(E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) Phenol Ameliorates MPTP-Induced Dopaminergic Neurodegeneration by Inhibiting the STAT3 Pathway

Neuroinflammation is implicated in dopaminergic neurodegeneration. We have previously demonstrated that (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a selective signal transducer and activator of transcription 3 (STAT3) inhibitor, has anti-inflammatory properties in several inflammatory disease models. We investigated whether MMPP could protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic cell loss and behavioral impairment. Imprinting control region (ICR) mice (8 weeks old, n = 10 per group) were administered MMPP (5 mg/kg) in drinking water for 1 month, and injected with MPTP (15 mg/kg, four times with 2 h intervals) during the last 7 days of treatment. MMPP decreased MPTP-induced behavioral impairments in rotarod, pole, and gait tests. We also showed that MMPP ameliorated dopamine depletion in the striatum and inflammatory marker elevation in primary cultured neurons by high-performance liquid chromatography and immunohistochemical analysis. Increased activation of STAT3, p38, and monoamine oxidase B (MAO-B) were observed in the substantia nigra and striatum after MPTP injection, effects that were attenuated by MMPP treatment. Furthermore, MMPP inhibited STAT3 activity and expression of neuroinflammatory proteins, including ionized calcium binding adaptor molecule 1 (Iba1), inducible nitric oxide synthase (iNOS), and glial fibrillary acidic protein (GFAP) in 1-methyl-4-phenylpyridinium (MPP+; 0.5 mM)-treated primary cultured cells. However, mitogen-activated protein kinase (MAPK) inhibitors augmented the activity of MMPP. Collectively, our results suggest that MMPP may be an anti-inflammatory agent that attenuates dopaminergic neurodegeneration and neuroinflammation through MAO-B and MAPK pathway-dependent inhibition of STAT3 activation.

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Camel Milk Attenuates Rheumatoid Arthritis Via Inhibition of Mitogen Activated Protein Kinase Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000480527 ◽

2017 ◽

Vol 43 (2) ◽

pp. 540-552 ◽

Cited By ~ 17

Author(s):

Hany H. Arab ◽

Samir A. Salama ◽

Tamer M. Abdelghany ◽

Hany A. Omar ◽

El-Shaimaa A. Arafa ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mapk Pathway ◽

Lipid Peroxide ◽

Mitogen Activated Protein Kinase ◽

Camel Milk ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Anti Oxidant ◽

Cox 2 ◽

Anti Inflammatory

Background/Aims: Camel milk (CM) has shown beneficial anti-inflammatory actions in several experimental and clinical settings. So far, its effect on rheumatoid arthritis (RA) has not been previously explored. Thus, the current work aimed to evaluate the effects of CM in Adjuvant-induced arthritis and air pouch edema models in rats, which mimic human RA. Methods: CM was administered at 10 ml/kg orally for 3 weeks starting on the day of Freund’s adjuvant paw inoculation. The levels of TNF-α and IL-10 were measured by ELISA while the protein expression of NF-κBp65, COX-2 and iNOS was detected by immunohistochemistry. The expression of MAPK target proteins was assessed by Western blotting. Results: CM attenuated paw edema, arthritic index and gait score along with dorsal pouch inflammatory cell migration. CM lowered the TNF-α and augmented the anti-inflammatory IL-10 levels in sera and exudates of arthritic rats. It also attenuated the expression of activated NF-κBp65, COX-2 and iNOS in the lining of the dorsal pouch. Notably, CM inhibited the MAPK pathway signal transduction via lowering the phosphorylation of p38 MAPK, ERK1/2 and JNK1/2 in rat hind paws. Additionally, CM administration lowered the lipid peroxide and nitric oxide levels and boosted glutathione and total anti-oxidant capacity in sera and exudates of animals. Conclusion: The observed CM downregulation of the arthritic process may support the interest of CM consumption as an adjunct approach for the management of RA.

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Calcium-binding protein S100A6 interaction with VEGF receptors integrates signaling and trafficking pathways

10.1101/2021.07.29.454311 ◽

2021 ◽

Author(s):

Sreenivasan Ponnambalam ◽

Leyuan Bao ◽

Gareth W Fearnley ◽

Chi-Chuan Lin ◽

Adam F Odell ◽

...

Keyword(s):

Plasma Membrane ◽

Membrane Trafficking ◽

Calcium Binding ◽

Mapk Pathway ◽

Binding Protein ◽

Calcium Binding Protein ◽

Mitogen Activated Protein Kinase ◽

Tyrosine Kinase Domain ◽

Dependent Manner ◽

Endothelial Cell Function

The mammalian endothelium which lines all blood vessels responds to soluble factors which control vascular development and sprouting. Endothelial cells bind to vascular endothelial growth factor A via two different receptor tyrosine kinases (VEGFR1, VEGFR2) which regulate such cellular responses. The integration of VEGFR signal transduction and membrane trafficking is not well understood. Here, we used a yeast-based membrane protein screen to identify VEGFR-interacting factor(s) which modulate endothelial cell function. By screening a human endothelial cDNA library, we identified a calcium-binding protein, S100A6, which can interact with either VEGFR. We found that S100A6 binds in a calcium-dependent manner to either VEGFR1 or VEGFR2. S100A6 binding was mapped to the VEGFR2 tyrosine kinase domain. Depletion of S100A6 impacts on VEGF-A-regulated signaling through the canonical mitogen-activated protein kinase (MAPK) pathway. Furthermore, S100A6 depletion caused contrasting effects on biosynthetic VEGFR delivery to the plasma membrane. Co-distribution of S100A6 and VEGFRs on tubular profiles suggest the presence of transport carriers that facilitate VEGFR trafficking. We propose a mechanism whereby S100A6 acts as a calcium regulated switch which facilitates biosynthetic VEGFR trafficking from the TGN-to-plasma membrane. VEGFR-S100A6 interactions thus enable integration of signaling and trafficking pathways in controlling the endothelial response to VEGF-A.

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1-Carbomethoxy-β-Carboline, Derived from Portulaca oleracea L., Ameliorates LPS-Mediated Inflammatory Response Associated with MAPK Signaling and Nuclear Translocation of NF-κB

Molecules ◽

10.3390/molecules24224042 ◽

2019 ◽

Vol 24 (22) ◽

pp. 4042 ◽

Cited By ~ 3

Author(s):

Kim ◽

Park ◽

Jang ◽

Lee ◽

Park ◽

...

Keyword(s):

Nitric Oxide ◽

Nuclear Translocation ◽

Inflammatory Diseases ◽

Mapk Pathway ◽

Mapk Signaling ◽

Portulaca Oleracea ◽

Mitogen Activated Protein Kinase ◽

No Production ◽

Ionization Mass ◽

Anti Inflammatory

Portulaca oleracea is as a medicinal plant known for its neuroprotective, hepatoprotective, antidiabetic, antioxidant, anticancer, antimicrobial, antiulcerogenic, and anti-inflammatory activities. However, the specific active compounds responsible for the individual pharmacological effects of P. oleracea extract (95% EtOH) remain unknown. Here, we hypothesized that alkaloids, the most abundant constituents in P. oleracea extract, are responsible for its anti-inflammatory activity. We investigated the phytochemical substituents (compounds 1–22) using nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESI-MS) and screened their effects on NO production in lipopolysaccharide (LPS)-induced macrophages. Compound 20, 1-carbomethoxy-β-carboline, as an alkaloid structure, ameliorated nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and proinflammatory cytokines associated with the mitogen-activated protein kinase (MAPK) pathways, p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). Subsequently, we observed that compound 20 suppressed nuclear translocation of nuclear factor κB (NF-κB) using immunocytochemistry. Moreover, we recently reported that compound 8, trans-N-feruloyl-3’, 7’-dimethoxytyramine, was originally purified from P. oleracea extracts. Our results suggest that 1-carbomethoxy-β-carboline, the most effective anti-inflammatory agent among alkaloids in the 95% EtOH extract of P. oleracea, was suppressing the MAPK pathway and nuclear translocation of NF-κB. Therefore, P. oleracea extracts and specifically 1-carbomethoxy-β-carboline may be novel therapeutic candidates for the treatment of inflammatory diseases associated with the activation of MAPKs and NF-κB.

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IL1α and IL4 signalling in human ovarian surface epithelial cells

Journal of Endocrinology ◽

10.1530/joe-11-0081 ◽

2011 ◽

Vol 211 (3) ◽

pp. 273-283 ◽

Cited By ~ 17

Author(s):

Georgia Papacleovoulou ◽

Hilary O D Critchley ◽

Stephen G Hillier ◽

J Ian Mason

Keyword(s):

Wound Healing ◽

P38 Mapk ◽

Lysyl Oxidase ◽

Mapk Pathway ◽

Nuclear Factor Κb ◽

Mitogen Activated Protein Kinase ◽

Surface Epithelium ◽

Ovarian Surface ◽

Mrna Transcripts ◽

Anti Inflammatory

The human ovarian surface epithelium (hOSE) is a mesothelial layer that surrounds the ovary and undergoes injury and repair cycles after ovulation-associated inflammation. We previously showed that IL4 is a key regulator of progesterone bioavailability during post-ovulatory hOSE repair as it differentially up-regulated 3β-HSD1 and 3β-HSD2 mRNA transcripts and total 3β-hydroxysteroid dehydrogenase activity whereas it inhibited androgen receptor (AR) expression. We now show that the pro-inflammatory effect of IL1α on 3β-HSD1 expression is mediated by nuclear factor-κB (NF-κB), whereas its anti-inflammatory action on 3β-HSD2 expression is exerted via p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and NF-κB signalling pathways. The anti-inflammatory IL4 effects on 3β-HSD1 and 3β-HSD2 mRNA expression are mediated through STAT6 and PI3K signalling networks. IL4 effects on AR and 3β-HSD2 expression involve the p38 MAPK pathway. We also document that IL4 up-regulates lysyl oxidase (LOX) mRNA transcripts, a key gene for extracellular matrix (ECM) deposition and inhibits IL1α-induced expression of cyclooxygenase-2 (COX-2) mRNA, a gene involved in breakdown of ECM, showing a further role in post-ovulatory wound healing. We conclude that IL1α and IL4 actions in the post-ovulatory wound healing of hOSE cells are mediated by different signalling transduction pathways. The p38 MAPK signalling pathway may have possible therapeutic benefit in inflammation-associated disorders of the ovary, including cancer.

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Neferine Exerts Antioxidant and Anti-Inflammatory Effects on Carbon Tetrachloride-Induced Liver Fibrosis by Inhibiting the MAPK and NF-κB/IκBα Pathways

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/4136019 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Yuanyuan Wang ◽

Shaozhan Wang ◽

Rong Wang ◽

Shengnan Li ◽

Yongfang Yuan

Keyword(s):

Oxidative Stress ◽

Carbon Tetrachloride ◽

Liver Fibrosis ◽

Transforming Growth Factor ◽

Mapk Pathway ◽

Antioxidant Properties ◽

Mitogen Activated Protein Kinase ◽

Inflammatory Factors ◽

Potential Mechanism ◽

Anti Inflammatory

Reversible liver fibrosis is the consequence of diverse liver injuries. Oxidative stress combined with inflammation is the primary cause of carbon tetrachloride- (CCl4-) induced liver fibrosis. Neferine is a bibenzyl isoquinoline alkaloid, which has strong anti-inflammatory and antioxidant properties. The present study attempted to find its antiliver fibrosis effect and explore the potential mechanism to relieve oxidative stress and inflammation in rats with CCl4-induced liver fibrosis. Herein, we found that neferine noticeably mitigated fibrosis and improved liver function. Furthermore, neferine increased the activity of antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and catalase (CAT), but decreased the level of malondialdehyde (MDA). Neferine also decreased the levels of alpha-smooth muscle actin (α-SMA), transforming growth factor β1 (TGF-β1), and inflammatory factors. These results may demonstrate that neferine could effectively inhibit oxidative stress and inflammation in liver fibrosis. To account for the potential mechanism by which neferine relieves oxidative stress and inflammation in liver fibrosis rats, immunohistochemistry analyses and western blotting were performed. The results showed that neferine inhibited the mitogen-activated protein kinase (MAPK) pathway, as evidenced by the reduced phosphorylation of p38 MAPK, ERK 1/2, and JNK. And it inhibited the nuclear factor- (NF-) κB/IκBα pathway, as evidenced by preventing the translocation of NF-κB into nuclei. Our findings indicated a protective role for neferine, acting as an antioxidant and anti-inflammatory agent in CCl4-induced liver fibrosis.

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Thyroid hormone induces activation of mitogen-activated protein kinase in cultured cells

AJP Cell Physiology ◽

10.1152/ajpcell.1999.276.5.c1014 ◽

1999 ◽

Vol 276 (5) ◽

pp. C1014-C1024 ◽

Cited By ~ 148

Author(s):

Hung-Yun Lin ◽

Faith B. Davis ◽

Jennifer K. Gordinier ◽

Leon J. Martino ◽

Paul J. Davis

Keyword(s):

Thyroid Hormone ◽

Protein Kinase ◽

Nuclear Translocation ◽

Cultured Cells ◽

Mapk Pathway ◽

Interferon Γ ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Ifn Γ ◽

G Protein Coupled

Thyroid hormone [l-thyroxine (T4)] rapidly induced phosphorylation and nuclear translocation (activation) of mitogen-activated protein kinase (MAPK) in HeLa and CV-1 cells in the absence of cytokine or growth factor. A pertussis toxin-sensitive and guanosine 5′- O-(3-thiotriphosphate)-sensitive cell surface mechanism responsive to T4and agarose-T4, suggesting a G protein-coupled receptor, was implicated. Cells depleted of MAPK or treated with MAPK pathway inhibitors showed reduced activation of MAPK and of the signal transducer and activator of transcription STAT1α by T4; they also showed reduced T4potentiation of the antiviral action of interferon-γ (IFN-γ). T4treatment caused tyrosine-phosphorylated MAPK-STAT1α nuclear complex formation and enhanced Ser-727 phosphorylation of STAT1α, in the presence or absence of IFN-γ. STAT1α-deficient cells transfected with STAT1α containing an alanine-for-serine substitution at residue 727 (STAT1αA727) showed minimal T4-stimulated STAT1α activation. IFN-γ induced the antiviral state in cells containing wild-type STAT1α (STAT1αwt) or STAT1αA727; T4potentiated IFN-γ action in STAT1αwtcells but not in STAT1αA727cells. T4-directed STAT1α Ser-727 phosphorylation is MAPK mediated and results in potentiated STAT1α activation and enhanced IFN-γ activity.

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Ginsenoside Rg1 Downregulates the Shear Stress Induced MCP-1 Expression by Inhibiting MAPK Signaling Pathway

The American Journal of Chinese Medicine ◽

10.1142/s0192415x15500202 ◽

2015 ◽

Vol 43 (02) ◽

pp. 305-317 ◽

Cited By ~ 9

Author(s):

Jian He ◽

Yu-Lin Li

Keyword(s):

Shear Stress ◽

Mapk Pathway ◽

Inhibitory Effect ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Ginsenoside Rg1 ◽

Negative Effects ◽

Specific Chemical ◽

Mitogen Activated Protein ◽

Anti Inflammatory

Ginsenoside Rg1 has been reported to possess anti-inflammatory activities, but the effects of Rg1 on the shear induced MCP-1 upregulation mechanism on endothelial cells (ECs) remain to be determined. In this study, we show that Rg1 down modulates shear induced pro-inflammatory cytokine MCP-1 gene expression and monocytes adhesion without potential cell toxicity. The negative effects on monocytes adhesion is due to a decrease in MCP-1 protein release. Furthermore, the inhibitory effect of Rg1 on the phosphorylation level of ERK, p38, and JNK mitogen-activated protein kinase (MAPK) induced by shear stress (SS) is similar with that of specific chemical inhibitors for MAPK pathways activation. These results demonstrate that ginsenoside Rg1 inhibits the shear induced inflammation by suppressing the MAPK pathway. This suggests that Rg1 may serve as a novel anti-inflammatory agent for inflammation-induced cardiovascular diseases treatment.

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Glucocorticoids promote survival of anti-inflammatory macrophages via stimulation of adenosine receptor A3

Blood ◽

10.1182/blood-2009-10-247106 ◽

2010 ◽

Vol 116 (3) ◽

pp. 446-455 ◽

Cited By ~ 52

Author(s):

Katarzyna Barczyk ◽

Jan Ehrchen ◽

Klaus Tenbrock ◽

Martina Ahlmann ◽

Jessica Kneidl ◽

...

Keyword(s):

Adenosine Receptor ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Resolution Of Inflammation ◽

Downstream Signaling ◽

Inflammatory Monocytes ◽

A3 Adenosine Receptor ◽

Mitogen Activated Protein ◽

Anti Inflammatory ◽

Novel Strategy

Abstract Active resolution of inflammation is a previously unrecognized process essential for tissue homeostasis. Monocytes play a pivotal role in the generation as well as resolution of inflammation. Glucocorticoids (GCs) are widely used anti-inflammatory agents. We demonstrate that GCs exhibit antiapoptotic effects in monocytes resulting in differentiation to an anti-inflammatory phenotype. The molecular basis of this novel antiapoptotic effect is a prolonged activation of the extracellular signal regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway resulting in inhibition of caspase activities and expression of antiapoptotic genes via activation of c-Myc. We identified up-regulation and activation of A3 adenosine receptor (A3AR) as the initial trigger of this antiapoptotic pathway. In summary, we deciphered a novel molecular pathway promoting survival of anti-inflammatory monocytes. Specific activation of A3AR or its downstream signaling pathways may thus be a novel strategy to modulate inflammation in autoimmune disorders with fewer side effects via induction of inflammatory resolution rather than immunosuppression.

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Bioactive lipids in intervertebral disc degeneration and its therapeutic implications

Bioscience Reports ◽

10.1042/bsr20192117 ◽

2019 ◽

Vol 39 (10) ◽

Author(s):

Undurti N. Das

Keyword(s):

Intervertebral Disc ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Dependent Manner ◽

Bioactive Lipids ◽

Nucleus Pulposus Cells ◽

Jnk Pathway ◽

Anti Inflammatory ◽

Ivd Degeneration ◽

Inflammatory Molecules

Abstract Intervertebral disc (IVD) degeneration is not uncommon. It is estimated that approximately >60% of individuals above the age of 40 years suffer from IVD degeneration. Shan et al. showed that hyperglycemia can enhance apoptosis of anulus fibrosis cells in a JNK pathway and p38 mitogen-activated protein kinase (MAPK) pathway dependent fashion. Recent studies showed that IVD degeneration could be an inflammatory condition characterized by increased production of matrix metalloproteinases, TNF-α, nitric oxide, IL-6, IL-17, IL-9, and prostaglandin E2, and decreased formation of anti-inflammatory molecules such as lipoxin A4. This imbalance between pro- and anti-inflammatory molecules seem to activate JNK pathway and p38 MAPK pathway to induce apoptosis of anulus fibrosis and nucleus pulposus cells. The activation of production of PGE2 (due to activation of COX-2 pathway) seems to be dependent on p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner. These results imply that suppressing pro-inflammatory events in the disc by either augmenting anti-inflammatory events or suppressing production of pro-inflammatory molecules or both may form a logical step in the prevention and management of IVD degeneration.

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Dexamethasone-induced and estradiol-induced CREB activation and annexin 1 expression in CCRF-CEM lymphoblastic cells: evidence for the involvement of cAMP and p38 MAPK

Mediators of Inflammation ◽

10.1080/09629350310001633351 ◽

2003 ◽

Vol 12 (6) ◽

pp. 329-337 ◽

Cited By ~ 16

Author(s):

M. Castro-caldas ◽

A. F. Mendes ◽

C. B. Duarte ◽

M. C. F. Lopes

Keyword(s):

Steroid Hormones ◽

P38 Mapk ◽

Calcium Binding ◽

Binding Proteins ◽

Hormone Receptors ◽

Steroid Hormone Receptors ◽

Mitogen Activated Protein Kinase ◽

Annexin 1 ◽

Creb Activation ◽

Anti Inflammatory

Aims:Annexin 1 (ANXA1), a member of the annexin family of calcium-binding and phospholipid-binding proteins, is a key mediator of the anti-inflammatory actions of steroid hormones. We have previously demonstrated that, in the human lymphoblastic CCRF-CEM cell line, both the synthetic glucocorticoid hormone, dexamethasone (Dex), and the estrogen hormone, 17β-estradiol (E2β), induce the synthesis of ANXA1, by a mechanism independent of the activation of their nuclear receptors. Recently, it was reported that the gene coding for ANXA1 contains a cAMP-responsive element (CRE). In this work, we investigated whether Dex and E2β were able to induce the activation of CRE binding proteins (CREB) in the CCRF-CEM cells. Moreover, we studied the intracellular signalling pathways involved in CREB activation and ANXA1 synthesis in response to Dex and E2β; namely, the role of cAMP and the p38 mitogen-activated protein kinase (MAPK).Results:The results show that Dex and E2β were as effective as the cAMP analogue, dBcAMP, in inducing CREB activation. On the other hand, dBcAMP induced ANXA1 synthesis as effectively as these steroid hormones. Furthermore, the cAMP antagonist, Rp-8-Br-cAMPS, and the specific p38 MAPK inhibitor, SB203580, effectively prevented Dex-induced, E2β-induced and dBcAMP-induced CREB activation and ANXA1 synthesis.Conclusions:Taken together, our results suggest that, in CCRF-CEM cells, Dex-induced and E2β-induced ANXA1 expression requires the activation of the transcription factor CREB, which in turn seems to be mediated by cAMP and the p38 MAPK. These findings also suggest that, besides the nuclear steroid hormone receptors, other transcription factors, namely CREB, may play important roles in mediating the anti-inflammatory actions of glucocorticoids and oestrogen hormones.

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