scholarly journals Schisantherin A Attenuates Neuroinflammation in Activated Microglia: Role of Nrf2 Activation Through ERK Phosphorylation

2018 ◽  
Vol 47 (5) ◽  
pp. 1769-1784 ◽  
Author(s):  
Chuwen Li ◽  
Tongkai Chen ◽  
Hefeng Zhou ◽  
Chao Zhang ◽  
Yu Feng ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Therapeutic Potential ◽  
Erk Phosphorylation ◽  
Nrf2 Activation ◽  
Antioxidative Effects ◽  
Underlying Mechanisms ◽  
Oxidative Effects ◽  
Anti Inflammation ◽  
Schisantherin A

Background/Aims: In the present study, we investigated whether schisantherin A (StA) had anti-inflammatory effects under neuroinflammatory conditions. Methods: The effects of StA and its underlying mechanisms were examined in lipopolysaccharide (LPS)-activated BV-2 microglial cells by ELISA, qPCR, EMSA, Western blot, and IHC. Results: Firstly, we found that StA inhibited the inflammatory response in LPS-activated BV-2 microglia. Secondly, we found that StA suppressed LPS-induced activation of NF-κB via interfering with degradation of IκB and phosphorylation of IκB, IKK, PI3K/Akt, JNK, and p38 MAPK. Thirdly, StA conferred indirect antioxidative effects via quenching ROS and promoted expression of antioxidant enzymes, including HO-1 and NQO-1, via stimulating activation of Nrf2 pathways. Finally, we demonstrated that anti-neuroinflammatory actions of StA were dependent on ERK phosphorylation-mediated Nrf2 activation. Conclusion: StA induced ERK phosphorylation-mediated Nrf2 activation, which contributed to its anti-inflammation and anti-oxidation. The anti-neuroinflammatory and anti-oxidative effects of StA may show preventive therapeutic potential for various neuroinflammatory disorders.

scholarly journals Microglia Polarization in Alzheimer’s Disease: Mechanisms and a Potential Therapeutic Target

2021 ◽  
Vol 13 ◽  
Author(s):  
Qinqin Wang ◽  
Hongmei Yao ◽  
Wenyan Liu ◽  
Bailiu Ya ◽  
Hongju Cheng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Hyperphosphorylated Tau ◽  
M2 Microglia ◽  
Microglia Polarization ◽  
Underlying Mechanisms ◽  
Anti Inflammation

Neuroinflammation regulated by microglia is one of the important factors involved in the pathogenesis of Alzheimer’s disease (AD). Activated microglia exhibited phenotypes termed as M1 and M2 phenotypes separately. M1 microglia contribute to the development of inflammation via upregulating pro-inflammatory cytokines, while M2 microglia exert anti-inflammation effects through enhancing the expression of anti-inflammation factors. Moreover, M1 and M2 microglia could be mutually transformed under various conditions. Both M1 and M2 microglia are implicated in AD. Amyloid-β (Aβ) and hyperphosphorylated tau are two major components of AD pathological hallmarks, neuritic plaques, and neurofibrillary tangles. Both Aβ and hyperphosphorylated tau were involved in microglial activation and subsequent inflammation, which further contribute to neuronal and synaptic loss in AD. In this review, we summarized the roles of M1 and M2 microglia in AD and underlying mechanisms, which will provide an insight into the role of microglia in the pathogenesis of AD and highlight the therapeutic potential of modulating microglia.

scholarly journals Inflammasomes and the Maintenance of Hematopoietic Homeostasis: New Perspectives and Opportunities

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 309
Author(s):  
Lijing Yang ◽  
Mengjia Hu ◽  
Yukai Lu ◽  
Songling Han ◽  
Junping Wang
Keyword(s):  
Purinergic Receptors ◽  
Therapeutic Potential ◽  
Inflammasome Activation ◽  
Hematopoietic Stem ◽  
Hematopoietic Transplantation ◽  
Proliferation And Differentiation ◽  
Extracellular Stimuli ◽  
Transplantation Complications ◽  
Underlying Mechanisms

Hematopoietic stem cells (HSCs) regularly produce various blood cells throughout life via their self-renewal, proliferation, and differentiation abilities. Most HSCs remain quiescent in the bone marrow (BM) and respond in a timely manner to either physiological or pathological cues, but the underlying mechanisms remain to be further elucidated. In the past few years, accumulating evidence has highlighted an intermediate role of inflammasome activation in hematopoietic maintenance, post-hematopoietic transplantation complications, and senescence. As a cytosolic protein complex, the inflammasome participates in immune responses by generating a caspase cascade and inducing cytokine secretion. This process is generally triggered by signals from purinergic receptors that integrate extracellular stimuli such as the metabolic factor ATP via P2 receptors. Furthermore, targeted modulation/inhibition of specific inflammasomes may help to maintain/restore adequate hematopoietic homeostasis. In this review, we will first summarize the possible relationships between inflammasome activation and homeostasis based on certain interesting phenomena. The cellular and molecular mechanism by which purinergic receptors integrate extracellular cues to activate inflammasomes inside HSCs will then be described. We will also discuss the therapeutic potential of targeting inflammasomes and their components in some diseases through pharmacological or genetic strategies.

scholarly journals Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Yang Zhang ◽  
Weifang Liu ◽  
Yanqi Zhong ◽  
Qi Li ◽  
Mengying Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nlrp3 Inflammasome ◽  
Low Dose ◽  
Therapeutic Potential ◽  
Metabolic Phenotypes ◽  
Pyrin Domain ◽  
Underlying Mechanisms ◽  
And Oxidative Stress ◽  
Receptor Family

NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-κB signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-κB signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-κB signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-κB signaling and blocking transcription factor NF-κB1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-κB signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-κB/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-κB/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.

Gonadal rejuvenation of mice by GDF11

2021 ◽  
Author(s):  
Yang Zhou ◽  
Shousheng Ni ◽  
Congjun Li ◽  
Lili Song ◽  
Shicui Zhang
Keyword(s):  
Antioxidant Enzymes ◽  
Oral Delivery ◽  
Marker Enzymes ◽  
Slowing Down ◽  
Testicular Cells ◽  
Morphogenetic Protein ◽  
Aging Properties ◽  
Potential Improvement ◽  
Underlying Mechanisms

Abstract Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP11), has been shown to have rejuvenation and anti-aging properties, but little information is available regarding the role of GDF11 in reproductive system to date. In this study, we first confirmed the bioavailability of recombinant GDF11 (rGDF11) by oral delivery in mice. We also showed that dietary intake of rGDF11 had little influence on body and gonadal (ovary/testis) weights of recipient mice, indicating their general condition and physiology were not affected. Based on these findings, we started to test the function of rGDF11 in ovary and testis of mice and to explore the underlying mechanisms. It was found that to some extent, rGDF11 could attenuate the senescence of ovarian and testicular cells, and contribute to the recovery of ovarian and testicular endocrine functions. Moreover, rGDF11 could rescue the diminished ovarian reserve in female mice and enhance the activities of marker enzymes of testicular function (SDH and G6PD) in male mice, suggesting a potential improvement of fertility. Notably, rGDF11 markedly promoted the activities of antioxidant enzymes in the ovary and testis, and remarkably reduced the levels of lipid peroxidation, protein oxidation and ROS in the ovary and testis. Collectively, these results suggest that GDF11 can protect ovarian and testicular functions of aged mice via slowing down the generation of ROS through enhancing activities of antioxidant enzymes.

Therapeutic potential and biological role of endogenous antioxidant enzymes in multiple sclerosis pathology

2007 ◽  
Vol 56 (2) ◽  
pp. 322-330 ◽  
Author(s):  
Gerty Schreibelt ◽  
Jack van Horssen ◽  
Saskia van Rossum ◽  
Christine D. Dijkstra ◽  
Benjamin Drukarch ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Antioxidant Enzymes ◽  
Therapeutic Potential ◽  
Biological Role ◽  
Endogenous Antioxidant

scholarly journals Implications on the Therapeutic Potential of Statins via Modulation of Autophagy

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Armita Mahdavi Gorabi ◽  
Nasim Kiaie ◽  
Saeed Aslani ◽  
Thozhukat Sathyapalan ◽  
Tannaz Jamialahmadi ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tumor Metastasis ◽  
Inflammatory Cell ◽  
Therapeutic Potential ◽  
Lipid Lowering ◽  
Anticancer Effects ◽  
Autophagy Pathway ◽  
The One ◽  
Anti Inflammation

Statins, which are functionally known as 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) inhibitors, are lipid-lowering compounds widely prescribed in patients with cardiovascular diseases (CVD). Several biological and therapeutic functions have been attributed to statins, including neuroprotection, antioxidation, anti-inflammation, and anticancer effects. Pharmacological characteristics of statins have been attributed to their involvement in the modulation of several cellular signaling pathways. Over the past few years, the therapeutic role of statins has partially been attributed to the induction of autophagy, which is critical in maintaining cellular homeostasis and accounts for the removal of unfavorable cells or specific organelles within cells. Dysregulated mechanisms of the autophagy pathway have been attributed to the etiopathogenesis of various disorders, including neurodegenerative disorders, malignancies, infections, and even aging. Autophagy functions as a double-edged sword during tumor metastasis. On the one hand, it plays a role in inhibiting metastasis through restricting necrosis of tumor cells, suppressing the infiltration of the inflammatory cell to the tumor niche, and generating the release of mediators that induce potent immune responses against tumor cells. On the other hand, autophagy has also been associated with promoting tumor metastasis. Several anticancer medications which are aimed at inducing autophagy in the tumor cells are related to statins. This review article discusses the implications of statins in the induction of autophagy and, hence, the treatment of various disorders.

scholarly journals The Role of Autophagy at Nano/Bio Interface - Underlying Mechanisms and Therapeutic Potential in Cancer

2021 ◽  
Author(s):  
Liwei You ◽  
Zhenhan Feng ◽  
Yuliang Zhao ◽  
Huan Meng ◽  
Motao Zhu
Keyword(s):  
Therapeutic Potential ◽  
Underlying Mechanisms

scholarly journals Peptidylarginine Deiminase 2 in Host Immunity: Current Insights and Perspectives

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhenyu Wu ◽  
Patrick Li ◽  
Yuzi Tian ◽  
Wenlu Ouyang ◽  
Jessie Wai-Yan Ho ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Host Immunity ◽  
Preclinical Research ◽  
Post Translational Modifications ◽  
Different Types ◽  
Arginine Residues ◽  
Cell Death Signaling ◽  
Underlying Mechanisms ◽  
Novel Therapeutic Strategies

Peptidylarginine deiminases (PADs) are a group of enzymes that catalyze post-translational modifications of proteins by converting arginine residues into citrullines. Among the five members of the PAD family, PAD2 and PAD4 are the most frequently studied because of their abundant expression in immune cells. An increasing number of studies have identified PAD2 as an essential factor in the pathogenesis of many diseases. The successes of preclinical research targeting PAD2 highlights the therapeutic potential of PAD2 inhibition, particularly in sepsis and autoimmune diseases. However, the underlying mechanisms by which PAD2 mediates host immunity remain largely unknown. In this review, we will discuss the role of PAD2 in different types of cell death signaling pathways and the related immune disorders contrasted with functions of PAD4, providing novel therapeutic strategies for PAD2-associated pathology.

scholarly journals Paroxetine suppresses reactive microglia-mediated but not lipopolysaccharide-induced inflammatory responses in primary astrocytes

2019 ◽  
Author(s):  
Xiong Zhang ◽  
Lan-Bing Zhu ◽  
Jia-Hui He ◽  
Hong-Qiu Zhang ◽  
Shu-Ya Ji ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Minor Amount ◽  
Innate Immune Responses ◽  
Reactive Microglia ◽  
Tnf Α ◽  
Primary Astrocytes ◽  
Underlying Mechanisms ◽  
The Impact

Abstract Background Astrocytes are the most abundant glial cells in a brain that mediate inflammatory responses and provide trophic support for neurons. We have previously disclosed that paroxetine, a common selective serotonin reuptake inhibitor, ameliorates LPS-induced microglia activation. However, it remains elusive of the role of paroxetine in astrocytic responses. Methods Isolated primary astrocytes were pretreated with paroxetine and stimulated with different stimuli, lipopolysaccharide (LPS) or microglia conditioned medium pre-activated with LPS (M/Lps). Inflammatory and neurotrophic responses, underlying mechanisms and the impact on neuronal survival were assessed. Results Paroxetine had no impact on LPS-stimulated iNOS, TNF-α and IL-1β expression, but inhibited M/Lps-induced TNF-α and IL-1β expression in primary astrocytes. Paroxetine suppressed M/Lps- but not LPS-induced activation of NF-κB and had no impact on activation of MAPKs and STAT3. Incubation with the resulted astrocyte conditioned media caused no change in viability of SH-SY5Y cells. BDNF and MANF mRNA expressions were upregulated by M/Lps and paroxetine, respectively. However, M/Lps- or LPS-induced extracellular releases of NO, TNF-α and/or BDNF in astrocytes were in minor amount compared to those by microglia. Conclusions Paroxetine ameliorates the reactive microglia-mediated inflammatory responses in astrocytes partially via inhibition of NF-κB pathway, but has no impact on LPS-stimulated astrocyte activation. While the secondary astrocytic responses are not robust compared to the innate immune responses of microglia, our results support a therapeutic potential of paroxetine against neuroinflammation-associated neurological disorders such as Parkinson’s disease.

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