Stanniocalcin-1 Overexpression Prevents Depression-Like Behaviors Through Inhibition of the ROS/NF-κB Signaling Pathway

Background: Depression is a burdensome psychiatric disorder presenting with disordered inflammation and neural plasticity. We conducted this study with an aim to explore the effect of stanniocalcin-1 (STC1) on inflammation and neuron injury in rats with depression-like behaviors.Methods: A model of depression-like behaviors was established in Wistar rats by stress stimulation. Adeno-associated virus (AAV)-packaged STC1 overexpression sequence or siRNA against STC1 was introduced into rats to enhance or silence the STC1 expression. Moreover, we measured pro-inflammatory and anti-inflammatory proteins, superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) and reactive oxygen species (ROS) production. An in vitro model was induced in hippocampal neurons by CORT to explore the effect of STC1 on the neuron viability, toxicity and apoptosis. RT-qPCR and Western blot assay were employed to determine the expression of STC1 and nuclear factor κB (NF-κB) signaling pathway-related genes.Results: STC1 was under-expressed in the hippocampus of rats with depression-like behaviors, while its overexpression could reduce the depression-like behaviors in the stress-stimulated rats. Furthermore, overexpression of STC1 resulted in enhanced neural plasticity, reduced release of pro-inflammatory proteins, elevated SOD and CAT and diminished MDA level in the hippocampus of rats with depression-like behaviors. Overexpressed STC1 blocked the ROS/NF-κB signaling pathway, thereby enhancing the viability of CORT-treated neurons while repressing their toxicity and apoptosis.Conclusion: Collectively, overexpression of STC1 inhibits inflammation and protects neuron injury in rats with depression-like behaviors by inactivating the ROS/NF-κB signaling pathway.

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Role of ASM/Cer/TXNIP signaling module in the NLRP3 inflammasome activation

Lipids in Health and Disease ◽

10.1186/s12944-021-01446-4 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Jianjun Jiang ◽

Yining Shi ◽

Jiyu Cao ◽

Youjin Lu ◽

Gengyun Sun ◽

...

Keyword(s):

Signaling Pathway ◽

Nlrp3 Inflammasome ◽

Mrna Level ◽

Scavenger Receptor ◽

Nuclear Factor Κb ◽

Inflammasome Activation ◽

Mrna Levels ◽

Irreversible Inhibitor ◽

Nlrp3 Inflammasome Activation

Abstract Background This study aimed to explore the effects of ceramide (Cer) on NLRP3 inflammasome activation and their underlying mechanisms. Methods Lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-induced NLRP3 inflammasome activation in J774A.1 cells and THP-1 macrophages was used as an in vitro model of inflammation. Western blotting and real-time PCR (RT-PCR) were used to detect the protein and mRNA levels, respectively. IL-1β and IL-18 levels were measured by ELISA. ASM assay kit and immunofluorescence were used to detect ASM activity and Cer content. Results Imipramine, a well-known inhibitor of ASM, significantly inhibited LPS/ATP-induced activity of ASM and the consequent accumulation of Cer. Additionally, imipramine suppressed the LPS/ATP-induced expression of thioredoxin interacting protein (TXNIP), NLRP3, caspase-1, IL-1β, and IL-18 at the protein and mRNA level. Interestingly verapamil, a TXNIP inhibitor, suppressed LPS/ATP-induced activation of TXNIP/NLRP3 inflammasome but did not affect LPS/ATP-induced ASM activation and Cer formation. TXNIP siRNA and verapamil inhibited C2-Cer-induced upregulation of TXNIP and activation of the NLRP3 inflammasome. In addition, the pretreatment of cells with sulfo-N-succinimidyl oleate (SSO), an irreversible inhibitor of the scavenger receptor CD36, blocked Cer-induced upregulation of nuclear factor-κB (NF-κB) activity, TXNIP expression, and NLRP3 inflammasome activation. Inhibition of NF-κB activation by SN50 prevented Cer-induced upregulation of TXNIP and activation of the NLRP3 inflammasome but did not affect CD36 expression. Conclusion This study demonstrated that the ASM/Cer/TXNIP signaling pathway is involved in NLRP3 inflammasome activation. The results documented that the CD36-dependent NF-κB-TXNIP signaling pathway plays an essential role in the Cer-induced activation of NLRP3 inflammasomes in macrophages.

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Fucoidans from Cucumaria frondosa ameliorates renal interstitial fibrosis via inhibition of PI3K/Akt/NF-κB signaling pathway

Food & Function ◽

10.1039/d1fo03067a ◽

2022 ◽

Author(s):

Zhuo-yue Song ◽

Mengru Zhu ◽

Jun Wu ◽

Tian Yu ◽

Yao Chen ◽

...

Keyword(s):

Protein Kinase ◽

Signaling Pathway ◽

Interstitial Fibrosis ◽

Protein Kinase B ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Renal Interstitial Fibrosis ◽

Cucumaria Frondosa

The effects of Cucumaria frondosa polysaccharides (CFP) on renal interstitial fibrosis via regulating phosphatidylinositol-3-hydroxykinase/protein kinase-B/Nuclear factor-κB (PI3K/AKT/NF-κB) signaling pathway were investigated in vivo and in vitro in this research. A...

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A Network Pharmacology Approach to Predict the Proangiogenesis Mechanism of Huangqi-Honghua Herb Pair after Cerebral Ischemia

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/9834856 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Jinyi Cao ◽

Lu Lei ◽

Kai Wang ◽

Jing Sun ◽

Yi Qiao ◽

...

Keyword(s):

Cerebral Ischemia ◽

Signaling Pathway ◽

Target Genes ◽

Blood Stasis ◽

Blood Stasis Syndrome ◽

Network Pharmacology ◽

Western Blot Assay ◽

Medicinal Value ◽

Pharmacological Method

Objective. Huangqi-Honghua herb pair is known for its medicinal value to treat Qi deficiency and blood stasis syndrome with a long history in clinical practice. To understand its possible mechanism in a systematic study, a network pharmacological method was addressed. Methods. Detailed information on the HH compounds was obtained from two public databases, and oral bioavailability (OB) and drug-like (DL) of the compounds were evaluated. A correlation between HH compounds, its potential targets, and known targets was extrapolated, and the herb-compound-target-disease (H-C-T-D) network was established. Next, the pathway enrichment and essential genes were analyzed. Then, three key genes (VEGFA, VEGFR2, and eNOS), highly associated with angiogenesis, were screened and verified through western blot assay. Results. Out of 276 compounds, 21 HH compounds and 78 target genes regulating the major pathways associated with CI in the network are analyzed. The bioactive compounds in HH were active in various signal transduction pathways such as the toll-like receptor signaling pathway, VEGF signaling pathway, TNF signaling pathway, and HIF-1 signaling pathway are important pathways that may regulate anti-inflammatory, antiapoptotic, immune correlation, and antioxidative effects. The core genes are PTGS2, TNF, NOS2, IL6, BCL2, IL1B, SOD2, NOS3, SOD1, MMP9, and VEGFA. The in vitro results suggested that HH treatment could significantly elevate the expression of proangiogenic genes such as VEGFA, VEGFR2, and eNOS compared with OGD groups. Conclusions. Our results predict that HH may regulate the expression of VEGFA, VEGFR2, and eNOS via the VEGF and HIF-1 signaling pathway to promote angiogenesis and alleviate cerebral ischemia injury.

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Rutacecarpine Inhibits Angiogenesis by Targeting the VEGFR2 and VEGFR2-Mediated Akt/mTOR/p70s6k Signaling Pathway

Molecules ◽

10.3390/molecules23082047 ◽

2018 ◽

Vol 23 (8) ◽

pp. 2047 ◽

Cited By ~ 7

Author(s):

Lijun Ji ◽

Mingfei Wu ◽

Zeng Li

Keyword(s):

Enzyme Activity ◽

Western Blot ◽

Signaling Pathway ◽

Umbilical Vein ◽

Drug Candidate ◽

Regulation Mechanism ◽

Western Blot Assay ◽

Discovery Studio ◽

Inhibition Experiment

This study aimed to investigate the effect of Ru (Rut) on angiogenesis, and the underlying regulation mechanism of signal transduction. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, adhesion inhibition experiment, migration inhibition experiment, and chick embryo chorioallantoic membrane (CAM) assays were performed on models of angiogenesis. The potential targets of rutaecarpine (Ru) were reverse screened with Discovery Studio 2017. The interaction between the compound and target were detected by surface plasmon resonance (SPR), enzyme-activity experiment, and Western blot assay. The obtained results confirmed that Ru exhibited modest inhibitory activity against human umbilical vein endothelial cells (HUVECs) (IC50 =16.54 ± 2.4 μM) and remarkable inhibitive effect against the migration and adhesion of HUVECs, as well as significant anti-angiogenesis activities in the CAM assay. The possible targets of vascular endothelial growth factor receptor 2 (VEGFR2) were identified by computer-aided simulation. Results showed a good binding relationship between the ligand and target through molecular docking, and this relationship was confirmed by SPR analysis. Furthermore, enzyme-activity experiment and western blot assay showed that Ru remarkably inhibited the activity of VEGFR2 and blocked the VEGFR2-mediated Akt/ (mTOR)/p70s6k signaling pathway in vitro. Ru can be a potential drug candidate for cancer prevention and cancer therapy.

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Capsaicin inhibits the migration and invasion via the AMPK/NF-κB signaling pathway in esophagus sequamous cell carcinoma by decreasing matrix metalloproteinase-9 expression

Bioscience Reports ◽

10.1042/bsr20190819 ◽

2019 ◽

Vol 39 (8) ◽

Cited By ~ 2

Author(s):

Yong Guo ◽

Ning Liu ◽

Kun Liu ◽

Min Gao

Keyword(s):

Matrix Metalloproteinase ◽

Cell Carcinoma ◽

Signaling Pathway ◽

Nuclear Factor Κb ◽

Migration And Invasion ◽

Antitumor Effects ◽

Compound C ◽

Transwell Invasion Assay ◽

Tumor Types

Abstract Antitumor activity of Capsaicin has been studied in various tumor types, but its potency in esophageal squamous cell carcinoma (ESCC) remains to be elucidated. Here, we explored the molecular mechanism of the capsaicin-induced antitumor effects on ESCC Eca109 cells. Eca109 cells were treated with capsaicin in vitro, the migration and invasion capacities were significantly decreased by scratch assay and transwell invasion assay. Meanwhile, matrix metalloproteinase (MMP)-9 (MMP-9) expression levels were also obviously down-regulated by Western blot. However, phosphorylated AMPK levels were significantly up-regulated, and this effect was eliminated by the AMPK inhibitor Compound C treatment. In addition, capsaicin can enhance sirtuin1 (SIRT1) expression, which could activate nuclear factor-κB (NF-κB) through deacetylation, and activate AMPK inducing the phosphorylation of IκBα and nuclear localization of NF-κB p65. Overall, these results revealed that Capsaicin can inhibit the migration and invasion of ESCC cells via the AMPK/NF-κB signaling pathway.

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p62 acts as an oncogene and is targeted by miR-124-3p in glioma

Cancer Cell International ◽

10.1186/s12935-019-1004-x ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Danni Deng ◽

Kaiming Luo ◽

Hongmei Liu ◽

Xichen Nie ◽

Lian Xue ◽

...

Keyword(s):

Glioma Cells ◽

Nuclear Factor Κb ◽

Autophagic Flux ◽

Nuclear Factor ◽

Oxygen Species ◽

Human Glioma ◽

Protein Levels ◽

Novel Therapeutic

Abstract Background Glioma is the most common central nervous system (CNS) tumour. p62, an important autophagy adaptor, plays a crucial role in cancer. However, the role of p62 in the progression of glioma is poorly characterized. Methods We examined the expression of p62 in glioma tissues and cell lines. Then we investigated the function of p62 in vitro, and clarified the mechanism underlying the regulation of p62 expression. Results We revealed that p62 was upregulated at both the mRNA and protein levels in human glioma tissues irrelevant to isocitrate dehydrogenase (IDH) status. Then, we found that overexpression of p62 promoted glioma progression by promoting proliferation, migration, glycolysis, temozolomide (TMZ) resistance and nuclear factor κB (NF-κB) signalling pathway, and repressing autophagic flux and reactive oxygen species (ROS) in vitro. In accordance with p62 overexpression, knockdown of p62 exerted anti-tumour effects in glioma cells. Subsequently, we demonstrated that miR-124-3p directly targeted the 3′-UTR of p62 mRNA, leading to the downregulation of p62. Finally, we found that p62 function could be partially reversed by miR-124-3p overexpression. Conclusions Our results demonstrate that p62 can be targeted by miR-124-3p and acts as an oncogene in glioma, suggesting the potential value of p62 as a novel therapeutic target for glioma.

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Krüppel-Like Factor 6 Silencing Prevents Oxidative Stress and Neurological Dysfunction Following Intracerebral Hemorrhage via Sirtuin 5/Nrf2/HO-1 Axis

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.646729 ◽

2021 ◽

Vol 13 ◽

Author(s):

Jia Sun ◽

Jinzhong Cai ◽

Junhui Chen ◽

Siqiaozhi Li ◽

Xin Liao ◽

...

Keyword(s):

Oxidative Stress ◽

Intracerebral Hemorrhage ◽

Signaling Pathway ◽

Hippocampal Neurons ◽

Neuronal Apoptosis ◽

Neurological Dysfunction ◽

Heme Oxygenase 1 ◽

And Oxidative Stress

As a severe neurological deficit, intracerebral hemorrhage (ICH) is associated with overwhelming mortality. Subsequent oxidative stress and neurological dysfunction are likely to cause secondary brain injury. Therefore, this study sought to define the role of Krüppel-like factor 6 (KLF6) and underlying mechanism in oxidative stress and neurological dysfunction following ICH. An in vivo model of ICH was established in rats by injection of autologous blood, and an in vitro ICH cell model was developed in hippocampal neurons by oxyhemoglobin (OxyHb) exposure. Next, gain- and loss-of-function assays were performed in vivo and in vitro to clarify the effect of KLF6 on neurological dysfunction and oxidative stress in ICH rats and neuronal apoptosis and mitochondrial reactive oxygen species in OxyHb-induced hippocampal neurons. KLF6, nuclear factor erythroid 2–related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) were highly expressed in hippocampal tissues of ICH rats, whereas sirtuin 5 (SIRT5) presented a poor expression. Mechanistically, KLF6 bound to the SIRT5 promoter and transcriptionally repressed SIRT5 to activate the Nrf2/HO-1 signaling pathway. KLF6 silencing alleviated neurological dysfunction and oxidative stress in ICH rats and diminished oxidative stress and neuronal apoptosis in OxyHb-induced neurons, whereas SIRT5 overexpression negated its effect. To sum up, KLF6 silencing elevated SIRT5 expression to inactivate the Nrf2/HO-1 signaling pathway, thus attenuating oxidative stress and neurological dysfunction after ICH.

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6′-O-Galloylpaeoniflorin Attenuates Osteoclasto-genesis and Relieves Ovariectomy-Induced Osteoporosis by Inhibiting Reactive Oxygen Species and MAPKs/c-Fos/NFATc1 Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.641277 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wenjie Liu ◽

Gang Xie ◽

Guixin Yuan ◽

Dantao Xie ◽

Zhen Lian ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Signaling Pathway ◽

Reactive Oxygen ◽

Bone Diseases ◽

Cell Counting ◽

Specific Gene ◽

Oxygen Species ◽

Ovariectomized Mice

Emerging evidence suggests bright prospects of some natural antioxidants in the treatment of osteoporosis. 6′-O-Galloylpaeoniflorin (GPF), an antioxidant isolated from peony roots (one of very widely used Oriental medicines, with various anti-inflammatory, antitumor, and antioxidant activities), shows a series of potential clinical applications. However, its effects on osteoporosis remain poorly investigated. The current study aimed to explore whether GPF can attenuate osteoclastogenesis and relieve ovariectomy-induced osteoporosis via attenuating reactive oxygen species (ROS), and investigate the possible mechanism. After the culture of primary murine bone marrow-derived macrophages/monocytes were induced by the use of macrophage colony-stimulating factor (M-CSF) and the receptor activator of NF-κB ligand (RANKL) and then treated with GPF. Cell proliferation and viability were assessed by Cell Counting Kit-8 (CCK-8) assay. Thereafter, the role of GPF in the production of osteoclasts and the osteogenic resorption of mature osteoclasts were evaluated by tartrate-resistant acid phosphatase (TRAP) staining, podosome belt formation, and resorption pit assay. Western blotting and qRT-PCR examination were performed to evaluate proteins’ generation and osteoclast-specific gene levels, respectively. The ROS generation in cells was measured in vitro by 2′,7′-Dichlorodi-hydrofluorescein diacetate (DCFH-DA). Ovariectomy-induced osteoporosis mouse administered with GPF or vehicle was performed to explore the in vivo potential of GPF, then a micro-CT scan was performed in combination with histological examination for further analysis. GPF suppressed the formation of osteoclasts and podosome belts, as well as bone resorption when induced by RANKL through affecting intracellular ROS activity, MAPKs signaling pathway, and subsequent NFATc1 translocation and expression, as well as osteoclast-specific gene expression in vitro. In vivo study suggested that exposure to GPF prevented osteoporosis-related bone loss in the ovariectomized mice. These findings indicate that GPF attenuates osteoclastogenesis and relieves ovariectomy-induced osteoporosis by inhibiting ROS and MAPKs/c-Fos/NFATc1 signaling pathway. This suggested that GPF may be potentially used to treat bone diseases like periodontitis, rheumatoid arthritis, and osteoporosis associated with osteoclasts.

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