Design of balanced COX inhibitors based on anti-inflammatory and/or COX-2 inhibitory ascidian metabolites

Ju, Zhiran,Su, Mingzhi,Hong, Jongki,La Kim, Eun,Moon, Hyung Ryong,Chung, Hae Young,Kim, Suhkmann,Jung, Jee H. S.E.C.T. [etc.] 2019 European journal of medicinal chemistry Vol.180 No.-

<P><B>Abstract</B></P> <P>The aim of this study was to design and synthesize COX-1/COX-2 balanced inhibitors incorporating the structural motifs of anti-inflammatory ascidian metabolites. We designed a series of substituted indole analogs that incorporate the key structures of the ascidian metabolites, herdmanines C and D. The synthesized analogs were tested for their inhibitory activity against COX-1 and COX-2, and compound <B>5m</B>, which displayed balanced inhibition, was further evaluated for in vitro anti-inflammatory activity. Compound <B>5m</B> suppressed the expression of pro-inflammatory factors, including iNOS, COX-2, TNF-α, and IL-6 in LPS-stimulated murine RAW264.7 macrophages. The reduction of PGE<SUB>2</SUB>, NO, and ROS was also observed, together with the suppression of NF-κB, IKK, and IκBα phosphorylation. Our results characterized <B>5m</B> as a COX-1/COX-2 balanced inhibitor that subsequently caused ROS inhibition and NF-κB suppression, and culminated in the suppression of iNOS, COX-2, TNF-α, and IL-6 expression.</P> <P><B>Highlights</B></P> <P> <UL> <LI> New balanced cyclooxygenase (COX-1 and COX-2) inhibitors were designed based on anti-inflammatory ascidian metabolites. </LI> <LI> l COX-1 and COX-2 inhibitory activity of these analogues was evaluated <I>in vitro</I>. </LI> <LI> Compound <B>5m</B> showed substantial anti-inflammatory activity <I>via</I> inhibition of the NF-κB (nuclear factor-kappa B) pathway. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Design of PPAR-γ agonist based on algal metabolites and the endogenous ligand 15-deoxy-Δ^{12, 14}-prostaglandin J₂

Ju, Zhiran,Su, Mingzhi,Hong, Jongki,Ullah, Sultan,La Kim, Eun,Zhao, Chang-Hao,Moon, Hyung Ryong,Kim, Suhkmann,Jung, Jee H. Elsevier 2018 European journal of medicinal chemistry Vol.157 No.-

<P><B>Abstract</B></P> <P>In a previous study, we synthesized endocyclic enone jasmonate derivatives that function as anti-inflammatory and PPAR-γ-activating entities by using key functional moieties of anti-inflammatory algal metabolites. Herein, we designed additional derivatives containing an exocyclic enone moiety that resembles the key structure of the natural PPAR-γ ligand, 15-deoxy-Δ<SUP>12, 14</SUP>-prostaglandin J<SUB>2</SUB> (15 d-PGJ<SUB>2</SUB>). The exocyclic enone moiety of 15 d-PGJ<SUB>2</SUB> is essential for covalent bonding with the Cys<SUP>285</SUP> residue in the PPAR-γ ligand-binding domain (LBD). <I>In silico</I> analysis of the designed compounds indicated that they may form hydrogen bonds with key amino acid residues in the PPAR-γ LBD, and thus, secure a position in the bioactive cavity in a similar fashion as does rosiglitazone and 15 d-PGJ<SUB>2</SUB>. By a luciferase reporter assay on rat liver Ac2F cells, the synthesized compounds were evaluated for PPAR-γ transcriptional activity. The differential PPAR-γ transcriptional activities of the geometric and enantiomeric isomers of the selected analog were also evaluated; based on our results, the enantiopure compound (+)-(<I>R,E</I>)-<B>6a1</B> was suggested as a potential PPAR-γ ligand.</P> <P><B>Highlights</B></P> <P> <UL> <LI> New PPAR-γ ligands were designed based on algal metabolites and endogenous ligand. </LI> <LI> Synthetic analogs were evaluated for PPAR-γ activation by luciferase reporter assay. </LI> <LI> The stereoisomers of the selected analog were compared for PPAR-γ activation. </LI> <LI> (+)-(<I>R</I>,<I>E</I>)-<B>6a1</B> was proposed as a potential PPAR-γ agonist. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Characterization of porcine cytokine inducible SH2-containing protein gene and its association with piglet diarrhea traits

Buyue Niu,Dongchun Guo,Zhiran Liu,Xiaofei Han,Xibiao Wang 아세아·태평양축산학회 2017 Animal Bioscience Vol.30 No.12

Objective: The cytokine inducible SH2-containing protein (CISH), which might play a role in porcine intestine immune responses, was one of the promising candidate genes for piglet anti-disease traits. An experiment was conducted to characterize the porcine CISH (pCISH) gene and to evaluate its genetic effects on pig anti-disease breeding. Methods: Both reverse transcription polymerase chain reaction (RT-PCR) and PCR were performed to obtain the sequence of pCISH gene. A pEGFP-C1-CISH vector was constructed and transfected into PK-15 cells to analysis the distribution of pCISH. The sequences of individuals were compared with each other to find the polymorphisms in pCISH gene. The association analysis was performed in Min pigs and Landrace pigs to evaluate the genetic effects on piglet diarrhea traits. Results: In the present research, the coding sequence and genomic sequence of pCISH gene was obtained. Porcine CISH was mainly localized in cytoplasm. TaqI and HaeIII PCR restriction fragment length polymorphism (RFLP) assays were established to detect single nucleotide polymorphisms (SNPs); A-1575G in promoter region and A2497C in Intron1, respectively. Association studies indicated that SNP A-1575G was significantly associated with diarrhea index of Min piglets (p<0.05) and SNP A2497C was significantly associated with the diarrhea trait of both Min pig and Landrace piglets (p<0.05). Conclusion: This study suggested that the pCISH gene might be a novel candidate gene for pig anti-disease traits, and further studies are needed to confirm the results of this preliminary research.

Anti-metastatic Effect of Natural Product-motivated Synthetic PPAR-γ Ligands

Li, Dan-dan,Wang, Ying,Ju, Zhiran,Kim, Eun La,Hong, Jongki,Jung, Jee H. The Korean Society of Pharmacognosy 2022 Natural Product Sciences Vol.28 No.2

Colorectal cancer is one of the most common cancers globally, ranking second for the number of cancer-related deaths. Metastasis has been reported as the main cause of death in patients with colorectal cancer. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a transcription factor that functions as a tumor suppressor by inhibiting cellular proliferation, migration, and invasion. In our previous efforts to generate natural product-motivated PPAR-γ ligands, the compounds 1 and 2 were obtained. These compounds activated PPAR-γ and inhibited the migration and invasion of HCT116 colorectal cancer cells, and they were also found to inhibit the epithelial-to-mesenchymal transition, which is a key process in cancer metastasis. Compounds 1 and 2 upregulated expression of the epithelial marker (E-cadherin), and downregulated expression of the mesenchymal marker (N-cadherin) and transcriptional factor (Snail). Therefore, the PPAR-γ agonists 1 and 2 could serve as a valuable model for the study on anti-metastatic leads for the treatment of colorectal cancer.

Interaction between Brucella melitensis 16M and small ubiquitin-related modifier 1 and E2 conjugating enzyme 9 in mouse RAW264.7 macrophages

Jihai Yi,Yueli Wang,Qifeng Li,Huan Zhang,Zhiran Shao,XiaoYu Deng,Jinke He,Chencheng Xiao,Zhen Wang,Yong Wang,Chuangfu Chen 대한수의학회 2019 Journal of Veterinary Science Vol.20 No.5

Brucella is an intracellular pathogen that invades a host and settles in its immune cells; however, the mechanism of its intracellular survival is unclear. Modification of small ubiquitin-related modifier (SUMO) occurs in many cellular activities. E2 conjugating enzyme 9 (Ubc9) is the only reported ubiquitin-conjugating enzyme that links the SUMO molecule with a target protein. Brucella's intracellular survival mechanism has not been studied with respect to SUMO-related proteins and Ubc9. Therefore, to investigate the relationship between Brucella melitensis 16M and SUMO, we constructed plasmids and cells lines suitable for overexpression and knockdown of SUMO1 and Ubc9 genes. Brucella 16M activated SUMO1/Ubc9 expression in a time-dependent manner, and Brucella 16M intracellular survival was inhibited by SUMO1/Ubc9 overexpression and promoted by SUMO1/Ubc9 depletion. In macrophages, Brucella 16M-dependent apoptosis and immune factors were induced by SUMO1/Ubc9 overexpression and restricted by SUMO1/Ubc9 depletion. We noted no effect on the expressions of SUMO1 and Ubc9 in B. melitensis 16M lipopolysaccharide-prestimulated mouse RAW264.7 macrophages. Additionally, intracellular survival of the 16MΔVirB2 mutant was lower than that of Brucella 16M (p < 0.05). VirB2 can affect expression levels of Ubc9, thereby increasing intracellular survival of Brucella in macrophages at the late stage of infection. Collectively, our results demonstrate that B. melitensis 16M may use the VirB IV secretion system of Brucella to interact with SUMO-related proteins during infection of host cells, which interferes with SUMO function and promotes pathogen survival in host cells.