|
1
|
Thakur BK, Malaise Y, Choudhury SR, Neustaeter A, Turpin W, Streutker C, Copeland J, Wong EOY, Navarre WW, Guttman DS, Jobin C, Croitoru K, Martin A. Dietary fibre counters the oncogenic potential of colibactin-producing Escherichia coli in colorectal cancer. Nat Microbiol 2025; 10:855-870. [PMID: 40033140 DOI: 10.1038/s41564-025-01938-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 01/14/2025] [Indexed: 03/05/2025]
Abstract
Diet, microbiome, inflammation and host genetics have been linked to colorectal cancer development; however, it is not clear whether and how these factors interact to promote carcinogenesis. Here we used Il10-/- mice colonized with bacteria previously associated with colorectal cancer: enterotoxigenic Bacteroides fragilis, Helicobacter hepaticus or colibactin-producing (polyketide synthase-positive (pks+)) Escherichia coli and fed either a low-carbohydrate (LC) diet deficient in soluble fibre, a high-fat and high-sugar diet, or a normal chow diet. Colonic polyposis was increased in mice colonized with pks+ E. coli and fed the LC diet. Mechanistically, mucosal inflammation was increased in the LC-diet-fed mice, leading to diminished colonic PPAR-γ signalling and increased luminal nitrate levels. This promoted both pks+ E. coli growth and colibactin-induced DNA damage. PPAR-γ agonists or supplementation with dietary soluble fibre in the form of inulin reverted inflammatory and polyposis phenotypes. The pks+ E. coli also induced more polyps in mismatch-repair-deficient mice by inducing a senescence-associated secretory phenotype. Moreover, oncogenic effects were further potentiated by inflammatory triggers in the mismatch-repair-deficient model. These data reveal that diet and host genetics influence the oncogenic potential of a common bacterium.
Collapse
Affiliation(s)
| | - Yann Malaise
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | | | - Anna Neustaeter
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Williams Turpin
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Catherine Streutker
- Department of Laboratory Medicine, Unity Health Toronto, Toronto, Ontario, Canada
| | - Julia Copeland
- Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, Ontario, Canada
| | - Erin O Y Wong
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - William W Navarre
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - David S Guttman
- Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, Ontario, Canada
- Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Christian Jobin
- Department of Infectious Diseases and Pathology, University of Florida College of Veterinary Medicine, Gainesville, FL, USA
| | - Kenneth Croitoru
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Alberto Martin
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|
|
2
|
Ohene-Nyako M, Persons AL, Forsyth C, Keshavarzian A, Napier TC. Matrix Metalloproteinase-9 Signaling Regulates Colon Barrier Integrity in Models of HIV Infection. J Neuroimmune Pharmacol 2024; 19:57. [PMID: 39499375 DOI: 10.1007/s11481-024-10158-2] [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: 05/24/2022] [Accepted: 10/18/2024] [Indexed: 11/07/2024]
Abstract
Infection with human immunodeficiency virus (HIV) increases risk for maladies of the gut barrier, which promotes sustained systemic inflammation even in virally controlled patients. We previously revealed morphological disorganization of colon epithelial barrier proteins in HIV-1 transgenic (Tg) rats. The current study evaluated mechanisms that may underlie gut barrier pathology induced by toxic HIV-1 proteins. Methamphetamine (meth) use is prevalent among HIV-infected individuals, and meth can exaggerate morbidity of HIV infection. Thus, we determined whether meth exposure worsened HIV-associated gut pathology using colon samples from HIV-1 Tg and non-Tg rats that self-administered meth 2 h/day for 21 days. Immunoblotting was conducted for occludin (a gut barrier protein) and matrix metalloproteinase-9 (MMP-9; a proteinase regulator of occludin). Colon levels of occludin were decreased, and MMP-9 levels and activity were increased in HIV-1 Tg rats. A Pearson correlation revealed an inverse relationship between occludin levels and MMP-9 activity. Doses of meth that were self-administered by Tg rats were lower than other rat models. Meth-induced trends in non-Tg rats were not significant, and meth did not exaggerate effects seen in Tg rats. Accordingly, only the HIV-effects on epithelial function were explored further. Transepithelial resistance (TER) across a monolayer of human colon epithelial cells (Caco-2) was used to examine treatments with the HIV-1 toxic protein, Tat, and the ability of pioglitazone, a PPARγ agonist that inhibits MMP-9, to mitigate Tat-induced changes. Exposure to Tat for 24 h decreased TER, which co-occurred with decreases in levels of barrier tight junction proteins (occludin, claudin-1, and zonula occludens-1) and with increases in the level and activity of MMP-9. Pretreatment or post-treatment with pioglitazone respectively prevented and restored Tat-induced impairments of Caco-2 barrier. Thus, while low doses of meth did not alter barrier proteins in the current study, exposure to HIV-1 proteins disrupted the gut barrier, and this action involved a dysregulation of MMP-9.
Collapse
Affiliation(s)
- Michael Ohene-Nyako
- Department of Pharmacology, Rush University Medical Center, 1735 W. Harrison Street Cohn Research Building Suite #424, Chicago, IL, 60612, USA
- The Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298-0614, USA
| | - Amanda L Persons
- Department of Physician Assistant Studies, Rush University Medical Center, Chicago, IL, USA
- The Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA
| | - Christopher Forsyth
- Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, IL, USA
- Department of Anatomy & Cell Biology, Rush University Medical Center, Chicago, IL, USA
- The Center for Integrated Microbiome & Chronobiology Research, Rush University Medical Center, Chicago, IL, USA
| | - Ali Keshavarzian
- Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, IL, USA
- Department of Anatomy & Cell Biology, Rush University Medical Center, Chicago, IL, USA
- Department of Physiology and Biophysics, Rush University Medical Center, Chicago, IL, USA
- The Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA
| | - T Celeste Napier
- Department of Pharmacology, Rush University Medical Center, 1735 W. Harrison Street Cohn Research Building Suite #424, Chicago, IL, 60612, USA.
- Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL, USA.
- The Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA.
| |
Collapse
|
|
3
|
Wang M, Sun P, Chai X, Liu YX, Li L, Zheng W, Chen S, Zhu X, Zhao S. Reconstituting gut microbiota-colonocyte interactions reverses diet-induced cognitive deficits: The beneficial of eucommiae cortex polysaccharides. Theranostics 2024; 14:4622-4642. [PMID: 39239516 PMCID: PMC11373620 DOI: 10.7150/thno.99468] [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: 06/11/2024] [Accepted: 07/22/2024] [Indexed: 09/07/2024] Open
Abstract
Rationale: Consumption of a high-fat diet (HFD) has been implicated in cognitive deficits and gastrointestinal dysfunction in humans, with the gut microbiota emerging as a pivotal mediator of these diet-associated pathologies. The introduction of plant-based polysaccharides into the diet as a therapeutic strategy to alleviate such conditions is gaining attention. Nevertheless, the mechanistic paradigm by which polysaccharides modulate the gut microbiota remains largely undefined. This study investigated the mechanisms of action of Eucommiae cortex polysaccharides (EPs) in mitigating gut dysbiosis and examined their contribution to rectifying diet-related cognitive decline. Methods: Initially, we employed fecal microbiota transplantation (FMT) and gut microbiota depletion to verify the causative role of changes in the gut microbiota induced by HFD in synapse engulfment-dependent cognitive impairments. Subsequently, colonization of the gut of chow-fed mice with Escherichia coli (E. coli) from HFD mice confirmed that inhibition of Proteobacteria by EPs was a necessary prerequisite for alleviating HFD-induced cognitive impairments. Finally, supplementation of HFD mice with butyrate and treatment of EPs mice with GW9662 demonstrated that EPs inhibited the expansion of Proteobacteria in the colon of HFD mice by reshaping the interactions between the gut microbiota and colonocytes. Results: Findings from FMT and antibiotic treatments demonstrated that HFD-induced cognitive impairments pertaining to neuronal spine loss were contingent on gut microbial composition. Association analysis revealed strong associations between bacterial taxa belonging to the phylum Proteobacteria and cognitive performance in mice. Further, introducing E. coli from HFD-fed mice into standard diet-fed mice underscored the integral role of Proteobacteria proliferation in triggering excessive synaptic engulfment-related cognitive deficits in HFD mice. Crucially, EPs effectively counteracted the bloom of Proteobacteria and subsequent neuroinflammatory responses mediated by microglia, essential for cognitive improvement in HFD-fed mice. Mechanistic insights revealed that EPs promoted the production of bacteria-derived butyrate, thereby ameliorating HFD-induced colonic mitochondrial dysfunction and reshaping colonocyte metabolism. This adjustment curtailed the availability of growth substrates for facultative anaerobes, which in turn limited the uncontrolled expansion of Proteobacteria. Conclusions: Our study elucidates that colonocyte metabolic disturbances, which promote Proteobacteria overgrowth, are a likely cause of HFD-induced cognitive deficits. Furthermore, dietary supplementation with EPs can rectify behavioral dysfunctions associated with HFD by modifying gut microbiota-colonocyte interactions. These insights contribute to the broader understanding of the modulatory effects of plant prebiotics on the microbiota-gut-brain axis and suggest a potential therapeutic avenue for diet-associated cognitive dysfunction.
Collapse
Affiliation(s)
- Mengli Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Penghao Sun
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Xuejun Chai
- College of Basic Medicine, Xi'an Medical University, Xi'an, Shaanxi 710000, China
| | - Yong-Xin Liu
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, Guangdong 518120, China
| | - Luqi Li
- Life Science Research Core Services, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Wei Zheng
- College of Resources and Environment Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Shulin Chen
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Xiaoyan Zhu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Shanting Zhao
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| |
Collapse
|
|
4
|
Chen T. Unveiling the significance of inducible nitric oxide synthase: Its impact on cancer progression and clinical implications. Cancer Lett 2024; 592:216931. [PMID: 38701892 DOI: 10.1016/j.canlet.2024.216931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/14/2024] [Accepted: 04/29/2024] [Indexed: 05/05/2024]
Abstract
The intricate role of inducible nitric oxide synthase (iNOS) in cancer pathophysiology has garnered significant attention, highlighting the complex interplay between tumorigenesis, immune response, and cellular metabolism. As an enzyme responsible for producing nitric oxide (NO) in response to inflammatory stimuli. iNOS is implicated in various aspects of cancer development, including DNA damage, angiogenesis, and evasion of apoptosis. This review synthesizes the current findings from both preclinical and clinical studies on iNOS across different cancer types, reflecting the variability depending on cellular context and tumor microenvironment. We explore the molecular mechanisms by which iNOS modulates cancer cell growth, survival, and metastasis, emphasizing its impact on immune surveillance and response to treatment. Additionally, the potential of targeting iNOS as a therapeutic strategy in cancer treatment is examined. By integrating insights from recent advances, this review aims to elucidate the significant role of iNOS in cancer and pave the way for novel diagnostic and therapeutic approaches.
Collapse
Affiliation(s)
- Tong Chen
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, 43210, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA.
| |
Collapse
|
|
5
|
Hamilton HL, Kinscherf NA, Balmer G, Bresque M, Salamat SM, Vargas MR, Pehar M. FABP7 drives an inflammatory response in human astrocytes and is upregulated in Alzheimer's disease. GeroScience 2024; 46:1607-1625. [PMID: 37688656 PMCID: PMC10828232 DOI: 10.1007/s11357-023-00916-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 08/15/2023] [Indexed: 09/11/2023] Open
Abstract
Alzheimer's disease (AD), the most common cause of dementia in the elderly, is characterized by the accumulation of intracellular neurofibrillary tangles, extracellular amyloid plaques, and neuroinflammation. In partnership with microglial cells, astrocytes are key players in the regulation of neuroinflammation. Fatty acid binding protein 7 (FABP7) belongs to a family of conserved proteins that regulate lipid metabolism, energy homeostasis, and inflammation. FABP7 expression is largely restricted to astrocytes and radial glia-like cells in the adult central nervous system. We observed that treatment of primary hippocampal astrocyte cultures with amyloid β fragment 25-35 (Aβ25-35) induces FABP7 upregulation. In addition, FABP7 expression is upregulated in the brain of APP/PS1 mice, a widely used AD mouse model. Co-immunostaining with specific astrocyte markers revealed increased FABP7 expression in astrocytes. Moreover, astrocytes surrounding amyloid plaques displayed increased FABP7 staining when compared to non-plaque-associated astrocytes. A similar result was obtained in the brain of AD patients. Whole transcriptome RNA sequencing analysis of human astrocytes differentiated from induced pluripotent stem cells (i-astrocytes) overexpressing FABP7 identified 500 transcripts with at least a 2-fold change in expression. Gene Ontology enrichment analysis identified (i) positive regulation of cytokine production and (ii) inflammatory response as the top two statistically significant overrepresented biological processes. We confirmed that wild-type FABP7 overexpression induces an NF-κB-driven inflammatory response in human i-astrocytes. On the other hand, the expression of a ligand-binding impaired mutant FABP7 did not induce NF-κB activation. Together, our results suggest that the upregulation of FABP7 in astrocytes could contribute to the neuroinflammation observed in AD.
Collapse
Affiliation(s)
- Haylee L Hamilton
- Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin-Madison, 600 Highland Avenue, CSC K6/447, Madison, WI, 53792, USA
- Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Noah A Kinscherf
- Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin-Madison, 600 Highland Avenue, CSC K6/447, Madison, WI, 53792, USA
| | - Garrett Balmer
- Department of Neurology, University of Wisconsin-Madison, Madison, WI, USA
| | - Mariana Bresque
- Department of Neurology, University of Wisconsin-Madison, Madison, WI, USA
| | - Shahriar M Salamat
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA
- Department of Neurological Surgery, University of Wisconsin Madison, Madison, WI, USA
| | - Marcelo R Vargas
- Department of Neurology, University of Wisconsin-Madison, Madison, WI, USA
| | - Mariana Pehar
- Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin-Madison, 600 Highland Avenue, CSC K6/447, Madison, WI, 53792, USA.
- Geriatric Research Education Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
| |
Collapse
|
|
6
|
Su Z, Wang J, Xiao C, Zhong W, Liu J, Liu X, Zhu YZ. Functional role of Ash2l in oxLDL induced endothelial dysfunction and atherosclerosis. Cell Mol Life Sci 2024; 81:62. [PMID: 38280036 PMCID: PMC10821849 DOI: 10.1007/s00018-024-05130-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 01/11/2024] [Accepted: 01/15/2024] [Indexed: 01/29/2024]
Abstract
Endothelial injury and dysfunction in the artery wall fuel the process of atherosclerosis. As a key epigenetic regulator, Ash2l (Absent, small, or homeotic-Like 2) is involved in regulating vascular injury and its complications. However, the role of Ash2l in atherosclerosis has not yet been fully elucidated. Here, we found increased Ash2l expression in high-cholesterol diet-fed ApoE-/- mice and oxidized LDL (oxLDL) treated endothelial cells (ECs). Furthermore, Ash2l promoted the scavenger receptors transcription by catalyzing histone H3 lysine 4 (H3K4) trimethylation at the promoter region of transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) and triggered the activation of the pro-inflammatory nuclear factor-kappa B (NF-κB) by enhancing interaction between CD36 and toll-like receptor 4 (TLR4). Meanwhile, enhanced expression of scavenger receptors drove more oxLDL uptake by ECs. In vivo studies revealed that ECs-specific Ash2l knockdown reduced atherosclerotic lesion formation and promoted fibrous cap stability in the aorta of ApoE-/- mice, which was partly associated with a reduced endothelial activation by suppressing scavenger receptors and the uptake of lipids by ECs. Collectively, our findings identify Ash2l as a novel regulator that mediates endothelial injury and atherosclerosis. Targeting Ash2l may provide valuable insights for developing novel therapeutic candidates for atherosclerosis.
Collapse
Affiliation(s)
- Zhenghua Su
- School of Pharmacy, Human Phenome Institute, Fudan University, Shanghai, 201203, China
| | - Jinghuan Wang
- School of Pharmacy, Human Phenome Institute, Fudan University, Shanghai, 201203, China
| | - Chenxi Xiao
- School of Pharmacy, Human Phenome Institute, Fudan University, Shanghai, 201203, China
| | - Wen Zhong
- School of Pharmacy, Human Phenome Institute, Fudan University, Shanghai, 201203, China
| | - Jiayao Liu
- School of Pharmacy, Human Phenome Institute, Fudan University, Shanghai, 201203, China
| | - Xinhua Liu
- School of Pharmacy, Human Phenome Institute, Fudan University, Shanghai, 201203, China.
- Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, 825, Zhangheng Road, Pudong New District, Shanghai, China.
| | - Yi Zhun Zhu
- School of Pharmacy, Human Phenome Institute, Fudan University, Shanghai, 201203, China.
- State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy and 1st affiliate hospital, Macau University of Science and Technology, Macau, China.
- School of Pharmacy, Macau University of Science and Technology Taipa, Macau, China.
| |
Collapse
|
|
7
|
Qi J, Li L, Yan X, Hua W, Zhou Z. Sappanone A Alleviates the Severity of Carbon Tetrachloride-Induced Liver Fibrosis in Mice. Antioxidants (Basel) 2023; 12:1718. [PMID: 37760020 PMCID: PMC10526100 DOI: 10.3390/antiox12091718] [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: 07/14/2023] [Revised: 08/28/2023] [Accepted: 09/01/2023] [Indexed: 09/29/2023] Open
Abstract
Liver fibrosis is a major challenge to global health because of its various complications, including cirrhosis and hepatocarcinoma, while no effective treatment is available for it. Sappanone A (SA) is a homoisoflavonoid extracted from the heartwood of Caesalpinia sappan Linn. with anti-inflammatory and antioxidant properties. However, the effects of SA on hepatic fibrosis remain unknown. This study aimed to investigate the protective effects of SA on carbon tetrachloride (CCl4)-induced liver fibrosis in mice. To establish a liver fibrosis model, mice were treated intraperitoneally (i.p.) with CCl4 for 4 weeks. SA (25, 50, and 100 mg/kg body weight) was i.p. injected every other day during the same period. Our data indicated that SA decreased liver injury, fibrotic responses, and inflammation due to CCl4 exposure. Consistently, SA reduced oxidative stress and its-mediated hepatocyte death in fibrotic livers. Of note, SA could not directly affect the activation of hepatic stellate cells. Mechanistically, SA treatment lessened oxidative stress-triggered cell death in hepatocytes after CCl4 exposure. SA down-regulated the expression of M1 macrophage polarization markers (CD86 and iNOS) and up-regulated the expression of M2 macrophage polarization markers (CD163, IL-10, and Arg1) in livers and macrophages. Meanwhile, SA induced the activation of peroxisome proliferator-activated receptor gamma (PPARγ). However, decreased inflammatory responses and the trend of M2 macrophage polarization provided by SA were substantially abolished by SR202 (a PPARγ inhibitor) treatment in macrophages. Additionally, SA treatment promoted fibrosis regression. Taken together, our findings revealed that treatment with SA alleviated CCl4-induced fibrotic liver in mice through suppression of oxidative stress-mediated hepatocyte death and promotion of M2 macrophage polarization via PPARγ. Thus, SA might pave the way for a new hepatoprotective agent to treat liver fibrosis.
Collapse
Affiliation(s)
- Jing Qi
- Department of Biochemistry and Molecular Biology, The School of Basic Medical Sciences, Fujian Medical University, No. 1, Xuefu North Road, University Town, Fuzhou 350122, China;
| | - Lanqian Li
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China; (L.L.); (W.H.)
| | - Xueqing Yan
- Department of Biochemistry and Molecular Biology, The School of Basic Medical Sciences, Fujian Medical University, No. 1, Xuefu North Road, University Town, Fuzhou 350122, China;
| | - Wenxi Hua
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China; (L.L.); (W.H.)
- Diagnostic Pathology Center, Fujian Medical University, Fuzhou 350122, China
| | - Zixiong Zhou
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China; (L.L.); (W.H.)
- Diagnostic Pathology Center, Fujian Medical University, Fuzhou 350122, China
| |
Collapse
|
|
8
|
Souza-Tavares H, Miranda CS, Vasques-Monteiro IML, Sandoval C, Santana-Oliveira DA, Silva-Veiga FM, Fernandes-da-Silva A, Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas. World J Gastroenterol 2023; 29:4136-4155. [PMID: 37475842 PMCID: PMC10354577 DOI: 10.3748/wjg.v29.i26.4136] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/26/2023] [Accepted: 06/13/2023] [Indexed: 07/10/2023] Open
Abstract
The world is experiencing reflections of the intersection of two pandemics: Obesity and coronavirus disease 2019. The prevalence of obesity has tripled since 1975 worldwide, representing substantial public health costs due to its comorbidities. The adipose tissue is the initial site of obesity impairments. During excessive energy intake, it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs. The pancreas is one of the organs most affected by obesity. Once lipotoxicity becomes chronic, there is an increase in insulin secretion by pancreatic beta cells, a surrogate for type 2 diabetes mellitus (T2DM). These alterations threaten the survival of the pancreatic islets, which tend to become dysfunctional, reaching exhaustion in the long term. As for the liver, lipotoxicity favors lipogenesis and impairs beta-oxidation, resulting in hepatic steatosis. This silent disease affects around 30% of the worldwide population and can evolve into end-stage liver disease. Although therapy for hepatic steatosis remains to be defined, peroxisome proliferator-activated receptors (PPARs) activation copes with T2DM management. Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways, leading to insulin resistance relief, improved thermogenesis, and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation. This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases, focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.
Collapse
Affiliation(s)
| | | | | | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Osorno 5310431, Chile
- Departamento de Ciencias Preclínicas, Universidad de la Frontera, Temuco 4780000, Chile
| | | | | | | | - Vanessa Souza-Mello
- Department of Anatomy, Rio de Janeiro State University, Rio de Janeiro 20551030, Brazil
| |
Collapse
|
|
9
|
Tang J, Li X, Li W, Cao C. Octanoic Acid-rich Enteral Nutrition Alleviated Acute Liver Injury Through PPARγ/STAT-1/MyD88 Pathway in Endotoxemic Rats. In Vivo 2023; 37:1609-1618. [PMID: 37369501 PMCID: PMC10347904 DOI: 10.21873/invivo.13246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023]
Abstract
BACKGROUND/AIM Acute liver injury is the hallmark of organ failure in sepsis. Enteral nutrition (EN) is an important clinical therapeutic measure in septic patients. However, the therapeutic effect of EN alone is not obvious. Here, we investigated whether octanoic acid (OA)-rich EN alleviated acute liver injury through PPARγ/STAT-1/MyD88 pathway in endotoxemic rats. MATERIALS AND METHODS First, rats were randomly divided into four groups: Sham, Lipopolysaccharide (LPS), LPS+EN and LPS+EN+OA groups to investigate the effect of OA-rich EN on LPS-induced acute liver injury in endotoxemic rats. Then rats were randomly divided into five groups: Sham, LPS, LPS+EN+OA, LPS+EN+OA+SR202 (SR) and LPS+ pioglitazone (PI) groups to examine whether OA-rich EN alleviated acute liver injury through the PPARγ/STAT-1/MyD88 pathway. Rats received nutrition support via a gastric tube for 3 days. We evaluated the liver histology, apoptosis, liver enzymes and inflammatory cytokine levels in the liver and serum. PPARγ/STAT-1/MyD88 pathway was also measured. RESULTS OA-rich EN inhibited the phosphorylation of STAT-1 and the activity of MyD88 by activating PPARγ and alleviating LPS-induced acute liver injury more effectively than EN alone in endotoxemic rats. The use of SR counteracted the effect of OA-rich EN on acute liver injury. Meanwhile, PI showed effects similar to OA-rich EN in endotoxemic rats. CONCLUSION OA-rich EN alleviated acute liver injury through PPARγ/STAT-1/MyD88 pathway in endotoxemic rats.
Collapse
Affiliation(s)
- Jiabao Tang
- Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Xiaohua Li
- Department of Thyroid and Breast Surgery, Suzhou Wuzhong People's Hospital, Suzhou, P.R. China
| | - Wei Li
- Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, P.R. China;
| | - Chun Cao
- Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, P.R. China;
| |
Collapse
|
|
10
|
Zhou HF, Yang C, Li JY, He YY, Huang Y, Qin RJ, Zhou QL, Sun F, Hu DS, Yang J. Quercetin serves as the major component of Xiang-lian Pill to ameliorate ulcerative colitis via tipping the balance of STAT1/PPARγ and dictating the alternative activation of macrophage. JOURNAL OF ETHNOPHARMACOLOGY 2023; 313:116557. [PMID: 37142141 DOI: 10.1016/j.jep.2023.116557] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 05/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The traditional Chinese herbal formula, Xiang-lian Pill (XLP), is commonly prescribed for ulcerative colitis (UC) patients to relieve their clinical symptom. Nonetheless, the underlying cellular and molecular mechanisms of XLP's anti-UC effect remain incompletely understood. AIM OF THE STUDY To evaluate the therapeutic effect and elucidate the possible working mechanisms of XLP in UC treatment. The major active component of XLP was also characterized. MATERIALS AND METHODS Colitis was induced in C57BL/6 mice with 3% dextran sulfate sodium (DSS) dissolved in drinking water for 7 consecutive days. The UC mice were grouped and treated with XLP (3640 mg/kg) or vehicle orally during the procedure of DSS induction. Mouse body weight, disease activity index (DAI) score and colon length were recorded. Histopathological changes and inflammatory cell infiltration were evaluated by pathological staining and flow cytometric analysis (FACS). Network pharmacology, bioinformatic analysis, widely targeted and targeted metabolomics analysis were performed to screen the potential effective ingredients and key targets. Bone marrow derived macrophages (BMDMs), peripheral blood mononuclear cells (PBMCs), RAW264.7 and THP-1 cells were used to dissect the anti-inflammatory effect of XLP. RESULTS Oral administration of XLP ameliorated DSS induced mouse colitis, as evidenced by reduced DAI and colonic inflammatory destruction. FACS results demonstrated that XLP treatment effectively restored immune tolerance in colon, inhibited the generation of monocyte derived macrophages and skewed macrophage polarization into M2 phenotype. Network pharmacology analysis suggested that innate effector modules related to macrophage activation comprise the major targets of XLP, and the counter-regulatory STAT1/PPARγ signaling possibly serves as the critical downstream pathway. Subsequent experiments unveiled an imbalance of STAT1/PPARγ signaling in monocytes derived from UC patients, and validated that XLP suppressed LPS/IFN-γ induced macrophage activation (STAT1 mediated) but facilitated IL-4 induced macrophage M2 polarization (PPARγ dependent). Meanwhile, our data showed that quercetin served as the major component of XLP to recapitulate the regulatory effect on macrophages. CONCLUSION Our findings revealed that quercetin serves as the major component of XLP that regulates macrophage alternative activation via tipping the balance of STAT1/PPARγ, which provides a mechanistic explanation for the therapeutic effect of XLP in UC treatment.
Collapse
Affiliation(s)
- Hai-Feng Zhou
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Chao Yang
- Department of Geratology, Hubei Provincial Hospital of Integrated Chinese & Western Medicine, Wuhan, 430015, China.
| | - Jun-Yi Li
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Yu-Yao He
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Yun Huang
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
| | - Ren-Jie Qin
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Qiao-Li Zhou
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Fei Sun
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, 430030, China.
| | - De-Sheng Hu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Jia Yang
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| |
Collapse
|
|
11
|
Su Y, Liang J, Zhang M, Zhao M, Xie X, Wang X, Pan Z, Huang S, Yan R, Wang Q, Zhou L, Luo X. Wogonin regulates colonocyte metabolism via PPARγ to inhibit Enterobacteriaceae against dextran sulfate sodium-induced colitis in mice. Phytother Res 2023; 37:872-884. [PMID: 36451541 DOI: 10.1002/ptr.7677] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 10/04/2022] [Accepted: 11/01/2022] [Indexed: 12/02/2022]
Abstract
To investigate the potential effects and mechanism of wogonin on dextran sulfate sodium (DSS)-induced colitis, 70 male mice were administered wogonin (12.5, 25, 50 mg·kg-1 ·d-1 , i.g.) for 10 days, meanwhile, in order to induce colitis, the mice were free to drink 3% DSS for 6 days. We found that wogonin could obviously ameliorate DSS-induced colitis, including preventing colon shortening and inhibiting pathological damage. In addition, wogonin could increase the expression of PPARγ, which not only restores intestinal epithelial hypoxia but also inhibits iNOS protein to reduce intestinal nitrite levels. All these effects facilitated a reduction in the abundance of Enterobacteriaceae in DSS-induced colitis mice. Therefore, compared with the DSS group, the number of Enterobacteriaceae in the intestinal flora was significantly reduced after administration of wogonin or rosiglitazone by 16s rDNA technology. We also verified that wogonin could promote the expression of PPARγ mRNA and protein in Caco-2 cells, and this effect disappeared when PPARγ signal was inhibited. In conclusion, our study suggested that wogonin can activate the PPARγ signal of the Intestinal epithelium to ameliorate the Intestinal inflammation caused by Enterobacteriaceae bacteria expansion.
Collapse
Affiliation(s)
- Yulin Su
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Junjie Liang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Meiling Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Meng Zhao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xueqian Xie
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaojing Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zengfeng Pan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shaowei Huang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Rong Yan
- Department of Gastroenterology, The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qing Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lian Zhou
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xia Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| |
Collapse
|
|
12
|
Ballav S, Biswas B, Sahu VK, Ranjan A, Basu S. PPAR-γ Partial Agonists in Disease-Fate Decision with Special Reference to Cancer. Cells 2022; 11:3215. [PMID: 36291082 PMCID: PMC9601205 DOI: 10.3390/cells11203215] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/03/2022] [Accepted: 10/09/2022] [Indexed: 11/16/2023] Open
Abstract
Peroxisome proliferator-activated receptor-γ (PPAR-γ) has emerged as one of the most extensively studied transcription factors since its discovery in 1990, highlighting its importance in the etiology and treatment of numerous diseases involving various types of cancer, type 2 diabetes mellitus, autoimmune, dermatological and cardiovascular disorders. Ligands are regarded as the key determinant for the tissue-specific activation of PPAR-γ. However, the mechanism governing this process is merely a contradictory debate which is yet to be systematically researched. Either these receptors get weakly activated by endogenous or natural ligands or leads to a direct over-activation process by synthetic ligands, serving as complete full agonists. Therefore, fine-tuning on the action of PPAR-γ and more subtle modulation can be a rewarding approach which might open new avenues for the treatment of several diseases. In the recent era, researchers have sought to develop safer partial PPAR-γ agonists in order to dodge the toxicity induced by full agonists, akin to a balanced activation. With a particular reference to cancer, this review concentrates on the therapeutic role of partial agonists, especially in cancer treatment. Additionally, a timely examination of their efficacy on various other disease-fate decisions has been also discussed.
Collapse
Affiliation(s)
- Sangeeta Ballav
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Bini Biswas
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Vishal Kumar Sahu
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Amit Ranjan
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Soumya Basu
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| |
Collapse
|
|
13
|
The Breast Cancer Protooncogenes HER2, BRCA1 and BRCA2 and Their Regulation by the iNOS/NOS2 Axis. Antioxidants (Basel) 2022; 11:antiox11061195. [PMID: 35740092 PMCID: PMC9227079 DOI: 10.3390/antiox11061195] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/01/2022] [Accepted: 06/06/2022] [Indexed: 02/04/2023] Open
Abstract
The expression of inducible nitric oxide synthase (iNOS; NOS2) and derived NO in various cancers was reported to exert pro- and anti-tumorigenic effects depending on the levels of expression and the tumor types. In humans, the breast cancer level of iNOS was reported to be overexpressed, to exhibit pro-tumorigenic activities, and to be of prognostic significance. Likewise, the expression of the oncogenes HER2, BRCA1, and BRCA2 has been associated with malignancy. The interrelationship between the expression of these protooncogenes and oncogenes and the expression of iNOS is not clear. We have hypothesized that there exist cross-talk signaling pathways between the breast cancer protooncogenes, the iNOS axis, and iNOS-mediated NO mutations of these protooncogenes into oncogenes. We review the molecular regulation of the expression of the protooncogenes in breast cancer and their interrelationships with iNOS expression and activities. In addition, we discuss the roles of iNOS, HER2, BRCA1/2, and NO metabolism in the pathophysiology of cancer stem cells. Bioinformatic analyses have been performed and have found suggested molecular alterations responsible for breast cancer aggressiveness. These include the association of BRCA1/2 mutations and HER2 amplifications with the dysregulation of the NOS pathway. We propose that future studies should be undertaken to investigate the regulatory mechanisms underlying the expression of iNOS and various breast cancer oncogenes, with the aim of identifying new therapeutic targets for the treatment of breast cancers that are refractory to current treatments.
Collapse
|
|
14
|
Leach DA, Fernandes RC, Bevan CL. Cellular specificity of androgen receptor, coregulators, and pioneer factors in prostate cancer. ENDOCRINE ONCOLOGY (BRISTOL, ENGLAND) 2022; 2:R112-R131. [PMID: 37435460 PMCID: PMC10259329 DOI: 10.1530/eo-22-0065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 09/08/2022] [Indexed: 07/13/2023]
Abstract
Androgen signalling, through the transcription factor androgen receptor (AR), is vital to all stages of prostate development and most prostate cancer progression. AR signalling controls differentiation, morphogenesis, and function of the prostate. It also drives proliferation and survival in prostate cancer cells as the tumour progresses; given this importance, it is the main therapeutic target for disseminated disease. AR is also essential in the surrounding stroma, for the embryonic development of the prostate and controlling epithelial glandular development. Stromal AR is also important in cancer initiation, regulating paracrine factors that excite cancer cell proliferation, but lower stromal AR expression correlates with shorter time to progression/worse outcomes. The profile of AR target genes is different between benign and cancerous epithelial cells, between castrate-resistant prostate cancer cells and treatment-naïve cancer cells, between metastatic and primary cancer cells, and between epithelial cells and fibroblasts. This is also true of AR DNA-binding profiles. Potentially regulating the cellular specificity of AR binding and action are pioneer factors and coregulators, which control and influence the ability of AR to bind to chromatin and regulate gene expression. The expression of these factors differs between benign and cancerous cells, as well as throughout disease progression. The expression profile is also different between fibroblast and mesenchymal cell types. The functional importance of coregulators and pioneer factors in androgen signalling makes them attractive therapeutic targets, but given the contextual expression of these factors, it is essential to understand their roles in different cancerous and cell-lineage states.
Collapse
Affiliation(s)
- Damien A Leach
- Division of Cancer, Imperial Centre for Translational & Experimental Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK
| | - Rayzel C Fernandes
- Division of Cancer, Imperial Centre for Translational & Experimental Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK
| | - Charlotte L Bevan
- Division of Cancer, Imperial Centre for Translational & Experimental Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK
| |
Collapse
|
|
15
|
Toobian D, Ghosh P, Katkar GD. Parsing the Role of PPARs in Macrophage Processes. Front Immunol 2021; 12:783780. [PMID: 35003101 PMCID: PMC8727354 DOI: 10.3389/fimmu.2021.783780] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Cells are richly equipped with nuclear receptors, which act as ligand-regulated transcription factors. Peroxisome proliferator activated receptors (PPARs), members of the nuclear receptor family, have been extensively studied for their roles in development, differentiation, and homeostatic processes. In the recent past, there has been substantial interest in understanding and defining the functions of PPARs and their agonists in regulating innate and adaptive immune responses as well as their pharmacologic potential in combating acute and chronic inflammatory disease. In this review, we focus on emerging evidence of the potential roles of the PPAR subtypes in macrophage biology. We also discuss the roles of dual and pan PPAR agonists as modulators of immune cell function, microbial infection, and inflammatory diseases.
Collapse
Affiliation(s)
- Daniel Toobian
- Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA, United States
| | - Pradipta Ghosh
- Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA, United States
- Rebecca and John Moore Comprehensive Cancer Center, University of California San Diego, San Diego, CA, United States
- Department of Medicine, University of California San Diego, San Diego, CA, United States
- Veterans Affairs Medical Center, La Jolla, CA, United States
| | - Gajanan D. Katkar
- Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA, United States
| |
Collapse
|
|
16
|
Wei YX, Zheng KY, Wang YG. Gut microbiota-derived metabolites as key mucosal barrier modulators in obesity. World J Gastroenterol 2021; 27:5555-5565. [PMID: 34588751 PMCID: PMC8433617 DOI: 10.3748/wjg.v27.i33.5555] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/24/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
A significant breakthrough in the field of obesity research was the demonstration that an obese phenotype could be manipulated by modulating the gut microbiota. An important next step is to elucidate a human-relevant “map’’ of microbiota-host interactions that regulate the metabolic health of the host. An improved understanding of this crosstalk is a prerequisite for optimizing therapeutic strategies to combat obesity. Intestinal mucosal barrier dysfunction is an important contributor to metabolic diseases and has also been found to be involved in a variety of other chronic inflammatory conditions, including cancer, neurodegeneration, and aging. The mechanistic basis for intestinal barrier dysfunction accompanying metabolic disorders remains poorly understood. Understanding the molecular and cellular modulators of intestinal barrier function will help devise improved strategies to counteract the detrimental systemic consequences of gut barrier breakage. Changes in the composition and function of the gut microbiota, i.e., dysbiosis, are thought to drive obesity-related pathogenesis and may be one of the most important drivers of mucosal barrier dysfunction. Many effects of the microbiota on the host are mediated by microbiota-derived metabolites. In this review, we focus on several relatively well-studied microbial metabolites that can influence intestinal mucosal homeostasis and discuss how they might affect metabolic diseases. The design and use of microbes and their metabolites that are locally active in the gut without systemic side effects are promising novel and safe therapeutic modalities for metabolic diseases.
Collapse
Affiliation(s)
- Yan-Xia Wei
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Kui-Yang Zheng
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Yu-Gang Wang
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| |
Collapse
|
|
17
|
Takala R, Ramji DP, Andrews R, Zhou Y, Burston J, Choy E. Anti-inflammatory and immunoregulatory effects of pinolenic acid in rheumatoid arthritis. Rheumatology (Oxford) 2021; 61:992-1004. [PMID: 34080609 PMCID: PMC8889292 DOI: 10.1093/rheumatology/keab467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 05/18/2021] [Indexed: 11/23/2022] Open
Abstract
Objectives In pre-clinical studies, pinolenic acid (PNLA), an omega-6-polyunsaturated fatty acid from pine nuts, has shown anti-inflammatory effects. We aimed to investigate the effect of PNLA in human cell lines and peripheral blood mononuclear cells (PBMCs) from RA patients and healthy controls (HCs). Methods A modified Boyden chamber was used to assess chemokine-induced migration of THP-1 monocytes. Macropinocytosis was assessed using Lucifer yellow and oxidized low-density lipoprotein (oxLDL) uptake using DiI-labelled oxLDL in THP-1 macrophages and human monocyte-derived macrophages (HMDMs). IL-6, TNF-α and prostaglandin E2 (PGE2) release by lipopolysaccharide (LPS)-stimulated PBMCs from RA patients and HCs was measured by ELISA. The transcriptomic profile of PNLA-treated, LPS-activated PBMCs was investigated by RNA-sequencing. Results PNLA reduced THP-1 cell migration by 55% (P < 0.001). Macropinocytosis and DiI-oxLDL uptake were reduced by 50% (P < 0.001) and 40% (P < 0.01), respectively, in THP-1 macrophages and 40% (P < 0.01) and 25% (P < 0.05), respectively, in HMDMs. PNLA reduced IL-6 and TNF-α release from LPS-stimulated PBMCs from RA patients by 60% (P < 0.001) and from HCs by 50% and 35%, respectively (P < 0.01). PNLA also reduced PGE2 levels in such PBMCs from RA patients and HCs (P < 0.0001). Differentially expressed genes whose expression was upregulated included pyruvate dehydrogenase kinase-4, plasminogen activator inhibitor-1, fructose bisphosphatase1 and N-Myc downstream-regulated gene-2, which have potential roles in regulating immune and metabolic pathways. Pathway analysis predicted upstream activation of the nuclear receptors peroxisome proliferator-activated receptors involved in anti-inflammatory processes, and inhibition of nuclear factor-κB and signal transducer and activator of transcription 1. Conclusions PNLA has immune-metabolic effects on monocytes and PBMCs that are pathogenic in RA and atherosclerosis. Dietary PNLA supplementation may be beneficial in RA.
Collapse
Affiliation(s)
- Rabaa Takala
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.,College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, Cardiff, UK
| | - Dipak P Ramji
- College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, Cardiff, UK
| | - Robert Andrews
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - You Zhou
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.,Systems Immunity University Research Institute, Cardiff University, Cardiff, UK
| | - James Burston
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - Ernest Choy
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.,CREATE Centre, Division of infection and immunity, School of Medicine, Cardiff University, Cardiff, UK.,University Hospital of Wales, Rheumatology, Cardiff, UK
| |
Collapse
|
|
18
|
Bago Á, Íñiguez MA, Serrador JM. Nitric Oxide and Electrophilic Cyclopentenone Prostaglandins in Redox signaling, Regulation of Cytoskeleton Dynamics and Intercellular Communication. Front Cell Dev Biol 2021; 9:673973. [PMID: 34026763 PMCID: PMC8137968 DOI: 10.3389/fcell.2021.673973] [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: 02/28/2021] [Accepted: 04/01/2021] [Indexed: 12/16/2022] Open
Abstract
Nitric oxide (NO) and electrophilic cyclopentenone prostaglandins (CyPG) are local mediators that modulate cellular response to oxidative stress in different pathophysiological processes. In particular, there is increasing evidence about their functional role during inflammation and immune responses. Although the mechanistic details about their relationship and functional interactions are still far from resolved, NO and CyPG share the ability to promote redox-based post-translational modification (PTM) of proteins that play key roles in cellular homeostasis, signal transduction and transcription. NO-induced S-nitrosylation and S-glutathionylation as well as cyclopentenone-mediated adduct formation, are a few of the main PTMs by which intra- and inter-cellular signaling are regulated. There is a growing body of evidence indicating that actin and actin-binding proteins are susceptible to covalent PTM by these agents. It is well known that the actin cytoskeleton is key for the establishment of interactions among leukocytes, endothelial and muscle cells, enabling cellular activation and migration. In this review we analyze the current knowledge about the actions exerted by NO and CyPG electrophilic lipids on the regulation of actin dynamics and cytoskeleton organization, and discuss some open questions regarding their functional relevance in the regulation of intercellular communication.
Collapse
Affiliation(s)
- Ángel Bago
- Interactions with the Environment Program, Immune System Development and Function Unit, Centro de Biología Molecular "Severo Ochoa" (CBMSO), CSIC-UAM, Madrid, Spain
| | - Miguel A Íñiguez
- Interactions with the Environment Program, Immune System Development and Function Unit, Centro de Biología Molecular "Severo Ochoa" (CBMSO), CSIC-UAM, Madrid, Spain.,Departamento de Biología Molecular, Universidad Autónoma de Madrid, Madrid, Spain
| | - Juan M Serrador
- Interactions with the Environment Program, Immune System Development and Function Unit, Centro de Biología Molecular "Severo Ochoa" (CBMSO), CSIC-UAM, Madrid, Spain
| |
Collapse
|
|
19
|
Bravo-Ruiz I, Medina MÁ, Martínez-Poveda B. From Food to Genes: Transcriptional Regulation of Metabolism by Lipids and Carbohydrates. Nutrients 2021; 13:nu13051513. [PMID: 33946267 PMCID: PMC8145205 DOI: 10.3390/nu13051513] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 04/28/2021] [Indexed: 12/31/2022] Open
Abstract
Lipids and carbohydrates regulate gene expression by means of molecules that sense these macronutrients and act as transcription factors. The peroxisome proliferator-activated receptor (PPAR), activated by some fatty acids or their derivatives, and the carbohydrate response element binding protein (ChREBP), activated by glucose-derived metabolites, play a key role in metabolic homeostasis, especially in glucose and lipid metabolism. Furthermore, the action of both factors in obesity, diabetes and fatty liver, as well as the pharmacological development in the treatment of these pathologies are indeed of high relevance. In this review we present an overview of the discovery, mechanism of activation and metabolic functions of these nutrient-dependent transcription factors in different tissues contexts, from the nutritional genomics perspective. The possibility of targeting these factors in pharmacological approaches is also discussed. Lipid and carbohydrate-dependent transcription factors are key players in the complex metabolic homeostasis, but these factors also drive an adaptive response to non-physiological situations, such as overeating. Possibly the decisive role of ChREBP and PPAR in metabolic regulation points to them as ideal therapeutic targets, but their pleiotropic functions in different tissues makes it difficult to "hit the mark".
Collapse
Affiliation(s)
- Inés Bravo-Ruiz
- Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, E-29071 Málaga, Spain; (I.B.-R.); (M.Á.M.)
| | - Miguel Ángel Medina
- Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, E-29071 Málaga, Spain; (I.B.-R.); (M.Á.M.)
- Instituto de Investigación Biomédica de Málaga (IBIMA), E-29071 Málaga, Spain
- CIBER de Enfermedades Raras (CIBERER), E-29071 Málaga, Spain
| | - Beatriz Martínez-Poveda
- Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, E-29071 Málaga, Spain; (I.B.-R.); (M.Á.M.)
- Instituto de Investigación Biomédica de Málaga (IBIMA), E-29071 Málaga, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), E-28029 Madrid, Spain
- Correspondence:
| |
Collapse
|
|
20
|
Dixon ED, Nardo AD, Claudel T, Trauner M. The Role of Lipid Sensing Nuclear Receptors (PPARs and LXR) and Metabolic Lipases in Obesity, Diabetes and NAFLD. Genes (Basel) 2021; 12:genes12050645. [PMID: 33926085 PMCID: PMC8145571 DOI: 10.3390/genes12050645] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/23/2021] [Accepted: 04/23/2021] [Indexed: 12/11/2022] Open
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are metabolic disorders characterized by metabolic inflexibility with multiple pathological organ manifestations, including non-alcoholic fatty liver disease (NAFLD). Nuclear receptors are ligand-dependent transcription factors with a multifaceted role in controlling many metabolic activities, such as regulation of genes involved in lipid and glucose metabolism and modulation of inflammatory genes. The activity of nuclear receptors is key in maintaining metabolic flexibility. Their activity depends on the availability of endogenous ligands, like fatty acids or oxysterols, and their derivatives produced by the catabolic action of metabolic lipases, most of which are under the control of nuclear receptors. For example, adipose triglyceride lipase (ATGL) is activated by peroxisome proliferator-activated receptor γ (PPARγ) and conversely releases fatty acids as ligands for PPARα, therefore, demonstrating the interdependency of nuclear receptors and lipases. The diverse biological functions and importance of nuclear receptors in metabolic syndrome and NAFLD has led to substantial effort to target them therapeutically. This review summarizes recent findings on the roles of lipases and selected nuclear receptors, PPARs, and liver X receptor (LXR) in obesity, diabetes, and NAFLD.
Collapse
Affiliation(s)
| | | | | | - Michael Trauner
- Correspondence: ; Tel.: +43-140-4004-7410; Fax: +43-14-0400-4735
| |
Collapse
|
|
21
|
Viedma-Poyatos Á, González-Jiménez P, Langlois O, Company-Marín I, Spickett CM, Pérez-Sala D. Protein Lipoxidation: Basic Concepts and Emerging Roles. Antioxidants (Basel) 2021; 10:295. [PMID: 33669164 PMCID: PMC7919664 DOI: 10.3390/antiox10020295] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 12/13/2022] Open
Abstract
Protein lipoxidation is a non-enzymatic post-translational modification that consists of the covalent addition of reactive lipid species to proteins. This occurs under basal conditions but increases in situations associated with oxidative stress. Protein targets for lipoxidation include metabolic and signalling enzymes, cytoskeletal proteins, and transcription factors, among others. There is strong evidence for the involvement of protein lipoxidation in disease, including atherosclerosis, neurodegeneration, and cancer. Nevertheless, the involvement of lipoxidation in cellular regulatory mechanisms is less understood. Here we review basic aspects of protein lipoxidation and discuss several features that could support its role in cell signalling, including its selectivity, reversibility, and possibilities for regulation at the levels of the generation and/or detoxification of reactive lipids. Moreover, given the great structural variety of electrophilic lipid species, protein lipoxidation can contribute to the generation of multiple structurally and functionally diverse protein species. Finally, the nature of the lipoxidised proteins and residues provides a frameshift for a complex interplay with other post-translational modifications, including redox and redox-regulated modifications, such as oxidative modifications and phosphorylation, thus strengthening the importance of detailed knowledge of this process.
Collapse
Affiliation(s)
- Álvaro Viedma-Poyatos
- Department of Structural and Chemical Biology, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (C.S.I.C.), 28040 Madrid, Spain
| | - Patricia González-Jiménez
- Department of Structural and Chemical Biology, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (C.S.I.C.), 28040 Madrid, Spain
| | - Ophélie Langlois
- College of Health & Life Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
| | - Idoia Company-Marín
- College of Health & Life Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
| | - Corinne M Spickett
- College of Health & Life Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
| | - Dolores Pérez-Sala
- Department of Structural and Chemical Biology, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (C.S.I.C.), 28040 Madrid, Spain
| |
Collapse
|
|
22
|
Protracted rosiglitazone treatment exacerbates inflammation in white adipose tissues of adipocyte-specific Nfe2l1 knockout mice. Food Chem Toxicol 2020; 146:111836. [DOI: 10.1016/j.fct.2020.111836] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 09/30/2020] [Accepted: 10/24/2020] [Indexed: 12/22/2022]
|
|
23
|
Peroxisome Proliferator-Activated Receptors as Molecular Links between Caloric Restriction and Circadian Rhythm. Nutrients 2020; 12:nu12113476. [PMID: 33198317 PMCID: PMC7696073 DOI: 10.3390/nu12113476] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 11/04/2020] [Accepted: 11/09/2020] [Indexed: 02/06/2023] Open
Abstract
The circadian rhythm plays a chief role in the adaptation of all bodily processes to internal and environmental changes on the daily basis. Next to light/dark phases, feeding patterns constitute the most essential element entraining daily oscillations, and therefore, timely and appropriate restrictive diets have a great capacity to restore the circadian rhythm. One of the restrictive nutritional approaches, caloric restriction (CR) achieves stunning results in extending health span and life span via coordinated changes in multiple biological functions from the molecular, cellular, to the whole-body levels. The main molecular pathways affected by CR include mTOR, insulin signaling, AMPK, and sirtuins. Members of the family of nuclear receptors, the three peroxisome proliferator-activated receptors (PPARs), PPARα, PPARβ/δ, and PPARγ take part in the modulation of these pathways. In this non-systematic review, we describe the molecular interconnection between circadian rhythm, CR-associated pathways, and PPARs. Further, we identify a link between circadian rhythm and the outcomes of CR on the whole-body level including oxidative stress, inflammation, and aging. Since PPARs contribute to many changes triggered by CR, we discuss the potential involvement of PPARs in bridging CR and circadian rhythm.
Collapse
|
|
24
|
Methane-Rich Saline Protects Against Sepsis-Induced Liver Damage by Regulating the PPAR-γ/NF-κB Signaling Pathway. Shock 2020; 52:e163-e172. [PMID: 30601406 DOI: 10.1097/shk.0000000000001310] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Sepsis, a life-threatening organ dysfunction due to a dysregulated response to infection, is a common complication of major surgery. Previous studies have shown that methane possesses protective properties. This study aims to investigate the protective effect of methane-rich saline (MRS) on sepsis-induced liver injury. In an in vivo experiment, C57BL/6 mice received cecal ligation and puncture to create a septic model followed by MRS treatment (10 mL/kg, ip treatment) 30 min and 12 h after the operation. We found that methane effectively decreased the serum aspartate aminotransferase, alanine aminotransferase and liver index, as well as the liver pathological damage, and reduced the localized infiltration of inflammatory cells. Methane suppressed the expression of the toll-like receptor 4/nuclear factor-kappa B (NF-κB) signaling pathway and stimulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) during sepsis, which inhibited the activation of NF-κB and decreased the level of inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and interleukin-1β. Moreover, we found that MRS treatment relieved reactive oxygen species (ROS) damage by upregulating heme oxygenase-1, superoxide dismutase and glutathione, and downregulating malondialdehyde, which was consistent with the results of dihydroethidium fluorescent staining. MRS treatment also regulated apoptosis-related proteins, such as Bax, Bcl-2, and caspase-3. In the in vitro experiment, HepG2 cells received inflammatory stimulation induced by LPS followed by methane-rich medium (MRM) treatment. We found that MRM alleviated the inflammatory damage, ROS damage and regulated the expression of PPAR-γ/NF-κB. Our data indicated that methane treatment prevented liver damage in sepsis via anti-inflammatory, anti-oxidative, and anti-apoptotic properties that involved the PPAR-γ/ NF-κB signaling pathway.
Collapse
|
|
25
|
Cell-Based Therapeutic Approaches for Cystic Fibrosis. Int J Mol Sci 2020; 21:ijms21155219. [PMID: 32718005 PMCID: PMC7432606 DOI: 10.3390/ijms21155219] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/20/2020] [Accepted: 07/20/2020] [Indexed: 01/01/2023] Open
Abstract
Cystic Fibrosis (CF) is a chronic autosomal recessive disease caused by defects in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic Fibrosis affects multiple organs but progressive remodeling of the airways, mucus accumulation, and chronic inflammation in the lung, result in lung disease as the major cause of morbidity and mortality. While advances in management of CF symptoms have increased the life expectancy of this devastating disease, and there is tremendous excitement about the potential of new agents targeting the CFTR molecule itself, there is still no curative treatment. With the recent advances in the identification of endogenous airway progenitor cells and in directed differentiation of pluripotent cell sources, cell-based therapeutic approaches for CF have become a plausible treatment method with the potential to ultimately cure the disease. In this review, we highlight the current state of cell therapy in the CF field focusing on the relevant autologous and allogeneic cell populations under investigation and the challenges associated with their use. In addition, we present advances in induced pluripotent stem (iPS) cell approaches and emerging new genetic engineering methods, which have the capacity to overcome the current limitations hindering cell therapy approaches.
Collapse
|
|
26
|
Affiliation(s)
- Mariana X Byndloss
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
| |
Collapse
|
|
27
|
Peroxisome Proliferator-Activated Receptors and Caloric Restriction-Common Pathways Affecting Metabolism, Health, and Longevity. Cells 2020; 9:cells9071708. [PMID: 32708786 PMCID: PMC7407644 DOI: 10.3390/cells9071708] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/14/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023] Open
Abstract
Caloric restriction (CR) is a traditional but scientifically verified approach to promoting health and increasing lifespan. CR exerts its effects through multiple molecular pathways that trigger major metabolic adaptations. It influences key nutrient and energy-sensing pathways including mammalian target of rapamycin, Sirtuin 1, AMP-activated protein kinase, and insulin signaling, ultimately resulting in reductions in basic metabolic rate, inflammation, and oxidative stress, as well as increased autophagy and mitochondrial efficiency. CR shares multiple overlapping pathways with peroxisome proliferator-activated receptors (PPARs), particularly in energy metabolism and inflammation. Consequently, several lines of evidence suggest that PPARs might be indispensable for beneficial outcomes related to CR. In this review, we present the available evidence for the interconnection between CR and PPARs, highlighting their shared pathways and analyzing their interaction. We also discuss the possible contributions of PPARs to the effects of CR on whole organism outcomes.
Collapse
|
|
28
|
Killoy KM, Harlan BA, Pehar M, Vargas MR. FABP7 upregulation induces a neurotoxic phenotype in astrocytes. Glia 2020; 68:2693-2704. [PMID: 32619303 DOI: 10.1002/glia.23879] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 06/07/2020] [Accepted: 06/07/2020] [Indexed: 01/15/2023]
Abstract
Fatty acid binding proteins (FABPs) are key regulators of lipid metabolism, energy homeostasis, and inflammation. They participate in fatty acid metabolism by regulating their uptake, transport, and availability of ligands to nuclear receptors. In the adult brain, FABP7 is especially abundant in astrocytes that are rich in cytoplasmic granules originated from damaged mitochondria. Mitochondrial dysfunction and oxidative stress have been implicated in the neurodegenerative process observed in amyotrophic lateral sclerosis (ALS), either as a primary cause or as a secondary component of the pathogenic process. Here we investigated the expression of FABP7 in animal models of human superoxide dismutase 1 (hSOD1)-linked ALS. In the spinal cord of symptomatic mutant hSOD1-expressing mice, FABP7 is upregulated in gray matter astrocytes. Using a coculture model, we examined the effect of increased FABP7 expression in astrocyte-motor neuron interaction. Our data show that FABP7 overexpression directly promotes an NF-κB-driven pro-inflammatory response in nontransgenic astrocytes that ultimately is detrimental for motor neuron survival. Addition of trophic factors, capable of supporting motor neuron survival in pure cultures, did not prevent motor neuron loss in cocultures with FABP7 overexpressing astrocytes. In addition, astrocyte cultures obtained from symptomatic hSOD1-expressing mice display upregulated FABP7 expression. Silencing endogenous FABP7 in these cultures decreases the expression of inflammatory markers and their toxicity toward cocultured motor neurons. Our results identify a key role of FABP7 in the regulation of the inflammatory response in astrocytes and identify FABP7 as a potential therapeutic target to prevent astrocyte-mediated motor neuron toxicity in ALS.
Collapse
Affiliation(s)
- Kelby M Killoy
- Biomedical Sciences Training Program, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Benjamin A Harlan
- Biomedical Sciences Training Program, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Mariana Pehar
- Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Marcelo R Vargas
- Department of Neurology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| |
Collapse
|
|
29
|
Redox Regulation of PPAR γ in Polarized Macrophages. PPAR Res 2020; 2020:8253831. [PMID: 32695149 PMCID: PMC7350077 DOI: 10.1155/2020/8253831] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 04/28/2020] [Accepted: 05/12/2020] [Indexed: 12/12/2022] Open
Abstract
The peroxisome proliferator-activated receptor (PPARγ) is a central mediator of cellular lipid metabolism and immune cell responses during inflammation. This is facilitated by its role as a transcription factor as well as a DNA-independent protein interaction partner. We addressed how the cellular redox milieu in the cytosol and the nucleus of lipopolysaccharide (LPS)/interferon-γ- (IFNγ-) and interleukin-4- (IL4-) polarized macrophages (MΦ) initiates posttranslational modifications of PPARγ, that in turn alter its protein function. Using the redox-sensitive GFP2 (roGFP2), we validated oxidizing and reducing conditions following classical and alternative activation of MΦ, while the redox status of PPARγ was determined via mass spectrometry. Cysteine residues located in the zinc finger regions (amino acid fragments AA 90-115, AA 116-130, and AA 160-167) of PPARγ were highly oxidized, accompanied by phosphorylation of serine 82 in response to LPS/IFNγ, whereas IL4-stimulation provoked minor serine 82 phosphorylation and less cysteine oxidation, favoring a reductive milieu. Mutating these cysteines to alanine to mimic a redox modification decreased PPARγ-dependent reporter gene transactivation supporting a functional shift of PPARγ associated with the MΦ phenotype. These data suggest distinct mechanisms for regulating PPARγ function based on the redox state of MΦ.
Collapse
|
|
30
|
Shelton CD, Byndloss MX. Gut Epithelial Metabolism as a Key Driver of Intestinal Dysbiosis Associated with Noncommunicable Diseases. Infect Immun 2020; 88:e00939-19. [PMID: 32122941 PMCID: PMC7309626 DOI: 10.1128/iai.00939-19] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In high-income countries, the leading causes of death are noncommunicable diseases (NCDs), such as obesity, cancer, and cardiovascular disease. An important feature of most NCDs is inflammation-induced gut dysbiosis characterized by a shift in the microbial community structure from obligate to facultative anaerobes such as Proteobacteria This microbial imbalance can contribute to disease pathogenesis by either a depletion in or the production of microbiota-derived metabolites. However, little is known about the mechanism by which inflammation-mediated changes in host physiology disrupt the microbial ecosystem in our large intestine leading to disease. Recent work by our group suggests that during gut homeostasis, epithelial hypoxia derived from peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent β-oxidation of microbiota-derived short-chain fatty acids limits oxygen availability in the colon, thereby maintaining a balanced microbial community. During inflammation, disruption in gut anaerobiosis drives expansion of facultative anaerobic Enterobacteriaceae, regardless of their pathogenic potential. Therefore, our research group is currently exploring the concept that dysbiosis-associated expansion of Enterobacteriaceae can be viewed as a microbial signature of epithelial dysfunction and may play a greater role in different models of NCDs, including diet-induced obesity, atherosclerosis, and inflammation-associated colorectal cancer.
Collapse
Affiliation(s)
- Catherine D Shelton
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Mariana X Byndloss
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| |
Collapse
|
|
31
|
Fan Q, Nørgaard RC, Grytten I, Ness CM, Lucas C, Vekterud K, Soedling H, Matthews J, Lemma RB, Gabrielsen OS, Bindesbøll C, Ulven SM, Nebb HI, Grønning-Wang LM, Sæther T. LXRα Regulates ChREBPα Transactivity in a Target Gene-Specific Manner through an Agonist-Modulated LBD-LID Interaction. Cells 2020; 9:cells9051214. [PMID: 32414201 PMCID: PMC7290792 DOI: 10.3390/cells9051214] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/19/2020] [Accepted: 05/07/2020] [Indexed: 01/02/2023] Open
Abstract
The cholesterol-sensing nuclear receptor liver X receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in regulating glucose and lipid metabolism in the liver. More knowledge of their mechanistic interplay is needed to understand their role in pathological conditions like fatty liver disease and insulin resistance. In the current study, LXR and ChREBP co-occupancy was examined by analyzing ChIP-seq datasets from mice livers. LXR and ChREBP interaction was determined by Co-immunoprecipitation (CoIP) and their transactivity was assessed by real-time quantitative polymerase chain reaction (qPCR) of target genes and gene reporter assays. Chromatin binding capacity was determined by ChIP-qPCR assays. Our data show that LXRα and ChREBPα interact physically and show a high co-occupancy at regulatory regions in the mouse genome. LXRα co-activates ChREBPα and regulates ChREBP-specific target genes in vitro and in vivo. This co-activation is dependent on functional recognition elements for ChREBP but not for LXR, indicating that ChREBPα recruits LXRα to chromatin in trans. The two factors interact via their key activation domains; the low glucose inhibitory domain (LID) of ChREBPα and the ligand-binding domain (LBD) of LXRα. While unliganded LXRα co-activates ChREBPα, ligand-bound LXRα surprisingly represses ChREBPα activity on ChREBP-specific target genes. Mechanistically, this is due to a destabilized LXRα:ChREBPα interaction, leading to reduced ChREBP-binding to chromatin and restricted activation of glycolytic and lipogenic target genes. This ligand-driven molecular switch highlights an unappreciated role of LXRα in responding to nutritional cues that was overlooked due to LXR lipogenesis-promoting function.
Collapse
Affiliation(s)
- Qiong Fan
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway; (Q.F.); (K.V.); (C.B.)
| | - Rikke Christine Nørgaard
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway; (R.C.N.); (C.M.N.); (C.L.); (H.S.); (J.M.); (S.M.U.); (H.I.N.); (L.M.G.-W.)
| | - Ivar Grytten
- Department of Informatics, Faculty of Mathematics and Natural Sciences, University of Oslo, N-0317 Oslo, Norway;
| | - Cecilie Maria Ness
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway; (R.C.N.); (C.M.N.); (C.L.); (H.S.); (J.M.); (S.M.U.); (H.I.N.); (L.M.G.-W.)
| | - Christin Lucas
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway; (R.C.N.); (C.M.N.); (C.L.); (H.S.); (J.M.); (S.M.U.); (H.I.N.); (L.M.G.-W.)
| | - Kristin Vekterud
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway; (Q.F.); (K.V.); (C.B.)
| | - Helen Soedling
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway; (R.C.N.); (C.M.N.); (C.L.); (H.S.); (J.M.); (S.M.U.); (H.I.N.); (L.M.G.-W.)
| | - Jason Matthews
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway; (R.C.N.); (C.M.N.); (C.L.); (H.S.); (J.M.); (S.M.U.); (H.I.N.); (L.M.G.-W.)
| | - Roza Berhanu Lemma
- Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, N-0317 Oslo, Norway; (R.B.L.); (O.S.G.)
| | - Odd Stokke Gabrielsen
- Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, N-0317 Oslo, Norway; (R.B.L.); (O.S.G.)
| | - Christian Bindesbøll
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway; (Q.F.); (K.V.); (C.B.)
| | - Stine Marie Ulven
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway; (R.C.N.); (C.M.N.); (C.L.); (H.S.); (J.M.); (S.M.U.); (H.I.N.); (L.M.G.-W.)
| | - Hilde Irene Nebb
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway; (R.C.N.); (C.M.N.); (C.L.); (H.S.); (J.M.); (S.M.U.); (H.I.N.); (L.M.G.-W.)
| | - Line Mariann Grønning-Wang
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway; (R.C.N.); (C.M.N.); (C.L.); (H.S.); (J.M.); (S.M.U.); (H.I.N.); (L.M.G.-W.)
| | - Thomas Sæther
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway; (Q.F.); (K.V.); (C.B.)
- Correspondence: ; Tel.: +47-22-851510
| |
Collapse
|
|
32
|
Isoniazid promotes the anti-inflammatory response in zebrafish associated with regulation of the PPARγ/NF-κB/AP-1 pathway. Chem Biol Interact 2020; 316:108928. [DOI: 10.1016/j.cbi.2019.108928] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 12/05/2019] [Accepted: 12/15/2019] [Indexed: 12/26/2022]
|
|
33
|
Mrowka P, Glodkowska-Mrowka E. PPARγ Agonists in Combination Cancer Therapies. Curr Cancer Drug Targets 2019; 20:197-215. [PMID: 31814555 DOI: 10.2174/1568009619666191209102015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/03/2019] [Accepted: 11/01/2019] [Indexed: 12/15/2022]
Abstract
Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear receptor acting as a transcription factor involved in the regulation of energy metabolism, cell cycle, cell differentiation, and apoptosis. These unique properties constitute a strong therapeutic potential that place PPARγ agonists as one of the most interesting and widely studied anticancer molecules. Although PPARγ agonists exert significant, antiproliferative and tumoricidal activity in vitro, their anticancer efficacy in animal models is ambiguous, and their effectiveness in clinical trials in monotherapy is unsatisfactory. However, due to pleiotropic effects of PPARγ activation in normal and tumor cells, PPARγ ligands interact with many antitumor treatment modalities and synergistically potentiate their effectiveness. The most spectacular example is a combination of PPARγ ligands with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). In this setting, PPARγ activation sensitizes leukemic stem cells, resistant to any previous form of treatment, to targeted therapy. Thus, this combination is believed to be the first pharmacological therapy able to cure CML patients. Within the last decade, a significant body of data confirming the benefits of the addition of PPARγ ligands to various antitumor therapies, including chemotherapy, hormonotherapy, targeted therapy, and immunotherapy, has been published. Although the majority of these studies have been carried out in vitro or animal tumor models, a few successful attempts to introduce PPARγ ligands into anticancer therapy in humans have been recently made. In this review, we aim to summarize shines and shadows of targeting PPARγ in antitumor therapies.
Collapse
Affiliation(s)
- Piotr Mrowka
- Department of Biophysics and Human Physiology, Medical University of Warsaw, Warsaw, Poland
| | - Eliza Glodkowska-Mrowka
- Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Warsaw, Poland.,Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| |
Collapse
|
|
34
|
Tseng V, Sutliff RL, Hart CM. Redox Biology of Peroxisome Proliferator-Activated Receptor-γ in Pulmonary Hypertension. Antioxid Redox Signal 2019; 31:874-897. [PMID: 30582337 PMCID: PMC6751396 DOI: 10.1089/ars.2018.7695] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Peroxisome proliferator-activated receptor-gamma (PPARγ) maintains pulmonary vascular health through coordination of antioxidant defense systems, inflammation, and cellular metabolism. Insufficient PPARγ contributes to pulmonary hypertension (PH) pathogenesis, whereas therapeutic restoration of PPARγ activity attenuates PH in preclinical models. Recent Advances: Numerous studies in the past decade have elucidated the complex mechanisms by which PPARγ in the pulmonary vasculature and right ventricle (RV) protects against PH. The scope of PPARγ-interconnected pathways continues to expand and includes induction of antioxidant genes, transrepression of inflammatory signaling, regulation of mitochondrial biogenesis and bioenergetic integrity, control of cell cycle and proliferation, and regulation of vascular tone through interactions with nitric oxide and endogenous vasoactive molecules. Furthermore, PPARγ interacts with an extensive regulatory network of transcription factors and microRNAs leading to broad impact on cell signaling. Critical Issues: Abundant evidence suggests that targeting PPARγ exerts diverse salutary effects in PH and represents a novel and potentially translatable therapeutic strategy. However, progress has been slowed by an incomplete understanding of how specific PPARγ pathways are critically disrupted across PH disease subtypes and lack of optimal pharmacological ligands. Future Directions: Recent studies indicate that ligand-induced post-translational modifications of the PPARγ receptor differentially induce therapeutic benefits versus adverse side effects of PPARγ receptor activation. Strategies to selectively target PPARγ activity in diseased cells of pulmonary circulation and RV, coupled with development of ligands designed to specifically regulate post-translational PPARγ modifications, may unlock the full therapeutic potential of this versatile master transcriptional and metabolic regulator in PH.
Collapse
Affiliation(s)
- Victor Tseng
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, Georgia.,Atlanta Veterans Affairs Medical Center, Decatur, Georgia
| | - Roy L Sutliff
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, Georgia.,Atlanta Veterans Affairs Medical Center, Decatur, Georgia
| | - C Michael Hart
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, Georgia.,Atlanta Veterans Affairs Medical Center, Decatur, Georgia
| |
Collapse
|
|
35
|
Yan W, Cao Y, Yang H, Han N, Zhu X, Fan Z, Du J, Zhang F. CB1 enhanced the osteo/dentinogenic differentiation ability of periodontal ligament stem cells via p38 MAPK and JNK in an inflammatory environment. Cell Prolif 2019; 52:e12691. [PMID: 31599069 PMCID: PMC6869632 DOI: 10.1111/cpr.12691] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 07/16/2019] [Accepted: 08/09/2019] [Indexed: 12/15/2022] Open
Abstract
Objectives Periodontitis is an inflammatory immune disease that causes periodontal tissue loss. Inflammatory immunity and bone metabolism are closely related to periodontitis. The cannabinoid receptor I (CB1) is an important constituent of the endocannabinoid system and participates in bone metabolism and inflammation tissue healing. It is unclear whether CB1 affects the mesenchymal stem cell (MSC) function involved in periodontal tissue regeneration. In this study, we revealed the role and mechanism of CB1 in the osteo/dentinogenic differentiation of periodontal ligament stem cells (PDLSCs) in an inflammatory environment. Materials and methods Alkaline phosphatase (ALP) activity, Alizarin Red staining, quantitative calcium analysis and osteo/dentinogenic markers were used to assess osteo/dentinogenic differentiation. Real‐time RT‐PCR and Western blotting were employed to detect gene expression. Results CB1 overexpression or CB1 agonist (10 µM R‐1 Meth) promoted the osteo/dentinogenic differentiation of PDLSCs. Deletion of CB1 or the application of CB1 antagonist (10 µM AM251) repressed the osteo/dentinogenic differentiation of PDLSCs. The activation of CB1 enhanced the TNF‐α‐ and INF‐γ‐impaired osteo/dentinogenic differentiation potential in PDLSCs. Moreover, CB1 activated p38 MAPK and JNK signalling and repressed PPAR‐γ and Erk1/2 signalling. Inhibition of JNK signalling could block CB1‐activated JNK and p38 MAPK signalling, while CB1 could activate p38 MAPK and JNK signalling, which was inhibited by TNF‐α and INF‐γ stimulation. Conclusions CB1 was able to enhance the osteo/dentinogenic differentiation ability of PDLSCs via p38 MAPK and JNK signalling in an inflammatory environment, which might be a potential target for periodontitis treatment.
Collapse
Affiliation(s)
- Wanhao Yan
- Department of Periodontology, Capital Medical University School of Stomatology, Beijing, China.,Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
| | - Yangyang Cao
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
| | - Haoqing Yang
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
| | - Nannan Han
- Department of Periodontology, Capital Medical University School of Stomatology, Beijing, China.,Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
| | - Xinling Zhu
- Department of Periodontology, Capital Medical University School of Stomatology, Beijing, China.,Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
| | - Zhipeng Fan
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
| | - Juan Du
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
| | - Fengqiu Zhang
- Department of Periodontology, Capital Medical University School of Stomatology, Beijing, China
| |
Collapse
|
|
36
|
Song J, Kim YS, Lee DH, Lee SH, Park HJ, Lee D, Kim H. Neuroprotective effects of oleic acid in rodent models of cerebral ischaemia. Sci Rep 2019; 9:10732. [PMID: 31341184 PMCID: PMC6656890 DOI: 10.1038/s41598-019-47057-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 06/06/2019] [Indexed: 01/02/2023] Open
Abstract
Oleic acid (OA) is released from brain phospholipids after cerebral ischaemia; however, its role in ischaemic injury remains unknown. We hypothesised that OA has neuroprotective effects after cerebral ischaemia, which may be exerted through peroxisome proliferator-activated receptor gamma (PPAR-γ) activation, since OA is an endogenous ligand of PPAR-γ. The effects of OA administration were evaluated in rodent models of middle cerebral artery occlusion (MCAO), photothrombosis, and four-vessel occlusion (4-VO). We determined the time window of therapeutic opportunity and examined the ability of the PPAR-γ antagonist GW9662 to reverse OA’s protective effects after MCAO. We found that OA administration decreased the MCAO-induced infarct volume and functional deficits, photothrombosis-induced infarct volume, and 4-VO-induced hippocampal neuronal death. Additionally, OA was highly efficacious when administered up to 3 h after MCAO. Pre-treatment with GW9662 abolished the inhibitory effects of OA on the infarct volume and immunoreactivity of key inflammatory mediators in the ischaemic cortex. Our results indicate that OA has neuroprotective effects against transient and permanent focal cerebral ischaemia, as well as global cerebral ischaemia. It may have therapeutic value for the ischaemic stroke treatment with a clinically feasible therapeutic window. The OA-mediated neuroprotection might be attributable to its anti-inflammatory actions through PPAR-γ activation.
Collapse
Affiliation(s)
- Jungbin Song
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea
| | - Young-Sik Kim
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea
| | - Dong Hwan Lee
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea
| | - Sung Hyun Lee
- Korea Institute of Science and Technology for Eastern Medicine (KISTEM) NeuMed Inc., 88 Imun-ro, Dongdaemun-gu, Seoul, 02440, Republic of Korea
| | - Hyo Jin Park
- Korea Institute of Science and Technology for Eastern Medicine (KISTEM) NeuMed Inc., 88 Imun-ro, Dongdaemun-gu, Seoul, 02440, Republic of Korea
| | - Donghun Lee
- Department of Herbal Pharmacology, College of Korean Medicine, Gachon University, 1342 Seongnamdae-ro, Sujeong-gu, Seongnam-si, Gyeonggi-do, 13120, Republic of Korea.
| | - Hocheol Kim
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
| |
Collapse
|
|
37
|
Uddin MS, Kabir MT, Jakaria M, Mamun AA, Niaz K, Amran MS, Barreto GE, Ashraf GM. Endothelial PPARγ Is Crucial for Averting Age-Related Vascular Dysfunction by Stalling Oxidative Stress and ROCK. Neurotox Res 2019; 36:583-601. [PMID: 31055770 DOI: 10.1007/s12640-019-00047-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 04/01/2019] [Accepted: 04/11/2019] [Indexed: 02/07/2023]
Abstract
Aging plays a significant role in the progression of vascular diseases and vascular dysfunction. Activation of the ADP-ribosylation factor 6 and small GTPases by inflammatory signals may cause vascular permeability and endothelial leakage. Pro-inflammatory molecules have a significant effect on smooth muscle cells (SMC). The migration and proliferation of SMC can be promoted by tumor necrosis factor alpha (TNF-α). TNF-α can also increase oxidative stress in SMCs, which has been identified to persuade DNA damage resulting in apoptosis and cellular senescence. Peroxisome proliferator-activated receptor (PPAR) acts as a ligand-dependent transcription factor and a member of the nuclear receptor superfamily. They play key roles in a wide range of biological processes, including cell differentiation and proliferation, bone formation, cell metabolism, tissue remodeling, insulin sensitivity, and eicosanoid signaling. The PPARγ activation regulates inflammatory responses, which can exert protective effects in the vasculature. In addition, loss of function of PPARγ enhances cardiovascular events and atherosclerosis in the vascular endothelium. This appraisal, therefore, discusses the critical linkage of PPARγ in the inflammatory process and highlights a crucial defensive role for endothelial PPARγ in vascular dysfunction and disease, as well as therapy for vascular aging.
Collapse
Affiliation(s)
- Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh.
| | | | - Md Jakaria
- Department of Applied Life Sciences, Graduate School, Konkuk University, Chungju, South Korea
| | | | - Kamal Niaz
- Department of Pharmacology and Toxicology, Faculty of Bio-Sciences, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
| | - Md Shah Amran
- Department of Pharmaceutical Chemistry, University of Dhaka, Dhaka, Bangladesh
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, DC, Colombia.,Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia. .,Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
| |
Collapse
|
|
38
|
Ginsenoside Rf inhibits cyclooxygenase-2 induction via peroxisome proliferator-activated receptor gamma in A549 cells. J Ginseng Res 2018; 43:319-325. [PMID: 30976170 PMCID: PMC6437553 DOI: 10.1016/j.jgr.2018.11.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 11/14/2018] [Accepted: 11/26/2018] [Indexed: 12/11/2022] Open
Abstract
Background Ginsenoside Rf is a ginseng saponin found only in Panax ginseng that affects lipid metabolism. It also has neuroprotective and antiinflammatory properties. We previously showed that Korean Red Ginseng (KRG) inhibited the expression of cyclooxygenase-2 (COX-2) by hypoxia via peroxisome proliferator–activated receptor gamma (PPARγ). The aim of the current study was to evaluate the possibility of ginsenoside Rf as an active ingredient of KRG in the inhibition of hypoxia-induced COX-2 via PPARγ. Methods The effects of ginsenoside Rf on the upregulation of COX-2 by hypoxia and its antimigration effects were evaluated in A549 cells. Docking of ginsenoside Rf was performed with the PPARγ structure using Surflex-Dock in Sybyl-X 2.1.1. Results PPARγ protein levels and peroxisome proliferator response element promoter activities were promoted by ginsenoside Rf. Inhibition of COX-2 expression by ginsenoside Rf was blocked by the PPARγ-specific inhibitor, T0070907. The PPARγ inhibitor also blocked the ability of ginsenoside Rf to suppress cell migration under hypoxia. The docking simulation results indicate that ginsenoside Rf binds to the active site of PPARγ. Conclusions Our results demonstrate that ginsenoside Rf inhibits hypoxia induced-COX-2 expression and cellular migration, which are dependent on PPARγ activation. These results suggest that ginsenoside Rf has an antiinflammatory effect under hypoxic conditions. Moreover, docking analysis of ginsenoside Rf into the active site of PPARγ suggests that the compound binds to PPARγ in a position similar to that of known agonists.
Collapse
|
|
39
|
Nor Effa SZ, Yaacob NS, Mohd Nor N. Crosstalk between PPARγ Ligands and Inflammatory-Related Pathways in Natural T-Regulatory Cells from Type 1 Diabetes Mouse Model. Biomolecules 2018; 8:E135. [PMID: 30400642 PMCID: PMC6315476 DOI: 10.3390/biom8040135] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 08/24/2018] [Accepted: 08/28/2018] [Indexed: 02/07/2023] Open
Abstract
Immunomodulation, as a means of immunotherapy, has been studied in major research and clinical laboratories for many years. T-Regulatory (Treg) cell therapy is one of the modulators used in immunotherapy approaches. Similarly, nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ) has extensively been shown to play a role as an immuno-modulator during inflammation. Given their mutual roles in downregulating the immune response, current study examined the influence of PPARγ ligands i.e., thiazolidinedione (TZD) class of drugs on Forkhead Box P3 (Foxp3) expression and possible crosstalk between PPARγ and nTreg cells of Non-Obese Diabetes (NOD) and Non-Obese Diabetes Resistant (NOR) mice. Results showed that TZD drug, ciglitazone and natural ligand of PPARγ 15d-prostaglandin downregulated Foxp3 expression in activated nTreg cells from both NOD and NOR mice. Interestingly, addition of the PPARγ inhibitor, GW9662 further downregulated Foxp3 expression in these cells from both mice. We also found that PPARγ ligands negatively regulate Foxp3 expression in activated nTreg cells via PPARγ-independent mechanism(s). These results demonstrate that both natural and synthetic PPARγ ligands capable of suppressing Foxp3 expression in activated nTreg cells of NOD and NOR mice. This may suggest that the effect of PPARγ ligands in modulating Foxp3 expression in activated nTreg cells is different from their reported effects on effector T cells. Given the capability to suppress Foxp3 gene, it is possible to be tested as immunomodulators in cancer-related studies. The co-lateral use of PPARγ ligands in nTreg cells in inducing tolerance towards pseudo-self antigens as in tumor microenvironment may uphold beneficial outcomes.
Collapse
Affiliation(s)
- S Zulkafli Nor Effa
- School of Health Sciences, Universiti Sains Malaysia, Kelantan, Kubang Kerian 16150, Malaysia.
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Bertam, Kepala Batas 13200, Malaysia.
| | - Nik Soriani Yaacob
- School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Kubang Kerian 16150, Malaysia.
| | - Norazmi Mohd Nor
- School of Health Sciences, Universiti Sains Malaysia, Kelantan, Kubang Kerian 16150, Malaysia.
| |
Collapse
|
|
40
|
Chrysin attenuates interstitial fibrosis and improves cardiac function in a rat model of acute myocardial infarction. J Mol Histol 2018; 49:555-565. [DOI: 10.1007/s10735-018-9793-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 08/23/2018] [Indexed: 12/19/2022]
|
|
41
|
Nelson VL, Nguyen HCB, Garcìa-Cañaveras JC, Briggs ER, Ho WY, DiSpirito JR, Marinis JM, Hill DA, Lazar MA. PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism. Genes Dev 2018; 32:1035-1044. [PMID: 30006480 PMCID: PMC6075146 DOI: 10.1101/gad.312355.118] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 05/24/2018] [Indexed: 01/04/2023]
Abstract
The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPARγ ligand, in a PPARγ-dependent manner. Moreover, PPARγ is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARγ dramatically affects the oxidation of glutamine. Both glutamine and PPARγ have been implicated in alternative activation (AA) of macrophages, and PPARγ was required for interleukin 4 (IL4)-dependent gene expression and stimulation of macrophage respiration. Indeed, unstimulated macrophages lacking PPARγ contained elevated levels of the inflammation-associated metabolite itaconate and express a proinflammatory transcriptome that, remarkably, phenocopied that of macrophages depleted of glutamine. Thus, PPARγ functions as a checkpoint, guarding against inflammation, and is permissive for AA by facilitating glutamine metabolism. However, PPARγ expression is itself markedly increased by IL4. This suggests that PPARγ functions at the center of a feed-forward loop that is central to AA of macrophages.
Collapse
Affiliation(s)
- Victoria L Nelson
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Hoang C B Nguyen
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Juan C Garcìa-Cañaveras
- Lewis-Sigler Institute for Integrative Genomics, Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA
| | - Erika R Briggs
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Wesley Y Ho
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Joanna R DiSpirito
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Jill M Marinis
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - David A Hill
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
| | - Mitchell A Lazar
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Philadelphia, Pennsylvania 19104, USA
| |
Collapse
|
|
42
|
Li J, Liu YP. The roles of PPARs in human diseases. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2018; 37:361-382. [PMID: 30036119 DOI: 10.1080/15257770.2018.1475673] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Peroxisome proliferator-activated receptors (PPARs), as members of nuclear hormone receptor superfamily, can be activated by binding natural or synthetic ligands. The use of related ligands has revealed many potential roles for PPARs in the pathogenesis of some human metabolic disorders and inflammatory-related disease. Based on the previous studies, this review primarily concluded the current progress of knowledge regarding the specific biological activity of PPARs in cancers, atherosclerosis, and type 2 diabetes mellitus, providing a foundation for the potential therapeutic use of PPAR ligands in human diseases.
Collapse
Affiliation(s)
- Jingjing Li
- a Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province , Sichuan Agricultural University , Chengdu , China
| | - Yi-Ping Liu
- a Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province , Sichuan Agricultural University , Chengdu , China
| |
Collapse
|
|
43
|
Shi L, Lin Q, Yang T, Nie Y, Li X, Liu B, Shen J, Liang Y, Tang Y, Luo F. Oral administration of Lentinus edodes β-glucans ameliorates DSS-induced ulcerative colitis in mice via MAPK-Elk-1 and MAPK-PPARγ pathways. Food Funct 2018; 7:4614-4627. [PMID: 27747357 DOI: 10.1039/c6fo01043a] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
To evaluate the anti-inflammatory effect of β-glucans from Lentinus edodes, and its molecular mechanism, the dextran sulfate sodium salt (DSS) induced colitis model of mice and the LPS-stimulated RAW264.7 cell inflammation model were used in this study. 40 ICR male mice were randomly divided into 4 groups: Control, DSS (DSS treated only), DSS + low-βGs (500 mg kg-1 d-1) and DSS + high-βGs (1000 mg kg-1 d-1). The body weight of the mice with Lentinus edodes β-glucan supplementation increased significantly compared to the DSS group and the disease activity index (DAI) was improved in both βG-treated groups. Compared with the DSS group, histopathological analysis showed that the infiltration of inflammatory cells of both βG-treated groups decreased significantly in colonic tissues. Furthermore, oral administration of β-glucans decreases the concentration of malondialdehyde (MDA) and myeloperoxidase (MPO) and inhibits the expression of iNOS and several inflammatory factors: TNF-α, IL-1β and IL-6 as well as nitric oxide (NO) of the colonic tissues. The mitogen-activated protein kinase (MAPK) pathway is closely related to the expression of pro-inflammatory factors. In the DSS-induced colitis model and the LPS-stimulated RAW264.7 cell model, βGs inhibited the expression of pro-inflammatory factors and blocked the phosphorylation of JNK/ERK1/2 and p38; βGs also suppress the phosphorylation of Elk-1 at Ser84 and the phosphorylation of PPARγ at Ser112. Altogether, these results suggest that Lentinus edodes βGs could inhibit the DSS-induced ulcerative colitis and decrease inflammatory factor expressions. The molecular mechanism may be involved in suppressing MAPK signaling and inactivation of Elk-1 and activation of PPARγ.
Collapse
Affiliation(s)
- Limin Shi
- Laboratory of Molecular Nutrition, College of Food Science and Engineering, National Engineering Laboratory for Rice and Byproduct Deep Processing, Central South University of Forestry and Technology, Changsha, 410004, PR China.
| | - Qinlu Lin
- Laboratory of Molecular Nutrition, College of Food Science and Engineering, National Engineering Laboratory for Rice and Byproduct Deep Processing, Central South University of Forestry and Technology, Changsha, 410004, PR China.
| | - Tao Yang
- Laboratory of Molecular Nutrition, College of Food Science and Engineering, National Engineering Laboratory for Rice and Byproduct Deep Processing, Central South University of Forestry and Technology, Changsha, 410004, PR China.
| | - Ying Nie
- Laboratory of Molecular Nutrition, College of Food Science and Engineering, National Engineering Laboratory for Rice and Byproduct Deep Processing, Central South University of Forestry and Technology, Changsha, 410004, PR China.
| | - Xinhua Li
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, 410008, PR China
| | - Bo Liu
- Laboratory of Molecular Nutrition, College of Food Science and Engineering, National Engineering Laboratory for Rice and Byproduct Deep Processing, Central South University of Forestry and Technology, Changsha, 410004, PR China.
| | - Junjun Shen
- Laboratory of Molecular Nutrition, College of Food Science and Engineering, National Engineering Laboratory for Rice and Byproduct Deep Processing, Central South University of Forestry and Technology, Changsha, 410004, PR China.
| | - Ying Liang
- Laboratory of Molecular Nutrition, College of Food Science and Engineering, National Engineering Laboratory for Rice and Byproduct Deep Processing, Central South University of Forestry and Technology, Changsha, 410004, PR China.
| | - Yiping Tang
- Laboratory of Molecular Nutrition, College of Food Science and Engineering, National Engineering Laboratory for Rice and Byproduct Deep Processing, Central South University of Forestry and Technology, Changsha, 410004, PR China.
| | - Feijun Luo
- Laboratory of Molecular Nutrition, College of Food Science and Engineering, National Engineering Laboratory for Rice and Byproduct Deep Processing, Central South University of Forestry and Technology, Changsha, 410004, PR China.
| |
Collapse
|
|
44
|
Flores-Bastías O, Karahanian E. Neuroinflammation produced by heavy alcohol intake is due to loops of interactions between Toll-like 4 and TNF receptors, peroxisome proliferator-activated receptors and the central melanocortin system: A novel hypothesis and new therapeutic avenues. Neuropharmacology 2018; 128:401-407. [DOI: 10.1016/j.neuropharm.2017.11.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 10/26/2017] [Accepted: 11/03/2017] [Indexed: 02/06/2023]
|
|
45
|
Brennan KM, Oh SY, Yiannikouris A, Graugnard DE, Karrow NA. Differential Gene Expression Analysis of Bovine Macrophages after Exposure to the Penicillium Mycotoxins Citrinin and/or Ochratoxin A. Toxins (Basel) 2017; 9:toxins9110366. [PMID: 29137202 PMCID: PMC5705981 DOI: 10.3390/toxins9110366] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 11/08/2017] [Accepted: 11/09/2017] [Indexed: 12/03/2022] Open
Abstract
Mycotoxins produced by fungal species commonly contaminate livestock feedstuffs, jeopardizing their health and diminishing production. Citrinin (CIT) and ochratoxin A (OTA) are mycotoxins produced by Penicillium spp. and commonly co-occur. Both CIT and OTA can modulate immune response by inhibiting cell proliferation and differentiation, altering cell metabolism, and triggering programmed cell death. The objective of this study was to determine the effects of sublethal exposure (i.e., the concentration that inhibited cell proliferation by 25% (IC25)) to CIT, OTA or CIT + OTA on the bovine macrophage transcriptome. Gene expression was determined using the Affymetrix Bovine Genome Array. After 6 h of exposure to CIT, OTA or CIT + OTA, the number of differentially expressed genes (DEG), respectively, was as follows: 1471 genes (822 up-regulated, 649 down-regulated), 5094 genes (2611 up-regulated, 2483 down-regulated) and 7624 genes (3984 up-regulated, 3640 down-regulated). Of these, 179 genes (88 up-regulated, 91 down-regulated) were commonly expressed between treatments. After 24 h of exposure to CIT, OTA or CIT + OTA the number of DEG, respectively, was as follows: 3230 genes (1631 up-regulated, 1599 down-regulated), 8558 genes (4167 up-regulated, 4391 down-regulated), and 10,927 genes (6284 up-regulated, 4643 down-regulated). Of these, 770 genes (247 up-regulated, 523 down-regulated) were commonly expressed between treatments. The categorization of common biological functions and pathway analysis suggests that the IC25 of both CIT and OTA, or their combination, induces cellular oxidative stress, a slowing of cell cycle progression, and apoptosis. Collectively, these effects contribute to inhibiting bovine macrophage proliferation.
Collapse
Affiliation(s)
- Kristen M Brennan
- Center for Animal Nutrigenomics and Applied Animal Nutrition, Alltech Inc., Nicholasville, KY 40356, USA.
| | - Se-Young Oh
- Department of Animal Biosciences, University of Guelph, Guelph, ON N1G2W1, Canada.
| | - Alexandros Yiannikouris
- Center for Animal Nutrigenomics and Applied Animal Nutrition, Alltech Inc., Nicholasville, KY 40356, USA.
| | - Daniel E Graugnard
- Center for Animal Nutrigenomics and Applied Animal Nutrition, Alltech Inc., Nicholasville, KY 40356, USA.
| | - Niel A Karrow
- Department of Animal Biosciences, University of Guelph, Guelph, ON N1G2W1, Canada.
| |
Collapse
|
|
46
|
Li C, Chen K, Kang H, Yan Y, Liu K, Guo C, Qi J, Yang K, Wang F, Guo L, He C, Deng L. Double-stranded RNA released from damaged articular chondrocytes promotes cartilage degeneration via Toll-like receptor 3-interleukin-33 pathway. Cell Death Dis 2017; 8:e3165. [PMID: 29095435 PMCID: PMC5775407 DOI: 10.1038/cddis.2017.534] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 09/13/2017] [Accepted: 09/13/2017] [Indexed: 12/19/2022]
Abstract
Pattern recognition receptors (PRRs), including Toll-like receptor 3 (TLR3), are involved in arthritic responses; however, whether interleukin-33 (IL-33) is involved in TLR3-mediated cartilage degeneration is unknown. Here, we found that IL-33 was abundantly increased in chondrocytes of osteoarthritis, especially the chondrocytes of weight-bearing cartilage. Furthermore, double-stranded RNA (dsRNA) released from damaged articular chondrocytes induced by mechanical stretching upregulated IL-33 expression to a greater degree than IL-1β and tumor necrosis factor-α. dsRNA induced IL-33 expression via the TLR3-p38 mitogen-activated protein kinase-nuclear factor-κB (NF-κB) pathway. In addition, formation of the p65 and peroxisome proliferator-activated receptor-γ transcriptional complex was required for dsRNA-induced IL-33 expression. IL-33, in turn, acted on chondrocytes to induce matrix metalloproteinase-1/13 and inhibit type II collagen expression. These findings reveal that dsRNA released from damaged articular chondrocytes promotes cartilage degeneration via the TLR3-IL-33 pathway.
Collapse
Affiliation(s)
- Changwei Li
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
| | - Kaizhe Chen
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
- Department of Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
| | - Hui Kang
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Yufei Yan
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
- Department of Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
| | - Kewei Liu
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
| | - Changjun Guo
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
| | - Jin Qi
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
| | - Kai Yang
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
| | - Fei Wang
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
| | - Lei Guo
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
| | - Chuan He
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
- Department of Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
| | - Lianfu Deng
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China
| |
Collapse
|
|
47
|
Silveira LS, Pimentel GD, Souza CO, Biondo LA, Teixeira AAS, Lima EA, Batatinha HAP, Rosa Neto JC, Lira FS. Effect of an acute moderate-exercise session on metabolic and inflammatory profile of PPAR-α knockout mice. Cell Biochem Funct 2017; 35:510-517. [DOI: 10.1002/cbf.3308] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 06/23/2017] [Accepted: 09/17/2017] [Indexed: 11/05/2022]
Affiliation(s)
- Loreana S. Silveira
- Exercise and Immunometabolism Research Group, Department of Physical Education; Universidade Estadual Paulista; Presidente Prudente SP Brazil
| | - Gustavo D. Pimentel
- Clinical and Sports Nutrition Research Laboratory (Labince); Nutrition Faculty (FANUT)-Federal University of Goiás (UFG); Goiânia GO Brazil
| | - Camila O. Souza
- Immunometabolism Research Group, Institute of Biomedical Sciences; University of São Paulo (USP); São Paulo SP Brazil
| | - Luana A. Biondo
- Immunometabolism Research Group, Institute of Biomedical Sciences; University of São Paulo (USP); São Paulo SP Brazil
| | - Alexandre Abílio S. Teixeira
- Immunometabolism Research Group, Institute of Biomedical Sciences; University of São Paulo (USP); São Paulo SP Brazil
| | - Edson A. Lima
- Immunometabolism Research Group, Institute of Biomedical Sciences; University of São Paulo (USP); São Paulo SP Brazil
| | - Helena A. P. Batatinha
- Immunometabolism Research Group, Institute of Biomedical Sciences; University of São Paulo (USP); São Paulo SP Brazil
| | - José C. Rosa Neto
- Immunometabolism Research Group, Institute of Biomedical Sciences; University of São Paulo (USP); São Paulo SP Brazil
| | - Fábio S. Lira
- Exercise and Immunometabolism Research Group, Department of Physical Education; Universidade Estadual Paulista; Presidente Prudente SP Brazil
| |
Collapse
|
|
48
|
Sutton MT, Fletcher D, Episalla N, Auster L, Kaur S, Gwin MC, Folz M, Velasquez D, Roy V, van Heeckeren R, Lennon DP, Caplan AI, Bonfield TL. Mesenchymal Stem Cell Soluble Mediators and Cystic Fibrosis. ACTA ACUST UNITED AC 2017; 7. [PMID: 29291140 DOI: 10.4172/2157-7633.1000400] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Human Mesenchymal stem cells (hMSCs) secrete products (supernatants) that are anti-inflammatory and antimicrobial. We have previously shown that hMSCs decrease inflammation and Pseudomonas aeruginosa infection in the in vivo murine model of Cystic Fibrosis (CF). Cystic Fibrosis (CF) is a genetic disease in which pulmonary infection and inflammation becomes the major cause of morbidity and mortality. Our studies focus on determining how MSCs contribute to improved outcomes in the CF mouse model centering on how the MSCs impact the inflammatory response to pathogenic organisms. We hypothesize that MSCs secrete products that are anti-inflammatory in scenarios of chronic pulmonary infections using the murine model of infection and inflammation with a specific interest in Pseudomonas aeruginosa (gram negative). Further, our studies will identify whether the MSCs are impacting this inflammatory response through the regulation of peroxisome proliferator activator receptor gamma (PPARγ) which aides in decreasing inflammation.
Collapse
Affiliation(s)
- Morgan T Sutton
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,National Center of Regenerative Medicine, Case Western Reserve University, Cleveland Ohio 44106-4948.,School of Medicine, Case Western Reserve University, Cleveland Ohio 44106-4948.,School of Engineering, Case Western Reserve University, Cleveland Ohio 44106-4948.,Hathaway Brown School, Shaker Heights Ohio 44122.,Summer Programs in Undergraduate Research, Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland Ohio 44106-4948
| | - David Fletcher
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Nicole Episalla
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,Department of Biology, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Lauren Auster
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,Department of Biology, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Sukhmani Kaur
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,Hathaway Brown School, Shaker Heights Ohio 44122
| | - Mary Chandler Gwin
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,Summer Programs in Undergraduate Research, Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland Ohio 44106-4948
| | - Michael Folz
- School of Engineering, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Dante Velasquez
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,National Center of Regenerative Medicine, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Varun Roy
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,School of Medicine, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Rolf van Heeckeren
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Donald P Lennon
- Department of Biology, Case Western Reserve University, Cleveland Ohio 44106-4948.,Skeletal Research Center, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Arnold I Caplan
- Department of Biology, Case Western Reserve University, Cleveland Ohio 44106-4948.,Skeletal Research Center, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Tracey L Bonfield
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,National Center of Regenerative Medicine, Case Western Reserve University, Cleveland Ohio 44106-4948.,School of Medicine, Case Western Reserve University, Cleveland Ohio 44106-4948.,Skeletal Research Center, Case Western Reserve University, Cleveland Ohio 44106-4948
| |
Collapse
|
|
49
|
Cippitelli A, Domi E, Ubaldi M, Douglas JC, Li HW, Demopulos G, Gaitanaris G, Roberto M, Drew PD, Kane CJM, Ciccocioppo R. Protection against alcohol-induced neuronal and cognitive damage by the PPARγ receptor agonist pioglitazone. Brain Behav Immun 2017; 64:320-329. [PMID: 28167117 PMCID: PMC5482782 DOI: 10.1016/j.bbi.2017.02.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 01/25/2017] [Accepted: 02/01/2017] [Indexed: 01/08/2023] Open
Abstract
Binge alcohol drinking has emerged as a typical phenomenon in young people. This pattern of drinking, repeatedly leading to extremely high blood and brain alcohol levels and intoxication is associated with severe risks of neurodegeneration and cognitive damage. Mechanisms involved in excitotoxicity and neuroinflammation are pivotal elements in alcohol-induced neurotoxicity. Evidence has demonstrated that PPARγ receptor activation shows anti-inflammatory and neuroprotective properties. Here we examine whether treatment with the PPARγ agonist pioglitazone is beneficial in counteracting neurodegeneration, neuroinflammation and cognitive damage produced by binge alcohol intoxication. Adult Wistar rats were subjected to a 4-day binge intoxication procedure, which is commonly used to model excessive alcohol consumption in humans. Across the 4-day period, pioglitazone (0, 30, 60mg/kg) was administered orally twice daily at 12-h intervals. Degenerative cells were detected by fluoro-jade B (FJ-B) immunostaining in brain regions where expression of pro-inflammatory cytokines was also determined. The effects of pioglitazone on cognitive function were assessed in an operant reversal learning task and the Morris water maze task. Binge alcohol exposure produced selective neuronal degeneration in the hippocampal dentate gyrus and the adjacent entorhinal cortex. Pioglitazone reduced FJ-B positive cells in both regions and prevented alcohol-induced expression of pro-inflammatory cytokines. Pioglitazone also rescued alcohol-impaired reversal learning in the operant task and spatial learning deficits in the Morris water maze. These findings demonstrate that activation of PPARγ protects against neuronal and cognitive degeneration elicited by binge alcohol exposure. The protective effect of PPARγ agonist appears to be linked to inhibition of pro-inflammatory cytokines.
Collapse
Affiliation(s)
- Andrea Cippitelli
- School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino (MC) 62032, Italy
| | - Esi Domi
- School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino (MC) 62032, Italy
| | - Massimo Ubaldi
- School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino (MC) 62032, Italy
| | - James C. Douglas
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Hong Wu Li
- School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino (MC) 62032, Italy
| | | | | | - Marisa Roberto
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, USA
| | - Paul D. Drew
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Cynthia J. M. Kane
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Roberto Ciccocioppo
- School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino (MC) 62032, Italy.
| |
Collapse
|
|
50
|
Luczak E, Wieczfinska J, Sokolowska M, Pniewska E, Luczynska D, Pawliczak R. Troglitazone, a PPAR-γ agonist, decreases LTC 4 concentration in mononuclear cells in patients with asthma. Pharmacol Rep 2017; 69:1315-1321. [PMID: 29128815 DOI: 10.1016/j.pharep.2017.05.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 05/06/2017] [Accepted: 05/11/2017] [Indexed: 01/18/2023]
Abstract
BACKGROUND Asthma is an inflammatory disorder with multiple mediators involved in the inflammatory response. Despite several attempts, no new anti-inflammatory drugs have been registered for asthma treatment for several years. However, thiazolidinediones, peroxisome proliferator-activated receptor agonists, have demonstrated some anti-inflammatory properties in various experimental settings. The aim of this study was to assess the influence of troglitazone on LTC4 and 15-HETE concentrations. It also evaluates TNF-induced eotaxin synthesis in peripheral blood mononuclear cells from 14 patients with mild asthma and 13 healthy controls. METHODS PBMCs were isolated from the whole blood of the asthmatics and healthy subjects and pretreated with 0.1, 1 or 10μM of Troglitazone. The cells were then exposed to 10-6M calcium jonophore or 10ng/ml TNF. The production and release of LTC4, 15-HETE and eotaxin were then assessed. RESULTS Troglitazone caused a dose-dependent inhibition in LTC4 synthesis in both asthmatics and healthy subjects. Troglitazone did not influence 15-HETE or eotaxin production in either asthmatic patients or in healthy individuals. CONCLUSION Due to its inhibition of LTC4 synthesis, troglitazone therapy is an interesting potential therapeutic approach in asthma and other LTC4 related inflammatory disorders.
Collapse
Affiliation(s)
- Emilia Luczak
- Department of Immunopathology, Medical University of Lodz, Łódź, Poland
| | | | - Milena Sokolowska
- Department of Immunopathology, Medical University of Lodz, Łódź, Poland; Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland
| | - Ewa Pniewska
- Department of Immunopathology, Medical University of Lodz, Łódź, Poland
| | - Daria Luczynska
- Department of Immunopathology, Medical University of Lodz, Łódź, Poland
| | - Rafał Pawliczak
- Department of Immunopathology, Medical University of Lodz, Łódź, Poland.
| |
Collapse
|