Anti-inflammation Compound Research Articles

Identification of the Anti-Inflammatory Compound, Paeoniflorigenone, in Radix Paeoniae Alba for the Treatment of Polycystic Ovary Syndrome Through Network Pharmacology and Molecular Docking

Introduction: Polycystic ovary syndrome (PCOS) is a common endocrine disease that is characterized by chronic inflammation. Baishao (radix paeoniae alba, RPA), classified as a top-grade herbal medicine in TCM, has anti-inflammatory, immune adjustment, and anti-oxidative activities. RPA has been used to treat PCOS in clinical practice, but its potential mechanism of action is unclear. This study aimed at exploring the potential mechanism of RPA in PCOS treatment and to investigate the anti-inflammatory constituents of RPA. Methods: The TCMSP database was used to screen the potential active compounds of RPA. On the other hand, the possible target genes of PCOS were collected from the TTD, DrugBank, GeneCard, OMIM, and PharmGKB databases. The PPI network of RPA–PCOS target genes was established by STRING, and the visual network among RPA, ingredients, disease and potential target genes was constructed in Cytoscape. The bioactivity and potential mechanism of RPA in PCOS treatment were analyzed by GO and KEGG enrichment approaches. Furthermore, molecular docking was utilized to indicate the best compounds of RPA binding with TNF-α. Results: Fifty-four potential target genes were filtered and gathered from RPA and PCOS. Visual network indicated that 8 ingredients in RPA, β-sitosterol, ( + )-catechin, palbinone, sitosterol, mairin, kaempferol, paeoniflorigenone, and paeoniflorin, were closely correlated with 54 possible therapeutic target genes. The possible pathways relating the treatment of PCOS by RPA mainly contained the TNF, lipid atherosclerosis, C-type lectin receptor, and AGE-RAGE signal pathways. Paeoniflorigenone was the optimal anti-inflammatory compound of RPA to bind with TNF-α in molecular docking analysis. Conclusion: This study manifested that the most effective anti-inflammation compound of RPA was paeoniflorigenone and provided a potential therapeutic strategy for PCOS treatment.

Predicting for anti-(mutant) SARS-CoV-2 and anti-inflammation compounds of Lianhua Qingwen Capsules in treating COVID-19

BackgroundLianhua Qingwen Capsules (LHQW) is a traditional Chinese medicine prescription commonly used to treat viral influenza in China. There has been sufficient evidence that LHQW could effectively treat COVID-19. Nevertheless, the potential anti-(mutant) SARS-CoV-2 and anti-inflammation compounds in LHQW are still vague.MethodsThe compounds of LHQW and targets were collected from TCMSP, TCMID, Shanghai Institute of Organic Chemistry of CAS database, and relevant literature. Autodock Vina was used to carry out molecular docking. The pkCSM platform to predict the relevant parameters of compound absorption in vivo. The protein–protein interaction (PPI) network was constructed by the STRING database. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was carried out by Database for Annotation, Visualization, and Integrated Discovery (DAVID). The anti-(mutant) SARS-CoV-2 and anti-inflammation networks were constructed on the Cytoscape platform.Results280 compounds, 16 targets related to SARS-CoV-2, and 54 targets related to cytokine storm were obtained by screening. The key pathways Toll-like receptor signaling, NOD-like receptor signal pathway, and Jak-STAT signaling pathway, and the core targets IL6 were obtained by PPI network and KEGG pathway enrichment analysis. The network analysis predicted and discussed the 16 main anti-SARS-CoV-2 active compounds and 12 main anti-inflammation active compounds. Ochnaflavone and Hypericin are potential anti-mutant virus compounds in LHQW.ConclusionsIn summary, this study explored the potential anti-(mutant) SARS-CoV-2 and anti-inflammation compounds of LHQW against COVID-19, which can provide new ideas and valuable references for discovering active compounds in the treatment of COVID-19.

A carrier-free metal-organic hybrid nanoassembly with combination anti-viral and hepato-protective activity for hepatitis B treatment.

Hepatitis B represents a major global public health burden, which is caused by the hepatitis B virus (HBV) with a high infection rate. Although several anti-HBV drugs have been developed for clinical treatment of hepatitis B, the current therapeutic strategies still suffer from undeniable adverse effects, insufficient efficacy after systemic administration and chronic inflammation. Here, we develop a carrier-free metal-organic hybrid nanoassembly that is co-loaded with tenofovir (TFV), an anti-viral agent and phosphorylated glycyrrhetinic acid (GAP), an anti-inflammatory compound (TFV/GAP/NA) to enhance the anti-HBV effect and alleviate the inflammatory response for hepatitis B treatment. The nanoassembly is easily prepared through the ionic interactions between the anionic phosphonate/phosphate groups from TFV/GAP and the zirconium cation, which has a stable nanostructure and a high drug-loading capacity. The nanoassembly prolongs the circulation time with reduced drug leakage in the blood and elevates drug accumulation in the liver after intravascular administration. After internalization mediated by the GAP ligand-GA receptor interaction, TFV/GAP/NA disassembles by the phosphatase-triggered degradation of the phosphate ester bonds in GAP and releases TFV, GAP and GA within the HBV-positive hepatocytes. The released TFV interferes with the HBV polymerase to inhibit the viral DNA replication, while the released GAP and GA suppress the pro-inflammatory protein expression. In mouse models, treatment with TFV/GAP/NA inhibits HBV production and alleviates inflammation-mediated liver injury.

Metabolic mechanism and anti-inflammation effects of sinomenine and its major metabolites N-demethylsinomenine and sinomenine-N-oxide

AimsSinomenine (SIN) is clinically used as an anti-rheumatic drug. However, the metabolic and pharmacological mechanisms of SIN combined with its metabolites are unclear. This study aims to explore the cyclic metabolic mechanism of SIN, the anti-inflammation effects of SIN and its major metabolites (N-demethylsinomenine (DS) and sinomenine-N-oxide (SNO)), and the oxidation property of SNO. Materials and methodsSIN was administrated to rats via gavage. Qishe pills (a SIN-containing drug) were orally administrated to humans. The bio-samples were collected to identify SIN's metabolites. Enzymatic and non-enzymatic incubations were used to reveal SIN's metabolic mechanism. Impacts of SIN, SNO and DS on the inflammation-related cytokine's levels and nuclear translocation of NF-κB were evaluated in LPS-induced Raw264.7 cells. ROS induced by SNO (10 μM) was also assessed. Key findingsCYP3A4 and ROS predominantly mediated the formation of SNO, and CYP3A4 and CYP2C19 primarily mediated the formation of DS. Noteworthily, SNO underwent N-oxide reduction both enzymatically, by xanthine oxidase (XOD), and non-enzymatically, by ferrous ion and heme moiety. The levels of IL-6 and TNF-α and nuclear translocation of NF-κB were ameliorated after pretreatment of SIN in LPS-induced Raw264.7 cells, while limited attenuations were observed after pretreatment of DS (SNO) even at 200 μM. In contrast, SNO induced ROS production. SignificanceThis study elucidated that SIN underwent both enzymatic and non-enzymatic cyclic metabolism and worked as the predominant anti-inflammation compound, while SNO induced ROS production, suggesting more studies of SIN combined with SNO and DS are necessary in case of DDI and potential toxicities.

Matrine ameliorates cognitive deficits via inhibition of microglia mediated neuroinflammation in an Alzheimer's disease mouse model.

Amyloid β (Aβ) induced microglial activation and attendant neuroinflammation play pivotal roles in Alzheimer's disease (AD) pathogenesis. Matrine is a natural anti-inflammation compound from the Chinese herbal medicine Sophora flavescens Ait. (Kushen). This study aimed to investigate the effects of matrine on memory deficit and neuroinflammation in an oligomeric Aβ (oAβ)-induced AD mice model. Whether microglial activation and NADPH oxidase were involved in these effects were further studied. Different doses of matrine (10, 20, or 40 mg/kg) were intragastrically administered once a day after intracerebroventricular oAβ injection (2.5 μg/μl, 4 μl). 15 days after the oAβ injection, behavioral experiments including novel object recognition (NOR) test and Morris water maze (MWM) test were performed. 21 days after the oAβ injection, concentration of ROS, TNF-α, IL-1β and IL-6 as well as expression of NADPH oxidase subunits gp91phox and p47phox in mice hippocampal tissues were assessed, and microglial activation were evaluated by Iba-1 immunohistochemical staining. Results of NOR test and MWM test revealed that oAβ injection could remarkably impair learning and memory function in AD mice, and matrine administration could significantly ameliorate the impairment. ROS, TNF-α, IL-1β and IL-6 levels increased after oAβ injection, while matrine could significantly reduce the concentrations of these inflammatory factors. OAβ induced protein expression of NADPH oxidase subunits gp91phox and p47phox were also significantly reduced by matrine. Iba-1 immunohistochemistry results showed less activated microglia in matrine-treated mice brain. These results indicate that matrine could ameliorate learning and memory impairment and neuroinflammation induced by oAβ injection. These effects were found to be mediated through inhibition of microglial activation and NADPH oxidase expression in hippocampal tissue. The results suggest that matrine may be a valuable natural compound with therapeutic potential against AD.

The Effect of Potato (Solanum tuberosum L.) Skin Extract on Alkaline Phosphatase Level in Periodontitis

Periodontitis is a chronic inflammation on tooth supporting tissues leads to alveolar bone resorption and tooth loss. Increase of alkaline phosphatase (ALP) level is found in periodontitis condition. Potato skin extract is known for its antioxidant and antiinflammation compounds therefore presumably potential as adjuvant therapy for periodontitis. This study aim was to know the effect of oral intake of potato skin extract on alveolar bone ALP and serum ALP level in model periodontitis Sprague dawley rats. Type of the study was experimental with posttest-only control group design. Thirty-five male Sprague dawley rats were divided into five groups: healthy control, negative control (aquadest-treated periodontitis), and potato skin extract- treated periodontitis in three different concentrations (25%, 50%, 75%). After 14-day treatments, ALP level on alveolar bone and blood serum samples from each group were measured using UV-Vis spectrophotometer. The results showed both alveolar bone ALP and serum ALP level were lower in potato skin extract-treated periodontitis groups in comparison to negative control group. Statistic analysis using One-way Anova showed significant difference of ALP level amongst groups (p<0.05). Post-hoc LSD test showed significant differences of ALP level between each treated and control groups (p<0.05). This study concluded potato skin extract decreased ALP level, with concentration 75% showed lowest both ALP levels of alveolar bone and serum samples, indicated alveolar bone remodeling. Moreover, it is suggested that ALP level in serum can represent ALP level on alveolar bone tissues in periodontitis condition.

Real-time monitoring of IL-6 and IL-10 reporter expression for anti-inflammation activity in live RAW 264.7 cells

In previous study, we suggested that the interleukin (IL)-6 and IL-10 could serve as a good biomarker for anti-inflammation that related to chronic inflammatory disease. Recently, we are finding new anti-inflammation compounds from natural products by screening of IL-6 and IL-10 levels. Although, we could measure IL-6 and IL-10 levels by several methods. However, all methods could not measure continuous kinetic of IL-6 and IL-10 levels. Most methods have multiple steps and take a long time. Therefore, there is no a suitable method for screening. To this end, we established IL-6 and IL-10 promoter assay which can monitor with reference gene as Glyceraldehyde 3-phosphate dehydrogenase (gapdh) promoter in living single cell. It could determine IL-6 and IL-10 levels continuously in real-time within two steps. We evaluated IL-6 and IL-10 reporter expression in LPS-induced RAW 264.7 cells with well-known anti-inflammatory compounds such as quercetin, xanthones, β-D-glucan and dexamethasone. As the results, the expression of IL-6 and IL-10 reporters were strongly induced by LPS. The expression of IL-6 reporter was inhibited by all anti-inflammation compounds in LPS-induced RAW 264.7 cells. The expression of IL-10 reporter was inhibited by quercetin, xanthones and dexamethasone in LPS-induced RAW 264.7 cells. While, expression of IL-10 reporter was induced by β-D-glucan. These results indicated that this assay could use for determination of IL-6 and IL-10 reporter expression in LPS-induced RAW 264.7 cells for anti-inflammation activity. Moreover, the results showed that natural compounds have an effect on the time course of IL-6 and IL-10 expressions. Therefore, real-time monitoring has a merit for natural compounds screening. We suggested that this assay could serve as a compound screening assay for anti-inflammation activity.

Strong dual-crosslinked hydrogels for ultrasound-triggered drug delivery

Hydrogels that can respond to dynamic forces either from endogenous biological activities or from external mechanical stimuli show great promise as novel drug delivery systems (DDS). However, it remains challenging to engineer hydrogels that specifically respond to externally applied mechanical forces with minimal basal drug leakage under normal stressful physiological conditions. Here we present an ultrasound responsive hydrogel-based DDS with special dual-crosslinked nanoscale network architecture. The covalent crosslinks endow the hydrogel high mechanical stability and greatly suppress deformation-triggered drug release. Meanwhile, the dynamic covalent boronate ester linkages between hydrogel backbone and the anti-inflammation compound, tannic acid (TA), allow effective ultrasound-triggered pulsatile release of TA. As such, the hydrogel shows distinct drug release profiles under compression and ultrasound. A proof-of-principle demonstration of the suppression of inflammation activation of macrophage upon ultrasound-triggered release of TA was also illustrated. We anticipate that this novel hydrogel-based drug delivery system can be used for the treatment of inflammatory diseases on load-bearing tissues, such as muscle and cartilage.

Anti-inflammation compounds from the seedpods of Pongamia pinnata (L.) Pierre guided by the bioactivity and UPLC-HRESIMS.

Pongamiapinnata (Linn.) Pierre has anti-inflammatory activity and could significantly decrease serum tumor necrosis factor-α and IL-10 in arthritic rats. Previous research indicated the typical chemical constituent in P. pinnata is furanoflavone. Guided by anti-inflammatory active assay and UPLC-HRESIMS chromatography, 22 compounds were isolated from the ethanol extract of P. pinnata seedpods. One novel furanoflavone, 4'-hydroxypinnatin, was elucidated by HRESIMS, 1D- and 2D-NMR spectra. The 21 known compounds, including 9 furanoflavone, were identified by comparing their NMR data with the previous data in reference. In the known compounds, 5 were isolated for the first time from the species. The anti-inflammatory activities were assayed by assessing LPS-induced NO production in BV-2 cells. 12 compounds can inhibit the production of NO without cytotoxicity at concentration of 50μM. Among them, compounds 4 can significantly inhibit the production of NO, with the IC50 value of 31.36μM.

Bioassay-guided fractionation of ethyl acetate extract from Armillaria mellea attenuates inflammatory response in lipopolysaccharide (LPS) stimulated BV-2 microglia

BackgroundArmillaria mellea (A. mellea) is a traditional Chinese medicinal and edible mushroom, which is proved to possess a lot of biological activities, including anti-oxidation, immunopotentiation, anti-vertigo and anti-aging activities. However, little information is available in regard to its neuroprotection activity in inflammation-mediated neurodegenerative diseases. PurposeWe have found that A. mellea has an anti-inflammatory activity in LPS-induced RAW264.7 cells in our previous study. The objective of this study is to investigate the anti-neuroinflammatory mechanism of a bioassay-guided fractionation (Fr.2) and its active components/compounds. MethodsCompounds were isolated by preparative high performance liquid chromatography (pre-HPLC) and their structures were established by mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopic analyses. The anti-neuroinflammatory effect of Fr.2 and each compounds were investigated in lipopolysaccharide (LPS)-stimulated murine microglia cell lineBV-2. ResultsWe demonstrated that Fr.2 significantly decreased the production of inflammation mediator nitric oxide (NO) and inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1beta (IL-1β) in a dose-dependent manner (10, 30, 100µg/ml). In addition, Fr.2 markedly down-regulated the phosphorylation levels of nuclear factor kappa B p65 (NF-κB p65), inhibitory κB-α (IκB-α) and c-Jun N-terminal kinases (JNKs) pathways. Sevens compounds were isolated from Fr.2, among them, three compounds, 5-hydroxymethylfurfural (CP1), vanillic acid (CP4) and syringate (CP5) were reported for the first time in A. mellea. NO and inflammatory cytokines (TNF-α, IL-6, IL-1β) secretion indicated that daidzein (CP6) and genistein (CP7) showed a more outstanding anti-inflammation potential at non-toxic concentrations (10, 30, 100µM) than the other five compounds. ConclusionsIn conclusion, Fr.2 may have therapeutic potential for neurodegenerative diseases by inhibiting inflammatory mediators and suppress inflammation pathway in activated microglia. Daidzein and genistein may serve as the effective anti-inflammation compounds of Fr.2.

Curcumin inhibits tumor proliferation induced by neutrophil elastase through the upregulation of α1-antitrypsin in lung cancer

Lung carcinogenesis is a complex process in an unregulated inflammatory environment. Curcumin has been extensively investigated as a multi-target anti-tumor and anti-inflammation compound. In this paper, we demonstrate a novel inflammation-related mechanism for curcumin-induced inhibition of lung tumor growth. We found that neutrophil elastase, an important regulator of inflammatory processes, directly triggered tumor cell proliferation in human lung adenocarcinoma A549 cells, and curcumin could completely suppress the excess tumor proliferation induced by neutrophil elastase. α1-antitrypsin is synthesized by tumor cells and is the natural inhibitor of neutrophil elastase. We found that curcumin counteracted the decrease of α1-antitrypsin induced by neutrophil elastase by inducing the promoter activity of α1-antitrypsin and promoting its expression in A549 cells. The inhibition of neutrophil elastase-induced proliferation by curcumin was dependent on the PI3K/Akt pathway. Knockdown of α1-antitrypsin by siRNA further enhanced the tumor cell proliferation induced by neutrophil elastase and significantly blocked the anti-proliferation effect of curcumin against neutrophil elastase. Curcumin remarkably inhibited the primary tumor growth of Lewis lung carcinoma (LLC) in C57BL/6 mice. We further showed that curcumin upregulated the level of α1-antitrypsin in primary tumor tissue by promoting its local expression, and the protein level of neutrophil elastase in tumor tissue was obviously decreased in mice treated with curcumin. Overall, our results suggest that neutrophil elastase and α1-antitrypsin play important roles in modulating lung tumor proliferation in inflammatory microenvironment and curcumin inhibits neutrophil elastase-induced tumor proliferation via upregulating α1-antitrypsin expression in vitro and in vivo.

Anti-inflammatory effects of ethanol extract from Melilotus suaveolens Ledeb: Involvement of pro- and anti-inflammatory cytokines and mediators

Melilotus suaveolens Ledeb is an annual or biennial plant of Melilotus genus in the Leguminosae family, which was used for treatment of inflammation-related diseases. The paper aims to investigate the anti-inflammatory mechanisms of ethanol extracts from M. suaveolens Ledeb. RAW 264.7 cells were stimulated with 10 ng/ml lipopolysaccharide (LPS) and intervened with 1 to 10 μg/ml ethanol extracts of M. suaveolens Ledeb. Several pro-inflammatory cytokines and mediators including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-1β and tumour necrosis factor-α (TNF-α) were studied by the method of enzyme-linked immunosorbent assay (ELISA) analysis, real time – polymerase chain reaction (RT-PCR) and western blot, respectively. The anti-inflammatory cytokines and mediators, such as IL-10 and heme oxygenase-1 (HO-1), were also investigated by the same method. The activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was studied using immunocytochemistry assay. Meanwhile, high performance liquid chromatography (HPLC) fingerprint was used to elucidate the active compounds in the extracts. The results showed that the extracts of M. suaveolens Ledeb have an anti-inflammatory effect by down-regulation of pro-inflammatory cytokines and mediators, such as iNOS, COX-2, IL-1β and TNF-α gene expression through the suppression of NF-κB activation. At the same time, the extracts increased anti-inflammatory cytokines and mediators IL-10 and HO-1. HPLC fingerprint chromatography of the M. suaveolens Ledeb extracts showed that coumarin is one of the main anti-inflammation compounds present in the plant, which is likely to be the basis of its anti-inflammation effect. The findings demonstrated that ethanol extracts from M. suaveolens Ledeb have great anti-inflammatory activities, which may be due to its dual effects on antagonizing pro-inflammatory and augmenting anti-inflammatory mediators. Key words: Melilotus suaveolens Ledeb, ethanol extract, anti-inflammatory effects, pro-inflammatory cytokines and mediators, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), anti-inflammatory cytokines and mediators.

PENGARUH PEMBERIAN PENTAGAMAVUNON-0 PADA AKTIVITAS GLUTATION-S-TRANSFERASE PADA HATI TIKUS SECARA IN VIVO

ABSTRACT Glutathione S-transferase is amount of enzymes catalyze conjugation reac-tion of glutathione (GSH) with electrofilic endogen compound or electrofilic xenobiotic. At the particular cancer there is increasing GST, especially on mu and phi class that it cause therapy on cancer cell by citostatic drug (commonly as electrofilic compound) not effectively. Pentagamavunon-0 (PGV-0) is antiinflammation compound. Base on in vivo research denoted this compound has five times strengthened than curcumin to inhibit GST enzyme activity. But using PGV-0 by in vivo to GST activity never report or publish yet. This research was done by measuring isolated GST enzyme activity from rat liver was given in vivo PGV-0, with nine groups treatment. Each group consist of control group without treatment, control group CMC-Na 0.5 % per oral and intraperitoneal DMSO, group with doses treatment of PGV-0 20, 40, 80 and 160 mg/Kg BB per oral, rat group was given benzo(a)pirene (BP) 1 mg/Kg BB i.p. and group was given BP 1 mg/Kg BB i. p. and PGV-0 80 mg/Kg BB per oral. GST enzyme activity is measured from reaction of conjugate GSH and DCNB that it’s absorption/minute. Base on rate (absorption/minute) GST enzyme activity can be accounted. Then inhibition percentage can be accounted from each rat treatment compared with control without treatment and solvent control. Analyze use statistic test (Kruskal-Wallis then continued by Mann-Whitney test), to know specific different of GST class mu enzyme activity in rat liver at each treatments group. Result research denoted that PGV-0 give inhibition effect to GST class mu activity of rat liver by in vivo. Doses level did not give proportional result to GST class mu activity of rat liver. Doses level of PGV-0 give optimum result to GST class mu activity of rat liver inhibition at 80 mg/Kg BB with inhibition value 19,99 % compared with CMC-Na as solvent. Key word: pentagamavunon-0, in vivo, glutathione S-transferase, inhibition