The protective effects of activating Sirt1/NF-κB pathway for neurological disorders

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Yanhong Song ◽  
Ziyi Wu ◽  
Ping Zhao

Abstract Sirt1, a member of the sirtuins family, is a nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase. It can be involved in the regulation of several processes including inflammatory response, apoptosis, oxidative stress, energy metabolism, and autophagy by exerting deacetylation. Nuclear factor-κB (NF-κB), a crucial nuclear transcription factor with specific DNA binding sequences, exists in almost all cells and plays a vital role in several biological processes involving inflammatory response, immune response, and apoptosis. As the hub of multiple intracellular signaling pathways, the activity of NF-κB is regulated by multiple factors. Sirt1 can both directly deacetylate NF-κB and indirectly through other molecules to inhibit its activity. We would like to emphasize that Sirt1/NF-κB is a signaling pathway that is closely related to neuroinflammation. Many recent studies have demonstrated the neuroprotective effects of Sirt1/NF-κB signaling pathway activation applied to the treatment of neurological related diseases. In this review, we focus on new advances in the neuroprotective effects of the Sirt1/NF-κB pathway. First, we briefly review Sirt1 and NF-κB, two key molecules of cellular metabolism. Next, we discuss the connection between NF-κB and neuroinflammation. In addition, we explore how Sirt1 regulates NF-κB in nerve cells and relevant evidence. Finally, we analyze the therapeutic effects of the Sirt1/NF-κB pathway in several common neuroinflammation-related diseases.

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Guo Zu ◽  
Jing Guo ◽  
Ningwei Che ◽  
Tingting Zhou ◽  
Xiangwen Zhang

Abstract Ginsenoside Rg1 (Rg1) is one of the major bioactive ingredients in Panax ginseng, and it attenuates inflammation and apoptosis. The aims of our study were to explore the potential of Rg1 for the treatment of intestinal I/R injury and to determine whether the protective effects of Rg1 were exerted through the Wnt/β-catenin signaling pathway. In this study, Rg1 treatment ameliorated inflammatory factors, ROS and apoptosis that were induced by intestinal I/R injury. Cell viability was increased and cell apoptosis was decreased with Rg1 pretreatment following hypoxia/reoxygenation (H/R) in the in vitro study. Rg1 activated the Wnt/β-catenin signaling pathway in both the in vivo and in vitro models, and in the in vitro study, the activation was blocked by DKK1. Our study provides evidence that pretreatment with Rg1 significantly reduces ROS and apoptosis induced by intestinal I/R injury via activation of the Wnt/β-catenin pathway. Taken together, our results suggest that Rg1 could exert its therapeutic effects on intestinal I/R injury through the Wnt/β-catenin signaling pathway and provide a novel treatment modality for intestinal I/R injury.


2021 ◽  
Author(s):  
Yang Zheng ◽  
Yunqi Li ◽  
Xianwen Ran ◽  
Di Wang ◽  
Xianghui Zheng ◽  
...  

Abstract The inflammatory response of macrophages has been reported to play a critical role in atherosclerosis. The inflammatory state of macrophages is modified by epigenetic reprogramming. m6A RNA methylation is an epigenetic modification of RNAs. However, little is known about the potential roles and underlying mechanisms of m6A modification in macrophage inflammation. Herein, we showed that the expression of the m6A modification “writer” Mettl14 was increased in coronary heart disease and LPS-stimulated THP-1 cells. Knockdown of Mettl14 promoted M2 polarization of macrophages, inhibited foam cell formation and decreased migration. Mechanistically, the expression of Myd88 and IL-6 was decreased in Mettl14 knockdown cells. Through m6A modification, Mettl14 regulated the stability of Myd88 mRNA. Furthermore, Myd88 affected the transcription of IL-6 via the distribution of p65 in nuclei rather than directly regulating the expression of IL-6 through m6A modification. In vivo, Mettl14 gene knockout significantly reduced the inflammatory response of macrophages and the development of atherosclerotic plaques. Taken together, our data demonstrate that Mettl14 plays a vital role in macrophage inflammation in atherosclerosis via the NF-κB/IL-6 signaling pathway, suggesting that Mettl14 may be a promising therapeutic target for the clinical treatment of atherosclerosis.


2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Min Xie ◽  
Meijian Wang ◽  
Wei Liu ◽  
Min Xu ◽  
Pan Shang ◽  
...  

Diabetic encephalopathy is a type of central diabetic neuropathy resulting from diabetes mainly manifested as cognitive impairments. However, its underlying pathogenesis and effective treatment strategies remain unclear. In the present study, we investigated the effect of Lipin1, a phosphatidic acid phosphatase enzyme, on the pathogenesis of diabetic encephalopathy. We found that in vitro, Lipin1 exerts protective effects on high glucose-induced reductions of PC12 cell viability, while in vivo, Lipin1 is downregulated within the CA1 hippocampal region in a type I diabetes rat model. Increased levels of Lipin1 within the CA1 region are accompanied with protective effects including amelioration of dendritic spine and synaptic deficiencies, phosphorylation of the synaptic plasticity-related proteins, LIM kinase 1 (p-limk1) and cofilin, as well as increases in the synthesis of diacylglycerol (DAG), and the expression of phosphorylated protein kinase D (p-PKD). These effects are associated with the rescue of cognitive disorders as shown in this rat model of diabetes. In contrast, knockdown of Lipin1 within the CA1 region enhanced neuronal abnormalities and the genesis of cognitive impairment in rats. These results suggest that Lipin1 may exert neuroprotective effects involving the PKD/Limk/Cofilin signaling pathway and may serve as a potential therapeutic target for diabetic encephalopathy.


2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hyun-Hee Park ◽  
Myung-Hoon Han ◽  
Hojin Choi ◽  
Young Joo Lee ◽  
Jae Min Kim ◽  
...  

Abstract Amlodipine, a L-type calcium channel blocker, has been reported to have a neuroprotective effect in brain ischemia. Mitochondrial calcium overload leads to apoptosis of cells in neurologic diseases. We evaluated the neuroprotective effects of amlodipine camsylate (AC) on neural stem cells (NSCs) injured by oxygen glucose deprivation (OGD) with a focus on mitochondrial structure and function. NSCs were isolated from rodent embryonic brains. Effects of AC on cell viability, proliferation, level of free radicals, and expression of intracellular signaling proteins were assessed in OGD-injured NSCs. We also investigated the effect of AC on mitochondrial structure in NSCs under OGD by transmission electron microscopy. AC increased the viability and proliferation of NSCs. This beneficial effect of AC was achieved by strong protection of mitochondria. AC markedly enhanced the expression of mitochondrial biogenesis-related proteins and mitochondrial anti-apoptosis proteins. Together, our results indicate that AC protects OGD-injured NSCs by protecting mitochondrial structure and function. The results of the present study provide insight into the mechanisms underlying the protective effects of AC on NSCs.


2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Zhao Gao ◽  
Xinghua Chen ◽  
Kai Zhu ◽  
Ping Zeng ◽  
Guohua Ding

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.


2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Kexin Yan ◽  
Hongyuan Zhou ◽  
Meng Wang ◽  
Haitao Li ◽  
Rui Sang ◽  
...  

Our previous reports have shown that Inonotus obliquus polysaccharide (IOP) has protective effects against Toxoplasma gondii (T. gondii) infection in vivo. The aim of the present research is to explore the in vitro anti-inflammatory effects of IOP and its mechanism in RAW264.7 macrophages infected by T. gondii. In this study, it is indicated that IOP decreased the excessive secretion of inflammatory cytokines tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-4, and IL-6 in T. gondii-infected RAW264.7 macrophages. IOP effectively suppressed the mRNA expression of these cytokines and chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α). Moreover, IOP inhibited the phosphorylation of inhibitor kappa B kinase α/β (IKKα/β), inhibitor κBα (IκBα), p65 in nuclear factor-kappa B (NF-κB) signaling pathway and p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK1/2) in mitogen-activated protein kinases (MAPKs) signaling pathway. Meantime, IOP prevented NF-κB p65 and c-Jun translocation from the cytoplasm to the nucleus. Further, IOP downregulated the protein expression of toll-like receptor 2 (TLR2) and TLR4 in T. gondii-infected RAW264.7 macrophages. The above results suggest that IOP can inhibit the inflammatory response infected with T. gondii via regulating TLR2/TLR4-NF-κB/MAPKs pathways and exerting its anti-T. gondii role in vitro.


2021 ◽  
Vol 2021 ◽  
pp. 1-31
Author(s):  
Baoyue Zhang ◽  
Wenwen Lian ◽  
Jun Zhao ◽  
Zhe Wang ◽  
Ailin Liu ◽  
...  

Oxidative stress and neuroinflammation have been demonstrated to be linked with Alzheimer’s disease (AD). In this study, we examined the protective effects of DL0410 in aging rats and explored the underlying mechanism against oxidative damage and neuroinflammation, which was then validated in LPS-stimulated BV2 microglia. We firstly investigated the improvement effects of DL0410 on learning and memory abilities and explored the potential mechanisms in D-gal-induced aging rats. An 8-week treatment with DL0410 significantly improved the learning and cognitive function of D-gal-stimulated Alzheimer’s-like rats in the Morris water maze test, step-down test, and novel object recognition test, and the therapeutic effect of DL0410 at 10 mg/kg was even better than that of donepezil. What is more, the results showed that DL0410 alleviated neuron injury, increased the number of synapses, and improved the level of postsynaptic density protein 95 (PSD95) in the hippocampus and cortex. Next, we examined the protective effects of DL0410 against oxidative damage and neuroinflammation. Our observations indicated that DL0410 reduced the production of harmful oxidation products and promoted the antioxidative system, decreased the levels of proinflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6), and increased anti-inflammatory cytokines IL-10. Moreover, DL0410 inhibited the activation of astrocytes and microglia and suppressed the activation of the TLR4/MyD88/NF-κB signaling pathway. The anti-inflammation effect of DL0410 was further confirmed in LPS-stimulated BV2 cells, and the results showed that DL0410 reduced the level of inflammatory factors and inhibited the activation of the TLR4/MyD88/TRAF6/NF-κB signaling pathway in BV2 microglia. Molecular docking results indicated that DL0410 occupied the LPS recognition site in the TLR4/MD2 complex. Furthermore, the enhanced expression of claudin-1, claudin-5, occludin, CX43, and ZO-1 indicated that DL0410 protected the blood-brain barrier (BBB) integrity. Together, these results suggest that DL0410 exerts neuroprotective effects against hippocampus and cortex injury induced by D-galactose, and the possible mechanisms include antioxidative stress, antineuroinflammation, improving synaptic plasticity, and maintaining BBB integrity, which is mediated by the TLR4/MyD88/NF-κB signaling pathway inhibition. We suggest that DL0410 is a promising candidate for AD treatment.


2021 ◽  
Author(s):  
Qianyun Nie ◽  
Wenjuan Dong ◽  
Baoyu Shen ◽  
Genmeng Yang ◽  
Hao Yu ◽  
...  

Abstract Methamphetamine (MA) abuse is a major global public health problem, with cardiovascular issues becoming an increasingly recognized complication. Cannabidiol (CBD) has gained recent attention, due to its various pharmacological properties. However, whether CBD has therapeutic effects on MA-induced cardiotoxicity remains unknown. In the present study, we investigated whether CBD has a protective or therapeutic effect on MA-induced cardiac damage in rats via the protein kinase A (PKA)/cyclic adenosine monophosphate response element-binding (CREB) signaling pathway. Thirty rats were randomly divided into five groups. The rats were administered MA by intraperitoneal injection (IP) once a day for 4 weeks, with CBD (40 or 80 mg/kg, IP) treatment 1 h prior to the MA injections. Body and heart weights were measured, and morphological changes were determined using hematoxylin & eosin and Masson’s trichrome staining. The serum levels of interleukin-6 (IL-6) and IL-10 were detected using enzyme linked immunosorbent assay (ELISA) kits. The protein expression levels of PKA, phospho-PKA (p-PKA), CREB, phospho-CREB (p-CREB) and cardiac troponin I (cTnI) in the myocardium were detected by western blot analysis. Results showed that the heart-to-body weight ratio increased significantly following MA administration but decreased with CBD treatment. Chronic administration of MA resulted in a cardiac inflammatory response and progressive development of fibrosis, while CBD treatment attenuated these lesions in a dose-dependent manner. MA administration increased IL-6 but decreased IL-10 levels, which were reversed by CBD pretreatment. Moreover, MA significantly increased the cTnI level, but this was decreased by CBD treatment at 80 mg/kg. The protein expression levels of PKA, p-PKA, CREB, and p-CREB increased following MA administration, but significantly decreased with CBD treatment. Overall, these results indicate that chronic MA administration leads to cardiotoxicity, including cardiac inflammatory response, fibrosis, and myocardial necrosis, but these effects can be attenuated by CBD pretreatment. Our research suggests a potential application of CBD for MA-induced cardiotoxicity, which may attenuate inflammatory response and necrosis through the PKA/CREB signaling pathway.


Author(s):  
Xifeng Wang ◽  
Xiaomin Xu ◽  
Yu peng Yang ◽  
Xin Xin ◽  
Zekang Li ◽  
...  

IntroductionThe high mortality of sepsis is closely related to disorder of coagulation induced by endothelial inflammatory response. Our aim is to investigate the protective effects of Dihydromyricetin (DHM) on endothelial cells in sepsis and the endoplasmic reticulum (ER) stress mechanism.Material and methodsIn vivo, we conducted an animal study for which fifty male Wistar rats were randomly and equally divided into five groups: sham group, cecal ligation and puncture (CLP) group and three CLP+ DHM (50, 100, 150 mg/kg) groups, the DHM was orally administered 2 h after CLP for 3 days (once per day). In vitro, human umbilical vein endothelial cells (HUVECs) were treated with DHM (50μmol) for 24 h after stimulation by lipopolysaccharide (LPS). In the inhibition groups, reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC, 3 mmol) and endoplasmic reticulum (ER) stress inhibitor (STF-083010, 10 μmol) were incubated prior to LPS.ResultsOur results indicated that DHM (150 mg/kg) alleviated the histopathological injury of endothelium, decreased the release of inflammatory cytokines and adhesion molecules such as interleukin-1β (IL-1β), interleukin-6 (IL-6) , tumor necrosis factor alpha (TNF-α), vascular cell adhesion molecule 1 (VCAM-1) and endothelin-1 (ET-1), and inhibited the production of ROS production. In addition, we found that DHM ameliorated ER damage, significantly decreased the protein expressions of IRE1α/NF-κB signaling pathway.ConclusionsDHM treatment alleviated inflammatory response of endothelial cells in sepsis through the IRE1α/NF-κB signaling pathway triggered by oxidative stress. This study provided experimental rationale for the treatment of DHM on therapy of sepsis.


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