Bridelia ferrugineaProduces Antineuroinflammatory Activity through Inhibition of Nuclear Factor-kappa B and p38 MAPK Signalling

Bridelia ferrugineais commonly used in traditional African medicine (TAM) for treating various inflammatory conditions. Extracts from the plant have been shown to exhibit anti-inflammatory property in a number ofin vivomodels. In this study the influence ofB. ferruginea(BFE) on the production of PGE2, nitrite, and proinflammatory cytokines from LPS-stimulated BV-2 microglia was investigated. The effects of BFE on cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein expressions were evaluated in LPS-activated rat primary microglia. The roles of NF-κB and MAPK signalling in the actions of BFE were also investigated. BFE (25–200 μg) inhibited the production of PGE2, nitrite, tumour necrosis factor-α(TNFα), and interleukin-6 (IL-6) as well as COX-2 and iNOS protein expressions in LPS-activated microglial cells. Further studies to elucidate the mechanism of anti-inflammatory action of BFE revealed interference with nuclear translocation of NF-κBp65 through mechanisms involving inhibition of IκB degradation. BFE prevented phosphorylation of p38, but not p42/44 or JNK MAPK. It is suggested thatBridelia ferrugineaproduces anti-inflammatory action through mechanisms involving p38 MAPK and NF-κB signalling.

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Nerolidol Mitigates Colonic Inflammation: An Experimental Study Using both In Vivo and In Vitro Models

Nutrients ◽

10.3390/nu12072032 ◽

2020 ◽

Vol 12 (7) ◽

pp. 2032

Author(s):

Vishnu Raj ◽

Balaji Venkataraman ◽

Saeeda Almarzooqi ◽

Sanjana Chandran ◽

Shreesh K. Ojha ◽

...

Keyword(s):

Nuclear Translocation ◽

In Vitro Models ◽

Mrna Levels ◽

Colonic Inflammation ◽

Tnf Α ◽

Cox 2 ◽

Anti Inflammatory ◽

Ht 29

Nerolidol (NED) is a naturally occurring sesquiterpene alcohol present in various plants with potent anti-inflammatory effects. In the current study, we investigated NED as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J) were administered 3% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colitis. Six groups received either vehicle alone or DSS alone or DSS with oral NED (50, 100, and 150 mg/kg body weight/day by oral gavage) or DSS with sulfasalazine. Disease activity index (DAI), colonic histology, and biochemical parameters were measured. TNF-α-treated HT-29 cells were used as in vitro model of colonic inflammation to study NED (25 µM and 50 µM). NED significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue Myeloperoxidase (MPO) concentrations, neutrophil and macrophage mRNA expression (CXCL2 and CCL2), and proinflammatory cytokine content (IL-1β, IL-6, and TNF-α) both at the protein and mRNA level were significantly reduced by NED. The increase in content of the proinflammatory enzymes, COX-2 and iNOS induced by DSS were also significantly inhibited by NED along with tissue nitrate levels. NED promoted Nrf2 nuclear translocation dose dependently. NED significantly increased antioxidant enzymes activity (Superoxide dismutase (SOD) and Catalase (CAT)), Hemeoxygenase-1 (HO-1), and SOD3 mRNA levels. NED treatment in TNF-α-challenged HT-29 cells significantly decreased proinflammatory chemokines (CXCL1, IL-8, CCL2) and COX-2 mRNA levels. NED supplementation attenuates colon inflammation through its potent antioxidant and anti-inflammatory activity both in in vivo and in vitro models of colonic inflammation.

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New Substituted 5-Benzylideno-2-Adamantylthiazol[3,2-b][1,2,4]Triazol-6(5H)ones as Possible Anti-Inflammatory Agents

Molecules ◽

10.3390/molecules26030659 ◽

2021 ◽

Vol 26 (3) ◽

pp. 659

Author(s):

Christophe Tratrat ◽

Michelyne Haroun ◽

Aliki Paparisva ◽

Charalmpos Kamoutsis ◽

Anthi Petrou ◽

...

Keyword(s):

Inhibitory Effect ◽

Cyclooxygenase Inhibitors ◽

Good Prediction ◽

Docking Analysis ◽

Cox 2 ◽

Anti Inflammatory ◽

Almost All ◽

Inflammatory Action ◽

Cox 1

Background: Inflammation is a complex response to noxious stimuli promoted by the release of chemical mediators from the damaged cells. Metabolic products of arachidonic acid, produced by the action of cyclooxygenase and lipoxygenase, play important roles in this process. Several non-steroidal anti-inflammatory drugs act as cyclooxygenase inhibitors. However, almost all of them have undesired side effects. Methods: Prediction of the anti-inflammatory action of the compounds was performed using PASS Program. The anti-inflammatory activity was evaluated by the carrageenan paw edema test. COX and LOX inhibitory actions were tested using ovine COX-1, human recombinant COX-2 and soybean LOX-1, respectively. Docking analysis was performed using Autodock. Results: All designed derivatives had good prediction results according to PASS and were synthesized and experimentally evaluated. The compounds exhibited in vivo anti-inflammatory action with eleven being equal or better than indomethacin. Although, some of them had no or low inhibitory effect on COX-1/2 or LOX, certain compounds exhibited COX-1 inhibition much higher than naproxen and COX-2 inhibition, well explained by Docking analysis. Conclusions: A number of compounds with good anti-inflammatory action were obtained. Although, some exhibited remarkable COX inhibitory action this activity did not follow the anti-inflammatory results, indicating the implication of other mechanisms.

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Fatty Ethanolamide of Bertholletia Excelsa Triglycerides (Brazil nuts): Anti-Inflammatory Action and Acute Toxicity Evaluation in Zebrafish (Danio rerio)

10.21203/rs.3.rs-437833/v1 ◽

2021 ◽

Author(s):

Yesica Fernanda Quitian-Useche ◽

Brenda Lorena Sánchez-Ortiz ◽

Swanny Ferreira Borges ◽

Benilson Ramos ◽

Gisele Custódio de Souza ◽

...

Keyword(s):

Danio Rerio ◽

In Silico ◽

Biological Effects ◽

Bertholletia Excelsa ◽

In Vivo Models ◽

Fatty Amides ◽

Cox 2 ◽

Anti Inflammatory ◽

Inflammatory Action

Abstract Fatty amides (N-alkylamides) are a group of bioactive lipids widely distributed in microorganisms, animals, and plants. The low yield in the extraction process of spilantol, a grease amide, which has been related mainly to diverse biological effects, compromises its application on a large scale. Thus, this study proposed an alternative to the synthesis of fatty amides from Bertholletia excelsa (AGBe) oil, with a chemical structure similar to that of spilantol. In vivo models induced by carrageenan were used in Zebrafish (Danio rerio). In in vivo studies, oral AGBe produced no signs of toxicity. In the histopathological study, AGBe did not cause significant changes in the main metabolizing organs (liver, kidneys, and intestines). In the anti-inflammatory evaluation, all doses (45 mg/kg, 500 mg/kg, and 1000 mg/kg) were effective, significantly reducing edema and producing a dose-response effect when compared to spilantol. In the in silico study, with the use of molecular docking, he showed that among the AGBe, the molecules 18:1, ω-7-ethanolamine and 18:1, ω-9-ethanolamine stood out, which had 21 interactions for COX-2 and 20 interactions for PLA2, respectively, surpassing the spilantol standard with 15 interactions for COX-2 and PLA2. The hypothesis of anti-inflammatory action was confirmed in the in silico study, demonstrating the involvement of AGBe in the process of inhibiting the enzymes COX-2 and PLA2. Therefore, based on all the results obtained and the fact that until the dose of 1000 mg/kg, orally, in zebrafish, it was not possible to determine the LD50, it can be said that AGBe is effective and safe for the activity anti-inflammatory.

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Design, Synthesis, Characterization and in silico molecular docking studies and in vivo anti-inflammatory Activity of Pyrazoline clubbed Thiazolinone Derivatives

Letters in Organic Chemistry ◽

10.2174/1570178617999201106113114 ◽

2020 ◽

Vol 17 ◽

Author(s):

Deepak Kumar Singh ◽

Mayank Kulshreshtha ◽

Yogesh Kumar ◽

Pooja A Chawla ◽

Akash Ved ◽

...

Keyword(s):

Molecular Docking ◽

Biological Activities ◽

Inflammatory Activity ◽

Standard Drug ◽

Docking Score ◽

Chemical Structures ◽

Cox 2 ◽

Anti Inflammatory ◽

Cox 1

Background: The pyrazolines give the reactions of aliphatic derivatives, resembling unsaturated compounds in their behavior towards permanganate and nascent hydrogen. This nucleus has been associated with various biological activities including inflammatory. Thiazolinone is a heterocyclic compound that contains both sulfur and nitrogen atom with a carbonyl group in their structure.Thiazolinone and their derivatives have attracted continuing interest because of their various biological activities, such as anti-inflammatory, antimicrobial, anti-proliferative, antiviral, anticonvulsant etc. The aim of the research was to club pyrazoline nucleus with thiazolinone in order to have significantanti-inflammatory activity. The synthesized compounds were chemically characterized for the establishment of their chemical structures and to evaluate as anti-inflammatory agent. Method: In the present work, eight derivatives of substituted pyrazoline (PT1-PT8) were synthesized by a three step reaction.The compounds were subjected to spectral analysis by Infrared, Mass and Nuclear magnetic resonance spectroscopy and elemental analysis data. All the synthesized were evaluated for their in vivo anti-inflammatory activity. The synthesized derivatives were evaluated for their affinity towards target COX-1 and COX-2, using indomethacin as the reference compound molecular docking visualization through AutoDock Vina. Results: Compounds PT-1, PT-3, PT-4 and PT-8 exhibited significant anti-inflammatory activity at 3rd hour being 50.7%, 54.3%, 52.3% and 57% respectively closer to that of the standard drug indomethacin (61.9%).From selected anti-inflammatory targets, the synthesized derivatives exhibited better interaction with COX-1 and COX-2 receptor, where indomethacin showed docking score of -6.5 kJ/mol, compound PT-1 exhibited highest docking score of -9.1 kJ/mol for COX-1 and compound PT-8 having docking score of 9.4 kJ/mol for COX-2. Conclusion: It was concluded that synthesized derivatives have more interaction with COX-2 receptors in comparison to the COX-1 receptors because the docking score with COX-2 receptors were very good. It is concluded that the synthesized derivatives (PT-1 to PT-8) are potent COX-2 inhibitors.

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Protective Effect of Membrane-Free Stem Cells against Lipopolysaccharide and Interferon-Gamma-Stimulated Inflammatory Responses in RAW 264.7 Macrophages

International Journal of Molecular Sciences ◽

10.3390/ijms22136894 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6894

Author(s):

Mei Tong He ◽

Hye Sook Park ◽

Young Sil Kim ◽

Ah Young Lee ◽

Eun Ju Cho

Keyword(s):

Nitric Oxide ◽

Stem Cells ◽

Interferon Gamma ◽

Mapk Signaling ◽

Raw 264.7 ◽

Raw 264.7 Macrophages ◽

Protein Expressions ◽

Ifn Γ ◽

Cox 2 ◽

Anti Inflammatory

Recently, adipose-derived stem cells (ADSCs) are considered to be ideal for application in cell therapy or tissue regeneration, mainly due to their wide availability and easy access. In this study, we examined the anti-inflammatory effects of membrane-free stem cell extract (MFSC-Ex) derived from ADSCs against lipopolysaccharide (LPS)/interferon-gamma (IFN-γ) on RAW 264.7 macrophage cells. Exposure of RAW macrophages to LPS and IFN-γ stimuli induced high levels of nitric oxide (NO), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2) production. However, pretreatment with MFSC-Ex inhibited LPS/IFN-γ-induced these pro-inflammatory mediators. To clarify the molecular mechanisms underlying the anti-inflammatory property of MFSC-Ex, we analyzed nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) protein expressions by Western blotting. Our study showed that treatment of MFSC-Ex significantly down-regulated inducible nitric oxide synthase (iNOS) and COX-2 protein expressions. Furthermore, phosphorylation of extracellular signal-regulated kinase (ERK) and p38 was also blocked by treatment with MFSC-Ex, indicating that inhibitory effect of MFSC-Ex on MAPK signaling cascade may attribute to inactivation of NF-κB. From these findings, we suggest that MFSC-Ex exert anti-inflammatory activities, which suppressed LPS/IFN-γ-induced production of NO, COX-2 and PGE2 by regulation of NF-κB and MAPK signaling pathway in RAW 264.7 macrophages. In conclusion, MFSC-Ex might provide a new therapeutic opportunity to treatment of inflammatory-related diseases.

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Design and Synthesis of Novel Ibuprofen Derivatives as Selective COX-2 inhibitors and potential anti-inflammatory agents: Evaluation of PGE2, TNF-α, IL-6 and histopathological study

Medicinal Chemistry ◽

10.2174/1573406417666210809162636 ◽

2021 ◽

Vol 17 ◽

Author(s):

Peter Amir Halim ◽

Hala Bakr El-Nassan ◽

Yara Sayed El-Dash

Keyword(s):

Carboxylic Acid ◽

Gastric Mucosa ◽

Docking Simulation ◽

Histopathological Study ◽

Acid Moiety ◽

Rat Serum ◽

Tnf Α ◽

Cox 2 ◽

Anti Inflammatory

Background: The reported binding mode of ibuprofen in the COX-2 binding site indicated that the carboxylic group binds with Arg-120 and Tyr-355 at the entrance of the cyclooxygenase channel and does not extend into the pocket. This accounted for the non-selectivity of ibuprofen. Based on this fact, we assumed that extending the length of the carboxylic acid moiety in ibuprofen and adding more bulky rigid groups as well as bulky groups carrying H-bonding functions might increase the selectivity and reduce the side effects of ibuprofen while maintaining its analgesic and anti-inflammatory activities. Objective: In this work, four series of ibuprofen derivatives were designed and prepared. The compounds were designed by increasing the length of the carboxylate group along with the incorporation of large hydrophobic groups. Method: Four series of ibuprofen derivatives were synthesized starting from ibuprofen. Their chemical structure was confirmed by spectral data. All the compounds were tested for their COX inhibitory activity. Results : The best COX-2 activity and selectivity were obtained with compounds 5c and 5d, which were subjected to further in vivo testing (carrageenan-induced paw edema, rat serum PGE2, TNF- α and IL-6, hot plate latency test) to investigate their anti-inflammatory and analgesic activities as well as their effects on the gastric mucosa. The anti-inflammatory activity of both compounds was comparable to that of ibuprofen, diclofenac, and indomethacin. Both compounds suppressed the production of PGE2 as well as the rat serum concentrations of both TNF-α and IL-6. This potent anti-inflammatory and analgesic behavior was not accompanied by any effect on the gastric mucosa. Docking simulation studies of the two compounds explained the higher selectivity for the COX-2 enzyme. Conclusion: Potent and selective ibuprofen derivatives can be successively obtained by extending the length of the carboxylic acid moiety in ibuprofen and adding more bulky rigid groups as well as bulky groups with H-bonding functions.

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Dangguijakyak-San Protects against 1-Methyl-4-phenyl-1,2,3,6,-tetrahydropyridine-Induced Neuronal Damage via Anti-Inflammatory Action

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/976270 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Deok-Sang Hwang ◽

Hyo Geun Kim ◽

Jun-Bock Jang ◽

Myung Sook Oh

Keyword(s):

Neuronal Damage ◽

Cell Damage ◽

Substantia Nigra Pars Compacta ◽

Inflammatory Factors ◽

Dopaminergic Cell ◽

Therapeutic Implications ◽

Anti Inflammatory ◽

Inflammatory Action

Dangguijakyak-san (DJS), a famous traditional Korean multiherbal medicine, has been used to treat gynecological and neuro-associated disease. Recent studies demonstrated that DJS has multiple bioactivities including neuroprotection. In the present study, we were to investigate the effect of DJS and its mechanism in anin vitroandin vivomodel of Parkinson’s disease (PD). In primary mesencephalic culture system, DJS attenuated the dopaminergic cell damage induced by 1-methyl-4-phenylpyridine toxicity, and it inhibited production of inflammatory factors such as tumor necrosis factorα(TNF-α), nitric oxide (NO), and activation of microglial cells. Then, we confirmed the effect of DJS in a mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the pole test, DJS at 50 mg/kg/day for 5 days showed increase of motor activity showing shortened time to turn and locomotor activity compared with the MPTP only treated mice. In addition, DJS significantly protected nigrostriatal dopaminergic neuron from MPTP stress. Moreover, DJS showed inhibition of gliosis in the substantia nigra pars compacta. These results have therapeutic implications for DJS in the treatment of PD via anti-inflammatory effects.

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2-Substituted Benzoxazoles as Potent Anti-Inflammatory Agents: Synthesis, Molecular Docking and In Vivo Anti-Ulcerogenic Studies

Medicinal Chemistry ◽

10.2174/1573406418666211220125344 ◽

2021 ◽

Vol 18 ◽

Author(s):

Iqra Hamid ◽

Humaira Nadeem ◽

Sameen Fatima Ansari ◽

Sonia Khiljee ◽

Inzamam Abbasi ◽

...

Keyword(s):

Side Effects ◽

Therapeutic Interventions ◽

Binding Potential ◽

Spectroscopic Techniques ◽

Standard Drug ◽

Cox 2 ◽

Anti Inflammatory ◽

Cox 2 Inhibitors ◽

Protein Pocket

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are the commonly used therapeutic interventions of inflammation and pain that competitively inhibit the cyclooxygenase (COX) enzymes. Several side effects like gastrointestinal and renal toxicities are associated with the use of these drugs. The therapeutic anti-inflammatory benefits of NSAIDs are produced by the inhibition of COX-2 enzymes, while undesirable side effects arise from the inhibition of COX-1 enzymes. Objectives: In the present study, a new series of 2-substituted benzoxazole derivatives 2(a-f) and 3(a-e) were synthesized in our lab as potent anti-inflammatory agents with outstanding gastro-protective potential. The new analogs 2(a-f) and 3(a-e) were designed depending upon the literature review to serve as ligands for the development of selective COX-2 inhibitors. Methods: The synthesized analogs were characterized using different spectroscopic techniques (FTIR, 1HNMR, 13CNMR) and elemental analysis. All synthesized compounds were screened for their binding potential in the protein pocket of COX-2 and evaluated for their anti-inflammatory potential in animals using the carrageenan-induced paw edema method. Further 5 compounds were selected to assess the in vivo anti-ulcerogenic activity in an ethanol-induced anti-ulcer rat model. Results: Five compounds (2a, 2b, 3a, 3b and 3c) exhibited potent anti-inflammatory activity and significant binding potential in the COX-2 protein pocket. Similarly, these five compounds demonstrated a significant gastro-protective effect (p<0.01) in comparison to the standard drug, Omeprazole. Conclusion: Depending upon our results, we hypothesize that 2-substituted benzoxazole derivatives have excellent potential to serve as candidates for the development of selective anti-inflammatory agents (COX-2 inhibitors). However, further assessments are required to delineate their underlying mechanisms.

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2,5-disubstituted-4-thiazolidinones: Synthesis, anti-inflammatory, free radical scavenging potentials and structural insights through molecular docking

Letters in Organic Chemistry ◽

10.2174/1570178618666210706111055 ◽

2021 ◽

Vol 18 ◽

Author(s):

Jagseer Singh ◽

Pooja A Chawla ◽

Rohit Bhatia ◽

Shamsher Singh

Keyword(s):

Free Radicals ◽

Antioxidant Activities ◽

Radical Scavenging ◽

Assay Method ◽

Acidic Group ◽

Active Compounds ◽

Cox 2 ◽

Anti Inflammatory

: The present work reports synthesis and screening of fifteen 2,5-disubstituted-4-thiazolidinones with different substitutions of varied arylidene groups at imino. The structures of the compounds were confirmed by spectral characterization. The compounds were subjected to in vivo anti-inflammatory and in vitro antioxidant activities. The derivatives possessed remarkable activities quite close to standard drugs used. Unlike conventional non-selective NSAIDs, the synthesized compounds did not contain any acidic group, thereby ensuring a complete cure from ulcers. To further substantiate the claim for safer derivatives, the active compounds were docked against the cyclooxygenase (COX)-2 enzyme. It was found that 4-fluorophenylimino substituent at 2- position and 3-nitro moiety on a 5-benzylidene nucleus of the 4-thiazolidinone derivative fitted in the COX-2 binding pocket. The compounds exhibited remarkable activity in scavenging free radicals, as depicted by the DPPH assay method. The structure-activity relationship was also established in the present work with respect to the nature and position of the substituents. The active compounds were evaluated for drug-like nature under Lipinski’s rule of five, and the toxicity behaviour of active compounds was predicted using ADMETlab software. The compounds have the potential to target degenerative disorders associated with inflammation and the generation of free radicals.

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Bakuchiol Suppresses Inflammatory Responses Via the Downregulation of the p38 MAPK/ERK Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms20143574 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3574 ◽

Cited By ~ 4

Author(s):

Hye-Sun Lim ◽

Yu Jin Kim ◽

Bu-Yeo Kim ◽

Soo-Jin Jeong

Keyword(s):

Mrna Expression ◽

P38 Mapk ◽

Inflammatory Responses ◽

Mitogen Activated Protein Kinase ◽

Enzyme Linked Immunosorbent Assay ◽

Mice Model ◽

Tnf Α ◽

Cox 2

The purpose of the present study was to evaluate the effects of bakuchiol on the inflammatory response and to identify the molecular mechanism of the inflammatory effects in a lipopolysaccharide (LPS)-stimulated BV-2 mouse microglial cell line and mice model. The production of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) was measured by enzyme-linked immunosorbent assay. The mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, and IL-6 was measured using reverse transcription–polymerase chain reaction analysis. Mitogen-activated protein kinase (MAPK) phosphorylation was determined by western blot analysis. In vitro experiments, bakuchiol significantly suppressed the production of PGE2 and IL-6 in LPS-stimulated BV-2 cells, without causing cytotoxicity. In parallel, bakuchiol significantly inhibited the LPS-stimulated expression of iNOS, COX-2, and IL-6 in BV-2 cells. However, bakuchiol had no effect on the LPS-stimulated production and mRNA expression of TNF-α or on LPS-stimulated c-Jun NH2-terminal kinase phosphorylation. In contrast, p38 MAPK and extracellular signal-regulated kinase (ERK) phosphorylation were inhibited by bakuchiol. In vivo experiments, Bakuchiol reduced microglial activation in the hippocampus and cortex tissue of LPS-injected mice. Bakuchiol significantly suppressed LPS-injected production of TNF-α and IL-6 in serum. These results indicate that the anti-neuroinflammatory effects of bakuchiol in activated microglia are mainly regulated by the inhibition of the p38 MAPK and ERK pathways. We suggest that bakuchiol may be beneficial for various neuroinflammatory diseases.

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