scholarly journals An In Vitro Verification of the Effects of Paeoniflorin on Lipopolysaccharide-Exposed Microglia

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Qiliang Chen ◽  
Yaojun Liu ◽  
Yuanyuan Zhang ◽  
Xinyu Jiang ◽  
Yuqin Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Nuclear Factor Kappa B ◽  
Brain Injuries ◽  
Enzyme Linked Immunosorbent Assay ◽  
Neuroprotective Effects ◽  
Polymerase Chain ◽  
New Treatment ◽  
Culture Supernatants

Background. The neuroprotective effects of Paeoniflorin (PF) are well known. Most of the evidence was verified in vivo. We attempted to perform an in vitro verification of the effects of PF in microglia. Methods. A lipopolysaccharide- (LPS-) exposed microglia model was employed. An enzyme-linked immunosorbent assay was used to measure the levels of cytokines in the culture supernatants. A real-time polymerase chain reaction was performed to measure the mRNA expression of cytokines and M1- and M2-like genes. A western blot analysis was used to examine the expression of proteins associated with the nuclear factor-kappa B (NF-κB) signaling pathway. Results. We found that the administration of PF reversed the inflammatory response induced by LPS. It downregulated proinflammatory cytokines and upregulated anti-inflammatory cytokines. This, in turn, alleviated the oxidative injuries, downregulated the expression of M1-like genes, and upregulated the expression of M2-like genes. PF can also reverse the changes in proteins associated with the NF-κB signaling pathway induced by LPS. Conclusions. We provided evidence obtained in vitro concerning the neuroprotective effects of PF via suppressing activation of microglia, which might be associated with the NF-κB signaling pathway. These findings contribute to obtaining a deeper understanding of PF, a potential new treatment for brain injuries.

scholarly journals Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

2020 ◽  
Vol 2020 ◽  
pp. 1-27 ◽  
Author(s):  
Samuele Maramai ◽  
Mohamed Benchekroun ◽  
Moustafa T. Gabr ◽  
Samir Yahiaoui
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Event ◽  
Neuroprotective Effects ◽  
New Agents ◽  
Major Health ◽  
New Treatment ◽  
Neuronal Functions

Neurodegenerative diseases represent nowadays one of the major health problems. Despite the efforts made to unveil the mechanism leading to neurodegeneration, it is still not entirely clear what triggers this phenomenon and what allows its progression. Nevertheless, it is accepted that neurodegeneration is a consequence of several detrimental processes, such as protein aggregation, oxidative stress, and neuroinflammation, finally resulting in the loss of neuronal functions. Starting from these evidences, there has been a wide search for novel agents able to address more than a single event at the same time, the so-called multitarget-directed ligands (MTDLs). These compounds originated from the combination of different pharmacophoric elements which endowed them with the ability to interfere with different enzymatic and/or receptor systems, or to exert neuroprotective effects by modulating proteins and metal homeostasis. MTDLs have been the focus of the latest strategies to discover a new treatment for Alzheimer’s disease (AD), which is considered the most common form of dementia characterized by neurodegeneration and cognitive dysfunctions. This review is aimed at collecting the latest and most interesting target combinations for the treatment of AD, with a detailed discussion on new agents with favorable in vitro properties and on optimized structures that have already been assessed in vivo in animal models of dementia.

scholarly journals Paeoniflorin Attenuates Inflammatory Pain by Inhibiting Microglial Activation and Akt-NF-κB Signaling in the Central Nervous System

2018 ◽  
Vol 47 (2) ◽  
pp. 842-850 ◽  
Author(s):  
Bo Hu ◽  
Guangtao Xu ◽  
Xiaomin Zhang ◽  
Long Xu ◽  
Hong Zhou ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Signaling Pathway ◽  
Inflammatory Pain ◽  
Microglial Activation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Pain Model ◽  
The Central Nervous System

Background/Aims: Paeoniflorin (PF) is known to have anti-inflammatory and paregoric effects, but the mechanism underlying its analgesic effect remains unclear. The aim of this study was to clarify the effect of PF on Freund’s complete adjuvant (CFA)-induced inflammatory pain and explore the underlying molecular mechanism. Methods: An inflammatory pain model was established by intraplantar injection of CFA in C57BL/6J mice. After intrathecal injection of PF daily for 8 consecutive days, thermal and mechanical withdrawal thresholds, the levels of inflammatory factors TNF-α, IL-1β and IL-6, microglial activity, and the expression of Akt-NF-κB signaling pathway in the spinal cord tissue were detected by animal ethological test, cell culture, enzyme-linked immunosorbent assay, immunofluorescence histochemistry, and western blot. Results: PF inhibited the spinal microglial activation in the CFA-induced pain model. The production of proinflammatory cytokines was decreased in the central nervous system after PF treatment both in vivo and in vitro. PF further displayed a remarkable effect on inhibiting the activation of Akt-NF-κB signaling pathway in vivo and in vitro. Conclusion: These results suggest that PF is a potential therapeutic agent for inflammatory pain and merits further investigation.

scholarly journals The Neuroprotective Effects of Insulin-Like Growth Factor 1 via the Hippo/YAP Signaling Pathway is Mediated by the PI3K/AKT Pathway Following Cerebral Ischemia-Reperfusion Injury

2021 ◽  
Author(s):  
Pian Gong ◽  
Yichun Zou ◽  
Wei Zhang ◽  
Qi Tian ◽  
Shoumeng Han ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Neuronal Death ◽  
Infarct Volume ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Neuroprotective Effects

Abstract Insulin-like growth factor 1 (IGF-1) exhibits neuroprotective properties, such as vasodilatory and anti-inflammatory effects following ischemic stroke. However, the specific molecular mechanisms of action of IGF-1 following ischemic stroke remain elusive. We wanted to explore whether IGF-1 regulates Hippo/YAP signaling pathway, potentially via activation of the PI3K/AKT signaling pathway to exert its neuroprotective effects following ischemic stroke. In the in vitro study, we used oxygen–glucose deprivation to injure cultured PC12 and SH-5YSY cells, and cortical primary neurons. Cell viability was measured using CCK-8 assay. For the in vivo analyses, Sprague–Dawley rats were subjected to middle cerebral artery occlusion; neurological function was assessed using the neurological deficit score; infarct volume was measured using triphenyltetrazolium chloride staining, and neuronal death and apoptosis was evaluated by TUNEL staining, H&E staining and Nissl staining. Western blot was used to measure the levels of YAP/TAZ, PI3K and phosphorylated AKT (p-AKT) both in vitro and in vivo. We found that IGF-1 induced activation of YAP/TAZ, which resulted in improved cell viability in vitro, and decreased neurological deficits, neuronal death and apoptosis, and cerebral infarct volume in vivo. Notably, the neuroprotective effects of IGF-1 were reversed by an inhibitor of the PI3K/AKT signaling pathway, LY294002, which not only reduced expressions of PI3K and p-AKT, but also down-regulated expression of YAP/TAZ, leading to aggravation of neurological dysfunction. These findings indicate that neuroprotective effect of IGF-1 is partly realized by up-regulation of YAP/TAZ, which is mediated by activation of the PI3K/AKT signaling pathway following cerebral ischemic stroke.

Breast Milk and Saliva Lactoferrin Levels and Postnatal Cytomegalovirus Infection

2020 ◽  
Author(s):  
Kristin E. D. Weimer ◽  
Hunter Roark ◽  
Kimberley Fisher ◽  
C. Michael Cotten ◽  
David A. Kaufman ◽  
...  
Keyword(s):  
Breast Milk ◽  
Very Low Birth Weight ◽  
Quantitative Polymerase Chain Reaction ◽  
Neutralization Assay ◽  
Enzyme Linked Immunosorbent Assay ◽  
Lactating Mothers ◽  
Life Threatening ◽  
Polymerase Chain

Abstract Objective Very low birth weight preterm infants are at risk for life-threatening infections in the NICU. Breast milk protects against infections but carries the risk of infection by cytomegalovirus (CMV) shed in mother's milk. Lactoferrin is a breast milk and saliva protein with potent neutralizing activity against CMV. Study Design VLBW, maternal breast milk fed infants in the NICU and their lactating mothers were enrolled and followed for 3 months/discharge. Breast milk and infant saliva samples were collected biweekly. Maternal CMV status was determined on breast milk. CMV was measured using quantitative polymerase chain reaction and lactoferrin by enzyme-linked immunosorbent assay. Results In an in vitro neutralization assay, the IC90 of purified human lactoferrin against CMV was 2.08 ng/mL. Bovine lactoferrins were more potent, IC90s > 10-fold higher. Lactoferrin was detected in all breast milk (median: 3.3 × 106 ng/mL) and saliva (median: 84.4 ng/swab) samples. Median CMV load in breast milk was 893 copies/mL. There was no correlation between breast milk lactoferrin concentration and CMV load. Five infants acquired postnatal CMV. There was no difference in saliva or breast milk lactoferrin concentration for mother–infant pairs and postnatal CMV acquisition. Conclusion Lactoferrin neutralizes CMV in vitro, but concentrations in breast milk and saliva are likely too low for effective neutralization in vivo.

scholarly journals Inflammatory events drive neural stem cell migration by elevating stromal-derived factor 1 alpha

STEMedicine ◽  
2020 ◽  
Vol 1 (3) ◽  
pp. e59
Author(s):  
Ziyun Jiang ◽  
Mingliang Tang
Keyword(s):  
Stem Cell ◽  
Neural Stem Cell ◽  
Microglial Activation ◽  
Brain Injuries ◽  
Glucose Deprivation ◽  
Potential Interaction ◽  
Enzyme Linked Immunosorbent Assay ◽  
Migration Assay

Background: Ischemic stroke is the most common cause of ischemia-related death globally. Brain injuries due to stroke and trauma are typically followed by inflammation reactions within the central nervous system (CNS). Neural stem cell (NSC)-based therapeutic strategies show great potential for treating stroke and ischemia-mediated brain injuries, and migration of NSCs is a critical step involved in NSC-based therapy. Methods: In order to examine the effects of microglial activation upon ischemia and stroke on NSC behaviors, oxygen-glucose deprivation (OGD) in vitro model was established for mimicking in vivo stroke and ischemia pathological conditions in this study. By combining of enzyme-linked immunosorbent assay, migration assay, Western blot and immunostaining, we found that OGD insult induced microglial activation by releasing cytokines and chemokines. Results: The conditioned media (CM) of OGD-treated groups impaired the proliferation and capability of neurosphere formation. Moreover, we found the stromal cell-derived factor 1α/CXC chemokine receptor 4 (CXCR4) pathway was an active player that facilitated the migration of NSCs, since a CXCR4 specific antagonist AMD3100 was able to impair NSC migration both in vitro and in vivo. Conclusion: The current study presents a potential interaction between NSC behaviors and microglial activation underlying brain injuries, such as ischemia and stroke. More importantly, we reveal the underlying mechanisms of microglia-induced NSC migration under OGD conditions and it should be beneficial to stem cell-based therapies to treat acute brain injuries.

scholarly journals HDAC inhibition protects degenerating cone photoreceptors in vivo

2016 ◽  
Author(s):  
Dragana Trifunović ◽  
Blanca Arango-Gonzalez ◽  
Antonella Comitato ◽  
Melanie Barth ◽  
Ayse Sahaboglu ◽  
...  
Keyword(s):  
Cell Death ◽  
Trichostatin A ◽  
Treatment Options ◽  
Hdac Inhibition ◽  
Neuroprotective Effects ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
New Treatment ◽  
Future Therapy

AbstractRetinal diseases caused by cone photoreceptor cell death are devastating as the patients are experiencing loss of accurate and color vision. Understanding the mechanisms of cone cell death and the identification of key players therein could provide new treatment options. We studied the neuroprotective effects of a histone deacetylase inhibitor, Trichostatin A (TSA), in a mouse model of inherited, primary cone degeneration (cpfl1). We show that HDAC inhibition protects cones in vitro, in retinal explant cultures. More importantly, in vivo a single TSA injection increased cone survival for up to 10 days post-injection. In addition, the abnormal, incomplete cone migration pattern in the cpfl1 retina was significantly improved by HDAC inhibition. These findings suggest a crucial role for HDAC activity in primary cone degeneration and highlight a new avenue for future therapy developments for cone dystrophies and diseases associated with impaired cone migration.

scholarly journals HKDC1 promotes the tumorigenesis and glycolysis in lung adenocarcinoma via regulating AMPK/mTOR signaling pathway

2020 ◽  
Author(s):  
Xinyu Wang ◽  
Bowen Shi ◽  
Yue Zhao ◽  
Qijue Lu ◽  
Xiang Fei ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Signaling Pathway ◽  
Clinicopathological Characteristics ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Promising Therapeutic Target ◽  
Bioinformatics Study ◽  
Polymerase Chain

Abstract Background: Hexokinase domain component 1 (HKDC1) plays an oncogenic role in certain types of cancer, such as lymphoma, liver cancer, and breast cancer. Previous bioinformatics study revealed that HKDC1 was significantly upregulated in lung adenocarcinoma (LUAD). However, its biological functions and potential mechanism in LUAD have not been studied. Methods: We performed bioinformatics analysis, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, immunohistochemistry, and a series of functional assays in vitro and in vivo to investigate the roles of HKDC1 in LUAD. Results: We discovered that HKDC1 was highly expressed in LUAD tissues and cell lines, and the positive expression of HKDC1 was correlated with aberrant clinicopathological characteristics in LUAD patients. Furthermore, HKDC1 could serve as a prognostic predictor for LUAD patients. Overexpression of HKDC1 promoted proliferation, migration, invasion, glycolysis, EMT and tumorigenicity, whereas knockdown of HKDC1 produced the opposite functional effects. Mechanistically, HKDC1 could regulate the AMPK/mTOR signaling pathway to perform its biological function. Conclusions: Our findings suggest that HKDC1 plays an oncogenic role in LUAD. Targeting this gene may provide a promising therapeutic target to delay LUAD progression.

scholarly journals Agmatine Alleviates Epileptic Seizures and Hippocampal Neuronal Damage by Inhibiting Gasdermin D-Mediated Pyroptosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xueying Li ◽  
Jiahe Lin ◽  
Yingjie Hua ◽  
Jiaoni Gong ◽  
Siqi Ding ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Neuronal Damage ◽  
Epileptic Seizures ◽  
Inhibitory Effect ◽  
Enzyme Linked Immunosorbent Assay ◽  
Nissl Staining ◽  
Neuroprotective Effects ◽  
Cellular Inflammation

Background: Epilepsy is a common neurological disease, and neuroinflammation is one of the main contributors to epileptogenesis. Pyroptosis is a type of pro-inflammatory cell death that is related to epilepsy. Agmatine, has anti-inflammatory properties and exerts neuroprotective effects against seizures. Our study investigated the effect of agmatine on the core pyroptosis protein GSDMD in the context of epilepsy.Methods: A chronic epilepsy model and BV2 microglial cellular inflammation model were established by pentylenetetrazole (PTZ)-induced kindling or lipopolysaccharide (LPS) stimulation. H&E and Nissl staining were used to evaluate hippocampal neuronal damage. The expression of pyroptosis and inflammasome factors was examined by western blotting, quantitative real-time PCR, immunofluorescence and enzyme-linked immunosorbent assay (ELISA).Results: Agmatine disrupted the kindling acquisition process, which decreased seizure scores and the incidence of full kindling and blocked hippocampal neuronal damage. In addition, agmatine increased BV2 microglial cell survival in vitro and alleviated seizures in vivo by suppressing the levels of PTZ-induced pyroptosis. Finally, the expression of TLR4, MYD88, phospho-IκBα, phospho-NF-κB and the NLRP3 inflammasome was significantly upregulated in LPS-induced BV2 microglial cells, while agmatine suppressed the expression of these proteins.Conclusions: Our results indicate that agmatine affects epileptogenesis and exerts neuroprotective effects by inhibiting neuroinflammation, GSDMD activation, and pyroptosis. The inhibitory effect of agmatine on pyroptosis was mediated by the suppression of the TLR4/MYD88/NF-κB/NLRP3 inflammasome pathway. Therefore, agmatine may be a potential treatment option for epilepsy.

scholarly journals HKDC1 Promotes the Tumorigenesis and Glycolysis in Lung Adenocarcinoma via AMPK/mTOR Signaling Pathway

2020 ◽  
Author(s):  
Xinyu Wang ◽  
Qijue Lu ◽  
Yue Zhao ◽  
Xiang Fei ◽  
Jianglong Chen ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Signaling Pathway ◽  
Clinicopathological Characteristics ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Functional Effect ◽  
Promising Therapeutic Target ◽  
Polymerase Chain

Abstract Background: Hexokinase domain component 1 (HKDC1) belongs to the fifth hexokinase, which plays an oncogenic role in lymphoma, liver cancer, and breast cancer, as reported. However, its biological functions in lung adenocarcinoma (LUAD) has not been studied. Methods: We applied bioinformatics analysis, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, immunohistochemistry, and a series of functional assays in vitro and in vivo to investigate the roles of HKDC1 in LUAD. Results: We discovered that HKDC1 was highly expressed in LUAD tissues and cell lines, and the positive expression of HKDC1 was correlated with aberrant clinicopathological characteristics in LUAD patients. Besides, HKDCI could be served as a prognostic predictor for LUAD patients. Overexpression of HKDC1 promoted the proliferation, migration, invasion, glycolysis, EMT and tumorgenicity, whereas knockdown of HKDC1 produced the opposite functional effect. Mechanistically, HKDC1 could regulate the AMPK/mTOR signaling pathway to perform its biological function. Conclusions: Our findings suggested that HKDC1 plays an oncogenic role in LUAD. Targeting this gene may provide a promising therapeutic target to delay LUAD progress.

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