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Epidermal growth factor receptor (EGFR) inhibitors represent the first-line treatment of non-small-cell lung cancer (NSCLC). However, the emergence of acquired drug resistance and side effects largely encumbered their application in clinic. The emerging technology proteolysis targeting chimera (PROTAC) could be an alternative strategy to overcome these problems. Herein, we reported the discovery of EGFR

C-Abl is involved in various biological processes and plays an important role in neurodegenerative diseases, especially Parkinson's disease (PD). Previous studies have found that nilotinib shows a neuroprotective effect in cell and animal models of PD by inhibiting the activation of c-Abl. But the low blood-brain barrier permeability and potential toxicity limit the further use of nilotinib in PD. Based on molecular modeling studies, a series of 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives were designed and synthesized. In particular, compound 9a exhibited significant inhibitory activity against c-Abl and a potent neuroprotective effect against MPPsup+/sup-induced SH-SY5Y cell death. Moreover, 9a not only displayed lower cell toxicity compared with nilotinib, but also showed higher oral bioavailability and proper permeability of the blood-brain barrier. This paper provides 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives as a new scaffold for c-Abl inhibitor with potential neuroprotective effect.

As a promising therapeutic target for gout, hURAT1 has attracted increasing attention. In this work, we identified a novel scaffold of hURAT1 inhibitors from a personal natural product database of verified herb-treated gout. First, we constructed more than 800 natural compounds from Chinese medicine that were verified to treat gout. Following the application of both shape-based and docking-based virtual screening (VS) methods, taking into account the shape similarity and flexibility of the target, we identified isopentenyl dihydroflavones that might inhibit hURAT1. Specifically, 9 compounds with commercial availability were tested with biochemical assays for the inhibition of 14C-uric acid uptake in high-expression hURAT1 cells (HEK293-hURAT1), and their structure-activity relationship was evaluated. As a result, 8-isopentenyl dihydroflavone was identified as a novel scaffold of hURAT1 inhibitors since isobavachin (DHF3) inhibited hURAT1 with an IC50 value of 0.39 ± 0.17 μM, which was comparable to verinurad with an IC50 value of 0.32 ± 0.23 μM. Remarkably, isobavachin also displayed an eminent effect in the decline of serum uric acid in vivo experiments. Taken together, isobavachin is a promising candidate for the treatment of hyperuricemia and gout.

The epidermal growth factor receptor (EGFR) kinase inhibitors Gefitinib, Erlotinib, Afatinib and Osimertinib have been approved for the treatments of non-small cell lung cancer patients harboring sensitive EGFR mutations, but resistance arises rapidly. To date all approved EGFR inhibitors are ATP-competitive inhibitors, highlighting the need for therapeutic agents with alternative mechanisms of action. Allosteric kinase inhibitors offer a promising new therapeutic strategy to ATP-competitive inhibitors. The mutant-selective allosteric EGFR inhibitors EAI045 exhibited higher potency for EGFRL858R&T790M compared to WT, which was also effective in EGFR-mutant models including those harboring the C797S mutation. However, it was not effective as a single-agent inhibitor, and require the co-administration of the anti-EGFR antibody Cetuximab. Further efforts produced a more potent analog JBJ-04-125-02, which can inhibit cell proliferation as a single-agent inhibitor. In the present study, molecular dynamics simulations and free energy calculations were performed and revealed the detailed inhibitory mechanism of JBJ-04-125-02 as more potent EGFR inhibitor. Moreover, the energy difference between HOMO and LUMO calculated by DFT implied the higher interaction of JBJ-04-125-02 than EAI045 in the active site of the EGFR. The identified key features obtained from the molecular modeling enabled us to design novel EGFR allosteric inhibitors. Communicated by Ramaswamy H. Sarma

Aiming to explore novel BRAFV600E and VEGFR-2 dual inhibitors, a series of 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed, synthesized and biologically evaluated in this study. Most of the synthesized 1H-pyrazolo[3,4-d]pyrimidine compounds displayed moderate to high potent activity in both enzymatic and cellular proliferation assays. Among these compounds, 9e, 9g, 9m and 9u showed remarkably high inhibitory activities against both BRAFV600E and VEGFR-2 kinase comparable to positive control Sorafenib. Particularly, compound 9u also showed potent anti-proliferative activity against BRAFV600E-expressing A375 (IC50 = 1.74 μM) and H-29 (IC50 = 6.92 μM) as well as VEGFR-2-expressing HUVEC (IC50 = 5.89 μM), which was also comparable to Sorafenib. Furthermore, kinase selectivity profile showed that 9u had almost poor or no significant inhibitory activity against wild-type BRAF and 15 other tested protein kinases. Flow cytometric analysis showed that compound 9u mainly arrested the A375 and HUVEC cell lines in the G0/G1 stage with a concentration-dependent effect. In addition, the molecular docking and molecular dynamics simulations suggested that 9u adopted a similar binding pattern with Sorafenib at the ATP-binding sites of BRAFV600E and VEGFR-2. Taken together, these results indicated that compound 9u may serve as novel lead compound in research on more effective BRAFV600E and VEGFR-2 dual inhibitors.

With the aim of discovering potential and selective inhibitors targeting ROS1 kinase, we rationally designed, synthesized and evaluated two series of novel 2-amino-pyridine derivatives with 1-phenylethoxy at C-3 and C-4 position. The enzymic assays results indicated that six of the new compounds 13b-13d and 14a-14c showed remarkably higher inhibitory activities against ROS1 kinase. The most promising compounds, 13d and 14c displayed the most desired ROS1 inhibitory activity with IC50 values of 440 nM and 370 nM respectively. Furthermore, 13d and 14c displayed ROS1 inhibitory selectivity of about 7-fold and 12-fold, relative to that of ALK sharing about 49% amino acid sequence homology in the kinase domains. They also showed good anti-proliferative effects against ROS1-addicted HCC78 cell lines with the IC50 values of 8.1 μM and 65.3 μM, respectively. Moreover, molecular docking and molecular dynamics simulation studies disclosed that compound 14c and 13d shared similar binding poses with Crizotinib except the selective binding site of ROS1. It also gave a probable molecular explanation for their activity and selectivity, which the methoxyl group in benzene ring was the crucial to the selectivity to ROS1 versus ALK.

In this paper, we designed and synthesized two analog compounds M1 and T1 that have a Michael acceptor warhead. Although only slightly diversity existed in the structures of M1 and T1, their inhibitory activities against wild type epidermal growth factor receptor (EGFRWT) and T790M/L858R mutant epidermal growth factor receptor (EGFRT790M/L858R) were significant different. Thus, multiple computational approaches were applied to investigate the interactions between the compounds with EGFRWT and EGFRT790M/L858R in order to explore the effect of different compounds. The molecular docking and MD simulations were performed to study the intermolecular interactions between compounds and EGFR. The binding free energy revealed that M1-EGFRWT and M1-EGFRT790M/L858R complexes have stronger binding affinity compared with the corresponding T1-EGFRWT and T1-EGFRT790M/L858R complexes, respectively. And the binding free energy decompositions for each residue analysis indicated that the van der Waals interactions are the major contributor to enhance the compounds to bind with EGFR. In addition, covalent binding complexes of M1-EGFRWT and M1-EGFRT790M/L858R were constructed and studied. Moreover, quantum mechanics method was applied to investigate the reaction mechanism of covalent binding of the compound and EGFR. The results will provide the details of structural and energetic information to develop potent covalent EGFR inhibitors in the future.

ALK and ROS1 kinases have become promising therapeutic targets since Crizotinib was used to treat non-small-cell lung cancer clinically. Aiming to explore new potent inhibitors, a series of 2-amino-4-(1-piperidine) pyridine derivatives that stabilized a novel DFG-shifted conformation in the kinase domain of ALK were designed and synthesized on the base of lead compound A. Biological evaluation highlighted that most of these new compounds could also potently inhibit ROS1 kinase, leading to the promising inhibitors against both ROS1 and ALK. Among them, the representative compound 2e stood out potent anti-proliferative activity against ALK-addicted H3122 and ROS1-addicted HCC78 cell lines (IC50 = 6.27 μM and 10.71 μM, respectively), which were comparable to that of Crizotinib. Moreover, 2e showed impressive enzyme activity against clinically Crizotinib-resistant ALKL1196M with an IC50 value of 41.3 nM, which was about 2-fold more potent than that of Crizotinib. 2e also showed potent inhibitory activity in about 6-fold superior to Crizotinib (IC50: 104.7 nM vs. 643.5 nM) in Ba/F3 cell line harboring ROS1G2032R. Furthermore, molecular modeling disclosed that all the representative inhibitors could dock into the active site of ALK and ROS1, which gave a probable explanation of anti Crizotinib-resistant mutants. These results indicated that our work has established a path forward for the generation of anti Crizotinib-resistant ALK/ROS1 dual inhibitors.

Three series of novel quinazoline and pyrido[2,3-d]pyrimidine derivatives were designed, synthesized and evaluated for their ability to inhibit EGFR tyrosine kinase and a panel of five human cancer cell lines (MCF-7, A549, BT-474, SK-BR-3, and MDA-MB-231). Bioassay results indicated that five of these prepared compounds (12c-12e and 13c-13d) exhibited remarkably higher inhibitory activities against EGFR and SK-BR-3 cell line. Compounds 12c and 12e displayed the most potent EGFR inhibitory activity (IC50 = 2.97 nM and 3.58 nM, respectively) and good anti-proliferative effect against SK-BR-3 cell with the IC50 values of 3.10 μM and 5.87 μM, respectively. Furthermore, molecular docking and molecular dynamics simulation studies verified that compound 12c and 12e shared similar binding pattern with gefitinib in the binding pocket of EGFR. MM-GBSA binding free energy revealed that the compound 12c and 12e have almost the same inhibitory activity against EGFR as gefitinib, and that the dominating effect of van der Waals interactions drives the binding process.

A novel small molecule tyrosine kinase inhibitor 6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1'-methylspiro[indoline-3,4'-piperidine]-2-one (SMU-B) had good activity against ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) targets in non-small-cell lung cancer. The excellent bioactivity of SMU-B highlights the importance of determining its metabolic traits, which could provide meaningful information for further pharmacokinetic studies of SMU-B. In this work, we studied the metabolism of SMU-B in human liver microsomes. Three metabolites of SMU-B were identified by a quadrupole-time of flight tandem mass spectrometer (Q-TOF-MS), and the metabolic pathways of SMU-B were demethylation, dehydrogenation and oxidation. CYP3A4/5 was the principal isoform involved in SMU-B metabolism, as shown by chemical inhibition and recombination human enzyme studies. Additionally, a predication with a molecular docking model confirmed that SMU-B could interact with the active sites of CYP3A4 and CYP3A5. This study illuminates the metabolic profile of the anti-tumor drug SMU-B, which will accelerate its clinical use.

Marine environments are known to be a new source of structurally diverse bioactive molecules. In this paper, we identified a porphyrin derivative of Pyropheophorbide a (PPa) from the mussel Musculus senhousei (M. senhousei) that showed broad anti-influenza A virus activity in vitro against a panel of influenza A viral strains. The analysis of the mechanism of action indicated that PPa functions in the early stage of virus infection by interacting with the lipid bilayer of the virion, resulting in an alteration of membrane-associated functions, thereby blocking the entry of enveloped viruses into host cells. In addition, the anti-influenza A virus activity of PPa was further assessed in mice infected with the influenza A virus. The survival rate and mean survival time of mice were apparently prolonged compared with the control group which was not treated with the drug. Therefore, PPa and its derivatives may represent lead compounds for controlling influenza A virus infection.

Lung cancer is the leading cause of cancer death, and epidermal growth factor receptor (EGFR) kinase domain mutations are a common cause of non-small-cell lung cancer (NSCLC), a major subtype of lung cancers. Patients harboring most of these mutations respond well to the EGFR inhibitors Gefitinib and Erlotinib initially, but soon develop resistance to them due to the emergence of the gatekeeper mutation T790M. The new-generation inhibitors such as AZD9291, HM61713, CO-1686 and WZ4002 can overcome T790M through covalent binding to Cys 797, but ultimately lose their efficacy upon the emergence of the C797S mutation that abolishes the covalent bonding. Allosteric inhibitors EAI001 and EAI045 are a new type of EGFR inhibitors that bind to EGFR away from the ATP-binding site and not relying on Cys 797. In this study, molecular dynamics simulations and free energy calculations were carried out on EAI001 and EAI045 in complex with EGFR, revealing the detailed inhibitory mechanism of EAI001 and EAI045 as EGFR allosteric inhibitor, which was expected to provide a basis for rational drug design of the EGFR allosteric inhibitors. Communicated by Ramaswamy H. Sarma.

Aiming to explore novel BRAF

Vascular endothelial growth factors receptor-2 (VEGFR-2) inhibitors have been proved as very effective anticancer agents. Structurally similar ligands 1 and 2 show almost the same inhibitory activities against VEGFR-2, but they bind to the enzyme in distinct binding mode. Ligand 1 targets DFG-in active conformation of VEGFR-2, known as Type I inhibitor. On the other hand, ligand 2 targets DFG-out inactive conformation of VEGFR-2, known as Type II inhibitor or allosteric kinase inhibitor. Ligand 2 shows high inhibitory activity, while the compound 3, a close analog of 2 with the cyclopropylamide replaced by tert-butylamide, exhibits drastically diminished potency. In this work, molecular dynamics simulations and free energy calculations were performed on inhibitors 1-3 binding to active and inactive conformation of VEGFR-2. Molecular dynamics simulations find that the active conformation binding to Type I inhibitor 1 appears more flexible when compared to the unbound form. In contrast, binding of Type II inhibitor 2 to the inactive conformation helps to stabilize the inactive conformation of the protein. Binding free energy calculations verify that inhibitors 1 and 2 have almost the same activities against VEGFR-2, and that ligand 1 binds to and stabilizes the DFG-in conformation of VEGFR-2, which is in agree with the experimental observation. Molecular dynamics simulations and binding free energy calculations of 3 binding to VEGFR-2 can give a good explanation of the drastically diminished potency. Free energy analysis revealed that van der Waals interactions provided the substantial driving force for the binding process. The important hydrophobic property of the terminal 4-Cl phenyl was required to be Type II inhibitors. Furthermore, per-residue free energy decomposition analysis revealed that the most favorable contribution came from Leu840, Val848, Ala866, Lys868, Leu889, Val899, Thr916, Phe918, Cys919, Leu1035, Cys1045, Asp1046, and Phe1047. These results are expected to be useful for future rational design of novel potent VEGFR-2 inhibitors.

The mechanisms of dimerization of α-synuclein from full-length monomers and their structural features have been investigated through molecular dynamics simulations in this study. The dimerization of α-syn plays a critical role in the fibrillogenesis mechanism and could initiate and trigger α-syn to aggregate by conformational transforming. According to the alignment between three regions of α-syn monomer, eight diverse starting structures have been constructed. However, only five configurations show the dimeric structures, and the detailed properties of three dimers of them are discussed. During the simulations, both identical α-syn peptides (P1 and P2) of these three dimers reduce the high contents of α-helix from their native folded structures, while the contents of β-sheet increase. Antiparallel β-hairpin motifs within the α-syn peptide are formed by intramolecular interactions. The β-hairpin regions are adjacent to the nonamyloid β component (NAC) of α-syn, and these structural features are consistent with the experimental observation. Moreover, intermolecular β-sheets also are generated between P1 and P2 through hydrogen bonding interactions. The dimers produce both intramolecular β-hairpin and intermolecular β-sheet characters; the former is presented in monomer and oligomer of α-syn, and the latter occurs in the fibril structure. The simulations also show several other interactions such as hydrophobic interactions and salt-bridges, which would contribute to making the α-syn dimers more stable with the aforementioned effects. The results may pave the way to design small molecules to inhibit the dimerization in order to block the aggregation of α-syn in the future.

Since deregulation of the tyrosine-kinase receptor c-Met is implicated in several human cancers and is an attractive target for small-molecule-drug discovery, we report herein the synthesis of 2,3,4,5-tetrahydro-8-[1-(quinolin-6-ylmethyl)-1H-1,2,3-triazolo[4,5-b]pyrazin-6-yl]-1H-pyrido[4,3-b]indoles 4a–4c and 2,3,4,5-tetrahydro-8-[3-(quinolin-6-ylmethyl)-1,2,4-triazolo[4,3-b]pyridazin-6-yl]-1H-pyrido[4,3-b]indoles 5a–5c. These indole derivatives demonstrated inhibition of c-Met kinase activity. Concurrently, five key intermediates were synthesized. These compounds could be prepared in good yields.

To investigate whether geniposide, an iridoid glucoside extracted from gardenia jasminoides ellis fruits, inhibits cell adhesion to human umbilical vein endothelial cells (HUVECs) induced by high glucose and its underlying mechanisms.HUVECs were isolated from human umbilical cords and cultured. The adhesion of monocytes to HUVECs was determined using fluorescence-labeled monocytes. The mRNA and protein levels of vascular cell adhesion molecule-1 (VCAM-1) and endothelial selectin (E-selectin) were measured using real-time RT-PCR and ELISA. Reactive oxygen species (ROS) production was measured using a fluorescent probe. The amounts of nuclear factor-kappa B (NF-kappaB) and inhibitory factor of NF-kappaB (IkappaB) were determined using Western blot analysis. The translocation of NF-kappaB from the cytoplasm to the nucleus was determined using immunofluorescence.Geniposide (10-20 mumol/L) inhibited high glucose (33 mmol/L)-induced adhesion of monocytes to HUVECs in a dose-dependent manner. This compound (5-40 mumol/L) also inhibited high glucose-induced expression of VCAM-1 and E-selectin at the gene and protein levels. Furthermore, geniposide (5-20 micromol/L) decreased ROS production and prevented IkappaB degradation in the cytoplasm and NF-kappaB translocation from the cytoplasm to the nucleus in HUVECs.Geniposide inhibits the adhesion of monocytes to HUVECs and the expression of CAMs induced by high glucose, suggesting that the compound may represent a new treatment for diabetic vascular injury. The mechanism underlying this inhibitory effect may be related to the inhibition of ROS overproduction and NF-kappaB signaling pathway activation by geniposide.

Matrine is one of the main bioactive alkaloids ofSophora flavescensAiton, which has been widely used to treat various diseases in China. These diseases include viral hepatitis, liver fibrosis, cardiac arrhythmia, skin diseases, and tumors. However, matrine is also the main toxic compound of this herb, and the available biomarkers are not reliable in detecting or quantifying matrine risk. Metabolomics is a powerful tool used to identify early toxicity biomarkers that are specific indicators of damage to biosystems. This study aimed to find the potential biomarkers of the matrine-induced toxic effects in rats and HepG2 cells. The toxicological effects of rats induced by matrine could be derived from the elevated taurine and trimethylamine N-oxide levels and the depletion in hippurate and tricarboxylic acid cycle intermediates, such as 2-oxoglutarate, citrate, and succinate in the urine. Cell metabolomics revealed that the levels of alanine, choline, glutathione, lactate, phosphocholine, and cholesterol showed dose-dependent decreases, whereas the levels of taurine, fatty acid, and unsaturated fatty acid showed dose-dependent increases. Overall, a significant perturbation of metabolites in response to high dose of matrine was observed bothin vivoandin vitro, and the selected metabolites particularly represent an attractive marker for matrine-induced toxicity.

In this paper, a specific design strategy targeting c-met kinase was reported based on docking modeling and topomer comparative molecular field analysis (Topomer CoMFA). A novel U-shape conformation which is distinct from the literature was demonstrated by molecular docking among 68 U-shape c-met inhibitors. According to the docking results, two Topomer CoMFA models with high predictive ability were established based on the two fragment rule. The results from both docking and topomer CoMFA showed that the π-π stacking interaction with Tyr1230 and the hydrogen bond with hinge region play an important role in inhibitory activity. Furthermore, the flexible linker and the adjacent solvent group would be favorable to stabilize the conformation and to enhance the two interactions mentioned above. Based on our patent, 14 new compounds were designed by our design strategy. The binding mode exhibited as expected and their activities were predicted by topomer CoMFA model. The preliminary biological tests showed most of them have potent activity to c-met kinase. Our study would provide guidelines to design some new U-shaped c-met inhibitors with new scaffolds and optimize the current molecules.

Acute lung injury is a life-threatening syndrome characterized by overwhelming lung inflammation and increased microvascular permeability, which causes a high mortality rate worldwide. The dry root of Peucedanum praeruptorum Dunn has been long used to treat respiratory diseases in China. In the present study, Praeruptorin A, C, D and E (PA, PC, PD and PE), four pyranocoumarins extracted from this herb, have been investigated for the pharmacological effects in experimental lung injury mouse models. In lipopolysaccharide (LPS) challenged mice, PA and PC did not show protective effect against lung injury at the dose of 80 mg/kg. However, PD and PE significantly inhibited the infiltration of activated polymorphonuclear leukocytes (PMNs) and decreased the levels of TNF-α and IL-6 in bronchoalveolar lavage fluid at the same dose. There was no statistically significant difference between PD and PE group. Further study demonstrated that PD and PE suppressed protein extravasations in bronchoalveolar lavage fluid, attenuated myeloperoxidase (MPO) activity and the pathological changes in the lung. Both PD and PE suppressed LPS induced Nuclear Factor-kappa B (NF-κB) pathway activation in the lung by decreasing the cytoplasmic loss of Inhibitor κB-α (IκB-α) protein and inhibiting the translocation of p65 from cytoplasm to nucleus. We also extended our study to acid-induced acute lung injury and found that these two compounds protected mice from hydrochloric acid (HCl)-induced lung injury by inhibiting PMNs influx, IL-6 release and protein exudation. Taken together, these results suggested that PD and PE might be useful in the therapy of lung injury.

Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of spiro[indoline-3, 4′-piperidine]-2-ones were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibitory effect on c-Met with IC50 values of 0.0147–17 μM in TR-FRET-based assay and IC50 values of 1.56–1400 μM in cell-based assay. Furthermore, our docking experiments verified the results and explained the molecular mechanism of eminent activities to c-Met.

Tie-2, a kind of endothelial cell tyrosine kinase receptor, is required for embryonic blood vessel development and tumor angiogenesis. Several compounds that showed potent activity toward this attractive anticancer drug target in the assay have been reported. In order to investigate the structure-activity correlation of indolocarbazole series compounds and modify them to improve their selectivity and activity, 3D-QSAR models were built using CoMFA and CoMSIA methods and molecular docking was used to check the results. Based on the common sketch align, two good QSAR models with high predictabilities (CoMFA model: q2 = 0.823, r2 = 0.979, CoMSIA model: q2 = 0.804, r2 = 0.967) were obtained and the contour maps obtained from both models were applied to identify the influence on the biological activity. Molecular docking was then used to confirm the results. Combined with the molecular docking results, the detail binding mode between the ligands and Tie-2 was elucidated, which enabled us to interpret the structure-activity relationship. These satisfactory results not only offered help to comprehend the action mechanism of indolocarbazole series compounds, but also provide new information for the design of new potent inhibitors.

The anti-inflammatory effect of methyl-1-hydroxy-2-naphthoate (MHNA), a novel naphthol derivative, was evaluated in the lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages. The release of nitric oxide (NO), interleukin-1beta (IL-1β) and interleukin-6 (IL-6) were detected by the Griess reagent and ELISA methods. The protein expressions of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) were examined by Western blotting. The mRNA expressions of IL-1β, IL-6, iNOS and COX-2 were determined by real-time PCR. Activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) pathways were detected by Western blotting, reporter gene assay and electrophoretic mobility shift assay. MHNA significantly inhibited the release of NO, IL-1β and IL-6 as well as the protein expression of iNOS and COX-2 in LPS-stimulated macrophages. It also inhibited the mRNA expression of iNOS, COX-2, IL-1β and IL-6. Further studies indicated that MHNA inhibited LPS-induced increases in NF-κB DNA-binding activity and NF-κB transcriptional activity as well as IκB-α degradation and NF-κB translocation in a dose-dependent manner. Meanwhile, the activation of p38 MAPK and c-Jun N-terminal kinases (JNK) induced by LPS were decreased by MHNA. MHNA inhibits the LPS-induced inflammatory response in murine macrophages via suppression of NF-κB and MAPKs signaling pathways activation.