The Novel HDAC8 Inhibitor WK2-16 Attenuates Lipopolysaccharide-Activated Matrix Metalloproteinase-9 Expression in Human Monocytic Cells and Improves Hypercytokinemia In Vivo

Jan, Jing-Shiun; Chou, Yung Chen; Cheng, Yu Wen; Chen, Chih Kuang; Huang, Wei; Hsiao, George

doi:10.3390/ijms18071394

Cited by 17 publications

(14 citation statements)

References 64 publications

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“…Our results showed no effect of compounds 17, 8, and CA on the IκBα levels and MAPKs activity, see Figure 6. Similar effects were also referred for a synthetic derivative of CA, WK2-16 ((E)-N-hydroxy-4-methoxy-2-(biphenyl-4-yl)cinnamide) [34,40]. It was proposed that WK2-16 could influence transcription factors YY-1 and STAT-1/-3.…”

Section: Nf-b Activity [% Of Dmso]supporting

confidence: 53%

“…Cinnamic acid alone and several CA derivatives demonstrated the ability to influence the activity or expression of the pro-inflammatory transcription factor NF-κB in previous studies [15,33]. The effect of N-arylcinnamamide derivatives with the modified cinnamyl phenyl ring on NF-κB activity was studied by Chen et al [23] as well as by Jan et al [34], but the effect of derivatives with the unchanged cinnamyl moiety is described here for the first time. Apart from compounds 1 and 4, all anilides were able to significantly attenuate the lipopolysaccharide (LPS)-induced NF-κB activation by 10% to 27% in the non-toxic concentrations of 2 and 0.5 µM (used for compounds 10 (R = 3,4-Cl), 11 (R = 3,5-Cl), 13 (R = 3,5-CF 3 ) with the lowest cell viability), see Figure 3.…”

Section: Inhibition Of Nf-κb Activity and Cell Signaling In Vitromentioning

confidence: 76%

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Investigation of Anti-Inflammatory Potential of N-Arylcinnamamide Derivatives

et al. 2019

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A series of sixteen ring-substituted N-arylcinnamanilides, previously described as highly antimicrobially effective against a wide spectrum of bacteria and fungi, together with two new derivatives from this group were prepared and characterized. Moreover, the molecular structure of (2E)-N-(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide as a model compound was determined using single-crystal X-ray analysis. All the compounds were tested for their anti-inflammatory potential, and most tested compounds significantly attenuated the lipopolysaccharide-induced NF-κB activation and were more potent than the parental cinnamic acid. (2E)-N-[2-Chloro-5-(trifluoromethyl)phenyl]-3-phenylprop-2-enamide, (2E)-N-(2,6-dibromophenyl)-3-phenylprop-2-enamide, and (2E)-N-(2,5-dichlorophenyl)-3-phenylprop-2-enamide demonstrated the highest inhibition effect on transcription factor NF-κB at the concentration of 2 µM and showed a similar effectiveness as the reference drug prednisone. Several compounds also decreased the level of TNF-α. Nevertheless, subsequent tests showed that the investigated compounds affect neither IκBα level nor MAPKs activity, which suggests that the N-arylcinnamanilides may have a different mode of action to prednisone. The modification of the C (2,5) or C (2,6) positions of the anilide core by rather lipophilic and bulky moieties seems to be preferable for the anti-inflammatory potential of these compounds.Molecules 2019, 24, 4531 2 of 15 drugs are directly obtained from plants or fungi or are "nature-inspired" [11]. One such molecule is cinnamic acid (CA). It is a small organic molecule, which can be found in many kinds of plants in pure form or as a part of more complicated structures. CA and its natural and synthetic derivatives possess many interesting biological effects, such as antimicrobial [12,13], anticancer [14], anti-oxidant [13], and anti-inflammatory activities [15].N-Arylcinnamides represent a group of synthetic derivatives of CA. This group of compounds possesses several potentially active moieties-styryl, amide (peptide-like [16]) bond, and aryl [17][18][19][20][21][22]. Thus, cinnamides can be considered as a privilege structure or a scaffold (a part) of more complex molecules in medicinal chemistry [23,24] The series of N-arylcinnamide derivatives presented in this work was previously tested for their anti-microbial activity (compounds 1-15 and 17) [25,26], and three new derivatives 16 and 18 were prepared and characterized. Based on the concepts of polypharmacology, multifactorial diseases, and multitarget drugs [27], as well as the above-mentioned results, a group of eighteen N-arylcinnamanilides was chosen for the screening of their ability to moderate the inflammation-like reaction in vitro. Results and Discussion ChemistryThe investigated compounds (previously published compounds 1-15 and 17 [25] and two new compounds, 16 and 18) were prepared using a one-step microwave-assisted synthesis, see Scheme 1. Briefly, the carboxyl group of CA was activated with phosphorus trichloride, and then...

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Section: Nf-b Activity [% Of Dmso]supporting

confidence: 53%

Section: Inhibition Of Nf-κb Activity and Cell Signaling In Vitromentioning

confidence: 76%

Investigation of Anti-Inflammatory Potential of N-Arylcinnamamide Derivatives

et al. 2019

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“…Specific blockade of HDAC8 inhibited the release of proinflammatory cytokines, such as TNF-α and IL-1β, from monocytes in response to LPS in vitro and in vivo [19]. Our previous study revealed that a novel HDAC8 inhibitor, ( E )-N-hydroxy-4-methoxy-2-(biphenyl-4-yl)cinnamide (WK2-16), attenuated the production of inflammatory mediators, such as matrix metalloproteinases (MMPs) and IL-6, in monocytic THP-1 cells and decreased serum TNF-α and IL-6 levels in an endotoxemic mouse model [20]. Therefore, HDAC8 inhibitors may be therapeutic in the treatment of neuroinflammation-mediated diseases.…”

Section: Introductionmentioning

confidence: 99%

HDAC8 Inhibitor WK2-16 Therapeutically Targets Lipopolysaccharide-Induced Mouse Model of Neuroinflammation and Microglial Activation

Lin

Yen

Kuo

et al. 2019

IJMS

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Glial activation and neuroinflammatory processes play important roles in the pathogenesis of brain abscess and neurodegenerative diseases. Activated glial cells can secrete various proinflammatory cytokines and neurotoxic mediators, which contribute to the exacerbation of neuronal cell death. The inhibition of glial activation has been shown to alleviate neurodegenerative conditions. The present study was to investigate the specific HDAC8 inhibitor WK2-16, especially its effects on the neuroinflammatory responses through glial inactivation. WK2-16 significantly reduced the gelatinolytic activity of MMP-9, and expression of COX-2/iNOS proteins in striatal lipopolysaccharide (LPS)-induced neuroinflammation in C57BL/6 mice. The treatment of WK2-16 markedly improved neurobehavioral deficits. Immunofluorescent staining revealed that WK2-16 reduced LPS-stimulated astrogliosis and microglial activation in situ. Consistently, cellular studies revealed that WK2-16 significantly suppressed LPS-induced mouse microglia BV-2 cell proliferation. WK2-16 was proven to concentration-dependently induce the levels of acetylated SMC3 in microglial BV-2 cells. It also reduced the expression of COX-2/iNOS proteins and TNF-α production in LPS-activated microglial BV-2 cells. The signaling studies demonstrated that WK2-16 markedly inhibited LPS-activated STAT-1/-3 and Akt activation, but not NF-κB or MAPK signaling. In summary, the HDAC8 inhibitor WK2-16 exhibited neuroprotective effects through its anti-neuroinflammation and glial inactivation properties, especially in microglia in vitro and in vivo.

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“…NO #88-7346-88 TNF-α, #88-7066-2 IL-6, and #88-7010-88 IL-1β, eBioscience; San Diego, CA, USA). The quantitative levels of the cytokines were analyzed as previously described [58].…”

Section: Methodsmentioning

confidence: 99%

Hirsutanol A Attenuates Lipopolysaccharide-Mediated Matrix Metalloproteinase 9 Expression and Cytokines Production and Improves Endotoxemia-Induced Acute Sickness Behavior and Acute Lung Injury

et al. 2019

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Activated human monocytes/macrophages, which increase the levels of matrix metalloproteinases (MMPs) and pro-inflammatory cytokines, are the essential mechanisms for the progression of sepsis. In the present study, we determined the functions and mechanisms of hirsutanolA (HA), which is isolated from the red alga-derived marine fungus Chondrostereum sp. NTOU4196, on the production of pro-inflammatory mediators produced from lipopolysaccharide (LPS)-treated THP-1 cells. Our results showed that HA suppressed LPS-triggered MMP-9-mediated gelatinolysis and expression of protein and mRNA in a concentration-dependent manner without effects on TIMP-1 activity. Also, HA significantly attenuated the levels of TNF-α, IL-6, and IL-1β from LPS-treated THP-1 cells. Moreover, HA significantly inhibited LPS-mediated STAT3 (Tyr705) phosphorylation, IκBα degradation and ERK1/2 activation in THP-1 cells. In an LPS-induced endotoxemia mouse model, studies indicated that HA pretreatment improved endotoxemia-induced acute sickness behavior, including acute motor deﬁcits and anxiety-like behavior. HA also attenuated LPS-induced phospho-STAT3 and pro-MMP-9 activity in the hippocampus. Notably, HA reduced pathologic lung injury features, including interstitial tissue edema, inﬁltration of inﬂammatory cells and alveolar collapse. Likewise, HA suppressed the induction of phospho-STAT3 and pro-MMP-9 in lung tissues. In conclusion, our results provide pharmacological evidence that HA could be a useful agent for treating inflammatory diseases, including sepsis.

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The Novel HDAC8 Inhibitor WK2-16 Attenuates Lipopolysaccharide-Activated Matrix Metalloproteinase-9 Expression in Human Monocytic Cells and Improves Hypercytokinemia In Vivo

Cited by 17 publications

References 64 publications

Investigation of Anti-Inflammatory Potential of N-Arylcinnamamide Derivatives

Investigation of Anti-Inflammatory Potential of N-Arylcinnamamide Derivatives

HDAC8 Inhibitor WK2-16 Therapeutically Targets Lipopolysaccharide-Induced Mouse Model of Neuroinflammation and Microglial Activation

Hirsutanol A Attenuates Lipopolysaccharide-Mediated Matrix Metalloproteinase 9 Expression and Cytokines Production and Improves Endotoxemia-Induced Acute Sickness Behavior and Acute Lung Injury

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