Genetic dissection of systemic autoimmune disease in Nrf2-deficient mice

2004 ◽  
Vol 18 (3) ◽  
pp. 261-272 ◽  
Author(s):  
Jiang Li ◽  
Thor D. Stein ◽  
Jeffrey A. Johnson
Keyword(s):  
Oxidative Stress ◽  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Autoimmune Disorder ◽  
Multiple Organ ◽  
Systemic Autoimmune Disease ◽  
Lipid Peroxidation Product ◽  
Antioxidant Genes

Systemic lupus erythematosus (SLE) is an autoimmune disorder with immune-complex deposition that affects multiple organs. Previous studies have suggested the involvement of oxidative stress and apoptosis in SLE, but no clear link to etiology has been established. Here we show that mice deficient in a transcription factor responsible for controlling the expression of numerous detoxification and antioxidant genes develop an autoimmune disease with multiple organ pathologies that closely resembles human SLE. Aged female mice with a knockout of nuclear factor, erythroid-derived 2, like 2 (nrf2) are prone to develop antibodies against double-stranded DNA and the Smith antigen as well as IgG, IgM, and C3 deposition in kidney, liver, heart, and brain. Prior to the development of autoimmune antibodies and organ pathology, oxidative damage occurs in the liver and kidney as indicated by the increased levels of the DNA oxidation marker 8-hydroxydeoxyguanosine and the later increase in the lipid peroxidation product malondialdehyde. Gene expression profiles demonstrate an early decrease in numerous antioxidant and detoxification genes in the livers and altered levels of cytokines and T and B cell-specific genes in the spleens of nrf2 knockout mice. These data strongly suggest that a deficiency in detoxification and increased oxidative stress can result in the development of a systemic autoimmune disease.

scholarly journals Influence of Iron on Cytotoxicity and Gene Expression Profiles Induced by Arsenic in HepG2 Cells

2019 ◽  
Vol 16 (22) ◽  
pp. 4484
Author(s):  
Yonghua Wang ◽  
Yuxuan Liu ◽  
Su Liu ◽  
Bing Wu
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Hepg2 Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Interactive Effects ◽  
Lipid Peroxidation Product ◽  
Biological Processes ◽  
Mitochondrial Depolarization ◽  
Peroxidation Product

The toxicity of arsenic (As) could be influenced by many environmental factors and elements. Iron (Fe) is one of the elements that could be involved in As-induced toxicity. In this study, the interactive effects of Fe and As in HepG2 cells were analyzed based on cytotoxicity and transcriptomic analyses. The results showed that Fe could decrease cell viability and increase mitochondrial depolarization induced by As exposure. Oxidative stress and damage have been proven to be one of the main mechanisms of As toxicity. Our results showed that Fe increased the generation of reactive oxygen species (ROS) and lipid peroxidation product malondialdehyde (MDA) induced by As exposure. Microarray analysis further verified that Fe increased the alteration of gene expression and biological processes related to oxidative stress, cell proliferation, and the apoptotic signaling pathway caused by As exposure. Both results of cytotoxicity and transcriptomic analyses suggest that an increase of Fe in the human body could increase the As-induced toxicity, which should be considered during the health risk assessment of As.

scholarly journals Riboceine Rescues Auranofin-Induced Craniofacial Defects in Zebrafish

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1964
Author(s):  
Megan Leask ◽  
Catherine Carleton ◽  
Bryony Leeke ◽  
Trent Newman ◽  
Joseph Antoun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Developmental Disorders ◽  
Oral Surgery ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Zebrafish Embryos ◽  
Craniofacial Abnormalities ◽  
Antioxidant Genes ◽  
Common Group ◽  
Craniofacial Defects

Craniofacial abnormalities are a common group of congenital developmental disorders that can require intensive oral surgery as part of their treatment. Neural crest cells (NCCs) contribute to the facial structures; however, they are extremely sensitive to high levels of oxidative stress, which result in craniofacial abnormalities under perturbed developmental environments. The oxidative stress-inducing compound auranofin (AFN) disrupts craniofacial development in wildtype zebrafish embryos. Here, we tested whether the antioxidant Riboceine (RBC) rescues craniofacial defects arising from exposure to AFN. RBC rescued AFN-induced cellular apoptosis and distinct defects of the cranial cartilage in zebrafish larvae. Zebrafish embryos exposed to AFN have higher expression of antioxidant genes gstp1 and prxd1, with RBC treatment partially rescuing these gene expression profiles. Our data suggest that antioxidants may have utility in preventing defects in the craniofacial cartilage owing to environmental or genetic risk, perhaps by enhancing cell survival.

scholarly journals Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma

2020 ◽  
Vol 318 (3) ◽  
pp. G419-G427 ◽  
Author(s):  
Tatsuhide Nabeshima ◽  
Shin Hamada ◽  
Keiko Taguchi ◽  
Yu Tanaka ◽  
Ryotaro Matsumoto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cancer Progression ◽  
Stress Responses ◽  
Target Genes ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Related Factor ◽  
Loss Of Function ◽  
P53 Expression ◽  
Nrf2 Activation

The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/ p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/ p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/ p53 expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma. NEW & NOTEWORTHY The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response in cancer cells. Addition of the liver-specific Keap1 deletion to mice harboring mutant K-ras and p53 accelerated cholangiocarcinoma formation, together with the hallmarks of Nrf2 activation. This process involved the expansion of Sox9-positive cells, indicating increased differentiation toward the cholangiocyte phenotype.

scholarly journals Drug-Induced Gingival Overgrowth in an 8-Year-Old Girl: A Case Report

2021 ◽  
Vol 13 (3) ◽  
pp. 109-112
Author(s):  
Parviz Torkzaban ◽  
Amir Talaie
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Case Report ◽  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Immunological Tolerance ◽  
Systemic Autoimmune Disease ◽  
Channel Blockers ◽  
Systemic Lupus ◽  
Drug Induced ◽  
Gingival Overgrowth

Systemic lupus erythematosus is a systemic autoimmune disease that involves multi organs. Genetic, endocrine, immunological, and environmental factors influence the loss of immunological tolerance against self-antigens leading to the formation of pathogenic autoantibodies that cause tissue damage through multiple mechanisms. The gingival overgrowth can be caused by three factors: noninflammatory, hyperplastic reaction to the medication; chronic inflammatory hyperplasia; or a combined enlargement due to chronic inflammation and drug-induced hyperplasia. Drug-Induced Gingival Overgrowth is associated with the use of three major classes of drugs, namely anticonvulsants, calcium channel blockers, and immunosuppressants. Due to recent indications for these drugs, their use continues to grow.

scholarly journals Effect of Sulforaphane and 5-Aza-2’-Deoxycytidine on Melanoma Cell Growth

Medicines ◽  
2019 ◽  
Vol 6 (3) ◽  
pp. 71 ◽  
Author(s):  
Tung-chin Chiang ◽  
Brian Koss ◽  
L. Joseph Su ◽  
Charity L. Washam ◽  
Stephanie D. Byrum ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Growth ◽  
Gene Transcription ◽  
Melanoma Cell ◽  
Dna Methyltransferase ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Epigenetic Modifications ◽  
Driving Mechanism ◽  
Epigenetic Drug

Background: UV exposure-induced oxidative stress is implicated as a driving mechanism for melanoma. Increased oxidative stress results in DNA damage and epigenetic dysregulation. Accordingly, we explored whether a low dose of the antioxidant sulforaphane (SFN) in combination with the epigenetic drug 5-aza-2’-deoxycytidine (DAC) could slow melanoma cell growth. SFN is a natural bioactivated product of the cruciferous family, while DAC is a DNA methyltransferase inhibitor. Methods: Melanoma cell growth characteristics, gene transcription profiles, and histone epigenetic modifications were measured after single and combination treatments with SFN and DAC. Results: We detected melanoma cell growth inhibition and specific changes in gene expression profiles upon combinational treatments with SFN and DAC, while no significant alterations in histone epigenetic modifications were observed. Dysregulated gene transcription of a key immunoregulator cytokine—C-C motif ligand 5 (CCL-5)—was validated. Conclusions: These results indicate a potential combinatorial effect of a dietary antioxidant and an FDA-approved epigenetic drug in controlling melanoma cell growth.

scholarly journals Mechanistic Paradigms of Natural Plant Metabolites as Remedial Candidates for Systemic Lupus Erythromatosus

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1049
Author(s):  
Acharya Balkrishna ◽  
Pallavi Thakur ◽  
Shivam Singh ◽  
Swami Narsingh Chandra Dev ◽  
Anurag Varshney
Keyword(s):  
Lupus Erythematosus ◽  
Intracellular Signaling ◽  
Drug Targets ◽  
Symptomatic Relief ◽  
Autoimmune Disorder ◽  
Multiple Organ ◽  
Plant Metabolites ◽  
Systemic Lupus ◽  
Disease Heterogeneity ◽  
Natural Plant

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving a dysregulated immune response which ultimately leads to multiple organ failure. Several immunological and cellular checkpoints are available as drug targets. However, the available chemosynthetic drugs such as non-steroidal anti-inflammatory drugs and corticosteroids provide limited therapy with extreme toxicities. Moreover, the disease heterogeneity in SLE is very difficult to manage by a single drug component. Hence, it is imperative to utilize the holistic capabilities of natural plant products as immunomodulators and intracellular signaling regulators, thereby providing an auxiliary option of treatment. Additionally, the herbal drugs also serve as symptomatic relief providers, thereby serving as a prophylactic remedy in case of cerebrovascular, hepatic, nephropathological, hematological, cardiopulmonary, mucocutaneous and musculoskeletal manifestations of SLE. The present review attempts to showcase the current state of knowledge regarding the utility of plant-derived phyto-metabolites with their probable mechanistic roles in treating SLE, by means of targeting the signaling cascade, proinflammatory cytokine production and B–T cell co-stimulation. It is hoped that further preclinical and clinical studies will be embarked upon in order to understand the underlying therapeutic and mechanistic aspects of these medicinal herbs.

scholarly journals Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus

2005 ◽  
Vol 202 (2) ◽  
pp. 321-331 ◽  
Author(s):  
Sean R. Christensen ◽  
Michael Kashgarian ◽  
Lena Alexopoulou ◽  
Richard A. Flavell ◽  
Shizuo Akira ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Critical Role ◽  
Systemic Autoimmune Disease ◽  
Toll Like Receptor ◽  
Autoantibody Production ◽  
Nuclear Antigens ◽  
Deficient Mice

Systemic autoimmune disease in humans and mice is characterized by loss of immunologic tolerance to a restricted set of self-nuclear antigens. Autoantigens, such as double-stranded (ds) DNA and the RNA-containing Smith antigen (Sm), may be selectively targeted in systemic lupus erythematosus because of their ability to activate a putative common receptor. Toll-like receptor 9 (TLR9), a receptor for CpG DNA, has been implicated in the activation of autoreactive B cells in vitro, but its role in promoting autoantibody production and disease in vivo has not been determined. We show that in TLR9-deficient lupus-prone mice, the generation of anti-dsDNA and antichromatin autoantibodies is specifically inhibited. Other autoantibodies, such as anti-Sm, are maintained and even increased in TLR9-deficient mice. In contrast, ablation of TLR3, a receptor for dsRNA, did not inhibit the formation of autoantibodies to either RNA- or DNA-containing antigens. Surprisingly, we found that despite the lack of anti-dsDNA autoantibodies in TLR9-deficient mice, there was no effect on the development of clinical autoimmune disease or nephritis. These results demonstrate a specific requirement for TLR9 in autoantibody formation in vivo and indicate a critical role for innate immune activation in autoimmunity.

An autosomal recessive DNASE1L3-related autoimmune disease with unusual clinical presentation mimicking systemic lupus erythematosus

Lupus ◽  
2016 ◽  
Vol 26 (7) ◽  
pp. 768-772 ◽  
Author(s):  
A Carbonella ◽  
G Mancano ◽  
E Gremese ◽  
F S Alkuraya ◽  
N Patel ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Autosomal Recessive ◽  
Multiple Organ ◽  
Systemic Lupus ◽  
Risk Variants ◽  
Separate Condition ◽  
Hypocomplementemic Urticarial Vasculitis Syndrome ◽  
Three Sisters

We describe the third family in the world, after Arabian and Turkish ones, displaying an autosomal recessive autoimmune disease (AID), mimicking systemic lupus erythematosus (SLE), with unusual manifestations due to a homozygous frame-shift variant in DNASE1L3. SLE is a complex AID characterized by multiple organ involvement. Genetic risk variants identified account for only 15% of SLE heritability. Rare Mendelian forms have been reported, including DNASE1L3-related SLE. Through specific genetic tests we identified a homozygous 2 bp-deletion c.289_290delAC (NM_004944.2) in DNASE1L3, predicting frameshift and premature truncation (p.Thr97Ilefs*2). The same mutation was previously reported in three sisters, born from consanguineous parents and affected with hypocomplementemic urticarial vasculitis syndrome (HUVS). As approximately 50% of individuals affected with HUVS develop SLE, it is still unclear whether it is a SLE sub-phenotype or a separate condition.

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