scholarly journals Post-transcriptional modulation of Dscam1 enhances axonal growth in development and after injury

2017 ◽  
Author(s):  
Marta Koch ◽  
Maya Nicolas ◽  
Marlen Zschaetzsch ◽  
Natalie de Geest ◽  
Annelies Claeys ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Axonal Growth ◽  
Cns Injury ◽  
Jnk Pathway ◽  
Protein Levels ◽  
Injury Model ◽  
Central Nervous Systems ◽  
Transcriptional Modulation ◽  
Biochemical Analyses ◽  
Fat Facets

AbstractInjury to the adult central nervous systems (CNS) results in severe long-term disability because damaged CNS connections rarely regenerate. Although several axon regeneration regulators have been proposed, intrinsic regenerative mechanisms remain largely unexplored. Here, we use a Drosophila CNS injury model to identify a novel pro-regeneration signaling pathway. We conducted a genetic screen of approximately three hundred candidate genes and identified three strong inducers of axonal growth and regeneration: the Down Syndrome Cell Adhesion Molecule (Dscam1), the de-ubiquitinating enzyme Fat Facets (Faf)/Usp9x and the Jun N-Terminal Kinase (JNK) pathway transcription factor Kayak (Kay)/Fos. Genetic and biochemical analyses link these genes in a common signaling pathway whereby Faf stabilizes Dscam1 protein levels, by acting on the 3’-UTR of its mRNA, and Dscam1 acts upstream of the growth-promoting JNK signal. The mammalian homolog of Faf, Usp9x/FAM, shares both the regenerative and Dscam1 stabilizing activities, suggesting a conserved mechanism.

scholarly journals A Fat-Facets-Dscam1-JNK Pathway Enhances Axonal Growth in Development and after Injury

2018 ◽  
Vol 11 ◽  
Author(s):  
Marta Koch ◽  
Maya Nicolas ◽  
Marlen Zschaetzsch ◽  
Natalie de Geest ◽  
Annelies Claeys ◽  
...  
Keyword(s):  
Axonal Growth ◽  
Jnk Pathway ◽  
Fat Facets

scholarly journals Protective Effects of 6,7,4′-Trihydroxyflavanone on Hypoxia-Induced Neurotoxicity by Enhancement of HO-1 through Nrf2 Signaling Pathway

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 341 ◽  
Author(s):  
Hyun-Su Lee ◽  
Gil-Saeng Jeong
Keyword(s):  
Signaling Pathway ◽  
Neurodegenerative Disorders ◽  
Nuclear Translocation ◽  
Protoporphyrin Ix ◽  
Protective Role ◽  
Osteoclast Formation ◽  
Protective Effects ◽  
Protein Levels ◽  
Nrf2 Signaling Pathway ◽  
Pre Treatment

Since hypoxia-induced neurotoxicity is one of the major causes of neurodegenerative disorders, including the Alzheimer’s disease, continuous efforts to find a novel antioxidant from natural products are required for public health. 6,7,4′-trihydroxyflavanone (THF), isolated from Dalbergia odorifera, has been shown to inhibit osteoclast formation and have an antibacterial activity. However, no evidence has reported whether THF has a protective role against hypoxia-induced neurotoxicity. In this study, we found that THF is not cytotoxic, but pre-treatment with THF has a cytoprotective effect on CoCl2-induced hypoxia by restoring the expression of anti-apoptotic proteins in SH-SY5y cells. In addition, pre-treatment with THF suppressed CoCl2-induced hypoxia-related genes including HIF1α, p53, VEGF, and GLUT1 at the mRNA and protein levels. Pre-treatment with THF also attenuated the oxidative stress occurred by CoCl2-induced hypoxia by preserving antioxidant proteins, including SOD and CAT. We revealed that treatment with THF promotes HO-1 expression through Nrf2 nuclear translocation. An inhibitor assay using tin protoporphyrin IX (SnPP) confirmed that the enhancement of HO-1 by pre-treatment with THF protects SH-SY5y cells from CoCl2-induced neurotoxicity under hypoxic conditions. Our results demonstrate the advantageous effects of THF against hypoxia-induced neurotoxicity through the HO-1/Nrf2 signaling pathway and provide a therapeutic insight for neurodegenerative disorders.

scholarly journals Kyungheechunggan-Tang-01, a New Herbal Medication, Suppresses LPS-Induced Inflammatory Responses through JAK/STAT Signaling Pathway in RAW 264.7 Macrophages

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Hee-Soo Han ◽  
Eungyeong Jang ◽  
Ji-Sun Shin ◽  
Kyung-Soo Inn ◽  
Jang-Hoon Lee ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Molecular Data ◽  
Mrna Levels ◽  
Protein Levels ◽  
Stat3 Phosphorylation ◽  
Stat Signaling ◽  
Cox 2 ◽  
Anti Inflammatory

Medicinal plants have been used as alternative therapeutic tools to alleviate inflammatory diseases. The objective of this study was to evaluate anti-inflammatory properties of Kyungheechunggan-tang- (KCT-) 01, KCT-02, and Injinchunggan-tang (IJCGT) as newly developed decoctions containing 3–11 herbs in LPS-induced macrophages. KCT-01 showed the most potent inhibitory effects on LPS-induced NO, PGE2, TNF-α, and IL-6 production among those three herbal formulas. In addition, KCT-01 significantly inhibited LPS-induced iNOS and COX-2 at protein levels and expression of iNOS, COX-2, TNF-α, and IL-6 at mRNA levels. Molecular data revealed that KCT-01 attenuated the activation of JAK/STAT signaling cascade without affecting NF-κB or AP-1 activation. In ear inflammation induced by croton oil, KCT-01 significantly reduced edema, MPO activity, expression levels of iNOS and COX-2, and STAT3 phosphorylation in ear tissues. Taken together, our findings suggest that KCT-01 can downregulate the expression of proinflammatory genes by inhibiting JAK/STAT signaling pathway under inflammatory conditions. This study provides useful data for further exploration and application of KCT-01 as a potential anti-inflammatory medicine.

scholarly journals (Pro)renin receptor regulates autophagy and apoptosis in podocytes exposed to high glucose

2015 ◽  
Vol 309 (3) ◽  
pp. E302-E310 ◽  
Author(s):  
Caixia Li ◽  
Helmy M. Siragy
Keyword(s):  
Signaling Pathway ◽  
High Glucose ◽  
Caspase 3 ◽  
Mtor Signaling ◽  
Autophagic Flux ◽  
Bafilomycin A1 ◽  
Mtor Signaling Pathway ◽  
Autophagosome Formation ◽  
Podocyte Injury ◽  
Protein Levels

High glucose reduces autophagy and enhances apoptosis of podocytes. Previously, we reported that high glucose induced podocyte injury through upregulation of the (pro)renin receptor (PRR). We hypothesized that increasing PRR reduces autophagy and increases apoptosis of mouse podocytes exposed to high glucose via activation of the PI3K/Akt/mTOR signaling pathway. Mouse podocytes were cultured in normal (5 mmol/l) or high (25 mmol/l) d-glucose for 48 h. High glucose significantly increased mRNA and protein levels of PRR, phosphorylation of PI3K/Akt/mTOR, and p62. In contrast, high glucose decreased activation of UNC-51-like kinase-1 (ULK1) by phosphorylating Ser757 and protein levels of microtubule-associated protein-1 light chain 3B (LC3B)-II and Lamp-2. Bafilomycin A1 increased LC3BII and p62 accumulation in high-glucose-treated cells. High glucose reduced the autophagic flux. Confocal microscopy studies showed significant reduction in the protein level of LC3B in response to high glucose. Cyto-ID autophagy staining showed a significant decrease in autophagosome formation with high glucose. In the absence of PRR, activation of Akt with sc-79 or mTOR with MHY-1485 increased p62 accumulation. Caspase-3/7 activity and apoptosis monitored by TUNEL assay were significantly increased in podocytes treated with high glucose. PRR siRNA significantly reversed the effects of high glucose. Based on these data, we conclude that high glucose decreases autophagy and increases apoptosis in mouse podocytes through the PRR/PI3K/Akt/mTOR signaling pathway.

scholarly journals Loureirin B Inhibits Hypertrophic Scar Formation via Inhibition of the TGF-β1-ERK/JNK Pathway

2015 ◽  
Vol 37 (2) ◽  
pp. 666-676 ◽  
Author(s):  
Ting He ◽  
Xiaozhi Bai ◽  
Longlong Yang ◽  
Lei Fan ◽  
Yan Li ◽  
...  
Keyword(s):  
Hypertrophic Scar ◽  
Ex Vivo ◽  
Scar Tissue ◽  
Scar Formation ◽  
Jnk Pathway ◽  
Protein Levels ◽  
Mapk Inhibitors ◽  
Hypertrophic Scar Tissue ◽  
Loureirin B ◽  
Tgf Β1

Background/Aims: Our previous study confirmed that Loureirin B (LB) can inhibit hypertrophic scar formation. However, the mechanism of LB-mediated inhibition of scar formation is still unknown. Methods: Immunohistochemistry was used to detect expression of Col1, FN and TGF-β1 in skin and scar tissue. Fibroblasts were stimulated with TGF-β1 to mimic scar formation. LB or MAPK inhibitors were used to study the pathways involved in the process. Western blotting was used to evaluate the expression of p-JNK, p-ERK, p-p38, Col1 and FN. The contractile capacity of fibroblasts was evaluated using a gel contraction assay. Tissues were cultured ex vivo with LB to further investigate the participation of ERK and JNK in the LB-mediated inhibition of scar formation. Results: FN and Col1 were up regulated in hypertrophic scars. LB down regulated p-ERK and p-JNK in TGF-β1-stimulated fibroblasts, while levels of phosphorylated p38 did not change. The down regulation of p-ERK and p-JNK was associated with a reduction of Col1 and FN. Similarly, inhibition of ERK and JNK down regulated the expression of Col1 and FN in TGF-β1-stimulated fibroblasts. LB down regulated protein levels of p-ERK and p-JNK in cultured hypertrophic scar tissue ex vivo. Conclusions: This study suggests that LB can inhibit scar formation through the ERK/JNK pathway.

scholarly journals Anti-Inflammatory Effect of Auranofin on Palmitic Acid and LPS-Induced Inflammatory Response by Modulating TLR4 and NOX4-Mediated NF-κB Signaling Pathway in RAW264.7 Macrophages

2021 ◽  
Vol 22 (11) ◽  
pp. 5920
Author(s):  
Hyun Hwangbo ◽  
Seon Yeong Ji ◽  
Min Yeong Kim ◽  
So Young Kim ◽  
Hyesook Lee ◽  
...  
Keyword(s):  
Palmitic Acid ◽  
Signaling Pathway ◽  
Chronic Inflammation ◽  
Inhibitory Effect ◽  
Simultaneous Treatment ◽  
Monocyte Chemoattractant Protein 1 ◽  
Protein Levels ◽  
Raw264.7 Macrophages ◽  
Anti Inflammatory ◽  
Factor Α

Chronic inflammation, which is promoted by the production and secretion of inflammatory mediators and cytokines in activated macrophages, is responsible for the development of many diseases. Auranofin is a Food and Drug Administration-approved gold-based compound for the treatment of rheumatoid arthritis, and evidence suggests that auranofin could be a potential therapeutic agent for inflammation. In this study, to demonstrate the inhibitory effect of auranofin on chronic inflammation, a saturated fatty acid, palmitic acid (PA), and a low concentration of lipopolysaccharide (LPS) were used to activate RAW264.7 macrophages. The results show that PA amplified LPS signals to produce nitric oxide (NO) and various cytokines. However, auranofin significantly inhibited the levels of NO, monocyte chemoattractant protein-1, and pro-inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor-α, and IL-6, which had been increased by co-treatment with PA and LPS. Moreover, the expression of inducible NO synthase, IL-1β, and IL-6 mRNA and protein levels increased by PA and LPS were reduced by auranofin. In particular, the upregulation of NADPH oxidase (NOX) 4 and the translocation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) induced by PA and LPS were suppressed by auranofin. The binding between the toll-like receptor (TLR) 4 and auranofin was also predicted, and the release of NO and cytokines was reduced more by simultaneous treatment with auranofin and TLR4 inhibitor than by auranofin alone. In conclusion, all these findings suggested that auranofin had anti-inflammatory effects in PA and LPS-induced macrophages by interacting with TLR4 and downregulating the NOX4-mediated NF-κB signaling pathway.

Discussion On The Mechanism of Que In The Treatment of Breast Neoplasms And Immune Prevention And Treatment

2021 ◽  
Author(s):  
Dan Qiu ◽  
Xianxin Yan ◽  
Xinqin Xiao ◽  
Guijuan Zhang ◽  
Yanqiu Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Breast Neoplasms ◽  
Signaling Pathway ◽  
Immune Regulation ◽  
Γδ T Cells ◽  
Protein Levels ◽  
Stat1 Signaling ◽  
Mcf 7

Abstract Background: The precancerous disease of breast cancer is an inevitable stage in the emergence and development of breast neoplasms. Breast cancer (BC) is a common malignant tumor in female worldwide. A large number of literatures have proved that, as antitumor drugs, flavonoid compounds can promote proliferation and immune regulation of T cell. Many researchers believe that Quercetin (Que) has great potential in the field of anti-breast cancer. Besides that, γδ T cells are a class of non-traditional T cells, which have long attracted attention due to their potential in immunotherapy. Above all, JAK/STAT1 signaling pathway is closely related to the immunity.MethodsIn the experiment designed in this paper, we first used Que, one of the flavonoids, to screen the target gene. Then, MCF-10A, MCF-10AT, MCF-7 and MDA-MB231 BC cells were co-cultured with Que for 24h and 48h, apoptosis was found in some the cells. We then cultured Que with γδ T cells and found that Que can promote the proliferation of Vδ2 T cell subsets of γδ T cells, thus enhancing the killing effect of γδ T cells. Western blot was use to showed the change of JAK/STAT1 signaling pathway related proteins after the Que was co-cultured with MCF-10AT and MCF-7 for 48h.ResultsNetwork pharmacology has shown that Que related pathways include the JAK/STAT1 signaling pathway and are associated with precancerous breast cancers. Que induced apoptosis of MCF-10AT, MCF-7 and MDA-MB-231 in a time and concentration-dependent manner. Most importantly, Que can promote the differentiation of γδ T cells into the Vδ2 T cell subpopulation, this means that Que and γδ T cells may play a synergistic role in killing tumor cells and cellular immune regulation. In addition, our results showed that Que can increase in protein levels of IFNγ-R, p-JAK2 and p-STAT1, while the concomitant decrease protein levels of PD-L1.ConclusionsIn conclusion, Que plays a synergistic role in killing BC cells and promoting apoptosis by regulating the expression of IFNγ-R, p-JAK2, p-STAT1, and PD-L1 in the JAK/STAT1 signaling pathway and promoting the regulation of γδ T cells. Que may be a potential drug for the prevention of precancerous breast cancer and adjuvant treatment of BC.

Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy

2001 ◽  
Vol 281 (6) ◽  
pp. R2048-R2058 ◽  
Author(s):  
Abram M. Madiehe ◽  
Ling Lin ◽  
Christy White ◽  
H. Doug Braymer ◽  
George A. Bray ◽  
...  
Keyword(s):  
Dna Binding ◽  
Signaling Pathway ◽  
Leptin Receptor ◽  
Binding Activity ◽  
Janus Kinase ◽  
Adrenal Steroids ◽  
Western Blots ◽  
Protein Levels ◽  
Dna Binding Activity ◽  
Stat Signaling

Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the development of many forms of obesity in rodents, including those that are leptin or leptin receptor deficient. Obesity is associated with hyperleptinemia and leptin resistance. We hypothesized that glucocorticoids impair leptin receptor signaling and that removal thereof would activate the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway. The inhibitory effect of leptin (2.5 μg icv) on food intake was enhanced in ADX rats. A combination of ribonuclease protection assays, RT-PCR, Western blots, and mobility shift assays was used to evaluate the leptin signaling pathway in whole hypothalami from sham-operated, ADX and corticosterone-replaced ADX (ADX-R) Sprague-Dawley rats that were treated acutely with either saline vehicle or leptin intracerebroventricularly. ADX increased the expression of leptin receptor mRNA, increased STAT-3 mRNA and protein levels, induced constitutive STAT-3 phosphorylation and DNA binding activity, and also reduced suppressor of cytokine signaling-3 (SOCS-3) mRNA and protein levels. ADX and leptin treatment increased STAT-3 phosphorylation, but with no concomitant increase in DNA binding activity. Leptin and ADX decreased NPY mRNA expression, but their combination did not further decrease NPY mRNA. Corticosterone supplementation of ADX rats partially reversed many of these effects. In conclusion, ADX through activation of STAT-3 and inhibition of SOCS-3 activates the JAK-STAT signaling pathway. These effects most probably explain the ability to prevent the development of obesity by removal of adrenal steroids.

scholarly journals Nonstructural 3 Protein of Hepatitis C Virus Modulates the Tribbles Homolog 3/Akt Signaling Pathway for Persistent Viral Infection

2016 ◽  
Vol 90 (16) ◽  
pp. 7231-7247 ◽  
Author(s):  
Si C. Tran ◽  
Tu M. Pham ◽  
Lam N. Nguyen ◽  
Eun-Mee Park ◽  
Yun-Sook Lim ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Viral Infection ◽  
Er Stress ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Hcv Rna ◽  
Akt Signaling Pathway ◽  
Protein Levels ◽  
Persistent Viral Infection ◽  
Infected Cells

ABSTRACTHepatitis C virus (HCV) infection often causes chronic hepatitis, liver cirrhosis, and ultimately hepatocellular carcinoma. However, the mechanisms underlying HCV-induced liver pathogenesis are still not fully understood. By transcriptome sequencing (RNA-Seq) analysis, we recently identified host genes that were significantly differentially expressed in cell culture-grown HCV (HCVcc)-infected cells. Of these, tribbles homolog 3 (TRIB3) was selected for further characterization. TRIB3 was initially identified as a binding partner of protein kinase B (also known as Akt). TRIB3 blocks the phosphorylation of Akt and induces apoptosis under endoplasmic reticulum (ER) stress conditions. HCV has been shown to enhance Akt phosphorylation for its own propagation. In the present study, we demonstrated that both mRNA and protein levels of TRIB3 were increased in the context of HCV replication. We further showed that promoter activity of TRIB3 was increased by HCV-induced ER stress. Silencing of TRIB3 resulted in increased RNA and protein levels of HCV, whereas overexpression of TRIB3 decreased HCV replication. By employing an HCV pseudoparticle entry assay, we further showed that TRIB3 was a negative host factor involved in HCV entry. Bothin vitrobinding and immunoprecipitation assays demonstrated that HCV NS3 specifically interacted with TRIB3. Consequently, the association of TRIB3 and Akt was disrupted by HCV NS3, and thus, TRIB3-Akt signaling was impaired in HCV-infected cells. Moreover, HCV modulated TRIB3 to promote extracellular signal-regulated kinase (ERK) phosphorylation, activator protein 1 (AP-1) activity, and cell migration. Collectively, these data indicate that HCV exploits the TRIB3-Akt signaling pathway to promote persistent viral infection and may contribute to HCV-mediated pathogenesis.IMPORTANCETRIB3 is a pseudokinase protein that acts as an adaptor in signaling pathways for important cellular processes. So far, the functional involvement of TRIB3 in virus-infected cells has not yet been demonstrated. We showed that both mRNA and protein expression levels of TRIB3 were increased in the context of HCV RNA replication. Gene silencing of TRIB3 increased HCV RNA and protein levels, and thus, overexpression of TRIB3 decreased HCV replication. TRIB3 is known to promote apoptosis by negatively regulating the Akt signaling pathway under ER stress conditions. Most importantly, we demonstrated that the TRIB3-Akt signaling pathway was disrupted by NS3 in HCV-infected cells. These data provide evidence that HCV modulates the TRIB3-Akt signaling pathway to establish persistent viral infection.

Sign in / Sign up

Export Citation Format

Share Document