Obesity-induced upregulation of miR-483-5p impairs the function and identity of pancreatic ß-cells.

AIM: To assess the expression and function of miR-483-5p in diabetic ß cells. METHODS: The expression of miR-483-5p was evaluated in the pancreatic islets of obesity mouse models by quantitative reverse transcription polymerase chain reaction. Dual-luciferase activity, and western blotting assays, were utilized for miR-483-5p target gene verification. Mice with ß cell-specific miR-483-5p downregulation were studied under metabolic stress (i.e. a high-fat diet) condition. Lineage tracing was used to determine ß-cell fate. RESULTS: miR-483-5p increased in the islets of obese mouse models. Expression levels of miR-483-5p were significantly upregulated with the treatment of high glucose and palmitate, in both MIN6 cells and mouse islets. Overexpression of miR-483-5p in ß cells results in impaired insulin secretion and ß-cell identity. Cell lineage-specific analyses revealed that miR-483-5p overexpression deactivated ß-cell identity genes (insulin, Pdx1 and MafA) and derepressed ß-cell dedifferentiation (Ngn3) genes. miR-483-5p downregulation in ß cells of high-fat diet-fed mice alleviated diabetes and improved glucose intolerance by enhancing insulin secretory capacity. These detrimental effects of miR-483-5p relied on its seed sequence recognition and repressed expression of its target genes Pdx1 and MafA, two crucial markers of ß-cell maturation. CONCLUSIONS: These findings indicate that the miR-483-5p-mediated reduction of mRNAs specifies ß-cell identity as a contributor to ß-cell dysfunction via the loss of cellular differentiation.

M1 macrophage-derived exosomes impair beta cell insulin secretion via miR-212-5p by targeting SIRT2 and inhibiting Akt/GSK-3ß/ß-catenin pathway in mice.

AIMS/HYPOTHESIS: Macrophage levels are elevated in pancreatic islets, and the resulting inflammatory response is a major contributor to beta cell failure during obesity and type 2 diabetes mellitus. Previous studies by us and others have reported that exosomes released by macrophages play important roles in mediating cell-to-cell communication, and represent a class of inflammatory factors involved in the inflammatory process associated with type 2 diabetes mellitus. However, to date, no reports have demonstrated the effect of macrophage-derived exosomes on beta cells, and little is known regarding their underlying mechanisms in beta cell injury. Thus, we aimed to study the impact of macrophage-derived exosomes on islet beta cell injury in vitro and in vivo. METHODS: The phenotypic profiles of islet-resident macrophages were analysed in C57BL/6J mice fed a high-fat diet (HFD). Exosomes were collected from the medium of cultured bone marrow-derived macrophages (BMDMs) and from isolated islet-resident macrophages of HFD-fed mice (HFD-Exos). The role of exosomes secreted by inflammatory M1 phenotype BMDMs (M1-Exos) and HFD-Exos on beta cell function was assessed. An miRNA microarray and quantitative real-time PCR (qPCR) were conducted to test the level of M1-Exos-derived miR-212-5p in beta cells. Then, miR-212-5p was overexpressed or inhibited in M1-Exos or beta cells to determine its molecular and functional impact. RESULTS: M1-polarised macrophages were enriched in the islets of obese mice. M1 macrophages and islet-resident macrophages of HFD-fed mice impaired beta cell insulin secretion in an exosome-dependent manner. miR-212-5p was notably upregulated in M1-Exos and HFD-Exos. Enhancing the expression of miR-212-5p impaired beta cell insulin secretion. Blocking miR-212-5p elicited a significant improvement in M1-Exos-mediated beta cell insulin secretion during injury. Mechanistically, M1-Exos mediated an intercellular transfer of the miR-212-5p, targeting the sirtuin 2 gene and regulating the Akt/GSK-3ß/ß-catenin pathway in recipient beta cells to restrict insulin secretion. CONCLUSIONS/INTERPRETATION: A novel exosome-modulated mechanism was delineated for macrophage-beta cell crosstalk that drove beta cell dysfunction and should be explored for its therapeutic utility.

Lentinan protects against pancreatic ß-cell failure in chronic ethanol consumption-induced diabetic mice via enhancing ß-cell antioxidant capacity.

Chronic ethanol consumption is a well-established independent risk factor for type 2 diabetes mellitus (T2DM). Recently, increasing studies have confirmed that excessive heavy ethanol exerts direct harmful effect on pancreatic ß-cell mass and function, which may be a mechanism of pancreatic ß-cell failure in T2DM. In this study, we evaluated the effect of Lentinan (LNT), an active ingredient purified from the bodies of Lentinus edodes, on pancreatic ß-cell apoptosis and dysfunction caused by ethanol and the possible mechanisms implicated. Functional studies reveal that LNT attenuates chronic ethanol consumption-induced impaired glucose metabolism in vivo. In addition, LNT ameliorates chronic ethanol consumption-induced ß-cell dysfunction, which is characterized by reduced insulin synthesis, defected insulin secretion and increased cell apoptosis. Furthermore, mechanistic assays suggest that LNT enhances ß-cell antioxidant capacity and ameliorates ethanol-induced oxidative stress by activating Nrf-2 antioxidant pathway. Our results demonstrated that LNT prevents ethanol-induced pancreatic ß-cell dysfunction and apoptosis, and therefore may be a potential pharmacological agent for preventing pancreatic ß-cell failure associated with T2DM and stress-induced diabetes.

Transcription factor Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in rodent models.

AIMS/HYPOTHESIS: 'Glucotoxicity' is a term used to convey the negative effect of hyperglycaemia on beta cell function; however, the underlying molecular mechanisms that impair insulin secretion and gene expression are poorly defined. Our objective was to define the role of transcription factor v-ets avian erythroblastosis virus E26 oncogene homologue 1 (Ets-1) in beta cell glucotoxicity. METHODS: Primary islets and Min6 cells were exposed to high glucose and Ets-1 expression was measured. Recombinant adenovirus and transgenic mice were used to upregulate Ets-1 expression in beta cells in vitro and in vivo, and insulin secretion was assessed. The binding activity of H3/H4 histone on the Ets-1 promoter, and that of forkhead box (FOX)A2, FOXO1 and Ets-1 on the Pdx-1 promoter was measured by chromatin immunoprecipitation and quantitative real-time PCR assay. RESULTS: High glucose induced upregulation of Ets-1 expression and hyperacetylation of histone H3 and H4 at the Ets-1 gene promoter in beta cells. Ets-1 overexpression dramatically suppressed insulin secretion and biosynthesis both in vivo and in vitro. Besides, Ets-1 overexpression increased the activity of FOXO1 but decreased that of FOXA2 binding to the pancreatic and duodenal homeobox 1 (PDX-1) homology region 2 (PH2), resulting in inhibition of Pdx-1 promoter activity and downregulation of PDX-1 expression and activity. In addition, high glucose promoted the interaction of Ets-1 and FOXO1, and the activity of Ets-1 binding to the Pdx-1 promoter. Importantly, PDX-1 overexpression reversed the defect in pancreatic beta cells induced by Ets-1 excess, while knockdown of Ets-1 prevented hyperglycaemia-induced dysfunction of pancreatic beta cells. CONCLUSIONS/INTERPRETATION: Our observations suggest that Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in type 2 diabetes.

Visceral adipocyte-derived extracellular vesicle miR-27a-5p elicits glucose intolerance by inhibiting pancreatic ß-cell insulin secretion.

Pancreatic ß-cell dysfunction caused by obesity can be associated with alterations in the levels of microRNAs (miRNAs). However, the role of miRNAs in such processes remains elusive. Here, we show that pancreatic islet miR-27a-5p, which is markedly increased in obese mice and impairs insulin secretion, is mainly delivered by visceral adipocyte-derived extracellular vesicles (EVs). Depleting miR-27a-5p significantly improves insulin secretion and glucose intolerance in db/db mice. Supporting the function of EVs' miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p-containing EVs shows their distribution in mouse pancreatic islets. Tracing the injected AAV-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat results in upregulating miR-27a-5p in EVs and serum, and elicits mouse pancreatic ß-cell dysfunction. Mechanistically, miR-27a-5p directly targets L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduces insulin secretion in ß-cells. Overexpressing mouse CaV1.2 largely abolishes the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EVs' miR-27a-5p in visceral adipocyte-mediated pancreatic ß-cell dysfunction in obesity-associated type 2 diabetes mellitus.

(-)-Epigallocatechin 3-gallate protects pancreatic ß-cell against excessive autophagy-induced injury through promoting FTO degradation.

Excessive macroautophagy/autophagy leads to pancreatic ß-cell failure that contributes to the development of diabetes. Our previous study proved that the occurrence of deleterious hyperactive autophagy attributes to glucolipotoxicity-induced NR3C1 activation. Here, we explored the potential protective effects of (-)-epigallocatechin 3-gallate (EGCG) on ß-cell-specific NR3C1 overexpression mice in vivo and NR3C1-enhanced ß cells in vitro. We showed that EGCG protects pancreatic ß cells against NR3C1 enhancement-induced failure through inhibiting excessive autophagy. RNA demethylase FTO (FTO alpha-ketoglutarate dependent dioxygenase) caused diminished m6A modifications on mRNAs of three pro-oxidant genes (Tlr4, Rela, Src) and, hence, oxidative stress occurs; by contrast, EGCG promotes FTO degradation by the ubiquitin-proteasome system in NR3C1-enhanced ß cells, which alleviates oxidative stress, and thereby prevents excessive autophagy. Moreover, FTO overexpression abolishes the beneficial effects of EGCG on ß cells against NR3C1 enhancement-induced damage. Collectively, our results demonstrate that EGCG protects pancreatic ß cells against NR3C1 enhancement-induced excessive autophagy through suppressing FTO-stimulated oxidative stress, which provides novel insights into the mechanisms for the anti-diabetic effect of EGCG.Abbreviation 3-MA: 3-methyladenine; AAV: adeno-associated virus; Ad: adenovirus; ALD: aldosterone; AUC: area under curve; ßNR3C1 mice: pancreatic ß-cell-specific NR3C1 overexpression mice; Ctrl: control; CHX: cycloheximide; DEX: dexamethasone; DHE: dihydroethidium; EGCG: (-)-epigallocatechin 3-gallate; FTO: FTO alpha-ketoglutarate dependent dioxygenase; GSIS: glucose-stimulated insulin secretion; HFD: high-fat diet; HG: high glucose; i.p.: intraperitoneal; IOD: immunofluorescence optical density; KSIS: potassium-stimulated insulin secretion; m6A: N6-methyladenosine; MeRIP-seq: methylated RNA immunoprecipitation sequencing; NO: nitric oxide; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NR3C1-Enhc.: NR3C1-enhancement; NAC: N-acetylcysteine; NC: negative control; PBS: phosphate-buffered saline; PI: propidium iodide; OCR: oxygen consumption rate; Palm.: palmitate; RELA: v-rel reticuloendotheliosis viral oncogene homolog A (avian); RNA-seq: RNA sequencing; O2.-: superoxide anion; SRC: Rous sarcoma oncogene; ROS: reactive oxygen species; T2D: type 2 diabetes; TEM: transmission electron microscopy; TLR4: toll-like receptor 4; TUNEL: terminal dUTP nick-end labeling; UTR: untranslated region; WT: wild-type.

NR3C1/Glucocorticoid receptor activation promotes pancreatic ß-cell autophagy overload in response to glucolipotoxicity.

Diabetes is a complex and heterogeneous disorder characterized by chronic hyperglycemia. Its core cause is progressively impaired insulin secretion by pancreatic ß-cell failures, usually upon a background of preexisting insulin resistance. Recent studies demonstrate that macroautophagy/autophagy is essential to maintain architecture and function of ß-cells, whereas excessive autophagy is also involved in ß-cell dysfunction and death. It has been poorly understood whether autophagy plays a protective or harmful role in ß-cells, while we report here that it is dependent on NR3C1/glucocorticoid receptor activation. We proved that deleterious hyperactive autophagy happened only upon NR3C1 activation in ß-cells under glucolipotoxic conditions, which eventually promoted diabetes. The transcriptome and the N6-methyladenosine (m6A) methylome revealed that NR3C1-enhancement upregulated the RNA demethylase FTO (fat mass and obesity associated) protein in ß-cells, which caused diminished m6A modifications on mRNAs of four core Atg (autophagy related) genes (Atg12, Atg5, Atg16l2, Atg9a) and, hence, hyperactive autophagy and defective insulin output; by contrast, FTO inhibition, achieved by the specific FTO inhibitor Dac51, prevented NR3C1-instigated excessive autophagy activation. Importantly, Dac51 effectively alleviated impaired insulin secretion and glucose intolerance in hyperglycemic ß-cell specific NR3C1 overexpression mice. Our results determine that the NR3C1-FTO-m6A modifications-Atg genes axis acts as a key mediator of balanced autophagic flux in pancreatic ß-cells, which offers a novel therapeutic target for the treatment of diabetes.Abbreviations: 3-MA: 3-methyladenine; AAV: adeno-associated virus; Ac: acetylation; Ad: adenovirus; AL: autolysosome; ATG: autophagy related; AUC: area under curve; Baf A1: bafilomycin A1; ßNR3C1 mice: pancreatic ß-cell-specific NR3C1 overexpression mice; cFBS: charcoal-stripped FBS; Ctrl: control; ER: endoplasmic reticulum; FTO: fat mass and obesity associated; GC: glucocorticoid; GRE: glucocorticoid response element; GSIS: glucose-stimulated insulin secretion assay; HFD: high-fat diet; HG: high glucose; HsND: non-diabetic human; HsT2D: type 2 diabetic human; i.p.: intraperitoneal injected; KSIS: potassium-stimulated insulin secretion assay; m6A: N6-methyladenosine; MeRIP-seq: methylated RNA immunoprecipitation sequencing; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NR3C1-Enhc.: NR3C1-enhancement; NC: negative control; Palm.: palmitate; RNA-seq: RNA sequencing; T2D: type 2 diabetes; TEM: transmission electron microscopy; UTR: untranslated region; WT: wild-type.

Lentinan confers protection against type 1 diabetes by inducing regulatory T cell in spontaneous non-obese diabetic mice.

BACKGROUND: Lentinan (LNT) is a complex fungal component that possesses effective antitumor and immunostimulating properties. However, there is a paucity of studies regarding the effects and mechanisms of LNT on type 1 diabetes. OBJECTIVE: In the current study, we investigated whether an intraperitoneal injection of LNT can diminish the risk of developing type 1 diabetes (T1D) in non-obese diabetic (NOD) mice and further examined possible mechanisms of LNT's effects. METHODS: Pre-diabetic female NOD mice 8 weeks of age, NOD mice with 140-160 mg/dL, 200-230 mg/dL or 350-450 mg/dL blood glucose levels were randomly divided into two groups and intraperitoneally injected with 5 mg/kg LNT or PBS every other day. Then, blood sugar levels, pancreas slices, spleen, PnLN and pancreas cells from treatment mice were examined. RESULTS: Our results demonstrated that low-dosage injections (5 mg/kg) of LNT significantly suppressed immunopathology in mice with autoimmune diabetes but increased the Foxp3+ regulatory T cells (Treg cells) proportion in mice. LNT treatment induced the production of Tregs in the spleen and PnLN cells of NOD mice in vitro. Furthermore, the adoptive transfer of Treg cells extracted from LNT-treated NOD mice confirmed that LNT induced Treg function in vivo and revealed an enhanced suppressive capacity as compared to the Tregs isolated from the control group. CONCLUSION: LNT was capable of stimulating the production of Treg cells from naive CD4 + T cells, which implies that LNT exhibits therapeutic values as a tolerogenic adjuvant and may be used to reverse hyperglycaemia in the early and late stages of T1D.

Calcium Binding Protein S100A16 Expedites Proliferation, Invasion and Epithelial-Mesenchymal Transition Process in Gastric Cancer.

Gastric cancer (GC) is one of the most common malignant tumors of the digestive system, listed as the second cause of cancer-related deaths worldwide. S100 Calcium Binding Protein A16 (S100A16) is an acidic calcium-binding protein associated with several types of tumor progression. However, the function of S100A16 in GC is still not very clear. In this study, we analyzed S100A16 expression with the GEPIA database and the UALCAN cancer database. Meanwhile, 100 clinical GC samples were used for the evaluation of its role in the prognostic analysis. We found that S100A16 is significantly upregulated in GC tissues and closely correlated with poor prognosis in GC patients. Functional studies reveal that S100A16 overexpression triggers GC cell proliferation and migration both in vivo and in vitro; by contrast, S100A16 knockdown restricts the speed of GC cell growth and mobility. Proteomic analysis results reveal a large S100A16 interactome, which includes ZO-2 (Zonula Occludens-2), a master regulator of cell-to-cell tight junctions. Mechanistic assay results indicate that excessive S100A16 instigates GC cell invasion, migration, and epithelial-mesenchymal transition (EMT) via ZO-2 inhibition, which arose from S100A16-mediated ZO-2 ubiquitination and degradation. Our results not only reveal that S100A16 is a promising candidate biomarker in GC early diagnosis and prediction of metastasis, but also establish the therapeutic importance of targeting S100A16 to prevent ZO-2 loss and suppress GC metastasis and progression.

HRD1, an Important Player in Pancreatic ß-Cell Failure and Therapeutic Target for Type 2 Diabetic Mice.

Inadequate insulin secretion in response to glucose is an important factor for ß-cell failure in type 2 diabetes (T2D). Although HMG-CoA reductase degradation 1 (HRD1), a subunit of the endoplasmic reticulum-associated degradation complex, plays a pivotal role in ß-cell function, HRD1 elevation in a diabetic setting contributes to ß-cell dysfunction. We report in this study the excessive HRD1 expression in islets from humans with T2D and T2D mice. Functional studies reveal that ß-cell-specific HRD1 overexpression triggers impaired insulin secretion that will ultimately lead to severe hyperglycemia; by contrast, HRD1 knockdown improves glucose control and response in diabetic models. Proteomic analysis results reveal a large HRD1 interactome, which includes v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), a master regulator of genes implicated in the maintenance of ß-cell function. Furthermore, mechanistic assay results indicate that HRD1 is a novel E3 ubiquitin ligase that targets MafA for ubiquitination and degradation in diabetic ß-cells, resulting in cytoplasmic accumulation of MafA and in the reduction of its biological function in the nucleus. Our results not only reveal the pathological importance of excessive HRD1 in ß-cell dysfunction but also establish the therapeutic importance of targeting HRD1 in order to prevent MafA loss and suppress the development of T2D.

Ets1-Mediated Acetylation of FoxO1 Is Critical for Gluconeogenesis Regulation during Feed-Fast Cycles.

The homeostatic balance of hepatic glucose uptake and production is exquisitely controlled by hormonal signals during feed-fast cycles. FoxO1, a transcription factor that functions in the regulation of glucose homeostasis, undergoes posttranslational modifications, such as acetylation, in response to hormonal signals, yet the mechanism remains poorly elucidated. Through expression profiling of 324 co-factors of CBP, a well-known acetyl-transferase of FoxO1, we identify Ets1 as a modulator of FoxO1 acetylation that is highly associated with feed-fast cycles. Mechanistic assays suggest that Ets1 enhances FoxO1 acetylation through the formation of a complex with CBP, which further promotes FoxO1 nuclear exclusion and inhibits its binding to gluconeogenic promoters. Functional studies further reveal that Ets1 inhibits gluconeogenesis under physiological and diabetes statuses, while the hyperinsulinemic-euglycemic clamp assay suggests hepatocyte Ets1 knockout mice have enhanced hepatic glucose production. Our study identifies Ets1 as an enhancer of FoxO1 acetylation and a repressor of hepatic gluconeogenesis in response to hormonal signals.

Porous Graphene-Confined Fe-K as Highly Efficient Catalyst for CO2 Direct Hydrogenation to Light Olefins.

We devised iron-based catalysts with honeycomb-structured graphene (HSG) as the support and potassium as the promoter for CO2 direct hydrogenation to light olefins (CO2-FTO). Over the optimal FeK1.5/HSG catalyst, the iron time yield of light olefins amounted to 73 µmolCO2 gFe-1 s-1 with high selectivity of 59%. No obvious deactivation occurred within 120 h on stream. The excellent catalytic performance is attributed to the confinement effect of the porous HSG on the sintering of the active sites and the promotion effect of potassium on the activation of inert CO2 and the formation of iron carbide active for CO2-FTO.

TIMP-1 and CD82, a promising combined evaluation marker for PDAC.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a widely secreted protein that regulates cell motility, proliferation, and apoptosis. Although it is recognized that TIMP-1-tetraspanin CD63 regulates epithelial cell apoptosis and proliferation, how TIMP-1 controls cell motility is not well understood. In this study, we identify tetraspanin CD82 (also called KAI1) as a component of the promiscuous TIMP-1 interacting protein complex on cell surface of human pancreatic adenocarcinoma cells. CD82 directly binds to TIMP-1 N-terminal region through its large extracellular loop and co-localizes with TIMP-1 in both cancer cell lines and clinical samples. Moreover, CD82 facilitates membrane-bound TIMP-1 endocytosis, which significantly contributes to the anti-migration effect of TIMP-1. CD82 silencing partially eliminates these functions. TIMP-1 and CD82 expression status in patients with pancreatic ductal adenocarcinoma (PDAC) might demonstrate future usefulness as a differentiation marker and give us new insight into tumorigenic metastatic potential.

Epigallocatechin-3-Gallate Inhibits Ethanol-Induced Apoptosis Through Neurod1 Regulating CHOP Expression in Pancreatic ß-Cells.

Epiga-llocatechin-3-gallate (EGCG) is one kind of polyphenol abundant extracted from green tea which has a potent antidiabetic activity. However, the molecular mechanisms mediating the protection procession of EGCG are still unclear. The aim of this study was to investigate the protective effect of EGCG on pancreatic ß-cells exposed to ethanol and the possible underlying mechanisms. To observe the effect of EGCG, we assessed apoptosis in ßTC-6 and INS-1 cells, which were in complete medium containing 60 mM ethanol, or coincubation with different concentration of EGCG. We also evaluated the roles of Neurod1 in CHOP expression and ethanol-mediated damage through plasmid overexpression. Treatment with EGCG decreased CHOP expression and apoptosis, whereas its treatment increased Neurod1 expression in ethanol-treated ßTC-6 and INS-1 cells. Overexpression of Neurod1 caused the decrease of CHOP expression and apoptosis in ethanol-treated cells. Furthermore, Neurod1 inhibited CHOP expression by deacetylation of Histone H4 at the CHOP gene promoter. In addition, EGCG partially restores the activity of Neurod1 binding to CHOP promoter in ethanol-treated cells. In conclusion, EGCG protected ß-cell against ethanol-induced ß-cell apoptosis by Neurod1 regulating CHOP expression.

Aldosterone induces clonal ß-cell failure through glucocorticoid receptor.

Aldosterone excess causes insulin resistance in peripheral tissues and directly impairs the function of clonal ß-cell. The aim of this study was to investigate the molecular mechanisms involved in the aldosterone-induced impairment of clonal ß-cells. As expected, aldosterone induced apoptosis and ß-cell dysfunction, including impairment of insulin synthesis and secretion, which were reversed by Glucocorticoid receptor (GR) antagonists or GR-specific siRNA. However, mineralocorticoid receptor (MR) antagonists or MR-specific siRNA had no effect on impairment of clonal ß-cells induced by aldosterone. Besides, aldosterone significantly decreased expression and activity of MafA, while activated JNK and p38 MAPK in a GR-dependent manner. In addition, JNK inhibitors (SP600125) and/or p38 inhibitors (SB203580) could abolish the effect of aldosterone on MafA expression and activity. Importantly, overexpression of JNK1 or p38 reversed the protective effect of a GR antagonist on the decrease of MafA expression and activity. Furthermore, aldosterone inhibits MafA expression at the transcriptional and post-transcriptional level through activation of JNK and p38, respectively. Consequently, overexpression of MafA increased synthesis and secretion of insulin, and decreased apoptosis in clonal ß-cells exposed to aldosterone. These findings identified aldosterone as an inducer of clonal ß-cell failure that operates through the GR-MAPK-MafA signaling pathway.