Pomiferin Exerts Anti-Neuroinflammatory Effects Through Activating Akt /Nrf2 Pathway and Inhibiting NF-κB pathway

doi:10.21203/rs.3.rs-718549/v1

Download PDF

Research

Pomiferin Exerts Anti-Neuroinflammatory Effects Through Activating Akt /Nrf2 Pathway and Inhibiting NF-κB pathway

https://doi.org/10.21203/rs.3.rs-718549/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background:Neurodegenerative diseases are associated with neuroinflammation. However, the pro-inflammatory mediators produced during the occurrence of neuroinflammation will damage neurons and aggravate the process of neurodegenerative diseases. Therefore, inhibiting neuroinflammation may be an effective way to alleviate neurodegenerative diseases. The orange mulberry brass has a wide range of anti - oxidation and anti - inflammatory effects in peripheral tissues. However, it is not clear whether it inhibits neuroinflammation.

Methods:In our experiment, we studied the effect of Pomiferin on BV2 cell inflammation and its mechanism with Quantitative PCR, ELISA and western blot.

Results:The results showed that Pomiferin inhibited the production of ROS, NO and proinflammatory mediators (IL-6, TNF-α, iNOS, COX2) in BV2 cells. Further mechanism studies showed that Pomiferin activated the Akt /Nrf2 pathway and inhibited the NF-κB pathway.

Conclusion: Our study demonstrated that Pomiferin exerts anti-neuroinflammatory effects through activating Akt /Nrf2 pathway and inhibiting NF-κB pathway.

Integrative & Complementary Medicine

Clinical Pharmacology

Pomiferin

neuroinflammation

BV2

Akt /Nrf2 pathway

NF-κB pathway

Degenerative diseases are diseases in which the structure or function of neurons is gradually lost, including death, leading to dysfunction, such as Parkinson's disease (PD), Alzheimer's disease (Alzheimer's disease) and Huntington's disease (HD) etc. These diseases are mainly characterized by neurodegeneration in one or more parts of the central nervous system, with a long course and complex pathogenesis[1–3]. At present, it can only be alleviated in the early stage clinically, and there is no effective cure. Therefore, it is of great significance to study the pathogenesis of neurodegenerative diseases and search for effective therapeutic drugs.

Studies have shown that neuroimmunity and inflammatory responses are involved in the process of neurodegenerative diseases[4–6]. In the event of disease, immune cells are activated in large numbers and flock to the site of injury to remove harmful factors and repair damaged tissue. However, persistent inflammatory response leads to excessive activation of local immune cells in the central nervous system and accumulation of large amounts of toxic mediators such as IL-6, TNF-α, NO and PEG2, which further damages peripheral neurons and aggravates the progression of neurodegenerative disease[7, 8]. Therefore, it is of great significance to suppress the overactivation of immune cells and the neuroinflammatory response caused by it for the remission of neurogenic diseases.

Pomiferin is a kind of flavonoids extracted from the fruit of the orange mulberry. Studies show that Pomiferin s has anti - oxidation and anti - inflammatory effects. In the oxidative damage model, Pomiferin has a protective effect on the DNA damage caused by catalpa glucoside, showing a strong antioxidant activity[9, 10]. In macrophages, Pomiferin activates the nuclear factor infrared 2-related factor 2 (Nrf2), triggers the transcription of antioxidant genes, exerts the antioxidant effect and the degradation of IκB α, and plays an anti-inflammatory role[11, 12]. In human skin fibroblasts (NHDF) and normal human skin keratinocytes, Pomiferin can upregulate antioxidant genes such as ACLY, AQP3 and COX1[13, 14].Given its extensive antioxidant and anti-inflammatory activity, we hypothesized that Pomiferin might have an effect on neuroinflammation. Therefore, the purpose of this study was to explore the effect and mechanism of Pomiferin on neuroinflammation.

Reagent

LPS (from Escherichia coli, O55:B55) was obtained from Sigma (Aldrich, St. Louis, MO, USA) Fetal bovine serum (FBS), trypsin and DMEM high-glucose medium were purchased from (Gibco, Grand Island, NY, USA). Penicillin and streptomycin were purchased from Invitrogen (Carlsbad, CA, USA). Pomiferin (> 98%purity; Pufei De Biotech, chengdu, China) was dissolved in DMSO (Sigma Aldrich St Louis, MO, USA). MK2206 (an Akt inhibitor) and brusatol (BT, a Nrf2 inhibitor) were purchased from Selleck (Shanghai Blue Wood Chemical Co., Ltd. China). ROS, LDH, NO detection kit and CCK-8 reagent were purchased from Beyotime Biotechnology (Shanghai, China).

Cell culture

We incubated BV2 cells (purchased from shanghai Binsui Biological (Shanghai, China)) in complete medium (high glucose, 10% FBS, 100 U/mL penicillin, 100 µg/mL streptomycin) in a 5% carbon dioxide cell incubator at 37℃. The cell culture medium is replaced daily. When the density reached about 80%, the cells were digested with 0.05% trypsin and subcultured into new cell culture flask.

CCK-8 assay

When the density of BV2 cells inoculated in 96-well plates reached about 50%, the cells were treated with different concentrations of Pomiferin (0.25 µM, 0.5 µM, 1 µM,) and LPS (500 ng/mL) for 24 h. Then we added CCK-8 diluent to each well and incubated it in a cell incubator for 2 h. After that, the survival rate of the cells was measured at the absorbance of 450 nm.

LDH assay

When the density of BV2 cells inoculated in 96-well plates reached about 80%, the complete culture medium was changed to incomplete culture medium. Then the cells were treated with different concentrations of Pomiferin (0.25 µM, 0.5 µM, 1 µM,) and LPS (500 ng/mL) for 24 h. After that, according to the instructions of the LDH detection kit, the LDH working fluid was added to the 96-well plates, and the release of LDH was detected according to the LDH manufacturer’s instructions.

ROS measurement

When the density of BV2 cells inoculated in 96-well plates reached about 80%, we added Pomiferin (1µM) and LPS (500 ng/mL) to treat the cells for 12 h. Then the ROS level was measured with a ROS detection kit according to the manufacturer’s instructions.

NO measurement

When the density of BV2 cells inoculated in 96-well plates reached about 80%, we added Pomiferin (1µM) and LPS (500 ng/mL) to treat the cells for 12 h, and obtained the cell supernatant. Then the concentration of NO in the supernatant was measured using a NO detection kit according to the NO manufacturer’s instructions.

Quantitative PCR

When the density of BV2 cells inoculated in 96-well plates reached about 80%, the complete culture medium was changed to incomplete culture medium. We added Pomiferin (1µM) and LPS (100 ng/mL) to treat the cells for 12 h, and extracted RNA using the Trizol reagent (Sigma-Aldrich, St. Louis, MO, USA). RNA is reverse-transcribed into cDNA using the Prime Script®1stStrand cDNA Synthesis Kit (Roche, South San Francisco, CA, USA). After that, the mRNA level of IL-6, TNF-α, iNOS and COX-2 were measured with Quanti Tect SYBR Green RT-PCR Kit (Takara Biotechnology, Ltd., Kyoto, Japan) according to the ELISA manufacturer’s instructions. Primer sequences refer to previous studies[15, 16].

ELISA

When the density of BV2 cells inoculated in 96-well plates reached about 80%, the complete culture medium was changed to incomplete culture medium. We added Pomiferin (1µM) and LPS (500 ng/mL) to treat the cells for 24 h, and obtained the cell supernatant. The protein concentration of IL-6 and TNF-α in the supernatant was measured according to the ELISA manufacturer’s instructions.

Western blot

Total cell proteins were extracted using a protein extraction kit according to the manufacturer’s instructions (Beyotime Biotechnology, Shanghai, China). A total of 50 µg of protein was added to the well for electrophoresis. After electrophoresis, the proteins were transferred to fibrous PVDF membranes (Millipore, Billerica, MA, USA). Then the membrane was placed in 5% skim milk powder and sealed for 4 h. After that, the membrane was incubated with the primary antibody at 4℃ for 12 h and the secondary antibody at room temperature for 2 h. After cleaning with a membrane wash solution, the membrane is colorized with an ECL luminescent solution and the proteins are imaged with a protein imager. All primary antibodies are purchased from Abcam (Cambridge, UK) and the secondary antibody is purchased from Biological Technology (Wuhan, China).

Data analysis

All data were presented in mean ± SD form and analyzed using SPSS 19.1 software. One-way analysis of variance was used to compare the different groups. P values < 0.05 were considered statistically significant.

Effect of Pomiferin on the growth of BV2 cells

In order to study whether Pomiferin has toxic effects, BV2 cells were treated with LPS (100 ng/mL) and different concentrations of Pomiferin (0.25 µM, 0.5 µM, 1 µM), and then the effects of Pomiferin on the growth of BV2 cells were detected by CCK-8 (Fig. 2A) and LDH(Fig. 2B) experiments. The results showed that LPS and Pomiferin had no toxic effects on BV2 cells.

Effect of Pomiferin on expression of ROS and NO in BV2 cells

In the process of oxidative stress, ROS and NO are produced, which accumulate in large amounts and damage the surrounding tissues. In order to study the effect of Pomiferin, we treated BV2 cells with LPS (100 ng/mL) and Pomiferin (1 µM) for 12 h, and then detected the effect of Pomiferin on the production of ROS (Fig. 3A) and NO (Fig. 3B) in BV2 cells. The results showed that Pomiferin inhibited the production of ROS and NO.

Effect of Pomiferin on Akt /Nrf2 pathway in BV2 cells

Akt signaling pathway is involved in basic cellular processes. Nuclear factor erythroid2-related factor 2(Nrf2) is an important protective transcription factor that generally exists in various organisms and cellules. Studies have shown that Akt/ Nrf2 is involved in the regulation of oxidative stress[17, 18]. In order to investigate the mechanism of action of Pomiferin, we studied the effect of Pomiferin on Akt and Nrf2 pathways. The results showed that Pomiferin promoted the phosphorylation of Akt and the nuclear translocation of Nrf2.Then we treated BV2 cells with MK2206 (an Akt inhibitor, 10 µM) and BT (a Nrf2 inhibitor, 200 nM) for 6 h, and studied the effects of Pomiferin on ROS and NO after blocking Akt or Nrf2 pathway. The results showed that MK2206 or BT treatment weakened the inhibition of Pomiferin on ROS and NO. These results proved that Pomiferin inhibited the production of ROS and NO through the Akt/Nrf2 pathway.

Effect of Pomiferin on the expression of proinflammatory factors in BV2 cells

Continued oxidative stress usually leads to an inflammatory response, and abnormal inflammatory responses produce large amounts of proinflammatory factors (IL-6 and TNF-α), causing damage to neurons. Therefore, we treated BV2 cells with LPS (100 ng/mL) and Pomiferin (1 µM)for 12 h (mRNA) and 24 h (protein), and then detected the effect of Pomiferin on the production of proinflammatory factors (IL-6 and TNF-α) in BV2 cells via quantitative PCR and ELISA methods. The results showed that Pomiferin inhibited the mRNA(Fig. 5A, B) and protein(Fig. 5C, D) expression of proinflammatory factors (IL-6 and TNF-α).

Effect of Pomiferin on the expression of proinflammatory enzymes in BV2 cells

In order to further study the effect of Pomiferin on inflammation, we treated BV2 cells with LPS (100 ng/mL) and Pomiferin (1 µM) for 12 h (mRNA) and 24 h (protein), and then detected the effect of Pomiferin on the production of proinflammatory proteinase (iNOS and COX2) in BV2 cells via quantitative PCR and western blot methods. The results showed that Pomiferin inhibited the mRNA(Fig. 6A, B) and protein(Fig. 5C, D, E) expression of proinflammatory proteinase (iNOS and COX2).

Effect of Pomiferin on NF-κB and MAPK pathways in BV2 cells

NF-κB and MAPK pathways are classical inflammatory pathways, whose activation regulates transcription of inflammatory mediators[19, 20]. To investigate the anti-inflammatory mechanism of Pomiferin, we treated BV2 cells with Pomiferin (1 µM) and LPS (100 ng/mL), and then examined the effects of Pomiferin on activation of NF-κB and MAPK pathways. The results showed that orange mulberry brass inhibited the activation of NF-κB(Fig. 7A, C, D, E) and MAPK(Fig. 7B, F, G, H) pathways in BV2 cells.

In our study, we reported that Pomiferin exerts anti-inflammatory effects by inhibiting the production of ROS, NO and pro-inflammatory mediators (IL-6, TNF-α, iNOS, COX2) in microglia through activating Akt /Nrf2 pathway and inhibiting NF-κB pathway (Fig. 8).

As a flavonoid extracted from the fruit of Moraceae, Pomiferin has been reported to regulate oxidative stress[21–23]. In our experiment, we examined the effects of Pomiferin on the production of ROS and NO in BV2 cells. The results showed that Pomiferin inhibited the production of ROS and NO. The Akt pathway or PI3K-Akt pathway is the transduction pathway of signals corresponding to extracellular survival and growth. Activated Akt mediates downstream reactions by phosphorylation of a series of intracellular proteins that regulate cell survival, growth, proliferation, cell migration, and angiogenesis[24–26]. In our study, we examined the effect of Pomiferin on Akt phosphorylation, and the results showed that Pomiferin treatment promoted the phosphorylation of Akt. Nrf2 is a key factor in the regulation of oxidative stress, and its activation can regulate a variety of genes related to oxidative stress. Under normal circumstances, Nrf2 is located in the cytoplasm and does not play a role. After activation, Nrf2 translocates into the nucleus and binds with the antioxidant reaction elements to form the Nrf2-ARE signaling pathway, thereby regulating the expression of a series of downstream antioxidant genes and proteins and playing the antioxidant role[27–29]. In our experiment, we investigated the effect of Pomiferin on Nrf2 activation and found that Pomiferin promoted the nuclear translocation of Nrf2. Further studies showed that the inhibitors of Akt and Nrf2 could weaken the inhibition of ROS and NO by Pomiferin. It is suggested that Pomiferin inhibits the production of ROS and NO in BV2 cells by activating Akt and Nrf2 pathways.

The imbalance of oxidative and antioxidant reactions in the body will lead to oxidative stress. Continued and complex oxidative stress can trigger an inflammatory response in the body. Inflammation can lead to the imbalance of oxidation and antioxidant reactions in the body[30–32]. Therefore, regulation of oxidative stress plays an important role in inhibiting inflammatory response. The main pathological feature of neurodegenerative diseases is the degenerative loss of neurons. Inflammation plays an important role in this process[33–35]. Therefore, the inhibition of inflammatory response is of great significance in the treatment of neurodegenerative diseases. In our experiment, we examined the effect of Pomiferin on the production of pro-inflammatory mediators in BV2 cells and found that Pomiferin inhibited the production of pro-inflammatory mediators in BV2 cells.

NF-κB (enhanced κ-light chain of nuclear factor B) is a protein complex that plays a key role in regulating the immune response to infection. Its target genes are involved in immune response, inflammatory response, cell proliferation, anti-apoptosis, etc. When the cells were stimulated, IκBα kinase in the cytoplasm was activated, and part of IκBα was phosphorylated, part of IκBα was degraded by ubiquitination, and the p65 subunit associated with it was dissociated and phosphorylated[36–38]. In our experiment, we investigated the effect of Pomiferin on NF-κB activation and found that Pomiferin inhibited the phosphorylation of IκBα and p65 and the ubiquitination degradation of IκBα. MAPK (Mitogen-activated protein kinase) is a group of important transmitters that can be activated by different extracellular stimuli and make signals from the cell surface to the nucleus. It consists of ERK, JNK and P38[39, 40].In our experiment, we detected the effect of Pomiferin on the activation of MAPK pathway, and the results showed that Pomiferin had no effect on the activation of MAPK pathway.

Our study found that Pomiferin inhibited microglial inflammation by activating the Akt /Nrf2 pathway and inhibiting the NF-κB pathway. In addition, the unique pharmacological properties and easy availability of Pomiferin suggest that it may be a candidate drug for anti-neuroinflammation. Our experiment has laid a certain foundation for further study of the effect of Pomiferin.

ROS: reactive oxygen species

NO: nitric oxide

NF-κB : enhanced κ-light chain of nuclear factor B

MAPK :mitogen-activated protein kinase

TNF-α : tumor necrosis factor α

Akt: ser-ine-threonine protein kinase

Nrf2: nuclear factor erythroid-2-related factor 2

ERK: extracellular signal-regulated kinase

Ethics approval and consent to participate

Not applicable

Consent for publication

Written informed consent for publication was obtained from all participants.

Availability of data and materials

The datasets used or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

All authors claim that there is no conflict of interest.

Funding

This work was supported by Research Funding Program of Norman Bethune Biomedical Engineering Center (Grant Nos.BQEGCZX2019025) and Jilin Scientific and Technological Development Program (No. 20200404148YY).

Authors' contributions

Y.Z. and J.W. conceived the concept and experiments. YX.S. designed some parts of experiment. Y.S. carried out the experiment and collected data. Y.Z. wrote the manuscript, and all authors reviewed and commented on the manuscript.

Acknowledgements

In memory of Mr. Ga Sun for his encouragement and unwavering support which sustained me though frustration and depression.

Mead, B.; Berry, M.; Logan, A.; Scott, R.; Leadbeater, W.; Scheven, B.A. Stem cell treatment of degenerative eye disease. Stem Cell Research 2015, 14.
Kassem, M.; Abdallah, B.M. Human bone-marrow-derived mesenchymal stem cells: biological characteristics and potential role in therapy of degenerative diseases. Cell & Tissue Research 2008, 331, 157-163.
Ristow, M. Neurodegenerative disorders associated with diabetes mellitus. Journal of Molecular Medicine-jmm 2004, 82, 510-529.
Gao, H.M.; Hong, J.S. Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends in Immunology 2008, 29, 357-365.
Li, L.; Acioglu, C.; Heary, R.F.; Elkabes, S. Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases. Brain Behavior and Immunity 2020.
Kaushik, K.; Deepak; Basu; Anirban. A Friend in Need May Not be a Friend Indeed: Role of Microglia in Neurodegenerative Diseases. CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) 2013.
Mcgeer, E.G.; Mcgeer, P.L. Inflammatory Cytokines in the CNS. Cns Drugs 1997, 7, 214-228.
Matyszak, M.K. Inflammation in the CNS: balance between immunological privilege and immune responses. Progress in Neurobiology 1998, 56, 19-35.
Diopan, V.; Babula, P.; Shestivska, V.; Adam, V.; Zemlicka, M.; Dvorska, M.; Hubalek, J.; Trnkova, L.; Havel, L.; Kizek, R. Electrochemical and spectrometric study of antioxidant activity of pomiferin, isopomiferin, osajin and catalposide. J Pharm Biomed Anal 2008, 48, 127-133.
Gruber, J.V.; Holtz, R.; Sikkink, S.K.; Tobin, D.J. In vitro and ex vivo examination of topical Pomiferin treatments. Fitoterapia 2014, 94.
Hoek, J.; Toniolo, A.; Neuwirth, O.; Bolego, C. Prenylated and Geranylated Flavonoids Increase Production of Reactive Oxygen Species in Mouse Macrophages but Inhibit the Inflammatory Response. Journal of Natural Products 2013, 76.
Moon, H.I. Effect of osajin and pomiferin on antidiabetic effects from normal and streptozotocin-induced diabetic rats. Natural product communications 2014, 9.
Gruber, J.V.; Holtz, R. Examining the Genomic Influence of Skin Antioxidants In Vitro. Mediators of Inflammation 2010, 2010, 1-10.
Florian, T.; Necas, J.; Ba Rtosikova, L.; Klusakova, J.; Suchy, V.; Naggara, E.; Janostikova, E.; Ba Rtosik, T. Effects of prenylated isoflavones osajin and pomiferin in premedication on heart ischemia-reperfusion. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2006.
Wei; Hou; Siyi; Hu; Zhenzhong; Su; Qi; Wang; Guangping; Meng. Myricetin attenuates LPS-induced inflammation in RAW 264.7 macrophages and mouse models. Future Medicinal Chemistry 2018.
Tingting; Guo; Zhenzhong; Wang; Wei; Hou; Junyao; Lin; Zhang; Jie. Vanillin protects lipopolysaccharide-induced acute lung injury by inhibiting ERK1/2, p38 and NF-κB pathway. Future medicinal chemistry 2019, 11, 2081-2094.
Antioxidant effects of ginkgolides and bilobalide against cerebral ischemia injury by activating the Akt/Nrf2 pathway in vitro and in vivo. Cell stress & chaperones 2019.
Wen, Z.; Hou, W.; Wei, W.; Yang, Z.; Lei, S. 6'- O -Galloylpaeoniflorin Attenuates Cerebral Ischemia Reperfusion-Induced Neuroinflammation and Oxidative Stress via PI3K/Akt/Nrf2 Activation. Oxidative Medicine and Cellular Longevity,2018,(2018-3-25) 2018, 2018, 1-14.
Zhao, W.; Ma, L.; Cai, C.; Gong, X. Caffeine Inhibits NLRP3 Inflammasome Activation by Suppressing MAPK/NF-κB and A2aR Signaling in LPS-Induced THP-1 Macrophages. International Journal of Biological Sciences 2019, 15, 1571-1581.
Li, Z.; Chen, C.; Zhu, X.; Li, Y.; Yu, R.; Xu, W. Glycyrrhizin Suppresses RANKL-Induced Osteoclastogenesis and Oxidative Stress Through Inhibiting NF-κB and MAPK and Activating AMPK/Nrf2. Calcified Tissue International 2018.
Necas, J.; Bartosíková, L.; Florian, T.; Klusáková, J.; Lisková, M. Protective effects of the flavonoids osajin and pomiferin on heart ischemia - Reperfusion. Ceská a Slovenská farmacie: casopis Ceské farmaceutické spolecnosti a Slovenské farmaceutické spolecnosti 2006, 55, 168-174.
Huayu; Xiong; Yan; Wang; Xiuhua; Zhang; Yong; YeShengfu; Wang. Evaluation of antioxidative capacity via measurement of the damage of DNA using an electrochemical biosensor and an ionic liquid solvent. Microchimica Acta 2012.
Yang, R.X. In vitro and in vivo studies of antioxidant and anti-breast cancer activities of pomiferin. University of Guelph (Canada). 2009.
Brendan; D.; Manning; and; Lewis; C.; Cantley. AKT/PKB Signaling: Navigating Downstream. Cell 2007.
Gang, S.; Ouyang, G.; Bao, S. The activation of Akt/PKB signaling pathway and cell survival. Journal of Cellular & Molecular Medicine 2010, 9, 59-71.
DavdFuon; Jan-Phppraon; Mcca, M.; JasonFonana; YasushFujo; KnnhWash; Frank, H.; AndrasPapapropouos; Sssa, W. erratum: Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. nature 1999.
Nguyen, T.; Nioi, P.; Pickett, C.B. The Nrf2-Antioxidant Response Element Signaling Pathway and Its Activation by Oxidative Stress. Journal of Biological Chemistry 2009, 284, 13291.
Kobayashi, M.; Yamamoto, M. Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal 2005, 7, 385.
Kensler, T.W.; Wakabayashi, N.; Biswal, S. Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway. Annual Review of Pharmacology and Toxicology 2013
Vento, M.; Moro, M.; Escrig, R.; Arruza, L.; Villar, G.; Izquierdo, I.; Roberts, L.J.; Arduini, A.; Escobar, J.J.; Sastre, J. Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease. Pediatrics 2009, 124, e439.
Quiroz, Y.; Ferrebuz, A.; Romero, F.; Vaziri, N.D.; Rodriguez-Iturbe, B. Melatonin ameliorates oxidative stress, inflammation, proteinuria, and progression of renal damage in rats with renal mass reduction. American Journal of Physiology Renal Physiology 2008, 294, F336.
Rosenson, R.S.; Stafforini, D.M. Modulation of oxidative stress, inflammation, and atherosclerosis by lipoprotein-associated phospholipase A2. Journal of Lipid Research 2012, 53, 1767-1782.
Floyd, R.A. Neuroinflammatory processes are important in neurodegenerative diseases: an hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development. Free Radical Biology & Medicine 1999, 26, 1346-1355.
Cuzzola, V.F.; Ciurleo, R.; Giacoppo, S.; Marino, S.; Bramanti, P. Role of Resveratrol and its Analogues in the Treatment of Neurodegenerative Diseases: Focus on Recent Discoveries. CNS & neurological disorders drug targets 2011, 10, 849-862.
Wilms, H.; Claasen, J.; Röhl, C.; Sievers, J.; Deuschl, G.; Lucius, R. Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: evidence from activated microglial cells in vitro. Neurobiology of Disease 2003, 14, 417-424.
ldwin, B.; Albert, S. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annual Review of Immunology 1996, 14, 649.
Baeuerle, P. Function and activation of NF-kappa B in the immune system. Annual Review of Immunology 1994, 12, 141.
Verma, I.M.; Stevenson, J.K.; Schwarz, E.M.; Antwerp, D.V.; Miyamoto, S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes & Development 1995, 9, 2723.
Seger, R.; Wexler, S. The MAPK Signaling Cascades. Encyclopedia of Cell Biology 2016, 3, 122-127.
Seger, R.; Krebs, E.G. Protein kinases .7. The MAPK signaling cascade. Faseb Journal 1995, 9, 726-735.

Download PDF

Version 1

posted

You are reading this latest preprint version

Pomiferin Exerts Anti-Neuroinflammatory Effects Through Activating Akt /Nrf2 Pathway and Inhibiting NF-κB pathway

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Status:

Version 1