canada; Department of Physiology & Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Stacy Muise
- Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Matthew L Workentine
- Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Joe J Harrison
- Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Amol Bhargava
- Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Paul L Beck
- Department of Medicine, Division of Gastroenterology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Kevin P Rioux
- Department of Medicine, Division of Gastroenterology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Gordon Webb McKnight
- Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada
| | - John L Wallace
- Department of Physiology & Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada
| | - Andre G Buret
- Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 4N1, Canada; Department of Physiology & Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
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50
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The Na+-D-glucose cotransporters SGLT1 and SGLT2 are targets for the treatment of diabetes and cancer. Pharmacol Ther 2017; 170:148-165. [DOI: 10.1016/j.pharmthera.2016.10.017] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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