scholarly journals GLP-1 receptor regulates cell growth through regulating IDE expression level in Aβ1–42-treated PC12 cells

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Huajie Li ◽  
Liping Cao ◽  
Yi Ren ◽  
Ying Jiang ◽  
Wei Xie ◽  
...  
Keyword(s):  
Cell Growth ◽  
Signaling Pathway ◽  
Pc12 Cells ◽  
Neuronal Apoptosis ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Expression Level ◽  
Tunel Staining ◽  
Protective Effects ◽  
Insulin Degrading Enzyme

This study aimed to validate whether glucagon-like peptide-1 receptor (GLP-1R) / cyclic adenosine monophosphate (cAMP) / protein kinase (PKA) / insulin-degrading enzyme (IDE) signaling pathway was associated with neuronal apoptosis. We developed an animal model presenting both Alzheimer’s disease (AD) and type 2 diabetes (T2D), by crossing APP/PS1 mice (AD model) with streptozotocin (STZ)-treated mice (a T2D model). Neuronal apoptosis was detected by TUNEL staining and the expression levels of apoptosis-related proteins were examined by Western blotting. The viability of PC12 cells was analyzed by MTT assay and apoptosis of PC12 cells was detected by flow cytometry. The mRNA expression level was detected by qRT-PCR. T2D contributes to AD progress by prompting neuronal apoptosis and increasing expression of pro-apoptotic protein. β-Amyloid peptide1–42 (Aβ1–42) was shown to exert effects on inhibiting cell viability and prompting cell apoptosis of PC12 cells. However, GLP-1R agonist geniposide (Gen) significantly reversed them, exerting a protective role on PC12 cells. And IDE antagonist bacitracin (Bac) markedly reversed the protective effects of Gen on Aβ1–42-treated PC12 cells. Besides, Gen significantly reversed the effects of Aβ1–42 treatment on IDE expression, and the inhibitor of cAMP/PKA signaling pathway markedly reversed the effects of Gen on IDE expression level in Aβ1–42-treated PC12 cells. In conclusion, GLP-1R regulates cell growth, at least partially, through regulating cAMP/PKA/IDE signaling pathway in Aβ1–42-treated PC12 cells.

BAY 73-6691 Alters Neuron Plasticity and Phosphorylation of Tau Through Regulation of Cyclic Guanosine Monophosphate/Protein Kinase G/Cyclic Adenosine Monophosphate Response Element-Binding Protein Pathway

2021 ◽  
Vol 11 (2) ◽  
pp. 295-301
Author(s):  
Hui Jiang ◽  
Yan Zheng ◽  
Jie Ni ◽  
Yun Xu
Keyword(s):  
Synaptic Plasticity ◽  
Pc12 Cells ◽  
Senile Plaques ◽  
Protein A ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Protective Effects ◽  
Western Blots ◽  
Related Proteins

Alzheimer’s disease (AD) is one of neurodegenerative diseases characterized by cognitive and memory decline, accompanying with neurofibrillary tangles (NFTs) made of hyperphosphorylated tau protein and senile plaques (SP) accumulated by β-amyloid protein (Aβ). BAY 73-6691, an inhibitor of phosphodiesterase-9 (PDE-9), can improve learning and memory of elderly rats. However, the effects of BAY 73-6691 on neuroapoptotic and neuroinflammatory events, as well as synaptic plasticity of differentiated PC12 cells are remain unclear. In this work, we screened apoptotic cells induced by Aβ25-35 via flow cytometry. TNF-α, IL-1β, IL-6 secreted by PC12 cells were estimated by ELISA kits. The levels of cGMP, PKG and CREB mediated by BAY 73-6691 were assessed. Moreover, we conducted western blots analysis to evaluate the phosphorylation of tau and synaptic related proteins. Results showed that BAY 73-6691 could reduce Aβ25-35-triggered neuroapoptosis and neuroinflammation. Phosphorylation of tau was inhibited by BAY 73-6691, whereas sildenafil citrate (SC, an inhibitor of cGMP) partially weakened the effect of BAY 73-6691. Additionally, synaptic plasticity restored by BAY 73-6691 was also suppressed via SC. Taken together, BAY 73-6691 exhibited neuro protective effects, and altered tau phosphorylation as well as synaptic related proteins through cGMP/PKG/CREB pathway.

scholarly journals Isorhynchophylline Protects PC12 Cells Against Beta-Amyloid-Induced Apoptosis via PI3K/Akt Signaling Pathway

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Yan-Fang Xian ◽  
Zhi-Xiu Lin ◽  
Qing-Qiu Mao ◽  
Jian-Nan Chen ◽  
Zi-Ren Su ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Pc12 Cells ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Neuroprotective Effect ◽  
Protective Action ◽  
Protective Effects ◽  
Phosphorylated Akt ◽  
Induced Apoptosis

The neurotoxicity of amyloid-β(Aβ) has been implicated as a critical cause of Alzheimer’s disease. Isorhynchophylline (IRN), an oxindole alkaloid isolated fromUncaria rhynchophylla,exerts neuroprotective effect againstAβ25–35-induced neurotoxicityin vitro. However, the exact mechanism for its neuroprotective effect is not well understood. The present study aimed to investigate the molecular mechanisms underlying the protective action of IRN againstAβ25–35-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. Pretreatment with IRN significantly increased the cell viability, inhibited the release of lactate dehydrogenase and the extent of DNA fragmentation inAβ25–35-treated cells. IRN treatment was able to enhance the protein levels of phosphorylated Akt (p-Akt) and glycogen synthase kinase-3β(p-GSK-3β). Lithium chloride blockedAβ25–35-induced cellular apoptosis in a similar manner as IRN, suggesting that GSK-3βinhibition was involved in neuroprotective action of IRN. Pretreatment with LY294002 completely abolished the protective effects of IRN. Furthermore, IRN reversedAβ25–35-induced attenuation in the level of phosphorylated cyclic AMP response element binding protein (p-CREB) and the effect of IRN could be blocked by the PI3K inhibitor. These experimental findings unambiguously suggested that the protective effect of IRN againstAβ25–35-induced apoptosis in PC12 cells was associated with the enhancement of p-CREB expression via PI3K/Akt/GSK-3βsignaling pathway.

Matrine Protects PC12 Cells Against Aβ25–35-Induced Cytotoxicity, Oxidative Stress, Inflammation, Neuronal Apoptosis and Cell Senescence

2021 ◽  
Vol 11 (9) ◽  
pp. 1691-1697
Author(s):  
Huanli Zhang ◽  
Zhen Zhang
Keyword(s):  
Oxidative Stress ◽  
Cell Viability ◽  
Pc12 Cells ◽  
Neuronal Apoptosis ◽  
Inflammatory Responses ◽  
Neuronal Damage ◽  
Cell Senescence ◽  
Tunel Staining ◽  
Elisa Assay ◽  
Amyloid A

Background and Objectives: Beta-amyloid (Aβ) has pivotal functions in the pathogenesis of Alzheimer’s Disease (AD). The main purpose of this study is to explore the protective role and possible mechanisms of matrine against Aβ25–35-induced neurotoxicity in PC12 cells. Materials and Methods: A vitro model that involved Aβ25–35-induced neuronal damage in PC12 cells was adopted in the present study. Cell viability and apoptosis of PC12 cells were determined by CCK-8 assay and TUNEL staining, respectively. Intracellular ROS levels were determined by DCFH-DA probe and levels of TNFα, IL-6 and IL-1β were assessed by ELISA assay. In addition, telomerase reverse transcriptase (TERT) levels were determined by ELISA assay and telomere lengths were examined by real-time quantitative PCR analysis to assess telomerase activities. Furthermore, vital proteins related to cell apoptosis and hallmarks of senescence were detected by western blot analysis. Results: Matrine (10, 20, 50 μg/ml) dose-dependently protected cell viability against Aβ25–35 cytotoxicity in PC12 cells. Meanwhile, matrine at 10, 20, 50 μg/ml markedly reduced ROS production and downregulated the levels of TNFα, IL-6 and IL-1β in Aβ25–35-injuried PC12 cells. The results also proved that matrine may restore telomerase activities and telomere lengths in Aβ25–35-injuried PC12 cells by inhibiting inflammatory responses and oxidative stress. Neuronal apoptosis induced by Aβ25–35 were reversed upon cotreatment with matrine. Moreover, matrine markedly mitigated Aβ25–35 induced cell senescence in a concentration-dependentmanner. Conclusion: Our findings demonstrated that matrine protected PC12 cells against Aβ25–35-induced cytotoxicity, oxidative stress, inflammation, neuronal apoptosis and cell senescence.

scholarly journals Rh-CSF1 Attenuates Oxidative Stress and Neuronal Apoptosis via the CSF1R/PLCG2/PKA/UCP2 Signaling Pathway in a Rat Model of Neonatal HIE

2020 ◽  
Vol 2020 ◽  
pp. 1-20
Author(s):  
Xiao Hu ◽  
Shirong Li ◽  
Desislava Met Doycheva ◽  
Lei Huang ◽  
Cameron Lenahan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
Rat Model ◽  
Neuronal Apoptosis ◽  
Neuronal Degeneration ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Tunel Staining ◽  
Artery Ligation ◽  
Neuroprotective Effects

Oxidative stress (OS) and neuronal apoptosis are major pathological processes after hypoxic-ischemic encephalopathy (HIE). Colony stimulating factor 1 (CSF1), binding to CSF1 receptor (CSF1R), has been shown to reduce neuronal loss after hypoxic-ischemia- (HI-) induced brain injury. In the present study, we hypothesized that CSF1 could alleviate OS-induced neuronal degeneration and apoptosis through the CSF1R/PLCG2/PKA/UCP2 signaling pathway in a rat model of HI. A total of 127 ten-day old Sprague Dawley rat pups were used. HI was induced by right common carotid artery ligation with subsequent exposure to hypoxia for 2.5 h. Exogenous recombinant human CSF1 (rh-CSF1) was administered intranasally at 1 h and 24 h after HI. The CSF1R inhibitor, BLZ945, or phospholipase C-gamma 2 (PLCG2) inhibitor, U73122, was injected intraperitoneally at 1 h before HI induction. Brain infarct volume measurement, cliff avoidance test, righting reflex test, double immunofluorescence staining, western blot assessment, 8-OHdG and MitoSOX staining, Fluoro-Jade C staining, and TUNEL staining were used. Our results indicated that the expressions of endogenous CSF1, CSF1R, p-CSF1R, p-PLCG2, p-PKA, and uncoupling protein2 (UCP2) were increased after HI. CSF1 and CSF1R were expressed in neurons and astrocytes. Rh-CSF1 treatment significantly attenuated neurological deficits, infarct volume, OS, neuronal apoptosis, and degeneration at 48 h after HI. Moreover, activation of CSF1R by rh-CSF1 significantly increased the brain tissue expressions of p-PLCG2, p-PKA, UCP2, and Bcl2/Bax ratio, but reduced the expression of cleaved caspase-3. The neuroprotective effects of rh-CSF1 were abolished by BLZ945 or U73122. These results suggested that rh-CSF1 treatment attenuated OS-induced neuronal degeneration and apoptosis after HI, at least in part, through the CSF1R/PLCG2/PKA/UCP2 signaling pathway. Rh-CSF1 may serve as therapeutic strategy against brain damage in patients with HIE.

scholarly journals Interleukin-4 gene expression in activated human T lymphocytes is regulated by the cyclic adenosine monophosphate-dependent signaling pathway

Blood ◽  
1996 ◽  
Vol 87 (2) ◽  
pp. 691-698 ◽  
Author(s):  
P Borger ◽  
HF Kauffman ◽  
DS Postma ◽  
E Vellenga
Keyword(s):  
T Lymphocytes ◽  
Signaling Pathway ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Interleukin 4 ◽  
Con A ◽  
Activated T Cells ◽  
Gm Csf ◽  
Dose Dependent ◽  
Dependent Signaling Pathway

In the present study, we have investigated the involvement of the cyclic adenosine monophosphate (cAMP)-dependent signaling pathway on interleukin-4 (IL-4) gene expression in freshly isolated human T lymphocytes. 2′–0-dibutyryl cAMP (db-cAMP) and prostaglandin E2 (PGE2) were used to directly and indirectly activate the protein kinase A pathway. Northern analysis showed that concanavalin A (Con A)-, anti- CD3 (alpha CD3)-, or anti-CD3 plus anti-CD28 (alpha CD3/alpha CD28)- induced accumulation of IL-4 mRNA was inhibited by db-cAMP (10(-3) mol/L). Db-cAMP showed a steep dose-dependent inhibition; concentrations or = 10(-4) mol/L did not affect IL-4 mRNA accumulation. In contrast, GM-CSF mRNA expression showed a wider dose- dependent range; 10(-5) mol/L db-cAMP still affected GM-CSF accumulation. PGE2 inhibited the Con A- and alpha CD3/alpha CD28- induced accumulation of IL-4 mRNA in a dose-dependent fashion. Con A- induced IL-4 mRNA was inhibited by 10(-4) to 10(-7) mol/L PGE2; alpha CD3/alpha CD28-induced IL-4 mRNA was inhibited by 10(-5) to 10(-8) mol/L PGE2. Nuclear run-on experiments showed that the inhibitory effects of db-cAMP and PGE2 were accomplished at transcriptional level in Con A-activated T cells, whereas changes at transcriptional and posttranscriptional level were involved in alpha CD3/alpha CD28- activated T lymphocytes. In contrast to Con A and alpha CD3/alpha CD28 activation, phorbol myristate acetate plus A23187-induced IL-4 mRNA expression was insensitive to the inhibitory effect of db-cAMP and PGE2. Moreover, it appeared that the sensitivity for cAMP-mediated downregulation could not be blocked by stimulation T lymphocytes with alpha CD3/alpha CD28 in the presence of IL-2, IL-7, IL-10, IL-12, or a combination of these cytokines. Finally, it was shown that, in accordance with the mRNA studies, db-cAMP and PGE2 suppressed the IL-4 secretion in Con A- and alpha CD3/alpha CD28-activated T cells. In conclusion, these data show that IL-4 expression is negatively regulated by the protein kinase A-dependent signaling pathway by transcriptional and posttranscriptional mechanisms that depend on costimulatory signals.

scholarly journals Mel1c Mediated Monochromatic Light-Stimulated IGF-I Synthesis through the Intracellular Gαq/PKC/ERK Signaling Pathway

2019 ◽  
Vol 20 (7) ◽  
pp. 1682
Author(s):  
Shujie Ning ◽  
Zixu Wang ◽  
Jing Cao ◽  
Yulan Dong ◽  
Yaoxing Chen
Keyword(s):  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Monochromatic Light ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Erk Signaling ◽  
Sham Operation ◽  
Intracellular Signaling Pathway ◽  
Igf I

Previous studies have demonstrated that monochromatic light affects plasma melatonin (MEL) levels, which in turn regulates hepatic insulin-like growth factor I (IGF-I) secretion via the Mel1c receptor. However, the intracellular signaling pathway initiated by Mel1c remains unclear. In this study, newly hatched broilers, including intact, sham operation, and pinealectomy groups, were exposed to either white (WL), red (RL), green (GL), or blue (BL) light for 14 days. Experiments in vivo showed that GL significantly promoted plasma MEL formation, which was accompanied by an increase in the MEL receptor, Mel1c, as well as phosphorylated extracellular regulated protein kinases (p-ERK1/2), and IGF-I expression in the liver, compared to the other light-treated groups. In contrast, this GL stimulation was attenuated by pinealectomy. Exogenous MEL elevated the hepatocellular IGF-I level, which is consistent with increases in cyclic adenosine monophosphate (cAMP), Gαq, phosphorylated protein kinase C (p-PKC), and p-ERK1/2 expression. However, the Mel1c selective antagonist prazosin suppressed the MEL-induced expression of IGF-I, Gαq, p-PKC, and p-ERK1/2, while the cAMP concentration was barely affected. In addition, pretreatment with Ym254890 (a Gαq inhibitor), Go9863 (a PKC inhibitor), and PD98059 (an ERK1/2 inhibitor) markedly attenuated MEL-stimulated IGF-I expression and p-ERK1/2 activity. These results indicate that Mel1c mediates monochromatic GL-stimulated IGF-I synthesis through intracellular Gαq/PKC/ERK signaling.

scholarly journals Rottlerin Reduces cAMP/CREB-Mediated Melanogenesis via Regulation of Autophagy

2019 ◽  
Vol 20 (9) ◽  
pp. 2081 ◽  
Author(s):  
Nurinanda Prisky Qomaladewi ◽  
Mi-Yeon Kim ◽  
Jae Youl Cho
Keyword(s):  
Signaling Pathway ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Camp Response Element Binding ◽  
Sequential Process ◽  
Camp Response Element ◽  
Melanin Production ◽  
Melanocyte Stimulating Hormone ◽  
Cellular Autophagy

Melanogenesis is the sequential process of melanin production by melanocytes in order to protect the skin from harmful stimuli. Melanogenesis is disrupted by radiation exposure, which results in the differentiation of melanocytes into melanoma. Recently, some methods have been developed to maintain the instability of melanogenesis in melanoma by activating cellular autophagy. However, there is still a lack of knowledge about how autophagy is involved in the regulation of melanogenesis in melanoma cells. Here, we used rottlerin as an autophagy inducer to investigate the role of the cyclic adenosine monophosphate (cAMP)/cAMP response element binding (CREB) signaling pathway in melanogenesis. We found that rottlerin can inhibit melanin production by targeting cAMP, which is initially activated by alpha-melanocyte stimulating hormone (α-MSH). Our findings suggest that rottlerin has a pivotal role as an autophagy inducer in the regulation of melanogenesis by targeting the cAMP/CREB signaling pathway.

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