|
1
|
Achary ST, Gupta P, Rajput A, Sohkhia W, Bonam SR, Sahu BD. Phytochemicals Targeting Inflammatory Pathways in Alcohol-Induced Liver Disease: A Mechanistic Review. Pharmaceuticals (Basel) 2025; 18:710. [PMID: 40430529 PMCID: PMC12115344 DOI: 10.3390/ph18050710] [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: 04/05/2025] [Revised: 05/06/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
Alcoholic beverages play a significant role in social engagement worldwide. Excessive alcohol causes a variety of health complications. Alcohol-induced liver disease (ALD) is responsible for the bulk of linked fatalities. The activation of immune mechanisms has a crucial role in developing ALD. No effective medication promotes liver function, shields the liver from harm, or aids in hepatic cell regeneration. Alcohol withdrawal is one of the most beneficial therapies for ALD patients, which improves the patient's chances of survival. There is a crucial demand for safe and reasonably priced approaches to treating it. Exploring naturally derived phytochemicals has been a fascinating path, and it has drawn attention in recent years to modulators of inflammatory pathways for the prevention and management of ALD. In this review, we have discussed the roles of various immune mechanisms in ALD, highlighting the importance of intestinal barrier integrity and gut microbiota, as well as the roles of immune cells and hepatic inflammation, and other pathways, including cGAS-STING, NLRP3, MAPK, JAK-STAT, and NF-kB. Further, this review also outlines the possible role of phytochemicals in targeting these inflammatory pathways to safeguard the liver from alcohol-induced injury. We highlighted that targeting immunological mechanisms using phytochemicals or herbal medicine may find a place to counteract ALD. Preclinical in vitro and in vivo investigations have shown promising results; nonetheless, more extensive work is required to properly understand these compounds' mechanisms of action. Clinical investigations are very crucial in transferring laboratory knowledge into effective patient therapy.
Collapse
Affiliation(s)
- Swati Tirunal Achary
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati 781101, India
| | - Prerna Gupta
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati 781101, India
| | - Apoorva Rajput
- Vaccine Immunology Laboratory, Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
- Academy of Scientific and Innovative Research, Ghaziabad 201002, India
| | - Wanphidabet Sohkhia
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati 781101, India
| | - Srinivasa Reddy Bonam
- Vaccine Immunology Laboratory, Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
- Academy of Scientific and Innovative Research, Ghaziabad 201002, India
| | - Bidya Dhar Sahu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati 781101, India
| |
Collapse
|
|
2
|
Zhu X, Cai L, Liu J, Zhu W, Cui C, Ouyang D, Ye J. Effect of seabuckthorn seed protein and its arginine-enriched peptides on combating memory impairment in mice. Int J Biol Macromol 2023; 232:123409. [PMID: 36706884 DOI: 10.1016/j.ijbiomac.2023.123409] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 01/26/2023]
Abstract
The current study characterized the combating memory impairment effect of seabuckthorn seed protein (SSP) and the arginine (Arg)-enriched peptides (SSPP) on d-galactose-induced brain aging in mice. The Arg content in SSP and SSPP were 10.11 and 17.82 g/100 g, respectively. Seven Arg peptides (Ile/Leu-Arg, Arg-Glu, Asp-Arg-Pro, Arg-Try-Ala, Glu-Arg-Ser, Val-Gly-Arg-Pro, and Lys-Thr-Glu-Arg) were identified from SSPP. The animal experiments of the Morris water maze and the step-down test indicated that the oral administration of SSP (0.25, 0.5, 1.0 mg/g·d) and SSPP (0.25, 0.5, 1.0 mg/g·d) significantly (p < 0.05) reversed the learning and memory impairment symptoms. The activation of endothelial nitric oxide (NO) synthase and neuronal NO synthase were increased, and inducible NO synthase decreased after SSP and SSPP in the hippocampus compared to the model group, with the SSPP being quite effective. Moreover, the treatment significantly exhibited the ability to normalize the serum inflammatory cytokine levels (NF-ĸB, TNF-α, IL-6) and suppress the Arg-inducible nitric oxide (Arg-iNO) pathway. Therefore, SSP and SSPP ingestion reversed the behavioral learning and memory impairment symptoms possibly associated with the anti-inflammation and Arg-iNO pathway. Consumption of SSP and SSPP diets can be beneficial to memory impairment.
Collapse
Affiliation(s)
- Xiping Zhu
- College of Biological and Food Engineering, Anhui Polytechnic University, Wuhu 241000, Anhui, China
| | - Lei Cai
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, Guangdong, China
| | - Jinqi Liu
- College of Biological and Food Engineering, Anhui Polytechnic University, Wuhu 241000, Anhui, China
| | - Wen Zhu
- College of Biological and Food Engineering, Anhui Polytechnic University, Wuhu 241000, Anhui, China
| | - Chun Cui
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, Guangdong, China.
| | - Daofu Ouyang
- Perfect (Guangdong) Daily Necessities Co, Ltd, Zhongshan 528400, Guangdong, China
| | - Jianwen Ye
- Perfect (Guangdong) Daily Necessities Co, Ltd, Zhongshan 528400, Guangdong, China
| |
Collapse
|
|
3
|
Yang Y, Shao M, Cheng W, Yao J, Ma L, Wang Y, Wang W. A Pharmacological Review of Tanshinones, Naturally Occurring Monomers from Salvia miltiorrhiza for the Treatment of Cardiovascular Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:3801908. [PMID: 36793978 PMCID: PMC9925269 DOI: 10.1155/2023/3801908] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/23/2022] [Accepted: 11/25/2022] [Indexed: 02/09/2023]
Abstract
Cardiovascular diseases (CVDs) are a set of heart and blood vessel disorders that include coronary heart disease (CHD), rheumatic heart disease, and other conditions. Traditional Chinese Medicine (TCM) has definite effects on CVDs due to its multitarget and multicomponent properties, which are gradually gaining national attention. Tanshinones, the major active chemical compounds extracted from Salvia miltiorrhiza, exhibit beneficial improvement on multiple diseases, especially CVDs. At the level of biological activities, they play significant roles, including anti-inflammation, anti-oxidation, anti-apoptosis and anti-necroptosis, anti-hypertrophy, vasodilation, angiogenesis, combat against proliferation and migration of smooth muscle cells (SMCs), as well as anti-myocardial fibrosis and ventricular remodeling, which are all effective strategies in preventing and treating CVDs. Additionally, at the cellular level, Tanshinones produce marked effects on cardiomyocytes, macrophages, endothelia, SMCs, and fibroblasts in myocardia. In this review, we have summarized a brief overview of the chemical structures and pharmacological effects of Tanshinones as a CVD treatment to expound on different pharmacological properties in various cell types in myocardia.
Collapse
Affiliation(s)
- Ye Yang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese Medicine), Ministry of Education, Beijing, China
| | - Mingyan Shao
- Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese Medicine), Ministry of Education, Beijing, China
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Wenkun Cheng
- Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese Medicine), Ministry of Education, Beijing, China
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Junkai Yao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese Medicine), Ministry of Education, Beijing, China
| | - Lin Ma
- Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese Medicine), Ministry of Education, Beijing, China
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yong Wang
- Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese Medicine), Ministry of Education, Beijing, China
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Wei Wang
- Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese Medicine), Ministry of Education, Beijing, China
- Guangzhou University of Chinese Medicine, Guangzhou, China
| |
Collapse
|
|
4
|
Mobeen A, Puniya BL, Ramachandran S. A computational approach to investigate constitutive activation of
NF‐κB. Proteins 2022; 90:1944-1964. [DOI: 10.1002/prot.26388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 05/12/2022] [Accepted: 05/23/2022] [Indexed: 11/10/2022]
Affiliation(s)
- Ahmed Mobeen
- CSIR – Institute of Genomics & Integrative Biology, Sukhdev Vihar New Delhi India
- Academy of Scientific & Innovative Research (AcSIR) Ghaziabad Uttar Pradesh India
| | - Bhanwar Lal Puniya
- Department of Biochemistry University of Nebraska‐Lincoln Lincoln Nebraska USA
| | - Srinivasan Ramachandran
- CSIR – Institute of Genomics & Integrative Biology, Sukhdev Vihar New Delhi India
- Academy of Scientific & Innovative Research (AcSIR) Ghaziabad Uttar Pradesh India
| |
Collapse
|
|
5
|
Xun T, Lin Z, Wang X, Zhan X, Feng H, Gan D, Yang X. Advanced oxidation protein products downregulate CYP1A2 and CYP3A4 expression and activity via the NF-κB-mediated signaling pathway in vitro and in vivo. J Transl Med 2021; 101:1197-1209. [PMID: 34031539 PMCID: PMC8367815 DOI: 10.1038/s41374-021-00610-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 01/01/2023] Open
Abstract
Uremic toxin accumulation is one possible reason for alterations in hepatic drug metabolism in patients with chronic kidney disease (CKD). However, the types of uremic toxins and underlying mechanisms are poorly understood. In this study, we report the role of advanced oxidation protein products (AOPPs), a modified protein uremic toxin, in the downregulation of cytochromes P450 1A2 (CYP1A2) and P450 3A4 (CYP3A4) expression levels and activities. We found that AOPP accumulation in plasma in a rat CKD model was associated with decreased protein levels of CYP1A2 and CYP3A4. CYP1A2 and CYP3A4 metabolites (acetaminophen and 6β-hydroxytestosterone, respectively,) in liver microsomes were also significantly decreased. In human hepatocytes, AOPPs significantly decreased CYP1A2 and CYP3A4 protein levels in a dose- and time-dependent manner and downregulated their activities; however, bovine serum albumin (BSA), a synthetic precursor of AOPPs, had no effect on these parameters. The effect of AOPPs was associated with upregulation of p-IKKα/β, p-IκBα, p-NF-κB, and inflammatory cytokines protein levels and increases in p-IKKα/β/IKKα, p-IκBα/IκBα, and p-NF-κB/NF-κB phosphorylation ratios. Further, NF-kB pathway inhibitors BAY-117082 and PDTC abolished the downregulatory effects of AOPPs. These findings suggest that AOPPs downregulate CYP1A2 and CYP3A4 expression and activities by increasing inflammatory cytokine production and stimulating NF-κB-mediated signaling. Protein uremic toxins, such as AOPPs, may modify the nonrenal clearance of drugs in patients with CKD by influencing metabolic enzymes.
Collapse
Affiliation(s)
- Tianrong Xun
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Zhufen Lin
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Xiaokang Wang
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Xia Zhan
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Haixing Feng
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Danna Gan
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Xixiao Yang
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| |
Collapse
|
|
6
|
Padash Barmchi M, Thomas M, Thatte JV, Vats A, Zhang B, Cagan RL, Banks L. Inhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6. Sci Rep 2021; 11:1111. [PMID: 33441820 PMCID: PMC7807017 DOI: 10.1038/s41598-020-80193-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 12/15/2020] [Indexed: 11/14/2022] Open
Abstract
Human papillomavirus (HPV) is the leading cause of cervical cancer and has been implicated in several other cancer types including vaginal, vulvar, penile, and oropharyngeal cancers. Despite the recent availability of a vaccine, there are still over 310,000 deaths each year worldwide. Current treatments for HPV-mediated cancers show limited efficacy, and would benefit from improved understanding of disease mechanisms. Recently, we developed a Drosophila 'HPV 18 E6' model that displayed loss of cellular morphology and polarity, junctional disorganization, and degradation of the major E6 target Magi; we further provided evidence that mechanisms underlying HPV E6-induced cellular abnormalities are conserved between humans and flies. Here, we report a functional genetic screen of the Drosophila kinome that identified IKK[Formula: see text]-a regulator of NF-κB-as an enhancer of E6-induced cellular defects. We demonstrate that inhibition of IKK[Formula: see text] reduces Magi degradation and that this effect correlates with hyperphosphorylation of E6. Further, the reduction in IKK[Formula: see text] suppressed the cellular transformation caused by the cooperative action of HPVE6 and the oncogenic Ras. Finally, we demonstrate that the interaction between IKK[Formula: see text] and E6 is conserved in human cells: inhibition of IKK[Formula: see text] blocked the growth of cervical cancer cells, suggesting that IKK[Formula: see text] may serve as a novel therapeutic target for HPV-mediated cancers.
Collapse
Affiliation(s)
| | - Miranda Thomas
- International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
| | - Jayashree V Thatte
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Arushi Vats
- International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
| | - Bing Zhang
- Division of Biological Sciences, University of Missouri, Columbia, MO, USA
| | - Ross L Cagan
- Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Glasgow, Scotland, UK
| | - Lawrence Banks
- International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
| |
Collapse
|
|
7
|
NFKB1 gene rs28362491 ins/del variation is associated with higher susceptibility to myocardial infarction in a Chinese Han population. Sci Rep 2020; 10:19518. [PMID: 33177541 PMCID: PMC7658993 DOI: 10.1038/s41598-020-72877-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 09/07/2020] [Indexed: 12/20/2022] Open
Abstract
Myocardial infarction (MI), the leading cause of mortality and disability worldwide, is a disease in which multiple environmental and genetic factors are involved. Recently, researches suggested that insertion/deletion (ins/del) variation of NFKB1 gene rs28362491 is a functional polymorphism. In the present study, we aimed to explore the relation between variation of NFKB1 gene rs28362491 and MI by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 359 MI patients and 1085 control participants. Gensini score was used to evaluate the degree of coronary artery stenosis in MI patients. The plasma levels of interleukin-6 (IL-6), IL-8, malonaldehyde (MDA) and superoxide dismutase (SOD) were randomly measured by ELISA both in MI patients and control participants. We found that the detected frequencies of D allele (41.2% vs. 36.4%, P = 0.021) and DD genotype (17.5% vs. 12.0%, P = 0.022) were significantly higher in MI patients than in control participants. Compared with II or ID genotype carriers, the Gensini score in MI patients with DD genotype was 32-43% higher (both P < 0.001). Moreover, DD genotype carries had more diseased coronary arteries (P = 0.001 vs. II or ID genotype). Of note, IL-6 levels in MI patients carrying DD genotype were significantly higher than that in control participants and other genotype carriers in MI patients (both P < 0.05). In conclusion, NFKB1 gene rs28362491 DD genotype was associated with a higher risk of MI and more severe coronary artery lesion, which also had a potential influence on the level of inflammatory cytokine IL-6.
Collapse
|
|
8
|
Abo El-Magd NF, El-Karef A, El-Shishtawy MM, Eissa LA. Hepatoprotective effects of glycyrrhizin and omega-3 fatty acids on Nuclear Factor-kappa B pathway in thioacetamide-induced fibrosis in rats. ACTA ACUST UNITED AC 2019. [DOI: 10.1016/j.ejbas.2014.12.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- Nada F. Abo El-Magd
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Amro El-Karef
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | | | - Laila A. Eissa
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| |
Collapse
|
|
9
|
Acteoside ameliorates inflammatory responses through NFkB pathway in alcohol induced hepatic damage. Int Immunopharmacol 2019; 69:109-117. [PMID: 30703705 DOI: 10.1016/j.intimp.2019.01.020] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/28/2018] [Accepted: 01/11/2019] [Indexed: 02/08/2023]
|
|
10
|
Han XZ, Ma R, Chen Q, Jin X, Jin YZ, An RB, Piao XM, Lian ML, Quan LH, Jiang J. Anti-inflammatory action of Athyrium multidentatum extract suppresses the LPS-induced TLR4 signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2018; 217:220-227. [PMID: 29476961 DOI: 10.1016/j.jep.2018.02.031] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 02/17/2018] [Accepted: 02/18/2018] [Indexed: 06/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The aerial part of Athyrium multidentatum (Doll.) Ching (AM) is widely used in the northeastern region of China as an edible wild herb, but its medicinal value, especially its anti-inflammatory effect, has not been fully explored. AIM OF THE STUDY To investigate the anti-inflammatory activity of AM and clarify the anti-inflammatory mechanism involving the TLR4 signaling pathway using a lipopolysaccharide (LPS)-induced inflammatory model. MATERIALS AND METHODS AM ethanol extract was used as the experimental material to investigate the effect that the extract has on the production of pro-inflammatory mediators (NO, PGE2, TNF-α, IL-1β and IL-6); changes in LPS-induced peritoneal macrophages (PMs); and TLR4-mediated intracellular events, including MAPKs (ERK, JNK, and p38) and IκB-α in the MyD88-dependant pathway and IRF3, STAT1, and STAT3 in the TRIF-dependent pathway. In in vivo experiments, we established an LPS-induced acute lung injury (ALI) model and investigated the cell count and cytokine (TNF-α, IL-1β and IL-6) levels in bronchoalvelar lavage fluid (BALF) of C57BL6 mice. Histological changes in the lung tissues were observed with H&E staining. RESULTS AM extract inhibited NO and PGE2 by suppressing their synthetase (iNOS and COX-2) gene expression in LPS-induced PMs; the secretion of IL-6, IL-1β, and TNF-α also deceased via the down-regulation of mRNA levels. Furthermore, the TLR4-mediated intracellular events involved the phosphorylated forms of MAPKs (ERK, JNK) and IκB-α in the MyD88-dependent pathway and the TRIF-dependent pathway (IRF3, STAT1, STAT3), and the relevant proteins were expressed at low levels in the AM extract groups. In in vivo experiments, the cell count and cytokine (TNF-α, IL-1β and IL-6) levels in BALF decreased significantly in a dose-dependent manner in the AM extract groups. The lung tissue structure exhibited dramatic damage in the LPS group, and the damaged area decreased in the AM extract groups; in particular, the effect of 10 mg/kg extract was similar to that of the positive control dexamethasone (DEX). CONCLUSION The findings demonstrate that AM protects against LPS-induced acute lung injury by suppressing TLR4 signaling, provide scientific evidence to support further study of the safety of anti-inflammatory drugs and indicate that AM can be used as an anti-inflammatory and anti-injury agent to prevent pneumonia caused by microbial infection.
Collapse
MESH Headings
- Acute Lung Injury/chemically induced
- Acute Lung Injury/metabolism
- Acute Lung Injury/prevention & control
- Adaptor Proteins, Vesicular Transport/metabolism
- Animals
- Anti-Inflammatory Agents/isolation & purification
- Anti-Inflammatory Agents/pharmacology
- Cells, Cultured
- Cytokines/metabolism
- Dinoprostone/metabolism
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Female
- Ferns/chemistry
- Lipopolysaccharides
- Lung/drug effects
- Lung/metabolism
- Macrophages, Peritoneal/drug effects
- Macrophages, Peritoneal/metabolism
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Myeloid Differentiation Factor 88/metabolism
- Nitric Oxide/metabolism
- Phytotherapy
- Plant Components, Aerial
- Plant Extracts/isolation & purification
- Plant Extracts/pharmacology
- Plants, Medicinal
- Signal Transduction/drug effects
- Toll-Like Receptor 4/antagonists & inhibitors
- Toll-Like Receptor 4/metabolism
Collapse
Affiliation(s)
- Xiong-Zhe Han
- Key Laboratory of Natural Resource of Changbai Mountain and Functional Molecules (Ministry of Education), Ginseng Research Center of Changbai Mountain, Yanbian University, Yanji 133002, Jilin, China.
| | - Rui Ma
- Key Laboratory of Natural Resource of Changbai Mountain and Functional Molecules (Ministry of Education), Ginseng Research Center of Changbai Mountain, Yanbian University, Yanji 133002, Jilin, China.
| | - Qi Chen
- Key Laboratory of Natural Resource of Changbai Mountain and Functional Molecules (Ministry of Education), Ginseng Research Center of Changbai Mountain, Yanbian University, Yanji 133002, Jilin, China.
| | - Xin Jin
- Key Laboratory of Natural Resource of Changbai Mountain and Functional Molecules (Ministry of Education), Ginseng Research Center of Changbai Mountain, Yanbian University, Yanji 133002, Jilin, China.
| | - Yuan-Zhe Jin
- Key Laboratory of Natural Resource of Changbai Mountain and Functional Molecules (Ministry of Education), Ginseng Research Center of Changbai Mountain, Yanbian University, Yanji 133002, Jilin, China.
| | - Ren-Bo An
- Key Laboratory of Natural Resource of Changbai Mountain and Functional Molecules (Ministry of Education), Ginseng Research Center of Changbai Mountain, Yanbian University, Yanji 133002, Jilin, China.
| | - Xuan-Mei Piao
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea.
| | - Mei-Lan Lian
- Key Laboratory of Natural Resource of Changbai Mountain and Functional Molecules (Ministry of Education), Ginseng Research Center of Changbai Mountain, Yanbian University, Yanji 133002, Jilin, China.
| | - Lin-Hu Quan
- Key Laboratory of Natural Resource of Changbai Mountain and Functional Molecules (Ministry of Education), Ginseng Research Center of Changbai Mountain, Yanbian University, Yanji 133002, Jilin, China.
| | - Jun Jiang
- Key Laboratory of Natural Resource of Changbai Mountain and Functional Molecules (Ministry of Education), Ginseng Research Center of Changbai Mountain, Yanbian University, Yanji 133002, Jilin, China.
| |
Collapse
|
|
11
|
Shafaghati L, Razaghi-Moghadam Z, Mohammadnejad J. A Systems Biology Approach to Understanding Alcoholic Liver Disease Molecular Mechanism: The Development of Static and Dynamic Models. Bull Math Biol 2017; 79:2450-2473. [PMID: 28849551 DOI: 10.1007/s11538-017-0336-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 08/18/2017] [Indexed: 12/11/2022]
Abstract
Alcoholic liver disease (ALD) is a complex disease characterized by damages to the liver and is the consequence of excessive alcohol consumption over years. Since this disease is associated with several pathway failures, pathway reconstruction and network analysis are likely to explicit the molecular basis of the disease. To this aim, in this paper, a network medicine approach was employed to integrate interactome (protein-protein interaction and signaling pathways) and transcriptome data to reconstruct both a static network of ALD and a dynamic model for it. Several data sources were exploited to assemble a set of ALD-associated genes which further was used for network reconstruction. Moreover, a comprehensive literature mining reveals that there are four signaling pathways with crosstalk (TLR4, NF- [Formula: see text]B, MAPK and Apoptosis) which play a major role in ALD. These four pathways were exploited to reconstruct a dynamic model of ALD. The results assure that these two models are consistent with a number of experimental observations. The static network of ALD and its dynamic model are the first models provided for ALD which offer potentially valuable information for researchers in this field.
Collapse
Affiliation(s)
- Leila Shafaghati
- Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
| | | | - Javad Mohammadnejad
- Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
| |
Collapse
|
|
12
|
Brawek B, Liang Y, Savitska D, Li K, Fomin-Thunemann N, Kovalchuk Y, Zirdum E, Jakobsson J, Garaschuk O. A new approach for ratiometric in vivo calcium imaging of microglia. Sci Rep 2017; 7:6030. [PMID: 28729628 PMCID: PMC5519759 DOI: 10.1038/s41598-017-05952-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 06/07/2017] [Indexed: 11/09/2022] Open
Abstract
Microglia, resident immune cells of the brain, react to the presence of pathogens/danger signals with a large repertoire of functional responses including morphological changes, proliferation, chemotaxis, production/release of cytokines, and phagocytosis. In vitro studies suggest that many of these effector functions are Ca2+-dependent, but our knowledge about in vivo Ca2+ signalling in microglia is rudimentary. This is mostly due to technical reasons, as microglia largely resisted all attempts of in vivo labelling with Ca2+ indicators. Here, we introduce a novel approach, utilizing a microglia-specific microRNA-9-regulated viral vector, enabling the expression of a genetically-encoded ratiometric Ca2+ sensor Twitch-2B in microglia. The Twitch-2B-assisted in vivo imaging enables recording of spontaneous and evoked microglial Ca2+ signals and allows for the first time to monitor the steady state intracellular Ca2+ levels in microglia. Intact in vivo microglia show very homogenous and low steady state intracellular Ca2+ levels. However, the levels increase significantly after acute slice preparation and cell culturing along with an increase in the expression of activation markers CD68 and IL-1β. These data identify the steady state intracellular Ca2+ level as a versatile microglial activation marker, which is highly sensitive to the cell's environment.
Collapse
Affiliation(s)
- Bianca Brawek
- Institute of Physiology II, University of Tübingen, 72074, Tübingen, Germany
| | - Yajie Liang
- Institute of Physiology II, University of Tübingen, 72074, Tübingen, Germany
| | - Daria Savitska
- Institute of Physiology II, University of Tübingen, 72074, Tübingen, Germany
| | - Kaizhen Li
- Institute of Physiology II, University of Tübingen, 72074, Tübingen, Germany
| | | | - Yury Kovalchuk
- Institute of Physiology II, University of Tübingen, 72074, Tübingen, Germany
| | - Elizabeta Zirdum
- Institute of Physiology II, University of Tübingen, 72074, Tübingen, Germany
| | - Johan Jakobsson
- Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund, 221 84, Sweden
| | - Olga Garaschuk
- Institute of Physiology II, University of Tübingen, 72074, Tübingen, Germany.
| |
Collapse
|
|
13
|
Folic Acid Is Able to Polarize the Inflammatory Response in LPS Activated Microglia by Regulating Multiple Signaling Pathways. Mediators Inflamm 2016; 2016:5240127. [PMID: 27738387 PMCID: PMC5055986 DOI: 10.1155/2016/5240127] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Revised: 07/28/2016] [Accepted: 08/11/2016] [Indexed: 12/18/2022] Open
Abstract
We investigated the ability of folic acid to modulate the inflammatory responses of LPS activated BV-2 microglia cells and the signal transduction pathways involved. To this aim, the BV-2 cell line was exposed to LPS as a proinflammatory response inducer, in presence or absence of various concentrations of folic acid. The production of nitric oxide (NO) was determined by the Griess test. The levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-10 were determined by ELISA. Inducible NO synthase (iNOS), nuclear transcription factor-kappa B (NF-κB) p65, MAPKs protein, and suppressors of cytokine signaling (SOCS)1 and SOCS3 were analyzed by western blotting. TNF-α and IL-1β, as well as iNOS dependent NO production, resulted significantly inhibited by folic acid pretreatment in LPS-activated BV-2 cells. We also observed that folic acid dose-dependently upregulated both SOCS1 and SOCS3 expression in BV-2 cells, leading to an increased expression of the anti-inflammatory cytokine IL-10. Finally, p-IκBα, which indirectly reflects NF-κB complex activation, and JNK phosphorylation resulted dose-dependently downregulated by folic acid pretreatment of LPS-activated cells, whereas p38 MAPK phosphorylation resulted significantly upregulated by folic acid treatment. Overall, these results demonstrated that folic acid was able to modulate the inflammatory response in microglia cells, shifting proinflammatory versus anti-inflammatory responses through regulating multiple signaling pathways.
Collapse
|
|
14
|
WU TAO, LIU TAO, ZHANG LI, XING LIANJUN, ZHENG PEIYONG, JI GUANG. Chinese medicinal formula, Qinggan Huoxue Recipe protects rats from alcoholic liver disease via the lipopolysaccharide-Kupffer cell signal conduction pathway. Exp Ther Med 2014; 8:363-370. [PMID: 25009584 PMCID: PMC4079449 DOI: 10.3892/etm.2014.1740] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Accepted: 02/12/2014] [Indexed: 12/20/2022] Open
Abstract
The Chinese medicinal formula, Qinggan (QG) Huoxue (HX) Recipe (R) exerts a range of pharmacological effects, including reversible steatosis, decreased levels of inflammatory cytokines and lipid peroxidation resistance. The aim of the present study was to determine the specific mechanisms of QGHXR hepatoprotection through the lipopolysaccharide-Kupffer cell (LPS-KC) signal conduction pathway in rats with alcoholic liver disease (ALD). ALD rats were exposed to the compound factors, QGR and HXR. Hematoxylin and eosin staining was conducted to evaluate the pathological changes in the liver following QGHXR treatment and an enzyme-linked immunosorbent assay was performed to measure the content of tumor necrosis factor (TNF)-α in the plasma. Immunohistochemical staining was conducted to examine the expression of cell differentiation antigen (CD) 68 and 14. In addition, western blot analysis and reverse transcription-polymerase chain reaction were used to measure the expression of Toll-like receptor 4 (TLR4), phosphorylated-extracellular regulated protein kinases (p-ERK), nuclear factor (NF)-κB, CD14 and TNF-α. Following stimulation with the compound factors, the rats exhibited increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, as well as marked pathological changes. Furthermore, the related molecules in the LPS-KC pathway were upregulated and QGHXR was identified to be effective in the LPS-KC signal conduction pathway in the ALD rats. QGHXR was superior to QGR and HXR in reducing the serum ALT and AST levels, regulating CD14, TLR4, NF-κB, ERK and TNF-α as well as improving the pathological changes. The results indicated that QGHXR therapy may provide a novel strategy for treating ALD via regulation of the related molecules in the LPS-KC signaling pathway.
Collapse
Affiliation(s)
- TAO WU
- Research Center of Chinese Medicine Therapy and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - TAO LIU
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - LI ZHANG
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - LIAN-JUN XING
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - PEI-YONG ZHENG
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - GUANG JI
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| |
Collapse
|
|
15
|
Ashour DS, Othman AA, Radi DA. Insights into regulatory molecules of intestinal epithelial cell turnover during experimental infection by Heterophyes heterophyes. Exp Parasitol 2014; 143:48-54. [PMID: 24852217 DOI: 10.1016/j.exppara.2014.05.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Revised: 04/27/2014] [Accepted: 05/11/2014] [Indexed: 12/24/2022]
Abstract
Heterophyiasis is an intestinal disease that remains endemic in many parts of the world, particularly the Nile Delta of Egypt and Southeast Asia, yet the populations at risk of infection expand throughout the world. The main histopathological feature of infection is villous atrophy, but the underlying factors are not well understood. Apoptosis of the villous epithelial cells was previously reported to be enhanced during intestinal parasitic infections; however, the role of Heterophyes heterophyes on enterocyte apoptosis was to be explored. Therefore, intestinal sections from mice experimentally infected with H. heterophyes were studied histopathologically and immunohistochemically for caspase-3 and NF-κB and compared to non-infected control mice. Atrophic villi covered by poorly differentiated epithelial cells were observed in the 2nd week post-infection. Also, we noted marked hyperplasia of the intestinal crypts with abundant inflammatory cellular infiltrate in the lamina propria, as well as apoptosis of cells lining the intestinal villi. Both caspase-3 and NF-κB showed positive staining in the intestinal epithelial cells with varying grades of intensity over the length of infection. Caspase-3 expression rose at the 2nd week p.i. then decreased over time, whereas NF-κB expression showed progressive increase throughout the weeks of infection. In conclusion, caspase-3 activation may be an important factor in the apoptotic pathway in early heterophyiasis, and, on the other hand, NF-κB seems to play a role in protecting the intestinal cells from excessive apoptosis. These observations may help open new avenues for tissue protective therapies that avoid or control the deleterious processes of apoptosis in various inflammatory conditions.
Collapse
Affiliation(s)
- Dalia S Ashour
- Department of Medical Parasitology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Ahmad A Othman
- Department of Medical Parasitology, Faculty of Medicine, Tanta University, Tanta, Egypt.
| | - Dina A Radi
- Department of Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
| |
Collapse
|
|
16
|
Histone deacetylase inhibition downregulates collagen 3A1 in fibrotic lung fibroblasts. Int J Mol Sci 2013; 14:19605-17. [PMID: 24084714 PMCID: PMC3821575 DOI: 10.3390/ijms141019605] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Revised: 08/27/2013] [Accepted: 09/11/2013] [Indexed: 12/15/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a deadly disease characterized by chronic inflammation and excessive collagen accumulation in the lung. Myofibroblasts are the primary collagen-producing cells in pulmonary fibrosis. Histone deacetylase inhibitor (HDACi) can affect gene expression, and some, such as suberoylanilide hydroxamic acid (SAHA), are US FDA approved for cancer treatment. In this study, we investigated SAHA’s effects on the expression of collagen III alpha 1 (COL3A1) in primary human IPF fibroblasts and in a murine model of pulmonary fibrosis. We observed that increased COL3A1 expression in IPF fibroblasts can be substantially reduced by SAHA treatment at the level of transcription as detected by RT-PCR; collagen III protein level was also reduced, as detected by Western blots and immunofluorescence. The deacetylation inhibitor effect of SAHA was verified by observing higher acetylation levels of both histone H3 and H4 in treated IPF cells. Chromatin immunoprecipitation (ChIP) experiments demonstrated that the reduced expression of COL3A1 by SAHA is with increased association of the repressive chromatin marker, H3K27Me3, and decreased association of the active chromatin marker, H3K9Ac. In our murine model of bleomycin-induced pulmonary fibrosis, the SAHA treated group demonstrated significantly less collagen III, as detected by immunohistochemistry. Our data indicate that the HDACi SAHA alters the chromatin associated with COL3A1, resulting in its decreased expression.
Collapse
|
|
17
|
Jana M, Pahan K. Gemfibrozil, a lipid lowering drug, inhibits the activation of primary human microglia via peroxisome proliferator-activated receptor β. Neurochem Res 2012; 37:1718-29. [PMID: 22528839 DOI: 10.1007/s11064-012-0781-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2012] [Revised: 04/04/2012] [Accepted: 04/07/2012] [Indexed: 12/27/2022]
Abstract
Microglial activation participates in the pathogenesis of various neuroinflammatory and neurodegenerative diseases. However, mechanisms by which microglial activation could be controlled are poorly understood. Peroxisome proliferator-activated receptors (PPAR) are transcription factors belonging to the nuclear receptor super family with diverse effect. This study underlines the importance of PPARβ/δ in mediating the anti-inflammatory effect of gemfibrozil, an FDA-approved lipid-lowering drug, in primary human microglia. Bacterial lipopolysachharides (LPS) induced the expression of various proinflammatory molecules and upregulated the expression of microglial surface marker CD11b in human microglia. However, gemfibrozil markedly suppressed proinflammatory molecules and CD11b in LPS-stimulated microglia. Human microglia expressed PPAR-β and -γ, but not PPAR-α. Interestingly, either antisense knockdown of PPAR-β or antagonism of PPAR-β by a specific chemical antagonist abrogated gemfibrozil-mediated inhibition of microglial activation. On the other hand, blocking of PPAR-α and -γ had no effect on gemfibrozil-mediated anti-inflammatory effect in microglia. These results highlight the fact that gemfibrozil regulates microglial activation by inhibiting inflammatory gene expression in a PPAR-β dependent pathway and further reinforce its therapeutic application in several neuroinflammatory and neurodegenerative diseases.
Collapse
Affiliation(s)
- Malabendu Jana
- Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison St., Suite 320, Chicago, IL 60612, USA
| | | |
Collapse
|
|
18
|
Sun H, Chen F, Wang X, Liu Z, Yang Q, Zhang X, Zhu J, Qiang L, Guo Q, You Q. Studies on gambogic acid (IV): Exploring structure-activity relationship with IκB kinase-beta (IKKβ). Eur J Med Chem 2012; 51:110-23. [PMID: 22472167 DOI: 10.1016/j.ejmech.2012.02.029] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Revised: 02/14/2012] [Accepted: 02/14/2012] [Indexed: 01/04/2023]
Abstract
Previously we have reported a series of gambogic acid's analogs and have identified a compound that possessed comparable in vitro growth inhibitory effect as gambogic acid. However, their target protein as well as the key pharmacophoric motifs on the target have not been identified yet. Herein we report that gambogic acid and its analogs inhibit the activity of IκB Kinase-beta (IKKβ) through suppressing the activation of TNFα/NF-κB pathway, which in turn induces A549 and U251 cell apoptosis. IKKβ can serve as one of gambogic acid's targets. The preparation of the compounds was carefully discussed in the article. Caged 4-oxa-tricyclo[4.3.1.0(3,7)]dec-2-one xanthone, which was identified as the pharmacophoric scaffold, represents a promising therapeutic agent for cancer and useful probe against NF-κB pathway.
Collapse
Affiliation(s)
- Haopeng Sun
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, China
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Amelioration of alcohol-induced hepatotoxicity by the administration of ethanolic extract of Sida cordifolia Linn. Br J Nutr 2012; 108:1256-63. [PMID: 22289614 DOI: 10.1017/s0007114511006568] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Sida cordifolia Linn. (Malvaceae) is a plant used in folk medicine for the treatment of the inflammation of oral mucosa, asthmatic bronchitis, nasal congestion and rheumatism. We studied the hepatoprotective activity of 50 % ethanolic extract of S. cordifolia Linn. against alcohol intoxication. The duration of the experiment was 90 d. The substantially elevated levels of toxicity markers such as alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transferase due to the alcohol treatment were significantly lowered in the extract-treated groups. The activity of antioxidant enzymes and glutathione content, which was lowered due to alcohol toxicity, was increased to a near-normal level in the co-administered group. Lipid peroxidation products, protein carbonyls, total collagen and hydroxyproline, which were increased in the alcohol-treated group, were reduced in the co-administered group. The mRNA levels of cytochrome P450 2E1, NF-κB, TNF-α and transforming growth factor-β1 were found to be increased in the alcohol-treated rats, and their expressions were found to be decreased in the co-administered group. These observations were reinforced by histopathological analysis. Thus, the present study clearly indicates that 50 % ethanolic extract of the roots of S. cordifolia Linn. has a potent hepatoprotective action against alcohol-induced toxicity, which was mediated by lowering oxidative stress and by down-regulating the transcription factors.
Collapse
|
|
20
|
Doyle PS, Zhou YM, Hsieh I, Greenbaum DC, McKerrow JH, Engel JC. The Trypanosoma cruzi protease cruzain mediates immune evasion. PLoS Pathog 2011; 7:e1002139. [PMID: 21909255 PMCID: PMC3164631 DOI: 10.1371/journal.ppat.1002139] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Accepted: 05/11/2011] [Indexed: 11/19/2022] Open
Abstract
Trypanosoma cruzi is the causative agent of Chagas' disease. Novel chemotherapy with the drug K11777 targets the major cysteine protease cruzain and disrupts amastigote intracellular development. Nevertheless, the biological role of the protease in infection and pathogenesis remains unclear as cruzain gene knockout failed due to genetic redundancy. A role for the T. cruzi cysteine protease cruzain in immune evasion was elucidated in a comparative study of parental wild type- and cruzain-deficient parasites. Wild type T. cruzi did not activate host macrophages during early infection (<60 min) and no increase in ∼P iκB was detected. The signaling factor NF-κB P65 colocalized with cruzain on the cell surface of intracellular wild type parasites, and was proteolytically cleaved. No significant IL-12 expression occurred in macrophages infected with wild type T. cruzi and treated with LPS and BFA, confirming impairment of macrophage activation pathways. In contrast, cruzain-deficient parasites induced macrophage activation, detectable iκB phosphorylation, and nuclear NF-κB P65 localization. These parasites were unable to develop intracellularly and survive within macrophages. IL 12 expression levels in macrophages infected with cruzain-deficient T. cruzi were comparable to LPS activated controls. Thus cruzain hinders macrophage activation during the early (<60 min) stages of infection, by interruption of the NF-κB P65 mediated signaling pathway. These early events allow T. cruzi survival and replication, and may lead to the spread of infection in acute Chagas' disease.
Collapse
Affiliation(s)
- Patricia S. Doyle
- Tropical Disease Research Unit and Sandler Center for Drug Discovery, Department of Pathology, University of California, San Francisco, California, United States of America
| | - Yuan M. Zhou
- Tropical Disease Research Unit and Sandler Center for Drug Discovery, Department of Pathology, University of California, San Francisco, California, United States of America
| | - Ivy Hsieh
- Tropical Disease Research Unit and Sandler Center for Drug Discovery, Department of Pathology, University of California, San Francisco, California, United States of America
| | - Doron C. Greenbaum
- Tropical Disease Research Unit and Sandler Center for Drug Discovery, Department of Pathology, University of California, San Francisco, California, United States of America
| | - James H. McKerrow
- Tropical Disease Research Unit and Sandler Center for Drug Discovery, Department of Pathology, University of California, San Francisco, California, United States of America
| | - Juan C. Engel
- Tropical Disease Research Unit and Sandler Center for Drug Discovery, Department of Pathology, University of California, San Francisco, California, United States of America
| |
Collapse
|
|
21
|
Nitroalkylation--a redox sensitive signaling pathway. Biochim Biophys Acta Gen Subj 2011; 1820:777-84. [PMID: 21723375 DOI: 10.1016/j.bbagen.2011.06.014] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Revised: 05/17/2011] [Accepted: 06/16/2011] [Indexed: 02/06/2023]
Abstract
Redox-sensitive posttranslational modification emerged as important signaling mechanisms. Besides other posttranslational modifications nitroalkylation by nitrated fatty acids mediate favorable anti-inflammatory effects. This review gives an overview of the generation and the reactivity of nitrated fatty acids. Additionally, it provides insights into the so far described pathways regulated by nitrated fatty acids. This article is part of a Special Issue entitled Regulation of Cellular Processes by S-nitrosylation.
Collapse
|
|
22
|
Gaur P, Munjal A, Lal SK. Influenza virus and cell signaling pathways. Med Sci Monit 2011; 17:RA148-54. [PMID: 21629204 PMCID: PMC3539548 DOI: 10.12659/msm.881801] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2010] [Accepted: 02/24/2011] [Indexed: 12/13/2022] Open
Abstract
Influenza viruses comprise a major class of human respiratory pathogens, responsible for causing morbidity and mortality worldwide. Influenza A virus, due to its segmented RNA genome, is highly subject to mutation, resulting in rapid formation of variants. During influenza infection, viral proteins interact with host proteins and exploit a variety of cellular pathways for their own benefit. Influenza virus inhibits the synthesis of these cellular proteins and facilitates expression of its own proteins for viral transcription and replication. Infected cell pathways are hijacked by an array of intracellular signaling cascades such as NF-κB signaling, PI3K/Akt pathway, MAPK pathway, PKC/PKR signaling and TLR/RIG-I signaling cascades. This review presents a research update on the subject and discusses the impact of influenza viral infection on these cell signaling pathways.
Collapse
Affiliation(s)
- Pratibha Gaur
- Virology Group, International Centre for Genetic Engineering & Biotechnology, Aruna Asaf Ali Road, New Delhi, India
| | - Ashok Munjal
- Department of Bioscience and Biotechnology, Banasthali University, Banasthali, Tonk, Rajasthan, India
| | - Sunil K. Lal
- Virology Group, International Centre for Genetic Engineering & Biotechnology, Aruna Asaf Ali Road, New Delhi, India
| |
Collapse
|
|
23
|
Mandrekar P. Epigenetic regulation in alcoholic liver disease. World J Gastroenterol 2011; 17:2456-64. [PMID: 21633650 PMCID: PMC3103803 DOI: 10.3748/wjg.v17.i20.2456] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2011] [Revised: 03/02/2011] [Accepted: 03/09/2011] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) is characterized by steatosis or fat deposition in the liver and inflammation, which leads to cirrhosis and hepatocellular carcinoma. Induction of target genes without involving changes in DNA sequence seems to contribute greatly to liver injury. Chromatin modifications including alterations in histones and DNA, as well as post-transcriptional changes collectively referred to as epigenetic effects are altered by alcohol. Recent studies have pointed to a significant role for epigenetic mechanisms at the nucleosomal level influencing gene expression and disease outcome in ALD. Specifically, epigenetic alterations by alcohol include histone modifications such as changes in acetylation and phosphorylation, hypomethylation of DNA, and alterations in miRNAs. These modifications can be induced by alcohol-induced oxidative stress that results in altered recruitment of transcriptional machinery and abnormal gene expression. Delineating these mechanisms in initiation and progression of ALD is becoming a major area of interest. This review summarizes key epigenetic mechanisms that are dysregulated by alcohol in the liver. Alterations by alcohol in histone and DNA modifications, enzymes related to histone acetylation such as histone acetyltransferases, histone deacetylases and sirtuins, and methylation enzymes such as DNA methyltransferases are discussed. Chromatin modifications and miRNA alterations that result in immune cell dysfunction contributing to inflammatory cytokine production in ALD is reviewed. Finally, the role of alcohol-mediated oxidative stress in epigenetic regulation in ALD is described. A better understanding of these mechanisms is crucial for designing novel epigenetic based therapies to ameliorate ALD.
Collapse
|
|
24
|
Jampana SC, Khan R. Pathogenesis of alcoholic hepatitis: Role of inflammatory signaling and oxidative stress. World J Hepatol 2011; 3:114-7. [PMID: 21731903 PMCID: PMC3124877 DOI: 10.4254/wjh.v3.i5.114] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2010] [Revised: 03/07/2011] [Accepted: 03/14/2011] [Indexed: 02/06/2023] Open
Abstract
Inflammatory signaling and oxidative stress are two major components in the pathogenesis of alcoholic hepatitis. Alcohol consumption results in translocation of gut bacteria into the portal system along with lipopolysaccharides that interact with toll-like receptors and results in the production of inflammatory and immunogenic mediators such as tumor necrosis factor-alpha (TNF-α) and interferons. Chronic consumption of alcohol causes priming of this process in which there is enhanced production of cytokines, interferon, interleukins, and TNF-α. Oxidative stress, genetic predisposition, and the unfolded protein response are other contributory mechanisms. Novel therapies aimed at these pathways may prevent, decrease, or delay the complications of alcoholic hepatitis.
Collapse
Affiliation(s)
- Sarat C Jampana
- Sarat C Jampana, Departments of Internal Medicine, University of TX Medical Branch, Galveston, TX 77555, United States
| | | |
Collapse
|
|
25
|
Feng D, Zhou Y, Xia M, Ma J. Folic acid inhibits lipopolysaccharide-induced inflammatory response in RAW264.7 macrophages by suppressing MAPKs and NF-κB activation. Inflamm Res 2011; 60:817-22. [PMID: 21528358 DOI: 10.1007/s00011-011-0337-2] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Revised: 04/04/2011] [Accepted: 04/08/2011] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE The aim of the present study was to investigate the effects of folic acid on the inflammatory responses to lipopolysaccharide (LPS) in RAW264.7 cells and the signal transduction pathways involved. METHODS RAW264.7 macrophages were used. The production of nitric oxide (NO) was determined by the Griess test. The protein levels and mRNA expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) were determined by ELISA and RT-PCR, respectively. The phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear nuclear factor-kappa B (NF-κB) p65 protein were analyzed by Western blotting. RESULTS Folic acid inhibited LPS-induced production of NO, TNF-α and IL-1β with decreased mRNAs of inducible nitric oxide synthase (iNOS), TNF-α and IL-1β. Further study showed that folic acid inhibited the LPS-induced phosphorylation of MAPKs and the nuclear translocation of NF-κB. CONCLUSION Folic acid inhibits the inflammatory response of RAW 264.7 cells to LPS through inhibiting the MAPKs and NF-κB pathways.
Collapse
Affiliation(s)
- Dan Feng
- Department of Preventive Medicine, School of Public Health, Sun Yat-sen University, 74 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China
| | | | | | | |
Collapse
|
|
26
|
Kinsenoside Isolated from Anoectochilus Formosanus Suppresses LPS-Stimulated Inflammatory Reactions in Macrophages and Endotoxin Shock in Mice. Shock 2011; 35:184-90. [DOI: 10.1097/shk.0b013e3181f0e7a3] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
27
|
Cole ET, Zhan Y, Abi Saab WF, Korchnak AC, Ashburner BP, Chadee DN. Mixed lineage kinase 3 negatively regulates IKK activity and enhances etoposide-induced cell death. BIOCHIMICA ET BIOPHYSICA ACTA 2009; 1793:1811-8. [PMID: 19782705 PMCID: PMC2788010 DOI: 10.1016/j.bbamcr.2009.09.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2009] [Revised: 08/21/2009] [Accepted: 09/18/2009] [Indexed: 11/26/2022]
Abstract
Mixed lineage kinase 3 (MLK3) is a mitogen activated protein kinase kinase kinase (MAP3K) that activates multiple MAPK signaling pathways. Nuclear factor kappa B (NF-kappaB) is a transcription factor that has important functions in inflammation, immunity and cell survival. We found that silencing mlk3 expression with RNA interference (RNAi) in SKOV3 human ovarian cancer epithelial cells and NIH-3T3 murine fibroblasts led to a reduction in the level of the inhibitor of kappa B alpha (IkappaBalpha) protein. In addition, we observed enhanced basal IkappaB kinase (IKK) activity in HEK293 cells transiently transfected with MLK3 siRNA and in NIH3T3 cells stably expressing MLK3 shRNA (shMLK3). Furthermore, the basal level of NF-kappaB-dependent gene transcription was elevated in shMLK3 cells. Silencing mlk3 expression conferred resistance of cells to etoposide-induced apoptotic cell death and overexpression of wild type MLK3 (MLK3-WT) or kinase-dead MLK3 (MLK3-KD) promoted apoptotic cell death and cleavage of poly (ADP-ribose) polymerase (PARP). Overexpression of MLK3-WT or MLK3-KD enhanced etoposide-induced apoptotic cell death and cleavage of PARP. These data suggest that MLK3 functions to limit IKK activity, and depleting MLK3 helps protect cells from etoposide-induced cell death through activation of IKK-dependent signaling.
Collapse
Affiliation(s)
- Eric T Cole
- Department of Biological Sciences, University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606, USA
| | | | | | | | | | | |
Collapse
|
|
28
|
Heat stress triggers apoptosis by impairing NF-kappaB survival signaling in malignant B cells. Leukemia 2009; 24:187-96. [PMID: 19924145 DOI: 10.1038/leu.2009.227] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nuclear factor-kappaB (NF-kappaB) is involved in multiple aspects of oncogenesis and controls cancer cell survival by promoting anti-apoptotic gene expression. The constitutive activation of NF-kappaB in several types of cancers, including hematological malignancies, has been implicated in the resistance to chemo- and radiation therapy. We have previously reported that cytokine- or virus-induced NF-kappaB activation is inhibited by chemical and physical inducers of the heat shock response (HSR). In this study we show that heat stress inhibits constitutive NF-kappaB DNA-binding activity in different types of B-cell malignancies, including multiple myeloma, activated B-cell-like (ABC) type of diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma presenting aberrant NF-kappaB regulation. Heat-induced NF-kappaB inhibition leads to rapid downregulation of the anti-apoptotic protein cellular inhibitor-of-apoptosis protein 2 (cIAP-2), followed by activation of caspase-3 and cleavage of the caspase-3 substrate poly(adenosine diphosphate ribose)polymerase (PARP), causing massive apoptosis under conditions that do not affect viability in cells not presenting NF-kappaB aberrations. NF-kappaB inhibition by the proteasome inhibitor bortezomib and by short-hairpin RNA (shRNA) interference results in increased sensitivity of HS-Sultan B-cell lymphoma to hyperthermic stress. Altogether, the results indicate that aggressive B-cell malignancies presenting constitutive NF-kappaB activity are sensitive to heat-induced apoptosis, and suggest that aberrant NF-kappaB regulation may be a marker of heat stress sensitivity in cancer cells.
Collapse
|
|
29
|
Feng D, Ling WH, Duan RD. Lycopene suppresses LPS-induced NO and IL-6 production by inhibiting the activation of ERK, p38MAPK, and NF-κB in macrophages. Inflamm Res 2009; 59:115-21. [DOI: 10.1007/s00011-009-0077-8] [Citation(s) in RCA: 135] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2009] [Accepted: 07/27/2009] [Indexed: 11/29/2022] Open
|
|
30
|
Abstract
The pathogenesis of alcoholic liver injury involves interactions of several intracellular signalling pathways in different cell types of the liver. Alcohol-induced sensitization of liver macrophages to portal endotoxin/lipopolysaccharide (LPS) is considered a hallmark of alcoholic liver disease (ALD). Intracellular mechanisms associated with LPS-induced signalling play a crucial role in the initiation and progression of alcoholic liver injury, and are being extensively explored. LPS recognition by Toll-like receptor 4 (TLR4) on macrophages and other cell types in the liver, activation of downstream signalling pathways culminating in activation of transcription factors such as NFkappaB, AP-1 leads to increased inflammatory cytokine production in ALD. In addition, LPS-induced MAPK such as ERK and p38 also contribute to liver injury. The importance of alcohol-induced reactive oxygen species and interactions with TLR pathways in macrophages leading to inflammation is becoming increasingly evident. Collectively, these signalling pathways induce pro- and anti-inflammatory cytokines that play an important role in ALD. In this review we describe the key signalling intermediates leading to alcohol-induced inflammation in alcoholic liver disease.
Collapse
Affiliation(s)
- Pranoti Mandrekar
- Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
| | | |
Collapse
|
|
31
|
Palempalli UD, Gandhi U, Kalantari P, Vunta H, Arner RJ, Narayan V, Ravindran A, Prabhu KS. Gambogic acid covalently modifies IkappaB kinase-beta subunit to mediate suppression of lipopolysaccharide-induced activation of NF-kappaB in macrophages. Biochem J 2009; 419:401-9. [PMID: 19140805 PMCID: PMC2741425 DOI: 10.1042/bj20081482] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
GA (gambogic acid) is a polyprenylated xanthone abundant in the resin of Garcinia morella and Garcinia hanburyi with a long history of use as a complementary and alternative medicine. The antitumour activity of GA has been well demonstrated and is thought to arise partly from the associated anti-inflammatory activity. Recent studies have indicated that the antitumour activity of GA is mediated by its ligation of TfR1 (transferrin receptor-1). Since the cellular expression of TfR1 is down-regulated by LPS (lipopolysaccharide), we hypothesized that an alternative pathway exists in immune cells, such as macrophages, where GA could mitigate the expression of pro-inflammatory genes. Here we demonstrate that GA inhibits the LPS-dependent expression of NF-kappaB (nuclear factor kappaB) target pro-inflammatory genes in macrophages. Western immunoblot, NF-kappaB-luciferase reporter and gel-shift analyses revealed that GA strongly blocked the activation of NF-kappaB induced by LPS, whereas 9,10-dihydro-GA, which lacks the reactive alpha,beta-unsaturated carbonyl group, was ineffective. Moreover, GA was able to decrease nuclear p65 levels in RAW264.7 macrophages, where the expression of TfR1 was down-regulated by RNA interference. in vitro kinase assays coupled with interaction studies using biotinylated GA as well as proteomic analysis demonstrated that IKKbeta [IkappaB (inhibitory kappaB) kinase-beta], a key kinase of the NF-kappaB signalling axis, was covalently modified by GA at Cys-179, causing significant inhibition of its kinase activity. Taken together, these results demonstrate the potent anti-inflammatory activity of GA.
Collapse
Affiliation(s)
| | | | - Parisa Kalantari
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802, USA
| | - Hema Vunta
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802, USA
| | - Ryan J. Arner
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802, USA
| | - Vivek Narayan
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802, USA
| | - Anand Ravindran
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802, USA
| | - K. Sandeep Prabhu
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802, USA
| |
Collapse
|
|
32
|
Leishmania mexicana: Inhibition of camptothecin-induced apoptosis of monocyte-derived dendritic cells. Exp Parasitol 2009; 121:199-207. [DOI: 10.1016/j.exppara.2008.10.020] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2008] [Revised: 10/03/2008] [Accepted: 10/24/2008] [Indexed: 11/19/2022]
|
|
33
|
Vunta H, Belda BJ, Arner RJ, Channa Reddy C, Vanden Heuvel JP, Sandeep Prabhu K. Selenium attenuates pro-inflammatory gene expression in macrophages. Mol Nutr Food Res 2008; 52:1316-23. [DOI: 10.1002/mnfr.200700346] [Citation(s) in RCA: 120] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
|
|
34
|
Zhu B, Liu Z, Wang P, Wu C, Xu H. A Nuclear Factor-κB Inhibitor BAY11-7082 Inhibits Interactions Between Human Endothelial Cells, T Cells, and Monocytes. Transplant Proc 2008; 40:2724-8. [DOI: 10.1016/j.transproceed.2008.07.129] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
|
35
|
Pascussi JM, Gerbal-Chaloin S, Drocourt L, Assénat E, Larrey D, Pichard-Garcia L, Vilarem MJ, Maurel P. Cross-talk between xenobiotic detoxication and other signalling pathways: clinical and toxicological consequences. Xenobiotica 2008; 34:633-64. [PMID: 15672753 DOI: 10.1080/00498250412331285454] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
1. Recent investigations on nuclear receptors and other transcription factors involved in the regulation of genes encoding xenobiotic metabolizing and transport systems reveal that xenobiotic-dependent signalling pathways are embedded in, and establish functional interactions with, a tangle of regulatory networks involving the glucocorticoid and oestrogen receptors, the hypoxia-inducible factor, the vitamin D receptor and other transcription factors/nuclear receptors controlling cholesterol/bile salt homeostasis and liver differentiation. 2. Such functional interferences provide new insight, first for understanding how xenobiotics might exert adverse effects, and second how physiopathological stimuli affect xenobiotic metabolism.
Collapse
Affiliation(s)
- J M Pascussi
- INSERM U632, Hepatic Physiopathology, Montpellier F-34293, France
| | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Gong R, Rifai A, Ge Y, Chen S, Dworkin LD. Hepatocyte growth factor suppresses proinflammatory NFkappaB activation through GSK3beta inactivation in renal tubular epithelial cells. J Biol Chem 2008; 283:7401-10. [PMID: 18201972 DOI: 10.1074/jbc.m710396200] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Activation of NFkappaB is a fundamental cellular event central to all inflammatory diseases. Hepatocyte growth factor (HGF) ameliorates both acute and chronic inflammation in a multitude of organ systems through modulating NFkappaB activity; nevertheless, the exact molecular mechanism remains uncertain. Here we report that HGF through inactivation of GSK3beta suppresses NFkappaB p65 phosphorylation specifically at position Ser-468. The Ser-468 of RelA/p65 situates in a GSK3beta consensus motif and could be directly phosphorylated by GSK3beta both in vivo and in vitro, signifying Ser-468 of RelA/p65 as a putative substrate for GSK3beta. In addition, the C terminus of RelA/p65 harbors a highly conserved domain homologue of the consensus docking sequence for GSK3beta. Moreover, this domain was required for efficient phosphorylation of Ser-468 and was indispensable for the physical interaction between RelA/p65 and GSK3beta. HGF substantially intercepted this interaction by inactivating GSK3beta. Functionally, phosphorylation of Ser-468 of RelA/p65 was required for the induced expression of a particular subset of proinflammatory NFkappaB-dependent genes. Diminished phosphorylation at Ser-468 by HGF resulted in a gene-specific inhibition of these genes' expression. The action of HGF on proinflammatory NFkappaB activation was consistently mimicked by a selective GSK3beta inhibitor or GSK3beta knockdown by RNA interference but largely abrogated in cells expressing the mutant uninhibitable GSK3beta. Collectively, our findings suggest that HGF has a potent suppressive effect on NFkappaB activation, which is mediated by GSK3beta, an important signaling transducer controlling RelA/p65 phosphorylation specificity and directing the transcription of selective proinflammatory cytokines implicated in inflammatory kidney disease.
Collapse
Affiliation(s)
- Rujun Gong
- Division of Kidney Disease and Hypertension, Department of Medicine, Brown University School of Medicine, Provindence, Rhode Island 02903, USA.
| | | | | | | | | |
Collapse
|
|
37
|
Abstract
Heat shock induced gene expression and other cellular responses help limit the damage caused by stress and thus facilitate cellular recovery. Cellular damage also triggers apoptotic cell death through several pathways. This paper briefly reviews interactions of the major heat shock proteins with components of the apoptotic pathways. Hsp90, which acts as a chaperone for unstable signal transducers to keep them poised for activation, interacts with RIP and Akt and promotes NF-kappa B mediated inhibition of apoptosis; in addition it also blocks some steps in the apoptotic pathways. Hsp70 is mostly anti-apoptotic and acts at several levels like inhibition of translocation of Bax into mitochondria, release of cytochrome c from mitochondria,formation of apoptosome and inhibition of activation of initiator caspases. Hsp70 also modulates JNK,NF-kappa B and Akt signaling pathways in the apoptotic cascade. In contrast, Hsp60 has both anti-and pro-apoptotic roles. Cytosolic Hsp60 prevents translocation of the pro-apoptotic protein Bax into mitochondria and thus promotes cell survival but it also promotes maturation of procaspase-3,essential for caspase mediated cell death. Our recent in vivo studies show that RNAi for the Hsp60D in Drosophila melanogaster prevents induced apoptosis. Hsp27 exerts its anti-apoptotic influence by inhibiting cytochrome c and TNF-mediated cell death. alpha beta crystallin suppresses caspase-8 and cytochrome c mediated activation of caspase-3. Studies in our laboratory also reveal that absence or reduced levels of the developmentally active as well as stress induced non-coding hsr omega transcripts, which are known to sequester diverse hnRNPs and related nuclear RNA-binding proteins,block induced apoptosis in Drosophila. Modulation of the apoptotic pathways by Hsps reflects their roles as "weak links" between various "hubs" in cellular networks. On the other hand, non-coding RNAs, by virtue of their potential to bind with multiple proteins,can act as "hubs" in these networks. In view of the integrative nature of living systems, it is not surprising that stress-induced genes,generally believed to primarily function in cell survival pathways, inhibit or even promote cell death pathways at multiple levels to ensure homeostasis at cell and/or organism level. The heat shock genes obviously do much more than merely help cells survive stress.
Collapse
Affiliation(s)
- Richa Arya
- Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi 221005, India
| | | | | |
Collapse
|
|
38
|
Kaileh M, Vanden Berghe W, Boone E, Essawi T, Haegeman G. Screening of indigenous Palestinian medicinal plants for potential anti-inflammatory and cytotoxic activity. JOURNAL OF ETHNOPHARMACOLOGY 2007; 113:510-6. [PMID: 17716845 DOI: 10.1016/j.jep.2007.07.008] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2006] [Revised: 07/10/2007] [Accepted: 07/10/2007] [Indexed: 05/16/2023]
Abstract
Organic extracts of 24 selected plant species, used by Palestinian traditional healers to treat different illnesses and diseases, were tested for their anti-inflammatory and anti-tumoral activities. The plant selection was based on existing ethnobotanic information and interviews with local healers. The extracts of the plants under investigation were tested for their potential anti-tumor (cytotoxic) effect on the murine fibrosarcoma L929sA cells, and on the human breast cancer cells MDA-MB231 and MCF7. Cytotoxicity screening models provide important preliminary data to select plant extracts with potential antineoplastic properties. MTT (Tetrazolium blue) colorimetric assay was used to evaluate the reduction of viability of cell cultures in the presence or absence of the extracts. The extract from Withania somnifera, L. Dunal (Solanaceae) presented an IC(50) value at 24h of 150 and 60 microg/ml, on L929sA and MCF7 cells, respectively, while the extract from Psidium guajava L. (Myrtaceae) presented an IC(50) value at 24h of 55 microg/ml on MCF7 cells. Other extracts examined, like Laurus nobilis L. (Lauraceae) and Salvia fruticosa M. (Labiatae), also displayed a remarkable activity. Additionally, as the nuclear transcription factor NFkappaB regulates the expression of various genes that play critical roles in apoptosis and immunomodulation, we further investigated the effect of nine promising plant extracts, withheld from the first cell viability screening on NFkappaB activation. The extracts showed variable degrees of NFkappaB-inhibitory activity. Whereas Withania somnifera extract demonstrated the strongest NFkappaB-inhibitory activity, other extracts derived from Laurus nobilis, Psidium guajava and Foeniculum vulgare M. (Umbiliferrae) also revealed immunomodulatory NFkappaB activities. These species are good candidates for further activity-monitored fractionation to identify active constituents.
Collapse
Affiliation(s)
- Mary Kaileh
- Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Department of Molecular Biology, Ghent University, K.L. Ledeganckstraat 35, B-9000 Gent, Belgium
| | | | | | | | | |
Collapse
|
|
39
|
Jana M, Jana A, Liu X, Ghosh S, Pahan K. Involvement of phosphatidylinositol 3-kinase-mediated up-regulation of I kappa B alpha in anti-inflammatory effect of gemfibrozil in microglia. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2007; 179:4142-52. [PMID: 17785853 PMCID: PMC2604815 DOI: 10.4049/jimmunol.179.6.4142] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The present study underlines the importance of PI3K in mediating the anti-inflammatory effect of gemfibrozil, a prescribed lipid-lowering drug for humans, in mouse microglia. Gemfibrozil inhibited LPS-induced expression of inducible NO synthase (iNOS) and proinflammatory cytokines in mouse BV-2 microglial cells and primary microglia. By overexpressing wild-type and dominant-negative constructs of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) in microglial cells and isolating primary microglia from PPAR-alpha-/- mice, we have demonstrated that gemfibrozil inhibits the activation of microglia independent of PPAR-alpha. Interestingly, gemfibrozil induced the activation of p85alpha-associated PI3K (p110beta but not p110alpha) and inhibition of that PI3K by either chemical inhibitors or dominant-negative mutants abrogated the inhibitory effect of gemfibrozil. Conversely, overexpression of the constitutively active mutant of p110 enhanced the inhibitory effect of gemfibrozil on LPS-induced expression of proinflammatory molecules. Similarly, gemfibrozil also inhibited fibrillar amyloid beta (Abeta)-, prion peptide (PrP)-, dsRNA (poly IC)-, HIV-1 Tat-, and 1-methyl-4-phenylpyridinium (MPP+)-, but not IFN-gamma-, induced microglial expression of iNOS. Inhibition of PI3K also abolished the inhibitory effect of gemfibrozil on Abeta-, PrP-, poly IC-, Tat-, and MPP+-induced microglial expression of iNOS. Involvement of NF-kappaB activation in LPS-, Abeta-, PrP-, poly IC-, Tat-, and MPP+-, but not IFN-gamma-, induced microglial expression of iNOS and stimulation of IkappaBalpha expression and inhibition of NF-kappaB activation by gemfibrozil via the PI3K pathway suggests that gemfibrozil inhibits the activation of NF-kappaB and the expression of proinflammatory molecules in microglia via PI3K-mediated up-regulation of IkappaBalpha.
Collapse
Affiliation(s)
- Malabendu Jana
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612
| | - Arundhati Jana
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612
| | - Xiaojuan Liu
- Section of Neuroscience, Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583
| | - Sankar Ghosh
- Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, School of Medicine, Yale University, New Haven, CT 06536
| | - Kalipada Pahan
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612
- Section of Neuroscience, Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583
| |
Collapse
|
|
40
|
Rydkina E, Sahni A, Silverman DJ, Sahni SK. Comparative analysis of host-cell signalling mechanisms activated in response to infection with Rickettsia conorii and Rickettsia typhi. J Med Microbiol 2007; 56:896-906. [PMID: 17577053 DOI: 10.1099/jmm.0.47050-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The Gram-negative intracellular bacteria Rickettsia conorii and Rickettsia typhi are the aetiological agents of Mediterranean spotted fever and endemic typhus, respectively, in humans. Infection of endothelial cells (ECs) lining vessel walls, and the resultant vascular inflammation and haemostatic alterations are salient pathogenetic features of both of these rickettsial diseases. An important consideration, however, is that dramatic differences in the intracellular motility and accumulation patterns for spotted fever versus typhus group rickettsiae have been documented, suggesting the possibility of unique and potentially different interactions with host cells. This study characterized and compared R. conorii- and R. typhi-mediated effects on cultured human ECs. The DNA-binding activity of nuclear transcription factor-kappaB (NF-kappaB) and the phosphorylation status of stress-activated p38 kinase were determined as indicators of NF-kappaB and p38 activation. R. conorii infection resulted in a biphasic activation of NF-kappaB, with an early increase in DNA-binding activity at 3 h, followed by a later peak at 24 h. The activated NF-kappaB species were composed mainly of RelA p65-p50 heterodimers and p50 homodimers. R. typhi infection of ECs resulted in only early activation of NF-kappaB at 3 h, composed primarily of p65-p50 heterodimers. Whilst R. conorii infection induced increased phosphorylation of p38 kinase (threefold mean induction) with the maximal response at 3 h, a considerably less-intense response peaking at about 6 h post-infection was found with R. typhi. Furthermore, mRNA expression of the chemokines interleukin (IL)-8 and monocyte chemoattractant protein-1 in ECs infected with either Rickettsia species was higher than the corresponding controls, but there were distinct differences in the secretion patterns for IL-8, suggesting the possibility of involvement of post-transcriptional control mechanisms or differences in the release from intracellular storage sites. Thus, the intensity and kinetics of host-cell responses triggered by spotted fever and typhus species exhibit distinct variations that could subsequently lead to differences in the extent of endothelial activation and inflammation and serve as important determinants of pathogenesis.
Collapse
Affiliation(s)
- Elena Rydkina
- Hematology-Oncology Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
| | - Abha Sahni
- Hematology-Oncology Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
| | - David J Silverman
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Sanjeev K Sahni
- Hematology-Oncology Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
| |
Collapse
|
|
41
|
Natarajan P, Narayanan S. Mycobacterium tuberculosisH37Rv induces monocytic release of interleukin-6 via activation of mitogen-activated protein kinases: inhibition byN-acetyl-l-cysteine. ACTA ACUST UNITED AC 2007; 50:309-18. [PMID: 17521393 DOI: 10.1111/j.1574-695x.2007.00256.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The release of proinflammatory cytokines after mycobacterial infection is a host immune response that may be propitious or deleterious to the host. Elevated levels of interleukin (IL)-6 are present in plasma of patients with active tuberculosis infection. The aim of this study was to investigate the role of mitogen-activated protein kinases in the secretion of interleukin-6 in THP-1 cells and human primary monocytes that were infected with Mycobacterium tuberculosis H37Rv, and its regulation by N-acetyl-L-cysteine, a potential antimycobacterial agent. Exposure of THP-1 human monocytes to M. tuberculosis H37Rv induced rapidly, in a time-dependent manner, the phosphorylation of mitogen-activated protein kinase kinase 3/6 and p38 mitogen-activated protein kinase, accompanied by an upregulation of interleukin-6. Using highly specific inhibitors of mitogen-activated protein kinase kinase-1, p38 mitogen-activated protein kinase and nuclear factor-kappaB, we found that extracellular-signal regulated kinase 1/2, p38 mitogen-activated protein kinase and nuclear factor-kappaB were essential for M. tuberculosis H37Rv-induced interleukin-6 production in human primary monocytes. Pretreatment with N-acetyl-L-cysteine reduced, in a dose-dependent manner, M. tuberculosis H37Rv-induced activation of mitogen-activated protein kinase kinase 3/6 and interleukin-6 production in THP-1 cells.
Collapse
|
|
42
|
Gautam SC, Gao X, Dulchavsky S. Immunomodulation by curcumin. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2007; 595:321-41. [PMID: 17569218 DOI: 10.1007/978-0-387-46401-5_14] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Turmeric, the bright yellow spice extracted from the tuberous rhizome of the plant Curcuma longa, has been used in traditional Indian and Chinese systems of medicine for centuries to treat a variety of ailments, including jaundice and hepatic disorders, rheumatism, anorexia, diabetic wounds, and menstrual difficulties. Most of the medicinal effects of turmeric have been attributed to curcumin, the principal curcumanoid found in turmeric. Recent evidence that curcumin exhibits strong anti-inflammatory and antioxidant activities and modulates the expression of transcription factors, cell cycle proteins, and signal transducing kinases has prompted the mechanism-based studies on the potential of curcumin to primarily prevent and treat cancer and inflammatory diseases. Little work has been done to study the effect of curcumin on the development of immune responses. This review discusses current knowledge on the immunomodulatory effects of curcumin on various facets of the immune response, including its effect on lymphoid cell populations, antigen presentation, humoral and cell-mediated immunity, and cytokine production.
Collapse
Affiliation(s)
- Subhash C Gautam
- Department of Surgery, Henry Ford Health System, Detroit, MI 48202, USA.
| | | | | |
Collapse
|
|
43
|
Wang J, Ma H, Wang J, Li Q, Li Y, Li J. Long-term n-3 polyunsaturated fatty acids administration ameliorates arteriosclerosis by modulating T-cell activity in a rat model of small intestine transplantation. Clin Chim Acta 2007; 381:124-30. [PMID: 17395171 DOI: 10.1016/j.cca.2007.02.043] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2006] [Revised: 02/02/2007] [Accepted: 02/20/2007] [Indexed: 11/29/2022]
Abstract
BACKGROUND Fish oil, rich in n-3 polyunsaturated fatty acids (n-3 PUFAs), has been found to reduce graft rejection and increase allografts survival. But these studies mainly focused on acute rejection. We imitated long-term fish oil administration to investigate the effects of n-3 PUFAs on graft arteriosclerosis, and T cells in a rat model of small intestine transplantation. METHODS From 2 weeks pre-transplantation to the 60th day post-transplantation, the Lewis rats were supplemented by gavage with phosphate buffer saline, corn oil and fish oil respectively. Total small intestine was heterotopically transplanted from F344 to Lewis rat. Graft arteriosclerosis was assessed by histological grading of intimal thickening. The expression of CD25 and CD154, IL-2 level, and NF-kappaB activation in T cells were analyzed by western blotting, ELISA, and electrophoretic mobility shift assay respectively. RESULTS Compared with corn oil, graft arteriosclerosis was ameliorated by fish oil significantly. The expression of CD25 and CD154, IL-2 level, and NF-kappaB activation were markedly reduced by fish oil. CONCLUSIONS Long-term n-3 PUFAs administration pre- and post-transplantation could inhibit T-cell activity by reducing CD154 expression and NF-kappaB activation, which might contribute to amelioration of graft arteriosclerosis.
Collapse
Affiliation(s)
- Jinhua Wang
- Department of General Surgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, Jiangsu 210002, PR China
| | | | | | | | | | | |
Collapse
|
|
44
|
Xu P, Zhou XJ, Chen LQ, Chen J, Xie Y, Lv LH, Hou XH. Pioglitazone attenuates the severity of sodium taurocholate-induced severe acute pancreatitis. World J Gastroenterol 2007; 13:1983-1988. [PMID: 17461502 PMCID: PMC4146978 DOI: 10.3748/wjg.v13.i13.1983] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2007] [Revised: 02/20/2007] [Accepted: 03/12/2007] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the effect of pioglitazone, a specific peroxisome proliferator-activated receptor-gamma (PPARgamma) ligand, on development of severe acute pancreatitis (SAP) and expression of nuclear factor-kappa B (NF-kappaB) and intercellular adhesion molecule-1 (ICAM-1) in the pancreas. METHODS Male Sprague-Dawley (SD) rats (160-200 g) were randomly allocated into three groups (n = 18 in each group): severe acute pancreatitis group, pioglitazone group, sham group. SAP was induced by retrograde infusion of 1 mL/kg body weight 5% sodium taurocholate (STC) into the biliopancreatic duct of male SD rats. Pioglitazone was injected intraperitoneally two hours piror to STC infusion. Blood and ascites were obtained for detecting amylase and ascitic capacity. Pancreatic wet/dry weight ratio, expression of NF-kappaB and ICAM-1 in pancreatic tissues were detected by immunohistochemical staining. Pancreatic tissue samples were stained with hematoxylin and eosin (HE) for routine optic microscopy. RESULTS Sham group displayed normal pancreatic structure. SAP group showed diffuse hemorrhage, necrosis and severe edema in focal areas of pancreas. There was obvious adipo-saponification in abdominal cavity. Characteristics such as pancreatic hemorrhage, necrosis, severe edema and adipo-saponification were found in pioglitazone group, but the levels of those injuries were lower in pioglitazone group than those in SAP group. The wet/dry pancreatic weight ratio, ascetic capacity, serum and ascitic activities of anylase in the SAP group were significantly higher than those in the sham group and pioglitazone group respectively (6969.50 +/- 1368.99 vs 2104.67 +/- 377.16, 3.99 +/- 1.22 vs 2.48 +/- 0.74, P < 0.01 or P < 0.05). According to Kusske criteria, the pancreatic histologic score showed that interstitial edema, inflammatory infiltration, parenchyma necrosis and parenchyma hommorrhage in SAP group significantly differed from those in the sham group and pioglitazone group (7.17 +/- 1.83 vs 0.50 +/- 0.55, 7.67 +/- 0.82 vs 6.83 +/- 0.75, P < 0.01, P < 0.05. The expression of NF-kappaB and ICAM-1 in sham group was lower than that in SAP group and pioglitazone group (0.50 +/- 0.55 vs 33 +/- 1.21, P < 0.01). There was a significant difference in the expression of NF-kappaB and ICAM-1 between SAP group and pioglitazone group (7.50 +/- 1.05 vs 11.33 +/- 1.75, 0.80 +/- 0.53 vs 1.36 +/- 0.54, P < 0.01 or P < 0.05) at 12 h after the induction of pancreatitis. CONCLUSION Pioglitazone attenuates the severity of SAP. The beneficial effect of pioglitazone is multifactorial due to its anti-inflammatory activities, most likely through the inhibition of ICAM-1 expression and NF-kappaB activation. Specific ligands of PPARgamma may represent the novel and effective means of clinical therapy for SAP.
Collapse
Affiliation(s)
- Ping Xu
- Department of Gastroente-rology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | | | | | | | | | | | | |
Collapse
|
|
45
|
Kielian T, Phulwani NK, Esen N, Syed MM, Haney AC, McCastlain K, Johnson J. MyD88-dependent signals are essential for the host immune response in experimental brain abscess. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2007; 178:4528-37. [PMID: 17372011 PMCID: PMC2094730 DOI: 10.4049/jimmunol.178.7.4528] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Brain abscesses form in response to a parenchymal infection by pyogenic bacteria, with Staphylococcus aureus representing a common etiologic agent of human disease. Numerous receptors that participate in immune responses to bacteria, including the majority of TLRs, the IL-1R, and the IL-18R, use a common adaptor molecule, MyD88, for transducing activation signals leading to proinflammatory mediator expression and immune effector functions. To delineate the importance of MyD88-dependent signals in brain abscesses, we compared disease pathogenesis using MyD88 knockout (KO) and wild-type (WT) mice. Mortality rates were significantly higher in MyD88 KO mice, which correlated with a significant reduction in the expression of several proinflammatory mediators, including but not limited to IL-1beta, TNF-alpha, and MIP-2/CXCL2. These changes were associated with a significant reduction in neutrophil and macrophage recruitment into brain abscesses of MyD88 KO animals. In addition, microglia, macrophages, and neutrophils isolated from the brain abscesses of MyD88 KO mice produced significantly less TNF-alpha, IL-6, MIP-1alpha/CCL3, and IFN-gamma-induced protein 10/CXCL10 compared with WT cells. The lack of MyD88-dependent signals had a dramatic effect on the extent of tissue injury, with significantly larger brain abscesses typified by exaggerated edema and necrosis in MyD88 KO animals. Interestingly, despite these striking changes in MyD88 KO mice, bacterial burdens did not significantly differ between the two strains at the early time points examined. Collectively, these findings indicate that MyD88 plays an essential role in establishing a protective CNS host response during the early stages of brain abscess development, whereas MyD88-independent pathway(s) are responsible for pathogen containment.
Collapse
Affiliation(s)
- Tammy Kielian
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
| | | | | | | | | | | | | |
Collapse
|
|
46
|
Savickiene J, Treigyte G, Borutinskaite V, Navakauskiene R, Magnusson KE. The Histone Deacetylase Inhibitor FK228 Distinctly Sensitizes the Human Leukemia Cells to Retinoic Acid-Induced Differentiation. Ann N Y Acad Sci 2006; 1091:368-84. [PMID: 17341629 DOI: 10.1196/annals.1378.081] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
FK228 (depsipeptide) is a novel histone deacetylase inhibitor (HDACI) that has shown therapeutical efficacy in clinical trials for malignant lymphoma. In this article, we examined in vitro effects of FK228 on human leukemia cell lines, NB4 and HL-60. FK228 alone (0.2-1 ng/mL) inhibited leukemia cell growth in a dose-dependent manner and induced death by apoptosis. FK228 had selective differentiating effects on two cell lines when used for 6 h before induction of granulocytic differentiation by retinoic acid (RA) or in combination with RA. These effects were accompanied by a time- and dose-dependent histone H4 hyper-acetylation or histone H3 dephosphorylation and alterations in DNA binding of NF-kappaB in association with cell death and differentiation. Pifithrin-alpha (PFT), an inhibitor of p53 transcriptional activity, protected only NB4 cells with functional p53 from FK228-induced apoptosis and did not interfere with antiproliferative activity in p53-negative HL-60 cells. In NB4 cells, PFT inhibited p53 binding to the p21 (Waf1/Cip1) promotor and induced DNA binding of NF-kappaB leading to enhanced cell survival. Thus, beneficial effects of FK228 on human promyelocytic leukemia may be exerted through the induction of differentiation or apoptosis via histone modification and selective involvement of transcription factors, such as NF-kappaB and p53.
Collapse
Affiliation(s)
- Jurate Savickiene
- Department of Developmental Biology, Institute of Biochemistry, LT-08662 Vilnius, Lithuania.
| | | | | | | | | |
Collapse
|
|
47
|
Sammons M, Wan SS, Vogel NL, Mientjes EJ, Grosveld G, Ashburner BP. Negative regulation of the RelA/p65 transactivation function by the product of the DEK proto-oncogene. J Biol Chem 2006; 281:26802-12. [PMID: 16829531 DOI: 10.1074/jbc.m600915200] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
NF-kappaB-mediated transcriptional activation is controlled at several levels including interaction with coregulatory proteins. To identify new proteins capable of modulating NF-kappaB-mediated activation, a cytoplasmic two-hybrid screen was performed using the p65 C-terminal transactivation domain as bait and identified the product of the DEK proto-oncogene. DEK is a ubiquitous nuclear protein that has been implicated in several types of cancer and autoimmune diseases. DEK appears to function in several nuclear processes including transcriptional repression and modulation of chromatin structure. Our data indicate that DEK functions as a transcriptional corepressor to repress NF-kappaB activity. DEK expression blocked p65-mediated activation of an NF-kappaB-dependent reporter gene and also inhibited TNFalpha-induced activation of the reporter gene. Chromatin Immunoprecipitation (ChIP) assays showed that DEK associates with the promoters of the NF-kappaB-regulated cIAP2 and IL-8 genes in untreated cells and dissociates from these promoters upon NF-kappaB binding in response to TNFalpha treatment. Moreover, the expression levels of an NF-kappaB-dependent reporter gene as well as the NF-kappaB-regulated Mcp-1 and IkappaBalpha genes is increased in DEK-/- cells compared with wild-type cells. ChIP assays on these promoters show enhanced and prolonged binding of p65 and increased recruitment of the P/CAF coactivator. Overall, these data provide further evidence that DEK functions to negatively regulate transcription.
Collapse
Affiliation(s)
- Morgan Sammons
- Department of Biological Sciences and Undergraduate Honors Program, University of Toledo, Toledo, Ohio 43606, and Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
| | | | | | | | | | | |
Collapse
|
|
48
|
Liu Z, Gao F, Tian Y. Effects of morphine, fentanyl and tramadol on human immune response. ACTA ACUST UNITED AC 2006; 26:478-81. [PMID: 17120754 DOI: 10.1007/s11596-006-0427-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Morphine has been reported to suppress human immune response. We aimed to observe the effects of morphine, fentanyl and tramadol on NF-kappa B and IL-2 from both laboratory and clinical perspective. Jurkat cells were incubated with ten times clinically relevant concentrations of morphine, fentanyl and tramadol before being stimulated with PMA. NF-kappa B binding activity and IL-2 levels were measured. In the clinical study, 150 consenting patients were randomized into 3 groups according to the analgesics used in them, namely, group morphine (M), group fentanyl (F) and group tramadol (T). IL-2 was measured preoperatively and 1, 3 and 24 h after operation. Consequently, NF-kappa B activation was suppressed by morphine and fentanyl but not by tramadol. IL-2 was significantly decreased by morphine and fentanyl but not by tramadol in vitro. In the PCA patients, IL-2 was decreased in group M and increased in group F postoperatively. Whereas in group T, IL-2 was unchanged 1 h after operation but was significantly elevated 3 and 24 h after operation. Our results showed that the inhibition of morphine on IL-2 was most probably related to its suppression on NF-kappa B. Fentanyl had different effects on human immune response in vitro and in vivo. Tramadol may have immune enhancing effect.
Collapse
Affiliation(s)
- Zhihen Liu
- Department of Anesthesiology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China
| | | | | |
Collapse
|
|
49
|
Savickiene J, Borutinskaite VV, Treigyte G, Magnusson KE, Navakauskiene R. The novel histone deacetylase inhibitor BML-210 exerts growth inhibitory, proapoptotic and differentiation stimulating effects on the human leukemia cell lines. Eur J Pharmacol 2006; 549:9-18. [PMID: 16978604 DOI: 10.1016/j.ejphar.2006.08.010] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2006] [Revised: 07/25/2006] [Accepted: 08/02/2006] [Indexed: 11/17/2022]
Abstract
Histone deacetylase inhibitors have a potent role in the strategy for the treatment of leukemias. BML-210 (N-(2-Aminophenyl)-N' phenyloctanol diamine) is the novel histone deacetylase inhibitor, and its mechanism of action has not been characterized. In this study, we examined the in vitro effects of BML-210 on the human leukemia cell lines (NB4, HL-60, THP-1, and K562). We found that BML-210 inhibits the growth of all cell lines and promotes apoptosis in a dose- and time-dependent manner. BML-210 alone induces HL-60 and K562 cell differentiation (up to 30%) to granulocytes and erythrocytes, respectively, and in combination with differentiation agents - all-trans retinoic acid and hemin, markedly potentates it. Those treatments cause G1 arrest and histone H4 acetylation, affects transcription factor NF-kappaB and Sp1 binding activity to their consensus sequences, the p21 or the FasL promoters, and influences expression of Sp1, NF-kappaB, p21 and FasL. These findings suggest that BML-210 could be a promising antileukemic agent to induce apoptosis and to modulate differentiation through the modulation of histone acetylation and gene expression.
Collapse
Affiliation(s)
- Jurate Savickiene
- Department of Developmental Biology, Institute of Biochemistry, LT-08662 Vilnius, Lithuania
| | | | | | | | | |
Collapse
|
|
50
|
Ludwig S, Pleschka S, Planz O, Wolff T. Ringing the alarm bells: signalling and apoptosis in influenza virus infected cells. Cell Microbiol 2006; 8:375-86. [PMID: 16469051 DOI: 10.1111/j.1462-5822.2005.00678.x] [Citation(s) in RCA: 175] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Small RNA viruses such as influenza viruses extensively manipulate host-cell functions to support their replication. At the same time the infected cell induces an array of defence mechanisms to fight the invader. These processes are mediated by a variety of intracellular signalling cascades. Here we will review the current knowledge of functional kinase signalling and apoptotic events in influenza virus infected cells and how these viruses have learned to misuse these cellular responses for efficient replication.
Collapse
Affiliation(s)
- Stephan Ludwig
- Institute of Molecular Virology (IMV) Westfaelische-Wilhelms-University, Von-Esmarch Str. 56, D-48161 Muenster, Germany.
| | | | | | | |
Collapse
|