Natural Glycoside Salidroside Ameliorates Orthopedic Surgery-Induced Cognitive Dysfunction Through Activating Adenosine 5‘-Monophosphate-Activated Protein Kinase Signaling in Mice

Abstract Background: Perioperative neurocognitive disorders (PND) are the most common postoperative complications with few therapeutic options. Salidroside, a plant-derived compound, has gained increased attention as treatment for various neurological diseases and particularly modifier of microglia-mediated neuroinflammation. However, the effect of salidroside on orthopedic surgery-induced cognitive dysfunction and the underlying mechanisms are largely unknown.Methods: The Morris water maze test was used to investigate potential effects of salidroside in the animal model of tibia fracturing with intramedullary fixation. Therapeutic mechanism and related signaling pathways of salidroside in PND were further investigated with animal tissues and microglial cultures in vitro by molecular biology tests.Results: Here we found that salidroside greatly attenuated cognitive impairment in mice after orthopedic surgery. Neuroinflammation in mouse hippocampus were also attenuated by salidroside. Meanwhile, salidroside treatment induced a switch in microglia polarization to the anti-inflammatory phenotype. In vitro, salidroside suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype to the anti-inflammatory phenotype. Mechanically, molecular docking studies revealed potential AMPK activation activity of salidroside. And salidroside did up-regulated the AMPK pathway proteins. Moreover, AMPK antagonist abolished the effects of salidroside in vivo and in vitro.Conclusions: Taken together, our results demonstrated that salidroside effectively suppressed PND by suppressing microglia-mediated neuroinflammation through activating AMPK pathway, and it might be a novel therapeutic approach for PND.

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The Neuroprotective Effects of Carvacrol on Ethanol-Induced Hippocampal Neurons Impairment via the Antioxidative and Antiapoptotic Pathways

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/4079425 ◽

2017 ◽

Vol 2017 ◽

pp. 1-17 ◽

Cited By ~ 8

Author(s):

Peng Wang ◽

Qian Luo ◽

Hui Qiao ◽

Hui Ding ◽

Yonggang Cao ◽

...

Keyword(s):

Oxidative Stress ◽

Western Blot ◽

Cognitive Dysfunction ◽

Hippocampal Neurons ◽

Morris Water Maze Test ◽

Oxidative Stress Biomarkers ◽

Neuroprotective Effects ◽

Stress Injury

Chronic alcohol consumption causes hippocampal neuronal impairment, which is associated with oxidative stress and apoptosis. Carvacrol is a major monoterpenic phenol found in essential oils from the family Labiatae and has antioxidative stress and antiapoptosis actions. However, the protective effects of carvacrol in ethanol-induced hippocampal neuronal impairment have not been fully understood. We explored the neuroprotective effects of carvacrol in vivo and in vitro. Male C57BL/6 mice were exposed to 35% ethanol for 4 weeks to establish ethanol model in vivo, and hippocampal neuron injury was simulated by 200 mM ethanol in vitro. Morris water maze test was performed to evaluate the cognitive dysfunction. The oxidative stress injury of hippocampal neurons was evaluated by measuring the levels of oxidative stress biomarkers. Histopathological examinations and western blot were performed to evaluate the apoptosis of neurons. The results showed that carvacrol attenuates the cognitive dysfunction, oxidative stress, and apoptosis of the mice treated with ethanol and decreases hippocampal neurons apoptosis induced by ethanol in vitro. In addition, western blot analysis revealed that carvacrol modulates the protein expression of Bcl-2, Bax, caspase-3, and p-ERK, without influence of p-JNK and p-p38. Our results suggest that carvacrol alleviates ethanol-mediated hippocampal neuronal impairment by antioxidative and antiapoptotic effects.

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Engineering of a Spider Peptide via Conserved Structure-Function Traits Optimizes Sodium Channel Inhibition In Vitro and Anti-Nociception In Vivo

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.742457 ◽

2021 ◽

Vol 8 ◽

Author(s):

H. Hu ◽

S. E. Mawlawi ◽

T. Zhao ◽

J. R. Deuis ◽

S. Jami ◽

...

Keyword(s):

Structure Function ◽

Visceral Pain ◽

Neurological Diseases ◽

Docking Studies ◽

Voltage Sensor ◽

Voltage Gated ◽

Channel Inhibition ◽

Voltage Sensor Domain

Venom peptides are potent and selective modulators of voltage-gated ion channels that regulate neuronal function both in health and in disease. We previously identified the spider venom peptide Tap1a from the Venezuelan tarantula Theraphosa apophysis that targeted multiple voltage-gated sodium and calcium channels in visceral pain pathways and inhibited visceral mechano-sensing neurons contributing to irritable bowel syndrome. In this work, alanine scanning and domain activity analysis revealed Tap1a inhibited sodium channels by binding with nanomolar affinity to the voltage-sensor domain II utilising conserved structure-function features characteristic of spider peptides belonging to family NaSpTx1. In order to speed up the development of optimized NaV-targeting peptides with greater inhibitory potency and enhanced in vivo activity, we tested the hypothesis that incorporating residues identified from other optimized NaSpTx1 peptides into Tap1a could also optimize its potency for NaVs. Applying this approach, we designed the peptides Tap1a-OPT1 and Tap1a-OPT2 exhibiting significant increased potency for NaV1.1, NaV1.2, NaV1.3, NaV1.6 and NaV1.7 involved in several neurological disorders including acute and chronic pain, motor neuron disease and epilepsy. Tap1a-OPT1 showed increased potency for the off-target NaV1.4, while this off-target activity was absent in Tap1a-OPT2. This enhanced potency arose through a slowed off-rate mechanism. Optimized inhibition of NaV channels observed in vitro translated in vivo, with reversal of nocifensive behaviours in a murine model of NaV-mediated pain also enhanced by Tap1a-OPT. Molecular docking studies suggested that improved interactions within loops 3 and 4, and C-terminal of Tap1a-OPT and the NaV channel voltage-sensor domain II were the main drivers of potency optimization. Overall, the rationally designed peptide Tap1a-OPT displayed new and refined structure-function features which are likely the major contributors to its enhanced bioactive properties observed in vivo. This work contributes to the rapid engineering and optimization of potent spider peptides multi-targeting NaV channels, and the research into novel drugs to treat neurological diseases.

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Wnt/β-catenin signaling regulates lipopolysaccharide-altered polarizations of RAW264.7 cells and alveolar macrophages in mouse lungs

European Journal of Inflammation ◽

10.1177/20587392211059362 ◽

2021 ◽

Vol 19 ◽

pp. 205873922110593

Author(s):

Jiali Yang ◽

Ying Wang ◽

Dandan Yang ◽

Jia Ma ◽

Shuang Wu ◽

...

Keyword(s):

Alveolar Macrophage ◽

Alveolar Macrophages ◽

Macrophage Polarization ◽

Raw264.7 Cells ◽

M1 Polarization ◽

Inflammatory Phenotype ◽

Inflammatory State ◽

Anti Inflammatory

Introduction Macrophages are capable of exerting both proinflammatory and anti-inflammatory functions in response to distinct environmental stimuli, by polarizing into classically inflammatory state (M1) and anti-inflammatory phenotype (M2), respectively. The Wnt/β-catenin signaling plays an important role in the tissue homeostasis and immune regulations, including the macrophage polarizations. However, the molecular mechanism of Wnt/β-catenin signaling in regulating alveolar macrophage polarization in an inflammatory state remains unclear. Methods The Wnt/β-catenin signaling-altered phenotypes of murine macrophage-like RAW264.7 cells in vitro and alveolar macrophage in vivo in both of naïve and lipopolysaccharide-induced inflammation states were accessed by immunoblotting and immunostaining assays. Results The activation of Wnt/β-catenin signaling inhibited macrophage M1 polarization, but promoted alternative M2 polarization in murine RAW264.7 cells under a naïve state. Interestingly, in an LPS-induced inflammation condition, the enhanced Wnt/β-catenin activity suppressed both M1 and M2 polarizations in RAW264.7 cells in vitro, and primary alveolar macrophages of LPS-challenged mice in vivo. Molecular analysis further demonstrated an involvement of Stat signing in regulating Wnt/β-catenin signaling-altered polarizations in mouse alveolar macrophages. Conclusion These results suggest a mechanism by which Wnt/β-catenin signaling modulates macrophage polarization in an inflammation state by regulating the Stat signaling pathway.

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In Silico, In Vitro, and In Vivo Antitumor and Anti-Inflammatory Evaluation of a Standardized Alkaloid-Enriched Fraction Obtained from Boehmeria caudata Sw. Aerial Parts

Molecules ◽

10.3390/molecules25174018 ◽

2020 ◽

Vol 25 (17) ◽

pp. 4018

Author(s):

Paula P. de Paiva ◽

Julia H. B. Nunes ◽

Fabiana R. Nonato ◽

Ana L. T. G. Ruiz ◽

Rafael R. T. Zafred ◽

...

Keyword(s):

Human Tumor ◽

Antitumor Agent ◽

Docking Studies ◽

In Vivo Studies ◽

Myeloperoxidase Activity ◽

Aerial Parts ◽

M Phase ◽

Anti Inflammatory

In the context of the cancer-inflammation relationship and the use of natural products as potential antitumor and anti-inflammatory agents, the alkaloid-enriched fraction of Boehmeriacaudata (BcAEF) aerial parts was evaluated. In vitro antiproliferative studies with human tumor cell lines showed high activity at low concentrations. Further investigation on NCI-H460 cells showed an irreversible effect on cell proliferation, with cell cycle arrest at G2/M phase and programmed cell death induction. Molecular docking studies of four alkaloids identified in BcAEF with colchicine’s binding site on β-tubulin were performed, suggesting (−)-C (15R)-hydroxycryptopleurine as the main inductor of the observed mitotic death. In vivo studies showed that BcAEF was able to reduce Ehrlich tumor volume progression by 30 to 40%. Checking myeloperoxidase activity, BcAEF reduced neutrophils migration towards the tumor. The in vivo anti-inflammatory activity was evaluated by chemically induced edema models. In croton oil-induced ear edema and carrageenan (CG)-induced paw edema models, BcAEF reduced edema around 70 to 80% together with inhibition of activation and/or migration of neutrophils to the inflammatory area. All together the results presented herein show BcAEF as a potent antitumor agent combining antiproliferative and anti-inflammatory properties, which could be further explored in (pre)clinical studies.

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Studies in 3,4-diaryl-1,2,5-oxadiazoles and their N-oxides: Search for better COX-2 inhibitors

Acta Pharmaceutica ◽

10.2478/v10007-007-0002-z ◽

2007 ◽

Vol 57 (1) ◽

pp. 13-30 ◽

Cited By ~ 20

Author(s):

Mange Yadav ◽

Shrikant Shirude ◽

Devendra Puntambekar ◽

Pinkal Patel ◽

Hetal Prajapati ◽

...

Keyword(s):

Enzyme Inhibition ◽

Docking Studies ◽

Inflammatory Activity ◽

Rat Paw Edema ◽

Cox 2 ◽

Anti Inflammatory ◽

Cox 2 Inhibitors ◽

Cox 1

Studies in 3,4-diaryl-1,2,5-oxadiazoles and theirN-oxides: Search for better COX-2 inhibitorsA series of 3,4-diaryl-1,2,5-oxadiazoles and 3,4-diaryl-1,2,5-oxadiazoleN-oxides were prepared and evaluated for COX-2 and COX-1 binding affinityin vitroand for anti-inflammatory activity by the rat paw edema method.p-Methoxy (p-OMe) substituted compounds 9, 21, 34, 41, 42 showed COX-2 enzyme inhibition higher than that showed by compounds with other substituents. 3,4-Di(4-methoxyphenyl)-1,2,5-oxadiazoleN-oxide (42) showed COX-2 enzyme inhibition of 54% at 22 μmol L-1and COX-1 enzyme inhibition of 44% at 88 μmol L-1concentrations, but showed very lowin vivoanti-inflammatory activity. Its deoxygenated derivative (21) showed lower COX-2 enzyme inhibition (26% at 22 μmol L-1) and higher COX-1 enzyme inhibition (53% at 88 μmol L-1) but, markedin vivoanti-inflammatory activity (71% at 25 mg kg-1)vs.celecoxib (48% at 12.5 mg kg-1). Molecular modeling (docking) studies showed that the methoxy group is positioned in the vicinity of COX-2 secondary pocket and it also participates in hydrogen bonding interactions in the COX-2 active site. These preliminary studies suggest thatp-methoxy (p-OMe) group in one of benzene rings may give potentially active leads in this series of oxadiazole/N-oxides.

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Exosomes derived from bMSCs inhibit neuroinflammatory after traumatic brain injury by influencing the IL-10/STAT3 signaling pathway

10.21203/rs.3.rs-151671/v1 ◽

2021 ◽

Author(s):

Liang Wen ◽

Yadong Wang ◽

Dongfeng Shen ◽

Peidong Zheng ◽

Mengdi Tu ◽

...

Keyword(s):

Brain Injury ◽

Neuronal Apoptosis ◽

Stat3 Pathway ◽

Marrow Mesenchymal Stem Cells ◽

Inflammatory Phenotype ◽

Microrna Sequencing ◽

Bv2 Microglia ◽

Anti Inflammatory

Abstract Exosomes are important membranous vesicles in several physiological and pathological processes. It is postulated that the microRNAs contained in the exosomes play the major roles in these processes. Exosomal microRNAs from bone marrow mesenchymal stem cells (bMSCs) have emerged as promising therapeutic agents against inflammation. However, its specific mechanism has not been clarified. The present study was designed to elucidate the underlying mechanism of bone marrow mesenchymal stem cells derived exosomes on neuroinflammation in vitro and in vivo.Methods: In vitro co-culture experiments were done to demonstrate the effects of bMSCs and bMSCs-derived exosomes on the polarization state of BV2 microglia cells. In vivo experiments were subsequently done to validate the role of exosomes derived from bMSCs in neuro-inflammation after brain injury. MicroRNA sequencing was then done to reveal the potential expanded diversity between bMSCs and exosomes derived from bMSCs. The microRNAs were then screened and quantified by quantitative polymerase chain reaction (qPCR) to identify the most significant miRNAs. Moreover, lentiviral transfection was performed to establish animal models with overexpressed and downregulated microRNA expression levels. The animal models were subsequently used to determine the effects of specific microRNAs on neuroinflammation after TBI and their possible mechanisms of action. Results: Both bMSCs and exosomes derived from bMSCs promoted the polarization of activated BV2 microglia cells to the anti-inflammatory phenotype. They inhibited the expression of pro-inflammatory cytokines but promoted the expression of anti-inflammatory cytokines. Exosomes derived from bMSCs played a stronger role in regulating the expression of inflammatory factors. In vivo animal-based experiments further revealed that the exosomes reduced neuronal apoptosis in the cortical area. They also promoted inhibition of neuroinflammation and transformation of microglia to anti-inflammatory phenotype. In addition, MicroRNA sequencing and subsequent analysis revealed that microRNA-181b was actively involved in the process. Subsequent lentiviral transfection studies revealed that overexpression of miR181b effectively reduced neuronal apoptosis and neuroinflammatory response after traumatic brain injury. Overexpression of microRNA181b also promoted the transformation of microglia to the anti-inflammatory phenotype. These effects were achieved through activation of the IL-10/STAT3 pathway.Conclusion: Exosome derived from bMSCs promotes the polarization of microglia to anti-inflammatory phenotype and inhibit neuroinflammation both in vitro and in vivo. They also reduce neuronal apoptosis and protect damaged brain tissue. The microRNA-181b plays a vital role in this process by activating the IL-10/STAT3 pathway. Our study indicates that IL-10/STAT3 pathway may be involved in neuroinflammatory progression and that up-regulation of the microRNA-181b is a potentially new therapeutic approach for neuroinflammation.

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Synthesis and Biological Evaluation of (E)-N’-Benzylidene-7-methyl-2-propyl-1H-benzo[d] imidazole-5-carbohydrazides as Antioxidant, Anti-inflammatory and Analgesic agents

Heterocyclic Communications ◽

10.1515/hc-2019-0009 ◽

2019 ◽

Vol 25 (1) ◽

pp. 27-38 ◽

Cited By ~ 2

Author(s):

Ramamurthy Katikireddy ◽

Ramu Kakkerla ◽

M. P. S. Murali Krishna ◽

Gandamalla Durgaiah ◽

Y. N. Reddy ◽

...

Keyword(s):

Analgesic Activity ◽

Aromatic Aldehydes ◽

Antioxidant Property ◽

Docking Studies ◽

Biological Evaluation ◽

Biological Data ◽

Analgesic Agents ◽

Anti Inflammatory

Abstract(E)-N’-Benzylidene-7-methyl-2-propyl-1H-benzo [d]imidazole-5-carbohydrazides (5a-r) have been synthesized from 7-methyl-2-propyl-1H-benzo[d]imidazole-5-carbohydrazide (3) by condensing with different aromatic aldehydes (4a-r). Title compounds (5a-r) were evaluated for in vitro antioxidant activity and based on their potential for antioxidant property, selected compounds 5d and 5m-p were screened for in vivo anti-inflammatory and analgesic activity. The results indicate that the compound 5o and 5p are effective against anti-inflammatory and analgesic activity. The biological data was further supported by molecular docking studies, which revealed the binding pattern and the affinity of the molecules in the active site of COX-2.

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2-Allylphenol Reduces IL-1β and TNF-α, Promoting Antinociception through Adenosinergic, Anti-Inflammatory, and Antioxidant Mechanisms

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/1346878 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14

Author(s):

Humberto de Carvalho Aragão Neto ◽

Diogo Vilar da Fonsêca ◽

Renan Marinho Braga ◽

Marcus Tullius Scotti ◽

Terezinha Weyne Araújo Borges do Nascimento ◽

...

Keyword(s):

In Silico ◽

Antinociceptive Effect ◽

Site Investigation ◽

Docking Studies ◽

A2a Receptors ◽

Proinflammatory Mediators ◽

Reduction Activity ◽

Anti Inflammatory

2-Allylphenol (2-AP) is a synthetic phenylpropanoid, structurally related to cardanol, thymol, and ortho-eugenol. Phenylpropanoids are described in the literature as being capable of promoting biological activity. Due to the similarity between 2-AP and other bioactive phenylpropanoids, the present research aims at evaluating the antioxidant, antinociceptive, and anti-inflammatory potential of 2-AP in silico, in vitro, and in vivo. At 30 min prior to the start of in vivo pharmacological testing, administration of 2-AP (25, 50, 75, and 100 mg/kg i.p.), morphine (6 mg/kg i.p.), dexamethasone (2 mg/kg s.c.), or vehicle alone was performed. In the acetic acid-induced abdominal writhing tests, pretreatment with 2-AP significantly reduced the number of abdominal writhes, as well as decreased licking times in the glutamate and formalin tests. Investigation of the mechanism of action using the formalin model led to the conclusion that the opioid system does not participate in its activity. However, the adenosinergic system is involved. In the peritonitis tests, 2-AP inhibited leukocyte migration and reduced releases of proinflammatory mediators TNF-α and IL-1β. In vitro antioxidant assays demonstrated that 2-AP presents significant ability to sequester superoxide radicals. In silico docking studies confirmed interaction between 2-AP and the adenosine A2a receptor through hydrogen bonds with the critical asparagine 253 residues present in the active site. Investigation of 2-AP demonstrated its nociception inhibition and ability to reduce reactive oxygen species. Its interaction with A2a receptors may well be related to proinflammatory cytokines TNF-α and IL-1β reduction activity, corroborating its antinociceptive effect.

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