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Ying-Hua Luo,1,* Cheng Wang,2,* Wan-Ting Xu,3,* Yu Zhang,3 Tong Zhang,3 Hui Xue,3 Yan-Nan Li,3 Zhong-Ren Fu,3 Ying Wang,4 Cheng-Hao Jin3– 5 1Department of Grass Science, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, 163319, People’s Republic of China; 2Pharmacy Department, Daqing Oilfield General Hospital, Daqing, 163001, People’s Republic of China; 3Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, People’s Republic of China; 4College of Food Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, People’s Republic of China; 5National Coarse Cereals Engineering Research Center, Daqing, 163319, People’s Republic of China*These authors contributed equally to this workCorrespondence: Cheng-Hao Jin; Ying Wang Email jinchenghao3727@qq.com; wychen156@163.comBackground: 18β-glycyrrhetinic acid (18β-Gly), which is extracted from licorice root, has various pharmacological properties; however, its anti-cancer effects on lung cancer cells have not been fully established.Purpose: In this study, we investigated the underlying molecular mechanisms of 18β-Gly.Results: Our results showed that 18β-Gly had significant cytotoxic effects and no apparent side effects. 18β-Gly induced mitochondria-dependent apoptosis of A549 lung cancer cells. In addition, after treatment with 18β-Gly, intracellular reactive oxygen species (ROS) levels were significantly increased, and G2/M cell cycle arrest and inhibition of cell migration were induced via the mitogen-activated protein kinase (MAPK)/signal transducer and activator of transcription 3 (STAT3)/nuclear factor kappa (NF-κB) signaling pathways. After pretreatment with the ROS scavenger N-acetyl-L-cysteine or MAPK inhibitors, the expression levels of phosphorylated p38 (p-p38), phosphorylated c-Jun N-terminal kinase, inhibitor of nuclear factor kappa B, cleaved caspase-3 (cle-cas-3), cleaved poly (ADP ribose) polymerase (cle-PARP), p-p53, p27, p21, and E-cadherin were decreased; and levels of phosphorylated extracellular signal-regulated kinase, p-STAT3, NF-κB, Bcl-2, cyclin B1, cyclase-dependent kinase 1/2 (CDK1/2), N-cadherin, vimentin, and snail homolog 1 (SNAI 1) were increased. In addition, the percentage of cells in the G2/M phase was decreased, and inhibition of migration was reduced.Conclusion: In summary, 18β-Gly induced apoptosis and G2/M cell cycle arrest and inhibited migration via the ROS/MAPK/STAT3/NF-κB signaling pathways in A549 lung cancer cells. Therefore, 18β-Gly is a novel promising candidate for the treatment of lung cancer.Keywords: 18β-glycyrrhetinic acid, lung cancer, apoptosis, cell cycle arrest, ROS, cell migration

Ya-Nan Sheng,1,* Ying-Hua Luo,2,* Shao-Bin Liu,3,* Wan-Ting Xu,3 Yu Zhang,3 Tong Zhang,3 Hui Xue,3 Wen-Bo Zuo,3 Yan-Nan Li,3 Chang-Yuan Wang,1,4 Cheng-Hao Jin1,3,4 1Department of Food Science and Engineering, College of Food Science, Heilongjiang Bayi Agricultural University, Daqing 163319, People’s Republic of China; 2Department of Grass Science, College of Animal Science & Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, People’s Republic of China; 3Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, People’s Republic of China; 4National Coarse Cereals Engineering Research Center, Daqing 163319, People’s Republic of China*These authors contributed equally to this workCorrespondence: Cheng-Hao Jin; Chang-Yuan WangDepartment of Food Science and Engineering, College of Food Science, Heilongjiang Bayi Agricultural University, Daqing 163319, People’s Republic of ChinaTel +86 13351747387; +86 13836961288Email jinchenghao3727@qq.com; 2633204897@qq.comBackground: Zeaxanthin, a carotenoid commonly found in plants, has a variety of biological functions including anti-cancer activity.Purpose: This study aimed to investigate the potential mechanisms of zeaxanthin in human gastric cancer cells.Methods: CCK-8 assay was used to examine the cytotoxic effect of zeaxanthin on human gastric cancer cells. Flow cytometry was used to analyse AGS cell cycle distribution and apoptosis status. Western blot analysis was used to detect the expression levels of cycle-related proteins (Cyclin A, Cyclin B1, CDK1/2, p21, and p27), apoptosis-related proteins (Bcl-2, Bad, caspase-3, PARP), MAPK, AKT, STAT3, and NF-κB.Results: CCK-8 assay showed that zeaxanthin has obvious cytotoxic effects on 12 types of human gastric cancer cells, but no obvious toxic effect on normal cells. In addition, flow cytometry and Western blotting results showed that zeaxanthin induces apoptosis by reducing mitochondrial membrane potential; increasing Cytochrome C, Bax, cleaved-caspase-3 (cle-cas-3), and cleaved-PARP (cle-PARP) expression levels; and decreasing Bcl-2, pro-caspase-3 (pro-cas-3), and pro-PARP expression levels. Additionally, zeaxanthin caused cell cycle arrest at the G2/M phase by increasing the levels of p21 and p27 and reduced the levels of AKT, Cyclin A, Cyclin B1, and Cyclin-dependent kinase 1/2 (CDK1/2). Furthermore, after zeaxanthin treatment, the expression levels of reactive oxygen species (ROS), p-JNK, p-p38, and I-κB increased, and the expression levels of p-ERK, p-AKT, STAT3, and NF-κB decreased. However, the ROS scavenger N-acetylcysteine (NAC) and MAPK inhibitors inhibited zeaxanthin-induced apoptosis, and under the action of zeaxanthin, MAPK regulated NF-κB and STAT3, and reduced their protein expression levels.Conclusion: Zeaxanthin has a potential effect against gastric cancer cells through the ROS-mediated MAPK, AKT, NF-κB, and STAT3 signaling pathways, and it is expected to become a new drug for the treatment of human gastric cancer.Keywords: zeaxanthin, ROS, gastric cancer, apoptosis, cell cycle arrest

Deng-hua Pan,1 Dong-yue Wen,1 Yi-huan Luo,2 Gang Chen,3 Hong Yang,1 Jun-qiang Chen,2 Yun He1 1Department of Ultrasonography, 2Department of Gastrointestinal Surgery, 3Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China Background: Growing evidence has demonstrated that Ki-67/MIB-1 has an effect on the clinical progression and prognosis in cancers. However, the diagnostic and prognostic values of Ki-67/MIB-1 in thyroid cancer remain unclear.Materials and methods: The meta-analysis was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies were retrieved from PubMed, EBSCO, EMBASE, ISI Web of Science, China National Knowledge Infrastructure, WanFang and Chinese VIP databases. MetaDiSc and STATA12.0 were used to analyze the meta-analysis. Fixed-effect analysis and random-effect analysis were applied to pool the relative ratio based on heterogeneity in this meta-analysis.Results: In the meta-analysis, 51 eligible studies were included. The pooled sensitivity of Ki-67/MIB-1 was 0.61 (95% confidence interval [CI]: 0.59–0.63) and specificity was 0.75 (95% CI: 0.74–0.77) in thyroid cancer. The pooled positive likelihood ratio was 3.19 (95% CI: 2.30–4.42) and negative likelihood ratio was 0.43 (95% CI: 0.35–0.54). In the diagnosis of thyroid cancer, the pooled diagnostic odds ratio of Ki-67/MIB-1 was 8.54 (95% CI: 5.03–14.49). The area under the symmetric receiver operating characteristic curve was 0.804 (standard error =0.031). Our results showed that there were statistical associations between Ki-67/MIB-1 and age (odds ratio [OR] =1.71, 95% CI: 1.14–2.57, P=0.010), tumor size (OR =1.86, 95% CI:1.17–2.96, P=0.008), lymph node metastasis (OR =2.49, 95% CI: 1.42–4.39, P=0.002), metastasis status (OR =6.96, 95% CI: 2.46–19.69, P

Wen-Ting Huang,1,* Han-Lin Wang,1,* Hong Yang,2 Fang-Hui Ren,1 Yi-Huan Luo,1 Chun-Qin Huang,1 Yue-Ya Liang,1 Hai-Wei Liang,1 Gang Chen,1 Yi-Wu Dang1 1Department of Pathology, 2Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China *These authors contributed equally to this work Purpose: To investigate the clinicopathological value and potential roles of microRNA-198 (miR-198) in hepatocellular carcinoma (HCC).Methods: Ninety-five formalin-fixed paraffin-embedded HCC and the para-cancerous liver tissues were gathered. Real-time reverse transcription quantitative polymerase chain reaction was applied to determine the miR-198 expression. The association between the miR-198 expression and clinicopathological features was examined. Meanwhile, potential target messenger RNAs of miR-198 in HCC were obtained from 14 miRNA prediction databases and natural language processing method, in which we pooled the genes related to the tumorigenesis and progression of HCC and classified them by their frequency. The selected target genes were finally analyzed in the Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway.Results: miR-198 expression was significantly lower in HCC than that in adjacent noncancerous liver tissues (1.30±0.72 vs 2.01±0.58, P

Yilin Tang,1,* Sha Han,1,* Tetsuya Asakawa,2,3 Yunhe Luo,1 Xiang Han,1 Baoguo Xiao,4 Qiang Dong,1,4 Liang Wang1,41Department of Neurology, Huashan Hospital of Fudan University, Shanghai, People’s Republic of China; 2Department of Neurosurgery, 3Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan; 4Institute of Neurology, Huashan Hospital of Fudan University, Shanghai, People’s Republic of China*These authors contributed equally tothis workAbstract: The past decade has resulted in an increase in the knowledge of molecular mechanisms underlying brain injury induced by intracerebral hemorrhage (ICH). Recent advances have provided a link between epigenetic modification and the regulation of gene expression. 5-hydroxymethylcytosine (5hmC) converted from 5-methylcytosine by the ten-eleven translocation (TET) family of proteins has emerged as a new epigenetic modification. While the dynamics of 5hmC during cerebral ischemia have recently been reported, whether 5hmC is involved in ICH remains unexplored. In this study, we investigated the effects of ICH on DNA hydroxymethylation. We showed that the global level of 5hmC rapidly decreased as early as 24hours after ICH and persisted until 72hours. Furthermore, the level of 5hmC in the CpG-rich regions of Akt2, Pdpk1 and Vegf genes was significantly decreased with a minimum level observed at 48hours or 72hours. Decreased 5hmC was observed in parallel with an increase in 5-methylcytosine over this time course, and mRNA levels of Akt2, Pdpk1 and Vegf were downregulated upon ICH injury. Finally, Tet1, Tet2 and Tet3 mRNA levels were dramatically decreased in the ICH brain. Our study for the first time established the correlation between DNA hydroxymethylation and ICH injury. Further investigations should examine whether 5hmC modification could be a therapeutic target for the treatment of ICH injury.Keywords: stroke, cerebral edema, DNA hydroxymethylation, TET protein

Jianjun Li,1,* Lu Liang,2,* Yongru Liu,2 Yihuan Luo,2 Xiaona Liang,2 Dianzhong Luo,2 Zhenbo Feng,2 Yiwu Dang,2 Lihua Yang,3 Gang Chen2 1Department of General Surgery, Western Branch, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Pathology, 3Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China *These authors contributed equally to this work Background: Recent studies showed that signal transducer and activator of transcription 4(STAT4) was downregulated in hepatocellular carcinoma (HCC) tissues. However, the role of STAT4 in HCC is still unknown. The aim of this study is to explore the association between STAT4 expression and other clinicopathological features in HCC and to test the effect of STAT4 on cell growth and apoptosis in vitro.Methods: STAT4 was evaluated by immunohistochemistry in 171 HCC and corresponding paraneoplastic liver, 37 cirrhosis, and 33 normal liver tissues. Association between STAT4 and clinicopathological parameters was analyzed. Meta-analysis on STAT4 in cancer was performed. The effect of STAT4 small interfering RNA (siRNA) on cell growth and cell apoptosis was also detected.Results: Positive rate of STAT4 was 29.2% (50/171) in HCC tissues, 53.2% (91/171) in paraneoplastic liver tissues, 64.9% (24/37) in cirrhosis tissues, and 72.7% (24/33) in normal liver tissues. STAT4 was upregulated in younger patients who were female, with single tumor node, early TNM stage, without portal vein tumor embolus, and α-fetoprotein (AFP)-positive tumors compared with the groups comprising older patients, males, and those with multiple tumor nodes, advanced TNM stage, with portal vein tumor embolus, and AFP negative tumors. Meta-analysis showed STAT4 was correlated with TNM stage (OR =0.50, 95% CI =0.30, 0.83, P=0.008) and age (OR =0.58, 95% CI=0.38, 0.95, P=0.032) in malignant tissues, and with AFP level (OR =1.76, 95% CI =1.06, 2.94, P=0.03) in HCC. STAT4 siRNA promoted growth and suppressed apoptosis of HepG2 cells.Conclusion: STAT4 might play a vital role in development of HCC, via influencing cell growth and apoptosis, as a tumor suppressor. Keywords: hepatocellular carcinoma, HCC, signal transducers and activators of transcription 4, STAT4, clinicopathological features, immunohistochemistry, meta-analysis, in vitro