Augusta University Discovers How Nrf2 Activator Preserves Sight in Retinal Degeneration Model

Augusta University Discovers How Nrf2 Activator Preserves Sight in Retinal Degeneration Model

AUGUSTA, Ga. (Dec. 6, 2017) – In an exciting breakthrough scientists have discovered that a common pain medication often prescribed for chronic pain  can help preserve vision in a model of severe, blinding retinal degeneration.

The vision preservation could activate one of the most powerful antioxidants in the human body known as Nrf2. This targets receptors to protect neurodegenerative diseases.

The drug is known as pentazocine, and is a receptor of sigma 1, a powerful natural antioxidant and Nrf2 activator.

“We are very, very pleased that we can now explore the mechanisms,”, mentioned Dr. Sylvia Smith, chair of the Department of Cellular Biology and Anatomy at the Medical College of Georgia at Augusta University and co-director of the James and Jean Culver Vision Discovery Institute at AU.

A new $1.14 million grant from the National Eye Institute is enabling research to explore the nrf2 protecting ability against sight-degrading conditions like retinitis pigmentosa, macular degeneration and glaucoma.

The protective power of activated Nrf2 through the Sigma 1 receptor (a well-established non-opioid pain receptor) is  an essential means to a healthy retina. Without the sigma 1 receptor, the Müller cells that support our photoreceptor cells are overpowered by oxidative stress (cellular damage) impacting oxygen supply and light to enable healthy vision.

The studies showing Pentazocine activating the sigma 1 receptor have been reported in the 2016  Journal Proceedings of the National Academy of Sciences.

 

How does it work?

The proteins Nrf2 and Keap1 and cul3, congregate quietly in the cell cytoplasm. Excess production of antioxidants by Nrf2 activation moves to the cell proteasome to be eliminated.

But if needed such as in a case of increased oxidative stressas manifest in conditions like retinitis pigmentosa and aging – Nrf2 and Keap1 response activates hundreds of natural antioxidants and cell protection genes.

“It can launch an almost amazing response to stress,” says Smith. “I think it’s arguably the most important antioxidant in cells.”

Dr. Bobby Thomas, neuroscientist in the MCG Department of Pharmacology and Toxicology, is a coinvestigator with Smith on these studies and also exploring the pathway in Parkinson’s disease.

Dr. Smith explains, “Millions of super metabolically active photoreceptor cells in the retina – some 125 million rods and 6 million cones – use a lot of oxygen constantly converting light into images. In the case of retinitis pigmentosa, it’s actually a genetic mutation that kills off the rods but their death creates so much oxidative stress that the cones also are lost in a “bystander” effect.

It’s the cones pentazocine appears to protect, which should enable individuals to maintain functional vision. Interestingly and inexplicably, the high oxidative stress increases the binding of pentazocine to the sigma 1 receptor.”

The studies are being done in mouse cone cells from the retina and the supportive Müller cells. Other collaborators include Dr. Graydon B. Gonsalvez, cell biologist in the MCG Department of Cellular Biology and Anatomy, and Dr. Alan Saul, neuroscientist and electrophysiologist in the MCG Department of Ophthalmology.

For further information contact https://www.augusta.edu/mcg/

1,2

1. Tang C, Li K, Yu Q, Jiang Q, Yao J, Cao C. Activation of Nrf2 by Ginsenoside Rh3 protects retinal pigment epithelium cells and retinal ganglion cells from UV. Free Radic Biol Med. February 2018. [PubMed]
2. Deliyanti D, Alrashdi S, Tan S, et al. Nrf2 Activation Is a Potential Therapeutic Approach to Attenuate Diabetic Retinopathy. Invest Ophthalmol Vis Sci. 2018;59(2):815-825. [PubMed]

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    New Protandim Study – International Formula Impact on Oxidative Stress

    New Protandim Study – International Formula Impact on Oxidative Stress

    LifeVantage Corporation announced a study on Protandim which was presented at the 2014 Experimental Biology Conference held April 26-30, 2014  in San Diego, California.

    Experimental Biology is an annual meeting attended by more than 14,000 scientists. The theme for 2014 was “Transforming the Future through Science.” The  Colorado State University study entitled Oxidative Stress is Decreased with Short-Term Protandim Use. The placebo-controlled double-blind study supplemented overweight/obese adults with ages from 45-69 for 30-days with LifeVantage’s Protandim international formula currently sold in Japan. The results indicated a significant reduction in markers of oxidative stress in subjects receiving this Protandim formulation.

    Dr. Shawn Talbott, LifeVantage Chief Science Officer of LifeVantage commented, “We are pleased to see clinical studies involving our unique products. This research will be added to our large and growing portfolio of scientific studies and builds on the growing collection of evidence supporting Nrf2 activation and oxidative stress reduction associated with Protandim. In addition, this study demonstrates that both of our formulations of Protandim are potent oxidative stress reducers. This allows us to offer people a powerful Nrf2 activator and oxidative stress reduction product in most jurisdictions.”

    Abstracts of the conference can be found at the Journal of the Federation of American Societies for Experimental Biology.Edit Post

    Rebecca Scalzo, Janelle Davis, Joseph Beals, Laurie Biela, Gregory Giordano, Hunter Paris Benjamin Miller, Karyn Hamilton, and Christopher Bell, (2014) Oxidative stress is decreased with short-term Protandim use when piperine is substituted for ashwagandha (LB399) FASEB J April 28:LB399.

    Other Protandim studies can be viewed at Protandim Pubmed Studies

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      Reversal of persistent fibrosis in aging by targeting nox4-Nrf2 redox imbalance – Sciencemag.org

      Reversal of persistent fibrosis in aging by targeting nox4-Nrf2 redox imbalance – Sciencemag.org

      Emphysema and honeycomb fibrosis

      Emphysema and honeycomb fibrosis (Photo credit: Pulmonary Pathology)

      A brand new article in Sciencemag.org presents a study demonstrating how pathological fibrosis increases with age, but how NRF2 activation in mice was able to reverse the damage and repair lung capacity and fibrosis (scar tissue) resolution.

      This is a promising study because the current treatments of pathological  and cystic fibrosis are costly and very time consuming. Persistent fibrosis in lungs of aged mice was caused by the loss of cellular redox balance. The mice in the study with low NRF2 expression had a higher incidence of progressive lung disease. Tissues from human lung samples demonstrated this same Nox4-Nrf2 imbalance.

      The abstract concludes with the following promising statement. “The studies suggest that restoration of Nox4-Nrf2 redox balance in myofibroblasts may be a therapeutic strategy in age-associated fibrotic disorders, potentially able to resolve persistent fibrosis or even reverse its progression.”

       

      Further research on the topic of Nrf2 and Fibrosis:

       

      Proteomic Analysis Reveals Novel Mechanisms by Which Polychlorinated Biphenyls Compromise the Liver Promoting Diet-Induced Steatohepatitis
      Hardesty JE, Wahlang B, Falkner KC, Shi H, Jin J, Zhou Y, Wilkey DW, Merchant ML, Watson CT, Feng W, Morris AJ, Hennig B, Prough RA and Cave MC
      Environmental pollution contributes to fatty liver disease pathogenesis. Polychlorinated biphenyl (PCB) exposures have been associated with liver enzyme elevation and suspected steatohepatitis in cohort studies. Male mice treated with the commercial PCB mixture, Aroclor 1260 (20 mg/kg), and fed high fat diet (HFD) for 12 weeks developed steatohepatitis. Receptor-based modes of action including inhibition of the epidermal growth factor (EGF) receptor were previously proposed, but other mechanisms likely exist. Objectives were to identify and validate the pathways, transcription factors, and mechanisms responsible for the steatohepatitis associated with PCB and HFD coexposures. Comparative proteomics analysis was performed in archived mouse liver samples from the aforementioned chronic exposure study. Pathway and transcription factor analysis (TFA) was performed, and selected results were validated. Liver proteomics detected 1103 unique proteins. Aroclor 1260 upregulated 154 and downregulated 93 of these. Aroclor 1260 + HFD coexposures affected 55 pathways including glutathione metabolism, intermediary metabolism, and cytoskeletal remodeling. TFA of Aroclor 1260 treatment demonstrated alterations in the function of 42 transcription factors including downregulation of NRF2 and key nuclear receptors previously demonstrated to protect against steatohepatitis (e.g., HNF4α, FXR, PPARα/δ/γ, etc.). Validation studies demonstrated that Aroclor 1260 significantly reduced HNF4α protein levels, while Aroclor 1260 + HFD reduced expression of the HNF4α target gene, albumin, in vivo. Aroclor 1260 attenuated EGF-dependent HNF4α phosphorylation and target gene activation in vitro. Aroclor 1260 reduced levels of NRF2, its target genes, and glutathione in vivo. Aroclor 1260 attenuated EGF-dependent NRF2 upregulation, in vitro. Aroclor 1260 indirectly activated hepatic stellate cells in vitro via induction of hepatocyte-derived TGFβ. PCB exposures adversely impacted transcription factors regulating liver protection, function, and fibrosis. PCBs, thus, compromised the liver by reducing its protective responses against nutritional stress to promote diet-induced steatohepatitis. The identified mechanisms by which environmental pollutants influence fatty liver disease pathogenesis require confirmation in humans.
      Nrf2 ameliorates DDC-induced sclerosing cholangitis and biliary fibrosis and improves the regenerative capacity of the liver
      Fragoulis A, Schenkel J, Herzog M, Schellenberg T, Jahr H, Pufe T, Trautwein C, Kensler TW, Streetz KL and Wruck CJ
      The Nrf2 pathway protects against oxidative stress and induces regeneration of various tissues. Here, we investigated whether Nrf2 protects from sclerosing cholangitis and biliary fibrosis and simultaneously induces liver regeneration. Diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was fed to Nrf2-KO mice (Nrf2-/-), mice with liver-specific hyper-activated Nrf2 (HKeap1-/-) and wild type (WT) littermates to induce cholangitis, liver fibrosis, and oval cell expansion. HKeap1-/--mice were protected from almost all DDC-induced injury compared to WT and Nrf2-/-. Liver injury in Nrf2-/- and WT mice was mostly similar, albeit Nrf2-/- suffered more from DDC diet as seen for several parameters. Nrf2 activity was especially important for the expression of the hepatic efflux transporters Abcg2 and Abcc2-4, which are involved in hepatic toxin elimination. Surprisingly, cell proliferation was more enhanced in Nrf2-/-- but also HKeap1-/--mice compared to WT. Interestingly, Nrf2-/--mice failed to sufficiently activate oval cell expansion after DDC-treatment and showed almost no resident oval cell population under control conditions. The resident oval cell population of untreated HKeap1-/--mice was increased and DDC-treatment resulted in a stronger oval cell expansion compared to WT. We provide evidence that Nrf2 activation protects from DDC-induced sclerosing cholangitis and biliary fibrosis. Moreover, our data establish a possible role of Nrf2 in oval cell expansion.
      Lonicera japonica Attenuates Carbon Tetrachloride-Induced Liver Fibrosis in Mice: Molecular Mechanisms of Action
      Miao H, Zhang Y, Huang Z, Lu B and Ji L
      Liver fibrosis is a worldwide clinical issue that generally causes hepatic cirrhosis. Lonicerae Japonicae Flos (dried flower buds of Lonicera japonica Thunb) is a traditional heat-clearing and detoxifying herbal medicine in China. This study aims to observe the protection of the water extract of Lonicerae Japonicae Flos (FL) from carbon tetrachloride (CCl)-induced liver fibrosis in mice. Liver fibrosis was induced in mice by intraperitoneal injection of 2 ml/kg CCl twice a week for 4 weeks. FL's attenuation of CCl-induced liver fibrosis in mice was evidenced by the results of Masson's trichrome and Sirius red staining, liver hydroxyproline content and serum amount of collagen IV. FL reduced hepatic stellate cells (HSCs) activation and reversed the epithelial-mesenchymal transition (EMT) process in mice treated with CCl. FL also alleviated liver oxidative stress injury and enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant signaling pathway in mice treated with CCl. Additionally, the main phenolic acids in FL including chlorogenic acid (CGA) and caffeic acid (CA) both reduced HSCs activation in vitro. In summary, FL attenuates CCl-induced liver fibrosis in mice by inhibiting HSCs activation, reversing EMT and reducing liver oxidative stress injury via inducing Nrf2 activation. CGA may be the main active compound contributing to the antifibrotic activity of FL.
      Fu Brick Tea Alleviates Chronic Kidney Disease of Rats with High Fat Diet Consumption through Attenuating Insulin Resistance in Skeletal Muscle
      Du H, Wang Q and Yang X
      Fu brick tea is a unique post-fermented dark tea product which undergoes controlled fermentation by "golden flower" fungus Eurotium cristatum. This study examined the effects of Fu brick tea aqueous extract (FTE) to alleviate insulin resistance, chronic kidney disease (CKD), and its regulatory mechanism in high fat diet (HFD)-induced obese rats. Sixteen-week administration of FTE at 400 mg/kg bw in rats significantly antagonized HFD-induced insulin resistance and CKD with elevations in serum leptin, TC, TG, LDL-C, blood urea nitrogen, uric acid, and creatinine levels, respectively ( p < 0.05). FTE treatment decreased the glomerular area, the thickness of basement membrane of renal tubules, and kidney fibrosis in HFD-fed rats. FTE alleviated insulin resistance through down-regulation of SIRP-α expression and activation of the insulin signaling Akt/GLUT4, FoxO1, and mTOR/S6K1 pathways in skeletal muscle. Furthermore, FTE prevented the HFD-caused kidney dysfunction and lipid or collagen accumulation, which was accompanied by the inhibition of GSK-3β phosphorylation and the action of PI3K/Akt and nuclear accumulation of Nrf2 in kidney. These results indicated that FTE alleviated insulin resistance and CKD through modulating insulin signal transduction cascades in skeletal muscle and enhanced the Nrf2 expression in kidney.
      Spermidine confers liver protection by enhancing NRF2 signaling through a MAP1S-mediated non-canonical mechanism
      Liu P, de la Vega MR, Dodson M, Yue F, Shi B, Fang D, Chapman E, Liu L and Zhang DD
      Spermidine, a naturally occurring polyamine, has been recognized as a caloric restriction mimetic that confers health benefits, presumably by inducing autophagy. Recent studies have reported that oral administration of spermidine protects against liver fibrosis and hepatocarcinogenesis through activation of MAP1S-mediated autophagy. NRF2 is a transcription factor that mediates cellular protection by maintaining the cell's redox, metabolic, and proteostatic balance. In this study, we demonstrate that spermidine is a non-canonical NRF2 inducer, and that MAP1S is a novel component of this non-canonical pathway of NRF2 activation. Mechanistically, MAP1S induces NRF2 signaling through two parallel mechanisms, both resulting in NRF2 stabilization: (i) MAP1S competes with KEAP1 for NRF2 binding via an ETGE motif, and (ii) MAP1S accelerates p62-dependent degradation of KEAP1 by the autophagy pathway. We further demonstrate that spermidine confers liver protection by enhancing NRF2 signaling. The importance of both NRF2 and p62-dependent autophagy in spermidine-mediated liver protection was confirmed using a carbon tetrachloride-induced liver fibrosis model in WT, Nrf2 , p62 and Nrf2 ;p62 mice, as the protective effect of spermidine was significantly reduced in NRF2 or p62 single knockout mice, and completely abolished in the double knockout mice. Our results demonstrate the pivotal role of NRF2 in mediating the health benefit of spermidine, particularly in the context of liver pathologies. This article is protected by copyright. All rights reserved.
      Disruption of CUL3-mediated ubiquitination causes proximal tubule injury and kidney fibrosis
      Saritas T, Cuevas CA, Ferdaus MZ, Kuppe C, Kramann R, Moeller MJ, Floege J, Singer JD and McCormick JA
      Cullin 3 (CUL3) is part of the ubiquitin proteasomal system and controls several cellular processes critical for normal organ function including the cell cycle, and Keap1/Nrf2 signaling. Kidney tubule-specific Cul3 disruption causes tubulointerstitial fibrosis, but little is known about the mechanisms. Therefore, we tested the hypothesis that dysregulation of the cell cycle and Keap1/Nrf2 pathway play a role in initiating the kidney injury upon Cul3 disruption. Cul3 deletion increased expression of cyclin E and p21, associated with uncontrolled proliferation, DNA damage, and apoptosis, all of which preceded proximal tubule injury. The cdk2-cyclin E inhibitor roscovitine did not prevent the effects of Cul3 deletion, but instead exacerbated the kidney injury. Injury occurred despite accumulation and activation of CUL3 substrate Keap1/Nrf2, proposed to be protective in kidney injury. Cul3 disruption led to progressive interstitial inflammation, functionally relevant renal fibrosis and death. Finally, we observed reduced CUL3 expression in several AKI and CKD mouse models and in fibrotic human kidney tissue. These data establish CUL3 knockout mice as a novel genetic CKD model in which dysregulation of the cell cycle may play a primary role in initiating tubule injury, and that CUL3 dysregulation could contribute to acute and fibrotic kidney disease.
      4-O-methylhonokiol ameliorates type 2 diabetes-induced nephropathy in mice likely by activation of AMPK-mediated fatty acid oxidation and Nrf2-mediated anti-oxidative stress
      Ma T, Zheng Z, Guo H, Lian X, Rane MJ, Cai L, Kim KS, Kim KT, Zhang Z and Bi L
      Diabetic nephropathy (DN) is one of the most serious long-term complications of type 2 diabetes (T2D). 4-O-methylhonokiol (MH) is one of the biologically active ingredients extracted from the Magnolia stem bark. In this study, we aim to elucidate whether treatment with MH can ameliorate or slow-down progression of DN in a T2D murine model and, if so, whether the protective response of MH correlates with AMPK-associated anti-oxidant and anti-inflammatory effects. To induce T2D, mice were fed normal diet (ND) or high fat diet (HFD) for 3 months to induce insulin resistance, followed by an intraperitoneal injection of STZ to induce hyperglycemia. Both T2D and control mice received gavage containing vehicle or MH once diabetes onset for 3 months. Once completing 3-month MH treatment, five mice from each group were sacrificed as 3 month time-point. The rest mice in each group were sacrificed 3 months later as 6 month time-point. In T2D mice, the typical DN symptoms were induced as expected, reflected by increased proteinuria, renal lipid accumulation and lipotoxic effects inducing oxidative stress, and inflammatory reactions, and final fibrosis. However, these typical DN changes were significantly prevented by MH treatment for 3 months and even at 3 months post-MH withdrawal. Mechanistically, MH renal-protection from DN may be related to lipid metabolic improvement and oxidative stress attenuation along with increases in AMPK/PGC-1α/CPT1B-mediated fatty acid oxidation and Nrf2/SOD2-mediated anti-oxidative stress. Results showed the preventive effect of MH on the renal oxidative stress and inflammation in DN.
      Losartan improves erectile function through suppression of corporal apoptosis and oxidative stress in rats with cavernous nerve injury
      Wang Y, Meng XH, Zhang QJ, Wang YM, Chen C, Wang YC, Zhou X, Ji CJ and Song NH
      This study aimed to investigate the functional and morphological changes in the corpus cavernosum after cavernous nerve (CN) injury or neurectomy and then reveal whether treatment with the angiotensin II Type 1 receptor antagonist losartan would improve erectile function as well as its potential mechanisms. A total of 48 10-week-old Sprague-Dawley male rats, weighing 300-350 g, were randomly divided into the following four groups (n = 12 per group): sham operation (Sham) group, bilateral cavernous nerve injury (BCNI) group, losartan-treated BCNI (BCNI + Losartan) group, and bilateral cavernous neurectomy (Neurectomy) group. Losartan was administered once daily by oral gavage at a dose of 30 mg kg day for 4 weeks starting on the day of surgery. The BCNI and the Neurectomy groups exhibited decreases in erectile response and increases in apoptosis and oxidative stress, compared with the Sham group. Treatment with losartan could have a modest effect on erectile function and significantly prevent corporal apoptosis and oxidative stress. The phospho-B-cell lymphoma 2 (Bcl-2)-associated death promoter (p-Bad)/Bad and phospho-the protein kinase B (p-AKT)/AKT ratios were substantially lower, while the Bcl-2-associated X protein (Bax)/Bcl-2 ratio, nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap-1), transforming growth factor-β 1 (TGF-β 1) and heme oxygenase-1 (HO-1) levels, and caspase-3 activity were higher in the BCNI and Neurectomy groups than in the Sham group. After 4 weeks of daily administration with losartan, these expression levels were remarkably attenuated compared with the BCNI group. Taken together, our results suggested that early administration of losartan after CN injury could slightly improve erectile function and significantly reduce corporal apoptosis and oxidative stress by inhibiting the Akt/Bad/Bax/caspase-3 and Nrf2/Keap-1 pathways.
      Rebaudioside A administration prevents experimental liver fibrosis: an in vivo and in vitro study of the mechanisms of action involved
      Casas-Grajales S, Reyes-Gordillo K, Cerda-García-Rojas CM, Tsutsumi V, Lakshman MR and Muriel P
      Rebaudioside A (Reb A) is a diterpenoid isolated from the leaves of Stevia rebaudiana (Bertoni) that has been shown to possess pharmacological activity, including anti-inflammatory and antioxidant properties. However, the ability of Reb A to prevent liver injury has not been evaluated. Therefore, we aimed to study the potential of Reb A (20 mg/kg; two times daily intraperitoneally) to prevent liver injury induced by thioacetamide (TAA) administration (200 mg/kg; three times per week intraperitoneally). In addition, cocultures were incubated with either lipopolysaccharide or ethanol. Antifibrotic, antioxidant and immunological responses were evaluated. Chronic TAA administration produced considerable liver damage and distorted the liver parenchyma with the presence of prominent thick bands of collagen. In addition, TAA upregulated the expression of α-smooth muscle actin, transforming growth factor-β1, metalloproteinases 9, 2 and 13, and nuclear factor kappaB and downregulated nuclear erythroid factor 2. Reb A administration prevented all of these changes. In cocultured cells, Reb A prevented the upregulation of genes implicated in fibrotic and inflammatory processes when cells were exposed to ethanol and lipopolysaccharide. Altogether, our results suggest that Reb A prevents liver damage by blocking oxidative processes via upregulation of nuclear erythroid factor 2, exerts immunomodulatory effects by downregulating the nuclear factor-κB system and acts as an antifibrotic agent by maintaining collagen content.
      CXA-10, a Nitrated Fatty Acid, is Renoprotective in Deoxycorticosterone Acetate-Salt Nephropathy
      Arbeeny C, Ling H, Smith MM, O'Brien S, Wawersik S, Ledbetter SR, McAlexander MA, Willette R and Jorkasky D
      Underlying pathogenic mechanisms in chronic kidney disease (CKD) include chronic inflammation, oxidant stress, and matrix remodeling associated with dysregulated NF-ĸB, NRF2 and SMAD signaling pathways, respectively. Important cytoprotective mechanisms activated by oxidative inflammatory conditions are mediated by nitrated fatty acids (NO2-FA) that covalently modify proteins to limit inflammation and oxidant stress. In the present study we evaluated the effects of chronic treatment with CXA-10 (10-nitro-9(E)-octadec-9-enoic acid) in the uni-nephrectomized deoxycorticosterone acetate (DOCA)-high salt mouse model of CKD. After 4 weeks of treatment, CXA-10 (2.5 mpk, p.o.) significantly attenuated increases in plasma cholesterol, heart weight and kidney weight observed in the model without impacting systemic arterial blood pressure. CXA-10 also reduced albuminuria, nephrinuria, glomerular hypertrophy and glomerulosclerosis in the model. Inflammatory (MCP-1) and fibrosis (collagen, fibronectin, PAI-1 and osteopontin) renal biomarkers were significantly reduced in the CXA-10 (2.5 mpk) group. The anti-inflammatory and anti-fibrotic effects, as well as glomerular protection were not observed in the enalapril treated group. Also, CXA-10 appears to exhibit hormesis as all protective effects observed in the low dose group were absent in the high dose group (12.5 mpk). Taken together, these findings demonstrate that at the appropriate dose, the nitrated fatty acid CXA-10 exhibits anti-inflammatory and anti-fibrotic effects in the kidney and limits renal injury in a model of CKD.
      Ligustrazin increases lung cell autophagy and ameliorates paraquat-induced pulmonary fibrosis by inhibiting PI3K/Akt/mTOR and hedgehog signalling via increasing miR-193a expression
      Liu MW, Su MX, Tang DY, Hao L, Xun XH and Huang YQ
      Reactive oxygen species (ROS) levels largely determine pulmonary fibrosis. Antioxidants have been found to ameliorate lung fibrosis after long-term paraquat (PQ) exposure. The effects of antioxidants, however, on the signalling pathways involved in PQ-induced lung fibrosis have not yet been investigated sufficiently. Here, we examined the impacts of ligustrazin on lung fibrosis, in particular ROS-related autophagy and pro-fibrotic signalling pathways, using a murine model of PQ-induced lung fibrosis.
      Protective Effect of Extract against Irradiation-Induced Acute Hepatitis
      Kuo TH, Kuo YH, Cho CY, Yao CJ, Lai GM and Chuang SE
      Radiotherapy for treatment of hepatocellular carcinoma causes severe side effects, including acute hepatitis and chronic fibrosis. Complementary and alternative medicine (CAM) has emerged as an important part of integrative medicine in the management of diseases. (AC), a valuable medicinal fungus originally found only in Taiwan, has been shown to possess anti-oxidation, vaso-relaxtation, anti-inflammation, anti-hepatitis, and anti-cancer effects. In this paper we evaluate the protective effects of ethanol extract of (ACE) against radiotoxicity both in normal liver cell line CL48 and in tumor-bearing mice. In CL48, ACE protects cells by eliminating irradiation-induced reactive oxygen species (ROS) through the induction of Nrf2 and the downstream redox system enzymes. The protective effect of ACE was also demonstrated in tumor-bearing mice by alleviating irradiation-induced acute hepatitis. ACE could also protect mice from CCl₄-induced hepatitis. Since both radiation and CCl₄ cause free radicals, these results indicate that ACE likely contains active components that protect normal liver cells from free radical attack and can potentially benefit hepatocellular carcinoma (HCC) patients during radiotherapy.
      Fasting reduces oxidative stress, mitochondrial dysfunction and fibrosis induced by renal ischemia-reperfusion injury
      Rojas-Morales P, León-Contreras JC, Aparicio-Trejo OE, Reyes-Ocampo JG, Medina-Campos ON, Jiménez-Osorio AS, González-Reyes S, Marquina-Castillo B, Hernández-Pando R, Barrera-Oviedo D, Sánchez-Lozada LG, Pedraza-Chaverri J and Tapia E
      Food deprivation protects against ischemia-reperfusion (IR) injury through unknown mechanisms. In an experimental rat model of acute IR injury, we found that preoperative fasting for 3 days protects rats from tubular damage and renal functional decline by increasing antioxidant protection independently of the NF-E2-related factor 2 (Nrf2), and by maintaining mitochondrial morphology and function. In addition, further analysis revealed that fasting protects against tubulointerstitial fibrosis. In summary, our results point out to fasting as a robust nutritional intervention to limit oxidative stress and mitochondrial dysfunction in early acute kidney injury and also to promote long-term protection against fibrosis.
      Effects of the SGLT-2 Inhibitor Canagliflozin on Adenine-Induced Chronic Kidney Disease in Rats
      Ali BH, Al Salam S, Al Suleimani Y, Al Za'abi M, Abdelrahman AM, Ashique M, Manoj P, Adham SA, Hartmann C, Schupp N and Nemmar A
      SGLT-2 inhibitors have been shown to be nephroprotective in diabetes. Here, we examined if one of these drugs (canagliflozin) could also ameliorate non-diabetic chronic kidney disease (CKD).
      Amelioration of diabetic nephropathy using pomegranate peel extract-stabilized gold nanoparticles: assessment of NF-κB and Nrf2 signaling system
      Manna K, Mishra S, Saha M, Mahapatra S, Saha C, Yenge G, Gaikwad N, Pal R, Oulkar D, Banerjee K and Das Saha K
      Diabetic nephropathy (DN), an end-stage renal disorder, has posed a menace to humankind globally, because of its complex nature and poorly understandable intricate mechanism. In recent times, functional foods as potential health benefits have been gaining attention of consumers and researchers alike. Rich in antioxidants, the peel and seed of pomegranate have previously demonstrated protection against oxidative-stress-related diseases, including cardiovascular disorders, diabetes, and cancer.

      JOIN OUR COMMUNITY.

      Reach Us

      Our mission is to provide an impartial review of the emerging research regarding Nrf2 activation.

      We welcome the involvement of those who have published peer review studies in this field. 

      Should you wish to contact us, please leave a message using the adjacent form. 

       

        Researching Nrf2? Leave us a message to collaborate

        Inflammation: A Major Contributor to Disease and Aging. Can Nrf2 Help Reduce It?

        Inflammation: A Major Contributor to Disease and Aging. Can Nrf2 Help Reduce It?

        English: PET scan of a human brain with Alzhei...

        As the boomer generation ages, it is probable that there will be more posts such as the one I saw this week from a friend on Facebook. Their plea was for suggestions and recommendations for a good solution to help alleviate the pain they were experiencing from inflammation.

        Externally, inflammation can be recognized by redness, swelling and pain. Internally, it is a lot more difficult to recognize and may well go undetected for long periods of time.  The effects of inflammation can also range from minor to chronic. An example of a minor case of inflammation may include bacteria causing an infection such as from a splinter piercing the skin. The more serious chronic inflammation may be a common factor in many age-related diseases such as Diabetes, arthritis, heart disease, cancer or Alzheimer’s.

        There are over 500 results on Pubmed.gov when searching for NRF2 and inflammation. A couple of examples of the positive role that NRF2 had on inflammation.

        The first study we will highlight is one called “Transcription Factor Nrf2 Regulates Inflammation” which was published in the Journal of Molecular and Cellular Biology. This inflammation. study dates back to 2003 in which two groups of mice with pleurisy were tested. The one group was treated with a Nrf2 activator, cyclooxygenase 2 inhibitor NS-398 the other group was not treated.  The conclusion of the study shows that the mice with elevated NRF2 had less inflammation than the mice that were not treated.

        “Administration of 15d-PGJ into the pleural space of NS-398-treated wild-type mice largely counteracted both the decrease in PrxI and persistence of neutrophil recruitment. In contrast, these changes did not occur in the Nrf2-deficient mice. These results demonstrate that Nrf2 regulates the inflammation process downstream of 15d-PGJ by orchestrating the recruitment of inflammatory cells and regulating the gene expression within those cells.”

        The following study “Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis.” Published in the
        European Journal of Immunology. shows the interaction between NRF2 and the inflammation-causing protein called inflammasome.

        Quoting from the study, “Here we have identified the oxidative stress-responsive transcription factor NF-E2-related 2 (Nrf2) as an essential positive regulator of inflammasome activation and IL-1-mediated vascular inflammation. We show that cholesterol crystals, which accumulate in atherosclerotic plaques, represent an endogenous danger signal that activates Nrf2 and the NLRP3 inflammasome.”

        So, in response to my friend looking for solutions to their inflammation concerns, we suggest researching further in Pubmed and other reputable journals as well as getting the advice of a healthcare professional.

        Here are the latest Nrf2 Studies regarding inflammation: 

         

        Neuro-protective effect of monomethyl fumarate on ischemia reperfusion injury in rats: Role of Nrf2/HO1 pathway in peri-infarct region
        Singh D, Reeta KH, Sharma U, Jagannathan NR, Dinda AK and Gupta YK
        Post stroke recanalization has been associated with increased risk of oxidative stress. Stimulating endogenous antioxidant pathway by activation of nuclear factor erythroid-2-related factor-2 (Nrf2) plays a key role in neuronal defense against inflammation and oxidative stress in penumbra. Here, we explored whether monomethyl fumarate (MMF) could produce neuro-protection after ischemia/reperfusion (I/R) injury via Nrf2/HO1 activation. In male SD rats, middle cerebral artery was occluded for 90 min and confirmed using Laser Doppler flowmeter. MMF (10, 20 and 40 mg/kg) was administered in two divided doses at 30 min post ischemia and 5-10 min after reperfusion. After 24 h, effect on neurobehavioral parameters, infarct damage by TTC staining and MRI, oxidative stress and inflammatory cytokines were assessed. Expression studies of nuclear Nrf2 and cytoplasmic HO1 were performed in peri-infarct cortex and striatum; followed by dual immunofluorescence study to check the specific cell type. I/R induced neurobehavioral deficits and infarct damage were significantly (p < 0.05) attenuated by MMF (20 and 40 mg/kg). MMF, 20 mg/kg, significantly normalized I/R induced altered redox status and increased levels of TNF-α, IL-1β in the ipsilateral cortex. MRI data showed significantly reduced infarct in cortex but not in striatum after MMF treatment. Expression of nuclear Nrf2 and cytoplasmic HO1 were significantly (p < 0.05) increased in peri-infarct cortex after treatment with MMF. Additionally, dual immunofluorescence showed increased Nrf2 expression in neurons and HO1 expression in neurons as well as astrocytes in peri-infarct cortex after MMF treatment. Our results show the neuro-protective potential of MMF probably by restricting the progression of damage from striatum to cortex through activation of Nrf2/HO1 pathway in peri-infarct cortex.
        4-O-methylhonokiol ameliorates type 2 diabetes-induced nephropathy in mice likely by activation of AMPK-mediated fatty acid oxidation and Nrf2-mediated anti-oxidative stress
        Ma T, Zheng Z, Guo H, Lian X, Rane MJ, Cai L, Kim KS, Kim KT, Zhang Z and Bi L
        Diabetic nephropathy (DN) is one of the most serious long-term complications of type 2 diabetes (T2D). 4-O-methylhonokiol (MH) is one of the biologically active ingredients extracted from the Magnolia stem bark. In this study, we aim to elucidate whether treatment with MH can ameliorate or slow-down progression of DN in a T2D murine model and, if so, whether the protective response of MH correlates with AMPK-associated anti-oxidant and anti-inflammatory effects. To induce T2D, mice were fed normal diet (ND) or high fat diet (HFD) for 3 months to induce insulin resistance, followed by an intraperitoneal injection of STZ to induce hyperglycemia. Both T2D and control mice received gavage containing vehicle or MH once diabetes onset for 3 months. Once completing 3-month MH treatment, five mice from each group were sacrificed as 3 month time-point. The rest mice in each group were sacrificed 3 months later as 6 month time-point. In T2D mice, the typical DN symptoms were induced as expected, reflected by increased proteinuria, renal lipid accumulation and lipotoxic effects inducing oxidative stress, and inflammatory reactions, and final fibrosis. However, these typical DN changes were significantly prevented by MH treatment for 3 months and even at 3 months post-MH withdrawal. Mechanistically, MH renal-protection from DN may be related to lipid metabolic improvement and oxidative stress attenuation along with increases in AMPK/PGC-1α/CPT1B-mediated fatty acid oxidation and Nrf2/SOD2-mediated anti-oxidative stress. Results showed the preventive effect of MH on the renal oxidative stress and inflammation in DN.
        Antioxidant and immunomodulatory activity induced by stevioside in liver damage: In vivo, in vitro and in silico assays
        Casas-Grajales S, Ramos-Tovar E, Chávez-Estrada E, Alvarez-Suarez D, Hernández-Aquino E, Reyes-Gordillo K, Cerda-García-Rojas CM, Camacho J, Tsutsumi V, Lakshman MR and Muriel P
        Stevioside is a diterpenoid obtained from the leaves of Stevia rebaudiana (Bertoni) that exhibits antioxidant, antifibrotic, antiglycemic and anticancer properties. Therefore, we aimed to study whether stevioside has beneficial effects in liver injury induced by long-term thioacetamide (TAA) administration and investigated the possible underlying molecular mechanism using in vivo, in vitro and in silico approaches.
        Modulation of cerulein-induced pancreatic inflammation by hydroalcoholic extract of curry leaf (Murraya koenigii)
        Khurana A, Sikha MS, Ramesh K, Venkatesh P and Godugu C
        This study was performed to study the in vitro and in vivo efficacy of hydroalcoholic extract of curry leaf (CLE) rich in carbazole alkaloids, against LPS-induced inflammation in Raw 264.7 macrophages and cerulein-induced acute pancreatitis, respectively. CLE was characterized by Fourier-transform infrared (FTIR) and liquid chromatography-mass spectrometry. Raw 264.7 cells were stimulated with LPS (2 μg/ml) and treated with CLE. The animals were treated with two doses of CLE (100 and 300 mg/kg). Plasma biochemistry, tissue lipid peroxidation, cytokines, and histological examination were evaluated. CLE was found to decently scavenge the activity of DPPH radical. It dose dependently suppressed nitrite production and oxidative stress in macrophages. CLE alleviated LPS-induced inflammation in macrophages as evident from the results of various inflammatory cytokines (IL-1β, IL-6, and TNF-α). In vivo, CLE reduced cerulein-induced pancreatic edema. CLE significantly abrogated the cerulein-induced lipid peroxidation, nitrite, MPO, and GSH levels. The inflammatory cytokines and p65-NFκB activity were significantly reduced by CLE. Mechanistically, CLE reduced the expression of NT, MPO, IL-1β, ICAM-1, and COX-2, and increased the expression of Nrf2. It reduced distant organ damage markers as well. We report for the first time that CLE holds substantial potential for the prevention of acute pancreatitis.
        Activation of Nrf2 signaling by Icariin protects against 6-OHDA-induced neurotoxicity
        Zhu L, Li D, Chen C, Wang G, Shi J and Zhang F
        Nerve damage is the main pathogenesis of neurodegenerative diseases. Recently, in search for a promising therapeutic target that could stop Neurodegenerative diseases progression, the anti-oxidant signaling pathway regulated by transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has attracted new hopes. Icariin (ICA) exhibited a battery of pharmacological properties, including anti-oxidation, anti-aging, anti-inflammation activities. Recent studies indicate ICA conferred neuroprotection against brain ischemic injury and neurodegenerative diseases. However, the mechanisms underlying ICA-mediated neuroprotection remain unelucidated. This study aimed at analyzing whether ICA evoked neuroprotection against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in PC12 cells and the mechanisms of action. ICA protected against 6-OHDA-induced neuronal damage, accompanied by the inhibition of cell apoptosis through the marked decreases in the Bax/Bcl-2 ratio, cytochrome C release and caspase-3 cleavage. In addition, the activation of Nrf2 signaling pathway was responsible for ICA-mediated neuroprotection. First, ICA relieved reactive oxygen species (ROS) accumulation and increased superoxide dismutase (SOD) generation via the activation of Nrf2 signaling. Second, Nrf2 knockdown by siRNA reversed ICA-mediated neuroprotection. These experiments offer a promising avenue to validate Nrf2 for a compelling target with ICA as a therapeutic strategy to enhance endogenous brain defense mechanisms against Neurodegenerative diseases. (Delete this sentence and change to "Together, these results suggested ICA-mediated neuroprotection might be attributable to the activation of Nrf2 pathway via anti-oxidative signaling pathways.") This article is protected by copyright. All rights reserved.
        Differential induction of nuclear factor-like 2 signature genes with toll-like receptor stimulation
        Ingram S, Mengozzi M, Sacre S, Mullen L and Ghezzi P
        Inflammation is associated with production of reactive oxygen species (ROS) and results in the induction of thioredoxin (TXN) and peroxiredoxins (PRDXs) and activation of nuclear factor-like 2 (Nrf2). In this study we have used the mouse RAW 264.7 macrophage and the human THP-1 monocyte cell line to investigate the pattern of expression of three Nrf2 target genes, PRDX1, TXN reductase (TXNRD1) and heme oxygenase (HMOX1), by activation of different Toll-like receptors (TLRs). We found that, while the TLR4 agonist lipopolysaccharide (LPS) induces all three genes, the pattern of induction with agonists for TLR1/2, TLR3, TLR2/6 and TLR7/8 differs depending on the gene and the cell line. In all cases, the extent of induction was HMOX1>TXNRD1>PRDX1. Since LPS was a good inducer of all genes in both cell lines, we studied the mechanisms mediating LPS induction of the three genes using mouse RAW 264.7 cells. To assess the role of ROS we used the antioxidant N-acetylcysteine (NAC). Only LPS induction of HMOX1 was inhibited by NAC while that of TXNRD1 and PRDX1 was unaffected. These three genes were also induced by phorbol myristate acetate (PMA), a ROS-inducer acting by activation of protein kinase C (PKC). The protein kinase inhibitor staurosporine inhibited the induction of all three genes by PMA but only that of HMOX1 by LPS. This indicates that activation of these genes by inflammatory agents is regulated by different mechanisms involving either ROS or protein kinases, or both.
        Embelin attenuates cisplatin-induced nephrotoxicity: Involving inhibition of oxidative stress and inflammation in addition with activation of Nrf-2/Ho-1 pathway
        Qin X, Meghana K, Sowjanya NL, Sushma KR, Krishna CG, Manasa J, Sita GJA, Gowthami M, Honeyshmitha D, Srikanth G and SreeHarsha N
        In kidneys, elevated levels of inflammatory cytokines and oxidative stress were observed in nephrotoxicity triggered by cisplatin. Embelin has the anti-inflammatory property. It also got anti-tumorigenic and antioxidant properties. In this research, we analyzed the actions of embelin on nephrotoxicity triggered by cisplatin and vital actions by which it increases antioxidant actions and corrects the inflammation after embelin administration during nephrotoxicity triggered by cisplatin. Kidney function markers including blood urea nitrogen; serum creatinine; the markers of oxidative stress like malondialdehyde (MDA), antioxidant systems like glutathione, superoxide dismutase, glutathione S-transferase, catalase, and glutathione reductase; inflammation markers like nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-1 beta (IL-1β); and the extent of nuclear factor-erythroid-2 p45-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) were determined. Histopathology studies of kidneys were also used to analyze nephrotoxicity induced by cisplatin. Treatment with embelin (25 and 50 mg/kg) upgrades the function of kidneys, by elevating antioxidant levels and reducing the MDA level in cisplatin-administered rats. Embelin treatment demonstrated a significant curtailment of oxidative stress as well as increased the activities of antioxidant enzymes, endogenously. Cisplatin upregulates cytokines (i.e., TNF-α and IL-1β) and NF-κB, and downregulates Nrf2 and HO-1. Embelin treatment also reduced the infiltration of neutrophils in the renal tubules and thus reduced the level of histological impairment. The outcome of this study implements that the signaling pathway of Nrf2/HO-1 may be the principal mechanism of embelin for protection from nephrotoxicity triggered by cisplatin, and thus, embelin diminishes oxidative stress and inflammation by impeding NF-κB. © 2019 BioFactors, 2019.
        CXA-10, a Nitrated Fatty Acid, is Renoprotective in Deoxycorticosterone Acetate-Salt Nephropathy
        Arbeeny C, Ling H, Smith MM, O'Brien S, Wawersik S, Ledbetter SR, McAlexander MA, Willette R and Jorkasky D
        Underlying pathogenic mechanisms in chronic kidney disease (CKD) include chronic inflammation, oxidant stress, and matrix remodeling associated with dysregulated NF-ĸB, NRF2 and SMAD signaling pathways, respectively. Important cytoprotective mechanisms activated by oxidative inflammatory conditions are mediated by nitrated fatty acids (NO2-FA) that covalently modify proteins to limit inflammation and oxidant stress. In the present study we evaluated the effects of chronic treatment with CXA-10 (10-nitro-9(E)-octadec-9-enoic acid) in the uni-nephrectomized deoxycorticosterone acetate (DOCA)-high salt mouse model of CKD. After 4 weeks of treatment, CXA-10 (2.5 mpk, p.o.) significantly attenuated increases in plasma cholesterol, heart weight and kidney weight observed in the model without impacting systemic arterial blood pressure. CXA-10 also reduced albuminuria, nephrinuria, glomerular hypertrophy and glomerulosclerosis in the model. Inflammatory (MCP-1) and fibrosis (collagen, fibronectin, PAI-1 and osteopontin) renal biomarkers were significantly reduced in the CXA-10 (2.5 mpk) group. The anti-inflammatory and anti-fibrotic effects, as well as glomerular protection were not observed in the enalapril treated group. Also, CXA-10 appears to exhibit hormesis as all protective effects observed in the low dose group were absent in the high dose group (12.5 mpk). Taken together, these findings demonstrate that at the appropriate dose, the nitrated fatty acid CXA-10 exhibits anti-inflammatory and anti-fibrotic effects in the kidney and limits renal injury in a model of CKD.
        Astragaloside IV Protects Against Oxidized Low-Density Lipoprotein (ox-LDL)-Induced Endothelial Cell Injury by Reducing Oxidative Stress and Inflammation
        Zhu Z, Li J and Zhang X
        BACKGROUND Endothelial injury is the main mechanism of atherosclerosis, and is caused by oxidized low-density lipoprotein (ox-LDL). Astragaloside IV (AS-IV) is the primary active ingredient of the Chinese herb Huangqi, and exhibits antioxidant and anti-inflammatory properties in cardiovascular diseases. This study investigated the protective effect of AS-IV in human umbilical vein endothelial cells (HUVECs). MATERIAL AND METHODS HUVEC cells were induced with ox-LDL to establish an in vitro atherosclerosis model. Then HUVECs were pretreated for 1 h with AS-IV at different concentrations (10, 20, and 50 μM) and then exposed to ox-LDL (100 μg/mL) for 48 h. The cell viability, lactate dehydrogenase (LDH) release, apoptosis, migration, intracellular reactive oxygen species (ROS), and NADPH oxidase activity of HUVECs were measured. qRT-PCR was performed to measure the mRNA expressions of Nrf2, HO-1, TNFalpha, and IL-6. Enzyme-linked immunosorbent assay (ELISA) was performed to measure the supernatant contents of TNFalpha and IL-6. RESULTS Exposure of HUVECs to ox-LDL reduced cell viability and migration, induced apoptosis, and increased intracellular ROS production and NADPH oxidase. Pretreatment with AS-IV (10, 20, and 50 μM) significantly enhanced the cell viability and migration, suppressed LDH release, apoptosis, ROS production, and NADPH oxidase in HUVECs, in a concentration-dependent manner. The AS-IV (50 μM) alone did not show significant differences from control. AS-IV increased mRNA expressions of Nrf2 and HO-1 and decreased mRNA expressions of TNFalpha and IL-6 in the ox-LDL-HUEVC cells. Furthermore, AS-IV reduced supernatant contents of TNFalpha and IL-6. CONCLUSIONS Astragaloside IV prevents ox-LDL-induced endothelial cell injury by reducing apoptosis, oxidative stress, and inflammatory response.
        Olive oil promotes wound healing of mice pressure injuries through NOS-2 and Nrf2
        Schanuel FS, Saguie BO and Monte-Alto-Costa A
        The pressure injury environment is characterized by overproduction of reactive oxygen species and exacerbated inflammation, which impair the healing of these lesions. Mediterranean-like diet may be a good intervention to improve the healing of pressure injury due to its anti-inflammatory and antioxidant components. So, this study evaluated the hypothesis that olive oil, as a main source of lipid in Mediterranean diet, could improve cutaneous wound healing of pressure injury in mice. Male Swiss mice were randomly divided into standard, olive oil or soybean oil plus olive oil groups and fat represented 10% of total calories in all groups. Four weeks after the beginning of diet administration, two cycles of ischemia-reperfusion (IR) by external application of two magnets disks were performed in the dorsal skin to induce pressure injury formation. Fourteen days after the end of the second IR cycle, olive oil based diet reduced neutrophils cells and cyclooxygenase-2 protein expression, increased nitric oxide synthase-2 and protein and lipid oxidation. Olive oil based diet also increased nuclear factor erythroid 2-related factor 2 protein expression and collagen type I precursor protein expression. In addition, olive oil based diet administration promoted wound closure 7, 10 and 14 days after the end of the second IR cycle. These findings support the hypothesis that olive oil based diet improves cutaneous wound healing of pressure injury in mice through the reduction of inflammation and stimulation of redox equilibrium.
        The protective effect of oleanolic acid on NMDA-induced MLE-12 cells apoptosis and lung injury in mice by activating SIRT1 and reducing NF-κB acetylation
        Peng XP, Li XH, Li Y, Huang XT and Luo ZQ
        Overactivation of the N-methyl-d-aspartate (NMDA) receptor promotes oxidative stress, aggravates the inflammatory response and induces excitotoxic lung injury. NMDA is a synthetic agonist that selectively activates the NMDA receptor. Oleanolic acid (OA) is a natural anti-inflammatory and antioxidant compound. This study investigated the effect and possible mechanism of OA on NMDA-induced acute lung injury (ALI) in mice. OA pretreatment alleviated NMDA-induced histological lung changes and ameliorated pulmonary oedema and pulmonary permeability. At the same time, OA inhibited inflammatory cell infiltration and decreased the levels of tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β in the lung and bronchoalveolar lavage fluid (BALF). OA markedly decreased malondialdehyde (MDA) production and increased the superoxide dismutase (SOD) and glutathione (GSH) contents of the lung in vivo. Meanwhile, we first found that NMDA increased LDH activity and decreased cell viability, and induced oxidative stress and apoptosis in mouse lung epithelial (MLE)-12 cells. By employing SRT1720 and sirtinol, the activator and inhibitor of sirtuin 1 (SIRT1), we found that SRT1720 partially eliminated the increase in ROS,and sirtinol further promoted the increase in ROS caused by NMDA. OA increased MLE-12 cells viability and attenuated oxidative stress after NMDA challenge in vitro. OA suppressed NMDA-induced MLE-12 cells apoptosis, while sirtinol inhibited the effect of OA. In addition, OA significantly upregulated the levels of SIRT1, nuclear-related factor 2(Nrf2) and Bcl-2 protein and downregulated the levels of acetylated nuclear factor-kappa B (NF-κB), NLRP3 and Bax protein. In conclusion, OA attenuated NMDA-induced excitotoxic lung injury, potentially through its anti-inflammatory, antioxidative stress and anti-apoptotic effects. The mechanism may be related to activating SIRT1 and reducing NF-κB acetylation.
        Z-Ligustilide protects vascular endothelial cells from oxidative stress and rescues high fat diet-induced atherosclerosis by activating multiple NRF2 downstream genes
        Zhu Y, Zhang Y, Huang X, Xie Y, Qu Y, Long H, Gu N and Jiang W
        Oxidative stress-induced endothelial dysfunction is considered to exert a vital role in the development of atherosclerotic coronary heart disease (CHD). NRF2 is a key transcriptional factor against oxidative stress through activation of multiple ARE-mediated genes. Z-Lig is derived from the Ligusticum species with antitumor, anti-inflammation and neuroprotection activities. However, the antioxidant potentials of Z-Lig on endothelial dysfunction and atherosclerosis have not been well elucidated. Therefore, in the present work, we appraise the cytoprotective property and anti-atherosclerosis effect of Z-Lig.
        Early life environment influences the trajectory of post-partum weight loss in adult female rats
        Aiken CE, Tarry-Adkins JL, Ashmore TJ and Ozanne SE
        The physiological processes of pregnancy and lactation require profound changes in maternal metabolism and energy balance. The timescale of metabolic reversion after pregnancy, in particular post-partum weight loss, is highly variable between individuals. Currently, mechanisms influencing post-partum metabolic recovery are not well understood. The hypothesis tested here is that, in common with other metabolic and obesity-related outcomes, capacity for post-partum weight loss is influenced by developmental programming.
        Signal Transduction, Ageing and Disease
        Zhang L, Yousefzadeh MJ, Suh Y, Niedernhofer LJ and Robbins PD
        Ageing is defined by the loss of functional reserve over time, leading to a decreased tissue homeostasis and increased age-related pathology. The accumulation of damage including DNA damage contributes to driving cell signaling pathways that, in turn, can drive different cell fates, including senescence and apoptosis, as well as mitochondrial dysfunction and inflammation. In addition, the accumulation of cell autonomous damage with time also drives ageing through non-cell autonomous pathways by modulation of signaling pathways. Interestingly, genetic and pharmacologic analysis of factors able to modulate lifespan and healthspan in model organisms and even humans have identified several key signaling pathways including IGF-1, NF-κB, FOXO3, mTOR, Nrf-2 and sirtuins. This review will discuss the roles of several of these key signaling pathways, in particular NF-κB and Nrf2, in modulating ageing and age-related diseases.
        Melatonin Inhibits Lipopolysaccharide-Induced Inflammation and Oxidative Stress in Cultured Mouse Mammary Tissue
        Yu GM and Tan W
        To determine whether melatonin can protect cultured mouse mammary tissue from lipopolysaccharide- (LPS-) induced damage, we investigated the effects of melatonin on the mRNA and protein levels of proinflammatory cytokines and chemokines in LPS-stimulated mammary tissue . This study also examined the IgG level in both cultured mammary tissue and the culture medium. In addition, we investigated the potential benefits of melatonin on the expression of antioxidant relative genes following LPS treatment in cultured mammary tissue and evaluated ROS level in the culture medium. The results demonstrate that melatonin inhibited the mRNA expression of , , , , , and and the production of these cytokines and chemokines and IgG in LPS-stimulated mouse mammary tissue . In addition, melatonin increased but decreased and mRNA expression after LPS stimulation. Similarly, the decreased level of dityrosine in the culture medium was increased by treatment with melatonin, while increased nitrite level was suppressed. This study confirms that melatonin inhibited LPS-induced inflammation and oxidative stress in cultured mouse mammary tissue. It might contribute to mastitis therapy while treating antibiotic resistance.

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          Spring Cleaning Damaged Proteins with Nrf2: Good for Huntington’s Disease and Other Neurodegenerative Disorders?

          Spring Cleaning Damaged Proteins with Nrf2: Good for Huntington’s Disease and Other Neurodegenerative Disorders?

          English: Complete neuron cell diagram. Neurons...

          English: Complete neuron cell diagram. Neurons (also known as neurones and nerve cells) are electrically excitable cells in the nervous system that process and transmit information. In vertebrate animals, neurons are the core components of the brain, spinal cord and peripheral nerves. (Photo credit: Wikipedia)

          A new study supported by grants from NINDS and the National Institute on Aging as well as funding provided by the Taube/Koret Center, the National Science Foundation , the Huntington’s Disease Society of America, the Milton Wexler Award, and the Hillblom Foundation shows that activating a gene known as NRF2 helps clear damaged proteins which slows down or could possibly prevent Huntington’s disease.

          The study published in Nature Chemical Biology explains how important it is to quickly clear damaged proteins from neurons. Cell survival may be affected by the speed at which damaged proteins are removed. In Huntington’s disease and other neurodegenerative disorders, damaged proteins become misshaped and abnormal. They envelope neurons and damage or  kill the nearby brain cells. Healthy bodies are able to control quality and quantity of protein levels, as well as is able to detect malformed proteins and flush them be fore they can do any damage through a process called proteostasis.

          The study broke new ground in developing and using a technique called optical pulse-labeling to measure how quickly damaged proteins get removed. “Before this new technique, there was no way to look at individual neurons and their capacity to handle proteins. This method provides a real-time readout of how fast proteins are turned over in neurons and gives us a look at some of the mechanisms involved,” said Margaret Sutherland, Ph.D., program director at NINDS.

          The research studied the impact of different forms of huntingtin, the protein in Huntington’s disease on neuron death and the symptoms of the disease. The experiments showed that the mutant form of huntingtin caused more rat cells to die than the normal healthy form of the protein.

          To test this idea, the researchers activated Nrf2, a protein known to regulate protein processing. When Nrf2 was turned on, the mean lifetime of huntingtin was shortened, and the neuron lived longer. The researchers discovered that neuronal survival is directly correlated with the amount of time a neuron is exposed to the mutant huntingtin protein. Improving proteostasis in Huntington’s brains may improve neuronal survival and slow down or even prevent the the progression of the disease.

          “Nrf2 seems like a potentially exciting therapeutic target. It is profoundly neuroprotective in our Huntington’s model and it accelerates the clearance of mutant huntingtin,” said Dr. Steven Finkbeiner, senior author of the paper.

          “These findings provide evidence that our brains have powerful coping mechanisms to deal with disease-causing proteins. The fact that some of these diseases don’t cause symptoms we can detect until the fourth or fifth decade of life, even when the gene has been present since birth, suggests that those mechanisms are pretty good,” said Dr. Finkbeiner.
          Other NRF2 Huntington studies on Pubmed.org:

          Impaired mitochondrial dynamics and Nrf2 signaling contribute to compromised responses to oxidative stress in striatal cells expressing full-length mutant huntingtin.

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            A New Nrf2 and Diabetes Study Underway

            A New Nrf2 and Diabetes Study Underway

            Age-standardised disability-adjusted life year...

            The American Diabetes Journal has details on an interesting NRF2 study currently in progress. Diabetes is a huge concern to many individuals and families. According to statistics published by the American Diabetes Association  more than 25.8 million children and adults in the United States in 2010 have diabetes. That accounts for 8.3% of the population. A whopping 79 million people have pre-diabetic symptoms. In 2010, there were 1.9 million new cases of diabetes in people aged 20 years and older.

            Complications from Diabetes

            The following complications may occur as a result of diabetes.

            • Heart disease and stroke
            • High blood pressure
            • Blindness
            • Kidney disease
            • Nervous system disease (Neuropathy)
            • Amputation

            The following study is highlighted on the American Diabetes Association (ADA) website.

            Nrf2 activator to prevent diabetic cardiomyopathy

            The study is being conducted by: Cai, Lu , M.D., Ph.D. University of Louisville, Louisville, Kentucky. It focuses on both Type 1 And Type 2 Diabetes. The study started January 1, 2011 and is anticipated to end December 31, 2013.

            Background:

            Oxidative stress is associated with over 200 diseases, including diabetes. A diabetic’s heart is easily damaged from oxidative stress. Consuming antioxidants directly is not an effective enough protector of the heart. This study attempts to stimulate the body’s own production of several antioxidant genes/proteins in the heart through  a pathway known as the Nrf2 pathway. Nrf2 is the master regulator which turns on several antioxidant enzymes in the body.

            According to the website, Dr. Cai’s group showed that mice without Nrf2 are more easily damaged by diabetes than mice with higher levels of Nrf2. The group used a compound known as Dh404 as their NRF2 activator. Their hope is that results of this study will be conclusive to provide a new medication to protect the heart from diabetes. The researchers state that although this a new approach to diabetes treatment, their initial research shows it to be “a feasible project since we have shown the importance of Nrf2 in protecting a diabetic heart, and also have the compound (Dh404) to increase cardiac Nrf2 in animals.”

            To be more specific regarding protecting the heart, this project investigates the effects of NRF2 on diabetic myocardial complications (diabetic cardiomyopathy).  When the results are presented, there will be an answer to whether Nrf2 is capable of preventing diabetes-induced oxidative and nitrosative stress and the resulting progression of diabetic cardiomyopathy.

            The researchers  hope that if their findings are positive, that they might find or develop some dietary supplements to up-regulate cardiovascular levels of Nrf2. They further hope that this NRF2 up-regulation of genes and proteins in the heart will be able to prevent diabetes-induced cardiovascular diseases.

            Dr. Cai is motivated to find a cure due to the fact that many of his friends and family have been inflicted with Diabetes, including his mother in 1999 at the age of 59 years of age.

            Dr. Cai believes that diabetes (both type I and type II) will be prevented or at least delayed if an early diagnosis and treatment can be implemented as a result of these and future studies. It is his hope that hypertension, cardiomyopathy, and stroke will be prevented through the enhancement of endogenous and exogenous antioxidants.

            There are over 150 NRF2/Diabetic studies published on Pubmed.

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