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Growth arrest and DNA damage-inducible 45 (GADD45) proteins are critical stress sensors rapidly induced in response to genotoxic/physiological stress and regulate many cellular functions. Even though the primary function of the proteins is to block the cell cycle, inhibit cell proliferation, promote cell apoptosis, and repair DNA damage to cope with the damage caused by internal and external stress on the body, evidence has shown that GADD45 also has the function to modulate innate and adaptive immunity and plays a broader role in inflammatory and autoimmune diseases. In this review, we focus on the immunomodulatory role of GADD45 in inflammatory and autoimmune diseases. First, we describe the regulatory factors that affect the expression of GADD45. Then, we introduce its immunoregulatory roles on immune cells and the critical signaling pathways mediated by GADD45. Finally, we discuss its immunomodulatory effects in various inflammatory and autoimmune diseases.

There are three homologous proteins (α, β and γ) in the growth arrest and DNA damage 45 (Gadd45) family. These proteins act as cellular responders to physiological and environmental stimuli. Gadd45β plays a significant role in the pathogenesis of liver diseases. Liver injury and growth stimulation increase expression of Gadd45β, which promotes cell survival, growth and proliferation in normal liver cells. By contrast, Gadd45β plays a role in promoting apoptosis and inhibiting tumour function in hepatocellular carcinoma (HCC). Currently, it is believed that Gadd45β benefits the liver through two different pathways: binding to MAPK kinase 6 (MKK6) to increase PCD induced by p38 (inhibiting tumours) or binding to constitutive androstane receptor (CAR) to jointly activate transcription of liver synthesis metabolism (promoting liver regeneration). This article aims to systematically review the role of Gadd45β in liver diseases, including its regulatory mechanism on expression and involvement in liver cell damage, inflammation, fibrosis and HCC. In conclusion, we explore the potential of targeting Gadd45β as a therapeutic strategy for liver diseases.

The nonsense-mediated mRNA decay (NMD) pathway functions to degrade both abnormal and wild-type mRNAs. NMD is essential for viability in most organisms, but the molecular basis for this requirement is unknown. Here we show that a single, conserved NMD target, the mRNA coding for the stress response factor growth arrest and DNA-damage inducible 45 (GADD45) can account for lethality in Drosophila lacking core NMD genes. Moreover, depletion of Gadd45 in mammalian cells rescues the cell survival defects associated with NMD knockdown. Our findings demonstrate that degradation of Gadd45 mRNA is the essential NMD function and, surprisingly, that the surveillance of abnormal mRNAs by this pathway is not necessarily required for viability. Messenger RNA (mRNA) molecules act as the templates from which proteins are made, and so control the amount of protein in a cell. Having too much of certain proteins can harm cells. Additionally, some mRNAs contain errors, and so can create faulty proteins that may also harm the cell. Cells have therefore developed ways to destroy excess or error-ridden mRNAs to avoid a deadly build up of proteins. One such quality control mechanism is called nonsense-mediated decay (NMD). This mechanism is so important that cells that cannot perform nonsense-mediated decay die, although it is not clear exactly what kills the cells. Now, Nelson et al. have found that fruit flies whose cells are unable to perform nonsense-mediated decay die because a harmful protein called Gadd45 builds up in the cells. In normal cells, nonsense-mediated decay destroys the mRNA that relays the instructions for making Gadd45, which keeps the amount of the Gadd45 protein in the cell low. Further experiments show that removing Gadd45 from cells that lack nonsense-mediated decay saves the flies. Removing Gadd45 from human and mouse cells that are unable to perform nonsense-mediated decay also allows these cells to survive. These findings imply that the only nonsense-mediated decay function needed for cells to live is the destruction of Gadd45 mRNA. This further implies that most faulty and normal mRNAs that are normally destroyed by nonsense-mediated decay do not cause the cells to die when nonsense-mediated decay is lost. Learning that creating faulty proteins when nonsense-mediated decay is lost is not necessarily harmful to cells opens new possibilities to treating numerous genetic diseases. In some diseases, cells can only produce faulty forms of a particular protein. Nonsense-mediated decay normally destroys all of these mutant proteins, but it may sometimes be better to have faulty versions of a protein than to have none of it. Safely getting rid of nonsense-mediated decay by also eliminating Gadd45 from cells may therefore be a treatment strategy worth exploring.

Introduction: Because of the increased production and application of manufactured Nano-TiO2 in the past several years, it is important to investigate its potential hazards. TiO2 is classified by IARC as a possible human carcinogen; however, the potential mechanism of carcinogenesis has not been studied clearly. The present study aimed to investigate the mechanism of DNA damage in rat lung and extra-pulmonary organs caused by TiO2nanoparticles. Methods: In the present study, SD rats were exposed to Nano-TiO2 by intratracheal injection at a dose of 0, 0.2, or 1 g/kg body weight. The titanium levels in tissues were detected by ICP-MS. Western blot was used to detect the protein expression levels. The DNA damage and oxidative stress were detected by comet assay and ROS, MDA, SOD, and GSH-Px levels, respectively. Results: The titanium levels of the 1 g/kg group on day-3 and day-7 were significantly increased in liver and kidney as well as significantly decreased in lung compared to day-1. ROS and MDA levels were statistically increased, whereas SOD and GSH-Px levels were statistically decreased in tissues of rats in dose-dependent manners after Nano-TiO2 treatment. PI3K, p-AKT/AKT, and p-FOXO3a/FOXO3a in lung, liver, and kidney activated in dose-dependent manners. The levels of DNA damage in liver, kidney, and lung in each Nano-TiO2 treatment group were significantly increased and could not recover within 7 days. GADD45α, ChK2, and XRCC1 in liver, kidney, and lung of rats exposed to Nano-TiO2 statistically increased, which triggered DNA repair. Conclusion: This work demonstrated that Ti could deposit in lung and enter extra-pulmonary organs of rats and cause oxidative stress, then trigger DNA damage through activating the PI3K-AKT-FOXO3a pathway and then promoting GADD45α, ChK2, and XRCC1 to process the DNA repair.

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a globally increasing metabolic disorder associated with serious health complications. The molecular mechanisms linking stress-response proteins to hepatic lipogenesis in MASLD remain poorly understood. Here, we identified GADD45β as a key suppressor of de novo lipogenesis through SIRT1 stabilization. In both methionine-choline-deficient (MCD) diet-fed mice and palmitic acid (PA)-treated hepatocytes, GADD45β deficiency exacerbated lipid accumulation and upregulated lipogenic genes (SREBP1, FASN, ACC). Mechanistically, GADD45β directly bound to SIRT1 and inhibited its ubiquitination, thereby prolonging SIRT1 protein stability. Enhanced SIRT1 stability increased AMPK phosphorylation, which suppressed SREBP1-mediated transcription of lipogenic targets. Crucially, hepatic overexpression of GADD45β reversed PA-induced steatosis in vitro. Our study uncovered a GADD45β/SIRT1-/AMPK axis as a central regulator of hepatic lipogenesis, proposing GADD45β as a therapeutic target for MASLD.

Broodiness in laying hens results in atrophy of the ovary and consequently decreases productivity. However, the regulatory mechanisms that drive ovary development remain elusive. Thus, we collected atrophic ovaries (AO) from 380-day-old broody chickens (BC) and normal ovaries (NO) from even-aged egg-laying hens (EH) for RNA sequencing. We identified 3,480 protein-coding transcripts that were differentially expressed (DE), including 1,719 that were down-regulated and 1,761 that were up-regulated in AO. There were 959 lncRNA transcripts that were DE, including 56 that were down-regulated and 903 that were up-regulated. Among the116 miRNAs that were DE, 79 were down-regulated and 37 were up-regulated in AO. Numerous DE protein-coding transcripts and target genes for miRNAs/lncRNAs were significantly enriched in reproductive processes, cell proliferation, and apoptosis pathways. A miRNA-intersection gene-pathway network was constructed by considering target relationships and correlation of the expression levels between ovary development-related genes and miRNAs. We also constructed a competing endogenous RNA (ceRNA) network by integrating competing relationships between protein-coding genes and lncRNA transcripts, and identified several lncRNA transcripts predicted to regulate the CASP6 , CYP1B1 , GADD45 , MMP2 , and SMAS2 genes. In conclusion, we discovered protein-coding genes, miRNAs, and lncRNA transcripts that are candidate regulators of ovary development in broody chickens.

By far, one of the best treatments for myocardial ischemia is reperfusion therapy. The primary liposoluble component of Danshen, a traditional Chinese herbal remedy, Tanshinone ⅡA, has been shown to have cardiac healing properties. The purpose of this work is to investigate the processes by which Tanshinone ⅡA influences myocardial ischemia-reperfusion injury (MIRI) in the H9C2 cardiac myoblast cell line, as well as the association between Tanshinone ⅡA and MIRI. The cardiac cells were divided into a normal group, a model group and Tanshinone ⅡA treatment groups. After 4 h of culture with the deprivation of oxygen and glucose, the cells were incubated normally for 2 h. The success of the model and the capacity of Tanshinone ⅡA to heal cardiac damage were validated by the outcomes of cell viability, morphology, and proliferation. The efficacy of Tanshinone ⅡA in treating MIRI was further confirmed by the scratch assay and biomarker measurement. The differentially expressed genes were examined using transcriptome sequencing. The Ataxia-Telangiectasia Mutated (ATM)/Growth Arrest and DNA Damage (GADD45)/Origin Recognition Complex (ORC) signaling pathway was identified as being crucial to this process by KEGG pathway analysis and GO enrichment. Molecular docking and RT-qPCR were used to confirm our results. The crucial function of the ATM/GADD45/ORC pathway was further confirmed by the addition of an ATM inhibitor, which inhibited the expression of ATM. Tanshinone ⅡA can relieve the myocardial ischemia-reperfusion injury in cardiac cells by activating the ATM/GADD45/ORC pathway.

The growth arrest and DNA damage inducible protein 45 (GADD45) family comprises stress-induced nuclear proteins that interact with DNA demethylases to facilitate DNA demethylation, thereby regulating diverse cellular processes including oxidative stress, DNA damage repair, apoptosis, proliferation, differentiation, inflammation, and neuroplasticity by modulating the expression patterns of specific genes. Widely expressed in the central nervous system, the GADD45 family plays a pivotal role in various neurological disorders, rendering it a potential therapeutic target for central nervous system diseases. This review presented a comprehensive overview of the expression patterns and potential mechanisms of action associated with each member of GADD45 family (GADD45α, GADD45β, and GADD45γ) in neurodevelopmental, neurodegenerative, and neuropsychiatric disorders, while also explored strategies to harness these mechanisms for intervention and treatment. Future research should prioritize the development of effective modulators targeting the GADD45 family for clinical trials aimed at treating central nervous system diseases.

The GADD45 proteins are induced in response to stress and have been implicated in the regulation of several cellular functions, including DNA repair, cell cycle control, senescence, and apoptosis. In this study, we investigate the role of D-GADD45 during Drosophila development and regeneration of the wing imaginal discs. We find that higher expression of D-GADD45 results in JNK-dependent apoptosis, while its temporary expression does not have harmful effects. Moreover, D-GADD45 is required for proper regeneration of wing imaginal discs. Our findings demonstrate that a tight regulation of D-GADD45 levels is required for its correct function both, in development and during the stress response after cell death.

Exposure to drugs of abuse produces robust transcriptional and epigenetic reorganization within brain reward circuits that outlives the direct effects of the drug and may contribute to addiction. DNA methylation is a covalent epigenetic modification that is altered following stimulant exposure and is critical for behavioral and physiological adaptations to drugs of abuse. Although activity-related loss of DNA methylation requires the Gadd45 (Growth arrest and DNA-damage-inducible) gene family, very little is known about how this family regulates activity within the nucleus accumbens or behavioral responses to drugs of abuse. Here, we combined genome-wide transcriptional profiling, pharmacological manipulations, electrophysiological measurements, and CRISPR tools with traditional knockout and behavioral approaches in rodent model systems to dissect the role of Gadd45b in dopamine-dependent epigenetic regulation and cocaine reward. We show that acute cocaine administration induces rapid upregulation of Gadd45b mRNA in the rat nucleus accumbens, and that knockout or site-specific CRISPR/Cas9 gene knockdown of Gadd45b blocks cocaine conditioned place preference. In vitro, dopamine treatment in primary striatal neurons increases Gadd45b mRNA expression through a dopamine receptor type 1 (DRD1)-dependent mechanism. Moreover, shRNA-induced Gadd45b knockdown decreases expression of genes involved in psychostimulant addiction, blocks induction of immediate early genes by DRD1 stimulation, and prevents DRD1-mediated changes in DNA methylation. Finally, we demonstrate that Gadd45b knockdown decreases striatal neuron action potential burst duration in vitro, without altering other electrophysiological characteristics. These results suggest that striatal Gadd45b functions as a dopamine-induced gene that is necessary for cocaine reward memory and DRD1-mediated transcriptional activity.