c-Jun NH2-terminal Kinase Activation Research Articles

HM-chromanone isolated from Portulaca oleracea L. alleviates insulin resistance and inhibits gluconeogenesis by regulating palmitate-induced activation of ROS/JNK in HepG2 cells.

Oxidative stress is a major cause of hepatic insulin resistance. This study investigated whether (E)-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (HM-chromanone), a homoisoflavonoid compound isolated from Portulaca oleracea L., alleviates insulin resistance and inhibits gluconeogenesis by reducing palmitate (PA)-induced reactive oxygen species (ROS)/c-Jun NH2-terminal kinase (JNK) activation in HepG2 cells. PA treatment (0.5mM) for 16h resulted in the highest production of ROS and induced insulin resistance in HepG2 cells. HM-chromanone, like N-acetyl-1-cysteine, significantly decreased PA-induced ROS production in the cells. HM-chromanone also significantly inhibited PA-induced JNK activation, showing a significant reduction in tumor necrosis factor and interleukin expression levels. Thus, HM-chromanone decreased the phosphorylation of Ser307 in insulin receptor substrate 1, while increasing phosphorylation of serine-threonine kinase (AKT), thereby restoring the insulin signaling pathway impaired by PA. HM-chromanone also significantly increased the phosphorylation of forkhead box protein O, thereby inhibiting the expression of gluconeogenic enzymes and reducing glucose production in PA-treated HepG2 cells. HM-chromanone also increased glycogen synthesis by phosphorylating glycogen synthase kinase-3β. Therefore, HM-chromanone may alleviate insulin resistance and inhibit gluconeogenesis by regulating PA-induced ROS/JNK activation in HepG2 cells.

Dexamethasone activates c-Jun NH2-terminal kinase (JNK) which interacts with GR and protects it from ubiquitin-mediated degradation in NSCLC cells

Dexamethasone-mediated pharmacological activation of the glucocorticoid receptor (GR) is widely used in the treatment regimen of hematological malignancies and solid cancers. However, DEX sensitivity towards patients primarily depends on the endogenous protein levels of GR. We observed that DEX treatment leads to an increase in GR protein levels despite inhibition of neo-protein synthesis in non-small cell lung cancer (NSCLC) cells. Mechanistically, DEX-stimulation concomitantly increased the JNK phosphorylation and GR protein levels, however the JNK stimulation preceds GR upregulation. Moreover, we also observed that DEX-mediated phosphorylation is partially mediated by upregulation in MEKK1 phosphorylation. Further, GR protein levels were significantly decreased in JNK inhibitor (JNKi, SP600125) treated cells whereas MG132 treatment restored GR levels indicating that DEX induced JNK activity regulated the GR protein levels through proteasomal-degradation pathway. Next, we showed that DEX led to JNK activation which physically interacts with GR and protects it from ubiquitination-mediated degradation. Furthermore, at basal level GR interacts with JNK in cytoplasm whereas upon DEX stimulation GR and pJNK both localized to nucleus and interact with each other. Next, we show that JNK-mediated GR stabilization affects its nuclear transcriptional functional activity in NSCLC cells. In line with these in vitro data, patient dataset analysis also shows that increased levels of both JNK and GR contributes towards better prognosis of NSCLC patients. Taken together, our data shows that DEX treatment may lead to positive feedback regulation of GR by activating JNK and thus highlights importance of GR-JNK crosstalk in NSCLC.

Isosteviol plays a protective role on hepatic ischemia and reperfusion injury in mice through MAPK/NF-κB signaling pathway.

Hepatic ischemia and reperfusion (I/R) injury is of common occurrence during liver surgery and transplantation, isosteviol (ISV) is an acid hydrolysate of stevioside, the major component of Stevia rebaudiana. Stevioside and its metabolites have been shown to have varieties of pharmacological activities, However, the effect of ISV on hepatic I/R injury has not determined. The purpose of this paper is to study the effect of ISV on mice with hepatic I/R injury and further investigate its underlying mechanism. The blood vessels supplying the left/middle lobe of the liver in mice were clamped to cause liver ischemia for 1h, and then removed the clamp to conduct reperfusion for 6 h. ISV or saline was injected intraperitoneally after reperfusion. The expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-10 in serum and tissues were evaluated by enzyme linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). The infiltration of neutrophils and macrophages into the liver tissue was determined by flow cytometry and myeloperoxidase. Liver hematoxylin-eosin (HE) staining, terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) and Annexin V probe were used to determine liver injury and hepatocyte apoptosis. western blots (WB) was used to investigate the activation of nuclear factor kappa-B (NF-κB) and c-JunNH2 terminal kinase (JNK), p38 and extracellular regulated protein kinase (ERK), while the expression of apoptosis-related proteins B-cell lymphoma-2 (BCL-2), BCL2-associated X protein (BAX), caspase-3 was detected. ISV reduced aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels to alleviate liver injury. ISV significantly reduced the release of inflammatory cytokines and the accumulation of liver neutrophils and macrophages. Meanwhile, ISV can promote the expression of anti-apoptosis-related protein BCL-2 and inhibit the expression of pro-apoptotic protein BAX and the activation of the protease caspase-3, and reduce the occurrence of hepatocyte apoptosis. Finally, ISV can reduce the phosphorylation level and activation of NF-κB, JNK, p38 and ERK. ISV inhibits the occurrence of inflammation and hepatocyte apoptosis through mitogen-activated protein kinase (MAPK)/NF-κB signaling pathway to relieve liver injury.

γ-mangostin attenuates amyloid-β42-induced neuroinflammation and oxidative stress in microglia-like BV2 cells via the mitogen-activated protein kinases signaling pathway

BackgroundOxidative stress (OS) and neuroinflammation are related to the pathogenic mechanism of Alzheimer's disease (AD). γ-Mangostin, a xanthone derivative obtained from mangosteen pericarp, could prevent their detrimental effects in AD. ObjectiveThis study focused on determining the role of γ-mangostin in protection against the amyloid-β (Aβ) 42 oligomers-induced OS and inflammation in microglial BV2 cells and investigating their precise mechanism of action. MethodsLactate dehydrogenase release assay and cell counting kit-8 assay were used to estimate the drug impact in BV2 cells and functional effects of the conditioned medium (supernatant of Aβ42 oligomers-/γ-mangostin-treated BV2 cells) on neuron-like SH-SY5Y and N2a cells. Quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay were carried out for detecting inflammatory factor contents. In addition, nitric oxide (NO) assay, an intracellular reactive oxygen species (ROS) assay, and qRT-PCR were performed to measure OS. Western blotting was used to explore the influence of γ-mangostin on the mitogen-activated protein kinase (MAPK) pathway. Resultsγ-Mangostin alleviated Aβ42 oligomer-induced inflammation by decreasing the levels of interleukin (IL) -6, IL-1β, and tumor necrosis factor-α, while attenuating OS through decreasing ROS/NO generation, and suppressing cyclo-oxygenase-2 and inducible NO synthase expressions. γ-Mangostin protected N2a and SH-SY5Ycells against the BV2 cell supernatant-induced toxicity following Aβ42 oligomer exposure. Furthermore, γ-mangostin inhibited c-Jun NH2-terminal kinase and p38 MAPK pathway activation. ConclusionThis study demonstrated that γ-mangostin could attenuate OS and inflammation resulting from Aβ42 oligomers, which also protect neurons against toxic medium-induced injury, suggesting that it may exert a protective effect in AD.

The Liver and Heart: How the Two Most Beloved “Babies” in the Human Body Communicate

The Liver and Heart: How the Two Most Beloved “Babies” in the Human Body Communicate

Effect of taxifolin/dapagliflozin combination on colistin-induced nephrotoxicity in rats

Colistin is an antimicrobial agent that is used in resistant gram-negative infections. Its most common dose-limiting adverse effect is nephrotoxicity. The objective of our study was to explore the possible effects of each of taxifolin and dapagliflozin alone and in combination on colistin-induced nephrotoxicity in rats. Sixty male rats were randomized into six groups: Control; colistin; colistin + taxifolin; colistin + dapagliflozin; colistin + carboxymethyl cellulose (CMC) and colistin + taxifolin + dapagliflozin. Dapagliflozin, taxifolin, and CMC were given daily for 7 days, 4 hours before colistin injection. Kidney weight/body weight ratio and renal function tests were determined. Renal tissue nerve growth factor-β (NGF-β), transforming growth factor beta 1 (TGF-β1), proinflammatory cytokines, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB) p65, signal transducer and activator of transcription 3 (STAT3), oxidative stress parameters, beclin-1 and c-Jun NH2-terminal kinase (JNK) activities were measured. Kidneys were examined histopathologically and immunohistochemically. Taxifolin and/or dapagliflozin induced significant improvement in the renal functions and oxidative stress parameters with significant increase in tissue Nrf2, STAT3 and NGF-β accompanied with significant decrease in kidney weight/body weight ratio, tissue proinflammatory cytokines, TGF-β1, NF-κB (p65), TLR4, beclin-1 and JNK activities and improved the histopathological picture when compared to rats treated with colistin alone. This improvement was significant with taxifolin/dapagliflozin combination compared to rats treated with each of these agents alone. So, we concluded that the combined use of taxifolin and dapagliflozin may confer a therapeutic tool for attenuation of colistin-induced nephrotoxicity.

Effect of dapagliflozin and/or L‐arginine on solid tumor model in mice: The interaction between nitric oxide, transforming growth factor‐beta 1, autophagy, and apoptosis

Nitric oxide was reported to play an essential role in various physiological and pathological processes in the body. Recent reports suggested that nitric oxide may affect the pathogenesis of cancer. Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor which is commonly used for type-2 diabetes mellitus management. The current work aimed to detect the potential impact of dapagliflozin and/or L-arginine on solid Ehrlich carcinoma (SEC) in mice. Six equal groups of male BALB/c mice were divided as follows: Control; SEC; SEC + Dapagliflozin; SEC + L-arginine; SEC + carboxymethyl cellulose, and SEC + Dapagliflozin + L-arginine group. Tumor volume, survival rate, tissue total nitrate/nitrite, paraoxonase-1, interleukin 1 alpha (IL-1α), and transforming growth factor-beta 1 (TGF-β1) were determined. Also, caspase 3, beclin-1, and c-Jun NH2-terminal kinase (JNK) activities were estimated in the tumor tissues. Sections of the tumor tissues were examined by histopathology and immunohistochemistry. Dapagliflozin and/or L-arginine induced a significant increment of the survival rate, tissue total nitrate/nitrite, paraoxonase-1, caspase 3, beclin-1 and JNK activities, significant lowering of the tumor volume, tissue TGF-β1, and IL-1α expression alongside an improvement of the histopathologic findings, versus the SEC group. Notably, the combination of dapagliflozin/L-arginine exerted more pronounced effects versus each agent alone. Dapagliflozin/L-arginine combination may confer a novel therapeutic line for cancer therapy.

Effect of L-thyroxine administration on long-term potentiation and accompanying mitogen-activated protein kinases in rats.

The present study investigated the differences in the activation of c-Jun NH2-terminal kinases (JNK), p38 mitogen-activated protein kinases (p38MAPK ), and extracellular signal-regulated kinases 1/2 (Erk1/2) 1hr after the induction of long-term potentiation (LTP) between rats with hyperthyroidism that was produced at two different stages of development. Hyperthyroidism was produced in rats by daily injections of L-thyroxine (T4, ip., 0.2mg/kg) to their dams for lactation period or to the rats itself during the young adult period. LTP was induced by application of high-frequency stimulation protocol. Five-min averages of the excitatory postsynaptic potential (EPSP) slopes and population spike (PS) amplitudes at the end of recording were averaged to measure the magnitude of LTP. Total and phosphorylated levels of Erk1/2, JNK, and P38-MAPK were assessed via western blotting in these hippocampi. LTP was found to be impaired in both groups of hyperthyroidisms, but this impairment observed together with increased expression and phosphorylation of ERK1/2, and increased phosphorylation of JNK in rats treated maternally with T4 compared to those treated adultly. These results suggest that excessiveness of thyroid hormone has longstanding effects on hippocampal function and may account for failed LTP in both early and relatively late stage of development depending on various molecular pathways, such as ERK1/2 and JNK.

Overexpression of cytochrome P450 2J2 and exogenous 11,12-EET suppress ER stress-induced apoptosis and promote autophagy in DM-induced rats

Background and Aims: When endoplasmic reticulum (ER) stress is excessive and/or prolonged, initiation of the apoptotic pathways is triggered by induction of C/EBP homologous protein (CHOP), activation of c-Jun NH2-terminal kinase (JNK), or cleavage of caspase-3. However, CYP epoxygenase 2J2 and its arachidonic acid metabolites epoxyeicosatrienoic acids (EETs) have a protective role on ER stress, little is known about the role of CYP2J2 and EETs in diabetic cardiomyopathy. In this study, we examined the effects of CYP2J2 overexpression and exogenous EETs on DM-induced rat hearts.

Inhibition of IRE1/JNK pathway in HK-2 cells subjected to hypoxia-reoxygenation attenuates mesangial cells-derived extracellular matrix production.

Endoplasmic reticulum (ER) stress and inflammatory responses play active roles in the transition of acute kidney injury (AKI) to chronic kidney disease (CKD). Inositol‐requiring enzyme 1 (IRE1) activates c‐Jun NH2‐terminal kinase (JNK) in ER stress. Tubular epithelial cells (TEC) are the main injury target and source of AKI inflammatory mediators. TEC injury may lead to glomerulosclerosis, however, the underlying mechanism remains unclear. Here, hypoxia/reoxygenation (H/R) HK‐2 cells were used as an AKI model. To determine the partial effects of TEC injury on the glomerulus, HK‐2 cells after H/R were co‐cultured with human renal mesangial cells (HRMC). H/R up‐regulated ER stress, IRE1/JNK pathway, IL‐6 and MCP‐1 in HK‐2 cells. Stimulation of HRMC with IL‐6 enhanced their proliferation and the expression of glomerulosclerosis‐associated fibronectin and collagen IV via signal transducer and activator of transcription 3 (STAT3) activation. Similar responses were observed in HRMC co‐cultured with HK‐2 cells after H/R. IRE1/JNK inhibition reversed these injury responses in HRMC. IRE1/JNK stable knock‐down in HK‐2 cells and shRNA‐mediated STAT3 depletion in HRMC confirmed their role in inflammation/glomerulosclerosis. These findings suggest that IRE1/JNK pathway mediates inflammation in TEC, affecting mesangial cells. The inhibition of this pathway could be a feasible approach to prevent AKI‐CKD transition.

Hepatocytic C-jun NH2 terminal kinase activity confers protection against cholestatic liver injury in mice

Hepatocytic C-jun NH2 terminal kinase activity confers protection against cholestatic liver injury in mice

COVID-19 transmission through host cell directed network of GPCR.

COVID-19 transmission through host cell directed network of GPCR.

Targeting DUSP16/TAK1 signaling alleviates hepatic dyslipidemia and inflammation in high fat diet (HFD)-challenged mice through suppressing JNK MAPK

Nonalcoholic fatty liver disease (NAFLD) is featured by hepatic steatosis, insulin resistance, lipid deposition and inflammation. However, the pathogenic mechanism of NAFLD is still poorly understood. Dual-specificity phosphatase 16 (DUSP16), a c-Jun N-terminal kinase-specific phosphatase, has been reported to negatively modulate the mitogen-activated protein kinases (MAPKs) signaling, and it has never been investigated in NAFLD progression. In the study, we identified that DUSP16 could directly interact with TAK1 in human hepatocytes. DUSP16 knockdown in the isolated primary hepatocytes stimulated by palmitate (PA) showed accelerated lipid deposition and inflammatory response, along with the exacerbated activation of c-Jun NH2-terminal kinase (JNK), Transforming growth factor β (TGF-β)-activated kinase (TAK1) and nuclear factor-κB (NF-κB) signaling pathways; however, the opposite results were detected in PA-treated hepatocytes with DUSP16 over-expression. The in vivo experiments confirmed that DUSP16 knockout significantly aggravated the metabolic disorder and insulin resistance in high fat diet (HFD)-challenged mice. In addition, HFD-provoked hepatic lipid accumulation and inflammation were further promoted in mice with DUSP16 knockout through the same molecular mechanism as detected in vitro. Herein, these findings demonstrated that DUSP16 could directly interact with TAK1 and negatively regulate JNK signaling to alleviate metabolic stress-induced hepatic steatosis, and thus could be considered as a promising new molecular target for NAFLD treatment.

PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death

5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the protocadherin 17 (PCDH17) gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between PCDH17 and 5-FU resistance in CRC remains unclear. Here, we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues, and high expression of PCDH17 was correlated with high BECN1 expression. Moreover, this expression profile contributed to superior prognosis and increased survival in CRC patients. Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death. Furthermore, autophagy played a dominant role in PCDH17-induced cell death, as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK. PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity. Mechanistically, we showed that c-Jun NH2-terminal kinase (JNK) activation was a key determinant in PCDH17-induced autophagy. The compound SP600125, an inhibitor of JNK, suppressed autophagy and 5-FU-induced cell death in PCDH17-reexpressing CRC cells. Taken together, our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death. PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.

Paxillin serine 178 phosphorylation in control of cell migration and metastasis formation through regulation of EGFR expression in breast cancer

Paxillin is a well-known multidomain scaffold protein that is involved in the regulation of cell-matrix adhesiondynamics, a process required for the tumor cell migration and invasion. Phosphorylation of the serine residue 178requires c-Jun NH2-terminal kinase (JNK) activation, which occurs downstream of epidermal growth factor receptor (EGFR)-mediated signaling and drives cell migration. In this study, we investigated the significance of paxillin Ser178 phosphorylation in breast cancer progression.We employed the rat mammary carcinoma MTLn3 cell line with which we established stabile variants of both wild type and mutant GFP-paxillin constructs. With those, we next performed several in vitro assays including cell proliferation, migration and focal adhesion dynamics. Finally, we monitored the metastatic spread of both cell line variants in an othrotopic mouse model for breast cancer.Here we show that expression of the phospho-defective mutant paxillinS178A in the metastatic mammary adenocarcinoma MTLn3 cell-line significantly decreased EGF-induced cell migration, which was correlated with impaired focal adhesion dynamics. Moreover, paxillinS178A attenuated lung metastasis formation in an orthotopic in vivo mammary gland tumor/metastasis model, demonstrating the importance of JNK-mediated paxillin phosphorylation in breast cancer progression. Expression of paxillinS178A caused a decrease in EGFR expression while re-expression of EGFR in MTLn3-paxillinS178A cells fully restored EGF-driven cell motility and focal adhesion dynamics. Furthermore, re-expression of EGFR in MTLn3-paxillinS178A rescued spontaneous metastasis from breast to lung.Overall our data show an important role for JNK-mediated paxillin Ser178 phosphorylation in the regulation of EGFR expression and thereby, in EGF-driven cell migration and metastasis formation.

6-Gingerol Attenuates Ischemia-Reperfusion-Induced Cell Apoptosis in Human AC16 Cardiomyocytes through HMGB2-JNK1/2-NF-κB Pathway.

Myocardial ischemia/reperfusion (I/R) injury is a key factor in deterioration of myocardial function. The c-Jun NH2-terminal kinase (JNK) activation and the transcription factor nuclear factor-kappaB (NF-κB) nuclear translocation have been found in I/R injury. 6-Gingerol, an important bioactive ingredient of ginger, has been reported to have cardiovascular pharmacological effects. However, the molecular mechanism through which it is beneficial is unclear. In this work, I/R induced the increase in the apoptosis and reactive oxygen species level in AC16 cardiomyocytes. 6-Gingerol administration decreased cardiomyocyte apoptosis and improved oxidative stress indexes. 6-Gingerol administration also inhibited I/R-induced HMGB2 expression upregulation and JNK activation and reduced Cleaved Poly(ADP-ribose) polymerases (PARP) and Caspase-3 expression. HMGB2 treatment mimicked the effect of I/R-induced cell damage, which was reversed by 6-gingerol administration. On the other hand, transcriptional activity of NF-κB was reduced in 6-gingerol treated cells. Thus, overall results indicated that 6-gingerol administration protected I/R-induced cardiomyocytes apoptosis via JNK/NF-κB pathway in the regulation of HMGB2. This work supported the efficacy of 6-gingerol on cardiovascular disease and partially revealed its mechanism, which was helpful for understanding the therapeutic effects of this natural drug.

Nanosecond pulsed electric fields enhanced chondrogenic potential of mesenchymal stem cells via JNK/CREB-STAT3 signaling pathway

BackgroundNanosecond pulsed electric fields (nsPEFs) can produce more significant biological effects than traditional electric fields and have thus attracted rising attention in developing medical applications based on short pulse duration and high field strength, such as effective cancer therapy. However, little is known about their effects on the differentiation of stem cells. Furthermore, mechanisms of electric fields on chondrogenic differentiation of mesenchymal stem cells (MSCs) remain elusive, and effects of electric fields on cartilage regeneration need to be verified in vivo. Here, we aimed to study the effects of nsPEFs on chondrogenic differentiation of MSCs in vitro and in vivo and further to explore the mechanisms behind the phenomenon.MethodsThe effects of nsPEF-preconditioning on chondrogenic differentiation of mesenchymal stem cells (MSCs) in vitro were evaluated using cell viability, gene expression, glycosaminoglycan (sGAG) content, and histological staining, as well as in vivo cartilage regeneration in osteochondral defects of rats. Signaling pathways were investigated with protein expression and gene expression, respectively.ResultsnsPEF-preconditioning with proper parameters (10 ns at 20 kV/cm, 100 ns at 10 kV/cm) significantly potentiated chondrogenic differentiation capacity of MSCs with upregulated cartilaginous gene expression and increased matrix deposition through activation of C-Jun NH2-terminal kinase (JNK) and cAMP-response element binding protein (CREB), followed by activation of downstream signal transducer and activator of transcription (STAT3). Implantation of nsPEF-preconditioned MSCs significantly enhanced cartilage regeneration in vivo, compared with implantation of non-nsPEF-preconditioned MSCs.ConclusionThis study demonstrates a unique approach of nsPEF treatment to potentiate the chondrogenic ability of MSCs through activation of JNK/CREB-STAT3 that could have translational potential for MSC-based cartilage regeneration.

Biochemical and Molecular Bases of Lead-Induced Toxicity in Mammalian Systems and Possible Mitigations.

The effects of lead exposure on mammals are reported to be devastating. Lead is present in all the abiotic environmental components such as brass, dust, plumbing fixtures, soil, water, and lead mixed imported products. Its continuous use for several industrial and domestic purposes has caused a rise in its levels, thereby posing serious threats to human health. The mechanisms involved in lead-induced toxicity primarily include free-radical-mediated generation of oxidative stress which directly imbalances the prooxidants and the antioxidants in body. The toxicity of lead involves damage primarily to major biomolecules (lipid, protein, and nucleic acids) and liver (hepatotoxicity), nervous system (neurotoxicity), kidney (nephrotoxicity) and DNA (genotoxicity), present in animals and humans. The activation of c-Jun NH2-terminal kinase, phosphoinositide 3-kinase, or Akt and p38 mitogen activated protein kinase signaling pathways are important for lead cytotoxicity. Lead increased apoptosis through signaling cascade and associated factors and significantly impairs cell differentiation and maturation. In addition, lead has great impact on metabolic pathways such as heme synthesis, thereby leading to the onset of anemia in lead exposed people. This review encompasses an updated account of varied aspects of lead-induced oxidative stress and the biomolecular consequences such as perturbations in physiological processes, apoptosis, carcinogenesis, hormonal imbalance, loss of vision, and reduced fertility and their possible remediation through synthetic (chelators) and natural compounds (plant-based principles). This paper is primarily concerned with the biomedical implications of lead-induced generation of free radical and the toxicity management in the mammalian system.

Glutathione S-transferase P deficiency induces glucose intolerance via JNK-dependent enhancement of hepatic gluconeogenesis.

Hepatic glutathione S-transferases (GSTs) are dysregulated in human obesity, nonalcoholic fatty liver disease, and diabetes. The multifunctional GST pi-isoform (GSTP) catalyzes the conjugation of glutathione with acrolein and inhibits c-Jun NH2-terminal kinase (JNK) activation. Herein, we tested whether GSTP deficiency disturbs glucose homeostasis in mice. Hepatic GST proteins were downregulated by short-term high-fat diet in wild-type (WT) mice concomitant with increased glucose intolerance, JNK activation, and cytokine mRNAs in the liver. Genetic deletion of GSTP did not affect body composition, fasting blood glucose levels, or insulin levels in mice maintained on a normal chow diet; however, compared with WT mice, the GSTP-null mice were glucose intolerant. In GSTP-null mice, pyruvate intolerance, reflecting increased hepatic gluconeogenesis, was accompanied by elevated levels of activated JNK, cytokine mRNAs, and glucose-6-phosphatase proteins in the liver. Treatment of GSTP-null mice with the JNK inhibitor 1,9-pyrazoloanthrone (SP600125) significantly attenuated pyruvate-induced hepatic gluconeogenesis and significantly altered correlations between hepatic cytokine mRNAs and metabolic outcomes in GSTP-null mice. Collectively, these findings suggest that hepatic GSTP plays a pivotal role in glucose handling by regulating JNK-dependent control of hepatic gluconeogenesis. Thus, hepatic GSTP-JNK dysregulation may be a target of new therapeutic interventions during early stages of glucose intolerance to prevent the worsening metabolic derangements associated with human obesity and its relentless progression to diabetes.

A new indanedione derivative alleviates symptoms of diabetes by modulating RAGE-NF-kappaB pathway in db/db mice

Accumulating evidence indicates that a number of tissues are damaged due to build-up of abnormal amount of Advanced Glycation End products (AGEs) in several diseases including diabetes. Currently AGE inhibitors are scarce in clinical use indicating a need for development of new anti-AGE agents. The aim of the current study is to identify the new AGE inhibitors and to decipher their mechanism of action for alleviating symptoms of diabetes in mice. Among several derivatives, one of the derivatives of indanedione, IDD-24 demonstrated highest inhibition of AGE formation and AGE mediated reactive oxygen species production in HepG-2 and mature 3T3-L1 adipocytes. In mice treated with IDD-24, reduction in serum AGE formation and expression of Receptor for AGEs (RAGE) was seen in IDD-24 treated db/db mice. In vivo, glycogen synthesis was also increased in muscle tissue. In adipocytes, anti-AGE agent restored AGEs' induced diminished glucose uptake in fat cells. Mice treated with IDD-24 exhibited increased glucose tolerance, increaed serum adiponectin levels and decreased insulin resistance. Deciphering mechanism of IDD-24 in diabetic mice, it was observed that nuclear factor-κB (NF-κB) and serine phosphorylation of Insulin receptor substrate-1 (IRS-1) declined, while diminished activation of c-Jun NH2-terminal kinase (JNK) appears to be partly responsible for restoration of insulin signaling. We conclude that IDD-24 can be a possible treatment target to address symptoms of diabetes.