scholarly journals The Gut Microbiota Metabolite Urolithin B Improves Cognitive Deficits by Inhibiting Cyt C-Mediated Apoptosis and Promoting the Survival of Neurons Through the PI3K Pathway in Aging Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Chen ◽  
Fuchao Chen ◽  
Jiexin Lei ◽  
Gaohua Wang ◽  
Benhong Zhou
Keyword(s):  
Cognitive Deficits ◽  
Molecular Mechanisms ◽  
Brain Aging ◽  
Neuroprotective Effect ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Interventions ◽  
Protective Effects ◽  
Cytochrome C Release ◽  
Aging Model ◽  
Urolithin B

Background: Despite considerable advances in pharmacotherapy, more effective therapeutic interventions for aging-related neurodegenerative disorders (NDs), such as Alzheimer’s disease (AD), remain limited. Urolithin B (UB), one of the major subcategories of urolithins (microbiota metabolites) found in various tissues after ellagitannin consumption, has been shown to possess antioxidant, anti-inflammatory, and antiapoptotic effects. However, the neuroprotective effect of UB on brain aging in mice and its potential mechanisms were still unknown.Methods: In the current research, we first assessed the ameliorative effects of UB on oxidative injury and apoptosis induced by H2O2 in neuro-2a cells. Then a subcutaneous injection of D-galactose in mice for 8 weeks was used to establish the aging model to evaluate the protective effects of UB. The capacity of memory and learning, alterations of hippocampus histology and corresponding molecular mechanisms were all evaluated.Results: The D-gal-induced accelerated aging model in vivo demonstrated that UB could significantly ameliorate deficits in learning and memory by inhibiting the accumulation of advanced glycation end products (AGEs) and elevating the expression and activity of Cu, Zn-SOD and CAT. Furthermore, UB downregulated the c-Jun N-terminal kinase (JNK) signaling pathway and prevented cytochrome c release from isolated mitochondria, thereby inhibiting neuronal apoptosis during the aging process. More importantly, UB stimulation of aging mice activated ERK and phosphoinositide 3-kinase (PI3K), leading to neuronal survival along with Akt and p44/42 mitogen-activated protein kinase (MAPK) phosphorylation and activation.Conclusion: In summary, UB effectively alleviated cognitive deficits and ameliorated brain aging-related conditions and could be considered a healthcare product to prevent aging-associated NDs such as AD.

scholarly journals The Gut Microbiota Metabolite Urolithin B Improves Cognitive Deficits by Inhibiting Cyt C-mediated Apoptosis and Promoting the Survival of Neurons Through the PI3K Pathway in Aging Mice

2021 ◽  
Author(s):  
chen peng ◽  
Fuchao Chen ◽  
Jiexin Lei ◽  
Gaohua Wang ◽  
Benhong Zhou
Keyword(s):  
Cognitive Deficits ◽  
Molecular Mechanisms ◽  
Brain Aging ◽  
Neuroprotective Effect ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Interventions ◽  
Protective Effects ◽  
Cytochrome C Release ◽  
Aging Model ◽  
Urolithin B

Abstract BackgroundDespite considerable advances in pharmacotherapy, more effective therapeutic interventions for aging-related neurodegenerative disorders (NDs), such as Alzheimer's disease (AD), remain limited. Urolithin B (UB), one of the major subcategories of urolithins (microbiota metabolites) found in various tissues after ellagitannin consumption, has been shown to possess antioxidant, anti-inflammatory, and antiapoptotic effects. However, the neuroprotective effect of UB on brain aging in mice and its potential mechanisms were still unknown. MethodsIn the current research, we first assessed the ameliorative effects of UB on oxidative injury and apoptosis induced by H2O2 in neuro-2a cells. Then a subcutaneous injection of D-galactose in mice for 8 weeks was used to establish the aging model to evaluate the protective effects of UB. The capacity of memory and learning, alterations of hippocampus histology and corresponding molecular mechanisms were all evaluated. ResultsThe D-gal-induced accelerated aging model in vivo demonstrated that UB could significantly ameliorate deficits in learning and memory by inhibiting the accumulation of advanced glycation end products (AGEs) and elevating the expression and activity of Cu, Zn-SOD and CAT. Furthermore, UB downregulated the c-Jun N-terminal kinase (JNK) signaling pathway and prevented cytochrome c release from isolated mitochondria, thereby inhibiting neuronal apoptosis during the aging process. More importantly, UB stimulation of aging mice activated ERK and phosphoinositide 3-kinase (PI3K), leading to neuronal survival along with Akt and p44/42 mitogen-activated protein kinase (MAPK) phosphorylation and activation. ConclusionIn summary, UB effectively alleviated cognitive deficits and ameliorated brain aging-related conditions and could be considered a healthcare product to prevent aging-associated NDs such as AD.

scholarly journals Isorhynchophylline Protects PC12 Cells Against Beta-Amyloid-Induced Apoptosis via PI3K/Akt Signaling Pathway

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Yan-Fang Xian ◽  
Zhi-Xiu Lin ◽  
Qing-Qiu Mao ◽  
Jian-Nan Chen ◽  
Zi-Ren Su ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Pc12 Cells ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Neuroprotective Effect ◽  
Protective Action ◽  
Protective Effects ◽  
Phosphorylated Akt ◽  
Induced Apoptosis

The neurotoxicity of amyloid-β(Aβ) has been implicated as a critical cause of Alzheimer’s disease. Isorhynchophylline (IRN), an oxindole alkaloid isolated fromUncaria rhynchophylla,exerts neuroprotective effect againstAβ25–35-induced neurotoxicityin vitro. However, the exact mechanism for its neuroprotective effect is not well understood. The present study aimed to investigate the molecular mechanisms underlying the protective action of IRN againstAβ25–35-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. Pretreatment with IRN significantly increased the cell viability, inhibited the release of lactate dehydrogenase and the extent of DNA fragmentation inAβ25–35-treated cells. IRN treatment was able to enhance the protein levels of phosphorylated Akt (p-Akt) and glycogen synthase kinase-3β(p-GSK-3β). Lithium chloride blockedAβ25–35-induced cellular apoptosis in a similar manner as IRN, suggesting that GSK-3βinhibition was involved in neuroprotective action of IRN. Pretreatment with LY294002 completely abolished the protective effects of IRN. Furthermore, IRN reversedAβ25–35-induced attenuation in the level of phosphorylated cyclic AMP response element binding protein (p-CREB) and the effect of IRN could be blocked by the PI3K inhibitor. These experimental findings unambiguously suggested that the protective effect of IRN againstAβ25–35-induced apoptosis in PC12 cells was associated with the enhancement of p-CREB expression via PI3K/Akt/GSK-3βsignaling pathway.

Vascular Protective Effects of Xanthotoxin and Its Action Mechanism in Rat Aorta and Human Vascular Endothelial Cells

2020 ◽  
Vol 57 (6) ◽  
pp. 313-324
Author(s):  
Li-Hua Cao ◽  
Ho Sub Lee ◽  
Zhe-Shan Quan ◽  
Yun Jung Lee ◽  
Yu Jin
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Molecular Mechanisms ◽  
Umbilical Vein ◽  
Neuroprotective Effect ◽  
Intercellular Adhesion Molecule ◽  
Dependent Manner ◽  
Protective Effects ◽  
Concentration Dependent Manner

<b><i>Objective:</i></b> Xanthotoxin (XAT) is a linear furanocoumarin mainly extracted from the plants <i>Ammi majus</i> L. XAT has been reported the apoptosis of tumor cells, anti-convulsant, neuroprotective effect, antioxidative activity, and vasorelaxant effects. This study aimed to investigate the vascular protective effects and underlying molecular mechanisms of XAT. <b><i>Methods:</i></b> XAT’s activity was studied in rat thoracic aortas, isolated with aortic rings, and human umbilical vein endothelial cells (HUVECs). <b><i>Results:</i></b> XAT induced endothelium-dependent vasodilation in a concentration-dependent manner in the isolated rat thoracic aortas. Removal of endothelium or pretreatment of aortic rings with L-NAME, 1<i>H</i>-[1,2,4]-oxadiazolo-[4,3-<i>a</i>]-quinoxalin-1-one, and wortmannin significantly inhibited XAT-induced relaxation. In addition, treatment with thapsigargin, 2-aminoethyl diphenylborinate, Gd<sup>3+</sup>, and 4-aminopyridine markedly attenuated the XAT-induced vasorelaxation. XAT increased nitric oxide production and Akt- endothelial NOS (eNOS) phosphorylation in HUVECs. Moreover, XAT attenuated the expression of TNF-α-induced cell adhesion molecules such as intercellular adhesion molecule, vascular cell adhesion molecule-1, and E-selectin. However, this effect was attenuated by the eNOS inhibitors L-NAME and asymmetric dimethylarginine. <b><i>Conclusions:</i></b> This study suggests that XAT induces vasorelaxation through the Akt-eNOS-cGMP pathway by activating the K<sub>V</sub> channel and inhibiting the L-type Ca<sup>2+</sup> channel. Furthermore, XAT exerts an inhibitory effect on vascular inflammation, which is correlated with the observed vascular protective effects.

scholarly journals Relief of Cadmium-Induced Intestinal Motility Disorder in Mice by Lactobacillus plantarum CCFM8610

2020 ◽  
Vol 11 ◽  
Author(s):  
Yang Liu ◽  
Jiangping Wu ◽  
Yue Xiao ◽  
Qing Liu ◽  
Leilei Yu ◽  
...  
Keyword(s):  
Stress Response ◽  
Lactobacillus Plantarum ◽  
Intestinal Motility ◽  
Molecular Mechanisms ◽  
Cellular Stress Response ◽  
Mitogen Activated Protein Kinase ◽  
Protective Mechanism ◽  
Protective Effects ◽  
Cd Toxicity ◽  
Cd Exposure

Cadmium (Cd) is a toxic metal inducing a range of adverse effects on organs including liver and kidneys. However, the underlying molecular mechanisms of Cd-induced intestinal toxicity through dietary intake is poorly studied. This study evaluated the toxic effects of Cd on intestinal physiology and confirmed the effectiveness of the protective mechanism of the probiotic Lactobacillus plantarum CCFM8610 against chronic Cd toxicity. After treatment with Cd, the HT-29 cell line was subjected to iTRAQ analysis, which revealed that changes in the proteomic profiles after Cd exposure were related to pathways involved in the stress response and carbohydrate metabolism. The results of an animal trial also indicated that 10 weeks of Cd exposure decreased the fecal water content and contractile response of colonic muscle strips in mice, and delayed the excretion time of the first black feces. L. plantarum CCFM8610 treatment provided protective effects against these Cd-induced intestinal motility dysfunctions by recovering the levels of neurotransmitters, including substance P, acetyl cholinesterase, vasoactive intestinal peptide, 5-hydroxytryptamine, calcitonin gene-related peptide, and nitric oxide, and suppressing the cellular stress response in mice (e.g., the inhibition of mitogen-activated protein kinase pathways). The administration of this probiotic was also observed to reduce Cd levels in the tissues and blood of the mice. Our results suggest a newly identified protective mechanism of probiotics against Cd toxicity that involves the recovery of intestinal motility and increase in fecal cadmium excretion.

scholarly journals Uncovering the Pharmacological Mechanism of Stemazole in the Treatment of Neurodegenerative Diseases Based on a Network Pharmacology Approach

2020 ◽  
Vol 21 (2) ◽  
pp. 427 ◽  
Author(s):  
Jing Zhang ◽  
Huajun Li ◽  
Yubo Zhang ◽  
Chaoran Zhao ◽  
Yizi Zhu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Target Prediction ◽  
Mapk Signaling ◽  
Scientific Basis ◽  
Mitogen Activated Protein Kinase ◽  
Network Pharmacology ◽  
Protective Effects ◽  
Mitogen Activated Protein

Stemazole exerts potent pharmacological effects against neurodegenerative diseases and protective effects in stem cells. However, on the basis of the current understanding, the molecular mechanisms underlying the effects of stemazole in the treatment of Alzheimer’s disease and Parkinson’s disease have not been fully elucidated. In this study, a network pharmacology-based strategy integrating target prediction, network construction, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and molecular docking was adopted to predict the targets of stemazole relevant to the treatment of neurodegenerative diseases and to further explore the involved pharmacological mechanisms. The majority of the predicted targets were highly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. RAC-alpha serine/threonine-protein kinase (AKT1), caspase-3 (CASP3), caspase-8 (CASP8), mitogen-activated protein kinase 8 (MAPK8), and mitogen-activated protein kinase 14 (MAPK14) are the core targets regulated by stemazole and play a central role in its anti-apoptosis effects. This work provides a scientific basis for further elucidating the mechanism underlying the effects of stemazole in the treatment of neurodegenerative diseases.

scholarly journals Combined Treatment with Three Natural Antioxidants Enhances Neuroprotection in a SH-SY5Y 3D Culture Model

Antioxidants ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 420 ◽  
Author(s):  
Marrazzo ◽  
Angeloni ◽  
Hrelia
Keyword(s):  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Biological Activities ◽  
Neuroprotective Effect ◽  
Combined Treatment ◽  
3D Culture ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Epigallocatechin Gallate ◽  
Therapeutic Interventions

Currently, the majority of cell-based studies on neurodegeneration are carried out on two-dimensional cultured cells that do not represent the cells residing in the complex microenvironment of the brain. Recent evidence has suggested that three-dimensional (3D) in vitro microenvironments may better model key features of brain tissues in order to study molecular mechanisms at the base of neurodegeneration. So far, no drugs have been discovered to prevent or halt the progression of neurodegenerative disorders. New therapeutic interventions can come from phytochemicals that have a broad spectrum of biological activities. On this basis, we evaluated the neuroprotective effect of three phytochemicals (sulforaphane, epigallocatechin gallate, and plumbagin) alone or in combination, focusing on their ability to counteract oxidative stress. The combined treatment was found to be more effective than the single treatments. In particular, the combined treatment increased cell viability and reduced glutathione (GSH) levels, upregulated antioxidant enzymes and insulin-degrading enzymes, and downregulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 and 2 in respect to peroxide-treated cells. Our data suggest that a combination of different phytochemicals could be more effective than a single compound in counteracting neurodegeneration, probably thanks to a pleiotropic mechanism of action.

scholarly journals DUSP12 acts as a novel endogenous protective signal against hepatic ischemia–reperfusion damage by inhibiting ASK1 pathway

2021 ◽  
Vol 135 (1) ◽  
pp. 161-166
Author(s):  
Renzo Boldorini ◽  
Nausicaa Clemente ◽  
Elisa Alchera ◽  
Rita Carini
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Mapk Pathway ◽  
Ischemia Reperfusion ◽  
Clinical Problem ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Interventions ◽  
Protective Effects ◽  
Hepatic Ischemia ◽  
Mitogen Activated Protein

Abstract Ischemia–reperfusion injury (IRI) consequent to major liver surgery is a still unmet clinical problem. The activation of endogenous systems of hepatoprotection can prevent the damaging effects of ischemia–reperfusion (IR) as shown by the phenomenon known as ‘ischemic preconditioning’. The identification of endogenous signal mediators of hepatoprotection is of main interest since they could be targeted in future therapeutic interventions. Qiu et al. recently reported in Clin. Sci. (Lond.) (2020) 134(17), 2279–2294, the discovery of a novel protective molecule against hepatic IR damage: dual-specificity phosphatase 12 (DUSP12). IR significantly decreased DUSP12 expression in liver whereas DUSP12 overexpression in hepatocytes protected IRI and DUSP12 deletion in DUSP12 KO mice exacerbated IRI. The protective effects of DUSP12 depended on apoptosis signal-regulating kinase 1 (ASK1) and acted through the inhibition of the ASK1-dependent kinases c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). These results enlighten DUSP12 as a novel intermediate negative regulator of the pro-inflammatory and pro-apoptotic ASK1/JNK-p38 MAPK pathway activated during hepatic IR and identify DUSP12 as potential therapeutic target for IRI.

scholarly journals Allium cepaExtract and Quercetin Protect Neuronal Cells from Oxidative Stress via PKC-εInactivation/ERK1/2 Activation

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Bo Kyung Lee ◽  
Yi-Sook Jung
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Antioxidant Activities ◽  
Neuroprotective Effect ◽  
Neuronal Cells ◽  
Mitogen Activated Protein Kinase ◽  
Protective Mechanism ◽  
Dependent Manner ◽  
Concentration Dependent Manner

Oxidative stress plays an important role in the pathophysiology of various neurologic disorders.Allium cepaextract (ACE) and their main flavonoid component quercetin (QCT) possess antioxidant activities and protect neurons from oxidative stress. We investigated the underlying molecular mechanisms, particularly those linked to the antioxidant effects of the ACE. Primary cortical neuronal cells derived from mouse embryos were preincubated with ACE or QCT for 30 min and exposed to L-buthionine sulfoximine for 4~24 h. We found that ACE and QCT significantly decreased neuronal death and the ROS increase induced by L-buthionine-S, R-sulfoximine (BSO) in a concentration-dependent manner. Furthermore, ACE and QCT activated extracellular signal-regulated kinase 1/2 (ERK1/2), leading to downregulation of protein kinase C-ε(PKC-ε) in BSO-stimulated neuronal cells. In addition, ACE and QCT decreased the phosphorylated levels of p38 mitogen-activated protein kinase. Our results provide new insight into the protective mechanism of ACE and QCT against oxidative stress in neuronal cells. The results suggest that the inactivation of PKC-εinduced by phosphorylating ERK1/2 is responsible for the neuroprotective effect of ACE and QCT against BSO-induced oxidative stress.

scholarly journals Advanced Evolution of Pathogenesis Concepts in Cardiomyopathies

2019 ◽  
Vol 8 (4) ◽  
pp. 520 ◽  
Author(s):  
Chia-Jung Li ◽  
Chien-Sheng Chen ◽  
Giou-Teng Yiang ◽  
Andy Po-Yi Tsai ◽  
Wan-Ting Liao ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Cell Loss ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Interventions ◽  
High Morbidity ◽  
Biomechanical Stress ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Systolic And Diastolic Function

Cardiomyopathy is a group of heterogeneous cardiac diseases that impair systolic and diastolic function, and can induce chronic heart failure and sudden cardiac death. Cardiomyopathy is prevalent in the general population, with high morbidity and mortality rates, and contributes to nearly 20% of sudden cardiac deaths in younger individuals. Genetic mutations associated with cardiomyopathy play a key role in disease formation, especially the mutation of sarcomere encoding genes and ATP kinase genes, such as titin, lamin A/C, myosin heavy chain 7, and troponin T1. Pathogenesis of cardiomyopathy occurs by multiple complex steps involving several pathways, including the Ras-Raf-mitogen-activated protein kinase-extracellular signal-activated kinase pathway, G-protein signaling, mechanotransduction pathway, and protein kinase B/phosphoinositide 3-kinase signaling. Excess biomechanical stress induces apoptosis signaling in cardiomyocytes, leading to cell loss, which can induce myocardial fibrosis and remodeling. The clinical features and pathophysiology of cardiomyopathy are discussed. Although several basic and clinical studies have investigated the mechanism of cardiomyopathy, the detailed pathophysiology remains unclear. This review summarizes current concepts and focuses on the molecular mechanisms of cardiomyopathy, especially in the signaling from mutation to clinical phenotype, with the aim of informing the development of therapeutic interventions.

scholarly journals Novel Mechanisms Related to DHA's Atheroprotective Effects in Endothelial Cells: Modulation of Histone H3 Modification via Activation of p38MAPK Signaling

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1258-1258
Author(s):  
Shiqi Huang ◽  
Carla Taylor ◽  
Peter Zahradka
Keyword(s):  
Endothelial Cells ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Histone H3 ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Protective Effects ◽  
Downstream Targets ◽  
Ea.Hy926 Cells

Abstract Objectives Docosahexaenoic acid (DHA) is known for its protective effects against cardiovascular disease, which has been the leading cause of death worldwide for 2 decades. The molecular mechanisms responsible for DHA's atheroprotective effects, however, remain largely unknown. DHA has been found to activate p38 mitogen-activated protein kinase (MAPK) differently in growing and quiescent human endothelial cells, which represent dysfunctional and healthy states in vivo, respectively. This study was designed to characterize the activation pattern of p38MAPK in endothelial cells in response to DHA treatment and to identify possible downstream targets by which DHA exerts its protective effects. Methods EA.hy926 cells were cultured on Matrigel-coated plates to sub-confluent, confluent, and quiescent states. The cells were treated with DHA to establish concentration (10 μM to 150 μM) and time course (10 min to 24 h) curves, with or without SB202190, a p38MAPK-specific inhibitor. The activation of p38MAPK and its downstream targets was quantified by Western blotting. Histone H3 modifications upon DHA treatment were tested with an ELISA-based kit. Results The activation of p38MAPK by DHA in EA.hy926 cells was concentration-, time-, and growth state-dependent. Upon p38MAPK inhibition, activation of mitogen and stress activated kinase 1 (MSK1), a downstream target of p38MAPK, declined. This reduction was attenuated by low concentrations of DHA in quiescent endothelial cells but not confluent or sub-confluent cells. Since MSK1 can act on histone H3 and other chromatin binding proteins like cAMP response element-binding protein (CREB), H3 modifications were monitored. In the confluent state, DHA caused a 6-fold increase in total H3, with a concomitant decrease in most methylation, acetylation, and phosphorylation marks, including H3K9me1/3, H3K27me2, H3K36me1/3, H3K9ac, H3K18ac, H3S10ph, and H3S28ph. Conclusions This study showed that DHA may exert its effects in endothelial cells via the p38MAPK signalling pathway, and MSK1 may be a downstream effector possibly leading to epigenetic changes. The results provide novel insights regarding DHA's atheroprotective actions and identify new therapeutic targets with potential for treating atherosclerosis. Funding Sources Research Manitoba, St Boniface Hospital Foundation-Research Without Borders.

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