Design, Synthesis and Investigation of the Potential Anti-Inflammatory Activity of 7-O-Amide Hesperetin Derivatives

To develop new anti-inflammatory agents, a series of 7-O-amide hesperetin derivatives was designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. All compounds showed inhibitory effect on LPS-induced NO production. Among them, 7-O-(2-(Propylamino)-2-oxoethyl)hesperetin (4d) and 7-O-(2-(Cyclopentylamino)-2-oxoethyl)hesperetin (4k) with hydrophobic side chains exhibited the most potent NO inhibitory activity (IC50 = 19.32 and 16.63 μM, respectively), showing stronger inhibitory effect on the production of pro- inflammatory cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) than indomethacin and celecoxib at 10 μM. The structure-activity relationships (SARs) suggested that the 7-O-amide unit was buried in a medium-sized hydrophobic cavity of the bound receptor. Furthermore, compound 4d could also significantly suppress the expression of inducible nitric oxide synthase enzymes (iNOS) and cyclooxygenase-2 (COX-2), through the nuclear factor-kappa B (NF-κB) signaling pathway.

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Curcumin protects liver inflammation by suppressing expression of inducible nitric oxide synthase in primary cultured rat hepatocytes

Functional Foods in Health and Disease ◽

10.31989/ffhd.v7i9.362 ◽

2017 ◽

Vol 7 (9) ◽

pp. 716 ◽

Cited By ~ 1

Author(s):

Richi Nakatake ◽

Hidehiko Hishikawa ◽

Hideyuki Matushima ◽

Yusuke Nakamura ◽

Morihiko Ishizaki ◽

...

Keyword(s):

Nitric Oxide ◽

Liver Injury ◽

Rat Hepatocytes ◽

No Production ◽

Type I ◽

Tnf Α ◽

Cultured Rat Hepatocytes ◽

Oxide Synthase ◽

Necrosis Factor ◽

Inducible Nitric Oxide

Background: Curcumin has beneficial effects on organ metabolism. However, there is little evidence that curcumin affects inflammatory mediators, such as tumor necrosis factor (TNF)-α and nitric oxide (NO). In an inflamed liver, proinflammatory cytokines stimulate liver cells, followed by the induction of inducible NO synthase (iNOS). Excessive NO produced by iNOS is one of the factors in liver injury. Therefore, inhibiting iNOS induction for preventing liver injury is important.Objective: This study aimed to investigate liver protective effects of curcumin by examining interleukin (IL)-1β-stimulated hepatocytes.Methods: Primary cultured rat hepatocytes were treated with IL-1β in the presence or absence of curcumin. Induction of NO production and iNOS, and the signaling pathway of iNOS were analyzed.Results: Simultaneous addition of IL-1β and curcumin decreased expression levels of iNOS protein and mRNA, resulting in inhibition of NO production. Curcumin also reduced mRNA expression of TNF-α and IL-6. Curcumin inhibited two essential signaling pathways for iNOS induction, NF-κB activation and type I IL-1 receptor upregulation. Transfection experiments revealed that curcumin reduced iNOS mRNA levels at the promoter activation and mRNA stabilization steps. Delayed administration of curcumin after IL-1β addition also inhibited iNOS induction.Conclusions: Curcumin affects induction of inflammatory mediators, such as iNOS and TNF-α, in part through the inhibition of NF-κB activation in hepatocytes. Curcumin may have therapeutic potential for organ injuries, including the liver.Key words: curcumin, inducible nitric oxide synthase, liver injury, primary cultured hepatocytes, nuclear factor-κB, type I interleukin-1 receptor, tumor necrosis factor-α.

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Anti-inflammatory Activity of Constituents Isolated from Terminalia chebula

Natural Product Communications ◽

10.1177/1934578x1400900721 ◽

2014 ◽

Vol 9 (7) ◽

pp. 1934578X1400900 ◽

Cited By ~ 4

Author(s):

Min Hye Yang ◽

Zulfiqar Ali ◽

Ikhlas A. Khan ◽

Shabana I. Khan

Keyword(s):

Nitric Oxide ◽

Cellular Level ◽

Inflammatory Activity ◽

No Production ◽

Terminalia Chebula ◽

Arjunolic Acid ◽

Cox 2 ◽

Anti Inflammatory ◽

Oxide Synthase ◽

Inducible Nitric Oxide

This study was aimed at the evaluation of the anti-inflammatory activity of twelve compounds isolated from the methanolic extract of fruits of Terminalia chebula. The activity was determined in terms of their ability to inhibit inducible nitric oxide synthase ( iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated macrophages. Two gallotannins [chebulinic acid (1) and 2,3,6-tri- O-galloyl-β-D-glucose (2)] and two triterpenoids [arjunic acid (3) and arjunolic acid (4)] efficiently reduced nitric oxide (NO) production with IC50 values of 53.4, 55.2, 48.8, and 38.0 μM, respectively. The protein expressions of iNOS and COX-2 were decreased in macrophages by treatment with compounds 1–4 (54–69% and 33–37%, respectively) at 50 μM. This is the first report of anti-inflammatory property of 1–4 mediated by inhibition of iNOS and COX-2 activities at the cellular level.

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Bioactive Diterpenes, Norditerpenes, and Sesquiterpenes from a Formosan Soft Coral Cespitularia sp.

Pharmaceuticals ◽

10.3390/ph14121252 ◽

2021 ◽

Vol 14 (12) ◽

pp. 1252

Author(s):

You-Cheng Lin ◽

Chi-Chien Lin ◽

Yi-Chia Chu ◽

Chung-Wei Fu ◽

Jyh-Horng Sheu

Keyword(s):

Nitric Oxide ◽

Soft Coral ◽

2D Nmr ◽

Inflammatory Protein ◽

Tnf Α ◽

Anti Inflammatory ◽

Factor Α ◽

Oxide Synthase ◽

Necrosis Factor ◽

Inducible Nitric Oxide

Chemical investigation of the soft coral Cespitularia sp. led to the discovery of twelve new verticillane-type diterpenes and norditerpenes: cespitulins H–O (1–8), one cyclic diterpenoidal amide cespitulactam L (9), norditerpenes cespitulin P (10), cespitulins Q and R (11 and 12), four new sesquiterpenes: cespilins A–C (13–15) and cespitulolide (16), along with twelve known metabolites. The structures of these metabolites were established by extensive spectroscopic analyses, including 2D NMR experiments. Anti-inflammatory effects of the isolated compounds were studied by evaluating the suppression of pro-inflammatory protein tumor necrosis factor-α (TNF-α) and nitric oxide (NO) overproduction, and the inhibition of the gene expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in lipopolysaccharide-induced dendritic cells. A number of these metabolites were found to exhibit promising anti-inflammatory activities.

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New Polyketides With Anti-Inflammatory Activity From the Fungus Aspergillus rugulosa

Frontiers in Pharmacology ◽

10.3389/fphar.2021.700573 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qianqian Xu ◽

Yuben Qiao ◽

Zijun Zhang ◽

Yanfang Deng ◽

Tianqi Chen ◽

...

Keyword(s):

Nuclear Translocation ◽

2D Nmr ◽

Inhibitory Effect ◽

Positive Control ◽

Inflammatory Activity ◽

M2 Macrophage ◽

No Production ◽

Inflammatory Factor ◽

Tnf Α ◽

Anti Inflammatory

Two new polyketide compounds, asperulosins A and B (1–2), and one new prenylated small molecule, asperulosin C (3), along with nine known compounds (4–12), were isolated and identified from a fungus Aspergillus rugulosa. Their structures were extensively elucidated via HRESIMS, 1D, and 2D NMR analysis. The absolute configurations of the new compounds were determined by the comparison of their electronic circular dichroism (ECD), calculated ECD spectra, and the detailed discussion with those in previous reports. Structurally, compounds 1 and 2 belonged to the polyketide family and were from different origins. Compound 2 was constructed by five continuous quaternary carbon atoms, which occur rarely in natural products. All of the isolates were evaluated for anti-inflammatory activity against the production of nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW264.7 cells. Among those, compounds 1 and 5 showed a significant inhibitory effect on NO production with IC50 values of 1.49 ± 0.31 and 3.41 ± 0.85 μM, respectively. Additionally, compounds 1 and 5 markedly increased the secretion of anti-inflammatory cytokine IL10 while suppressing the secretion of pro-inflammatory cytokines IL6, TNF-α, IFN-γ, MCP-1, and IL12. Besides, 1 and 5 inhibited the transcription level of pro-inflammatory macrophage markers IL6, IL1β, and TNF-α while remarkably elevating the anti-inflammatory factor IL10 and M2 macrophage markers ARG1 and CD206. Moreover, 1 and 5 restrained the expression and nuclear translocation of NF-κB, as well as its downstream signaling proteins COX-2 and iNOS. All these results suggest that 1 and 5 have potential as anti-inflammatory agents, with better or comparable activities than those of the positive control, dexamethasone.

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

Molecules ◽

10.3390/molecules25163573 ◽

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.

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In Vitro and In Vivo Anti-Inflammatory Activity of the Rhizomes of Globba pendula Roxb

Natural Product Communications ◽

10.1177/1934578x211055907 ◽

2021 ◽

Vol 16 (10) ◽

pp. 1934578X2110559

Author(s):

Le Minh Ha ◽

Ngo Thi Phuong ◽

Nguyen Thi Thu Hien ◽

Pham Thi Tam ◽

Do Thi Thao ◽

...

Keyword(s):

Ethyl Acetate ◽

Ethyl Acetate Extract ◽

Inhibitory Effect ◽

Potential Effect ◽

Inflammatory Activity ◽

No Production ◽

Anti Inflammatory ◽

Inflammatory Effect

In this study, we aimed at evaluating in vitro and in vivo anti-inflammatory activity of various extracts of the rhizomes of Globba pendula Roxb. Three extracts ( n-hexane, ethyl acetate, and water) were screened for their inhibitory effect on NO production by lipopolysaccharide-stimulated RAW 264.7 macrophages. The ethyl acetate extract of G. pendula rhizomes (EGP) showed a potential effect with an IC50 value of 32.45 µg/mL. For in vivo study, the ethyl acetate extract was further investigated for its anti-inflammatory effect using collagen antibody-induced arthritic mice (CAIA). The level of arthritis in experimental mice significantly reduced ( P < .05) after treatment with EGP at a dose of 500 mg/kg body weight (b.w.). This study also revealed that EGP is orally non-toxic. Ethyl p-methoxy cinamate was identified as the main constituent of EGP, which may result in its anti-inflammatory effect.

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Essential Oil of Myrtus communis Inhibits Inflammation in Rats by Reducing Serum IL-6 and TNF-α

Natural Product Communications ◽

10.1177/1934578x1100601034 ◽

2011 ◽

Vol 6 (10) ◽

pp. 1934578X1100601 ◽

Cited By ~ 8

Author(s):

Andrea Maxia ◽

Maria Assunta Frau ◽

Danilo Falconieri ◽

Manvendra Singh Karchuli ◽

Sanjay Kasture

Keyword(s):

Essential Oil ◽

Inflammatory Activity ◽

Myrtus Communis ◽

Ear Edema ◽

Tnf Α ◽

Cotton Pellet ◽

Anti Inflammatory ◽

Factor Α ◽

Necrosis Factor ◽

Serum Tumor Necrosis

The topical anti-inflammatory activity of the essential oil of Myrtus communis L. was studied using croton oil induced ear edema and myeloperoxidase (MPO) activity in mice, and cotton pellet induced granuloma, and serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in rats. On topical application, the oil exhibited a significant decrease in the ear edema as well as MPO activity. The oil also inhibited cotton pellet-induced granuloma and serum TNF-α and IL-6. It can be concluded that the essential oil of Myrtus communis reduces leukocyte migration to the damaged tissue and exhibits anti-inflammatory activity.

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Sageretia thea Inhibits Inflammation through Suppression of NF-κB and MAPK and Activation of Nrf2/HO-1 Signaling Pathways in RAW264.7 Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x19500198 ◽

2019 ◽

Vol 47 (02) ◽

pp. 385-403 ◽

Cited By ~ 10

Author(s):

Ha Na Kim ◽

Gwang Hun Park ◽

Su Bin Park ◽

Jeong Dong Kim ◽

Hyun Ji Eo ◽

...

Keyword(s):

Inhibitory Effect ◽

Mapk Signaling ◽

Inflammatory Activity ◽

Nuclear Accumulation ◽

Raw264.7 Cells ◽

No Production ◽

Immunodeficiency Virus ◽

Anti Oxidant ◽

Anti Inflammatory ◽

Signaling Activation

Sageretia thea (S. thea) commonly known as Chinese sweet plum or Chinese bird plum has been used for treating hepatitis and fevers in Korea and China. S. thea has been reported to exert anti-oxidant, anticancer and anti-human immunodeficiency virus activity. However, there is little study on the anti-inflammatory activity of S. thea. Thus, we evaluated the anti-inflammatory effect of extracts of leaves (ST-L) and branches (ST-B) from Sageretia thea in LPS-stimulated RAW264.7 cells. ST-L and ST-B significantly inhibited the production of the pro-inflammatory mediators such as NO, iNOS, COX-2, IL-1[Formula: see text] and IL-6 in LPS-stimulated RAW264.7 cells. ST-L and ST-B blocked LPS-induced degradation of I[Formula: see text]B-[Formula: see text] and nuclear accumulation of p65, which resulted in the inhibition of NF-[Formula: see text]B activation in RAW264.7 cells. ST-L and ST-B also attenuated the phosphorylation of ERK1/2, p38 and JNK in LPS-stimulated RAW264.7 cells. In addition, ST-L and ST-B increased HO-1 expression in RAW264.7 cells, and the inhibition of HO-1 by ZnPP reduced the inhibitory effect of ST-L and ST-B against LPS-induced NO production in RAW264.7 cells. Inhibition of p38 activation and ROS elimination attenuated HO-1 expression by ST-L and ST-B, and ROS elimination inhibited p38 activation induced by ST-L and ST-B. ST-L and ST-B dramatically induced nuclear accumulation of Nrf2, but this was significantly reversed by the inhibition of p38 activation and ROS elimination. Collectively, our results suggest that ST-L and ST-B exerts potential anti-inflammatory activity by suppressing NF-[Formula: see text]B and MAPK signaling activation, and activating HO-1 expression through the nuclear accumulation of Nrf2 via ROS-dependent p38 activation. These findings suggest that ST-L and ST-B may have great potential for the development of anti-inflammatory drug to treat acute and chronic inflammatory disorders.

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Phytosterols Suppress Phagocytosis and Inhibit Inflammatory Mediators via ERK Pathway on LPS-Triggered Inflammatory Responses in RAW264.7 Macrophages and the Correlation with Their Structure

Foods ◽

10.3390/foods8110582 ◽

2019 ◽

Vol 8 (11) ◽

pp. 582 ◽

Cited By ~ 5

Author(s):

Yuan ◽

Zhang ◽

Shen ◽

Jia ◽

Xie

Keyword(s):

Nitric Oxide ◽

Inflammatory Responses ◽

Ester Group ◽

No Production ◽

Raw264.7 Macrophages ◽

Extracellular Signal ◽

Tnf Α ◽

Anti Inflammatory ◽

Factor Α ◽

Oxide Synthase

Phytosterols, found in many commonly consumed foods, exhibit a broad range of physiological activities including anti-inflammatory effects. In this study, the anti-inflammatory effects of ergosterol, β-sitosterol, stigmasterol, campesterol, and ergosterol acetate were investigated in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Results showed that all phytosterol compounds alleviated the inflammatory reaction in LPS-induced macrophage models; cell phagocytosis, nitric oxide (NO) production, release of tumor necrosis factor-α (TNF-α), and expression and activity of pro-inflammatory mediator cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and phosphorylated extracellular signal-regulated protein kinase (p-ERK) were all inhibited. The anti-inflammatory activity of β-sitosterol was higher than stigmasterol and campesterol, which suggests that phytosterols without a double bond on C-22 and with ethyl on C-24 were more effective. However, inconsistent results were observed upon comparison of ergosterol and ergosterol acetate (hydroxy or ester group on C-3), which suggest that additional research is still needed to ascertain the contribution of structure to their anti-inflammatory effects.

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