Chemoenzymatic Synthesis of GDP-L-Fucose Derivatives as Potent and Selective -1,3-Fucosyltransferase Inhibitors

Wei-Che Hsieh,Yu-Nong Lin,Ting-Chien Lin,Chun-Hung Hans Lin 한국당과학회 2012 한국당과학회 학술대회 Vol.2012 No.1

Fucosyltransferases (FucTs) usually catalyze the final step of glycosylation and are critical to many biological processes. High levels of specific FucT activities are often associated with various cancers. Here we report the development of a chemoenzymatic method for synthesizing a library of GDP-L-fucose derivatives, followed by in situ screening for inhibitory activity against bacterial and human -1,3-FucTs (4). Several compounds incorporating appropriate hydrophobic moieties were identified from the initial screening. These were individually synthesized, purified and characterized in detail for their inhibition kinetics. Compound 5 had a Ki of 29 nM for human FucT-VI, and is 269 and 11 times more selective than for Helicobacter pylori FucT (Ki = 7.8 □ M) and for human FucT-V (Ki = 0.31 □ M).

Distal Mean Nocturnal Baseline Impedance Predicts Pathological Reflux of Isolated Laryngopharyngeal Reflux Symptoms

Hua-Nong Luo,Chen-Chi Wang,Ying-Cheng Lin,Chun-Yi Chuang,Yung-An Tsou,Ja-Chih Fu,Sheng-Shun Yang,Chi-Sen Chang,Han-Chung Lien 대한소화기 기능성질환∙운동학회 2023 Journal of Neurogastroenterology and Motility (JNM Vol.29 No.2

Background/AimsDiagnosis of isolated laryngopharyngeal reflux symptoms (ILPRS), ie, without concomitant typical reflux symptoms (CTRS), remains difficult. Mean nocturnal baseline impedance (MNBI) reflects impaired mucosal integrity. We determined whether esophageal MNBI could predict pathological esophagopharyngeal reflux (pH+) in patients with ILPRS. MethodsIn this cross-sectional study conducted in Taiwan, non-erosive or low-grade esophagitis patients with predominant laryngopharyngeal reflux symptoms underwent combined hypopharyngeal multichannel intraluminal impedance-pH monitoring when off acid suppressants. Participants were divided into the ILPRS (n = 94) and CTRS (n = 63) groups. Asymptomatic subjects without esophagitis (n = 25) served as healthy controls. The MNBI values at 3 cm and 5 cm above the lower esophageal sphincter (LES) and the proximal esophagus were measured. ResultsDistal but not proximal esophageal median MNBI values were significantly lower in patients with pH+ than in those with pH– (ILPRS in pH+ vs pH–: 1607 Ω vs 2709 Ω and 1885 Ω vs 2563 Ω at 3 cm and 5 cm above LES, respectively; CTRS in pH+ vs pH–: 1476 vs 2307 Ω and 1500 vs 2301 Ω at 3 cm and 5 cm above LES, respectively, P < 0.05 for all). No significant differences of any MNBI exist between any pH– subgroups and healthy controls. The areas under the receiver operating characteristic curve in the ILPRS group were 0.75 and 0.80, compared to the pH– subgroup and healthy controls (P < 0.001 for both), respectively. Interobserver reproducibility was good (Spearman correlation 0.93, P < 0.0001). ConclusionDistal esophageal MNBI predicts pathological reflux in patients with ILPRS.

Acidic Pelvic Drainage as a Predictive Factor For Anastomotic Leakage after Surgery for Patients with Rectal Cancer

Yang, Liu,Huang, Xin-En,Xu, Lin,Zhou, Xin,Zhou, Jian-Nong,Yu, Dong-Sheng,Li, Dong-Zheng,Guan, Xin Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.9

Purpose: To demonstrate the value of sequential determinations of pelvic drainage in the identification of increased risk of anastomotic leakage (AL) after anterior resection for rectal cancer with a double stapling technique. Patients and Methods: Between January 2004 and December 2011, data for the daily postoperative pH of pelvic drainage fluid in 753 consecutive patients with rectal cancer who initially underwent anterior resection with a double stapling technique were reviewed. All patients experienced a total mesorectal excision. Patients with anastomotic leakage (Group AL, n=57) were compared to patients without leakage (Group nAL, n=696). Patients with perioperatively abdominopelvic implants that were likely to affect pH value (determined at $25^{\circ}C$) other than leakage were excluded. Mean postoperative values were compared. Results: Anastomotic leakage was noted in 57 (7.6%) of 753 patients with rectal cancer. The diagnosis of AL was made between the $6^{th}$ and $12^{th}$ postoperative day (POD; mean $8^{th}$ POD). There was no significance of the daily average values of pH on POD1 & 2 in group AL while a significantly sharp declining mean pH value reached its diagnostic point of AL (p<0.001) on POD3. A cut-off value of 6.978 on the $3^{rd}$ POD maximized the sensitivity (98.7.0%) and specificity (94.7%) in assessing the risk of leakage. Conclusion: According to these results, an early and persistent declining of pH value of pelvic drainage fluid after rectal surgery with anastomosis, is a marker of AL. A cut-off value of 6.798 determined at $25^{\circ}C$ on POD3 maximizes sensitivity and specificity.

Role of MYH Polymorphisms in Sporadic Colorectal Cancer in China: A Case-control, Population-based Study

Yang, Liu,Huang, Xin-En,Xu, Lin,Zhou, Jian-Nong,Yu, Dong-Sheng,Zhou, Xin,Li, Dong-Zheng,Guan, Xin Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.11

Purpose: Biallelic germline variants of the 8-hydroxyguanine (8-OG) repair gene MYH have been associated with colorectal neoplasms that display somatic $G:C{\rightarrow}T:A$ transversions. However, the effect of single germline variants has not been widely studied, prompting the present investigation of monoallelic MYH variants and susceptibility to sporadic colorectal cancer (CRC) in a Chinese population. Patients and Methods: Between January 2006 and December 2012, 400 cases of sporadic CRC and 600 age- and sex-matched normal blood donors were screened randomly for 7 potentially pathogenic germline MYH exons using genetic testing technology. Variants of heterozygosity at the MYH locus were assessed in both sporadic cancer patients and healthy controls. Univariate and multivariate analyses were performed to determine risk factors for cancer onset. Results: Five monoallelic single nucleotide polymorphisms (SNPs) were identified in the 7 exon regions of MYH, which were detected in 75 (18.75%) of 400 CRC patients as well as 42 (7%) of 600 normal controls. The region of exon 1 proved to be a linked polymorphic region for the first time, a triple linked variant including exon 1-316 $G{\rightarrow}A$, exon 1-292 $G{\rightarrow}A$ and intron 1+11 $C{\rightarrow}T$, being identified in 13 CRC patients and 2 normal blood donors. A variant of base replacement, intron 10-2 $A{\rightarrow}G$, was identified in the exon 10 region in 21 cases and 7 controls, while a similar type of variant in the exon 13 region, intron 13+12 $C{\rightarrow}T$, was identified in 8 cases and 6 controls. Not the only but a newly missense variant in the present study, p. V463E (Exon 14+74 $T{\rightarrow}A$), was identified in exon 14 in 6 patients and 1 normal control. In exon 16, nt. 1678-80 del GTT with loss of heterozygosity (LOH) was identified in 27 CRC cases and 26 controls. There was no Y165C in exon 7 or G382D in exon 14, the hot-spot variants which have been reported most frequently in Caucasian studies. After univariate analysis and multivariate analysis, the linked variant in exon 1 region (p=0.002), intron 10-2 $A{\rightarrow}G$ (p=0.004) and p. V463E (p=0.036) in the MYH gene were selected as 3 independent risk factors for CRC. Conclusions: According to these results, the linked variant in Exon 1 region, Intron 10-2 $A{\rightarrow}G$ of base replacement and p. V463E of missense variant, the 3 heterozygosity variants of MYH gene in a Chinese population, may relate to the susceptibility to sporadic CRC. Lack of the hot-spot variants of Caucasians in the present study may due to the ethnic difference in MYH gene.

Upregulation and biological function of transmembrane protein 119 in osteosarcoma

Zhen-Huan Jiang,Jun Peng,Hui-Lin Yang,Xing-Li Fu,Jin-Zhi Wang,Lei Liu,Jian-Nong Jiang,Yong-Fei Tan,Zhi-Jun Ge 생화학분자생물학회 2017 Experimental and molecular medicine Vol.49 No.-

Osteosarcoma is suggested to be caused by genetic and molecular alterations that disrupt osteoblast differentiation. Recent studies have reported that transmembrane protein 119 (TMEM119) contributes to osteoblast differentiation and bone development. However, the level of TMEM119 expression and its roles in osteosarcoma have not yet been elucidated. In the present study, TMEM119 mRNA and protein expression was found to be up-regulated in osteosarcoma compared with normal bone cyst tissues. The level of TMEM119 protein expression was strongly associated with tumor size, clinical stage, distant metastasis and overall survival time. Moreover, gene set enrichment analysis (GSEA) of the Gene Expression Omnibus (GEO) GSE42352 dataset revealed TMEM119 expression in osteosarcoma tissues to be positively correlated with cell cycle, apoptosis, metastasis and TGF-β signaling. We then knocked down TMEM119 expression in U2OS and MG63 cells using small interfering RNA, which revealed that downregulation of TMEM119 could inhibit the proliferation of osteosarcoma cells by inducing cell cycle arrest in G0/G1 phase and apoptosis. We also found that TMEM119 knockdown significantly inhibited cell migration and invasion, and decreased the expression of TGF-β pathway-related factors (BMP2, BMP7 and TGF-β). TGF-β application rescued the inhibitory effects of TMEM119 knockdown on osteosarcoma cell migration and invasion. Further in vitro experiments with a TGF-β inhibitor (SB431542) or BMP inhibitor (dorsomorphin) suggested that TMEM119 significantly promotes cell migration and invasion, partly through TGF-β/BMP signaling. In conclusion, our data support the notion that TMEM119 contributes to the proliferation, migration and invasion of osteosarcoma cells, and functions as an oncogene in osteosarcoma.

Synthesis, and antioxidant, thrombin-inhibitory, and anticancer activities of hydroxybenzamide derivatives

Jin-Rui Wei,Kun Liu,Faquan Lin,Chunping He,Xuan Luo,Jiajia Zou,Wei He,Wenqian Nong,Cui-Wu Lin 한국응용생명화학회 2016 Applied Biological Chemistry (Appl Biol Chem) Vol.59 No.2

Four hydroxybenzamide derivatives were synthesized from protocatechuic acid. The antioxidant activities of these derivatives were evaluated in vitro using DPPH radical scavenging and reducing power assays. In addition, these compounds were subjected to a chromogenic thrombin-inhibitory assay using Chromozym-TH as the substrate. The anticancer effects of these derivatives were also investigated using the MTT assay in three human cancer cell lines. Four derivatives exhibited excellent DPPH radical scavenging activity and redox potential. Their highly inhibitory effect against thrombin may allow them to be utilized as novel micromolecule thrombin inhibitors. Furthermore, four derivatives demonstrated different inhibitory activities in three human cancer cell lines but showed minimal harmful effects on normal HUVEC cells. Therefore, hydroxybenzamide derivatives indicate the superior antioxidant, thrombin-inhibitory, and anticancer activities along with the excellent biocompatibility, which have the potential application in therapeutic interventions and disease prevention of cancer, thrombotic diseases, and aging.

Multivariate Analysis of the Prognosis of 37 Chondrosarcoma Patients

Yang, Zheng-Ming,Tao, Hui-Min,Ye, Zhao-Ming,Li, Wei-Xu,Lin, Nong,Yang, Di-Sheng Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.4

Objective: The current study aimedto screen for possible factors which affect prognosis of chondrosarcoma. Methods: Thirty seven cases were selected and analyzed statistically. The patients received surgical treatment at our hospital between December 2005 and March 2008. All of them had complete follow-up data. The survival rates were calculated by univariate analysis using the Kaplan-Meier method and tested by Log-rank. ${\chi}^2$ or Fisher exact tests were carried out for the numeration data. The significant indexes after univariate analysis were then analyzed by multivariate analysis using COX regression model. Based on the literature, factors of gender, age, disease course, tumor location, Enneking grades, surgical approaches, distant metastasis and local recurrence were examined. Results: Univariate analysis showed that there were significant differences in Enneking grades, surgical approaches and distant metastasis related to the patients' 3-year survival rate after surgery (P<0.001). No significant difference was not found in gender, age, disease course, tumor location or local recurrence (P>0.05). Multivariate analysis showed that Enneking grade (P=0.007) and surgical approaches (P=0.010) were independent factors affecting the prognosis of chondrosarcoma, but distant metastasis was not (P=0.942). Conclusion: Enneking grades, surgical approaches and distant metastasis are risk factors for prognosis of chondrosarcoma, among which the former two are independent factors.