|
1
|
Zhang PP, Li L, Qu HY, Chen GY, Xie MZ, Chen YK. Traditional Chinese medicine in the treatment of Helicobacter pylori-related gastritis: The mechanisms of signalling pathway regulations. World J Gastroenterol 2025; 31:96582. [PMID: 39839895 PMCID: PMC11684169 DOI: 10.3748/wjg.v31.i3.96582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 09/29/2024] [Accepted: 12/02/2024] [Indexed: 12/20/2024] Open
Abstract
Helicobacter pylori-associated gastritis (HPAG) is a common condition of the gastrointestinal tract. However, extensive and long-term antibiotic use has resulted in numerous adverse effects, including increased resistance, gastrointestinal dysfunction, and increased recurrence rates. When these concerns develop, traditional Chinese medicine (TCM) may have advantages. TCM is based on the concept of completeness and aims to eliminate pathogens and strengthen the body. It has the potential to prevent this condition while also boosting the rate of Helicobacter pylori eradication. This review elaborates on the mechanism of TCM treatment for HPAG based on cellular signalling pathways, which reflects the flexibility of TCM in treating diseases and the advantages of multi-level, multi-pathway, and multi-target treatments for HPAG.
Collapse
Affiliation(s)
- Pei-Pei Zhang
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Liang Li
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Hao-Yu Qu
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- School of Informatics, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Guang-Yu Chen
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Meng-Zhou Xie
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Yan-Kun Chen
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Precision Medicine Research and Development Center, Zhuhai Institute of Advanced Technology, Chinese Academy of Sciences, Zhuhai 519000, Guangdong Province, China
| |
Collapse
|
|
2
|
Wang X, Zhao G, Shao S, Yao Y. Helicobacter pylori triggers inflammation and oncogenic transformation by perturbing the immune microenvironment. Biochim Biophys Acta Rev Cancer 2024; 1879:189139. [PMID: 38897421 DOI: 10.1016/j.bbcan.2024.189139] [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: 04/08/2024] [Revised: 06/09/2024] [Accepted: 06/14/2024] [Indexed: 06/21/2024]
Abstract
The immune microenvironment plays a critical regulatory role in the pathogenesis of Helicobacter pylori (H. pylori). Understanding the mechanisms that drive the transition from chronic inflammation to cancer may provide new insights for early detection of gastric cancer. Although chronic inflammation is frequent in precancerous gastric conditions, the monitoring function of the inflammatory microenvironment in the progression from H. pylori-induced chronic inflammation to gastric cancer remains unclear. This literature review summarizes significant findings on how H. pylori triggers inflammatory responses and facilitates cancer development through the immune microenvironment. Furthermore, the implications for future research and clinical applications are also addressed. The review is divided into four main sections: inflammatory response and immune evasion mechanisms induced by H. pylori, immune dysregulation associated with gastric cancer, therapeutic implications, and future perspectives on H. pylori-induced gastric carcinogenesis with a focus on the immune microenvironment.
Collapse
Affiliation(s)
- Xiuping Wang
- Department of Clinical Laboratory, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangsu, China
| | - Guang Zhao
- Department of Clinical Laboratory, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangsu, China; Department of Emergency Medicine, Kunshan Hospital Affiliated to Jiangsu University, Kunshan 215300, Jiangsu, China
| | - Shihe Shao
- School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China.
| | - Yongliang Yao
- Department of Clinical Laboratory, Affiliated Kunshan Hospital of Jiangsu University, Kunshan 215300, Jiangsu, China.
| |
Collapse
|
|
3
|
Sun X, Cao S, Mao C, Sun F, Zhang X, Song Y. Post-translational modifications of p65: state of the art. Front Cell Dev Biol 2024; 12:1417502. [PMID: 39050887 PMCID: PMC11266062 DOI: 10.3389/fcell.2024.1417502] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 06/14/2024] [Indexed: 07/27/2024] Open
Abstract
P65, a protein subunit of NF-κB, is a widely distributed transcription factor in eukaryotic cells and exerts diverse regulatory functions. Post-translational modifications such as phosphorylation, acetylation, methylation and ubiquitination modulate p65 transcriptional activity and function, impacting various physiological and pathological processes including inflammation, immune response, cell death, proliferation, differentiation and tumorigenesis. The intricate interplay between these modifications can be antagonistic or synergistic. Understanding p65 post-translational modifications not only elucidates NF-κB pathway regulation but also facilitates the identification of therapeutic targets and diagnostic markers for associated clinical conditions.
Collapse
Affiliation(s)
- Xutao Sun
- Department of Typhoid, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shuo Cao
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Caiyun Mao
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Fengqi Sun
- Department of Pathology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Xuanming Zhang
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yunjia Song
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
| |
Collapse
|
|
4
|
Liu Q, Jiang X, Tu W, Liu L, Huang Y, Xia Y, Xia X, Shi Y. Comparative efficiency of differential diagnostic methods for the identification of BRAF V600E gene mutation in papillary thyroid cancer (Review). Exp Ther Med 2024; 27:149. [PMID: 38476918 PMCID: PMC10928970 DOI: 10.3892/etm.2024.12437] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 02/02/2024] [Indexed: 03/14/2024] Open
Abstract
V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) encodes a serine-threonine kinase. The V600E point mutation in the BRAF gene is the most common mutation, predominantly occurring in melanoma, and colorectal, thyroid and non-small cell lung cancer. Particularly in the context of thyroid cancer research, it is routinely employed as a molecular biomarker to assist in diagnosing and predicting the prognosis of papillary thyroid cancer (PTC), and to formulate targeted therapeutic strategies. Currently, several methods are utilized in clinical settings to detect BRAF V600E mutations in patients with PTC. However, the sensitivity and specificity of various detection techniques vary significantly, resulting in diverse detection outcomes. The present review highlights the advantages and disadvantages of the methods currently employed in medical practice, with the aim of guiding clinicians and researchers in selecting the most suitable detection approach for its high sensitivity, reproducibility and potential to develop targeted therapeutic regimens for patients with BRAF gene mutation-associated PTC.
Collapse
Affiliation(s)
- Qian Liu
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Xue Jiang
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Wenling Tu
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Lina Liu
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Ying Huang
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Yuxiao Xia
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Xuliang Xia
- Department of General Surgery, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| | - Yuhong Shi
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610000, P.R. China
| |
Collapse
|
|
5
|
Huang Z, Huang L, Ding J, Huang Y, Huang X, Li T. ILK inhibition reduces osteophyte formation through suppression of osteogenesis in BMSCs via Akt/GSK-3β/β-catenin pathway. Mol Biol Rep 2024; 51:421. [PMID: 38483756 DOI: 10.1007/s11033-024-09336-5] [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: 10/14/2023] [Accepted: 02/08/2024] [Indexed: 03/19/2024]
Abstract
BACKGROUND Osteophyte development is a common characteristic of inflammatory skeletal diseases. Elevated osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) participates in pathological osteogenesis. Integrin-linked kinase (ILK) positively regulates the osteoblastic differentiation of osteoprogenitors, but whether the ILK blockage prevents osteophytes and its potential mechanism is still unknown. Furthermore, the low-dose tumor necrosis factor-α (TNF-α) promotes osteogenic differentiation, but a lack of study reports on the relationship between this cytokine and ILK. OSU-T315 is a small ILK inhibitor, which was used to determine the effect of ILK inhibition on osteogenesis and osteophyte formation. METHODS AND RESULTS The osteogenesis of BMSCs was evaluated using Alizarin red S staining, alkaline phosphatase, collagen type I alpha 2 chain, and bone gamma-carboxyglutamate protein. The expression and phosphorylation of protein were assessed through western blot. Immunofluorescence was employed to display the distribution of β-catenin. microCT, hematoxylin-eosin, and safranin O/fast green staining were utilized to observe the osteophyte formation in collagen antibody-induced arthritis mice. We found that ILK blockage significantly declined calcium deposition and osteoblastic markers in a dose- and time-dependent manner. Furthermore, it lowered osteogenesis in the TNF-α-induced inflammatory microenvironment by diminishing the effect of ILK and inactivating the Akt/ GSK-3β/ β-catenin pathway. Nuclear β-catenin was descended by OSU-T315 as well. Finally, the ILK suppression restrained osteophyte formation but not inflammation in vivo. CONCLUSIONS ILK inhibition lowered osteogenesis in TNF-α-related inflammatory conditions by deactivating the Akt/ GSK-3β/ β-catenin pathway. This may be a potential strategy to alleviate osteophyte development in addition to anti-inflammatory treatment.
Collapse
Affiliation(s)
- Zhixiang Huang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, No. 466, Xingangzhong Road, Guangzhou, 510317, China
| | - Lixin Huang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, No. 466, Xingangzhong Road, Guangzhou, 510317, China
- Department of Rheumatology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Jiali Ding
- Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, No. 466, Xingangzhong Road, Guangzhou, 510317, China
- Guangdong Medical University, Zhanjiang, China
| | - Yukai Huang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, No. 466, Xingangzhong Road, Guangzhou, 510317, China
| | - Xuechan Huang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, No. 466, Xingangzhong Road, Guangzhou, 510317, China
| | - Tianwang Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
- Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, No. 466, Xingangzhong Road, Guangzhou, 510317, China.
- Guangdong Medical University, Zhanjiang, China.
- Department of Rheumatology and Immunology, Zhaoqing Central People's Hospital, Zhaoqing, China.
| |
Collapse
|
|
6
|
Sun XR, Yao ZM, Chen L, Huang J, Dong SY. Metabolic reprogramming regulates microglial polarization and its role in cerebral ischemia reperfusion. Fundam Clin Pharmacol 2023; 37:1065-1078. [PMID: 37339781 DOI: 10.1111/fcp.12928] [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: 08/14/2022] [Revised: 05/12/2023] [Accepted: 06/07/2023] [Indexed: 06/22/2023]
Abstract
The brain is quite sensitive to changes in energy supply because of its high energetic demand. Even small changes in energy metabolism may be the basis of impaired brain function, leading to the occurrence and development of cerebral ischemia/reperfusion (I/R) injury. Abundant evidence supports that metabolic defects of brain energy during the post-reperfusion period, especially low glucose oxidative metabolism and elevated glycolysis levels, which play a crucial role in cerebral I/R pathophysiology. Whereas research on brain energy metabolism dysfunction under the background of cerebral I/R mainly focuses on neurons, the research on the complexity of microglia energy metabolism in cerebral I/R is just emerging. As resident immune cells of the central nervous system, microglia activate rapidly and then transform into an M1 or M2 phenotype to correspond to changes in brain homeostasis during cerebral I/R injury. M1 microglia release proinflammatory factors to promote neuroinflammation, while M2 microglia play a neuroprotective role by secreting anti-inflammatory factors. The abnormal brain microenvironment promotes the metabolic reprogramming of microglia, which further affects the polarization state of microglia and disrupts the dynamic equilibrium of M1/M2, resulting in the aggravation of cerebral I/R injury. Increasing evidence suggests that metabolic reprogramming is a key driver of microglial inflammation. For example, M1 microglia preferentially produce energy through glycolysis, while M2 microglia provide energy primarily through oxidative phosphorylation. In this review, we highlight the emerging significance of regulating microglial energy metabolism in cerebral I/R injury.
Collapse
Affiliation(s)
- Xiao-Rong Sun
- Department of Pharmacology, School of Pharmacy, Bengbu Medical College, Bengbu, China
| | - Zi-Meng Yao
- Department of Pharmacology, School of Pharmacy, Bengbu Medical College, Bengbu, China
| | - Lei Chen
- Department of Pharmacology, School of Pharmacy, Bengbu Medical College, Bengbu, China
| | - Jie Huang
- Department of Pharmacology, School of Pharmacy, Bengbu Medical College, Bengbu, China
| | - Shu-Ying Dong
- Department of Pharmacology, School of Pharmacy, Bengbu Medical College, Bengbu, China
- Bengbu Medical College Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Bengbu, China
- Anhui Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu, China
| |
Collapse
|
|
7
|
Ahmed AU, Almasabi S, Firestein R, Williams BRG. Integrin-linked kinase expression in myeloid cells promotes colon tumorigenesis. Front Immunol 2023; 14:1270194. [PMID: 38077324 PMCID: PMC10710162 DOI: 10.3389/fimmu.2023.1270194] [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: 07/31/2023] [Accepted: 10/30/2023] [Indexed: 12/18/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common forms of cancer worldwide and treatment options for advanced CRC, which has a low 5-year survival rate, remain limited. Integrin-linked kinase (ILK), a multifunctional, scaffolding, pseudo-kinase regulating many integrin-mediated cellular processes, is highly expressed in many cancers. However, the role of ILK in cancer progression is yet to be fully understood. We have previously uncovered a pro-inflammatory role for myeloid-specific ILK in dextran sodium sulfate (DSS)-induced colitis. To establish a correlation between chronic intestinal inflammation and colorectal cancer (CRC), we investigated the role of myeloid-ILK in mouse models of CRC. When myeloid-ILK deficient mice along with the WT control mice were subjected to colitis-associated and APCmin/+-driven CRC, tumour burden was reduced by myeloid-ILK deficiency in both models. The tumour-promoting phenotype of macrophages, M2 polarization, in vitro was impaired by the ILK deficiency and the number of M2-specific marker CD206-expressing tumour-associated macrophages (TAMs) in vivo were significantly diminished in myeloid-ILK deficient mice. Myeloid-ILK deficient mice showed enhanced tumour infiltration of CD8+ T cells and reduced tumour infiltration of FOXP3+ T cells in colitis-associated and APCmin/+-driven CRC, respectively, with an overall elevated CD8+/FOXP3+ ratio suggesting an anti-tumour immune phenotypes. In patient CRC tissue microarrays we observed elevated ILK+ myeloid (ILK+ CD11b+) cells in tumour sections compared to adjacent normal tissues, suggesting a conserved role for myeloid-ILK in CRC development in both human and animal models. This study identifies myeloid-specific ILK expression as novel driver of CRC, which could be targeted as a potential therapeutic option for advanced disease.
Collapse
Affiliation(s)
- Afsar U Ahmed
- Centre for Cancer Research, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
| | - Saleh Almasabi
- Centre for Cancer Research, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
| | - Ron Firestein
- Centre for Cancer Research, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
| | - Bryan R G Williams
- Centre for Cancer Research, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
| |
Collapse
|
|
8
|
Liao Z, Li D, Liao S, Zeng Z, Liu J, Xie T, Hu B, Wang W, Hong X, Liu D, Yin L, Tang D, Dai Y. Proteomics profiling and lysine malonylation analysis in primary Sjogren's syndrome. J Proteomics 2023; 287:104977. [PMID: 37482272 DOI: 10.1016/j.jprot.2023.104977] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 07/11/2023] [Accepted: 07/16/2023] [Indexed: 07/25/2023]
Abstract
Primary Sjogren's Syndrome (pSS) is a chronic autoimmune disease, with unclear pathogenies. Lysine-malonylation (Kmal) as a novel post-translational modification (PTMs) was found associated with metabolic, immune, and inflammatory processes. For purpose of investigating the proteomic profile and functions of kmal in pSS, liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based analysis and bioinformatics analysis are performed based on twenty-eight pSS patients versus twenty-seven healthy controls (HCs). A total of 331 down-regulated proteins and 289 up-regulated proteins are observed in differentially expressed proteins (DEPs) of pSS. We discover the expression of transforming growth factor beta-1 (TGFB1) and CD40 ligand downregulate which enriches in the inflammatory associated pathway. Expression of signal transducer and activator of transcription 1-alpha/beta (STAT1) show upregulation and enrich in type I interferon signaling pathway and IL-27-mediated signaling pathway. In differentially malonylated proteins (DMPs) of pSS, we identify 3 proteins are down-regulated in 7 sites and 18 proteins are up-regulated in 19 sites. Expression of malonylated integrin-linked kinase (ILK) significantly enrich in the focal adhesion pathway. Together, our data provide evidence that downregulation of TGFB1 and CD40LG play a critical role in the inflammatory process of pSS, while upregulation of STAT1 may be associated with IL-27 immunity and pSS immune dysfunction. Moreover, kmal modification at the kinase domain of ILK may destabilize ILK that thus contributing to pSS pathogenies by regulating the focal adhesion pathway. SIGNIFICANCE: Our research offered the first characterization of Kmal, a newly identified form of lysine acylation in pSS, as well as proteomic data on individuals with pSS. In this study, we found that several key DMPs were associated with focal adhesion pathway, which contributes to the development of pSS. The present results provide an informative dataset for the future exploration of Kmal in pSS.
Collapse
Affiliation(s)
- Zhennan Liao
- Department of Nephrology, Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Guangzhou, China; China Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Dandan Li
- China Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Shengyou Liao
- China Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Zhipeng Zeng
- China Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Jiayi Liu
- China Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Ting Xie
- Department of Nephrology, Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Bo Hu
- Department of Nephrology, Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Wei Wang
- China Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Xiaoping Hong
- Department of Rheumatology and Immunology, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Dongzhou Liu
- Department of Rheumatology and Immunology, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Lianghong Yin
- Department of Nephrology, Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Guangzhou, China.
| | - Donge Tang
- China Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China.
| | - Yong Dai
- The First Affiliated Hospital, School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, China.
| |
Collapse
|
|
9
|
Gitau JK, Macharia RW, Mwangi KW, Ongeso N, Murungi E. Gene co-expression network identifies critical genes, pathways and regulatory motifs mediating the progression of rift valley fever in Bostaurus. Heliyon 2023; 9:e18175. [PMID: 37519716 PMCID: PMC10375796 DOI: 10.1016/j.heliyon.2023.e18175] [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: 08/01/2022] [Revised: 07/04/2023] [Accepted: 07/10/2023] [Indexed: 08/01/2023] Open
Abstract
Rift Valley Fever (RVF) is a mosquito-borne viral disease caused by the Rift Valley Fever Virus. The disease is a zoonosis that largely affects domestic animals, including sheep, goats, and cattle, resulting in severe morbidity and mortality marked by massive storm abortions. To halt human and livestock deaths due to RVF, the development of efficacious vaccines and therapeutics is a compelling and urgent priority. We sought to identify potential key modules (gene clusters), hub genes, and regulatory motifs involved in the pathogenesis of RVF in Bos taurus that are amenable to inhibition. We analyzed 39 Bos taurus RNA-Seq samples using the weighted gene co-expression network analysis (WGCNA) R package and uncovered significantly enriched modules containing genes with potential pivotal roles in RVF progression. Moreover, regulatory motif analysis conducted using the Multiple Expectation Maximization for Motif Elicitation (MEME) suite identified motifs that probably modulate vital biological processes. Gene ontology terms associated with identified motifs were inferred using the GoMo human database. The gene co-expression network constructed in WGCNA using 5000 genes contained seven (7) modules, out of which four were significantly enriched for terms associated with response to viruses, response to interferon-alpha, innate immune response, and viral defense. Additionally, several biological pathways implicated in developmental processes, anatomical structure development, and multicellular organism development were identified. Regulatory motifs analysis identified short, repeated motifs whose function(s) may be amenable to disruption by novel therapeutics. Predicted functions of identified motifs include tissue development, embryonic organ development, and organ morphogenesis. We have identified several hub genes in enriched co-expressed gene modules and regulatory motifs potentially involved in the pathogenesis of RVF in B. taurus that are likely viable targets for disruption by novel therapeutics.
Collapse
Affiliation(s)
- John K. Gitau
- University of Nairobi, Biochemistry Department, P.O Box 30197, 00100, Nairobi, Kenya
| | - Rosaline W. Macharia
- University of Nairobi, Biochemistry Department, P.O Box 30197, 00100, Nairobi, Kenya
| | - Kennedy W. Mwangi
- Jomo Kenyatta University of Agriculture and Technology, P.O Box 62000, 00200, Nairobi, Kenya
| | - Nehemiah Ongeso
- University of Nairobi, Biochemistry Department, P.O Box 30197, 00100, Nairobi, Kenya
| | - Edwin Murungi
- Kisii University, Department of Medical Biochemistry, P.O Box 408, 40200, Kisii, Kenya
| |
Collapse
|
|
10
|
Li L, Miao J, Shaheen N, Taleb SJ, Hu J, Ye Q, He J, Yan J, Mallampalli RK, Zhao J, Zhao Y. ISGylation of NF-κBp65 by SCF FBXL19 E3 Ligase Diminishes Endothelial Inflammation. Arterioscler Thromb Vasc Biol 2023; 43:674-683. [PMID: 36994728 PMCID: PMC10133096 DOI: 10.1161/atvbaha.122.318894] [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: 06/27/2022] [Accepted: 03/21/2023] [Indexed: 03/31/2023]
Abstract
BACKGROUND NF-κB (nuclear factor kappa B) plays a pivotal role in endothelial cell (EC) inflammation. Protein ISGylation is regulated by E3 ISG15 (interferon-stimulated gene 15) ligases; however, ISGylation of NF-κBp65 and its role in EC functions have not been investigated. Here, we investigate whether p65 is ISGylated and the role of its ISGylation in endothelial functions. METHODS In vitro ISGylation assay and EC inflammation were performed. EC-specific transgenic mice were utilized in a murine model of acute lung injury. RESULTS We find that NF-κBp65 is ISGylated in resting ECs and that the posttranslational modification is reversible. TNFα (tumor necrosis factor alpha) and endotoxin stimulation of EC reduce p65 ISGylation, promoting its serine phosphorylation through reducing its association with a phosphatase WIP1 (wild-type p53-induced phosphatase 1). Mechanistically, an SCF (Skp1-Cul1-F-box) protein E3 ligase SCFFBXL19 is identified as a new ISG15 E3 ligase that targets and catalyzes ISGylation of p65. Depletion of FBXL19 (F-box and leucine-rich repeat protein 19) increases p65 phosphorylation and EC inflammation, suggesting a negative correlation between p65 ISGylation and phosphorylation. Moreover, EC-specific FBXL19 overexpressing humanized transgenic mice exhibit reduced lung inflammation and severity of experimental acute lung injury. CONCLUSIONS Together, our data reveal a new posttranslational modification of p65 catalyzed by a previously unrecognized role of SCFFBXL19 as an ISG15 E3 ligase that modulates EC inflammation.
Collapse
Affiliation(s)
- Lian Li
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, the Ohio State University, Columbus, OH
| | - Jiaxing Miao
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, the Ohio State University, Columbus, OH
| | - Nargis Shaheen
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, the Ohio State University, Columbus, OH
| | - Sarah J. Taleb
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, the Ohio State University, Columbus, OH
| | - Jian Hu
- Department of Internal Medicine, the Ohio State University, Columbus, OH
| | - Qinmao Ye
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, the Ohio State University, Columbus, OH
| | - Jinshan He
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, the Ohio State University, Columbus, OH
| | - Jiasheng Yan
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, the Ohio State University, Columbus, OH
| | | | - Jing Zhao
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, the Ohio State University, Columbus, OH
- Department of Internal Medicine, the Ohio State University, Columbus, OH
| | - Yutong Zhao
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, the Ohio State University, Columbus, OH
- Department of Internal Medicine, the Ohio State University, Columbus, OH
| |
Collapse
|
|
11
|
Kao YS, Wang LC, Chang PC, Lin HM, Lin YS, Yu CY, Chen CC, Lin CF, Yeh TM, Wan SW, Wang JR, Ho TS, Chu CC, Zhang BC, Chang CP. Negative regulation of type I interferon signaling by integrin-linked kinase permits dengue virus replication. PLoS Pathog 2023; 19:e1011241. [PMID: 36930690 PMCID: PMC10057834 DOI: 10.1371/journal.ppat.1011241] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 03/29/2023] [Accepted: 02/25/2023] [Indexed: 03/18/2023] Open
Abstract
Dengue virus (DENV) infection can induce life-threatening dengue hemorrhagic fever/dengue shock syndrome in infected patients. DENV is a threat to global health due to its growing numbers and incidence of infection in the last 50 years. During infection, DENV expresses ten structural and nonstructural proteins modulating cell responses to benefit viral replication. However, the lack of knowledge regarding the cellular proteins and their functions in enhancing DENV pathogenesis impedes the development of antiviral drugs and therapies against fatal DENV infection. Here, we identified that integrin-linked kinase (ILK) is a novel enhancing factor for DENV infection by suppressing type I interferon (IFN) responses. Mechanistically, ILK binds DENV NS1 and NS3, activates Akt and Erk, and induces NF-κB-driven suppressor of cytokine signaling 3 (SOCS3) expression. Elevated SOCS3 in DENV-infected cells inhibits phosphorylation of STAT1/2 and expression of interferon-stimulated genes (ISGs). Inhibiting ILK, Akt, or Erk activation abrogates SOCS3 expression. In DENV-infected mice, the treatment of an ILK inhibitor significantly reduces viral loads in the brains, disease severity, and mortality rate. Collectively, our results show that ILK is a potential therapeutic target against DENV infection.
Collapse
Affiliation(s)
- Yi-Sheng Kao
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Li-Chiu Wang
- School of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Po-Chun Chang
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Heng-Ming Lin
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yee-Shin Lin
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Yi Yu
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan
| | - Chien-Chin Chen
- Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
- Department of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Chiou-Feng Lin
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Trai-Ming Yeh
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Shu-Wen Wan
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
| | - Jen-Ren Wang
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tzong-Shiann Ho
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
- Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chien-Chou Chu
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Bo-Cheng Zhang
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Peng Chang
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
- * E-mail:
| |
Collapse
|
|
12
|
Khaleel A, Zakariya AB, Niazi M, Qinna NA, Dayyih WA, Tarkhan AH. Pathway Analysis of Patients with Severe Acute Respiratory Syndrome. Drug Res (Stuttg) 2022; 72:466-472. [PMID: 35952682 DOI: 10.1055/a-1886-2094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
BACKGROUND Coronaviruses are emerging threats for human health, as demonstrated by the ongoing coronavirus disease 2019 (COVID-19) pandemic that is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is closely related to SARS-CoV-1, which was the cause of the 2002-2004 SARS outbreak, but SARS-CoV-1 has been the subject of a relatively limited number of studies. Understanding the potential pathways and molecular targets of SARS-CoV-1 will contribute to current drug repurposing strategies by helping to predict potential drug-disease associations. METHODS A microarray dataset, GSE1739, of 10 SARS patients and 4 healthy controls was downloaded from NCBI's GEO repository, and differential expression was identified using NCBI's GEO2R software. Pathway and enrichment analysis of the differentially expressed genes was carried out using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis, respectively. RESULTS Our findings show that the drugs dexamethasone, filgrastim, interferon alfacon-1, and levodopa were among the most significant upstream regulators of differential gene expression in SARS patients, while neutrophil degranulation was the most significantly enriched pathway. CONCLUSION An enhanced understanding of the pathways and molecular targets of SARS-CoV-1 in humans will contribute to current and future drug repurposing strategies, which are an essential tool to combat rapidly emerging health threats.
Collapse
Affiliation(s)
- Anas Khaleel
- Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
| | | | - Mohammad Niazi
- Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
| | - Nidal A Qinna
- University of Petra Pharmaceutical Center (UPPC), Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
| | | | | |
Collapse
|
|
13
|
Abdelmoaty MM, Machhi J, Yeapuri P, Shahjin F, Kumar V, Olson KE, Mosley RL, Gendelman HE. Monocyte biomarkers define sargramostim treatment outcomes for Parkinson's disease. Clin Transl Med 2022; 12:e958. [PMID: 35802825 PMCID: PMC9270000 DOI: 10.1002/ctm2.958] [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: 04/11/2022] [Revised: 06/11/2022] [Accepted: 06/17/2022] [Indexed: 12/26/2022] Open
Abstract
Background Dysregulation of innate and adaptive immunity heralds both the development and progression of Parkinson's disease (PD). Deficits in innate immunity in PD are defined by impairments in monocyte activation, function, and pro‐inflammatory secretory factors. Each influences disease pathobiology. Methods and Results To define monocyte biomarkers associated with immune transformative therapy for PD, changes in gene and protein expression were evaluated before and during treatment with recombinant human granulocyte‐macrophage colony‐stimulating factor (GM‐CSF, sargramostim, Leukine®). Monocytes were recovered after leukapheresis and isolation by centrifugal elutriation, before and 2 and 6 months after initiation of treatment. Transcriptome and proteome biomarkers were scored against clinical motor functions. Pathway enrichments from single cell‐RNA sequencing and proteomic analyses from sargramostim‐treated PD patients demonstrate a neuroprotective signature, including, but not limited to, antioxidant, anti‐inflammatory, and autophagy genes and proteins (LRRK2, HMOX1, TLR2, TLR8, RELA, ATG7, and GABARAPL2). Conclusions This monocyte profile provides an “early” and unique biomarker strategy to track clinical immune‐based interventions, but requiring validation in larger case studies.
Collapse
Affiliation(s)
- Mai M Abdelmoaty
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.,Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Giza, Egypt.,Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Jatin Machhi
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Pravin Yeapuri
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.,Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Farah Shahjin
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Vikas Kumar
- Mass Spectrometry and Proteomics Core, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Katherine E Olson
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - R Lee Mosley
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Howard E Gendelman
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.,Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| |
Collapse
|
|
14
|
Latour YL, Sierra JC, Finley JL, Asim M, Barry DP, Allaman MM, Smith TM, McNamara KM, Luis PB, Schneider C, Jacobse J, Goettel JA, Calcutt MW, Rose KL, Schey KL, Milne GL, Delgado AG, Piazuelo MB, Paul BD, Snyder SH, Gobert AP, Wilson KT. Cystathionine γ-lyase exacerbates Helicobacter pylori immunopathogenesis by promoting macrophage metabolic remodeling and activation. JCI Insight 2022; 7:e155338. [PMID: 35579952 PMCID: PMC9309056 DOI: 10.1172/jci.insight.155338] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 05/10/2022] [Indexed: 11/17/2022] Open
Abstract
Macrophages play a crucial role in the inflammatory response to the human stomach pathogen Helicobacter pylori, which infects half of the world's population and causes gastric cancer. Recent studies have highlighted the importance of macrophage immunometabolism in their activation state and function. We have demonstrated that the cysteine-producing enzyme cystathionine γ-lyase (CTH) is upregulated in humans and mice with H. pylori infection. Here, we show that induction of CTH in macrophages by H. pylori promoted persistent inflammation. Cth-/- mice had reduced macrophage and T cell activation in H. pylori-infected tissues, an altered metabolome, and decreased enrichment of immune-associated gene networks, culminating in decreased H. pylori-induced gastritis. CTH is downstream of the proposed antiinflammatory molecule, S-adenosylmethionine (SAM). Whereas Cth-/- mice exhibited gastric SAM accumulation, WT mice treated with SAM did not display protection against H. pylori-induced inflammation. Instead, we demonstrated that Cth-deficient macrophages exhibited alterations in the proteome, decreased NF-κB activation, diminished expression of macrophage activation markers, and impaired oxidative phosphorylation and glycolysis. Thus, through altering cellular respiration, CTH is a key enhancer of macrophage activation, contributing to a pathogenic inflammatory response that is the universal precursor for the development of H. pylori-induced gastric disease.
Collapse
Affiliation(s)
- Yvonne L. Latour
- Department of Pathology, Microbiology, and Immunology
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and
| | - Johanna C. Sierra
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jordan L. Finley
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and
| | - Mohammad Asim
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and
| | - Daniel P. Barry
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and
| | - Margaret M. Allaman
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and
| | - Thaddeus M. Smith
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and
| | - Kara M. McNamara
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and
- Program in Cancer Biology
| | | | - Claus Schneider
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pharmacology, and
| | - Justin Jacobse
- Department of Pathology, Microbiology, and Immunology
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and
| | - Jeremy A. Goettel
- Department of Pathology, Microbiology, and Immunology
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M. Wade Calcutt
- Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Kristie L. Rose
- Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Kevin L. Schey
- Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Ginger L. Milne
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Alberto G. Delgado
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and
| | - M. Blanca Piazuelo
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Bindu D. Paul
- Department of Psychiatry and Behavioral Sciences
- Department of Pharmacology and Molecular Sciences, and
| | - Solomon H. Snyder
- Department of Psychiatry and Behavioral Sciences
- Department of Pharmacology and Molecular Sciences, and
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Alain P. Gobert
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Keith T. Wilson
- Department of Pathology, Microbiology, and Immunology
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Program in Cancer Biology
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| |
Collapse
|
|
15
|
Yang Y, Song J, Liu N, Wei G, Liu S, Zhang S, Jiang N, Yang H, Du G. Salvianolic acid A relieves cognitive disorder after chronic cerebral ischemia: Involvement of Drd2/Cryab/NF-κB pathway. Pharmacol Res 2022; 175:105989. [PMID: 34800628 DOI: 10.1016/j.phrs.2021.105989] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 11/03/2021] [Accepted: 11/12/2021] [Indexed: 12/14/2022]
Abstract
Chronic cerebral ischemia (CCI) refers to long-term hypoperfusion of cerebral blood flow with the main clinical manifestations of progressive cognitive impairment. The pathological mechanism of CCI is complex, and there is a lack of effective treatments. Salvianolic acid A (SalA) is a neuroprotective extract of Salvia miltiorrhiza with the effects of anti-inflammation and anti-apoptosis. In this study, the effect of SalA on cognitive function and Drd2/Cryab/NF-κB signaling pathway in rats with CCI was investigated. Morris water maze and open field test were used to observe the effects of SalA on the cognitive function of CCI rats. The pathological changes in the brain were observed by HE, Nissl, and LFB staining. TUNEL staining, enzyme-linked immunosorbent assay, and western blot analysis were used to detect the inflammatory and apoptosis in the cortex and hippocampus. The expression of Drd2/Cryab/NF-κB pathway-related molecules and Drd2 localization were detected by western blotting and dual immunofluorescence, respectively. SH-SY5Y cells were exposed to chronic hypoglycemic and hypoxic injury in vitro, and Drd2 inhibitor haloperidol was used to verify the involved pathway. The results showed that SalA could improve the cognitive function of CCI rats, reduce pathological damage of cortex and hippocampus, inhibit neuroinflammation and apoptosis, and suppress the activation of NF-κB by regulating Drd2/Cryab pathway. And SalA inhibited NF-κB activation and nuclear translocation in SH-SY5Y cells by upregulating Drd2/Cryab pathway, which was reversed by haloperidol interference. In conclusion, SalA could relieve CCI-induced cognitive impairment in rats, at least partly through the Drd2/Cryab/NF-κB pathway.
Collapse
Affiliation(s)
- Yujiao Yang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China; Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Junke Song
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
| | - NanNan Liu
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China; College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, 280 Waihuan East Road, Panyu District, Guangdong 510006, PR China
| | - Guangyi Wei
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China; College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, 280 Waihuan East Road, Panyu District, Guangdong 510006, PR China
| | - Shan Liu
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China; College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, 280 Waihuan East Road, Panyu District, Guangdong 510006, PR China
| | - Sen Zhang
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Nan Jiang
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China; School of Pharmacy, Henan University, North Section of Jinming Avenue, Kaifeng 475004, Henan, PR China
| | - Haiguang Yang
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Guanhua Du
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China; Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
| |
Collapse
|
|
16
|
Swartzwelter BJ, Michelini S, Frauenlob T, Barbero F, Verde A, De Luca AC, Puntes V, Duschl A, Horejs-Hoeck J, Italiani P, Boraschi D. Innate Memory Reprogramming by Gold Nanoparticles Depends on the Microbial Agents That Induce Memory. Front Immunol 2021; 12:751683. [PMID: 34804037 PMCID: PMC8600232 DOI: 10.3389/fimmu.2021.751683] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 10/14/2021] [Indexed: 01/14/2023] Open
Abstract
Innate immune memory, the ability of innate cells to react in a more protective way to secondary challenges, is induced by exposure to infectious and other exogeous and endogenous agents. Engineered nanoparticles are particulate exogenous agents that, as such, could trigger an inflammatory reaction in monocytes and macrophages and could therefore be also able to induce innate memory. Here, we have evaluated the capacity of engineered gold nanoparticles (AuNPs) to induce a memory response or to modulate the memory responses induced by microbial agents. Microbial agents used were in soluble vs. particulate form (MDP and the gram-positive bacteria Staphylococcus aureus; β-glucan and the β-glucan-producing fungi C. albicans), and as whole microrganisms that were either killed (S. aureus, C. albicans) or viable (the gram-negative bacteria Helicobacter pylori). The memory response was assessed in vitro, by exposing human primary monocytes from 2-7 individual donors to microbial agents with or without AuNPs (primary response), then resting them for 6 days to allow return to baseline, and eventually challenging them with LPS (secondary memory response). Primary and memory responses were tested as production of the innate/inflammatory cytokine TNFα and other inflammatory and anti-inflammatory factors. While inactive on the response induced by soluble microbial stimuli (muramyl dipeptide -MDP-, β-glucan), AuNPs partially reduced the primary response induced by whole microorganisms. AuNPs were also unable to directly induce a memory response but could modulate stimulus-induced memory in a circumscribed fashion, limited to some agents and some cytokines. Thus, the MDP-induced tolerance in terms of TNFα production was further exacerbated by co-priming with AuNPs, resulting in a less inflammatory memory response. Conversely, the H. pylori-induced tolerance was downregulated by AuNPs only relative to the anti-inflammatory cytokine IL-10, which would lead to an overall more inflammatory memory response. These effects of AuNPs may depend on a differential interaction/association between the reactive particle surfaces and the microbial components and agents, which may lead to a change in the exposure profiles. As a general observation, however, the donor-to-donor variability in memory response profiles and reactivity to AuNPs was substantial, suggesting that innate memory depends on the individual history of exposures.
Collapse
Affiliation(s)
- Benjamin J. Swartzwelter
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Napoli, Italy
- Department Biosciences, Paris Lodron University of Salzburg (PLUS), Salzburg, Austria
| | - Sara Michelini
- Department Biosciences, Paris Lodron University of Salzburg (PLUS), Salzburg, Austria
| | - Tobias Frauenlob
- Department Biosciences, Paris Lodron University of Salzburg (PLUS), Salzburg, Austria
| | - Francesco Barbero
- Institut Català de Nanociència i Nanotecnologia (ICN2), Consejo Superior de Investigaciones Científicas (CSIC) and The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Alessandro Verde
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Napoli, Italy
| | - Anna Chiara De Luca
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Napoli, Italy
| | - Victor Puntes
- Institut Català de Nanociència i Nanotecnologia (ICN2), Consejo Superior de Investigaciones Científicas (CSIC) and The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
- Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain
| | - Albert Duschl
- Department Biosciences, Paris Lodron University of Salzburg (PLUS), Salzburg, Austria
| | - Jutta Horejs-Hoeck
- Department Biosciences, Paris Lodron University of Salzburg (PLUS), Salzburg, Austria
| | - Paola Italiani
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Napoli, Italy
| | - Diana Boraschi
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Napoli, Italy
- Stazione Zoologica Anton Dohrn, Napoli, Italy
- Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, China
| |
Collapse
|
|
17
|
Feng J, Ge C, Li W, Li R. 3-(3-Hydroxyphenyl)propionic acid, a microbial metabolite of quercetin, inhibits monocyte binding to endothelial cells via modulating E-selectin expression. Fitoterapia 2021; 156:105071. [PMID: 34743931 DOI: 10.1016/j.fitote.2021.105071] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/23/2021] [Accepted: 10/24/2021] [Indexed: 11/18/2022]
Abstract
Adhesion of monocytes to endothelial cells is an important initiating step in atherogenesis. One of the most abundant flavonoids in the diet, quercetin has been reported to inhibit monocyte adhesion to endothelial cells. However, it is poorly absorbed in the upper gastrointestinal tract during oral intake but rather is metabolized by the intestinal microbiota into various phenolic acids. Since the biological properties of the microbial metabolites of quercetin remain largely unknown, herein, we investigated how the microbial metabolite of quercetin, 3-(3-hydroxyphenyl)propionic acid (3HPPA) impact monocyte adhesion to endothelial cells. Direct treatment with 3HPPA for 24 h was not cytotoxic to human aortic endothelial cells (HAECs). Cotreatment with 3HPPA inhibited tumor necrosis factor α (TNFα)-induced adhesion of THP-1 monocytes to HAECs, and suppressed the upregulation of cell adhesion molecule E-selectin but not intercellular adhesion molecule 1 or vascular cell adhesion molecule 1. Furthermore, 3HPPA was found to inhibit TNFα-induced nuclear translocation and phosphorylation of the p65 subunit of nuclear factor κB (NF-κB). We conclude that 3HPPA mitigates the adhesion of monocytes to endothelial cells by suppressing the expression of the cell adhesion molecule E-selectin in HAECs via inhibition of the NF-κB pathway, providing additional evidence for the health benefits of dietary flavonoids and their microbial metabolites as therapeutic agents in atherosclerosis.
Collapse
Affiliation(s)
- Juan Feng
- College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen, Guangdong, People's Republic of China
| | - Chenchen Ge
- College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen, Guangdong, People's Republic of China
| | - Weixi Li
- College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen, Guangdong, People's Republic of China
| | - Rongsong Li
- College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen, Guangdong, People's Republic of China.
| |
Collapse
|
|
18
|
Peng C, Wu C, Xu X, Pan L, Lou Z, Zhao Y, Jiang H, He Z, Ruan B. Indole-3-carbinol ameliorates necroptosis and inflammation of intestinal epithelial cells in mice with ulcerative colitis by activating aryl hydrocarbon receptor. Exp Cell Res 2021; 404:112638. [PMID: 34015312 DOI: 10.1016/j.yexcr.2021.112638] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 05/02/2021] [Accepted: 05/05/2021] [Indexed: 12/12/2022]
Abstract
Ulcerative colitis (UC) is a disease characterized by inflammation and disruption of the intestinal epithelial barrier. Necroptosis plays a critical role in disease progression. Indole-3-carbinol (I3C), a natural dietary agonist of aryl hydrocarbon receptor (AHR), has shown alleviating effects on UC. However, its mechanisms of action have not been comprehensively elucidated. Therefore, we aimed at investigating the protective role of I3C in DSS-induced colitis mice models. I3C significantly ameliorated body weight loss, colon length shortening and colonic pathological damage in colitis mice, reduced disease activity index (DAI) and histological (HI) scores, as well as alleviated colonic necroptosis and inflammation. In vitro, I3C attenuated necroptosis and inflammation of colonoids and NCM460 cells. AHR, activated by I3C, inhibits activation of receptor-interacting protein kinase 1 (RIPK1) and the subsequent assembly of necrosome in a time-dependent manner, as well as suppressing NF-κB activation and decreasing TNF-α, IL-1β, IL-6 and IL-8 expression. Silencing of AHR aggravated necroptosis and inflammation of NCM460 cells, and did not be ameliorated by I3C. Furthermore, AHR activation induces the expression of inhibitor of apoptosis proteins (IAPs) and the ubiquitination of RIPK1. In conclusion, I3C exerts a protective effect in DSS-induced colitis mice models by alleviating the necroptosis and inflammation of IECs through activating AHR.
Collapse
Affiliation(s)
- Chunting Peng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, China
| | - Chensi Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, China
| | - Xiaolan Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, China
| | - Liya Pan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, China
| | - Zhuoqi Lou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, China
| | - Yanhong Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, China
| | - Haiyin Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, China
| | - Zebao He
- Department of Infectious Diseases, Taizhou Enze Medical Center (Group) Enze Hospital, Taizhou, Zhejiang, 318000, China
| | - Bing Ruan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, China.
| |
Collapse
|
|
19
|
Almasabi S, Ahmed AU, Boyd R, Williams BRG. A Potential Role for Integrin-Linked Kinase in Colorectal Cancer Growth and Progression via Regulating Senescence and Immunity. Front Genet 2021; 12:638558. [PMID: 34163519 PMCID: PMC8216764 DOI: 10.3389/fgene.2021.638558] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 03/08/2021] [Indexed: 01/10/2023] Open
Abstract
Integrin-linked kinase (ILK) has been implicated as a molecular driver and mediator in both inflammation and tumorigenesis of the colon. ILK functions as an adaptor and mediator protein linking the extracellular matrix with downstream signaling pathways. ILK is broadly expressed in many human tissues and cells. It is also overexpressed in many cancers, including colorectal cancer (CRC). Inflammation, as evidenced by inflammatory bowel disease (IBD), is one of the highest risk factors for initiating CRC. This has led to the hypothesis that targeting ILK therapeutically could have potential in CRC, as it regulates different cellular processes associated with CRC development and progression as well as inflammation in the colon. A number of studies have indicated an ILK function in senescence, a cellular process that arrests the cell cycle while maintaining active metabolism and transcription. Senescent cells produce different secretions collectively known as the senescence-associated secretory phenotype (SASP). The SASP secretions influence infiltration of different immune cells, either positively for clearing senescent cells or negatively for promoting tumor growth, reflecting the dual role of senescence in cancer. However, a role for ILK in senescence and immunity in CRC remains to be determined. In this review, we discuss the possible role for ILK in senescence and immunity, paying particular attention to the relevance of ILK in CRC. We also examine how activating Toll-like receptors (TLRs) and their agonists in CRC could trigger immune responses against cancer, as a combination therapy with ILK inhibition.
Collapse
Affiliation(s)
- Saleh Almasabi
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Cartherics, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Clinical Laboratory Sciences, Applied Medical Sciences, Najran University, Najran, Saudi Arabia.,Department of Molecular and Translational Sciences, Faculty of Medicine Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
| | - Afsar U Ahmed
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Richard Boyd
- Cartherics, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Bryan R G Williams
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
| |
Collapse
|
|
20
|
Integrin-Linked Kinase (ILK) Regulates Urinary Stem Cells Differentiation into Smooth Muscle via NF- κB Signal Pathway. Stem Cells Int 2021; 2021:6633111. [PMID: 33854551 PMCID: PMC8019365 DOI: 10.1155/2021/6633111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 02/28/2021] [Accepted: 03/09/2021] [Indexed: 11/17/2022] Open
Abstract
Objectives Urinary stem cells (USCs) have the capacity for unlimited growth and are promising tools for the investigations of cell differentiation and urinary regeneration. However, the limited life span significantly restricts their usefulness. This study is aimed at exploring the effect of integrin-linked kinase (ILK) on the smooth muscle cells (SMCs) differentiation of the dog USCs and investigating its molecular mechanism. Methods An immortalized USCs cell line with the molecular markers and biological functions was prepared. After successfully inducing the differentiation of USCs into SMCs, the expression level of the unique key factor and its mechanisms in this process was determined through real-time polymerase chain reaction, Western blot, or Immunofluorescence staining. Results We found that high cell density promoted USCs differentiation SMCs, and ILK was necessary for USCs differentiation into SMCs. Knocking down ILK decreased the expression of SMCs specific-marker, while using a selective ILK agonist increased the expression of SMCs specific-marker. Furthermore, ILK regulated SMCs differentiation in part through the activation of NF-κB pathway in USCs. A NF-κB activity assay showed overexpression of ILK could significantly upregulate NF-κB p50 expression, and NF-κB p50 acts as downstream signal molecular of ILK. Conclusion High cell density induces the differentiation of USCs into SMCs, and ILK is a key regulator of myogenesis. Furthermore, NF-κB signaling pathway might play a crucial role in this process.
Collapse
|
|
21
|
Wu C, Yang M, Liu R, Hu H, Ji L, Zhang X, Huang S, Wang L. Nicotine Reduces Human Brain Microvascular Endothelial Cell Response to Escherichia coli K1 Infection by Inhibiting Autophagy. Front Cell Infect Microbiol 2020; 10:484. [PMID: 33042863 PMCID: PMC7522313 DOI: 10.3389/fcimb.2020.00484] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 08/04/2020] [Indexed: 01/22/2023] Open
Abstract
Studies have shown that exposure to environmental tobacco smoke can increase the risk of bacterial meningitis, and nicotine is the core component of environmental tobacco smoke. Autophagy is an important way for host cells to eliminate invasive pathogens and resist infection. Escherichia coli K1 strain (E. coli K1) is the most common Gram-negative bacterial pathogen that causes neonatal meningitis. The mechanism of nicotine promoting E. coli K1 to invade human brain microvascular endothelial cells (HBMECs), the main component of the blood–brain barrier, is not clear yet. Our study found that the increase of HBMEC autophagy level during E. coli K1 infection could decrease the survival of intracellular bacteria, while nicotine exposure could inhibit the HBMEC autophagic response of E. coli K1 infection by activating the NF-kappa B and PI3K/Akt/mTOR pathway. We concluded that nicotine could inhibit HBMEC autophagy upon E. coli K1 infection and decrease the scavenging effect on E. coli K1, thus promoting the occurrence and development of neonatal meningitis.
Collapse
Affiliation(s)
- Chao Wu
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Mengzhen Yang
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Rui Liu
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.,Department of Human Anatomy, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Hanyang Hu
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Lulu Ji
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Xiaoli Zhang
- Department of Ultrasound Imaging, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shenghe Huang
- Kunming Key Laboratory of Children Infection and Immunity, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming, China.,Department of Pediatrics, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, United States
| | - Lin Wang
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, China
| |
Collapse
|
|
22
|
Silva JF, Olivon VC, Mestriner FLAC, Zanotto CZ, Ferreira RG, Ferreira NS, Silva CAA, Luiz JPM, Alves JV, Fazan R, Cunha FQ, Alves-Filho JC, Tostes RC. Acute Increase in O-GlcNAc Improves Survival in Mice With LPS-Induced Systemic Inflammatory Response Syndrome. Front Physiol 2020; 10:1614. [PMID: 32038294 PMCID: PMC6985589 DOI: 10.3389/fphys.2019.01614] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 12/23/2019] [Indexed: 12/29/2022] Open
Abstract
Sepsis is a systemic inflammatory response syndrome (SIRS) resulting from a severe infection that is characterized by immune dysregulation, cardiovascular derangements, and end-organ dysfunction. The modification of proteins by O-linked N-acetylglucosamine (O-GlcNAcylation) influences many of the key processes that are altered during sepsis, including the production of inflammatory mediators and vascular contractility. Here, we investigated whether O-GlcNAc affects the inflammatory response and cardiovascular dysfunction associated with sepsis. Mice received an intraperitoneal injection of lipopolysaccharide (LPS, 20 mg/Kg) to induce endotoxic shock and systemic inflammation, resembling sepsis-induced SIRS. The effects of an acute increase in O-GlcNAcylation, by treatment of mice with glucosamine (GlcN, 300 mg/Kg, i.v.) or thiamet-G (ThG, 150 μg/Kg, i.v.), on LPS-associated mortality, production and release of cytokines by macrophages and vascular cells, vascular responsiveness to constrictors and blood pressure were then determined. Mice under LPS-induced SIRS exhibited a systemic and local inflammatory response with increased levels of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α), as well as severe hypotension and vascular hyporesponsiveness, characterized by reduced vasoconstriction to phenylephrine. In addition, LPS increased neutrophil infiltration in lungs and produced significant lethality. Treatment with GlcN and ThG reduced systemic inflammation and attenuated hypotension and the vascular refractoriness to phenylephrine, improving survival. GlcN and ThG also decreased LPS-induced production of inflammatory cytokines by bone marrow-derived macrophages and nuclear transcription factor-kappa B (NF-κB) activation in RAW 264.7 NF-κB promoter macrophages. Treatment of mice with ThG increased O-glycosylation of NF-κB p65 subunit in mesenteric arteries, which was associated with reduced Ser536 phosphorylation of NF-κB p65. Finally, GlcN also increased survival rates in mice submitted to cecal ligation and puncture (CLP), a sepsis model. In conclusion, increased O-GlcNAc reduces systemic inflammation and cardiovascular disfunction in experimental sepsis models, pointing this pathway as a potential target for therapeutic intervention.
Collapse
Affiliation(s)
- Josiane Fernandes Silva
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | | | - Fabiola Leslie A C Mestriner
- Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Camila Ziliotto Zanotto
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Raphael Gomes Ferreira
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Nathanne Santos Ferreira
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | | | - João Paulo Mesquita Luiz
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Juliano Vilela Alves
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Rubens Fazan
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Fernando Queiróz Cunha
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Jose Carlos Alves-Filho
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Rita C Tostes
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| |
Collapse
|
|
23
|
Yue Y, Wang C, Benedict C, Huang G, Truongcao M, Roy R, Cimini M, Garikipati VNS, Cheng Z, Koch WJ, Kishore R. Interleukin-10 Deficiency Alters Endothelial Progenitor Cell-Derived Exosome Reparative Effect on Myocardial Repair via Integrin-Linked Kinase Enrichment. Circ Res 2019; 126:315-329. [PMID: 31815595 DOI: 10.1161/circresaha.119.315829] [Citation(s) in RCA: 119] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Rationale: Systemic inflammation compromises the reparative properties of endothelial progenitor cell (EPC) and their exosomes on myocardial repair, although the underlying mechanism of loss of function of exosomes from inflamed EPCs is still obscure. Objective: To determine the mechanisms of IL-10 (interleukin-10) deficient-EPC-derived exosome dysfunction in myocardial repair and to investigate if modification of specific exosome cargo can rescue reparative activity. Methods and Results: Using IL-10 knockout mice mimicking systemic inflammation condition, we compared therapeutic effect and protein cargo of exosomes isolated from wild-type EPC and IL-10 knockout EPC. In a mouse model of myocardial infarction (MI), wild-type EPC-derived exosome treatment significantly improved left ventricle cardiac function, inhibited cell apoptosis, reduced MI scar size, and promoted post-MI neovascularization, whereas IL-10 knockout EPC-derived exosome treatment showed diminished and opposite effects. Mass spectrometry analysis revealed wild-type EPC-derived exosome and IL-10 knockout EPC-derived exosome contain different protein expression pattern. Among differentially expressed proteins, ILK (integrin-linked kinase) was highly enriched in both IL-10 knockout EPC-derived exosome as well as TNFα (tumor necrosis factor-α)-treated mouse cardiac endothelial cell-derived exosomes (TNFα inflamed mouse cardiac endothelial cell-derived exosome). ILK-enriched exosomes activated NF-κB (nuclear factor κB) pathway and NF-κB-dependent gene transcription in recipient endothelial cells and this effect was partly attenuated through ILK knockdown in exosomes. Intriguingly, ILK knockdown in IL-10 knockout EPC-derived exosome significantly rescued their reparative dysfunction in myocardial repair, improved left ventricle cardiac function, reduced MI scar size, and enhanced post-MI neovascularization in MI mouse model. Conclusions: IL-10 deficiency/inflammation alters EPC-derived exosome function, content and therapeutic effect on myocardial repair by upregulating ILK enrichment in exosomes, and ILK-mediated activation of NF-κB pathway in recipient cells, whereas ILK knockdown in exosomes attenuates NF-κB activation and reduces inflammatory response. Our study provides new understanding of how inflammation may alter stem cell-exosome-mediated cardiac repair and identifies ILK as a target kinase for improving progenitor cell exosome-based cardiac therapies.
Collapse
Affiliation(s)
- Yujia Yue
- From the Center for Translational Medicine (Y.Y., C.W., C.B., G.H., M.T., R.R., M.C. V.N.S.G., Z.C., W.J.K., R.K.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - Chunlin Wang
- From the Center for Translational Medicine (Y.Y., C.W., C.B., G.H., M.T., R.R., M.C. V.N.S.G., Z.C., W.J.K., R.K.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - Cindy Benedict
- From the Center for Translational Medicine (Y.Y., C.W., C.B., G.H., M.T., R.R., M.C. V.N.S.G., Z.C., W.J.K., R.K.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - Grace Huang
- From the Center for Translational Medicine (Y.Y., C.W., C.B., G.H., M.T., R.R., M.C. V.N.S.G., Z.C., W.J.K., R.K.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - May Truongcao
- From the Center for Translational Medicine (Y.Y., C.W., C.B., G.H., M.T., R.R., M.C. V.N.S.G., Z.C., W.J.K., R.K.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - Rajika Roy
- From the Center for Translational Medicine (Y.Y., C.W., C.B., G.H., M.T., R.R., M.C. V.N.S.G., Z.C., W.J.K., R.K.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - Maria Cimini
- From the Center for Translational Medicine (Y.Y., C.W., C.B., G.H., M.T., R.R., M.C. V.N.S.G., Z.C., W.J.K., R.K.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - Venkata Naga Srikanth Garikipati
- From the Center for Translational Medicine (Y.Y., C.W., C.B., G.H., M.T., R.R., M.C. V.N.S.G., Z.C., W.J.K., R.K.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - Zhongjian Cheng
- From the Center for Translational Medicine (Y.Y., C.W., C.B., G.H., M.T., R.R., M.C. V.N.S.G., Z.C., W.J.K., R.K.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - Walter J Koch
- From the Center for Translational Medicine (Y.Y., C.W., C.B., G.H., M.T., R.R., M.C. V.N.S.G., Z.C., W.J.K., R.K.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA.,Department of Pharmacology and Medicine (W.J.K., R.K.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - Raj Kishore
- From the Center for Translational Medicine (Y.Y., C.W., C.B., G.H., M.T., R.R., M.C. V.N.S.G., Z.C., W.J.K., R.K.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA.,Department of Pharmacology and Medicine (W.J.K., R.K.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| |
Collapse
|
|
24
|
Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway. mBio 2019; 10:mBio.02174-19. [PMID: 31662455 PMCID: PMC6819659 DOI: 10.1128/mbio.02174-19] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Macrophages are professional immune cells that ingest and kill microbes. In this study, we show that different pathogenic bacteria induce the expression of cystathionine γ-lyase (CTH) in macrophages. This enzyme is involved in a metabolic pathway called the reverse transsulfuration pathway, which leads to the production of numerous metabolites, including cystathionine. Phagocytized bacteria use cystathionine to better survive in macrophages. In addition, the induction of CTH results in dysregulation of the metabolism of polyamines, which in turn dampens the proinflammatory response of macrophages. In conclusion, pathogenic bacteria can evade the host immune response by inducing CTH in macrophages. The reverse transsulfuration pathway is the major route for the metabolism of sulfur-containing amino acids. The role of this metabolic pathway in macrophage response and function is unknown. We show that the enzyme cystathionine γ-lyase (CTH) is induced in macrophages infected with pathogenic bacteria through signaling involving phosphatidylinositol 3-kinase (PI3K)/MTOR and the transcription factor SP1. This results in the synthesis of cystathionine, which facilitates the survival of pathogens within myeloid cells. Our data demonstrate that the expression of CTH leads to defective macrophage activation by (i) dysregulation of polyamine metabolism by depletion of S-adenosylmethionine, resulting in immunosuppressive putrescine accumulation and inhibition of spermidine and spermine synthesis, and (ii) increased histone H3K9, H3K27, and H3K36 di/trimethylation, which is associated with gene expression silencing. Thus, CTH is a pivotal enzyme of the innate immune response that disrupts host defense. The induction of the reverse transsulfuration pathway by bacterial pathogens can be considered an unrecognized mechanism for immune escape.
Collapse
|
|
25
|
Steimle A, Michaelis L, Di Lorenzo F, Kliem T, Münzner T, Maerz JK, Schäfer A, Lange A, Parusel R, Gronbach K, Fuchs K, Silipo A, Öz HH, Pichler BJ, Autenrieth IB, Molinaro A, Frick JS. Weak Agonistic LPS Restores Intestinal Immune Homeostasis. Mol Ther 2019; 27:1974-1991. [PMID: 31416777 PMCID: PMC6838991 DOI: 10.1016/j.ymthe.2019.07.007] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 06/27/2019] [Accepted: 07/08/2019] [Indexed: 02/07/2023] Open
Abstract
Generated by gram-negative bacteria, lipopolysaccharides (LPSs) are one of the most abundant and potent immunomodulatory substances present in the intestinal lumen. Interaction of agonistic LPS with the host myeloid-differentiation-2/Toll-like receptor 4 (MD-2/TLR4) receptor complex results in nuclear factor κB (NF-κB) activation, followed by the robust induction of pro-inflammatory immune responses. Here we have isolated LPS from a common gut commensal, Bacteroides vulgatus mpk (BVMPK), which provides only weak agonistic activity. This weak agonistic activity leads to the amelioration of inflammatory immune responses in a mouse model for experimental colitis, and it was in sharp contrast to strong agonists and antagonists. In this context, the administration of BVMPK LPS into mice with severe intestinal inflammation re-established intestinal immune homeostasis within only 2 weeks, resulting in the clearance of all symptoms of inflammation. These inflammation-reducing properties of weak agonistic LPS are grounded in the induction of a special type of endotoxin tolerance via the MD-2/TLR4 receptor complex axis in intestinal lamina propria CD11c+ cells. Thus, weak agonistic LPS represents a promising agent to treat diseases involving pathological overactivation of the intestinal immune system, e.g., in inflammatory bowel diseases.
Collapse
Affiliation(s)
- Alex Steimle
- Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany
| | - Lena Michaelis
- Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany
| | - Flaviana Di Lorenzo
- Department of Chemical Sciences, University of Naples Federico II, Naples, Italy
| | - Thorsten Kliem
- Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany
| | - Tobias Münzner
- Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany
| | - Jan Kevin Maerz
- Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany
| | - Andrea Schäfer
- Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany
| | - Anna Lange
- Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany
| | - Raphael Parusel
- Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany
| | - Kerstin Gronbach
- Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany
| | - Kerstin Fuchs
- Institute of Radiology, Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany
| | - Alba Silipo
- Department of Chemical Sciences, University of Naples Federico II, Naples, Italy
| | - Hasan Halit Öz
- Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany
| | - Bernd J Pichler
- Institute of Radiology, Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany
| | - Ingo B Autenrieth
- Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany
| | - Antonio Molinaro
- Department of Chemical Sciences, University of Naples Federico II, Naples, Italy
| | - Julia-Stefanie Frick
- Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.
| |
Collapse
|
|
26
|
Ge W, Hu Q, Fang X, Liu J, Xu J, Hu J, Liu X, Ling Q, Wang Y, Li H, Gao M, Jiang L, Yang Z, Tang W. LDK378 improves micro- and macro-circulation via alleviating STING-mediated inflammatory injury in a Sepsis rat model induced by Cecal ligation and puncture. JOURNAL OF INFLAMMATION-LONDON 2019; 16:3. [PMID: 30820191 PMCID: PMC6378711 DOI: 10.1186/s12950-019-0208-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 02/06/2019] [Indexed: 01/09/2023]
Abstract
Background Sepsis is a systemic inflammatory response syndrome caused by severe infections. LDK378, a second-generation ALK inhibitor, exhibits a potential anti-inflammatory function against sepsis. Micro- and macro-circulatory dysfunctions are pivotal elements of the pathogenesis of severe sepsis and septic shock. We hypothesized that LDK378 can improve micro- and macro-circulation of septic rats, therefore improving the outcome of survival via blocking the ALK-STING pathway to attenuate inflammatory injuries. Methods A septic rat model was established by the cecal ligation and puncture (CLP) method. A total of 60 rats were randomized into three groups: a sham group, CLP group, and CLP + LDK378 group (n = 20 in each group). Five rats were randomly selected from each group for the mechanism study; the remaining 15 rats in each group were involved in a survival curve examination. A sidestream dark field video microscope was used to record sublingual microcirculation and mean arterial pressure (MAP) and levels of inflammatory cytokine secretion were examined at 6 h, 30 h, and 54 h after CLP surgery. Expressions of TANK binding kinase 1 (TBK1) and its downstream targets were determined, and histological alterations to the heart, lungs, and kidneys were examined at 54 h after CLP surgery. Results We found the group that received LDK378 treatment showed increased MAP levels compared to the CLP group at 30 h and 54 h. Meanwhile, LDK378 ameliorated the perfused small vessel density and microvascular flow index, decreased the expression of TNF-a and IL-6, and upregulated the expression of IL-10 in comparison with the CLP group. LDK378 injections also downregulated the expression of TBK1 and its downstream targets. Furthermore, LDK378 treatment significantly reduced sepsis-induced organ injuries, therefore improving survival rates. Conclusions These findings demonstrate that LDK378 treatment can improve microcirculation and reduce organ injuries in CLP-induced septic rats via the regulation of inflammatory cytokine secretion and the downstream signaling components of the ALK-STING pathway.
Collapse
Affiliation(s)
- Weiwei Ge
- 1The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qiaohua Hu
- 2Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120 China
| | - Xiangshao Fang
- 2Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120 China
| | - Juanhua Liu
- 3The eastern hospital of the first affiliated hospital, Sun Yat-sen University, Guangzhou, China
| | - Jing Xu
- 4The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Juntao Hu
- 5The first Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xuefen Liu
- 2Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120 China
| | - Qin Ling
- 2Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120 China
| | - Yue Wang
- 2Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120 China
| | - He Li
- 1The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ming Gao
- 1The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Longyuan Jiang
- 2Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120 China
| | - Zhengfei Yang
- 2Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120 China.,6Weil Institute of Emergency and Critical Care Research, School of Medicine, Virginia Commonwealth University, Richmond, VA USA
| | - Wanchun Tang
- 2Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120 China.,6Weil Institute of Emergency and Critical Care Research, School of Medicine, Virginia Commonwealth University, Richmond, VA USA
| |
Collapse
|
|
27
|
Zhang D, Wen J, Zhou J, Cai W, Qian L. Milk Fat Globule Membrane Ameliorates Necrotizing Enterocolitis in Neonatal Rats and Suppresses Lipopolysaccharide-Induced Inflammatory Response in IEC-6 Enterocytes. JPEN J Parenter Enteral Nutr 2019; 43:863-873. [PMID: 30613991 DOI: 10.1002/jpen.1496] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 12/01/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND Evidence has provided support for the beneficial effects of milk fat globule membrane (MFGM) on inflammation in the intestinal tract. The objective of this study was to investigate the effects of MFGM on a rat model of necrotizing enterocolitis (NEC) and its potential mechanism of action. METHODS Sixty-two newborn Sprague Dawley rats were randomly divided into 4 experimental groups: Breast-fed normal, formula fed (FF), FF + 6 g/L MFGM, and FF + 12 g/L MFGM. The FF rats and the FF rats supplemented with MFGM were exposed to asphyxia/cold stress to induce NEC. Body weight, histological score, survival time, oxidative stress injury, enterocyte proliferation/apoptosis, and inflammatory response were assessed. Meanwhile, lipopolysaccharide (LPS)-stimulated IEC-6 enterocytes were used as a model to test the anti-inflammatory effects of MFGM. RESULTS Supplementation with 12 g/L MFGM alleviated body weight loss, reduced the incidence of NEC, increased the survival rate, and attenuated the severity of bowel damage in the NEC rat model. Furthermore, 12 g/L MFGM administration inhibited the protein expression of toll-like receptor 4 (TLR4) in the animal model. In IEC-6 enterocytes, the upregulation of TLR4, myeloid differentiation primary response gene 88 (MyD88), phosphorylated nuclear factor-κB (NF-κB) p65 subunit, and the nuclear translocation of NF-κBp65 induced by LPS was partially inhibited by MFGM pretreatment. CONCLUSION Our findings suggested that MFGM has beneficial effects on neonatal rats with NEC by suppressing inflammation via the TLR4/MyD88/NF-κB pathway.
Collapse
Affiliation(s)
- Dandan Zhang
- Shanghai Institute for Pediatric Research, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Wen
- Shanghai Institute for Pediatric Research, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jiefei Zhou
- Shanghai Institute for Pediatric Research, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Cai
- Shanghai Institute for Pediatric Research, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Linxi Qian
- Shanghai Institute for Pediatric Research, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
28
|
Ying L, Ferrero RL. Role of NOD1 and ALPK1/TIFA Signalling in Innate Immunity Against Helicobacter pylori Infection. Curr Top Microbiol Immunol 2019; 421:159-177. [PMID: 31123889 DOI: 10.1007/978-3-030-15138-6_7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The human pathogen Helicobacter pylori interacts intimately with gastric epithelial cells to induce inflammatory responses that are a hallmark of the infection. This inflammation is a critical precursor to the development of peptic ulcer disease and gastric cancer. A major driver of this inflammation is a type IV secretion system (T4SS) encoded by the cag pathogenicity island (cagPAI), present in a subpopulation of more virulent H. pylori strains. The cagPAI T4SS specifically activates signalling pathways in gastric epithelial cells that converge on the transcription factor, nuclear factor-κB (NF-κB), which in turn upregulates key immune and inflammatory genes, resulting in various host responses. It is now clear that H. pylori possesses several mechanisms to activate NF-κB in gastric epithelial cells and, moreover, that multiple signalling pathways are involved in these responses. Two of the dominant signalling pathways implicated in NF-κB-dependent responses in epithelial cells are nucleotide-binding oligomerisation domain 1 (NOD1) and a newly described pathway involving alpha-kinase 1 (ALPK1) and tumour necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein with forkhead-associated domain (TIFA). Although the relative roles of these two pathways in regulating NF-κB-dependent responses still need to be clearly defined, it is likely that they work cooperatively and non-redundantly. This chapter will give an overview of the various mechanisms and pathways involved in H. pylori induction of NF-κB-dependent responses in gastric epithelial cells, including a 'state-of-the-art' review on the respective roles of NOD1 and ALPK1/TIFA pathways in these responses.
Collapse
Affiliation(s)
- Le Ying
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, Clayton, VIC, Australia
| | - Richard L Ferrero
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, Clayton, VIC, Australia.
- Department of Molecular and Translational Medicine, Monash University, Clayton, VIC, Australia.
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
| |
Collapse
|
|
29
|
Pahlavani M, Wijayatunga NN, Kalupahana NS, Ramalingam L, Gunaratne PH, Coarfa C, Rajapakshe K, Kottapalli P, Moustaid-Moussa N. Transcriptomic and microRNA analyses of gene networks regulated by eicosapentaenoic acid in brown adipose tissue of diet-induced obese mice. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:1523-1531. [PMID: 30261280 PMCID: PMC6298436 DOI: 10.1016/j.bbalip.2018.09.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 09/01/2018] [Accepted: 09/17/2018] [Indexed: 12/11/2022]
Abstract
Brown adipose tissue (BAT) dissipates chemical energy as heat via thermogenesis and protects against obesity by increasing energy expenditure. However, regulation of BAT by dietary factors remains largely unexplored at the mechanistic level. We investigated the effect of eicosapentaenoic acid (EPA) on BAT metabolism. Male C57BL/6J (B6) mice were fed either a high-fat diet (HF, 45% kcal fat) or HF diet supplemented with EPA (HF-EPA, 6.75% kcal EPA) for 11 weeks. RNA sequencing (RNA-Seq) and microRNA (miRNA) profiling were performed on RNA from BAT using Illumina HiSeq and Illumina Genome Analyzer NextSeq, respectively. We conducted pathway analyses using ingenuity pathway analysis software (IPA®) and validated some genes and miRNAs using qPCR. We identified 479 genes that were differentially expressed (2-fold change, n = 3, P ≤ 0.05) in BAT from HF compared to HF-EPA. Genes negatively correlated with thermogenesis such as hypoxia inducible factor 1 alpha subunit inhibitor (Hif1an), were downregulated by EPA. Pathways related to thermogenesis such as peroxisome proliferator-activated receptor (PPAR) were upregulated by EPA while pathways associated with obesity and inflammation such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were downregulated by EPA. MiRNA profiling identified nine and six miRNAs that were upregulated and downregulated by EPA, respectively (log2 fold change > 1.25, n = 3, P ≤ 0.05). Key regulatory miRNAs which were involved in thermogenesis, such as miR-455-3p and miR-129-5p were validated using qPCR. In conclusion, the depth of transcriptomic and miRNA profiling revealed novel mRNA-miRNA interaction networks in BAT which are involved in thermogenesis, and regulated by EPA.
Collapse
Affiliation(s)
- Mandana Pahlavani
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, United States; Obesity Research Cluster, Texas Tech University, Lubbock, TX, United States
| | - Nadeeja N Wijayatunga
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, United States
| | - Nishan S Kalupahana
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, United States; Obesity Research Cluster, Texas Tech University, Lubbock, TX, United States; Department of Physiology, University of Peradeniya, Sri Lanka
| | - Latha Ramalingam
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, United States; Obesity Research Cluster, Texas Tech University, Lubbock, TX, United States
| | - Preethi H Gunaratne
- Department of Biology and Biochemistry, University of Houston, United States
| | - Cristian Coarfa
- Department of Molecular and Cell Biology, Houston, TX, United States
| | - Kimal Rajapakshe
- Department of Molecular and Cell Biology, Houston, TX, United States
| | - Pratibha Kottapalli
- Center for Biotechnology and Genomics, Texas Tech University, Lubbock, TX, United States
| | - Naima Moustaid-Moussa
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, United States; Obesity Research Cluster, Texas Tech University, Lubbock, TX, United States.
| |
Collapse
|
|
30
|
Induction of TNF, CXCL8 and IL-1β in macrophages by Helicobacter pylori secreted protein HP1173 occurs via MAP-kinases, NF-κB and AP-1 signaling pathways. Microb Pathog 2018; 125:295-305. [DOI: 10.1016/j.micpath.2018.09.037] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 09/06/2018] [Accepted: 09/24/2018] [Indexed: 02/07/2023]
|
|
31
|
Interaction of septin 7 and DOCK8 in equine lymphocytes reveals novel insights into signaling pathways associated with autoimmunity. Sci Rep 2018; 8:12332. [PMID: 30120291 PMCID: PMC6098150 DOI: 10.1038/s41598-018-30753-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 06/22/2018] [Indexed: 01/21/2023] Open
Abstract
The GTP-binding protein septin 7 is involved in various cellular processes, including cytoskeleton organization, migration and the regulation of cell shape. Septin 7 function in lymphocytes, however, is poorly characterized. Since the intracellular signaling role of septin 7 is dependent on its interaction network, interaction proteomics was applied to attain novel knowledge about septin 7 function in hematopoietic cells. Our previous finding of decreased septin 7 expression in blood-derived lymphocytes in ERU, a spontaneous animal model for autoimmune uveitis in man, extended the role of septin 7 to a potential key player in autoimmunity. Here, we revealed novel insights into septin 7 function by identification of DOCK8 as an interaction partner in primary blood-derived lymphocytes. Since DOCK8 is associated with important immune functions, our finding of significantly decreased DOCK8 expression and altered DOCK8 interaction network in ERU might explain changes in immune response and shows the contribution of DOCK8 in pathomechanisms of spontaneous autoimmune diseases. Moreover, our analyses revealed insights in DOCK8 function, by identifying the signal transducer ILK as a DOCK8 interactor in lymphocytes. Our finding of the enhanced enrichment of ILK in ERU cases indicates a deviant influence of DOCK8 on inter- and intracellular signaling in autoimmune disease.
Collapse
|
|
32
|
Duan C, Liu Y, Li Y, Chen H, Liu X, Chen X, Yue J, Zhou X, Yang J. Sulfasalazine alters microglia phenotype by competing endogenous RNA effect of miR-136-5p and long non-coding RNA HOTAIR in cuprizone-induced demyelination. Biochem Pharmacol 2018; 155:110-123. [PMID: 29944870 DOI: 10.1016/j.bcp.2018.06.028] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 06/22/2018] [Indexed: 01/17/2023]
Abstract
Sulfasalazine (SF) promotes remyelination and improves the outcome of multiple sclerosis (MS) patients. However, the underlining mechanism remains elusive. Here, we examined whether SF blocks microglia switching to a pro-inflammatory M1-like phenotype through a competing endogenous RNA (ceRNA) effects in cuprizone-induced demyelination. The microglia reprogramming effects of SF in the mice model of cuprizone-induced demyelination was measured by histological, immunohistochemical and molecular biological methods. We also measured the effects of the condition media from SF-treated microglia on the differentiation of OLN-93 cells. Insights of the mechanism of ceRNAs of miR-136-5p and long non-coding RNA (lncRNA) HOTAIR were gained from bioinformatic analysis, luciferase assays and RNA binding protein immunoprecipitation. Microglia switched to a pro-inflammatory M1-like phenotype in cuprizone induced-demyelination. Conversely, SF inhibited the M1-like polarization with the increased remyelination which was attenuated by microglia depletion. SF inhibited production of M1-like factors TNF-α and INF-γ in microglia, and thereby promoted the differentiation of OLN-93 oligodendrocytes. SF down-regulated lncRNA HOTAIR but up-regulated miR-136-5p, and thus inactivated AKT2-NF-κB in cuprizone-treated microglia. Importantly, lncRNA HOTAIR overexpression reversed the increased miR-136-5p expression by SF and thereby attenuated the inhibition of AKT2-mediated NF-κB activation. Mimic of miR-136-5p inhibited cuprizone-induced activation of AKT2-NF-κB in the microglia. In summary, SF blocks microglia switching to a pro-inflammatory M1-like phenotype by ceRNA effect of miR-136-5p and lncRNA HOTAIR in cuprizone-induced demyelination. Our findings show the therapeutic potential of SF for human MS probably by targeting epigenetic regulation in microglia.
Collapse
Affiliation(s)
- Chenfan Duan
- Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Yanzhuo Liu
- Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Ying Li
- Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Honglei Chen
- Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Xiaoxiao Liu
- Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis & Treatment, South-central University For Nationalities, Wuhan 430074, China
| | - Xuewei Chen
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, China
| | - Jiang Yue
- Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Xiaoyang Zhou
- Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan 430071, China
| | - Jing Yang
- Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
| |
Collapse
|
|
33
|
Alasseiri M, Ahmed AU, Williams BRG. Mechanisms and consequences of constitutive activation of integrin-linked kinase in acute myeloid leukemia. Cytokine Growth Factor Rev 2018; 43:1-7. [PMID: 29903521 DOI: 10.1016/j.cytogfr.2018.06.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 05/31/2018] [Accepted: 06/05/2018] [Indexed: 12/22/2022]
Abstract
Integrin-linked kinase (ILK) has emerged as a critical adaptor and mediator protein in cell signaling pathways that is commonly deregulated in acute myeloid leukemia (AML). This has led to the expectation that therapeutic targeting of ILK may be a useful option in treating leukemia. Although ILK can regulate many cellular processes, including cell differentiation, survival, migration, apoptosis and production of pro-inflammatory cytokines, its role in promoting AML is still unclear. However, its ability to mediate phosphorylation and regulate the important hematopoietic stem cell regulators protein kinase B (AKT) and glycogen synthase kinase-3β supports ILK as an attractive target for the development of novel anticancer therapeutics. In this review, we summarize the existing knowledge of ILK signaling and its impact on cytokines, paying particular attention to the relevance of ILK signaling in AML. We also discuss the rationale for targeting ILK in the treatment of AML and conclude with perspectives on the future of ILK-targeted therapy in AML.
Collapse
Affiliation(s)
- Mohammed Alasseiri
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia; Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, 71491, Saudi Arabia
| | - Afsar U Ahmed
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia
| | - Bryan R G Williams
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia.
| |
Collapse
|
|
34
|
Feige MH, Sokolova O, Pickenhahn A, Maubach G, Naumann M. HopQ impacts the integrin α5β1-independent NF-κB activation by Helicobacter pylori in CEACAM expressing cells. Int J Med Microbiol 2018; 308:527-533. [PMID: 29779861 DOI: 10.1016/j.ijmm.2018.05.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 05/03/2018] [Accepted: 05/13/2018] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori infection persists in more than half of the world's population and represents a risk factor for peptic ulcer disease and gastric cancer. Virulent strains of H. pylori carry a cag pathogenicity island (cagPAI), which encodes a type IV secretion system (T4SS) with the capability to inject the effector protein cytotoxin-associated gene A (CagA) into eukaryotic cells. Colonisation of the gastric epithelium by H. pylori provokes direct activation of the proinflammatory and survival factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). We investigated the impact of host cell receptor integrin α5β1 and the bacterial adhesin HopQ on the NF-κB activation. We found that H. pylori induced early T4SS-dependent, but CagA-independent canonical NF-κB signalling in polarized, apical infected NCI-N87 cells. Integrin-dependent CagA translocation was hardly detectable, as integrin β1 was sparsely located at the apical surface of polarized NCI-N87 cells. Knockdown experiments indicated that integrin α5β1 and integrin linked kinase (ILK) were dispensable for NF-κB activation in H. pylori infection. Thus, there exists no common mechanism, which mediates integrin α5β1-dependent H. pylori-triggered CagA translocation and the activation of NF-κB. Further, we report that H. pylori adhesin HopQ, which binds to a specific subset of carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), promotes canonical NF-κB activation in AGS and NCI-N87 cells, but not in HeLa cells, which are devoid of these CEACAMs. Noteworthy, these effects were not mediated by reduced adhesion, indicating additional functions of HopQ.
Collapse
Affiliation(s)
- Michael Hartmut Feige
- Otto von Guericke University, Institute of Experimental Internal Medicine, Medical Faculty, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Olga Sokolova
- Otto von Guericke University, Institute of Experimental Internal Medicine, Medical Faculty, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Anna Pickenhahn
- Otto von Guericke University, Institute of Experimental Internal Medicine, Medical Faculty, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Gunter Maubach
- Otto von Guericke University, Institute of Experimental Internal Medicine, Medical Faculty, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Michael Naumann
- Otto von Guericke University, Institute of Experimental Internal Medicine, Medical Faculty, Leipziger Str. 44, 39120 Magdeburg, Germany.
| |
Collapse
|
|
35
|
Selenoprotein S inhibits inflammation-induced vascular smooth muscle cell calcification. J Biol Inorg Chem 2018; 23:739-751. [PMID: 29721770 DOI: 10.1007/s00775-018-1563-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 04/24/2018] [Indexed: 12/12/2022]
Abstract
Vascular calcification is a prominent feature of many diseases including atherosclerotic cardiovascular disease (CVD), leading to high morbidity and mortality rates. A significant association of selenoprotein S (SelS) gene polymorphism with atherosclerotic CVD has been reported in epidemiologic studies, but the underlying mechanism is far from clear. To investigate the role of SelS in inflammation-induced vascular calcification, osteoblastic differentiation and calcification of vascular smooth muscle cells (VSMCs) induced by lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α were compared between the cells with and without SelS knockdown. LPS or TNF-α induced osteoblastic differentiation and calcification of VSMCs, as showed by the increases of runt-related transcription factor 2 (Runx2) protein levels, Runx2 and type I collagen mRNA levels, alkaline phosphatase activity, and calcium deposition content. These changes were aggravated when SelS was knocked down by small interfering RNA. Moreover, LPS activated both classical and alternative pathways of nuclear factor-κB (NF-κB) signaling in calcifying VSMCs, which were further enhanced under SelS knockdown condition. SelS knockdown also exacerbated LPS-induced increases of proinflammatory cytokines TNF-α and interleukin-6 expression, as well as increases of endoplasmic reticulum (ER) stress markers glucose-regulated protein 78 and inositol-requiring enzyme 1α expression in calcifying VSMCs. In conclusion, the present study suggested that SelS might inhibit inflammation-induced VSMC calcification probably by suppressing activation of NF-κB signaling pathways and ER stress. Our findings provide new understanding of the role of SelS in vascular calcification, which will be potentially beneficial to the prevention of atherosclerotic CVD.
Collapse
|
|
36
|
Mukwaya A, Lennikov A, Xeroudaki M, Mirabelli P, Lachota M, Jensen L, Peebo B, Lagali N. Time-dependent LXR/RXR pathway modulation characterizes capillary remodeling in inflammatory corneal neovascularization. Angiogenesis 2018; 21:395-413. [PMID: 29445990 PMCID: PMC5878196 DOI: 10.1007/s10456-018-9604-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 02/06/2018] [Indexed: 12/13/2022]
Abstract
Inflammation in the normally immune-privileged cornea can initiate a pathologic angiogenic response causing vision-threatening corneal neovascularization. Inflammatory pathways, however, are numerous, complex and are activated in a time-dependent manner. Effective resolution of inflammation and associated angiogenesis in the cornea requires knowledge of these pathways and their time dependence, which has, to date, remained largely unexplored. Here, using a model of endogenous resolution of inflammation-induced corneal angiogenesis, we investigate the time dependence of inflammatory genes in effecting capillary regression and the return of corneal transparency. Endogenous capillary regression was characterized by a progressive thinning and remodeling of angiogenic capillaries and inflammatory cell retreat in vivo in the rat cornea. By whole-genome longitudinal microarray analysis, early suppression of VEGF ligand-receptor signaling and inflammatory pathways preceded an unexpected later-phase preferential activation of LXR/RXR, PPARα/RXRα and STAT3 canonical pathways, with a concurrent attenuation of LPS/IL-1 inhibition of RXR function and Wnt/β-catenin signaling pathways. Potent downstream inflammatory cytokines such as Cxcl5, IL-1β, IL-6 and Ccl2 were concomitantly downregulated during the remodeling phase. Upstream regulators of the inflammatory pathways included Socs3, Sparc and ApoE. A complex and coordinated time-dependent interplay between pro- and anti-inflammatory signaling pathways highlights a potential anti-inflammatory role of LXR/RXR, PPARα/RXRα and STAT3 signaling pathways in resolving inflammatory corneal angiogenesis.
Collapse
Affiliation(s)
- Anthony Mukwaya
- Department of Ophthalmology, Faculty of Health Sciences, Institute for Clinical and Experimental Medicine, Linkoping University, 58183, Linköping, Sweden
| | - Anton Lennikov
- Department of Ophthalmology, Faculty of Health Sciences, Institute for Clinical and Experimental Medicine, Linkoping University, 58183, Linköping, Sweden
| | - Maria Xeroudaki
- Department of Ophthalmology, Faculty of Health Sciences, Institute for Clinical and Experimental Medicine, Linkoping University, 58183, Linköping, Sweden
| | - Pierfrancesco Mirabelli
- Department of Ophthalmology, Faculty of Health Sciences, Institute for Clinical and Experimental Medicine, Linkoping University, 58183, Linköping, Sweden
| | - Mieszko Lachota
- Department of Immunology, Medical University of Warsaw, Warsaw, Poland
| | - Lasse Jensen
- Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Beatrice Peebo
- Department of Ophthalmology, Faculty of Health Sciences, Institute for Clinical and Experimental Medicine, Linkoping University, 58183, Linköping, Sweden
| | - Neil Lagali
- Department of Ophthalmology, Faculty of Health Sciences, Institute for Clinical and Experimental Medicine, Linkoping University, 58183, Linköping, Sweden.
| |
Collapse
|
|
37
|
Liu Z, Zhu H, Dai X, Wang C, Ding Y, Song P, Zou MH. Macrophage Liver Kinase B1 Inhibits Foam Cell Formation and Atherosclerosis. Circ Res 2017; 121:1047-1057. [PMID: 28827412 PMCID: PMC5640502 DOI: 10.1161/circresaha.117.311546] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 08/13/2017] [Accepted: 08/21/2017] [Indexed: 01/01/2023]
Abstract
RATIONALE LKB1 (liver kinase B1) is a serine/threonine kinase and tumor suppressor, which regulates the homeostasis of hematopoietic cells and immune responses. Macrophages transform into foam cells upon taking-in lipids. No role for LKB1 in foam cell formation has previously been reported. OBJECTIVE We sought to establish the role of LKB1 in atherosclerotic foam cell formation. METHODS AND RESULTS LKB1 expression was examined in human carotid atherosclerotic plaques and in western diet-fed atherosclerosis-prone Ldlr-/- and ApoE-/- mice. LKB1 expression was markedly reduced in human plaques when compared with nonatherosclerotic vessels. Consistently, time-dependent reduction of LKB1 levels occurred in atherosclerotic lesions in western diet-fed Ldlr-/- and ApoE-/- mice. Exposure of macrophages to oxidized low-density lipoprotein downregulated LKB1 in vitro. Furthermore, LKB1 deficiency in macrophages significantly increased the expression of SRA (scavenger receptor A), modified low-density lipoprotein uptake and foam cell formation, all of which were abolished by blocking SRA. Further, we found LKB1 phosphorylates SRA resulting in its lysosome degradation. To further investigate the role of macrophage LKB1 in vivo, ApoE-/-LKB1fl/flLysMcre and ApoE-/-LKB1fl/fl mice were fed with western diet for 16 weeks. Compared with ApoE-/-LKB1fl/fl wild-type control, ApoE-/-LKB1fl/flLysMcre mice developed more atherosclerotic lesions in whole aorta and aortic root area, with markedly increased SRA expression in aortic root lesions. CONCLUSIONS We conclude that macrophage LKB1 reduction caused by oxidized low-density lipoprotein promotes foam cell formation and the progression of atherosclerosis.
Collapse
Affiliation(s)
- Zhaoyu Liu
- From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta
| | - Huaiping Zhu
- From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta
| | - Xiaoyan Dai
- From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta
| | - Cheng Wang
- From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta
| | - Ye Ding
- From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta
| | - Ping Song
- From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta
| | - Ming-Hui Zou
- From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta.
| |
Collapse
|
|
38
|
Hauck SM, Lepper MF, Hertl M, Sekundo W, Deeg CA. Proteome Dynamics in Biobanked Horse Peripheral Blood Derived Lymphocytes (PBL) with Induced Autoimmune Uveitis. Proteomics 2017; 17. [DOI: 10.1002/pmic.201700013] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 06/23/2017] [Indexed: 12/24/2022]
Affiliation(s)
- Stefanie M. Hauck
- Research Unit Protein Science, Helmholtz Center Munich; Research Center for Environmental Health (GmbH); Neuherberg Germany
| | - Marlen F. Lepper
- Research Unit Protein Science, Helmholtz Center Munich; Research Center for Environmental Health (GmbH); Neuherberg Germany
| | - Michael Hertl
- Department of Allergy and Dermatology; Philipps University of Marburg; Marburg Germany
| | - Walter Sekundo
- Department of Ophthalmology; Philipps University of Marburg; Marburg Germany
| | - Cornelia A. Deeg
- Experimental Ophthalmology; Philipps University of Marburg; Marburg Germany
- Chair for Animal Physiology, Department of Veterinary Sciences; LMU Munich; Munich Germany
| |
Collapse
|
|
39
|
Ahmed AU, Yim HCH, Alorro M, Ernst M, Williams BRG. Integrin-Linked Kinase Expression in Myeloid Cells Promotes Inflammatory Signaling during Experimental Colitis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2017; 199:2128-2139. [PMID: 28794235 DOI: 10.4049/jimmunol.1700125] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 07/19/2017] [Indexed: 12/15/2022]
Abstract
The pathology of inflammatory bowel diseases is driven by the inflammatory signaling pathways associated with mucosal epithelial damage. Myeloid cells are known to play an essential role in mediating epithelial inflammatory responses during injury. However, the precise role of these cells in stimulating intestinal inflammation and the subsequent tissue damage is unclear. In this article, we show that expression of integrin-linked kinase (ILK) in myeloid cells is critical for the epithelial inflammatory signaling during colitis induced by dextran sodium sulfate. Myeloid ILK (M-ILK) deficiency significantly ameliorates the pathology of experimental colitis. In response to dextran sodium sulfate, colonic infiltration of neutrophils and inflammatory cytokine production are impaired in M-ILK-deficient mice, and activation of epithelial NF-κB and PI3K signaling pathways are restricted by the M-ILK deficiency. In contrast, reduced epithelial damage in M-ILK-deficient mice is correlated with elevated levels of epithelial Stat3 activation and proliferation. Moreover, M-ILK-dependent inflammatory signaling in the mucosal epithelium can be therapeutically targeted by the pharmacological inhibition of ILK during experimental colitis. Collectively, these findings identify M-ILK as a critical regulator of epithelial inflammatory signaling pathways during colitis and, as a consequence, targeting M-ILK could provide therapeutic benefit.
Collapse
Affiliation(s)
- Afsar U Ahmed
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia
| | - Howard C H Yim
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia
| | - Mariah Alorro
- Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia; and
- School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia
| | - Matthias Ernst
- Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia; and
- School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia
| | - Bryan R G Williams
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia;
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia
| |
Collapse
|
|
40
|
Boro M, Balaji KN. CXCL1 and CXCL2 Regulate NLRP3 Inflammasome Activation via G-Protein-Coupled Receptor CXCR2. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2017; 199:1660-1671. [PMID: 28739876 DOI: 10.4049/jimmunol.1700129] [Citation(s) in RCA: 119] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 06/21/2017] [Indexed: 01/03/2025]
Abstract
Inflammation is an extensively concerted process that confers protection to the host encountering immune insult. The major inflammatory mediators include IL-1 family members, such as IL-1β, and the functional activation of such molecules is arbitrated by their regulated cleavage brought about by components of a multiprotein complex called inflammasome. In this context, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation often acts as a rate-limiting step in regulating critical cell-fate decisions in various inflammatory scenarios. In this study, we identify the G-protein-coupled receptor CXCR2 (recognizing chemokines CXCL1 and CXCL2) as another arm feeding into the regulated activation of NLRP3 inflammasome in macrophages. We demonstrate that in vivo blocking of CXCL1 and CXCL2 can significantly reduce the Mycobacterium tuberculosis-induced bioactive IL-1β production. Further, CXCL1 could amplify the inflammasome activation in in vivo mouse models of carrageenan-induced inflammation in footpads and air pouches. The mechanistic insights revealed CXCR2-driven protein kinase C μ-dependent integrin-linked kinase to be essential for CXCL1-mediated activation of NLRP3 inflammasome. Blocking the activity of integrin-linked kinase or protein kinase C μ either by small interfering RNA-mediated knockdown or pharmacological inhibitor compromised inflammasome activation and subsequent production of bioactive IL-1β. Taken together, our study demonstrates CXCR2-driven activation of NLRP3 inflammasome in macrophages and indicates a potential host-directed therapeutic target to limit the damaging inflammation associated with overt production of proinflammatory IL-1β.
Collapse
MESH Headings
- Animals
- Antibodies, Neutralizing/administration & dosage
- Cells, Cultured
- Chemokine CXCL1/immunology
- Chemokine CXCL1/metabolism
- Chemokine CXCL2/immunology
- Chemokine CXCL2/metabolism
- Humans
- Inflammasomes/metabolism
- Interleukin-1beta/immunology
- Macrophages/immunology
- Mice
- Mice, Inbred BALB C
- Mycobacterium tuberculosis/immunology
- NLR Family, Pyrin Domain-Containing 3 Protein/genetics
- NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
- RNA, Small Interfering/genetics
- Receptors, G-Protein-Coupled/immunology
- Receptors, G-Protein-Coupled/metabolism
- Receptors, Interleukin-8B/immunology
- Receptors, Interleukin-8B/metabolism
- Tuberculosis/immunology
Collapse
Affiliation(s)
- Monoranjan Boro
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India
| | | |
Collapse
|
|
41
|
Impellizzeri D, Cordaro M, Bruschetta G, Siracusa R, Crupi R, Esposito E, Cuzzocrea S. N-Palmitoylethanolamine-Oxazoline as a New Therapeutic Strategy to Control Neuroinflammation: Neuroprotective Effects in Experimental Models of Spinal Cord and Brain Injury. J Neurotrauma 2017; 34:2609-2623. [PMID: 28095731 DOI: 10.1089/neu.2016.4808] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Modulation of N-acylethanolamine-hydrolyzing acid amidase (NAAA) represents a potential alternative strategy in the treatment of neuroinflammation. Recent studies showed that pharmacological modulation of NAAA could be achieved with the oxazoline of palmitoylethanolamide (PEA; PEA-OXA). The aim of this study was to evaluate the neuroprotective effects of PEA-OXA in the secondary neuroinflammatory events induced by spinal and brain trauma in mice. Animals were subjected to spinal cord and brain injury models and PEA-OXA (10 mg/kg) was administered both intraperitoneally and orally 1 h and 6 h after trauma. PEA-OXA treatment markedly reduced the histological alterations induced by spinal cord injury (SCI) and traumatic brain injury (TBI) and ameliorated the motor function and behavioral deficits, as well. In addition, the expression of neurotrophic factors, such as glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, and neurotrophin-3 were increased by PEA-OXA treatment. Moreover, PEA-OXA also significantly decreased glial fibrillary acidic protein hyperexpression, the nuclear translocation of nuclear factor (NF)-κB, phosphorylation of Ser536 on the NF-κB subunit p65, and degradation of IκB-α, as well as diminished the expression of pro-inflammatory mediators such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase, tumor necrosis factor (TNF)-α and interleukin (IL)-1β. The modulation of intracellular NAAA by PEA-OXA treatment could thus represent a novel therapy to control neuroinflammatory conditions associated with SCI and TBI.
Collapse
Affiliation(s)
- Daniela Impellizzeri
- 1 Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina , Messina, Italy
| | - Marika Cordaro
- 1 Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina , Messina, Italy
| | - Giuseppe Bruschetta
- 1 Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina , Messina, Italy
| | - Rosalba Siracusa
- 1 Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina , Messina, Italy
| | - Rosalia Crupi
- 1 Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina , Messina, Italy
| | - Emanuela Esposito
- 1 Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina , Messina, Italy
| | - Salvatore Cuzzocrea
- 1 Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina , Messina, Italy .,2 Manchester Biomedical Research Centre, Manchester Royal Infirmary, School of Medicine, University of Manchester , United Kingdom
| |
Collapse
|
|
42
|
Suppression of LPS-induced NF-κB activity in macrophages by the synthetic aurone, (Z)-2-((5-(hydroxymethyl) furan-2-yl) methylene) benzofuran-3(2H)-one. Int Immunopharmacol 2017; 43:116-128. [DOI: 10.1016/j.intimp.2016.12.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/23/2016] [Accepted: 12/03/2016] [Indexed: 11/21/2022]
|
|
43
|
Pradère JP, Hernandez C, Koppe C, Friedman RA, Luedde T, Schwabe RF. Negative regulation of NF-κB p65 activity by serine 536 phosphorylation. Sci Signal 2016; 9:ra85. [PMID: 27555662 DOI: 10.1126/scisignal.aab2820] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Nuclear factor κB (NF-κB) is a master regulator of inflammation and cell death. Whereas most of the activity of NF-κB is regulated through the inhibitor of κB (IκB) kinase (IKK)-dependent degradation of IκB, IKK also phosphorylates subunits of NF-κB. We investigated the contribution of the phosphorylation of the NF-κB subunit p65 at the IKK phosphorylation site serine 536 (Ser(536)) in humans, which is thought to be required for the activation and nuclear translocation of NF-κB. Through experiments with knock-in mice (S534A mice) expressing a mutant p65 with an alanine-to-serine substitution at position 534 (the murine homolog of human Ser(536)), we observed increased expression of NF-κB-dependent genes after injection of mice with the inflammatory stimulus lipopolysaccharide (LPS) or exposure to gamma irradiation, and the enhanced gene expression was most pronounced at late time points. Compared to wild-type mice, S534A mice displayed increased mortality after injection with LPS. Increased NF-κB signaling in the S534A mice was at least in part explained by the increased stability of the S534A p65 protein compared to that of the Ser(534)-phosphorylated wild-type protein. Together, our results suggest that Ser(534) phosphorylation of p65 in mice (and, by extension, Ser(536) phosphorylation of human p65) is not required for its nuclear translocation, but instead inhibits NF-κB signaling to prevent deleterious inflammation.
Collapse
Affiliation(s)
| | - Céline Hernandez
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Christiane Koppe
- Department of Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Richard A Friedman
- Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center and Department of Biomedical Informatics, Columbia University, New York, NY 10032, USA
| | - Tom Luedde
- Department of Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, NY 10032, USA.
| |
Collapse
|
|
44
|
Brauer EK, Ahsan N, Dale R, Kato N, Coluccio AE, Piñeros MA, Kochian LV, Thelen JJ, Popescu SC. The Raf-like Kinase ILK1 and the High Affinity K+ Transporter HAK5 Are Required for Innate Immunity and Abiotic Stress Response. PLANT PHYSIOLOGY 2016; 171:1470-84. [PMID: 27208244 PMCID: PMC4902592 DOI: 10.1104/pp.16.00035] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Accepted: 04/29/2016] [Indexed: 05/04/2023]
Abstract
Plant perception of pathogen-associated molecular patterns (PAMPs) and other environmental stresses trigger transient ion fluxes at the plasma membrane. Apart from the role of Ca(2+) uptake in signaling, the regulation and significance of PAMP-induced ion fluxes in immunity remain unknown. We characterized the functions of INTEGRIN-LINKED KINASE1 (ILK1) that encodes a Raf-like MAP2K kinase with functions insufficiently understood in plants. Analysis of ILK1 mutants impaired in the expression or kinase activity revealed that ILK1 contributes to plant defense to bacterial pathogens, osmotic stress sensitivity, and cellular responses and total ion accumulation in the plant upon treatment with a bacterial-derived PAMP, flg22. The calmodulin-like protein CML9, a negative modulator of flg22-triggered immunity, interacted with, and suppressed ILK1 kinase activity. ILK1 interacted with and promoted the accumulation of HAK5, a putative (H(+))/K(+) symporter that mediates a high-affinity uptake during K(+) deficiency. ILK1 or HAK5 expression was required for several flg22 responses including gene induction, growth arrest, and plasma membrane depolarization. Furthermore, flg22 treatment induced a rapid K(+) efflux at both the plant and cellular levels in wild type, while mutants with impaired ILK1 or HAK5 expression exhibited a comparatively increased K(+) loss. Taken together, our results position ILK1 as a link between plant defense pathways and K(+) homeostasis.
Collapse
Affiliation(s)
- Elizabeth K Brauer
- The Boyce Thompson Institute for Plant Research, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Plant Pathology and Plant-Microbe Biology, Cornell University, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Biochemistry, University of Missouri, Christopher S. Bond Life Sciences Center, Columbia, Missouri 65211 (N.A., J.T.T.); Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803 (R.D., N.K.); and Robert W. Holley Center for Agriculture and Health, Agricultural Research Service, US Department of Agriculture, Cornell University, Ithaca, New York 14853 (A.E.C., M.A.P., L.V.K.)
| | - Nagib Ahsan
- The Boyce Thompson Institute for Plant Research, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Plant Pathology and Plant-Microbe Biology, Cornell University, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Biochemistry, University of Missouri, Christopher S. Bond Life Sciences Center, Columbia, Missouri 65211 (N.A., J.T.T.); Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803 (R.D., N.K.); and Robert W. Holley Center for Agriculture and Health, Agricultural Research Service, US Department of Agriculture, Cornell University, Ithaca, New York 14853 (A.E.C., M.A.P., L.V.K.)
| | - Renee Dale
- The Boyce Thompson Institute for Plant Research, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Plant Pathology and Plant-Microbe Biology, Cornell University, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Biochemistry, University of Missouri, Christopher S. Bond Life Sciences Center, Columbia, Missouri 65211 (N.A., J.T.T.); Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803 (R.D., N.K.); and Robert W. Holley Center for Agriculture and Health, Agricultural Research Service, US Department of Agriculture, Cornell University, Ithaca, New York 14853 (A.E.C., M.A.P., L.V.K.)
| | - Naohiro Kato
- The Boyce Thompson Institute for Plant Research, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Plant Pathology and Plant-Microbe Biology, Cornell University, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Biochemistry, University of Missouri, Christopher S. Bond Life Sciences Center, Columbia, Missouri 65211 (N.A., J.T.T.); Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803 (R.D., N.K.); and Robert W. Holley Center for Agriculture and Health, Agricultural Research Service, US Department of Agriculture, Cornell University, Ithaca, New York 14853 (A.E.C., M.A.P., L.V.K.)
| | - Alison E Coluccio
- The Boyce Thompson Institute for Plant Research, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Plant Pathology and Plant-Microbe Biology, Cornell University, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Biochemistry, University of Missouri, Christopher S. Bond Life Sciences Center, Columbia, Missouri 65211 (N.A., J.T.T.); Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803 (R.D., N.K.); and Robert W. Holley Center for Agriculture and Health, Agricultural Research Service, US Department of Agriculture, Cornell University, Ithaca, New York 14853 (A.E.C., M.A.P., L.V.K.)
| | - Miguel A Piñeros
- The Boyce Thompson Institute for Plant Research, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Plant Pathology and Plant-Microbe Biology, Cornell University, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Biochemistry, University of Missouri, Christopher S. Bond Life Sciences Center, Columbia, Missouri 65211 (N.A., J.T.T.); Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803 (R.D., N.K.); and Robert W. Holley Center for Agriculture and Health, Agricultural Research Service, US Department of Agriculture, Cornell University, Ithaca, New York 14853 (A.E.C., M.A.P., L.V.K.)
| | - Leon V Kochian
- The Boyce Thompson Institute for Plant Research, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Plant Pathology and Plant-Microbe Biology, Cornell University, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Biochemistry, University of Missouri, Christopher S. Bond Life Sciences Center, Columbia, Missouri 65211 (N.A., J.T.T.); Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803 (R.D., N.K.); and Robert W. Holley Center for Agriculture and Health, Agricultural Research Service, US Department of Agriculture, Cornell University, Ithaca, New York 14853 (A.E.C., M.A.P., L.V.K.)
| | - Jay J Thelen
- The Boyce Thompson Institute for Plant Research, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Plant Pathology and Plant-Microbe Biology, Cornell University, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Biochemistry, University of Missouri, Christopher S. Bond Life Sciences Center, Columbia, Missouri 65211 (N.A., J.T.T.); Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803 (R.D., N.K.); and Robert W. Holley Center for Agriculture and Health, Agricultural Research Service, US Department of Agriculture, Cornell University, Ithaca, New York 14853 (A.E.C., M.A.P., L.V.K.)
| | - Sorina C Popescu
- The Boyce Thompson Institute for Plant Research, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Plant Pathology and Plant-Microbe Biology, Cornell University, Ithaca, New York 14853 (E.K.B., S.C.P.); Department of Biochemistry, University of Missouri, Christopher S. Bond Life Sciences Center, Columbia, Missouri 65211 (N.A., J.T.T.); Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803 (R.D., N.K.); and Robert W. Holley Center for Agriculture and Health, Agricultural Research Service, US Department of Agriculture, Cornell University, Ithaca, New York 14853 (A.E.C., M.A.P., L.V.K.)
| |
Collapse
|
|
45
|
Krenn PW, Hofbauer SW, Pucher S, Hutterer E, Hinterseer E, Denk U, Asslaber D, Ganghammer S, Sternberg C, Neureiter D, Aberger F, Wickström SA, Egle A, Greil R, Hartmann TN. ILK Induction in Lymphoid Organs by a TNFα-NF-κB-Regulated Pathway Promotes the Development of Chronic Lymphocytic Leukemia. Cancer Res 2016; 76:2186-96. [PMID: 26837762 DOI: 10.1158/0008-5472.can-15-3379] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 01/18/2016] [Indexed: 11/16/2022]
Abstract
The proliferation of chronic lymphocytic leukemia (CLL) cells requires communication with the lymphoid organ microenvironment. Integrin-linked kinase (ILK) is a multifunctional intracellular adaptor protein that transmits extracellular signals to regulate malignant cell motility, metastasis, and cell-cycle progression, but is poorly characterized in hematologic malignancies. In this study, we investigated the role of ILK in the context of CLL and observed high ILK expression in patient samples, particularly in tumor cells harboring prognostic high-risk markers such as unmutated IGHV genes, high Zap70, or CD38 expression, or a signature of recent proliferation. We also found increased numbers of Ki67 (MKI67)-positive cells in regions of enhanced ILK expression in lymph nodes from CLL patients. Using coculture conditions mimicking the proliferative lymph node microenvironment, we detected a parallel induction of ILK and cyclin D1 (CCND1) expression in CLL cells that was dependent on the activation of NF-κB signaling by soluble TNFα. The newly synthesized ILK protein colocalized to centrosomal structures and was required for correct centrosome clustering and mitotic spindle organization. Furthermore, we established a mouse model of CLL in which B-cell-specific genetic ablation of ILK resulted in decelerated leukemia development due to reduced organ infiltration and proliferation of CLL cells. Collectively, our findings describe a TNFα-NF-κB-mediated mechanism by which ILK expression is induced in the lymph node microenvironment and propose that ILK promotes leukemogenesis by enabling CLL cells to cope with centrosomal defects acquired during malignant transformation. Cancer Res; 76(8); 2186-96. ©2016 AACR.
Collapse
Affiliation(s)
- Peter W Krenn
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria
| | - Sebastian W Hofbauer
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria
| | - Susanne Pucher
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria
| | - Evelyn Hutterer
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria
| | - Elisabeth Hinterseer
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria
| | - Ursula Denk
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria
| | - Daniela Asslaber
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria
| | - Sylvia Ganghammer
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria
| | - Christina Sternberg
- Department of Molecular Biology, Division of Molecular Tumor Biology, University of Salzburg, Salzburg, Austria
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University, Salzburg, Austria
| | - Fritz Aberger
- Department of Molecular Biology, Division of Molecular Tumor Biology, University of Salzburg, Salzburg, Austria
| | - Sara A Wickström
- Paul Gerson Unna Group 'Skin Homeostasis and Ageing,' Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Alexander Egle
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria
| | - Richard Greil
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria
| | - Tanja N Hartmann
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria.
| |
Collapse
|
|
46
|
Activated Integrin-Linked Kinase Negatively Regulates Muscle Cell Enhancement Factor 2C in C2C12 Cells. BIOMED RESEARCH INTERNATIONAL 2016; 2015:748470. [PMID: 26788505 PMCID: PMC4695646 DOI: 10.1155/2015/748470] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2015] [Revised: 11/25/2015] [Accepted: 11/29/2015] [Indexed: 01/28/2023]
Abstract
Our previous study reported that muscle cell enhancement factor 2C (MEF2C) was fully activated after inhibition of the phosphorylation activity of integrin-linked kinase (ILK) in the skeletal muscle cells of goats. It enhanced the binding of promoter or enhancer of transcription factor related to proliferation of muscle cells and then regulated the expression of these genes. In the present investigation, we explored whether ILK activation depended on PI3K to regulate the phosphorylation and transcriptional activity of MEF2C during C2C12 cell proliferation. We inhibited PI3K activity in C2C12 with LY294002 and then found that ILK phosphorylation levels and MEF2C phosphorylation were decreased and that MCK mRNA expression was suppressed significantly. After inhibiting ILK phosphorylation activity with Cpd22 and ILK-shRNA, we found MEF2C phosphorylation activity and MCK mRNA expression were increased extremely significantly. In the presence of Cpd22, PI3K activity inhibition increased MEF2C phosphorylation and MCK mRNA expression indistinctively. We conclude that ILK negatively and independently of PI3K regulated MEF2C phosphorylation activity and MCK mRNA expression in C2C12 cells. The results provide new ideas for the study of classical signaling pathway of PI3K-ILK-related proteins and transcription factors.
Collapse
|
|
47
|
Huang XP, Ding H, Lu JD, Tang YH, Deng BX, Deng CQ. Effects of the Combination of the Main Active Components of Astragalus and Panax notoginseng on Inflammation and Apoptosis of Nerve Cell after Cerebral Ischemia-Reperfusion. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2015; 43:1419-38. [DOI: 10.1142/s0192415x15500809] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Astragalus and Panax notoginseng are commonly used to treat cardio-cerebrovascular diseases in China and are often combined together to promote curative effect. We speculate that the enhancement of the combination on anticerebral ischemia injury may come from the main active components. The purpose of this work was to probe the effects and mechanisms of Astragaloside IV (the active component of Astragalus) combined with Ginsenoside Rg1, Ginsenoside Rb1, and Notoginsenoside R1 (the active components of P. notoginseng) to antagonize ischemia/reperfusion (I/R) injury via inflammation and apoptosis. C57BL/6 mice were randomly divided into sham, model, Astragaloside IV, Ginsenoside Rg1, Ginsenoside Rb1, Notoginsenoside R1, four active components combination, and Edaravone groups. After administration for 3 days, bilateral common carotid arteries (CCA) were occluded with artery clip for 20[Formula: see text]min followed by reperfusion for 24[Formula: see text]h. Our results showed that the survival rate of nerve cell in hippocampal CA1 decreased while the apoptotic rate increased, and the level of caspase-3 protein in brain tissues was elevated, the expressions of TNF-a, IL-1, and ICAM-1 mRNA as well as phosphorylated nuclear factor kappa B (NF-[Formula: see text]B) inhibitor protein [Formula: see text] (p-I[Formula: see text]Ba) in brain tissues were up-regulated, and the nuclear translocation rate of NF-[Formula: see text]B was raised. Additionally, the protein expressions of phosphorylated tyrosine kinase 1 (p-JAK1), phosphorylated signal transducer and activator of transcription-1 (p-STAT1), glucose regulated protein 78 (GRP78), caspase-12, and phosphorylated c-Jun N-terminal kinases 1/2 (p-JNK1/2) in brain tissues were also significantly strengthened after I/R for 24[Formula: see text]h. All drugs could increase neurocyte survival rate in hippocampal CA1, decrease the apoptotic rate, and inhibit caspase-3 protein expression, in contrast, the effects of four active components combination were better than those of active components alone. In addition, Astragaloside IV and Ginsenoside Rg1 could down-regulate the level of TNF-[Formula: see text], and ICAM-1 mRNA, respectively, Notoginsenoside R1 reduced both TNF-[Formula: see text] and ICAM-1 mRNA, and the combination of the 4 effective components had inhibitory effects on the expressions of TNF-[Formula: see text], IL-1[Formula: see text], and ICAM-1 mRNA. Astragaloside IV, Ginsenoside Rg1, Notoginsenoside R1, and 4 effective components combination were able to restrain the phosphorylation of I[Formula: see text]B[Formula: see text], and relieve the nuclear translocation rate of NF-[Formula: see text]B. Moreover, the effects of the combination are greater than those of active components alone. All drugs could suppress the phosphorylation of JAK1 induced by I/R; meanwhile the expression of p-STAT1 exhibited a decrease in Ginsenoside Rg1 and four active components combination groups. The decreases of p-JAK1 and p-STAT1 in the four active components combination group were more obvious than those in active components alone groups. Astragaloside IV, Ginsenoside Rg1, and Notoginsenoside R1 further augmented GRP78 expression caused by I/R, Notoginsenoside R1 attenuated caspase-12 protein expression, Astragaloside IV and Ginsenoside Rg1 lessened the phosphorylation of JNK1/2, and the four active components combination was capable of up-regulating GRP78 protein while down-regulating the expressions of caspase-12 and p-JNK1/2. Similarly, the effects of the four active components combination were greater than those of effective components alone. These suggested that the combination of the main active components of Astragalus and Panax notoginseng could strengthen protective effects on cerebral ischemia injury via anti-apoptosis and anti-inflammation, and the mechanisms might be associated with restraining the activation of NF-[Formula: see text]B and JAK1/STAT1 signal pathways and regulating endoplasmic reticulum stress (ERS) after cerebral ischemia.
Collapse
Affiliation(s)
- Xiao-Ping Huang
- Molecular Pathology Laboratory, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, P.R. China
| | - Huang Ding
- Key Laboratory of Hunan Province for Prevention and Treatment of Integrated, Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Changsha 410208, Hunan Province, P.R. China
| | - Jin-Dong Lu
- Key Laboratory of Hunan Universities for Cell biology and Molecular Techniques, Changsha 410208, Hunan Province, P.R. China
| | - Ying-Hong Tang
- Key Laboratory of Hunan Province for Prevention and Treatment of Integrated, Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Changsha 410208, Hunan Province, P.R. China
| | - Bing-Xiang Deng
- Key Laboratory of Hunan Universities for Cell biology and Molecular Techniques, Changsha 410208, Hunan Province, P.R. China
| | - Chang-Qing Deng
- Molecular Pathology Laboratory, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, P.R. China
| |
Collapse
|
|
48
|
Transcriptional Activation of Inflammatory Genes: Mechanistic Insight into Selectivity and Diversity. Biomolecules 2015; 5:3087-111. [PMID: 26569329 PMCID: PMC4693271 DOI: 10.3390/biom5043087] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 09/11/2015] [Accepted: 10/28/2015] [Indexed: 12/11/2022] Open
Abstract
Acute inflammation, an integral part of host defence and immunity, is a highly conserved cellular response to pathogens and other harmful stimuli. An inflammatory stimulation triggers transcriptional activation of selective pro-inflammatory genes that carry out specific functions such as anti-microbial activity or tissue healing. Based on the nature of inflammatory stimuli, an extensive exploitation of selective transcriptional activations of pro-inflammatory genes is performed by the host to ensure a defined inflammatory response. Inflammatory signal transductions are initiated by the recognition of inflammatory stimuli by transmembrane receptors, followed by the transmission of the signals to the nucleus for differential gene activations. The differential transcriptional activation of pro-inflammatory genes is precisely controlled by the selective binding of transcription factors to the promoters of these genes. Among a number of transcription factors identified to date, NF-κB still remains the most prominent and studied factor for its diverse range of selective transcriptional activities. Differential transcriptional activities of NF-κB are dictated by post-translational modifications, specificities in dimer formation, and variability in activation kinetics. Apart from the differential functions of transcription factors, the transcriptional activation of selective pro-inflammatory genes is also governed by chromatin structures, epigenetic markers, and other regulators as the field is continuously expanding.
Collapse
|
|
49
|
Sappanone A exhibits anti-inflammatory effects via modulation of Nrf2 and NF-κB. Int Immunopharmacol 2015; 28:328-36. [PMID: 26122134 DOI: 10.1016/j.intimp.2015.06.015] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 06/09/2015] [Indexed: 12/20/2022]
Abstract
UNLABELLED Homoisoflavonoids constitute a small class of natural products. In the present study, we investigated the anti-inflammatory effect of sappanone A (SPNA), a homoisoflavanone that is isolated from the heartwood of Caesalpinia sappan (Leguminosae), in murine macrophages. SPNA inhibited the production of nitric oxide (NO), prostaglandin E2 (PGE2) and interleukin-6 (IL-6) as well as the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and IL-6 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Moreover, SPNA protected C57BL/6 mice from LPS-induced mortality. Treatment of RAW264.7 cells with SPNA induced heme oxygenase (HO)-1 protein and mRNA expression and increased nuclear translocation of the nuclear factor-E2-related factor 2 (Nrf2) as well as the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1). Knockdown of Nrf2 by siRNA blocked SPNA-mediated HO-1 induction. SB203580, p38 mitogen-activated protein kinase (MAPK) inhibitor, blocked SPNA-induced HO-1 expression and nuclear translocation of Nrf2, suggesting that SPNA induces HO-1 expression by activating Nrf2 through the p38 MAPK pathway. Consistent with the notion that the Nrf2/HO-1 pathway has anti-inflammatory properties, inhibiting HO-1 significantly abrogated the anti-inflammatory effects of SPNA in LPS-stimulated RAW264.7 cells. Moreover, SPNA suppressed LPS-induced nuclear factor κB (NF-κB) activation via inhibiting Ser 536 phosphorylation and transcriptional activity of RelA/p65 subunit of NF-κB. Taken together, these findings suggest that SPNA exerts its anti-inflammatory effect by modulating the Nrf2 and NF-κB pathways, and may be a valuable compound to prevent or treat inflammatory diseases.
Collapse
|