Extracts from Dendropanax morbifera Leaves Have Modulatory Effects on Neuroinflammation in Microglia

2016 ◽  
Vol 44 (01) ◽  
pp. 119-132 ◽  
Author(s):  
Hyun-Jung Shim ◽  
Sinwoo Park ◽  
Ji-Won Lee ◽  
Hye-Jin Park ◽  
Seung-Hoon Baek ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Marker Genes ◽  
Cellular Mechanisms ◽  
Line Production ◽  
Bv2 Cells ◽  
Study Results ◽  
Dendropanax Morbifera ◽  
Pro Inflammatory Cytokines

Dendropanax morbifera (D. morbifera), a species endemic to Korea, is largely distributed throughout the southern part of the country. Its leaves, stems, roots, and seeds have been used as a form of alternative medicine for various diseases and neurological disorders including paralysis, stroke, and migraine. However, the molecular mechanisms that underlie the remedial effects of D. morbifera remain largely unknown. In this paper, extracts from D. morbifera leaves were prepared using ethyl acetate as a solvent (abbreviated as DMLE). The modulatory effects of DMLE on neuroinflammation were studied in a lipopolysaccharide (LPS)-stimulated BV2 murine microglial cell line. Production of pro-inflammatory cytokines, activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-[Formula: see text]B), and different M1/M2 activation states of microglia were examined. DMLE treatment suppressed the production of pro-inflammatory cytokines including tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text]), interleukin-6 (IL-6), and nitric oxide (NO) in LPS-stimulated BV2 cells. DMLE treatment also attenuated the activation of MAPKs and NF-[Formula: see text]B. In a novel discovery, we found that DMLE up-regulated the marker genes representing an alternative, anti-inflammatory M2 polarization, while suppressing the expression of the classical, pro-inflammatory M1 activation state genes. Here, we uncovered the cellular mechanisms underlying the beneficial effects of D. morbifera against neuroinflammation using BV2 microglia cells. These results strongly suggest that DMLE was able to counter the effects of LPS on BV2 cells via control of microglia polarization states. Additionally, study results indicated that DMLE may have therapeutic potential as a neuroinflammation-suppressing treatment for neurodegenerative diseases.

scholarly journals BASIC FIBROBLAST GROWTH FACTOR AND ADIPONECTIN IN ADOLESCENCE WITH JUVENILE IDIOPATHIC ARTHRITIS TREATED WITH METHOTREXATE

2020 ◽  
Vol 4 ◽  
pp. 70-76
Author(s):  
Liudmyla Parkhomenko ◽  
Larysa Strashok ◽  
Olga Pavlova
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Molecular Mechanisms ◽  
Fibroblast Growth ◽  
Cellular Mechanisms ◽  
Reactive Protein ◽  
Study Results ◽  
Methotrexate Dose

Methotrexate has been applied clinically for juvenile idiopathic arthritis (JIA) treatment for decades. It is recommended for use globally, according all modern guidelines. Despite the fact that fibrosis molecular mechanisms as well as methotrexate (MTX) elimination and fibrosis indexes were studied a lot there is still not enough information for adolescence. Adiponectin, fibroblast growth factor and fibrosis indexes in adolescents with JIA treated with methotrexate were studied in this work. The aim was to study dynamics of molecular-cellular mechanisms activation of fibrotic processes development in the liver in adolescents with juvenile idiopathic arthritis treated with methotrexate. Materials and methods: A total of 68 children with juvenile idiopathic arthritis, were enrolled in the study. 25 boys (36.8 %) and 43 girls (63.2 %) were examined. Children were divided into three groups in accordance with the methotrexate dose. The following data were analyzed: ESR (mm/hour), C-reactive protein (mg/l), Hemolytic activity (CU), circulating immune complexes, (g/l), ALT (U/l), AST (U/l), Adiponectin (mcg/ml), BFGF (pg/ml), APRI index, FIB-4 Score. Results: According to our results when patients start using MTX they have significantly positive effect. Therefore, when analyzing all parameters liver pathologies may occur before MTX use. When MTX used, its proinflammation and antifibrotic effects lead to normalization of all organs and systems, as well as joints and liver. Also, long-term MTX use can lead to adverse effects. Conclusions: So, it is important to control possible liver disorders in adolescence treated with MTX. According to our study results we find out that there are decreasing of liver damage parameters in patients which started using MTX.

Abstract 319: Small Molecule Gβγ Inhibition Attenuates Cardiac Fibroblast Inflammatory and Pro-Fibrotic Signaling

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Joshua G Travers ◽  
Fadia A Kamal ◽  
Michael S Burhans ◽  
Burns C Blaxall
Keyword(s):  
Myocardial Fibrosis ◽  
Inflammatory Cytokines ◽  
Small Molecule ◽  
Therapeutic Potential ◽  
Interstitial Fibrosis ◽  
Pressure Overload ◽  
Cardiac Fibroblast ◽  
Ventricular Compliance ◽  
Pro Inflammatory Cytokines

Heart failure (HF) is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Prolonged sympathetic overstimulation promotes excess signaling through G-protein Gβγ subunits and ultimately results in pathologic GRK2-mediated β-adrenergic receptor (β-AR) downregulation. We have recently demonstrated the therapeutic potential of the small molecule Gβγ-GRK2 inhibitor Gallein in limiting HF progression. Pathologic activation of the cardiac fibroblast (CF) induces the transition to a myofibroblast phenotype, which plays a fundamental role in myocardial fibrosis and remodeling. We hypothesized that Gβγ-GRK2 inhibition plays an important functional role in the CF to attenuate pathologic CF activation, inflammation and interstitial fibrosis. To explore the effect of Gβγ-GRK2 inhibition on inflammation and pro-fibrotic signaling, mice were subjected to 7 days of transverse aortic constriction, a pressure-overload model of HF. In addition to the attenuation in overall cardiac hypertrophy, animals treated with Gallein displayed reduced expression of pro-inflammatory cytokines, including macrophage inflammatory protein 1 alpha (MIP-1α) and MIP-1β, along with Interleukin-6, as assessed by qPCR. Gallein-treated animals also exhibited diminished pro-fibrotic signaling, as evidenced by a reduction in the expression of TGFβ, a major driver of myocardial fibrosis, and decreased expression of collagen. To recapitulate these findings in vitro, primary adult mouse ventricular fibroblasts were pathologically stimulated using Isoproterenol (ISO, β-AR agonist) or Angiotensin II and treated +/- Gallein for 24 hours. CFs treated with Gallein displayed an analogous reduction in the expression of these pro-inflammatory cytokines and collagen. In summary, these data suggest a potential therapeutic role for small molecule Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, inflammation and interstitial fibrosis. We believe this fibroblast-targeted approach will lead to the refinement of existing targets and compounds, and possibly the generation of novel therapeutics for the treatment of HF.

scholarly journals GSK5182, 4-Hydroxytamoxifen Analog, a New Potential Therapeutic Drug for Osteoarthritis

2020 ◽  
Vol 13 (12) ◽  
pp. 429
Author(s):  
Yunhui Min ◽  
Dahye Kim ◽  
Godagama Gamaarachchige Dinesh Suminda ◽  
Xiangyu Zhao ◽  
Mangeun Kim ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Small Molecule ◽  
Articular Chondrocytes ◽  
Therapeutic Potential ◽  
Inverse Agonist ◽  
Therapeutic Drug ◽  
Articular Chondrocyte ◽  
Orphan Nuclear Receptors ◽  
Genetic Ablation ◽  
Pro Inflammatory Cytokines

Estrogen-related receptors (ERRs) are the first identified orphan nuclear receptors. The ERR family consists of ERRα, ERRβ, and ERRγ, regulating diverse isoform-specific functions. We have reported the importance of ERRγ in osteoarthritis (OA) pathogenesis. However, therapeutic approaches with ERRγ against OA associated with inflammatory mechanisms remain limited. Herein, we examined the therapeutic potential of a small-molecule ERRγ inverse agonist, GSK5182 (4-hydroxytamoxifen analog), in OA, to assess the relationship between ERRγ expression and pro-inflammatory cytokines in mouse articular chondrocyte cultures. ERRγ expression increased following chondrocyte exposure to various pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Pro-inflammatory cytokines dose-dependently increased ERRγ protein levels. In mouse articular chondrocytes, adenovirus-mediated ERRγ overexpression upregulated matrix metalloproteinase (MMP)-3 and MMP-13, which participate in cartilage destruction during OA. Adenovirus-mediated ERRγ overexpression in mouse knee joints or ERRγ transgenic mice resulted in OA. In mouse joint tissues, genetic ablation of Esrrg obscured experimental OA. These results indicate that ERRγ is involved in OA pathogenesis. In mouse articular chondrocytes, GSK5182 inhibited pro-inflammatory cytokine-induced catabolic factors. Consistent with the in vitro results, GSK5182 significantly reduced cartilage degeneration in ERRγ-overexpressing mice administered intra-articular Ad-Esrrg. Overall, the ERRγ inverse agonist GSK5182 represents a promising therapeutic small molecule for OA.

scholarly journals BMP-7 attenuates adverse cardiac remodeling mediated through M2 macrophages in prediabetic cardiomyopathy

2014 ◽  
Vol 307 (5) ◽  
pp. H762-H772 ◽  
Author(s):  
Princess Urbina ◽  
Dinender K. Singla
Keyword(s):  
Cardiac Function ◽  
Inflammatory Cytokines ◽  
Cardiac Remodeling ◽  
Therapeutic Potential ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Citrate Buffer ◽  
Morphogenetic Protein ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

The main objective of this study was to determine whether or not monocyte infiltration occurs in the prediabetic (PD) heart and its role in PD cardiomyopathy. We hypothesized that the PD heart is significantly populated with monocytes and that bone morphogenetic protein (BMP)-7, a novel mediator of monocyte polarization, activates infiltrated monocytes into anti-inflammatory M2 macrophages, thereby inhibiting apoptosis and fibrosis and improving cardiac function. C57Bl6 mice were assigned to control, PD, or PD + BMP-7 groups. PD and PD + BMP-7 groups were administered streptozotocin (50 mg/kg), whereas control animals received sodium citrate buffer. Afterward, the PD + BMP-7 group was administered BMP-7 (200 μg/kg) for 3 days. Our data showed significantly increased infiltrated monocytes and associated pro-inflammatory cytokines, adverse cardiac remodeling, and heart dysfunction in the PD group ( P < 0.05). Interestingly, M2 macrophage differentiation and associated anti-inflammatory cytokines were enhanced and there were reduced adverse cardiac remodeling and improved cardiac function in the PD + BMP-7 group ( P < 0.05). In conclusion, our data suggest that PD cardiomyopathy is associated with increased monocyte infiltration and released proinflammatory cytokines, which contributes to adverse cardiac remodeling and cardiac dysfunction. Moreover, we report that BMP-7 possesses novel therapeutic potential in its ability to differentiate monocytes into M2 macrophages and confer cardiac protection in the PD heart.

scholarly journals Escin Increases the Survival Rate of LPS-Induced Septic Mice Through Inhibition of HMGB1 Release from Macrophages

2015 ◽  
Vol 36 (4) ◽  
pp. 1577-1586 ◽  
Author(s):  
Yajun Cheng ◽  
Hongrui Wang ◽  
Min Mao ◽  
Chao Liang ◽  
Yu Zhang ◽  
...  
Keyword(s):  
Survival Rate ◽  
Western Blot ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Post Treatment ◽  
Mrna Levels ◽  
Treatment Methods ◽  
Protein Levels ◽  
Qrt Pcr ◽  
Pro Inflammatory Cytokines

Background: Previous studies have described the effects of Escin on improving the survival rate of endotoxemic animals. The purpose of this study was to explore the molecular mechanisms of this potentially beneficial treatment. Methods: First, the survival rate of endotoxemic mice was monitored for up to 2 weeks after Escin pretreatment, Escin post-treatment, or Escin post-treatment + rHMGB1. The effects of Escin on the release of pro-inflammatory cytokines such as TNF-a, IL-1ß, IL-6 and HMGB1 in the serum of endotoxemic mice and LPS-induced macrophages were evaluated by ELISA. Furthermore, the mRNA and protein levels of HMGB1 in LPS-induced macrophages were measured by qRT-PCR and Western blot, respectively. Additionally, the release of pro-inflammatory cytokines such as TNF-a, IL-1ß, IL-6 was evaluated by ELISA in rHMGB1-induced macrophages. Finally, the protein levels and the activity of NF-κB in macrophages were checked by Western blot and ELISA, respectively. Results: Both pretreatment and post-treatment with Escin could improve the survival rate of endotoxemic mice, while exogenous rHMGB1 reversed this effect. In addition, Escin decreased the level of the pro-inflammatory cytokines TNF-a, IL-1ß, IL-6 and HMGB1 in endotoxemic mice and in LPS-induced macrophages. Escin could also inhibit the mRNA levels and activity of HMGB1. The release of the pro-inflammatory cytokines TNF-a, IL-1ß, IL-6 could be suppressed in rHMGB1-induced macrophages by Escin. Finally, Escin could suppress the activation of NF-κB in LPS-induced macrophages. Conclusion: Escin could improve the survival of mice with LPS-induced endotoxemia. This effect maybe meditated by reducing the release of HMGB1, resulting in the suppression of the release of pro-inflammatory cytokines.

scholarly journals Interferon-gamma and TNF-alpha synergistically enhance the immunomodulatory capacity of Endometrial-Derived Mesenchymal Stromal Cell secretomes by differential microRNA and extracellular vesicle release

2021 ◽  
Author(s):  
Maria de los Angeles de Pedro ◽  
Federica Marinaro ◽  
Esther Lopez ◽  
Maria Pulido ◽  
Francisco Miguel Sanchez Margallo ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Lymphocyte Activation ◽  
Extracellular Vesicle ◽  
Potent Effect ◽  
Inflammatory Reactions ◽  
Immunomodulatory Capacity ◽  
Pro Inflammatory Cytokines

Endometrial Mesenchymal Stromal Cells (endMSCs) can be easily isolated from menstrual blood by plastic adherence. These cells have a potent pro-angiogenic and immunomodulatory capacity, and their therapeutic effect is mediated by paracrine mechanisms where secretome have a key role. In this paper, we aimed to evaluate different priming conditions in endMSCs using pro-inflammatory cytokines and Toll-Like Receptor ligands. Our in vitro results revealed a synergistic and additive effect of IFNγ and TNFα on endMSCs. The combination of these pro-inflammatory cytokines significantly increased the release of Indoleamine 2,3-dioxygenase (IDO1) in endMSCs. Additionally, this study was focused on the phenotype of IFNγ/TNFα-primed endMSCs (endMSCs*). Here we found that immune system-related molecules such as CD49d, CD49e, CD54, CD56, CD58, CD63, CD126, CD152, or CD274 were significantly altered in endMSCs* when compared to control cells. Afterward, our study was completed with the characterization of released miRNAs by Next Generation Sequencing (NGS). Briefly, our system biology approaches demonstrated that endMSCs* showed an increased release of 25 miRNAs whose target genes were involved in immune response and inflammation. Finally, the cellular and molecular characterization was completed with in vitro functional assays. In summary, the relevance of our results lies in the therapeutic potential of endMSCs*. The differences in cell surface molecules involved in migration, adhesion and immunogenicity, allowed us to hypothesize that endMSCs* may have an optimal homing and migration capacity towards inflammatory lesions. Secondly, the analysis of miRNAs, target genes and the subsequent lymphocyte activation assays demonstrated that IFNγ/TNFα-primed secretome may exert a potent effect on the regulation of adverse inflammatory reactions.

scholarly journals Proteomic changes induced by harmine in human brain organoids reveal signaling pathways related to neuroprotection

2021 ◽  
Author(s):  
Karina Karmirian ◽  
Lívia Goto-Silva ◽  
Juliana Minardi Nascimento ◽  
Marcelo N Costa ◽  
José Alexandre Salerno ◽  
...  
Keyword(s):  
Human Brain ◽  
Intracellular Transport ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Therapeutic Potential ◽  
Antioxidant Activities ◽  
Cellular Mechanisms ◽  
Neuroprotective Effects ◽  
Vesicle Cycle ◽  
Neurotrophin Signaling

Harmine is a β-carboline found in Banisteriopsis caapi, a constituent of ayahuasca brew. Ayahuasca is consumed as a beverage in native Americans' sacred rituals and in religious ceremonies in Brazil. Throughout the years, the beneficial effects of ayahuasca to improve mental health and life quality have been reported, which propelled the investigation of its therapeutic potential to target neurological disorders such as depression and anxiety. Indeed, antidepressant effects of ayahuasca have been described, raising the question of which cellular mechanisms might underlie those effects. Previous animal studies describe potential neuroprotective mechanisms of harmine, including anti-inflammatory and antioxidant activities, and neurotrophin signaling activation. However, the cellular and molecular mechanisms modulated by harmine in human models remain less investigated. Here we analyzed the short-term changes in the proteome of human brain organoids treated with harmine using shotgun mass spectrometry. Harmine upregulates proteins related to synaptic vesicle cycle, cytoskeleton-dependent intracellular transport, cell cycle, glucose transporter-4 translocation, and neurotrophin signaling pathway. In addition, protein expression levels of Akt and phosphorylated CREB were increased after 24 hour-treatment. Our results shed light on the potential mechanisms that may underlie harmine-induced neuroprotective effects.

scholarly journals Anti-Inflammatory Effect of Pineapple Rhizome Bromelain through Downregulation of the NF-κB- and MAPKs-Signaling Pathways in Lipopolysaccharide (LPS)-Stimulated RAW264.7 Cells

2021 ◽  
Vol 43 (1) ◽  
pp. 93-106
Author(s):  
Orapin Insuan ◽  
Phornphimon Janchai ◽  
Benchaluk Thongchuai ◽  
Rujirek Chaiwongsa ◽  
Supaporn Khamchun ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Signaling Pathways ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Raw264.7 Cells ◽  
Nuclear Factor ◽  
Amino Terminal ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Bromelain is a mixture of proteolytic enzymes derived from pineapple (Ananas comosus) fruit and stem possessing several beneficial properties, particularly anti-inflammatory activity. However, the molecular mechanisms underlying the anti-inflammatory effects of bromelain are unclear. This study investigated the anti-inflammatory effects and inhibitory molecular mechanisms of crude and purified rhizome bromelains on lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophage cells. RAW264.7 cells were pre-treated with various concentrations of crude bromelain (CB) or purified bromelain (PB), and then treated with LPS. The production levels of pro-inflammatory cytokines and mediators, including nitric oxide (NO), interleukin (IL)-6, and tumor necrosis factor (TNF)-α were determined by Griess and ELISA assays. The expressions of inducible nitric oxide synthetase (iNOS), cyclooxygenase (COX)-2, nuclear factor kappa B (NF-κB), and mitogen-activated protein kinases (MAPKs)-signaling pathway-related proteins were examined by western blot analysis. The pre-treatment of bromelain dose-dependently reduced LPS-induced pro-inflammatory cytokines and mediators, which correlated with downregulation of iNOS and COX-2 expressions. The inhibitory potency of PB was stronger than that of CB. PB also suppressed phosphorylated NF-κB (p65), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha, extracellular signal-regulated kinases, c-Jun amino-terminal kinases, and p38 proteins in LPS-treated cells. PB then exhibited potent anti-inflammatory effects on LPS-induced inflammatory responses in RAW264.7 cells by inhibiting the NF-κB and MAPKs-signaling pathways.

Sign in / Sign up

Export Citation Format

Share Document