scholarly journals Protein kinases mediate anti-inflammatory effects of cannabidiol and estradiol against high glucose in cardiac sodium channels

2020 ◽  
Author(s):  
Mohamed A. Fouda ◽  
Peter C. Ruben
Keyword(s):  
Action Potential ◽  
Signaling Pathway ◽  
Protein Kinases ◽  
Inflammatory Mediators ◽  
High Glucose ◽  
Therapeutic Approach ◽  
Morbidity And Mortality ◽  
List Type ◽  
Long Qt ◽  
Anti Inflammatory

AbstractBackground and purposeCardiovascular anomalies are predisposing factors for diabetes-induced morbidity and mortality. Recently, we showed that high glucose induces changes in the biophysical properties of Nav1.5 that could be strongly correlated to diabetes-induced arrhythmia. However, the mechanisms underlying hyperglycemia-induced inflammation, and how inflammation provokes cardiac arrhythmia, are not well understood. We hypothesized that inflammation could mediate the high glucose-induced biophyscial changes on Nav1.5 through protein phosphorylation by protein kinases A and C. We also hypothesized that this signaling pathway is, at least partly, involved in the cardiprotective effects of CBD and E2.Experimental approachTo test these ideas, we used Chinese hamster ovarian (CHO) cells transiently co-transfected with cDNA encoding human Nav1.5 α-subunit under control, a cocktail of inflammatory mediators or 100 mM glucose conditions (for 24 hours). We used electrophysiological experiments and action potential modelling.Key ResultsInflammatory mediators, similar to 100 mM glucose, right shifted the voltage dependence of conductance and steady state fast inactivation and increased persistent current leading to computational prolongation of action potential (hyperexcitability) which could result in long QT3 arrhythmia. In addition, activators of PK-A or PK-C replicated the inflammation-induced gating changes of Nav1.5. Inhibitors of PK-A or PK-C, CBD or E2 mitigated all the potentially deleterious effects provoked by high glucose/inflammation.Conclusions and implicationsThese findings suggest that PK-A and PK-C may mediate the anti-inflammatory effects of CBD and E2 against high glucose-induced arrhythmia. CBD, via Nav1.5, may be a cardioprotective therapeutic approach in diabetic postmenopausal population.Bullet pointsWhat is already known:Arrhythmias are among the common cardiac causes of morbidity and mortality in diabetes-related hyperglycemia.One of the diabetes-induced arrhythmias is long-QT syndrome, caused by gating defects in the cardiac voltage-gated sodium channel (Nav1.5).What this study adds:Inflammation and subsequent activation of PK-A and PK-C mediate the high glucose-induced electrophysiological changes of Nav1.5 in a manner consistent with the gating defects that underlie long-QT arrhythmia.Cannabidiol and estradiol rescue the high glucose induced Nav1.5 gating defects through, at least partly, this signaling pathway.Clinical significance:Inflammation/PK-A and PK-C signaling pathway could be a potential therapeutic target to prevent arrhythmias associated with diabetes.Cannabidiol may be a therapeutic approach to prevent cardiac complications in diabetes, especially in postmenopausal populations due to the decreased levels of the cardioprotective estrogen.

scholarly journals Protein kinases mediate anti-inflammatory effects of cannabidiol and estradiol against high glucose in cardiac sodium channels

2020 ◽  
Author(s):  
Mohamed Fouda ◽  
Peter Ruben
Keyword(s):  
Action Potential ◽  
Protein Kinases ◽  
Inflammatory Mediators ◽  
High Glucose ◽  
Chinese Hamster ◽  
Strongly Correlated ◽  
Α Subunit ◽  
Prolongation Of Action Potential ◽  
Anti Inflammatory ◽  
Cardiac Sodium Channels

Background and purpose. Cardiovascular anomalies are predisposing factors for diabetes-induced morbidity and mortality. Recently, we showed that high glucose induces changes in the biophysical properties of Nav1.5 that could be strongly correlated to diabetes-induced arrhythmia. However, the mechanisms underlying hyperglycemia-induced inflammation, and how inflammation provokes cardiac arrhythmia, are not well understood. We hypothesized that inflammation could mediate the high glucose-induced biophyscial changes on Nav1.5 through protein phosphorylation by protein kinases A and C. We also hypothesized that this signaling pathway is, at least partly, involved in the cardiprotective effects of CBD and E2. Experimental approach. To test these ideas, we used Chinese hamster ovarian (CHO) cells transiently co-transfected with cDNA encoding human Nav1.5 α-subunit under control, a cocktail of inflammatory mediators or 100 mM glucose conditions (for 24 hours). We used electrophysiological experiments and action potential modelling. Key Results. Inflammatory mediators, similar to 100 mM glucose, right shifted the voltage dependence of conductance and steady state fast inactivation and increased persistent current leading to computational prolongation of action potential (hyperexcitability) which could result in long QT3 arrhythmia. In addition, activators of PK-A or PK-C replicated the inflammation-induced gating changes of Nav1.5. Inhibitors of PK-A or PK-C, CBD or E2 mitigated all the potentially deleterious effects provoked by high glucose/inflammation. Conclusions and implications. These findings suggest that PK-A and PK-C may mediate the anti-inflammatory effects of CBD and E2 against high glucose-induced arrhythmia. CBD, via Nav1.5, may be a cardioprotective therapeutic approach in diabetic postmenopausal population.

scholarly journals Protein Kinases Mediate Anti-Inflammatory Effects of Cannabidiol and Estradiol Against High Glucose in Cardiac Sodium Channels

2021 ◽  
Vol 12 ◽  
Author(s):  
Mohamed A. Fouda ◽  
Peter C. Ruben
Keyword(s):  
Action Potential ◽  
Protein Kinases ◽  
Inflammatory Mediators ◽  
High Glucose ◽  
Cho Cells ◽  
Chinese Hamster ◽  
Strongly Correlated ◽  
Α Subunit ◽  
Anti Inflammatory ◽  
Cardiac Sodium Channels

Background: Cardiovascular anomalies are predisposing factors for diabetes-induced morbidity and mortality. Recently, we showed that high glucose induces changes in the biophysical properties of the cardiac voltage-gated sodium channel (Nav1.5) that could be strongly correlated to diabetes-induced arrhythmia. However, the mechanisms underlying hyperglycemia-induced inflammation, and how inflammation provokes cardiac arrhythmia, are not well understood. We hypothesized that inflammation could mediate the high glucose-induced biophyscial changes on Nav1.5 through protein phosphorylation by protein kinases A and C. We also hypothesized that this signaling pathway is, at least partly, involved in the cardiprotective effects of cannabidiol (CBD) and 17β-estradiol (E2).Methods and Results: To test these ideas, we used Chinese hamster ovarian (CHO) cells transiently co-transfected with cDNA encoding human Nav1.5 α-subunit under control, a cocktail of inflammatory mediators or 100 mM glucose conditions (for 24 h). We used electrophysiological experiments and action potential modeling. Inflammatory mediators, similar to 100 mM glucose, right shifted the voltage dependence of conductance and steady-state fast inactivation and increased persistent current leading to computational prolongation of action potential (hyperexcitability) which could result in long QT3 arrhythmia. We also used human iCell cardiomyocytes derived from inducible pluripotent stem cells (iPSC-CMs) as a physiologically relevant system, and they replicated the effects produced by inflammatory mediators observed in CHO cells. In addition, activators of PK-A or PK-C replicated the inflammation-induced gating changes of Nav1.5. Inhibitors of PK-A or PK-C, CBD or E2 mitigated all the potentially deleterious effects provoked by high glucose/inflammation.Conclusion: These findings suggest that PK-A and PK-C may mediate the anti-inflammatory effects of CBD and E2 against high glucose-induced arrhythmia. CBD, via Nav1.5, may be a cardioprotective therapeutic approach in diabetic postmenopausal population.

scholarly journals Flavonoids Identified from KoreanScutellaria baicalensisGeorgi Inhibit Inflammatory Signaling by Suppressing Activation of NF-κB and MAPK in RAW 264.7 Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Gyeong-Eun Hong ◽  
Jin-A. Kim ◽  
Arulkumar Nagappan ◽  
Silvia Yumnam ◽  
Ho-Jeong Lee ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Mediators ◽  
Inflammatory Diseases ◽  
Mapk Signaling ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Two Dimensional Gel Electrophoresis ◽  
Necrosis Factor Alpha ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory

Scutellaria baicalensisGeorgi has been used as traditional medicine for treating inflammatory diseases, hepatitis, tumors, and diarrhea in Asia. Hence, we investigated the anti-inflammatory effect and determined the molecular mechanism of action of flavonoids isolated from KoreanS. baicalensisG. in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to examine cytotoxicity of the flavonoids at various concentrations of 10, 40, 70, and 100 µg/mL. No cytotoxicity was observed in RAW 264.7 cells at these concentrations. Furthermore, the flavonoids decreased production of inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase-2, interleukin-6, and tumor necrosis factor-alpha and inhibited phosphorylation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) in LPS-induced RAW 264.7 cells. Moreover, to identify the differentially expressed proteins in RAW 264.7 cells of the control, LPS-treated, and flavonoid-treated groups, two-dimensional gel electrophoresis and mass spectrometry were conducted. The identified proteins were involved in the inflammatory response and included PRKA anchor protein and heat shock protein 70 kD. These findings suggest that the flavonoids isolated fromS. baicalensisG. might have anti-inflammatory effects that regulate the expression of inflammatory mediators by inhibiting the NF-κB signaling pathway via the MAPK signaling pathway in RAW 264.7 cells.

scholarly journals The Acne-treatment Potential of Cinnamomum Camphora Chvar. Borneol Essential Oil in Vitro and in Vivo

2021 ◽  
Author(s):  
Shanshan Xiao ◽  
Hang Yu ◽  
Yunfei Xie ◽  
Yahui Guo ◽  
Jiajia Fan ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Mediators ◽  
Staphylococcus Epidermidis ◽  
Network Pharmacology ◽  
Dependent Manner ◽  
Tnf Α ◽  
Rabbit Ear ◽  
Inflammatory Skin ◽  
Anti Inflammatory

Abstract Background: Acne is one of the most common chronic inflammatory skin diseases, abnormal proliferation of keratinocytes can block the hair follicle sebaceous glands result in the formation of acne. Most drugs to treat acne can cause a variety of side effects, therefore, it is important to seek natural and safe complementary and alternative therapies.Methods: The inhibitory effects of BEO were determined on the proliferation of human keratinocyte (HaCaT) cells induced by heat-inactivated Staphylococcus epidermidis and release of the inflammatory mediators. Further, a component-target-signal pathway for BEO’s effects on acne was constructed through network pharmacology and the mechanism of BEO action was studied in vivo through the rabbit ear acne model.Results: BEO inhibited both cell proliferation, induced by heat-inactivated Staphylococcus epidermidis (p < 0.0001), and release of the inflammatory mediators TNF-α (p < 0.0001) and IL-1β (p < 0.05) in a dose-dependent manner (r = -0.9952, -0.9492), in a HaCaT cell-model of acne. A network pharmacology analysis of the chemical components of BEO characterized these effects as multi-component, multi-target and multi-pathway. All targets were mainly associated with metabolic pathways, the toll-like receptor signaling pathway and the NF-κB signaling pathway. BEO also reduced the severity of acne lesions, induced by intracutaneous injection of S. epidermidis in a rabbit ear acne model. The expression of inflammatory mediators and key signaling pathway components, including TLR2, AKT, P13K, NF-κB, TNF-α, IL-1β in rabbit ear, and TNF-α and IL-1 β in serum, were down-regulated (p < 0.05), indicating that BEO acts by inhibiting the pro-inflammatory TLR2/PI3K-AKT/NF-κB signaling pathway.Conclusion: The current results showed that BEO has clear potential for development into a natural and safe anti-inflammatory skin preparation, which is an effective alternative to conventional treatments containing antibiotics and synthetic anti-inflammatory agents.

scholarly journals Human mesenchymal stromal cells broadly modulate high glucose-induced inflammatory responses of renal proximal tubular cell monolayers

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Md Nahidul Islam ◽  
Tomás P. Griffin ◽  
Elizabeth Sander ◽  
Stephanie Rocks ◽  
Junaid Qazi ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Mesenchymal Stromal Cells ◽  
Inflammatory Mediators ◽  
Stromal Cells ◽  
High Glucose ◽  
Cell Monolayers ◽  
Proximal Tubular ◽  
Anti Inflammatory ◽  
Renal Proximal Tubular ◽  
Inflammatory Effect

Abstract Background Renal proximal tubular epithelial cells (RPTEC) are dysfunctional in diabetic kidney disease (DKD). Mesenchymal stromal cells (MSC) may modulate DKD pathogenesis through anti-inflammatory mediators. This study aimed to investigate the pro-inflammatory effect of extended exposure to high glucose (HG) concentration on stable RPTEC monolayers and the influence of MSC on this response. Methods Morphologically stable human RPTEC/TERT1 cell monolayers were exposed to 5 mM and 30 mM (HG) D-glucose or to 5 mM D-glucose + 25 mM D-mannitol (MAN) for 5 days with sequential immunoassays of supernatants and end-point transcriptomic analysis by RNA sequencing. Under the same conditions, MSC-conditioned media (MSC-CM) or MSC-containing transwells were added for days 4–5. Effects of CM from HG- and MAN-exposed RPTEC/MSC co-cultures on cytokine secretion by monocyte-derived macrophages were determined. Results After 72–80 h, HG resulted in increased RPTEC/TERT1 release of interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1 and neutrophil gelatinase-associated lipocalin (NGAL). The HG pro-inflammatory effect was attenuated by concentrated (10×) MSC-CM and, to a greater extent, by MSC transwell co-culture. Bioinformatics analysis of RNA sequencing data confirmed a predominant effect of HG on inflammation-related mediators and biological processes/KEGG pathways in RPTEC/TERT1 stable monolayers as well as the non-contact-dependent anti-inflammatory effect of MSC. Finally, CM from HG-exposed RPTEC/MSC transwell co-cultures was associated with attenuated secretion of inflammatory mediators by macrophages compared to CM from HG-stimulated RPTEC alone. Conclusions Stable RPTEC monolayers demonstrate delayed pro-inflammatory response to HG that is attenuated by close proximity to human MSC. In DKD, this MSC effect has potential to modulate hyperglycemia-associated RPTEC/macrophage cross-talk.

scholarly journals Trichosanthis Semen Suppresses Lipopolysaccharide-Induced Neuroinflammation by Regulating the NF-κB Signaling Pathway and HO-1 Expression in Microglia

Toxins ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 898
Author(s):  
Seungmin Lee ◽  
In Gyoung Ju ◽  
Yujin Choi ◽  
Sangsu Park ◽  
Myung Sook Oh
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Mediators ◽  
Interleukin 10 ◽  
Typical Feature ◽  
Heme Oxygenase 1 ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Inflammatory Action

Neuroinflammation, which is mediated by microglia that release various inflammatory cytokines, is a typical feature of neurodegenerative diseases (NDDs), such as Alzheimer’s disease and Parkinson’s disease. Hence, alleviating neuroinflammation by downregulating pro-inflammatory action, and upregulating anti-inflammatory action of microglia is an efficient therapeutic target for NDDs. In this study, we evaluated whether trichosanthis semen (TS), a dried ripe seed of Trichosanthes kirilowii Maximowicz, reduces lipopolysaccharide (LPS)-induced neuroinflammation by regulating microglial responses in vitro and in vivo. Our results presented that TS reduced the release of pro-inflammatory mediators, such as nitric oxide (NO), inducible NO synthase, tumor necrosis factor-α, interleukin-1β, and interleukin-6 via inhibition of the nuclear factor kappa B (NF-κB) signaling pathway in LPS-treated BV2 microglial cells. Moreover, TS induced anti-inflammatory mediators, such as interleukin-10, found in inflammatory zone 1, and chitinase 3-like 3 by the upregulation of heme oxygenase 1 (HO-1). We further confirmed that TS administration suppressed microglial activation, but enhanced HO-1 expression in LPS-injected mice. These results suggest that TS has anti-neuroinflammatory effects via inhibition of NF-κB signaling through the activation of HO-1, and that TS may be a therapeutical candidate for NDDs treatment.

Piper sarmentosum Roxb. Root Extracts Confer Neuroprotection by Attenuating Beta Amyloid-Induced Pro-Inflammatory Cytokines Released from Microglial Cells

2019 ◽  
Vol 16 (3) ◽  
pp. 251-260 ◽  
Author(s):  
Elaine Wan Ling Chan ◽  
Emilia Tze Ying Yeo ◽  
Kelly Wang Ling Wong ◽  
Mun Ling See ◽  
Ka Yan Wong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Mrna Expression ◽  
Inflammatory Mediators ◽  
Beta Amyloid ◽  
Microglial Cells ◽  
Root Extracts ◽  
Tnf Α ◽  
P38α Mapk ◽  
Anti Inflammatory ◽  
Bv2 Microglial Cells

<P>Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that eventually leads to severe cognitive impairment. Although the exact etiologies of AD still remain elusive, increasing evidence suggests that neuroinflammation cascades mediated by microglial cells are associated with AD. Piper sarmentosum Roxb. (PS) is a medicinal plant reported to possess various biological properties, including anti-inflammatory, anti-psychotic and anti-oxidant activity. However, little is known about the anti-inflammatory activity of PS roots despite their traditional use to treat inflammatory- mediated ailments. Objective: This study aimed to evaluate the anti-inflammatory and neuroprotective properties of extracts obtained from the roots of PS against beta-amyloid (Aβ)-induced microglial toxicity associated with the production of pro-inflammatory mediators. Method: BV2 microglial cells were treated with hexane (RHXN), dichloromethane (RDCM), ethyl acetate (REA) and methanol (RMEOH) extracts of the roots of PS prior to activation by Aβ. The production and mRNA expression of pro-inflammatory mediators were evaluated by Griess reagent, ELISA kits and RT-qPCR respectively. The phosphorylation status of p38α MAPK was determined via western blot assay. BV2 conditioned medium was used to treat SH-SY5Y neuroblastoma cells and the neuroprotective effect was assessed using MTT assay. Results: PS root extracts, in particular RMEOH significantly attenuated the production and mRNA expression of IL-1β, IL-6 and TNF-α in Aβ-induced BV2 microglial cells. In addition, RHXN, REA and RMEOH extracts significantly reduced nitric oxide (NO) level and the inhibition of NO production was correlated with the total phenolic content of the extracts. Further mechanistic studies suggested that PS root extracts attenuated the production of cytokines by regulating the phosphorylation of p38α MAPK in microglia. Importantly, PS root extracts have protective effects against Aβ-induced indirect neurotoxicity either by inhibiting the production of NO, IL-1β, IL-6, and TNF-α in BV2 cells or by protecting SHSY5Y cells against these inflammatory mediators. Conclusions: These findings provided evidence that PS root extracts confer neuroprotection against Aβ- induced microglial toxicity associated with the production of pro-inflammatory mediators and may be a potential therapeutic agent for inflammation-related neurological conditions including Alzheimer’s disease (AD).</P>

scholarly journals Anti-Inflammatory Effect of Simonsinol on Lipopolysaccharide Stimulated RAW264.7 Cells through Inactivation of NF-κB Signaling Pathway

Molecules ◽  
2020 ◽  
Vol 25 (16) ◽  
pp. 3573
Author(s):  
Lian-Chun Li ◽  
Zheng-Hong Pan ◽  
De-Sheng Ning ◽  
Yu-Xia Fu
Keyword(s):  
Nitric Oxide ◽  
Signaling Pathway ◽  
Morphological Changes ◽  
Raw264.7 Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Oxide Synthase ◽  
Necrosis Factor

Simonsinol is a natural sesqui-neolignan firstly isolated from the bark of Illicium simonsii. In this study, the anti-inflammatory activity of simonsinol was investigated with a lipopolysaccharide (LPS)-stimulated murine macrophages RAW264.7 cells model. The results demonstrated that simonsinol could antagonize the effect of LPS on morphological changes of RAW264.7 cells, and decrease the production of nitric oxide (NO), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) in LPS-stimulated RAW264.7 cells, as determined by Griess assay and enzyme-linked immunosorbent assay (ELISA). Furthermore, simonsinol could downregulate transcription of inducible nitric oxide synthase (iNOS), TNF-α, and IL-6 as measured by reverse transcription polymerase chain reaction (RT-PCR), and inhibit phosphorylation of the alpha inhibitor of NF-κB (IκBα) as assayed by Western blot. In conclusion, these data demonstrate that simonsinol could inhibit inflammation response in LPS-stimulated RAW264.7 cells through the inactivation of the nuclear transcription factor kappa-B (NF-κB) signaling pathway.

scholarly journals Non-Canonical Kinases and Substrates in Cancer Progression

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1628
Author(s):  
Francisco M. Vega
Keyword(s):  
Signaling Pathway ◽  
Protein Kinases ◽  
Cancer Progression ◽  
Cellular Protein

Cellular protein kinases remain the target of choice when the intention is to intervene in a particular signaling pathway leading to cancer progression [...]

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