Thioredoxin-Interacting Protein Gene Expression via MondoA Is Rapidly and Transiently Suppressed during Inflammatory Responses

Excessive apoptosis and inflammatory responses of nucleus pulposus (NP) cells induced by oxidative stress contribute to intervertebral disc degeneration (IVDD). Though some microRNAs are associated with IVDD, the specific microRNA that can mediate apoptotic and inflammatory responses of NP cells induced by oxidative stress synchronously still needs further identification. Here, we find that microRNA-623 (miR-623) is downregulated in IVDD and its expression is regulated by hypoxia-inducible factor-1α (HIF-1α) under oxidative stress conditions. Mechanistically, HIF-1α is observed to promote miR-623 expression by directly binding to its promoter region (−1,994/−1,987 bp). Functionally, miR-623 is found to work as an intermediator in alleviating apoptosis and inflammatory responses of NP cells induced by oxidative stress via regulating thioredoxin-interacting protein (TXNIP) expression by directly targeting its 3 ′ -untranslated region (3 ′ -UTR). Thus, on elucidating the expression and functional mechanisms of miR-623, our study suggests that miR-623 can be a valuable therapeutic target for treating oxidative stress-induced IVDD.

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Thioredoxin-interacting protein: an oxidative stress-related gene is upregulated by glucose in human prostate carcinoma cells

Journal of Molecular Endocrinology ◽

10.1677/jme-08-0033 ◽

2008 ◽

Vol 42 (3) ◽

pp. 205-214 ◽

Cited By ~ 17

Author(s):

See-Tong Pang ◽

Wen-Chi Hsieh ◽

Cheng-Keng Chuang ◽

Chun-Hsiang Chao ◽

Wen-Hui Weng ◽

...

Keyword(s):

Gene Expression ◽

Glucose Metabolism ◽

Prostate Carcinoma ◽

Promoter Activity ◽

Carcinoma Cells ◽

Human Prostate ◽

Response Element ◽

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

Human Prostate Carcinoma

Thioredoxin-interacting protein (TXNIP), also known as vitamin-D3 upregulated protein 1, interacts with reduced thioredoxin. This protein modulates the cellular redox state and plays a role in stress-induced cellular apoptosis. This study examined TXNIP gene expression in prostate cancer cells. In vitro studies by immunoblot assay have shown that elevated glucose levels (1–15 mM) upregulate TXNIP gene expression two- to fourfold in human prostate carcinoma cells (LNCaP) and hepatocellular carcinoma cells (HepG2). Transient gene expression assays reveal that the promoter activity of the TXNIP gene is upregulated by glucose, 3-O-methylglucose, and maltose, but not by mannitol. These results suggest that glucose and 3-O-methylglucose induce TXNIP expression through both glucose metabolism-dependent and -independent pathways. Cotransfection of a plasmid expression carbohydrate response element-binding protein (ChREBP) with a TXNIP reporter vector into LNCaP cells dramatically enhances reporter activity in a low glucose (1 mM) condition. The effects of glucose are apparently mediated in a region located −341 to −324 bp upstream of the translational starting point of the TXNIP gene as indicated by 5′-deletion and site-directed mutagenesis reporter assays. Mutation of the putative carbohydrate response element (ChoRE) from CACGAGGGCAGCACGAG to TTTGAGGGCAGCACGAG abolishes glucose upregulation of TXNIP promoter activity. The present study demonstrates that TXNIP is transcription induced in both LNCaP and HepG2 cells in an increased glucose metabolism-dependent or -independent response, and a putative glucose regulatory system including ChREBP and ChoRE is needed for glucose-induced TXNIP gene in human prostate carcinoma cells.

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MondoA senses adenine nucleotides: transcriptional induction of thioredoxin-interacting protein

Biochemical Journal ◽

10.1042/bj20121126 ◽

2013 ◽

Vol 453 (2) ◽

pp. 209-218 ◽

Cited By ~ 7

Author(s):

Kyoung-Sim Han ◽

Donald E. Ayer

Keyword(s):

Gene Expression ◽

Feedback Inhibition ◽

Adenine Nucleotide ◽

Adenine Nucleotides ◽

Interacting Protein ◽

Kinase Activation ◽

Thioredoxin Interacting Protein ◽

Glucose Homoeostasis ◽

Independent Effects ◽

Adenine Nucleotide Pool

The MondoA–Mlx transcription complex plays a pivotal role in glucose homoeostasis by activating target gene expression in response to G6P (glucose 6-phosphate), the first reaction intermediate in glycolysis. TXNIP (thioredoxin-interacting protein) is a direct and glucose-responsive target of MondoA that triggers a negative-feedback loop by restricting glucose uptake when G6P levels increase. We show in the present study that TXNIP expression is also activated by AICAR (5-amino-4-imidazolecarboxamide ribofuranoside) and adenosine. Using pharmacological inhibitors and genetic knockdowns of purine metabolic enzymes, we establish that TXNIP induction by AICAR and adenosine requires their cellular uptake and metabolism to adenine nucleotides. AICAR induction of TXNIP depended on MondoA, but was independent of AMPK (AMP-activated protein kinase) activation and calcium. The findings of the present study have two important implications. First, in addition to activating AMPK, AICAR may have AMPK-independent effects on gene expression by regulating MondoA–Mlx activity following its flux into the adenine nucleotide pool. Secondly, MondoA–Mlx complexes sense elevated levels of G6P and adenine nucleotides to trigger a TXNIP-dependent feedback inhibition of glycolysis. We propose that this mechanism serves as a checkpoint to restore metabolic homoeostasis.

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Modulatory Mechanisms of the NLRP3 Inflammasomes in Diabetes

Biomolecules ◽

10.3390/biom9120850 ◽

2019 ◽

Vol 9 (12) ◽

pp. 850 ◽

Cited By ~ 14

Author(s):

Sujuan Ding ◽

Sheng Xu ◽

Yong Ma ◽

Gang Liu ◽

Hongmei Jang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

Pyrin Domain ◽

Inflammatory Conditions ◽

Intestinal Lesions ◽

Treatment Of Diabetes ◽

Nlrp3 Inflammasomes

The inflammasome is a multiprotein complex that acts to enhance inflammatory responses by promoting the production and secretion of key cytokines. The best-known inflammasome is the NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin domain-containing 3) inflammasome. The evidence has shown that the NLRP3 inflammasome, IL-1β, thioredoxin-interacting protein (TXNIP), and pyroptosis play vital roles in the development of diabetes. This review summarizes the regulation of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) by NLRP3 via modulation of glucose tolerance, insulin resistance, inflammation, and apoptosis mediated by endoplasmic reticulum stress in adipose tissue. Moreover, NLRP3 participates in intestinal homeostasis and inflammatory conditions, and NLRP3-deficient mice experience intestinal lesions. The diversity of an individual’s gut microbiome and the resultant microbial metabolites determines the extent of their involvement in the physiological and pathological mechanisms within the gut. As such, further study of the interaction between the NLRP3 inflammasome and the complex intestinal environment in disease development is warranted to discover novel therapies for the treatment of diabetes.

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Interplay between Pur α and Egr-1 in the transcriptional regulation of amyloid precursor protein gene expression

Cell Biology International ◽

10.1042/cbi034s027c ◽

2010 ◽

Vol 34 (8) ◽

pp. S27-S27

Author(s):

Jianqi Cui ◽

Xiuying Pei ◽

Qian Zhang ◽

Bassel E. Sawaya ◽

Xiaohong Lu ◽

...

Keyword(s):

Gene Expression ◽

Transcriptional Regulation ◽

Amyloid Precursor Protein ◽

Protein Gene ◽

Precursor Protein ◽

Amyloid Precursor Protein Gene

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Transcriptomic phases of periodontitis lesions using the nonhuman primate model

Scientific Reports ◽

10.1038/s41598-021-88803-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jeffrey L. Ebersole ◽

Radhakrishnan Nagarajan ◽

Sreenatha Kirakodu ◽

Octavio A. Gonzalez

Keyword(s):

Gene Expression ◽

Nonhuman Primate ◽

Gingival Crevicular Fluid ◽

Inflammatory Responses ◽

Expression Profiles ◽

Lesion Detection ◽

Gingival Tissue ◽

Specific Gene ◽

Nonhuman Primate Model ◽

Primate Model

AbstractWe used a nonhuman primate model of ligature-induced periodontitis to identify patterns of gingival transcriptomic after changes demarcating phases of periodontitis lesions (initiation, progression, resolution). A total of 18 adult Macaca mulatta (12–22 years) had ligatures placed (premolar, 1st molar teeth) in all 4 quadrants. Gingival tissue samples were obtained (baseline, 2 weeks, 1 and 3 months during periodontitis and at 5 months resolution). Gene expression was analyzed by microarray [Rhesus Gene 1.0 ST Array (Affymetrix)]. Compared to baseline, a large array of genes were significantly altered at initiation (n = 6049), early progression (n = 4893), and late progression (n = 5078) of disease, with the preponderance being up-regulated. Additionally, 1918 genes were altered in expression with disease resolution, skewed towards down-regulation. Assessment of the genes demonstrated specific profiles of epithelial, bone/connective tissue, apoptosis/autophagy, metabolism, regulatory, immune, and inflammatory responses that were related to health, stages of disease, and tissues with resolved lesions. Unique transcriptomic profiles occured during the kinetics of the periodontitis lesion exacerbation and remission. We delineated phase specific gene expression profiles of the disease lesion. Detection of these gene products in gingival crevicular fluid samples from human disease may contribute to a better understanding of the biological dynamics of the disease to improve patient management.

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