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

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.

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Neuroprotective effect of NDEELNK from sea cucumber ovum against scopolamine-induced PC12 cells damage through enhancing energy metabolism and upregulation of PKA/BDNF/NGF signaling pathway

Food & Function ◽

10.1039/d1fo00631b ◽

2021 ◽

Author(s):

Yue Zhao ◽

Yifei Dong ◽

Qi Ge ◽

Pengbo Cui ◽

Na Sun ◽

...

Keyword(s):

Energy Metabolism ◽

Signaling Pathway ◽

Pc12 Cells ◽

Sea Cucumber ◽

Molecular Mechanisms ◽

Neuroprotective Effect ◽

Ngf Signaling ◽

Neuroprotective Function

The aim of study was to evaluate the neuroprotective function of sea cucumber ovum peptides-derived NDEELNK and explore underlying molecular mechanisms. NDEELNK exerted neuroprotective effect by improving the acetylcholine (ACh)...

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MiR-128-3p Post-Transcriptionally Inhibits WISP1 to Suppress Apoptosis and Inflammation in Human Articular Chondrocytes via the PI3K/AKT/NF-κB Signaling Pathway

Cell Transplantation ◽

10.1177/0963689720939131 ◽

2020 ◽

Vol 29 ◽

pp. 096368972093913

Author(s):

Shujun Chen ◽

Bo Li

Keyword(s):

Signaling Pathway ◽

Proinflammatory Cytokines ◽

Molecular Mechanisms ◽

Articular Chondrocytes ◽

Negative Regulator ◽

Luciferase Reporter ◽

Luciferase Reporter Gene ◽

Gene Assay ◽

Induced Apoptosis

In osteoarthritis (OA), the synthesis and decomposition of the extracellular matrix (ECM) are imbalanced. High expression levels of Wnt1-inducible signaling pathway protein 1 (WISP1) promote the synthesis of matrix metalloproteinases and induce the degradation of cartilage, which aggravates the OA. The aim of this study was to explore the role of miR-128-3p in the development of OA. In the present study, the expression of WISP1 and miR-128-3p in osteoarthritic tissues and chondrocytes was detected using quantitative reverse transcription PCR (RT-qPCR) and Western blotting. Then we predicted that WISP1 might be a potential target gene of miR-128-3p by TargetScan and verified using luciferase reporter gene assay. The effect of miR-128-3p or WISP1 on chondrocytes was evaluated by cell proliferation assay, apoptosis, and caspase-3 activity assay. To further reveal the molecular mechanisms of miR-128-3p in osteoarthritic development, the degradation of chondrocyte matrix and production of proinflammatory cytokines in osteoarthritic chondrocyte model were detected by ELISA. To mimic the osteoarthritic microenvironment in vitro studies, chondrocytes were stimulated with interleukin (IL)-1β, and then we found that the expression of miR-128-3p was downregulated. Overexpression of WISP1 inhibited the proliferation of chondrocytes, which induced apoptosis, degradation of chondrocyte matrix, production of proinflammatory cytokines, and activated the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Then, we identified that miR-128-3p was a negative regulator of WISP1 by directly targeting its 3′-untranslated region (UTR). Moreover, the PI3K allosteric activator 740 Y-P abolished the inhibition of miR-128-3p in apoptosis, degradation of chondrocyte matrix, and inflammation. Our results showed that miR-128-3p targets WISP1 to regulate chondrocyte proliferation, apoptosis, degradation of chondrocyte matrix, and production of proinflammatory cytokines via the PI3K/Akt/NF-κB pathway, which plays a suppressed role in OA.

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Dab1 Contributes to Angiotensin II-Induced Apoptosis via p38 Signaling Pathway in Podocytes

BioMed Research International ◽

10.1155/2017/2484303 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Zhao Gao ◽

Xinghua Chen ◽

Kai Zhu ◽

Ping Zeng ◽

Guohua Ding

Keyword(s):

Angiotensin Ii ◽

Signaling Pathway ◽

Underlying Mechanism ◽

Vital Role ◽

Protective Effects ◽

Ang Ii ◽

Induced Apoptosis ◽

End Stage ◽

Interfering Rna

Numerous studies have found that angiotensin II (Ang II) participates in podocyte apoptosis and exacerbates progression of end-stage kidney disease (ESKD). However, its underlying mechanism remains largely unexplored. As a homolog of Drosophila disabled (Dab) protein, Dab1 plays a vital role in cytoskeleton, neuronal migration, and proliferation. In the present study, our data revealed that Ang II-infused rats developed hypertension, proteinuria, and podocyte injury accompanied by Dab1 phosphorylation and increased reelin expression in kidney. Moreover, Ang II induced podocyte apoptosis in vitro. Dab1 phosphorylation and reelin expression in podocytes were increased after exposure to Ang II. Conversely, Dab1 small interfering RNA (siRNA) exerted protective effects on Ang II-induced podocyte apoptosis, resulting in decreased p38 phosphorylation and reelin expression. These results indicated that Dab1 mediated Ang II-induced podocyte apoptosis via p38 signaling pathway.

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Exploring the Mechanism of Panax notoginseng Saponins against Alzheimer’s Disease by Network Pharmacology and Experimental Validation

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/5730812 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Yixuan Jiang ◽

Shanliang Li ◽

Xiaoqin Xie ◽

Hemei Li ◽

Panling Huang ◽

...

Keyword(s):

Pc12 Cells ◽

Neuroprotective Effect ◽

Panax Notoginseng ◽

Network Pharmacology ◽

Protective Effects ◽

Panax Notoginseng Saponins ◽

Active Ingredients ◽

Target Disease ◽

And Function

Background. Panax notoginseng saponins (PNS) have been used for neurodegenerative disorders such as cerebral ischemia and Alzheimer’s disease (AD). Although increasing evidences show the neuron protective effects of PNS, the vital compounds and their functional targets remain elusive. To explore the potential functional ingredients of PNS for the AD treatment and their molecular mechanisms, an in vitro neuron injured model induced by Aβ was investigated, and the potential mechanism was predicted by network pharmacology approach and validated by molecular biology methods. Methods. Network pharmacology approach was used to reveal the relationship between ingredient-target disease and function-pathway of PNS on the treatment of AD. The active ingredients of PNS were collected from TCMSP, PubChem database, and literature mining in PubMed database. DrugBank and GeneCards database were used to predict potential targets for AD. The STRING database was performed to reveal enrichment of these target proteins, protein-protein interactions, and related pathways. Networks were visualized by utilizing Cytoscape software. The enrichment analysis was performed by the DAVID database. Finally, neuroprotective effect and predictive mechanism of PNS were investigated in an in vitro AD model established by Aβ25–35-treated PC12 cells. Results. An ingredient-target disease and function-pathway network demonstrated that 38 active ingredients were derived from PNS modulated 364 common targets shared by PNS and AD. GO and KEGG analysis, further clustering analysis, showed that mTOR signaling targets were associated with the neuroprotective effects of PNS. In Aβ-treated PC12 cells, PNS treatment improved neuroprotective effect, including mTOR inhibition and autophagy activation. Conclusions. Collectively, the protective effects of PNS on AD-neuron injury are related to the inhibition of mTOR and autophagy activation.

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Valproic Acid Promotes Human Glioma U87 Cells Apoptosis and Inhibits Glycogen Synthase Kinase-3β Through ERK/Akt Signaling

Cellular Physiology and Biochemistry ◽

10.1159/000447912 ◽

2016 ◽

Vol 39 (6) ◽

pp. 2173-2185 ◽

Cited By ~ 22

Author(s):

Chi Zhang ◽

Songlin Liu ◽

Xianrui Yuan ◽

Zhongliang Hu ◽

Haoyu Li ◽

...

Keyword(s):

Valproic Acid ◽

Molecular Mechanisms ◽

Glycogen Synthase ◽

Strong Suppression ◽

Pi3k Inhibitor Ly294002 ◽

Flow Cytometric ◽

Induced Apoptosis ◽

Hoechst Staining ◽

U87 Cells

Background: Valproic acid (VPA), an established antiepileptic drug, was assessed for antitumor activity, including its effects on glioblastoma, but its role has not been determined. Methods: In the present study, we investigated VPA-induced apoptosis effects on human U87 cells by cell viability, lactate dehydrogenase (LDH) release, TUNEL/Hoechst staining and flow cytometric in vitro, then we further explored the underlying molecular mechanisms using the selective antagonists PD98059, LY294002 and SB216763. Results: The data showed that VPA dose-dependent induction of glioma U87 cells to undergo apoptosis through the mitochondria-dependent pathway in vitro. VPA activated the ERK/Akt pathways by increasing their protein phosphorylation and in turn inhibited GKS3β activation by the induction of GKS3β phosphorylation. However, the MAPK inhibitor PD98059 and/or PI3K inhibitor LY294002 were able to antagonize the effects of VPA by abolishing ERK/Akt activations and cancelling GSK3β suppression, thus it impaired VPA apoptosis-inducing effects on glioma cells. Furthermore, the GSK3β inhibitor SB216763 caused a strong suppression of GSK3β activity, which showed similar effects of VPA on regulation of protein expression and apoptosis. Conclusion: These findings suggest that GSK3β may be the central hub for VPA-induced apoptosis and VPA can be further evaluated as a novel agent for glioma therapy.

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Protective effects of hederagenic acid on PC12 cells against the OGD/R-induced apoptosis via activating Nrf2/ARE signaling pathway

Medicinal Chemistry Research ◽

10.1007/s00044-019-02464-9 ◽

2019 ◽

Vol 29 (1) ◽

pp. 103-112 ◽

Cited By ~ 1

Author(s):

Huankai Yao ◽

Yeling Liu ◽

Guihua Zhu ◽

Yinyin Duan ◽

Huiling Wu ◽

...

Keyword(s):

Signaling Pathway ◽

Pc12 Cells ◽

Protective Effects ◽

Induced Apoptosis

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Resveratrol Protects PC12 Cell against 6-OHDA Damage via CXCR4 Signaling Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/730121 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Jing Zhang ◽

Wenchuang Fan ◽

Hui Wang ◽

Lihua Bao ◽

Guibao Li ◽

...

Keyword(s):

Signaling Pathway ◽

Pc12 Cells ◽

Molecular Mechanisms ◽

Neuronal Damage ◽

Neuroprotective Effect ◽

Immunofluorescent Staining ◽

Double Staining ◽

Polyphenolic Compound ◽

Neuroprotective Effects ◽

Cxcr4 Signaling

Resveratrol, herbal nonflavonoid polyphenolic compound naturally derived from grapes, has long been acknowledged to possess extensive biological and pharmacological properties including antioxidant and anti-inflammatory ones and may exert a neuroprotective effect on neuronal damage in neurodegenerative diseases. However, the underlying molecular mechanisms remain undefined. In the present study, we intended to investigate the neuroprotective effects of resveratrol against 6-OHDA-induced neurotoxicity of PC12 cells and further explore the possible mechanisms involved. For this purpose, PC12 cells were exposed to 6-OHDA in the presence of resveratrol (0, 12.5, 25, and 50 μM). The results showed that resveratrol increased cell viability, alleviated the MMP reduction, and reduced the number of apoptotic cells as measured by MTT assay, JC-1 staining, and Hoechst/PI double staining (allp<0.01). Immunofluorescent staining and Western blotting revealed that resveratrol averts 6-OHDA induced CXCR4 upregulation (p<0.01). Our results demonstrated that resveratrol could effectively protect PC12 cells from 6-OHDA-induced oxidative stress and apoptosis via CXCR4 signaling pathway.

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Selenium Attenuates Chronic Heat Stress-Induced Apoptosis via the Inhibition of Endoplasmic Reticulum Stress in Mouse Granulosa Cells

Molecules ◽

10.3390/molecules25030557 ◽

2020 ◽

Vol 25 (3) ◽

pp. 557 ◽

Cited By ~ 3

Author(s):

Yongjie Xiong ◽

Qirun Yin ◽

Erhui Jin ◽

Huatao Chen ◽

Shaojun He

Keyword(s):

Heat Stress ◽

Er Stress ◽

Granulosa Cells ◽

Molecular Mechanisms ◽

Caspase 3 ◽

Protective Action ◽

Protective Effects ◽

Expression Levels ◽

Induced Apoptosis

Heat stress induces apoptosis in various cells. Selenium, an essential micronutrient, has beneficial effects in maintaining the cellular physiological functions. However, its potential protective action against chronic heat stress (CHS)-induced apoptosis in granulosa cells and the related molecular mechanisms are not fully elucidated. In this study, we investigated the roles of selenium in CHS-induced apoptosis in mouse granulosa cells and explored its underlying mechanism. The heat treatment for 6–48 h induced apoptosis, potentiated caspase 3 activity, increased the expression levels of apoptosis-related gene BAX and ER stress markers, glucose-regulated protein 78 (GRP78), and CCAAT/enhancer binding protein homologous protein (CHOP) in mouse granulosa cells. The treatment with ER stress inhibitor 4-PBA significantly attenuated the adverse effects caused by CHS. Selenium treatment significantly attenuated the CHS- or thapsigargin (Tg, an ER stress activator)-induced apoptosis, potentiation of caspase 3 activity, and the increased protein expression levels of BAX, GRP78, and CHOP. Additionally, treatment of the cells with 5 ng/mL selenium significantly ameliorated the levels of estradiol, which were decreased in response to heat exposure. Consistently, administering selenium supplement alleviated the hyperthermia-caused reduction in the serum estradiol levels in vivo. Together, our findings indicate that selenium has protective effects on CHS-induced apoptosis via inhibition of the ER stress pathway. The current study provides new insights in understanding the role of selenium during the process of heat-induced cell apoptosis.

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Hederagenin Protects PC12 Cells Against Corticosterone-Induced Injury by the Activation of the PI3K/AKT Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.712876 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ruohong Lin ◽

Linlin Liu ◽

Marta Silva ◽

Jiankang Fang ◽

Zhiwei Zhou ◽

...

Keyword(s):

Pc12 Cells ◽

Molecular Mechanisms ◽

Glycogen Synthase ◽

Biological Activities ◽

Neuroprotective Effect ◽

Akt Pathway ◽

Triterpenoid Saponin ◽

Dependent Manner ◽

Neuroprotective Effects ◽

Concentration Dependent Manner

Depression is a prevalent psychiatric disorder and a leading cause of disability worldwide. Despite a variety of available treatments currently being used in the clinic, a substantial proportion of patients is unresponsive to these treatments, urging the development of more effective therapeutic approaches. Hederagenin (Hed), a triterpenoid saponin extracted from Fructus Akebiae, has several biological activities including anti-apoptosis, anti-hyperlipidemic and anti-inflammatory properties. Over the years, its potential therapeutic effect in depression has also been proposed, but the information is limited and the mechanisms underlying its antidepressant-like effects are unclear. The present study explored the neuroprotective effects and the potential molecular mechanisms of Hederagenin action in corticosterone (CORT)-injured PC12 cells. Obtained results show that Hederagenin protected PC12 cells against CORT-induced damage in a concentration dependent manner. In adittion, Hederagenin prevented the decline of mitochondrial membrane potential, reduced the production of intracellular reactive oxygen species (ROS) and decreased the apoptosis induced by CORT. The protective effect of Hederagenin was reversed by a specific phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and AKT (also known as protein kinase B) inhibitor MK2206, suggesting that the effect of Hederagenin is mediated by the PI3K/AKT pathway. In line with this, western blot analysis results showed that Hederagenin stimulated the phosphorylation of AKT and its downstream target Forkhead box class O 3a (FoxO3a) and Glycogen synthase kinase-3-beta (GSK3β) in a concentration dependent manner. Taken together, these results indicate that the neuroprotective effect of Hederagenin is likely to occur via stimulation of the PI3K/AKT pathway.

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VDAC1 Mediated Anticancer Activity of Gallic Acid in Human Lung Adenocarcinoma A549 Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520617666170912115441 ◽

2018 ◽

Vol 18 (2) ◽

pp. 255-262 ◽

Cited By ~ 5

Author(s):

Aikebaier Maimaiti ◽

Amier Aili ◽

Hureshitanmu Kuerban ◽

Xuejun Li

Keyword(s):

Western Blot ◽

Cell Viability ◽

Gallic Acid ◽

Molecular Mechanisms ◽

A549 Cells ◽

Dependent Manner ◽

Lung Carcinoma Cells ◽

Induced Apoptosis ◽

The Impact

Aims: Gallic acid (GA) is generally distributed in a variety of plants and foods, and possesses cell growth-inhibiting activities in cancer cell lines. In the present study, the impact of GA on cell viability, apoptosis induction and possible molecular mechanisms in cultured A549 lung carcinoma cells was investigated. Methods: In vitro experiments showed that treating A549 cells with various concentrations of GA inhibited cell viability and induced apoptosis in a dose-dependent manner. In order to understand the mechanism by which GA inhibits cell viability, comparative proteomic analysis was applied. The changed proteins were identified by Western blot and siRNA methods. Results: Two-dimensional electrophoresis revealed changes that occurred to the cells when treated with or without GA. Four up-regulated protein spots were clearly identified as malate dehydrogenase (MDH), voltagedependent, anion-selective channel protein 1(VDAC1), calreticulin (CRT) and brain acid soluble protein 1(BASP1). VDAC1 in A549 cells was reconfirmed by western blot. Transfection with VDAC1 siRNA significantly increased cell viability after the treatment of GA. Further investigation showed that GA down regulated PI3K/Akt signaling pathways. These data strongly suggest that up-regulation of VDAC1 by GA may play an important role in GA-induced, inhibitory effects on A549 cell viability.

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