Pachymic acid (PA) inhibits ferroptosis of cardiomyocytes via activation of the AMPK in mice with ischemia/reperfusion-induced myocardial injury.

Pachymic acid (PA) is a lanostane-type triterpenoid with various pharmacological effects. However, little is known about the effect of PA on myocardial infarction (MI) induced by ischemia/reperfusion (I/R). In this study, we aimed to investigate the protective effect of PA and its underlying mechanism. A cellular MI model was established by oxygen-glucose deprivation and reperfusion (OGD/R) treatment in HL-1 cardiomyocytes, and we found that OGD/R treatment decreased cell viability and glutathione peroxide (GSH-Px) activity, increased Fe2+ concentration and lactate dehydrogenase (LDH) activity, promoted malondialdehyde (MDA) and reactive oxygen species (ROS) production, and inhibited the expression of ferroptosis marker proteins SLC7A11 and GPX4 in a time-dependent manner. OGD/R-induced HL-1 cells were pretreated with different concentrations of PA (0, 20, 40, 60 µg/mL) for 24 h, and toxicological experiments showed that 150 µg/mL PA decreased cell viability, while low concentrations of PA had no toxic effect on cells. 20 µg/mL PA reversed the inhibitory effect of OGD/R on cell viability, reduced MDA and ROS production, and Fe2+ accumulation, increased GSH-Px activity and the expression of SLC7A11 and GPX4, and decreased LDH activity, especially at 60 µg/mL PA. Meanwhile, PA promoted the phosphorylation of IRS-1, AKT, and AMPK proteins in a dose-dependent manner. AICAR, an AMPK activator, inhibited ferroptosis, while STO-609, an AMPK inhibitor, largely abolished the effect of PA on OGD/R-induced ferroptosis of HL-1 cells. In addition, PA inhibited ferroptosis and myocardial I/R injury in wild-type mice and AMPK knockout (AMPK-/- ) mice. Collectively, PA inhibited ferroptosis of cardiomyocytes through activating of the AMPK pathway, thereby alleviating myocardial I/R injury in mice.

LncRNA Tug1 relieves the steatosis of SelenoF-knockout hepatocytes via sponging miR-1934-3p.

Metabolic dysfunction associated with fatty liver disease (MAFLD), always accompanied by disturbance of glucose and lipid metabolism, is becoming the most difficult obstacle in the next decades. In the current research, we uncover that the potent non-coding RNA Tug1, which is related to metabolic enzymes, regulates hepatocytes steatosis induced by sodium palmitate via miR-1934-3p absorbing. The knockdown of lncRNA-Tug1 distinctly rescues the increased expression level of glycolytic enzymes and fatty acid synthetase via releasing more mature miR-1934-3p in hepatocytes. Moreover, miR-1934-3p suppresses Selenoprotein F (SelenoF) through binding with the SelenoF 3'UTR effectors; importantly, we demonstrated that the deletion of SelenoF consistent with the lncRNA-Tug1's effecting on metabolism enzymes. In the current paper, the interaction of Tug1/miR-1934-3p/SelenoF was verified by the dual-luciferase reporter system, and IRS1/AKT pathway possesses the essential role in glucolipid metabolism when SelenoF is deleted. We concluded that lncRNA Tug1 functioned as ceRNA to alleviate steatosis and glycolysis in hepatocytes of C57BL/6 through adsorbing miR-1934-3p to release SelenoF and triggering IRS/AKT pathway. The Tug1/miR-1934-3p/SelenoF constructed the ceRNA interact network Selenoprotein F accelerates glucolipid metabolism via IRS1/AKT pathway SelenoF-/- alleviates steatosis in mice liver.

Quercetin ameliorated insulin resistance via regulating METTL3-mediated N6-methyladenosine modification of PRKD2 mRNA in skeletal muscle and C2C12 myocyte cell line.

BACKGROUND AND AIMS: N6-Methyladenosine (m6A) modification is involved in many pathological processes, including insulin resistance (IR). Quercetin (Que), a bioactive compound with strong antioxidant activity, has potential therapeutic effects on IR-related metabolic diseases. The aim of this study is to investigate the roles of m6A and Que in hyperinsulinemia. METHODS AND RESULTS: Male C57Bl/6 mice received a high-fat diet (HFD) for 8 weeks to establish an IR model. Que treatment reduced the body weight, blood glucose, plasma triglycerides (TG) and serum insulin, ameliorated IR, and decreased oxidative stress in HFD-fed mice. Cellular IR model was established in C2C12 cells by palmitic acid (PA) stimulation, and a noncytotoxic dose of Que was found to promote glucose uptake and inhibit oxidative stress. Moreover, methyltransferase-like 3 (METTL3) and serine-threonine kinase protein kinase D2 (PRKD2) was downregulated in skeletal muscle of HFD-fed mouse and in PA-induced C2C12 cells. The online bioinformatic tool SRAMP revealed that there were multiple m6A modification sites in the PRKD2 mRNA sequence. Downregulation of METTL3 enhanced PRKD2 expression by reducing m6A level and promoting mRNA stability in PRKD2 mRNA transcript. Que decreased m6A, METTL3, and phosphorylated insulin receptor substrate 1 (p-IRS1) levels, increased the protein expression of PRKD2, glucose transporter type 4 (GLUT4) and p-AKT, promoted glucose uptake, and reduced oxidative stress in PA-induced C2C12 cells. Moreover, METTL3 overexpression or PRKD2 silence reversed the inhibitory effects of Que on the levels of MDA and p-IRS1 and the promotive effects on glucose uptake, superoxide dismutase (SOD), GSH and GLUT4 and p-AKT levels. CONCLUSION: Que promoted glucose uptake, repressed oxidative stress and improved IR through METTL3-mediated m6A of PRKD2 mRNA.

Simiao Wan and its ingredients alleviate type 2 diabetes mellitus via IRS1/AKT2/FOXO1/GLUT2 signaling.

Background: Type 2 diabetes mellitus (T2DM) is a metabolic disease. Simiao Wan (SMW) is a commonly used clinical drug for hyperuricemia treatment. SMW has been confirmed to improve insulin resistance and is expected to be a novel hypoglycemic agent. However, the hypoglycemic bioactive ingredients and mechanisms of action of SMW are unclear. Objective: To explore the hypoglycemic effects and reveal the mechanisms of SMW and bioactive ingredients (SMW-BI). Study design and methods: The hypoglycemic effects of SMW and SMW-BI were verified in a mouse model of T2DM induced by streptozotocin (STZ) and a high-fat and high-sugar diet (HFSD). Network pharmacology was used to predict the mechanisms of SMW and SMW-BI. Histological analysis and real-time quantitative polymerase chain reaction (RT-qPCR) verified network pharmacology results. RT-qPCR results were further verified by immunofluorescence (IFC) and molecular docking. The correlation between proteins and biochemical indicators was analyzed by Spearman's correlation. Results: Chlorogenic acid, phellodendrine, magnoflorine, jateorhizine, palmatine, berberine, and atractydin were identified as SMW-BI. After 8 weeks of treatment, SMW and SMW-BI decreased the levels of fasting blood glucose (FBG), total cholesterol (TC), triacylglycerols (TG) and low-density lipoprotein cholesterol (LDL-C), increased the level of high-density lipoprotein cholesterol (HDL-C), alleviated weight loss, and increased serum insulin levels in T2DM mice. In addition, SMW and SMW-BI improved hepatocyte morphology in T2DM mice, decreased the number of adipocytes, and increased liver glycogen. Network pharmacological analysis indicated that SMW and SMW-BI may exert hypoglycemic by regulating insulin receptor substrate 1 (IRS1)/RAC-beta serine/threonine-protein kinase (AKT2)/forkhead box protein O1 (FOXO1)/glucose transporter type 2 (GLUT2) signaling. Moreover, correlation analysis showed that SMW and SMW-BI were associated with activation of IRS1, AKT2, and GLUT2, and inhibiting FOXO1. RT-qPCR revealed that SMW and SMW-BI could increase levels of IRS1, AKT2, and GLUT2 in the livers of T2DM mice and lower the level of FOXO1. Furthermore, immunofluorescence analysis showed that FOXO1 expression in the livers of T2DM mice decreased after oral administration of SMW and SMW-BI. Furthermore, molecular docking showed that SMW-BI could bind directly to IRS1 and AKT2. Conclusion: SMW and SMW-BI are potential hypoglycemic drugs that alleviate T2DM by regulating IRS1/AKT2/FOXO1 signaling. Our study provides a research idea for screening the bioactive ingredients in traditional Chinese medicine (TCM).

Effect of ß-Caryophyllene on insulin resistance in skeletal muscle of high fat diet and fructose-induced type-2 diabetic rats.

High fat diet feeding results in hyperglycemia and insulin resistance, which is a major pathological feature of type-2 diabetes mellitus. The use of oral hypoglycaemic drugs is limited due to its deleterious side effects and there is a need to find more efficacious agents for diabetes management. Hence, it is of interest to show the mechanism of action of ß-Caryophyllene on insulin signalling molecules in gastrocnemius muscle of high fat diet - induced type-2 diabetic rats. An oral effective dose of with ß-Caryophyllene (200 mg/kg b.wt) was given for 30 days to high fat diet (comprising 2% cholesterol, 1% cholic acid, 30% coconut oil, 67% conventional rat feed) and fructose fed type-2 diabetic rats to find out whether ß-Caryophyllene regulates IRS-1/Akt pathway of insulin signalling. The data shows that, ß-Caryophyllene treatment significantly increased the mRNA and protein expression of insulin receptor (IR) in diabetic rats whereas there is no significant difference in mRNA expression of insulin receptor-substrate-1 (IRS-1) was observed among groups. The Akt mRNAand GLUT-4mRNA and protein level were also improved in gastrocnemius muscle of type-2 diabetic rats. Thus, we concluded that ß-Caryophyllene could be used as potential phyto medicine for type-2 diabetes management.

Prolyl endopeptidase inhibitor Y-29794 blocks the IRS1-AKT-mTORC1 pathway and inhibits survival and in vivo tumor growth of triple-negative breast cancer.

Prolyl endopeptidase (PREP), also known as prolyl oligopeptidase (POP), is an enzyme that cleaves short peptides (<30 amino acids in length) on the C-terminal side of proline. PREP is highly expressed in multiple carcinomas and is a potential target for cancer therapy. A potent inhibitor of PREP, Y-29794, causes long-lasting inhibition of PREP in mouse tissues. However, there are no reports on Y-29794 effects on cancer cell and tumor proliferation. Using cell line models of aggressive triple-negative breast cancer (TNBC), we show here that Y-29794 inhibited proliferation and induced death in multiple TNBC cell lines. Cell death induced by Y-29794 coincided with inhibition of the IRS1-AKT-mTORC1 survival signaling pathway, although stable depletion of PREP alone was not sufficient to reduce IRS1-AKT-mTORC1 signaling or induce death. These results suggest that Y-29794 elicits its cancer cell killing effect by targeting other mechanisms in addition to PREP. Importantly, Y-29794 inhibited tumor growth when tested in xenograft models of TNBC in mice. Induction of cell death in culture and inhibition of xenograft tumor growth support the potential utility of Y-29794 or its derivatives as a treatment option for TNBC tumors.

Effect of the ZiBuPiYin Recipe on Diabetes-Associated Cognitive Decline in Zucker Diabetic Fatty Rats After Chronic Psychological Stress.

BACKGROUND: Cognitive impairment is a complication of type 2 diabetes mellitus (T2DM) that affects the central nervous system (CNS). Studies have shown that chronic psychological stress may promote the development of T2DM into diabetes-associated cognitive decline (DACD). Previously, cognitive impairment in T2DM was correlated predominantly with insulin resistance in the medial prefrontal cortex (mPFC). AIMS: We examined the effect of the ZiBuPiYin recipe (ZBPYR) on Zucker diabetic fatty (ZDF) rats and explored the impact of chronic stress on altered ß-amyloid (Aß) metabolism through insulin receptor substrate (IRS) 1/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway after the induction of chronic psychological stress. MAIN METHODS: After chronic psychological stress and drug treatment, cognitive function was observed via behavioral experiments. The activation of the hypothalamus-pituitary-adrenal (HPA) axis and levels of Aß were detected by enzyme-linked immunosorbent assay, and the expression of related proteins was evaluated by Western blotting. KEY FINDINGS: ZBPYR treatment significantly decreased anxious-like behaviors and plasma corticosterone (CORT) levels, and ameliorated learning and memory impairments of ZDF rats after chronic psychological stress. ZBPYR also reduced the deposition of Aß in the mPFC, improved brain insulin resistance, and modulated the mTOR-autophagy pathway. SIGNIFICANCE: ZBPYR may be a potential therapeutic application for the treatment of DACD induced by chronic psychological stress.

Beta-sitosterol attenuates insulin resistance in adipose tissue via IRS-1/Akt mediated insulin signaling in high fat diet and sucrose induced type-2 diabetic rats.

In our previous study, we have shown that ß-sitosterol (SIT) enhances glycemic control by increasing the activation of insulin receptor (IR) and glucose transporter 4 (GLUT4) proteins in adipose tissue. However, the possible role of SIT on the regulation of post-receptor insulin signal transduction is not known. Hence, the study was aimed to assess the effects of SIT on IRS-1/Akt mediated insulin signaling molecules in high-fat diet and sucrose induced type-2 diabetic rats. An oral effective dose of SIT (20 mg/kg b.wt) was given for 30 days to high fat-fed type-2 diabetic rats to find out whether SIT regulates IRS-1/Akt pathway of insulin signaling. The results showed that SIT attenuated the insulin receptor substrate-1 serine phosphorylation (p-IRS-1Ser636) (P = 0.0003). However, it up-regulated the mRNA expression of IR (P = 0.0036) and post-receptor insulin signaling molecules such as IRS-1 (P < 0.0001), ß-arrestin-2 (P < 0.0058), Akt (P = 0.0008), AS160 (P = 0.0030) and GLUT4 (P < 0.0001) with a concomitant increase in the levels of IRS-1(P < 0.0001), p-IRS1-1Tyr632 (P = 0.0014), Akt (P < 0.0001), p-AktSer473/Thr308 (P = 0.0006; P < 0.0001), AS160 and p-AS160Thr642 (P < 0.0001) compared with type-2 diabetic rats. In Silico analysis was also performed and it showed that SIT possesses the greater binding affinity with ß-arrestin-2, c-Src, and IRS-1 as well as Akt proteins and proved to attenuate insulin resistance as this study coincides with in vivo findings. Our present study clearly shows that SIT attenuates high fat diet-induced detrimental changes in adipose tissue. Therefore, it is concluded from the present findings that, SIT could be used as potential therapeutic phytomedicine for the management of type-2 diabetes.

Polyphenol-rich Trapa quadrispinosa pericarp extract ameliorates high-fat diet induced non-alcoholic fatty liver disease by regulating lipid metabolism and insulin resistance in mice.

In China, Trapa quadrispinosa (also called water caltrop) has long been used as a function food and folk medicine to treat diabetes mellitus for years. In the present study, the extract of T. quadrispinosa pericarp (TQPE) which mainly contains hydrolysable tannins was prepared to investigate the potential therapeutic action in non-alcoholic fatty liver disease (NAFLD) mice induced by high fat-diet (HFD). After the administration of TQPE (15, 30 mg/kg/day) for 8 weeks, the increased weight of body and liver were significantly suppressed. TQPE also ameliorated liver lipid deposition and reduced lipids parameters of blood in mice. Moreover, TQPE attenuated oxidative stress and showed a hepatoprotective effect in mice. TQPE was also found to decrease the value of homeostatic model assessment for insulin resistance. In addition, TQPE administration increased the phosphorylation of AMP-activated protein kinase (AMPK) and Acetyl-CoA carboxylase (ACC) and inhibited sterol regulatory element-binding protein (SREBP) in the liver tissue. Meanwhile, TQPE elevated insulin receptor substrate-1 (IRs-1) and protein kinase B (Akt) phosphorylation. These results reflected that, as a nature product, TQPE is a potential agent for suppressing the process of NAFLD via regulation of the AMPK/SREBP/ACC and IRs-1/Akt pathways.

A Comparative Peptidomic Characterization of Cultured Skeletal Muscle Tissues Derived From db/db Mice.

As an important secretory organ, skeletal muscle has drawn attention as a potential target tissue for type 2 diabetic mellitus (T2DM). Recent peptidomics approaches have been applied to identify secreted peptides with potential bioactive. However, comprehensive analysis of the secreted peptides from skeletal muscle tissues of db/db mice and elucidation of their possible roles in insulin resistance remains poorly characterized. Here, we adopted a label-free discovery using liquid chromatography tandem mass spectrometry (LC-MS/MS) technology and identified 63 peptides (42 up-regulated peptides and 21 down-regulated peptides) differentially secreted from cultured skeletal muscle tissues of db/db mice. Analysis of relative molecular mass (Mr), isoelectric point (pI) and distribution of Mr vs pI of differentially secreted peptides presented the general feature. Furthermore, Gene ontology (GO) and pathway analyses for the parent proteins made a comprehensive functional assessment of these differential peptides, indicating the enrichment in glycolysis/gluconeogenesis and striated muscle contraction processes. Intercellular location analysis pointed out most precursor proteins of peptides were cytoplasmic or cytoskeletal. Additionally, cleavage site analysis revealed that Lysine (N-terminal)-Alanine (C-terminal) and Lysine (N-terminal)-Leucine (C-terminal) represents the preferred cleavage sites for identified peptides and proceeding peptides respectively. Mapped to the precursors' sequences, most identified peptides were observed cleaved from creatine kinase m-type (KCRM) and fructose-bisphosphate aldolase A (Aldo A). Based on UniProt and Pfam database for specific domain structure or motif, 44 peptides out of total were positioned in the functional motif or domain from their parent proteins. Using C2C12 myotubes as cell model in vitro, we found several candidate peptides displayed promotive or inhibitory effects on insulin and mitochondrial-related pathways by an autocrine manner. Taken together, this study will encourage us to investigate the biologic functions and the potential regulatory mechanism of these secreted peptides from skeletal muscle tissues, thus representing a promising strategy to treat insulin resistance as well as the associated metabolic disorders.

Chenodeoxycholic Acid Ameliorates AlCl3-Induced Alzheimer's Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats.

Insulin resistance is a major risk factor for Alzheimer's disease (AD). Chenodeoxycholic acid (CDCA) and synthetic Farnesoid X receptor (FXR) ligands have shown promising outcomes in ameliorating insulin resistance associated with various medical conditions. This study aimed to investigate whether CDCA treatment has any potential in AD management through improving insulin signaling. Adult male Wistar rats were randomly allocated into three groups and treated for six consecutive weeks; control (vehicle), AD-model (AlCl3 50 mg/kg/day i.p) and CDCA-treated group (AlCl3 + CDCA 90 mg/kg/day p.o from day 15). CDCA improved cognition as assessed by Morris Water Maze and Y-maze tests and preserved normal histological features. Moreover, CDCA lowered hippocampal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and amyloid-beta 42 (Aß42). Although no significant difference was observed in hippocampal insulin level, CDCA reduced insulin receptor substrate-1 phosphorylation at serine-307 (pSer307-IRS1), while increased protein kinase B (Akt) activation, glucose transporter type 4 (GLUT4), peroxisome proliferator-activated receptor gamma (PPARγ) and glucagon-like peptide-1 (GLP-1). Additionally, CDCA activated cAMP response element-binding protein (CREB) and enhanced brain-derived neurotrophic factor (BDNF). Ultimately, CDCA was able to improve insulin sensitivity in the hippocampi of AlCl3-treated rats, which highlights its potential in AD management.

A Limonoid, 7-Deacetoxy-7-Oxogedunin (CG-1) from Andiroba (Carapa guianensis, Meliaceae) Lowers the Accumulation of Intracellular Lipids in Adipocytes via Suppression of IRS-1/Akt-Mediated Glucose Uptake and a Decrease in GLUT4 Expression.

Limonoids are phytochemicals with a variety of biological properties. In the present study, we elucidated the molecular mechanism of suppression of adipogenesis in adipocytes by a limonoid, 7-deacetoxy-7-oxogedunin (CG-1) from Carapa guianensis (Meliaceae), known as andiroba. CG-1 reduced the accumulation of intracellular triglycerides in a concentration-dependent manner. The expression levels of the adipogenic, lipogenic, and lipolytic genes were decreased by CG-1 treatment, whereas the glycerol release level was not affected. When CG-1 was added into the medium during days 0-2 of 6-days-adipogenesis, the accumulation of intracellular lipids and the mRNA levels of the adipogenesis-related genes were decreased. In addition, the phosphorylation level of insulin receptor substrate-1 (IRS-1) and Akt in the early phase of adipocyte differentiation (within 1 day after initiating adipocyte differentiation) was reduced by CG-1. Furthermore, insulin-activated translocation of glucose transporter 4 to the plasma membranes in adipocytes was suppressed by CG-1, followed by decreased glucose uptake into the cells. These results indicate that an andiroba limonoid CG-1 suppressed the accumulation of intracellular lipids in the early phase of adipocyte differentiation through repression of IRS-1/Akt-mediated glucose uptake in adipocytes.

Lack of ClC-2 Alleviates High Fat Diet-Induced Insulin Resistance and Non-Alcoholic Fatty Liver Disease.

BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. This study aims to investigate whether chloride channel 2 (ClC-2) is involved in high fat diet (HFD)-induced NAFLD and possible molecular mechanisms. METHODS: ClC-2 expression was liver-specifically downregulated using adeno-associated virus in C57BL/6 mice treated with a chow diet or HFD for 12 weeks. Peripheral blood and liver tissues were collected for biochemical and pathological estimation respectively. Western blotting was applied to detect the protein expressions of lipid synthesis-related enzymes and the phosphorylated level of IRS-1, Akt and mTOR. RESULTS: ClC-2 mRNA level was significantly increased in patients with non-alcoholic steatohepatitis, which positively correlated with the plasma levels of alanine transaminase (ALT), aspartate transaminase (AST) and insulin. Knockdown of ClC-2 in liver attenuated HFD-induced weight gain, obesity, hepatocellular ballooning, and liver lipid accumulation and fibrosis, accompanied by reduced plasma free fatty acid (FFA), triglyceride (TG), total cholesterol (TC), ALT, AST, glucose and insulin levels and homeostasis model of insulin resistance (HOMA-IR) value. Moreover, HFD-treated mice lacking ClC-2 showed inhibited hepatic lipid accumulation via regulating lipid metabolism through decreasing sterol regulatory element binding protein (SREBP)-1c expression and its downstream targeting enzymes such as fatty acid synthase (FAS), HMG-CoA reductase (HMGCR) and acetyl-Coenzyme A carboxylase (ACCα). In addition, in vivo and in vitro results demonstrated that ClC-2 downregulation in HFD-treated mice or HepG2 cells increased the sensitivity to insulin via activation of IRS-1/Akt/mTOR signaling pathway. CONCLUSION: Our present study reveals a critical role of ClC-2 in regulating metabolic diseases. Mice lacking ClC-2 are associated with a remarkably beneficial metabolic phenotype, suggesting that decreasing ClC-2 may be an attractive therapeutic strategy for the treatment of NAFLD.

Polyphenol-rich ethyl acetate fraction isolated from Molineria latifolia ameliorates insulin resistance in experimental diabetic rats via IRS1/AKT activation.

This study aimed to evaluate the effect of ethyl acetate fraction (EAF) isolated from Molineria latifolia rhizome as dietary interventions for type 2 diabetes mellitus (T2DM) and its underlying molecular mechanisms in vivo. Experimental rats were induced by high fat diet feeding coupled with combined exposure to streptozotocin and nicotinamide. Treatment with EAF improved glucose tolerance and lipid profiles, but the insulin secretion was unaltered. Gene expression analyses on insulin/adipocytokine signalling-related genes demonstrated tissue-specific transcriptional responses. In skeletal muscle and liver tissues, Socs1, Tnf and Mapk8 showed consistent transcript regulation. Furthermore, hepatic translational analyses revealed sensitization on proximal insulin signalling, with reduced expression of IRS1 serine phosphorylation, increased IRS1 tyrosine phosphorylation and increased phospho-AKT (Ser473). The present findings suggested that EAF exerted its effect by modulating insulin signalling, potentially via IRS1/AKT activation. The pharmacological attributes of EAF may implicate its potential therapeutic applications for diabetes management.

Airborne PM2.5-Induced Hepatic Insulin Resistance by Nrf2/JNK-Mediated Signaling Pathway.

Animal and epidemiological studies have suggested that exposure to airborne particulate matter (PM) with an aerodynamic diameter less than 2.5 µm (PM2.5) is associated with the risk of developing type 2 diabetes. However, the mechanism underlying this risk is poorly understood. In the present study, we investigated the effects of PM2.5 exposure on glucose homeostasis and related signaling pathways in mice. Wild-type and nuclear factor erythroid 2-related factor 2 (Nrf2) knockout (Nrf2-/-) C57BL/6 male mice were exposed to either ambient concentrated PM2.5 or filtered air (FA) for 12 weeks through a whole-body PM exposure system. At the end of the exposure, we assessed liver damage, and performed metabolic studies, gene expressions, as well as molecular signal transductions to determine the signaling pathways involving oxidative responses, insulin signaling, and glucose metabolism. Our results indicated that PM2.5 exposure for 12 weeks caused significant liver damage as evidenced by elevated levels of aminotransferase (AST) and alanine aminotransferase (ALT). Furthermore, PM2.5 exposure induced impaired glucose tolerance and inhibited glycogen synthesis, leading to hepatic insulin resistance indicated by higher glucose levels, higher area under the curve (AUC), and homeostasis model assessment of insulin resistance (HOMA-IR) values. We further found that PM2.5 exposure significantly increased the expressions of Nrf2 and Nrf2-regulated antioxidant genes. Moreover, PM2.5 exposure activated the c-Jun N-terminal kinase (JNK) signaling pathway and increased insulin receptor substrate-1 (IRS-1) phosphorylation at Ser307, but reduced protein kinase B phosphorylation at Ser473. Taken together, our study demonstrated PM2.5 exposure triggered Nrf2-mediated oxidative responses and activated the JNK-mediated inhibitory signaling pathway, resulting in hepatic insulin resistance.

Rosiglitazone attenuates cognitive function via altering hippocampal IRS-1/Akt signaling pathways in ob/ob mouse / 中国药理学通报

Aim To identify alteration in key molecular components related to memory formation and insulin signaling in the hippocampus after rosiglitazone was in-jected into the ob/ob mice to test whether cognitive dysfunction was pharmacologically reversed by regula-tion of rosiglitazone. Methods The age-matched mice were divided into three groups ( n=18 ): Saline-trea-ted WT mice ( WT-Saline);Saline-treated ob/ob mice ( ob/ob-Saline) and RSG-treated ob/ob mice ( ob/ob-RSG) through intraperitoneal injection of rosiglitazone ( RSG) . The random glucose levels were measured for 10 days during the intraperitoneal injection period. No-vel object recognition was performed before mice were sacrificed. Western blot was implemented to evaluate the following proteins: BACE1, p-Tau, p-IRS1,IRS1, p-Akt and Akt in hippocampal tissues. The Aβ1-40 levels were detected by ELISA Kit. Results The random blood glucose levels were significantly re-duced in ob/ob-RSG compared with ob/ob-saline. RSG treatment led to an increase in hippocampus-de-pendent cognition of ob/ob mice according to the novel object recognition. The proteins levels of BACE1, p-Tau and Aβ were lowered in RSG-treated ob/ob mice. Furthermore, RSG treatment up-regulated hippocampal p-IRS1/IRS1 and p-Akt/Akt ratio. Conclusion Ros-iglitazone ameliorates cognitive deficits in ob/ob mice through up-regulating insulin signaling pathways in the hippocampus.