NAG-1/GDF15 inhibits diabetic nephropathy via inhibiting AGE/RAGE-mediated inflammation signaling pathways in C57BL/6 mice and HK-2 cells.

Aims: Our previous studies showed that the nonsteroidal anti-inflammatory drug-activated gene-1, or growth differentiation factor-15 (NAG-1/GDF15) inhibits obesity and diabetes in mice. The current study aimed to examine the role and molecular mechanisms of NAG-1/GDF15 in diabetic nephropathy (DN), which is largely unknown.

Main Methods: Both male and female wild-type (Wt) C57BL/6 mice and mice overexpressing human NAG-1/GDF15 (transgenic, Tg) were used, which were induced by high-fat diet (HFD)/streptozotocin (STZ) to establish the mouse model of DN.

Overexpression of NAG-1/GDF15 prevents hepatic steatosis through inhibiting oxidative stress-mediated dsDNA release and AIM2 inflammasome activation.

Mitochondrial dysfunction and oxidative stress-mediated inflammasome activation play critical roles in the pathogenesis of the non-alcoholic fatty liver disease (NAFLD). Non-steroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1), or growth differentiation factor-15 (GDF15), is associated with many biological processes and diseases, including NAFLD. However, the role of NAG-1/GDF15 in regulating oxidative stress and whether this process is associated with absent in melanoma 2 (AIM2) inflammasome activation in NAFLD are unknown.

NAG-1/GDF15 protects against streptozotocin-induced type 1 diabetes by inhibiting apoptosis, preserving beta-cell function, and suppressing inflammation in pancreatic islets.

The loss of functional insulin-producing β-cells is a hallmark of type 1 diabetes mellitus (T1DM). Previously, we reported that the non-steroidal anti-inflammatory drug activated gene-1, or growth differentiation factor-15 (NAG-1/GDF15) inhibits obesity and improves insulin sensitivity in both genetic and dietary-induced obese mice. However, the regulatory role of NAG-1/GDF15 in the structure and function of β-cells and the prevention of T1DM is largely unknown.

The anti-diabetic effects of NAG-1/GDF15 on HFD/STZ-induced mice.

Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) plays a role in various diseases. Here, the anti-diabetic effects of NAG-1 were evaluated using a high-fat diet/streptozotocin-induced diabetic mouse model. NAG-1-overexpressing transgenic (NAG-1 Tg) mice exhibited lower body weight, fasting blood glucose levels, and serum insulin levels than wild-type (WT) mice.

Activation of TRPA1 by volatile organic chemicals leading to sensory irritation.

Many volatile organic chemicals (VOCs) have not been tested for sensory pulmonary irritation. Development of in vitro non-animal sensory irritation assay suitable for a large number of chemicals is needed to replace the mouse assay. An adverse outcome pathway (AOP) is designed to provide a clear description of the biochemical and cellular processes leading to toxicological effects or an adverse outcome.

Growth differentiation factor 15 (GDF15): A survival protein with therapeutic potential in metabolic diseases.

Growth Differentiation Factor 15 (GDF15), also known as NSAID activated gene-1 (NAG-1), is associated with a large number of biological processes and diseases, including cancer and obesity. GDF15 is synthesized as pro-GDF15, is dimerized, and is cleaved and secreted into the circulation as a mature dimer GDF15. Both the intracellular GDF15 and the circulating mature GDF15 are implicated in biological processes, such as energy homeostasis and body weight regulation.

Overproduction of growth differentiation factor 15 promotes human rhinovirus infection and virus-induced inflammation in the lung.

Human rhinovirus (HRV) is the most common virus contributing to acute exacerbations of chronic obstructive pulmonary disease (COPD) nearly year round, but the mechanisms have not been well elucidated. Recent clinical studies suggest that high levels of growth differentiation factor 15 (GDF15) protein in the blood are associated with an increased yearly rate of all-cause COPD exacerbations. Therefore, in the current study, we investigated whether GDF15 promotes HRV infection and virus-induced lung inflammation.

Reinterpreting the best biomarker of oxidative stress: The 8-iso-prostaglandin F2α/prostaglandin F2α ratio shows complex origins of lipid peroxidation biomarkers in animal models.

Oxidative stress is elevated in numerous environmental exposures and diseases. Millions of dollars have been spent to try to ameliorate this damaging process using anti-oxidant therapies. Currently, the best accepted biomarker of oxidative stress is the lipid oxidation product 8-iso-prostaglandin F2α (8-iso-PGF2α), which has been measured in over a thousand human and animal studies.

Expression of Human NSAID Activated Gene 1 in Mice Leads to Altered Mammary Gland Differentiation and Impaired Lactation.

Transgenic mice expressing human non-steroidal anti-inflammatory drug activated gene 1 (NAG-1) have less adipose tissue, improved insulin sensitivity, lower insulin levels and are resistant to dietary induced obesity. The hNAG-1 expressing mice are more metabolically active with a higher energy expenditure. This study investigates female reproduction in the hNAG-1 transgenic mice and finds the female mice are fertile but have reduced pup survival after birth.

NAG-1/GDF15 accumulates in the nucleus and modulates transcriptional regulation of the Smad pathway.

Protein dynamics, modifications and trafficking are all processes that can modulate protein activity. Accumulating evidence strongly suggests that many proteins have distinctive roles dependent on cellular location. Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) is a transforming growth factor-β (TGF-β) superfamily protein that has a role in cancer, obesity and inflammation.

Reinterpreting the best biomarker of oxidative stress: The 8-iso-PGF(2α)/PGF(2α) ratio distinguishes chemical from enzymatic lipid peroxidation.

The biomarker 8-iso-prostaglandin F2α (8-iso-PGF2α) is regarded as the gold standard for detection of excessive chemical lipid peroxidation in humans. However, biosynthesis of 8-iso-PGF2α via enzymatic lipid peroxidation by prostaglandin-endoperoxide synthases (PGHSs), which are significantly induced in inflammation, could lead to incorrect biomarker interpretation. To resolve the ambiguity with this biomarker, the ratio of 8-iso-PGF2α to prostaglandin F2α (PGF2α) is established as a quantitative measure to distinguish enzymatic from chemical lipid peroxidation in vitro, in animal models, and in humans.

hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling.

Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) or GDF15 is a divergent member of the transforming growth factor beta (TGF-β) superfamily and mice expressing hNAG-1/hGDF15 have been shown to be resistant to HFD-induced obesity and inflammation. This study investigated if hNAG-1 increases lifespan in mice and its potential mechanisms. Here we report that female hNAG-1 mice had significantly increased both mean and median life spans in two transgenic lines, with a larger difference in life spans in mice on a HFD than on low fat diet.

Obesity, rather than diet, drives epigenomic alterations in colonic epithelium resembling cancer progression.

While obesity represents one of several risk factors for colorectal cancer in humans, the mechanistic underpinnings of this association remain unresolved. Environmental stimuli, including diet, can alter the epigenetic landscape of DNA cis-regulatory elements affecting gene expression and phenotype. Here, we explored the impact of diet and obesity on gene expression and the enhancer landscape in murine colonic epithelium.

NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism.

Objective: Obesity is a major health problem associated with high morbidity and mortality. NSAID-activated gene (NAG-1) is a TGF-β superfamily member reported to alter adipose tissue levels in mice. We investigated whether hNAG-1 acts as a regulator of adiposity and energy metabolism.

Anti-tumor activity of non-steroidal anti-inflammatory drugs: cyclooxygenase-independent targets.

Non-steroidal anti-inflammatory drugs (NSAIDs) are used extensively for analgesic and antipyretic treatments. In addition, NSAIDs reduce the risk and mortality to several cancers. Their mechanisms in anti-tumorigenesis are not fully understood, but both cyclooxygenase (COX)-dependent and -independent pathways play a role.

Lower NLRP3 inflammasome activity in NAG-1 transgenic mice is linked to a resistance to obesity and increased insulin sensitivity.

Objective: The NLRP3 inflammasome plays an important regulatory role in obesity-induced insulin resistance. NSAID activated gene-1 (NAG-1) is a divergent member of the TGF-β superfamily. NAG-1 Tg mice are resistant to dietary- and genetic-induced obesity and have improved insulin sensitivity.

NAG-1/GDF15 transgenic mouse has less white adipose tissue and a reduced inflammatory response.

NAG-1/GDF15 is a TGF- β superfamily member with poorly characterized biological activity proposed to inhibit inflammatory cytokine production. Transgenic mice expressing human NAG-1/GDF15 (NAG-1 (Tg/Lox) ) are leaner with lower body weight and are resistant to chemically or genetically induced intestinal tumors. Because of the link between obesity, inflammation, and cancer, we examined whether these mice exhibit a reduced response to inflammatory stimuli.

Proteasome inhibitor MG132 induces NAG-1/GDF15 expression through the p38 MAPK pathway in glioblastoma cells.

The expression of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) is regulated by the p53 and Egr-1 tumor suppressor pathways. Many anti-cancer drugs and chemicals induce NAG-1 expression, but the mechanisms are not fully understood. Transgenic mice expressing human NAG-1 are resistant to intestinal and prostate cancer, suggesting that NAG-1 is a tumor suppressor.

The diverse roles of nonsteroidal anti-inflammatory drug activated gene (NAG-1/GDF15) in cancer.

Nonsteroidal anti-inflammatory drug (NSAID) activated gene-1, NAG-1, is a divergent member of the transforming growth factor-beta (TGF-β) superfamily that plays a complex but poorly understood role in several human diseases including cancer. NAG-1 expression is substantially increased during cancer development and progression especially in gastrointestinal, prostate, pancreatic, colorectal, breast, melanoma, and glioblastoma brain tumors. Aberrant increases in the serum levels of secreted NAG-1 correlate with poor prognosis and patient survival rates in some cancers.

COX inhibitors directly alter gene expression: role in cancer prevention?

Inflammation is an important contributor to the development and progression of human cancers. Inflammatory lipid metabolites, prostaglandins, formed from arachidonic acid by prostaglandin H synthases commonly called cyclooxygenases (COXs) bind to specific receptors that activate signaling pathways driving the development and progression of tumors. Inhibitors of prostaglandin formation, COX inhibitors, or nonsteroidal anti-inflammatory drugs (NSAIDs) are well documented as agents that inhibit tumor growth and with long-term use prevent tumor development.

The H6D variant of NAG-1/GDF15 inhibits prostate xenograft growth in vivo.

Background: Non-steroidal anti-inflammatory drug-activated gene (NAG-1), a divergent member of the transforming growth factor-beta superfamily, has been implicated in many cellular processes, including inflammation, early bone formation, apoptosis, and tumorigenesis. Recent clinical studies suggests that a C to G single nucleotide polymorphism at position 6 (histidine to aspartic acid substitution, or H6D) of the NAG-1 protein is associated with lower human prostate cancer incidence. The objective of the current study is to investigate the activity of NAG-1 H6D variant in prostate cancer tumorigenesis in vivo.

DNA methylation-mediated silencing of nonsteroidal anti-inflammatory drug-activated gene (NAG-1/GDF15) in glioma cell lines.

Nonsteroidal anti-inflammatory drug-activated gene, NAG-1, a transforming growth factor-β member, is involved in tumor progression and development. The association between NAG-1 expression and development and progression of glioma has not been well defined. Glioblastoma cell lines have lower basal expression of NAG-1 than other gliomas and normal astrocytes.

The role of NAG-1/GDF15 in the inhibition of intestinal polyps in APC/Min mice by sulindac.

The antitumor effects of nonsteroidal anti-inflammatory drugs (NSAID) are assumed to be due to the inhibition of COX activity, but COX-independent mechanisms may also play an important role. NSAID-activated gene (NAG-1/GDF15) is induced by NSAIDs and has antitumorigenic activities. To determine the contribution of COX-2 inhibition and NAG-1/GDF15 expression to the prevention of colon carcinogenesis by NSAIDs, we evaluated several sulindac derivatives [des-methyl (DM)-sulindac sulfide and its prodrug DM-sulindac] that do not inhibit COX-2 activity.

Resveratrol-induced apoptosis is mediated by early growth response-1, Krüppel-like factor 4, and activating transcription factor 3.

Resveratrol, a dietary phytoalexin readily available in the diet, is reported to possess antitumorigenic properties in several cancers, including colorectal. However, the underlying mechanism(s) involved is not completely understood. In the present study, we investigated the effect of resveratrol treatment on gene modulation in human colorectal cancer cells and identified activating transcription factor 3 (ATF3) as the most highly induced gene after treatment.