Revisiting Bupropion Anti-inflammatory Action: Involvement of the TLR2/TLR4 and JAK2/STAT3

Mapping Intimacies ◽

10.21203/rs.3.rs-313044/v1 ◽

2021 ◽

Author(s):

Alireza Karimollah ◽

Anahid Hemmatpur ◽

Taha Vahid

Keyword(s):

Target Genes ◽

Mononuclear Cells ◽

Poor Response ◽

Antidepressant Therapy ◽

Protein Levels ◽

Inflammatory Conditions ◽

Genes Expression ◽

Therapeutic Value ◽

Peripheral Mononuclear Cells ◽

Anti Inflammatory

Abstract There are accumulating reports regarding poor response to the common antidepressant therapy. Antidepressant resistance has often been associated with activation of the inflammatory system. Accordingly, major depressive disorder (MDD) patients displaying inflammation prior to the treatment are less responsive to antidepressants. We hypothesized that the inefficacy of antidepressant therapy in some patients could be due to the drugs’ inflammatory mode of action that remained overshadowed by their substantial therapeutic value. Bupropion is a common-used antidepressant that is prescribed for seasonal affective disorders and smoking cessation as well. Nevertheless, there are some reports regarding inflammation induction and depressive behavior exacerbation in response to bupropion. Here, we put a spot on bupropion and investigate the alterations of innate and adaptive immunity cytokines and the influence on immune signaling pathways. Therefore, we treated LPS-stimulated human peripheral mononuclear cells (PBMCs) with different doses of bupropion. Pro-/ anti-inflammatory cytokines (TNF-ɑ, IL-1ß, IL-17, and IL-10) on both transcriptional and translational levels are assessed as well as the involvement of the JAK2 /STAT3, TLR2, and TLR4 signaling in this process. Bupropion decreased IL-17A, TNF-ɑ, and IL-1ß protein levels in the cultures. Nonetheless, the results regarding the target genes expression were controversial. Surprisingly, TNF-ɑ and IL-17A genes expression increased following bupropion treatment. TLR2, TLR4, JAK2, and STAT3 gene expression also rose in response to bupropion. Our findings suggest that bupropion possesses pro-inflammatory properties especially at concentrations of 50 and 100 and would rather be co-administrated with anti-inflammatory agents at least in patients with inflammatory conditions.

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RNA-Seq Analysis of Activated PBMC Treated With LMWF5A Predicts an Anti-Inflammatory Mode of Action and Similar Drug Targets to Dexamethasone

10.21203/rs.3.rs-790987/v2 ◽

2021 ◽

Author(s):

Elizabeth D. Frederick ◽

Melissa A. Hausburg ◽

Gregory W. Thomas ◽

David Bar-Or

Keyword(s):

Drug Targets ◽

Mononuclear Cells ◽

Biological Effects ◽

Weight Fraction ◽

Interferon Γ ◽

Immunomodulatory Activity ◽

Peripheral Blood Mononuclear ◽

Inflammatory Conditions ◽

Anti Inflammatory ◽

Upstream Regulators

Abstract Background: The low molecular weight fraction of human serum albumin (LMWF5A) has immunomodulatory activity via its effects on multiple inflammatory mediators and is currently being evaluated for the treatment of hyperactive or persistent inflammatory conditions. To gain further insight into the mechanism of action (MOA) of LMWF5A, an investigation of its effects on activated immune cells was performed. Methods and Results: Peripheral blood mononuclear cells (PBMC) were treated with vehicle control or LMWF5A and stimulated with lipopolysaccharide (LPS), LPS/interferon γ, or interleukin (IL)-4/IL-13, and RNAseq was performed to determine differentially expressed genes (DEGs) within each condition. Unbiased Ingenuity Pathway Analysis (IPA) of DEGs revealed anti-inflammatory and pro-resolving activities for LMWF5A. Moreover, comparison to all IPA upstream regulators predicted that the LMWF5A MOA is opposite to pro-inflammatory regulators and significantly matches the activity of several anti-inflammatory molecules. These analyses identified the glucocorticoid dexamethasone (DEX) as the most significantly similar regulator to LMWF5A. To further explore similarities to DEX, LMWF5A DEGs were compared to two publicly available datasets of activated, DEX-treated PBMC. These comparisons showed continuity between predicted upstream regulators, affording further support to the hypothesis that LMWF5A acts in a manner like DEX. Nevertheless, not all LMWF5A-targeted DEGs showed directional regulation identical to DEX. Conclusions: This study further defines the MOA of LMWF5A and provides hypotheses for future investigations. Because of its predicted similar biological effects and known safety profile, LMWF5A could potentially be used to treat conditions that are supported for DEX with fewer or less harmful side effects.

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Baicalin-Induced Autophagy Preserved LPS-Stimulated Intestinal Cells from Inflammation and Alterations of Paracellular Permeability

International Journal of Molecular Sciences ◽

10.3390/ijms22052315 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2315

Author(s):

Valentina Rizzo ◽

Nadia Ferlazzo ◽

Monica Currò ◽

Gaetano Isola ◽

Marco Matarese ◽

...

Keyword(s):

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Paracellular Permeability ◽

Autophagic Flux ◽

Mrna Levels ◽

Intestinal Epithelial ◽

Beneficial Effects ◽

Protein Levels ◽

Inflammatory Conditions ◽

Anti Inflammatory

Several studies have demonstrated a relevant role of intestinal epithelial cells in the immune response and in chronic inflammatory conditions, including ulcers, colitis, and Crohn’s disease. Baicalin (BA), extracted from the root of Scutellaria baicalensis, has various beneficial healthy effects, including anti-inflammatory activity. However, few studies have evaluated BA effects on autophagic signaling in epithelial cell response to inflammatory stimuli. To explore possible beneficial effects of BA, HT-29 cells were exposed to lipopolysaccharide (LPS), in presence or absence of BA, for 4 h. We evaluated mRNA levels of autophagy-related genes and cytokines, triggering inflammatory response. Furthermore, the expression of claudin 1, involved in the regulation of paracellular permeability was analyzed. BA treatment repressed LPS-induced expression of TNF-α and IL-1β. The down-regulation of autophagy-related genes induced by LPS was counteracted by cell pretreatment with BA. Under these conditions, BA reduced the NF-κB activation caused by LPS. Also, BA restored mRNA and protein levels of claudin 1, which were reduced by LPS. In conclusion, in intestinal epithelial cells BA regulates the NF-κB activation and modulates both autophagic and inflammatory processes, leading to an improvement of paracellular permeability. These results suggest that the anti-inflammatory effects of BA can be associated to the regulation of autophagic flux.

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5-Dodecanolide, a Compound Isolated from Pig Lard, Presents Powerful Anti-Inflammatory Properties

Molecules ◽

10.3390/molecules26237363 ◽

2021 ◽

Vol 26 (23) ◽

pp. 7363

Author(s):

Xavier Capó ◽

Miquel Martorell ◽

Josep A. Tur ◽

Antoni Sureda ◽

Antoni Pons

Keyword(s):

Mononuclear Cells ◽

Octadecenoic Acid ◽

Resolvin D1 ◽

Hydroalcoholic Extract ◽

Inflammatory Agent ◽

Pork Lard ◽

Peripheral Mononuclear Cells ◽

Anti Inflammatory ◽

Main Components ◽

Inflammatory Effect

Background: Pork lard (PL) is traditionally used as an anti-inflammatory agent. We propose to demonstrate the anti-inflammatory properties of PL, and elucidate which compounds could be responsible for the anti-inflammatory effects. Methods: The anti-inflammatory effects of PL were tested in a rat model of zymosan-induced hind paw inflammation. Further, the hydroalcoholic extract from PL was obtained, the composition analyzed, and the anti-inflammatory activity of the extracts and isolated components assayed using immune cells stimulated with lipopolysaccharide (LPS). Results: Applying the ointment on the inflamed rat feet reduced the foot diameter, foot weight, and activities of antioxidant enzymes and inflammatory markers of circulating neutrophils. The main components of the hydroalcoholic extract were 5-dodecanolide, oleamide, hexadecanoic acid, 9-octadecenoic acid, hexadecanamide, and resolvin D1. Conclusions: PL reduces the immune response in an animal model stimulated with zymosan. Hydroalcoholic PL extract and its components (5-Dodecanolide, Oleamide, and Resolvin D1) exerted an anti-inflammatory effect on LPS-stimulated neutrophils and peripheral mononuclear cells reducing the capability to produce TNFα, as well as the activities of antioxidant and pro-inflammatory enzymes. These effects are attributable to 5-dodecanolide, although the effects of this compound alone do not reach the magnitude of the anti-inflammatory effects observed by the complete hydroalcoholic extract.

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Immunomodulatory Effects of Diterpene Quinone Derivatives from the Roots ofHorminum pyrenaicumin Human PBMC

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/2980295 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

K. Becker ◽

S. Schwaiger ◽

B. Waltenberger ◽

D. Fuchs ◽

C. K. Pezzei ◽

...

Keyword(s):

Natural Product ◽

Interferon Gamma ◽

Mononuclear Cells ◽

Immunomodulatory Effects ◽

Human Pbmc ◽

Human System ◽

Redox Biology ◽

Action Analysis ◽

Peripheral Mononuclear Cells ◽

Anti Inflammatory

Several phytochemicals were shown to interfere with redox biology in the human system. Moreover, redox biochemistry is crucially involved in the orchestration of immunological cascades. When screening for immunomodulatory compounds, the two interferon gamma- (IFN-γ-) dependent immunometabolic pathways of tryptophan breakdown via indoleamine 2,3-dioxygenase-1 (IDO-1) and neopterin formation by GTP-cyclohydrolase 1 (GTP-CH-I) represent prominent targets, as IFN-γ-related signaling is strongly sensitive to oxidative triggers. Herein, the analysis of these pathway activities in human peripheral mononuclear cells was successfully applied in a bioactivity-guided fractionation strategy to screen for anti-inflammatory substances contained in the root ofHorminum (H.) pyrenaicumL. (syn. Dragon’s mouth), the only representative of the monophyletic genusHorminum. Four abietane diterpene quinone derivatives (horminone, 7-O-acetylhorminone, inuroyleanol and its 15,16-dehydro-derivative, a novel natural product), two nor-abietane diterpene quinones (agastaquinone and 3-deoxyagastaquinone) and twoabeo18 (4 → 3) abietane diterpene quinones (agastol and its 15,16-dehydro-derivative) could be identified. These compounds were able to dose-dependently suppress the above mentioned pathways with different potency. Beside the description of new active compounds, this study demonstrates the feasibility of integrating IDO-1 and GTP-CH-I activity in the search for novel anti-inflammatory compounds, which can then be directed towards a more detailed mode of action analysis.

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The Herbal DrugMelampyrum pratenseL. (Koch): Isolation and Identification of Its Bioactive Compounds Targeting Mediators of Inflammation

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/395316 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 17

Author(s):

S. Vogl ◽

A. G. Atanasov ◽

M. Binder ◽

M. Bulusu ◽

M. Zehl ◽

...

Keyword(s):

Target Genes ◽

Luciferase Reporter ◽

Peroxisome Proliferator ◽

Luciferase Reporter Gene ◽

Isolation And Identification ◽

Protein Levels ◽

Proinflammatory Mediators ◽

Mediators Of Inflammation ◽

Anti Inflammatory

Melampyrum pratenseL. (Koch) is used in traditional Austrian medicine for the treatment of different inflammation-related conditions. In this work, we show that the extracts ofM. pratensestimulated peroxisome proliferator-activated receptors- (PPARs-)αand -γthat are well recognized for their anti-inflammatory activities. Furthermore, the extract inhibited the activation of the proinflammatory transcription factor NF-κB and induction of its target genes interleukin-8 (IL-8) and E-selectinin vitro. Bioassay-guided fractionation identified several active flavonoids and iridoids including melampyroside and mussaenoside and the phenolic compound lunularin that were identified in this species for the first time. The flavonoids apigenin and luteolin were distinguished as the main components accountable for the anti-inflammatory properties. Apigenin and luteolin effectively inhibited tumor necrosis factorα(TNF-α)-induced NF-κB-mediated transactivation of a luciferase reporter gene. Furthermore, the two compounds dose-dependently reduced IL-8 and E-selectin protein expression after stimulation with lipopolysaccharide (LPS) or TNF-αin endothelial cells (ECs). The iridoids melampyroside and mussaenoside prevented the elevation of E-selectin in LPS-stimulated ECs. Lunularin was found to reduce the protein levels of the proinflammatory mediators E-selectin and IL-8 in ECs in response to LPS. These data validate the ethnomedical use ofM. pratensefor the treatment of inflammatory conditions and point to the constituents accountable for its anti-inflammatory activity.

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miRNA-199a-5p functions as a tumor suppressor in prolactinomas

Open Chemistry ◽

10.1515/chem-2019-0036 ◽

2019 ◽

Vol 17 (1) ◽

pp. 506-515

Author(s):

Wang Jichao ◽

Guo Jing ◽

Wang Fei ◽

Cao Lei ◽

Liu Qian ◽

...

Keyword(s):

Target Gene ◽

Target Genes ◽

Mrna Levels ◽

Tissue Micro Array ◽

Invasive Group ◽

Protein Levels ◽

Non Invasive ◽

Genes Expression ◽

Micro Array ◽

Apoptosis Level

AbstractProlactinomas are the most frequently observed pituitary adenomas (PAs), and 5%–18% tumors were resistant to the dopamine agonists (DAs). MicroRNAs (miRNAs) dysfunction play a key role in tumorigenesis. Agilent miRNA and an expression chip were used for six prolactinomas and three normal pituitary specimens. Differentially expressed genes were confirmed by RT-qPCR. The level of DDR1 and SAT1 was determined with tissue micro-array (TMA) and western blot. A MMQ cell line was used for functional experiments. We have identified 5-miRNA and 12 target gene signatures of prolactinomas through gene ontology analysis. miRNA-199a-5p was selected for experiments that integrated the results from prolactinomas specimens and a rat prolactinoma model induced by 17-b-estradiol. Tumors with low miRNA-199a-5p had a significantly invasive behavior and a higher tumor volume (p<0.05). DDR1 and SAT1, target genes of miRNA-199a-5p, had higher H-scores in the invasive group than those of the non-invasive group through TMA. An overexpression of miRNA-119a-5p suppressed the PRL secretion and the cell viability through upregulated the apoptosis level in MMQ cells (p<0.01). Furthermore, we found the target genes expression of DDR1 and SAT1 were affected by miRNA-199a-5p regardless of mRNA levels or protein levels. This study provided evidence that downregulation of miRNA-199a-5p may contribute to prolactinoma tumorigenesis.

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Palmitate-Induced S1P Signaling Pathway Attenuates by Cchicoric Acid in Human Peripheral Blood Mononuclear Cells

10.21203/rs.3.rs-1035894/v1 ◽

2021 ◽

Author(s):

Zahra Arab Sadeghabadi ◽

Keihan Ghatreh Samani ◽

Fatemeh Yaghoubi ◽

rooholla mohseni

Keyword(s):

Signaling Pathway ◽

Peripheral Blood Mononuclear Cells ◽

Healthy Subjects ◽

Mononuclear Cells ◽

Newly Diagnosed ◽

Peripheral Blood Mononuclear ◽

Protein Levels ◽

Genes Expression ◽

Blood Mononuclear Cells ◽

Sphingosine 1 Phosphate

Abstract Objective: Sphingosine 1-phosphate (S1P) signaling pathway is involved in the pathogenesis of type 2 diabetes (T2D). So, targeting S1P signaling pathway could be considered as potential therapeutic target for T2D. The aim of this study was to investigate the effects of palmitate and chicoric acid (CA) on S1P signaling pathway in peripheral blood mononuclear cells (PBMCs) from newly diagnosed patients with T2D and healthy subjects. Materials and Methods: 20 newly diagnosed patients with T2D and 20 healthy subjects, aged 40-60 years, were enrolled in the study. PBMCs were isolated and treated with palmitate and CA. Then, Sphingosine kinase 1 (SPHK1) and Sphingosine 1-phosphate receptor 1 (S1PR1) genes expression were evaluated by real-time PCR and S1PR1 protein levels were quantified using ELISA.Results: Palmitate significantly increased SPHK1 and S1PR1 genes expression and S1PR1 protein levels in PBMCs of both patients and healthy subjects. However, CA ameliorates palmitate-increased SPHK1 and S1PR1 genes expression and S1PR1 levels in these cells. Furthermore, a significant positive correlation between SPHK1 and S1PR1 genes expression with the S1PR1 protein levels was observed. Conclusions: These data indicate that CA could be considered as a novel S1P signaling pathway inhibitor through down regulation of SPHK1 and S1PR1.

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