Carcinogenesis, Teratogenesis & Mutagenesis

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Investigations on anti-gastric cancer effects of licorice and dried ginger decoction

YU Yuehua, LIANG Huanxi, XIN Yumeng, SUN Zhenxiao

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (3): 219-226. DOI: 10.3969/j.issn.1004-616x.2022.03.009

Abstract （684）

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OBJECTIVE: Serum pharmacology was used to explore anti-gastric cancer effects of licorice and dried ginger decoction (LDGD) in vitro,and its anti-gastric cancer mechanism was discussed based on network pharmacology and molecular docking. METHODS: After intragastric administrations of LDGD in different proportions to mice,serum samples were extracted by taking blood from abdominal aorta.Effects of the drug containing serum on activities of human gastric cancer cells AGS and human umbilical vein endothelial cells HUVEC in vitro were observed using the MTT method.The "component target" network of LDGD against the gastric cancer cells was constructed by network pharmacology.Key targets of LDGD against the cancer cells were selected by constructing protein-protein interaction network (PPI).Possible biological functions and signal pathways of LDGD against the cancer cells were explored by the GO function and KEGG pathway enrichment analyses.The binding of 8 pharmacodynamic components in LDGD and key anti-gastric cancer targets reported in the literature were analyzed by molecular docking. RESULTS: In the serum pharmacology experiment,30% medicated serum with different proportions of LDGD had significant inhibitory effects on cell viability of AGS but had no significant inhibitory effect on HUVEC.A total of 101 active components of LDGD were obtained,and the key targets of LDGD in the gastric cancer cells were VEGFA,TNF-α,CASP3 and MYC.Bioinformatics enrichment analyses show that LDGD anti-gastric cancer effects may mainly regulate apoptosis signal,oxidative stress and reactive oxygen species response,as well as influence on TNF,p53 and other signal pathways.The results of molecular docking show that glycyrrhizic acid and liquiritin had strong affinity with VEGFA,and 6-gingerol had strong affinity with TNF-α. CONCLUSION: LDGD showed certain antitumor activities on gastric cancer cells.Through network pharmacology and molecular docking,the antitumor activities of LDGD involved regulating oxidative stress and acting on TNF,p53 and other signal pathways.In addition,glycyrrhizic OBJECTIVE: To study effects of Fuzi (aconite) extracts on proliferation and radiosensitization of human lung cancer A549 cells. METHODS: The cells were cultured and were divided into 4 groups:control,Fuzi extract,X-ray-irradiated,and Fuzi plus X-ray-irradiated groups. The control group was given culture medium,the Fuzi extract group was treated with IC₂₀30 μg/mL of Fuzi extract,the radiation group was given X-ray-irradiated,and the Fuzi plus X-ray-irradiated group were first treated with the Fuzi extract and then X-ray. After treatments,cell proliferation was detected by CCK-8 assay and colony formation assay was used to measure cell survival. Single-hit multi-target model was used to fit the survival curve and to calculate the sensitive enhancement ratio (SER). Apoptosis rates were detected by flow cytometry,and protein expression levels of Bax and Bcl-2 were detected by Western blot. RESULTS: Fuzi extract concentrations(<20 μg/mL) enhanced viability of A549 cells but increasing concentrations (>30 μg/mL) inhibited growth of the cells in a dose-dependent manner. The shoulder at the beginning of the survival curve in the Fuzi plus X-ray-irradiated group was slightly narrower, and the D₀values in the X-ray-irradiated and Fuzi plus X-ray-irradiated group were 1.83 Gy,1.48 Gy,and the SER was 1.24,respectively. The apoptosis rates were significantly increased in the Fuzi plus X-ray-irradiated group and were higher than that in both the Fuzi and X-ray irradiation groups (P<0.05). The results of Western blot show that protein expressions of Bax were increased but were decreased for Bcl-2 in the Fuzi extract versus the X-ray-irradiated groups. Bax and Bcl-2 protein levels were changed more significantly in the Fuzi plus X-ray-irradiated than the other groups (P<0.01). CONCLUSION: Fuzi extract at 30 μg/mL inhibited proliferation and enhanced radiosensitizing effects on human lung cancer A549 cells,and the mechanism may be related to the induction of apoptosis.

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Carcinogenesis, Teratogenesis & Mutagenesis 2024, 36 (3): 237-243. DOI: 10.3969/j.issn.1004-616x.2024.03.011

Abstract （657）

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Evaluation of a glycerol-induced acute kidney injury model in SD rats

ZHANG Huayun, YU Zhiqiang, YANG Zhiyu, MA Zhongchun

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (6): 455-458. DOI: 10.3969/j.issn.1004-616x.2022.06.009

Abstract （651）

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OBJECTIVE:To explore effects of intramuscular injection of glycerol on kidneys,the main blood storage organ,of rats. METHODS:Twenty-four healthy adult SPF SD rats (half male and half female) were randomly divided into four groups of six rats per group:control and test groups for each sex. After 24 hours of water deprivation,rats were given either normal saline or 50% glycerol normal saline at the dose of 10 mL/kg. After another 24 hours,anesthesia was performed and blood was collected through the abdominal aorta. The kidney,liver and spleen were removed surgically and examined for pathological damage. Urine samples were collected from their metabolic housing and examined for serum biochemistry,blood routine,urine routine and hemagglutination. RESULTS:The results showed that albumin (ALB) and red blood cell (RBC) in the glycerol male and female groups were reduced significantly (P<0.05),while creatinine (Crea),urea nitrogen (Urea),alanine aminotransferase (ALT) and platelet (PLT) were increased significantly (P<0.05). Total protein (TP) and specific gravity of urine (SG) of female animals in the glycerol group were reduced significantly,while aspartate aminotransferase (AST) was increased significantly (P<0.05). Pathological results showed that the renal tubules in the experimental groups were dilated,including clear tube type and protein tube type. The hepatic sinuses were dilated and the renal injury was the most obvious. CONCLUSION:Intramuscular injection of glycerol not only caused kidney damage,but also caused slight liver damage. In this glycerol-induced acute renal injury model,the degree of renal injury in male rats was lower than that in female rats.

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Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (3): 233-236. DOI: 10.3969/j.issn.1004-616x.2022.03.011

Abstract （607）

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JIANG Xiaoyan, YAN Dong, HE Yingxue, FAN Li, LIANG Chenqing

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (3): 237-241. DOI: 10.3969/j.issn.1004-616x.2022.03.012

Abstract （606）

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Application of an artificial intelligence-assisted system in cytological diagnosis of cervical lesions

GUO Xiao, LIU Ying, WANG Rui, LIAN Yali, DU Yun

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (5): 361-365. DOI: 10.3969/j.issn.1004-616x.2022.05.005

Abstract （581）

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OBJECTIVE: To analyze the application effects of artificial intelligence (AI) in cytological diagnosis of cervical lesions.METHODS: 2 719 cervical TCT specimens were collected.AI-assisted and manual diagnoses were performed on all specimens to compare their consistency.Histopathological results were used as the gold standard.The accuracy,sensitivity,specificity and area under ROC curve of AI-assisted diagnosis and manual diagnosis were compared.RESULTS: The results of AI-assisted cytological grading diagnosis were basically consistent with results of manual diagnosis.AI-assisted diagnosis of low-grade lesions and inflammation was more accurate than manual radiography (P<0.01).In the diagnosis of high-grade lesions and cancer,the sensitivity of AI diagnosis was 82.1%,higher than 48.3% of manual diagnosis.The specificity of AI diagnosis was 94.3%,slightly lower than 95.0% of manual diagnosis.The area under ROC curve of AIassisted diagnosis (AUC=0.882) was larger than that of manual diagnosis (AUC=0.717),and the difference was statistically significant (P<0.01).CONCLUSION: AI-assisted diagnosis showed high accuracy in the diagnosis of cervical cancer,which should improve the coverage rate and the quality of cervical cancer screening in the general population.

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A mechanistic study on irisin-mediated anti-inflammatory and antioxidant effects in cells

TU Yongmei, YU Weihua, PENG Jie, LIU Jiangzheng, LIU Rui, WU Hao, KONG Deqin, HE Gaihua, LI Wenli, WANG Chong

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (4): 247-254,261. DOI: 10.3969/j.issn.1004-616x.2022.04.001

Abstract （554）

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OBJECTIVE: To investigate mechanisms of antioxidant and anti-inflammatory effects mediated by Irisin in mouse macrophages RAW264.7. METHODS: RAW264.7 cells were treated with 200 ng/mL Irisin for 0, 24 and 48 h. Real-time PCR was used to detect mRNA expressions of anti-inflammatory factors (IL-10,Arg-1,and CD206),antioxidant genes (HO-1 and SOD2) and PPAR-γ. ELISA assay was used to detect IL-10, Arg-1 in cell supernatants. Commercial kits were used to determine antioxidant enzyme activities,and Western-blot and immunofluorescence to detect Nrf2 and PPAR-γ expression and localization. Furthermore, after 24 h with 100 ng/mL LPS stimulation of RAW264.7 and 4 h 200 ng/mL Irisin pretreatment, real-time PCR was used to detect pro-inflammatory cytokines. DCFH-DA and Mito-LX were used to detect ROS levels. PPAR-γ inhibitor T0070907 (30 μmol/mL) was pretreated for 4 h and 200 ng/mL Irisin for 24 h, real-time PCR was used to detect expressions of anti-inflammatory cytokines. RESULTS: Compared with the untreated cells,Irisin promoted the expression and release of anti-inflammatory factors such as IL-10, Arg-1 and CD206 (P<0.05). However, Irisin inhibited LPS-induced TNF-α and IL-6 mRNA expression (P<0.05), which indicated that Irisin has anti-inflammatory effects. In addition, Nrf2 nuclear translocation occurred after irisin treatment in RAW264.7 cells. Expressions and enzyme activities of HO-1 and SOD2 were significantly enhanced, and the contents of GSH increased (P<0.05). In response to Irisin stimulation, PPAR-γ expression was elevated and underwent nuclear translocation, while PPAR-γ inhibitor T0070907 blocked the Irisin-induced anti-inflammatory response (P<0.05). CONCLUSION: Irisin initiated macrophage M2-type polarization and anti-inflammatory responses through enhancement of PPAR-γ-related anti-inflammatory genes and Nrf2-related antioxidant enzymes. Therefore,Irisin may be a candidate drug for inflammation-related diseases.

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Effects of Mito-TEMPO treatment on nitrogen mustard-induced cytotoxicity in BEAS-2B cells

ZHAO Chenqian, XU Anqi, AI Duo, KONG Deqin, ZHANG Xiaodi, LI Wenli, HAI Chunxu, LIU Jiangzheng

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (3): 161-168. DOI: 10.3969/j.issn.1004-616x.2022.03.001

Abstract （550）

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OBJECTIVE: To investigate effects of mitochondrial-targeted antioxidant Mito-TEMPO on cytotoxicity which was induced by nitrogen mustard(HN2) in the human bronchial epithelial cell line BEAS-2B cells. METHODS: BEAS-2B cells were divided into four groups:normal control,Mito-TEMPO control,HN2exposure and Mito-TEMPO intervention groups. The two control groups were treated with serum-free medium containing DMSO(0.1%) or Mito-TEMPO(100 μmol/L) for 26 h,respectively. The HN2 exposure group was pretreated with DMSO-containing serum-free medium for 2 h,and then with HN2(8 μmol/L) for 24 h. The Mito-TEMPO intervention group was pretreated with Mito-TEMPO(100 μmol/L) for 2 h,and then co-treated with HN2(8 μmol/L) and Mito-TEMPO(100 μmol/L) for 24 h. Cell viability was detected by CCK-8 method,LDH activity in cell culture medium supernatant was detected by rate method,cell morphology was observed by inverted microscope,cell apoptosis was detected by Annexin V/PI probe method using flow cytometry,and mitochondrial membrane potential was detected by JC-1 probe. UV spectrophotometry were used to detect thecontent of ATP in cell homogenate. MitoSOX,DCFH-DA and DHE probe were used to detect the level ofmitochondrial ROS(reactive oxygen species), intracellular H2O2and intracellular total ROS respectively.RT-PCR was used to detect the mRNA expression levels of inflammatory factor TNFα and IL-6. RESULTS: Compared with the nitrogen mustard exposure group,the cell viability of the Mito-TEMPO intervention groupdecreased by about 42.6%(P<0.05),and the LDH level in the cell supernatant increased by about 73.5%(P<0.05), accompanied by increase of abnormal cell morphology. Compared with the HN2 exposure group, theMito-TEMPO intervention group showed the level of mitochondrial ROS decreased by 53.6%(P<0.05),and thelevel of intracellular H2O2and total ROS increased by 171%(P<0.05) and 43.4%(P<0.05) respectively.Mito-TEMPO intervention had no significant effects on changes of apoptosis ratio, mitochondrial membranepotential, ATP content, TNF-α and IL-6 mRNA expression levels caused by HN2 exposure(P>0.05). CONCLUSION: 100 μmol/L Mito-TEMPO intervention significantly promoted cell damage in the HN2exposure BEAS-2B cell model, and the mechanisms might be related to increase of intracellular H2O2andtotal ROS levels.

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Carcinogenesis, Teratogenesis & Mutagenesis 2024, 36 (3): 248-252. DOI: 10.3969/j.issn.1004-616x.2024.03.013

Abstract （529）

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Carcinogenesis, Teratogenesis & Mutagenesis 2023, 35 (2): 148-153. DOI: 10.3969/j.issn.1004-616x.2023.02.012

Abstract （505）

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Effects of four chemicals on the expression of oxidative stress-related genes in HaCaT cells

DUAN Huijuan, SUN Zhaogang, HAO Weidong, WEI Xuetao, CHU Hongqian

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (3): 192-199,205. DOI: 10.3969/j.issn.1004-616x.2022.03.005

Abstract （462）

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OBJECTIVE: To investigate effects of hydrogen peroxide,curcumin,quercetin and tert-butyl hydroquinone(tBHQ) on expressions of 84 oxidative stress-related genes. METHODS: HaCaT cells in logarithmic growth phase were used,and different concentrations of hydrogen peroxide,curcumin,quercetin and tert-butyl hydroquinone were applied.The concentrations were:hydrogen peroxide (0.5 and 1.25 mmol/L),curcumin (5 and 20μmol/L),quercetin (200 and 500μmol/L) and tert-butyl hydroquinone (10 and 50μmol/L) for 4 h and 24 h,respectively.Cytotoxicity of the test substances were evaluated by tetramethylthiazole blue (MTT).RNA samples were extracted and their qualities were evaluated.Then,expression levels of 84 oxidative stress-related genes in HaCaT cells were detected by quantitative real-time PCR (qPCR). RESULTS: MTT assay showed that the survival rate of HaCaT cells was less than 80% when the concentrations of hydrogen peroxide,curcumin and tert-butyl hydroquinone were>1 mmol/L,>10μmol/L and>50μmol/L,respectively.Quercetin did not show obvious cytotoxicity at the concentration of 1 000μmol/L.Resultsof qPCR showed that the four chemicals affected expressions of oxidative stress-related genes in HaCaT cells at different concentrations and at different times.The expression levels of some oxidative stress-related genes were increased,and otherswere decreased.Hydrogen peroxide increased expression of HMOX1,SPINK1 (1.25 mmol/L,4 h) but reduced that of CCL5 (1.25 mmol/L,24 h).Curcumin increased HMOX1,ALB (20μmol/L,4 h)expression but reduce that of GSR (20μmol/L,4 h) and other genes.Quercetin increased ALB,HMOX1 (500μmol/L,4 h) expressions but reduced expression of SEPP1 (500μmol/L,4 h).tert-butyl hydroquinone increased expression of EPX,HMOX1 (10μmol/L,4 h) but reduced that of AOX1 (10μmol/L,24 h),etc. CONCLUSION: Exposure to hydrogen peroxide,curcumin,quercetin and tert-butyl hydroquinone caused changes in expression of oxidative stress-related genes,especially increased expression the HMOX1 gene.Moreover,higher concentrations of the chemicals caused more changes than lower doses.

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Pharmacokinetic study of nano-cationic liposomes loaded with siRNA in mice

WEN Tianjiao, CHEN Xinran, BAI Jing, ZHENG Ying, WANG Yajuan, YU Peipei, CUI Jingxia

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (6): 445-448,462. DOI: 10.3969/j.issn.1004-616x.2022.06.007

Abstract （461）

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OBJECTIVE:To investigate pharmacokinetics siRNA drugs in vivo and to analyze advantages of liposomes as drug carriers. METHODS:A previously constructed siRNA expression plasmid was loaded into nano-invisible cationic liposomes and used for investigations:bare siRNA plasmid group and siRNA plasmid liposomes group. DNase I digestion and serum stability were evaluated. Then,20 μg bare plasmid siRNA and liposome siRNA plasmid were injected into mice through their tail veins,and blood samples were collected at 0 min,5 min,15 min,30 min,1 h,2 h,4 h,12 h,and 24 h,respectively. Quantitative real-time PCR (qPCR) was used to quantitatively detect liposomes in mice,and the concentrations of siRNA plasmid at each time point was calculated. RESULTS:The bare plasmids were completely degraded in DNaseⅠwithin 20 min,and the degradation of plasmid liposomes was slow,with (20.16±2.47)% DNA remaining at 24 h. The bare plasmid only remained (11.03±0.92)% at 20 min in 80% serum,and was basically degraded at 1 h. The plasmid liposomes remained (10.26±1.04)% at 24 h in 80% serum. The stability of siRNA expression plasmid in DNaseⅠand serum was significantly improved by using liposomes as a carrier (P<0.05). The half-life of liposomal encapsulated plasmids in mice was about 2 h,while that of naked plasmids was only 6 min,and the difference was statistically significant (P<0.05). CONCLUSION:In vivo detection of siRNA liposomes can be accomplished by qPCR. Cationic liposomes can protect nucleic acid drugs inside the body,which is an efficient delivery carrier. At the same time,liposomes can improve stability of drugs in vivo and prolong the action time of drugs.

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Fuzi extracts on proliferation and radiosensitization of lung cancer A549 cells

ZHANG Qi, LIU Yujun, ZHUANG Xibing, QIAO Tiankui

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (3): 227-232. DOI: 10.3969/j.issn.1004-616x.2022.03.010

Abstract （457）

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OBJECTIVE: To study effects of Fuzi (aconite) extracts on proliferation and radiosensitization of human lung cancer A549 cells. METHODS: The cells were cultured and were divided into 4 groups:control,Fuzi extract,X-ray-irradiated,and Fuzi plus X-ray-irradiated groups. The control group was given culture medium,the Fuzi extract group was treated with IC₂₀ 30 μg/mL of Fuzi extract,the radiation group was given X-ray-irradiated,and the Fuzi plus X-ray-irradiated group were first treated with the Fuzi extract and then X-ray. After treatments,cell proliferation was detected by CCK-8 assay and colony formation assay was used to measure cell survival. Single-hit multi-target model was used to fit the survival curve and to calculate the sensitive enhancement ratio (SER). Apoptosis rates were detected by flow cytometry,and protein expression levels of Bax and Bcl-2 were detected by Western blot. RESULTS: Fuzi extract concentrations(<20 μg/mL) enhanced viability of A549 cells but increasing concentrations (>30 μg/mL) inhibited growth of the cells in a dose-dependent manner. The shoulder at the beginning of the survival curve in the Fuzi plus X-ray-irradiated group was slightly narrower, and the D₀values in the X-ray-irradiated and Fuzi plus X-ray-irradiated group were 1.83 Gy,1.48 Gy,and the SER was 1.24,respectively. The apoptosis rates were significantly increased in the Fuzi plus X-ray-irradiated group and were higher than that in both the Fuzi and X-ray irradiation groups (P<0.05). The results of Western blot show that protein expressions of Bax were increased but were decreased for Bcl-2 in the Fuzi extract versus the X-ray-irradiated groups. Bax and Bcl-2 protein levels were changed more significantly in the Fuzi plus X-ray-irradiated than the other groups (P<0.01). CONCLUSION: Fuzi extract at 30 μg/mL inhibited proliferation and enhanced radiosensitizing effects on human lung cancer A549 cells,and the mechanism may be related to the induction of apoptosis.

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Predictive values of preoperative laboratory indices dNLR, SII and CRP/ALB on recurrences and metastases in breast cancer patient

WANG Xujuan, LUO Yongxin, LI Chenqiang, WANG Rujin, ZHENG Tingting

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (4): 284-288,323. DOI: 10.3969/j.issn.1004-616x.2022.04.007

Abstract （451）

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OBJECTIVE: To study predictive values of preoperative laboratory indexes[derived neutrophil to lymphocyte ratio (dNLR),systemic immune inflammatory index (SII),and C-reactive protein (CRP)/albumin (ALB)] on recurrences and metastases in breast cancer patients. METHODS: The patients who received surgical treatment and diagnosed with breast cancer by postoperative pathology in Sichuan Neijiang Second People's Hospital from April 2016 to April 2019 were selected as the research objects. Their clinical and pathological data, followed-up recurrences and metastases and disease-free survival times was collected. The Kaplan Meier curve of disease-free survival was drawn. Relationships between different clinicopathological data and disease-free survival were analyzed by log-rank test. Influencing factors of disease-free survival were analyzed by COX regression model. Predictive values of different indices on disease-free survival were analyzed using ROC curve. RESULTS: Log rank test of Kaplan-Meier curve of disease-free survival showed that the cumulative disease-free survival rates of breast patients with different tumor stage, lymph node metastasis, neutrophils to lymphocyte ratio,platelet to lymphocyte ratio,lymphocyte to monocyte ratio,dNLR,SII,and CRP/ALB were statistically different (log-rank χ²=12.020,5.332,3.923,4.948,15.340,22.970,5.496,all P< 0.05). COX regression model analyses showed that AJCC stage,dNLR,SII,CRP/ALB were the influencing factors of disease-free survival of breast cancer patients (P<0.05). ROC curve analyses showed that dNLR,SII and CRP/ALB alone had predictive values for disease free survival. Regression equations of dNLR,SII and CRP/ALB were obtained in the logistic model, which could be used as a combined index to predict disease-free survival of breast cancer patients. CONCLUSION: Laboratory indices dNLR,SII and CRP/ALB were related to postoperative recurrences and metastases of breast cancers. The combination of the three indices can provide a basis for prognosis evaluations.

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DNAJB6b enhanced invasion and migration abilities of colorectal cancer cells by activating the AKT pathway

CHEN Dingxiong, ZHU Yiqing, SHI Jianhong, CAI Yan, HAO Jiajie, WANG Mingrong, LIANG Jianwei, ZHANG Yu

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (3): 178-183. DOI: 10.3969/j.issn.1004-616x.2022.03.003

Abstract （438）

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OBJECTIVE: To investigate effects from over-expression of DnaJ heat shock protein family member B6 isoform b (DNAJB6b) on invasive and migration abilities of colorectal cancer (CRC) cells. METHODS: Expressions of DNAJB6b in cultured CRC cell lines DLD-1 and HCT116 were knocked down with small interfering RNA (siRNA) and short hairpin RNA (shRNA),respectively.Control cells were transfected with negative control siRNA and shRNA.Changes in protein levels were detected by Western blot.Changes of DNAJB6a and DNAJB6b mRNA levels in CRC specimens were statistically analyzed using the GEO dataset.DLD-1 and HCT116 cells were treated with PI3K/mTOR dual inhibitor BEZ235 and control cells were treated with solvents.Then,transwell invasion and migration assays were performed and the number of transmembrane cells were counted.Constitutively activated AKT (myr-Akt) was transiently-transfected into DNAJB6b stably-depleted DLD-1 and HCT116 cells (Referred as DLD-1-shD6b,HCT116-shD6b in this paper) and the controls were transfected with the empty vector.The rescue assay were conducted,changes in protein expression levels were detected by Western blot,and levels of cell invasion and migration were evaluated by Transwell assays. RESULTS: Compared with adjacent normal tissues,mRNA expressions of DNAJB6b but not DNAJB6a were significantly up-regulated in the CRC tissues (P<0.05).DNAJB6b depletion markedly reduced the p-Akt (Ser473) protein levels in DLD-1 and HCT116 cells compared with the control groups.The numbers of transmembrane cells treated by BEZ235 were significantly reduced compared to only about 20% of the control group (P<0.01).Resultsfrom the rescue assay showed that enforced expression of exogenous myr-Akt in DLD-1-shD6b and HCT116-shD6b cells up-regulated the p-Akt (Ser473) levels and prominently reversed the decreased number of transmembrane cells caused by DNAJB6b knockdown (P<0.01). CONCLUSION: DNAJB6b was up-regulated in CRC tissues,and its overexpression enhanced the invasion and migration abilities of CRC cells by activating the AKT pathway.Our observations suggest that these abnormal expressions played an oncogenic role in the development of CRC.

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Expression of melanoma-associated antigen A gene family in breast cancer and its clinical significance

FAN Xiaojie, LI Qingjing, GU Lina, SANG Meixiang, SHAN Baoen

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (3): 184-191. DOI: 10.3969/j.issn.1004-616x.2022.03.004

Abstract （438）

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OBJECTIVE: To investigate expressions of melanoma-associated antigen A family (MAGE-As)in peripheral blood and cancer tissues from breast cancer patients,and to analyze their relationships with clinical parameters. METHODS: Expression levels of MAGE-As mRNA in peripheral blood of 106 breast cancer patients and 30 healthy controls were detected by multi-nested PCR,and expression levels of MAGE-A1,A2,A3,A4 and A6 were identified by restriction endonuclease digestion method.Expressions of MAGE-As protein in paraffin-embedded tissues of cancer tissues were detected by immunohistochemistry.Correlations between expressions of MAGE-As mRNA in peripheral blood and of MAGE-As protein in corresponding tumor tissues were analyzed. RESULTS: Positive expression rate of MAGE-As mRNA in the blood samples from patients was 40.5%(43/106).Expression rates of MAGE-A1,A2,A3,A4 and A6 were 10.3%(11/106),19.8%(21/106),15.1%(16/106),13.2%(14/106) and 5.7%(6/106),respectively.The sequence of MAGE-As gene expressions was A2>A3>A4>A1>A6.The MAGE-As mRNA expression was positively correlated with age,tumor size,clinical stage and lymph node metastasis (P<0.05).Expressions of MAGE-As mRNA in blood samples of patients were positively correlated with expression of MAGE-As protein in corresponding tumor tissues (r=0.368,P<0.01).Positive expressions of MAGE-As subtypes (MAGE-A1,A2,A3,A4 and A6)were correlated with 5-year survival rates of breast cancer patients (P<0.01).MAGE-As expression and lymph node metastasis were independent prognostic factors for 5-year survival of these patients (all P<0.01). CONCLUSION: MAGE-As may be a specific biomarker for detection of circulating tumor cells in peripheral blood of breast cancer patients,and its expression was correlated with the prognosis of these patients.MAGE-As in peripheral blood of breast cancer patients may be useful as an important biomarker to monitor prognosis of breast cancer.

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Screening of plasma exosome microRNAs in patients with lung cancer

LIU Xia, GAO Zibo, DING Lihua, WU Yongjun

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (6): 407-412. DOI: 10.3969/j.issn.1004-616x.2022.06.001

Abstract （438）

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OBJECTIVE:Existence of miRNAs in plasma exosomes of lung cancer patients were screened to develop new methods for the screening and auxiliary diagnosis of lung cancers. METHODS:Plasma samples were collected from 6 lung cancer patients (3 adenocarcinomas,2 squamous carcinomas and 1 small cell lung cancer) and 4 healthy controls. Agilent Bioanalyzer was used for qualitative inspection of the extracted RNA. Plasma exosomal miRNA was analyzed by high-throughput sequencing. Target gene prediction was performed by TargetScan,PITA and miRNAorg database,and R software was applied for KEGG and GO analysis of target genes. RESULTS:The exosomal differential miRNA expression analyses showed that 142 miRNAs were expressed abnormally in the lung cancer group compared with to the normal group,with 62 miRNAs up-regulated and 80 miRNAs down-regulated. GO analysis showed that these abnormally-expressed (target) genes were mainly involved in DNA-based template transcription,transcriptional regulation and signal transduction,etc. The target KEGG analysis indicated that these target genes were mainly involved in axon guidance signaling pathway,calcium signaling pathway,and actin cytoskeleton regulation. CONCLUSION:Our data suggest that differentially expressed miRNAs may have good predictive potential for lung cancer metastasis. In addition,they may be candidate biomarkers for the screening and diagnosis of lung cancers.

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Down-expression of CENP-T and variation of its promoter region in BRCA

BI Jiaxin, WANG Xiaoxue, ZHAO Ruohan, HAN Xu, SONG Jie

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (5): 327-334. DOI: 10.3969/j.issn.1004-616x.2022.05.001

Abstract （434）

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OBJECTIVE: To explore expressions and biological functions of CENP-T in breast cancer,and to analyze the mutation and methylation status in gene promoter sequences.METHODS: Expressions of the CENP-T protein in 26 pairs of breast cancer tissues and adjacent normal breast tissues were detected by immunohistochemical method.Tissue genomic DNA was extracted and sequenced to analyze mutation of CENP-T in the promoter region and methylation levels of CpG islands in the promoter region after bisulfite modification.Western blot was used to detect CENP-T protein expression in three cell lines:MCF10A,MCF7 and MDA-MB-231.The MCF7 cell line was constructed by CENP-T siRNA transient transfection,and effects of the interference were evaluated using Western blot.After the knockdown,expressions of CENP-T,and proliferation ability were examined using the MTT and the plate colony formation assays.Cell cycle distribution and apoptosis were testified by flow cytometry.RESULTS: CENP-T protein expressions in the breast cancer group was significantly lower than that in the adjacent normal breast group (P<0.01).Three mutations of C1417T,C1545T and C1628G were detected in the CENT-P promoter region of breast cancer tissues,and the methylation levels were increased by 49.5%.After CENP-T knockdown,proliferation activities of the MCF7 cells were enhanced (P<0.05),colony formation abilities were enhanced (P<0.01),proportions of cells in the G2/M phase were significantly increased (P<0.01),and apoptosis rates were decreased (P<0.01).CONCLUSION: The down-regulation of CENP-T protein levels promoted proliferations of breast cancer cells which were associated with promoter region mutations and increased methylations.These results indicate that the downregulation of CENP-T expression was related to breast cancer risk.

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Carcinogenesis, Teratogenesis & Mutagenesis 2023, 35 (3): 231-235,239. DOI: 10.3969/j.issn.1004-616x.2023.03.014

Abstract （434）

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Carcinogenesis, Teratogenesis & Mutagenesis 2023, 35 (4): 310-315. DOI: 10.3969/j.issn.1004-616x.2023.04.012

Abstract （433）

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A network pharmacologymolecular docking study on mechanisms of Zhenqi Fuzheng granules on colorectal cancerrelated fatigue

CHENG Yanye, XI Wanwan, MAO Xueyang, WEI Tianyi, HU Hairui, LI Zhigang

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (5): 335-343. DOI: 10.3969/j.issn.1004-616x.2022.05.002

Abstract （430）

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OBJECTIVE: To explore mechanisms of Zhenqi Fuzheng granules in the treatment of colorectal cancer-related fatigue.METHODS: The main chemical components of Astragalus membranaceus and Ligustrum lucidum were obtained from the traditional Chinese medicine system pharmacology database and analysis platform (TCMSP),and the active components of Chinese medicine were screened according to ADME.The main targets of colorectal cancer-related fatigue were obtained through databases such as GeneCards and OMIM.The protein interaction analysis was carried out by using String platform,and the protein-protein interaction network (PPI) was constructed.The MCODE plug-in in CytoScape 3.7.2 was used to mine the potential protein function modules in the network.Metascape platform was used to analyze"drugs-componentstargets "and their biological processes and pathways involved,and then Cytoscape 3.7.2 software was used to construct a network of" Zhenqi Fuzheng Granules-colorectal cancer-related fatigue targets-pathways".Finally,the molecular docking was verified by AutoDock Vina1.1.2.RESULTS: The core active components of Zhenqi Fuzheng granules in the treatment of colorectal cancer-related fatigue were quercetin,luteolin,kaempferol,β-sitosterol and stamen isoflavones,and the core targets were AKT1,JUN,MMP9,VEGFA and so on.The results of molecular docking also proved that the above core components had good binding activity to the core targets.The biological pathway of Zhenqi Fuzheng granules in the treatment of colorectal cancer-related fatigue mainly acts on pathways in cancer,PI3K-AKT signaling pathway and so on.CONCLUSION: This study indicated the multi-component,multi-target and multi-pathway characteristics of Zhenqi Fuzheng granules in the treatment of colorectal cancer-related fatigue,and provided a basis for further research on the mechanism and clinical application of Zhenqi Fuzheng granules in the treatment of colorectal cancer-related fatigue.

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Growth inhibition of non-small cell lung cancers by Zaoci decotion in combination with cisplatin and gemcitabine

QI Jiankao, TANG Xiao, SUN Shihui, KOU Yanfang, CUI Zhiqin

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (5): 366-372,403. DOI: 10.3969/j.issn.1004-616x.2022.05.006

Abstract （429）

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OBJECTIVE: To investigate effects from Zaoci decotion in combinations with cisplatin and gemcitadine on growth inhibition of non-small cell lung cancers.METHODS: Fifty SPF-grade BALB/c nude mice were inoculated with A549 cell suspension in the axilla of the right forelimb against the back and used as a non-small cell lung cancer model.After successful modeling,inoculated mice were randomly divided into several groups:model,Zaoci decotion,gemcitabine combined with cisplatin (GP),cisplatin,and Zaoci decotion combined with GP.The model group was gavaged with saline (0.01 mL/g) per day;Zaoci decotion group gavaged with daily saponin soup (1 mL/mouse);GP group intraperitoneal injection with cisplatin (2 mg/kg) and gemcitabine (50 mg/kg) once every 3 days;cisplatin group intraperitoneal injection with cisplatin (2 mg/kg) for 1 time every 3 days;Zaoci decotion combined with GP regimen group daily gavage with Zaoci decotion (1 mL/mouse) and intraperitoneal injection with cisplatin (2 mg/kg) and gemcitabine (50 mg/kg) every 3 days.A total of 21 d of treatment was administered to each group.Tumor diameters were measured by vernier calipers at 3 d,7 d,14 d and 21 d of administrations;their weights were recorded after execution of the mice;tumor cell apoptoses were observed by TUNEL staining;tumor tissue Ki67,CD31,α-SMA and VEGF expressions were detected by immunohistochemistry;serum IL-4,IL-6 and TNF-α concentrations were detected by ELISA;tumor tissue Bax,Bcl-2 and Caspase-3 protein expressions were detected by Western blot.RESULTS: On the 21st day of administration,compared with the model group,tumor volumes and tumor weights in the Zaoci decotion,GP,cisplatin,and Zaoci decotion combined with GP groups were reduced significantly.The tumor volumes and tumor weights of the Zaoci decotion combined with GP group were the smallest (P<0.05).The apoptosis rates,Bax and Caspase-3 protein expressions were significantly higher,and Ki67 and Bcl-2 protein expressions were significantly lower in the Zaoci decotion combined with GP compared with the model group,the Zaoci decotion,the GP,and the cisplatin groups (P<0.05).Compared with the model group,the Zaoci decotion and the GP groups showed significantly lower IL-6 and TNF-α contents,and expressions of CD31,α-SMA and VEGF proteins (P<0.05).The contents of IL-4 were significantly higher in the Zaoci decotion combined with GP group (P<0.05).CONCLUSION: Zaoci decotion showed significant enhancing effects on the growth inhibition of non-small cell lung cancer by cisplatin combined with gemcitabine.The mechanism may be related to the inhibition of angiogenesis and induction of apoptosis.

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Effects of fluoride and arsenic alone and combined exposures on nephrotoxicity and autophagy in offspring rats

TIAN Xiaolin, YANG Lingling, ZHAO Qian, CHOU Yulan, SUN Zilong, NIU Ruiyan, YAN Xiaoyan

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (3): 169-177. DOI: 10.3969/j.issn.1004-616x.2022.03.002

Abstract （427）

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OBJECTIVE: To evaluate toxicity from chronic fluoride and arsenic exposures to kidneys during pregnancy through adulthood in rats,and to explore the potential regulatory mechanisms. METHODS: Rats were divided into four groups:control (distilled water),fluoride exposure (100 mg/L sodium fluoride),arsenic exposure (75 mg/L sodium arsenate),and fluoride and arsenic combined exposure (100 mg/L sodium fluoride+75 mg/L sodium arsenic) groups.The methods of exposure were as follows:from the first day of pregnancy to the 21st day after birth,offspring rats were exposed to fluoride and arsenic toxicity through maternal uterus and breast milk respectively.After weaning,exposure through free drinking water up to 120 days through the same method of exposure as the parents.The kidney coefficient was calculated after weighing the fresh kidney tissues of the offspring male rats.Pathological changes of glomerulus and tubules were observed by Masson staining and transmission electron microscopy.Expression intensity and distribution of autophagy-related proteins in glomerulus and tubules were determined by immunofluorescence technique. RESULTS: Compared with the control group,the renal organ coefficient of the arsenic exposure group was significantly increased (P<0.01).The degrees of renal fibrosis were aggravated after alone and combined exposure of fluoride and arsenic,and renal fibrosis was the most obvious in the fluoride exposed group.Hyperplasia of mesangial cells and vacuolation of mitochondria in podocytes were found in all exposed group.Typical autophagosomes in podocytes were found in the arsenic exposed group.Compared with the control group,the expression levels of autophagy related proteins Beclin1,LC3 and p62 in renal tissues were significantly increased after alone and combined exposure of fluoride and arsenic (P<0.05).Fluorescence intensity and fluorescence area of autophagy-related proteins of glomerulus and renal tubules were also markedly increased (P<0.01). CONCLUSION: Alone and combined exposures to fluoride and arsenic from pregnancy to adulthood induced toxic damage to glomerulus and tubules in renal tissues.Moreover,autophagy of kidney was associated with increasing expressions of autophagy related proteins Beclin1,LC3 and p62.

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A case-control study on expression of miR-101 cluster and risk of esophageal carcinomas

WANG Ting, ZHANG Wenwen, ZHANG Yongxin, ZENG Yong, WANG Junling, LI Chengyun

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (4): 273-278. DOI: 10.3969/j.issn.1004-616x.2022.04.005

Abstract （424）

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OBJECTIVE: To investigate relationships between expression of miR-101 gene cluster and risk of esophageal cancer. METHODS: Expression levels of the miR-101 gene cluster was analyzed using high-throughput detection miRNA gene chips and was verified using esophageal cancer RNA sequencing data in the cancer genome atlas (TCGA) database. In addition,total RNA was extracted from 33 patients' esophageal cancer tissues and adjacent tissues. These RNA samples were used to detect expression of the miR-101 gene cluster using real-time fluorescent quantitative PCR (qPCR). Relationships between abnormal expression of miRNA and risk of esophageal cancer were analyzed by logistic regression. The diagnostic efficacy of miR-101 gene cluster on esophageal cancer was evaluated using receiver operator characteristics curve (ROC). The Fisher test was used to analyze correlations between expression of miRNA in gene cluster and clinicopathological factors in the patients. RESULTS: High-throughput detection of miRNA chip and bioinformatics analyses of TCGA database showed that the expressions of mir-101-3p, mir-125a-5p and mir-145-5p were down regulated in esophageal carcinomas compared with normal esophageal tissues (P<0.05). qPCR results showed that expressions of the miR-101 gene cluster were low in esophageal cancers. Multivariate logistic regression analyses showed that expression levels of mir-101-3p, mir-127-5p and mir- 145-5p were negatively correlated with the risk of esophageal cancer[OR values were 0.717 (0.563,0.912),0.717 (0.534,0.962) and 0.597 (0.426,0.838),P< 0.05]. ROC analyses showed that AUCs of the miR-101 gene cluster was 0.753, 0.792, 0.763 and 0.800, respectively (P<0.05). In addition,expression levels of mir-101-3p and mir-145-5p were correlated with tumor size (P<0.05),and that of mir-125a-5p were correlated with lymph node metastasis (P<0.05). CONCLUSION: Expression of the miR-101 gene cluster was low in esophageal cancer tissues compared to adjacent normal tissues. The expressions can be used as dpotential biomarker for the diagnosis of esophageal cancer but their functions and regulatory mechanisms in the cancer process need to be further studied.

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Impact of CD68 macrophage infiltration on prognosis in primary small cell esophageal carcinoma

ZHANG Yuling, LIU Ditian, CHEN Chunfa

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (4): 279-283. DOI: 10.3969/j.issn.1004-616x.2022.04.006

Abstract （416）

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OBJECTIVE: To investigate infiltrations of different subtypes of tumor-associated macrophages in primary esophageal small cell carcinomas (PESC),and their relationships with clinico-pathological parameters and prognosis. METHODS: Clinico-pathological data of PESC from January 2000 to December 2019 in Cancer Hospital of the Shantou University Medical College were analyzed retrospectively. Infiltrations of the CD68 and CD163 macrophages were evaluated by immunohistochemistry. The Chi-square and Fisher's exact tests were used to evaluate their relationships with the clinico-pathological indices. Furthermore,Kaplan-meier and Multivariate Cox regression were used to analyze prognosis for PESC. RESULTS: CD68- and CD163-stained macrophages were located in cytoplasmic or membrane of tumor cells. CD68 macrophage infiltrations,specifically,were correlated with tumor T stages (χ²=6.336,r=-0.303,P=0.012). However,the infiltrations showed no association with the other clinico-pathological variables. Kaplan-meier analyses showed that the pTNM stage, number of surgical lymph node dissection, N stage, adjuvant chemotherapy and infiltration were associated with overall survival (P<0.05). Multivariate Cox regression analyses showed that pTNM stage, the number of lymph node dissection and the infiltration were independent prognostic factors. High infiltrations were significantly associated with overall survival compared with low infiltrations (Hazard ratio=0.340, 95% confidence interval 0.179-0.645; P=0.001). CONCLUSION: High infiltration of CD68 macrophages,but not CD163,was an independent prognostic factor for patients with PESC. Patients with high infiltrations had significantly favorable prognoses than those with low infiltration of CD68 macrophages.

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Role of IRAK4 in acetaminophen-induced acute liver cell injury

CAI Jiao, KONG Deqin, LONG Zi, PENG Jie, LIU Jiangzheng, LIU Rui, HAI Chunxu

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (4): 255-261. DOI: 10.3969/j.issn.1004-616x.2022.04.002

Abstract （416）

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OBJECTIVE: To investigate the role and mechanism of IRAK4 in acute liver cell injury induced by acetaminophen (APAP). METHODS: Human liver cell line L02 cells were divided into control and treatment groups. The latter were treated with 20 mmol/L APAP for 6,12 and 24 hours. Cell viability was detected by CCK-8 method,apoptosis rates were detected by flow cytometry combined with AnnexinV/PI double staining, mitochondrial changes were detected by MitoSOX and JC-1 fluorescence dye, relative expression levels of IRAK4 were detected by fluorescence quantitative PCR (qPCR) and Western blot,L02 cell viability, and apoptosis and mitochondrial reactive oxygen species (mtROS) were detected after silencing the IRAK4 gene. After treatment with 10 mmol/L N-acetylhemionine (NAC) for 24 hours,L02 cell viability was detected by CCK-8 method,and IRAK4 gene expression level was detected by qPCR. RESULTS: Compared with the control group,cell viabilities were reduced and apoptosis rates were significantly increased after the APAP treatment for 24 h (P<0.05). After 12 and 24 h treatments,the levels of mtROS increased significantly (P<0.05);mitochondrial membrane potential decreased significantly at different time points (P<0.05). qPCR and Western blot results showed that IRAK4 expression increased after treatment for 24 h (P<0.05). After silencing IRAK4 gene,compared with the control and APAP groups,cell viability increased,apoptosis decreased and mtROS decreased (P<0.05). Compared with APAP group,NAC treatment increased cell viability and decreased mRNA expression of IRAK4 gene (P<0.05). CONCLUSION: IRAK4 might be involved in APAP-induced acute liver cell injury and would be a therapeutic target of APAP liver cell injury.

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Analysis of 178 hair dyeing cosmetics using the bacterial reverse mutation assay

JIANG Yi, WU Jianhui, ZHU Suzhen, LI Peining, LIU Xiangmei

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (5): 384-387. DOI: 10.3969/j.issn.1004-616x.2022.05.009

Abstract （409）

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OBJECTIVE: To investigate mutagenic activities of 178 hair dyeing cosmetics using the bacterial reverse mutation test.METHODS: Mutagenicity of 178 hair dyeing cosmetics was detected by referring to the bacterial reverse mutation assay method in "Safety and Technical Standards for Cosmetics" (2015 edition).RESULTS: Among the 178 hair dyeing cosmetics,the positive rate of bacterial reverse mutation assay was 19.67%(35/178) with S₉ added;the positive rate was 3.93%(7/178) without S₉.Among the 35 mutagenic hair dye,35 were positive for TA98,and 34 and 31 were positive for 5 and 10 mg/dish with S₉ added.Without S₉,the number of positive tests at 2.5 and 5 mg/dish was 7 and 5,respectively.The number of positive detections of TA97a was 15.Under the condition of adding S₉,the number of positive detections at 5,10,and 20 mg/dish were 7,14,and 8,respectively.CONCLUSION: Among the 178 hair dyeing cosmetics,the numbers of positive detections of TA98 and TA97a were relatively large,and the positive doses mostly appeared in the 10 mg/dish,5 mg/dish (+S₉),and 2.5 mg/dish (-S₉).

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The related mechanism of morin in lipopolysaccharide induced acute lung injury

YU Jing, FENG Dandan, PAN Wensen

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (3): 213-218. DOI: 10.3969/j.issn.1004-616x.2022.03.008

Abstract （407）

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OBJECTIVE： To investigate mechanisms of morin in lipopolysaccharide (LPS)-induced acute lung injuries (ALI). METHODS： The ALI model was established by in vivo experiments in male C57BL/6 mice which were divided into four groups：control (saline)，LPS-treated ALI，LPS+morin (25 mg/kg)，and LPS+morin (50 mg/kg) groups. LPS (6 mg/kg) solution was instilled into the airways of mice through the trachea to stimulate bronchial and lung tissues after 3 days of intraperitoneal injection of morin solution at a concentration of 25 mg/kg or 50 mg/kg. Both lungs were harvested from each mouse. Some lung tissues were stained with HE and the others for measurements of ratio of lung wet mass to dry mass，and histopathological observations were conducted. Real-time quantitative PCR (qPCR) and Western blot were used to detect expressions of oxidative stress signaling pathway-related genes (NOX1，NOX4，Nrf2 and HO-1) in lung tissues. RESULTS： Compared with the control group，HE staining and the ratio of lung wet mass to dry mass showed that airway instillation of LPS successfully established a mouse model of acute lung injury，and morin can effectively alleviate the LPS-induced injury. The results of qPCR and Western blot experiments showed that expressions of Nrf2 and HO-1 were up-regulated in the lung tissue of the LPS-stimulated ALI model group (P<00.01)，compared with the control group. Morin treatment significantly reduced the expressions of NOX1 and NOX4 (P<00.05 or P<00.01). Furthermore， and morin treatment up-regulated expressions of Nrf2 and HO-1 to inhibit the occurrence of oxidative stress (P<00.05 or P<00.01)，compared with the ALI model group. CONCLUSION： Oxidative stress was involved with the occurrence and development of ALI. In addition，the Nrf2-HO-1 signaling pathway reduced the expression of NOX1 and NOX4 through the activation of morin，and inhibit oxidative stress，thereby slowing the alveolar edema and lung tissue fibrosis caused by LPS.

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Safety evaluation of glutathione with vitamin C tablets

LING Min, SHI Weiqing, ZHANG Wei, LIANG Jie

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (6): 467-470,575. DOI: 10.3969/j.issn.1004-616x.2022.06.012

Abstract （406）

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OBJECTIVE:Safety of glutathione with vitamin C tablets was preliminarily evaluated by feeding rats with the tablets for 30 days. METHODS:Glutathione with vitamin C tablets were given 417,834,1667 mg/kg (equivalent to 25,50,100 times of the recommended dose in human) to rats for 30 days. General activities of rats were observed every day,and their body weights and food intakes were recorded every week. After 30 days,serum biochemical and hematological indexes were detected. The main organs such as liver,kidney,spleen,stomach,testis were weighed and organ coefficients were calculated,and histopatho-logical examination was performed. RESULTS:During the test,the rats were generally in good condition. Compared with the control group,the body weights of rats in the test group were not significantly abnormal (P>0.05). Results of hematology and blood biochemical indexes were within the normal range (P>0.05). There was no significant difference in organ coefficients (P>0.05) and no obvious pathological changes were found in the organs of the high-dose group. CONCLUSION:Under the experimental conditions,glutathione with vitamin C tablets had no harmful effects in rats.

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Occurrence of the TMPRSS2::ETS fusion gene in Chinese patients with prostate cancer: a meta-analysis

ZHANG Jiawei, YUAN Qin, XU Xianrong, FANG Xuexian, CAO Yifei, YANG Jun

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (5): 344-352. DOI: 10.3969/j.issn.1004-616x.2022.05.003

Abstract （404）

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OBJECTIVE: To use meta-analysis for assessing the occurrence of TMPRSS2::ERG fusion gene in Chinese patients with prostate cancer.METHODS: A systematic search was conducted through PubMed,Web of Science,Google Scholar,China knowledge Resource Database (CNKI),Wanfang Medical online Database and VIP Database.The risk of bias was assessed using QUADAS-2 and a meta-analysis was performed using Stata12.0 and Review Manager 5.3 to evaluate the occurrence of TMPRSS2::ERG fusion gene in Chinese prostate cancer patients.RESULTS: A total of 16 articles were included.The incidence rate of TMPRSS2::ERG fusion gene in prostate cancer was 16.7%[95% CI (14.5%,18.8%)].Regarding the type of samples,biopsy specimens showed the incidence rate of fusion gene was 17.9%[95% CI (15.8%,20.1%)].When using immunohistochemistry (IHC) detection technology,the incidence rate of fusion gene was 16.6%[95% CI (13.0%,20.2%)].CONCLUSION: The occurrence of TMPRSS2::ERG fusion gene was low in Chinese prostate cancer patients,therefore,the TMPRSS2::ERG fusion gene cannot be used as a diagnostic marker for Chinese prostate cancer patients.

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Effects of Chaihushugan powder on the JAK2/STAT3 signaling pathway in rats with hepatic fibrosis

YANG Wubin, TANG Jinfeng, MI Benzhong

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (3): 200-205. DOI: 10.3969/j.issn.1004-616x.2022.03.006

Abstract （399）

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OBJECTIVE: To study effects of Chaihushugan powder on the JAK2/STAT3 signaling pathway in rats with early liver fibrosis. METHODS: Fifty SD rats were treated with CCl₄ and randomly divided into normal group (intraperitoneal injection of olive oil + intragastric administration of distilled water), model group(intraperitoneal injection of 40% CCl₄ olive oil solution+intragastric administration of distilled water),and low,medium and high dose groups of Chaihushugan powder (intraperitoneal injection of 40% CCl₄ olive oil solution+intragastric administration of 3.5, 6.3 and 12.6 g/kg crude drugs, respectively). After administration of Chaihushugan powder until the tenth week,general morphology was observed,and liver indices were measured.ALT and AST were determined by automatic biochemical analyzer. Changes of serum (HA,PCⅢ,Ⅳ-C) were detected by ELISA. Pathological changes of the hepatic fibrosis tissues in each group were observed by HE staining. mRNA expressions of JAK2 and STAT3 in liver tissues were detected by qPCR, and protein expressions of JAK2 and STAT3 in liver tissue were detected by Western blot. RESULTS: Compared with the normal group, levels of serum ALT,AST,HA,PCⅢ,Ⅳ-C in the model group were significantly increased(P<0.01). HE staining showed obvious edema of liver cells, with increased volume and inflammatory cell infiltration. Compared with the model group, different doses of Chaihushugan powder inhibited hepatocyte necrosis and inflammatory cell infiltration, and serum levels of ALT, AST, HA, PC Ⅲ ,and Ⅳ-C were significantly reduced (P<0.05 or P<0.01). The liver indices of rats in the middle and high dose groups of Chaihushugan powder decreased significantly (P<0.05). Each dose group of Chaihushugan powder inhibited the expression of JAK2, STAT3 mRNA and protein in liver tissues (P<0.05 or P<0.01). CONCLUSION: The protective effect of Chaihushugan powder on early hepatic fibrosis rats might be related to inhibition of the JAK2/STAT3 signaling pathway.

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Usefulness of dehydrated icaritin in maintaining the stemness of human urine-derived stem cells

ZHANG Yixue, ZHOU Ming, QIAO Yinggu, WANG Chengyu, SUN Zhenxiao

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (6): 449-454,458. DOI: 10.3969/j.issn.1004-616x.2022.06.008

Abstract （396）

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OBJECTIVE:To investigate effects of dehydrated icaritin (DICT) on the stemness of human urine-derived stem cells (hUSCs). METHODS:hUSCs were isolated by centrifugation at room temperature and cultured in vitro. Morphological observations of hUSCs was performed under inverted phase contrast microscope. The growth curve of hUSCs from 1-7 days was plotted according to MTT experiment. The surface markers of hUSCs were detected by flow cytometry. The control group of hUSCs culture medium and DICT treatment groups with concentrations of 0.5,1.0,1.5,2.0,2.5,3.0 μmol/L were set up. Cell viability of each group was measured by the tetramethylthiazole blue (MTT) assay from 1-7 days. Effects of 2.0 μmol/L DICT treatment of hUSCs on the expression of OCT-4 and C-MYC mRNA were measured by quantitative real-time PCR (qPCR) after 3 days. RESULTS:hUSCs with good morphology and high growth activity were successfully obtained. hUSCs expressed CD44 and CD90,surface markers of MSCs,but not CD34,surface marker of hematopoietic stem cells,and CD31,surface marker of endothelial cells. 2.0 μmol/L DICT treatment for 3-6 days significantly promoted proliferations of hUSCs,enhanced their growth viability (P<0.01),and up-regulated the mRNA expression of hUSCs stemness genes OCT-4 and C-MYC (P<0.01). CONCLUSION:DICT enhanced the stemness of hUSCs in vitro.

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Expression of HIF-1α, VEGF, Ki67 and serum proteins in large-cell lung cancer cell line xenografts and their relationship with numbers of functional blood vessels

WU Bao, BAI Yuqin, LI Dandan, YANG Zhanmin, KONG Fanlong

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (6): 439-444. DOI: 10.3969/j.issn.1004-616x.2022.06.006

Abstract （392）

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OBJECTIVE:To investigate expression of hypoxia-inducible factor-1α (HIF-1α),vascular endothelial growth factor (VEGF),Ki67,serum protein albumin,IgG1 and IgM,and their relationship with numbers of functional blood vessels in large-cell lung cancer (LCLC) Lu65 and Lu99 cell line xenografts in nude mice. METHODS:The LCLC cells were injected subcutaneously into the back of nude mice to establish a xenograft model,and the in vivo specimens were prepared by cryotechnique (IVCT). Protein (albumin,IgG1,IgM) protein expressions were determined. According to the expression of IgM protein in the extracellular matrix around blood vessels,the number of functional blood vessels and non-functional blood vessels were distinguished and counted. t test,[χ²] test and Spearman rank correlation analyses were used for statistical evaluations. RESULTS:Expression of HIF-1α protein was found in a few tumor cell nuclei in the Lu65 but not in the Lu99 xenograft tumors and the difference was statistically significant (P<0.05). Both VEGF and Ki67 proteins were highly expressed in the tumors. The expression levels of HIF-1α protein were not significantly correlated with the VEGF and Ki67 proteins. The numbers of functional blood vessels in Lu65 and Lu99 tumors were higher than that of non-functional blood vessels (P<0.05). CONCLUSION:The expression levels of HIF-1α protein in the Lu65 and Lu99 tumors had no significant correlation with the VEGF and Ki67 proteins but were related to cellular heterogeneity. On the other hand,the IVCT technology was useful in distinguishing functional from non-functional blood vessels. The numbers of functional blood vessels in both Lu65 and Lu99 tumors were higher than that of non-functional blood vessels. Whether serum proteins were capable of penetrating blood vessel walls may be related to their molecular weights and structures of blood vessels.

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Clinical values of combined FIB, FAR and serum tumor markers in diagnosis and progression of ESCC patients

CUI Wenxuan, JIAO Wenjing, ZHAO Wei, DU Yanyan, TIAN Guo, ZHANG Jinyan, MA Ming

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (4): 289-294,326. DOI: 10.3969/j.issn.1004-616x.2022.04.008

Abstract （392）

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OBJECTIVE: To investigate significance of fibrinogen (FIB), fibrinogen to albumin ratio (FAR) and serum tumor markers in the diagnosis and clinical progression of esophageal squamous cell carcinoma (ESCC). METHODS: Sixty-six ESCC patients who were admitted to the Fourth Hospital of Hebei Medical University from April 2018 to October 2021 were selected as the ESCC group. Clinicopathological data and laboratory test indexes of these patients at initial diagnosis were collected. Clinicopathological data,blood routine, coagulation function, biochemistry, serum tumor markers[including Carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC-Ag)] and other laboratory test indicators were collected at the time of initial diagnosis of ESCC patients. Another 30 healthy patients without benign and malignant tumors and cardiovascular diseases were selected as the control group. The differences among indicators between the two groups were compared,and expression levels of different results in different TNM stages were analyzed, and ROC curves was made to evaluate the predictive value of FIB, FAR, CEA and SCC- Ag for clinical propression of EXCC. Correlations between these indicators and clinicopathological features were analyzed. RESULTS: FIB, FAR, ratios of fibrinogen to prealbumin (FPR), ratios of neutrophil to lymphocyte (NLR) NLR and ratios of platelets to lymphocytes (PLR) in the ESCC group were significantly higher than those in the control group (P<0.05). The levels of FIB, FAR, CEA and SCC-Ag in stage III-IV were significantly higher than those in stage I-II. Meanwhile, ROC curves showed that FIB, FAR, CEA and SCC-Ag had predictive values for the clinical progression of ESCC (P<0.05),and combined detection of the four had higher diagnostic value for the clinical progress of ESCC. N stage and TNM stage in high FIB,FAR and SCC-Ag groups (which is object to the cut off value of ROC curve) were significantly higher than those in the low FIB,FAR and SCC-Ag groups (P<0.05). The maximum tumor diameters and T stages of patients with high FAR values were also significantly higher than those of patients with low values (P<0.05). TNM stages of patients with high CEA values were significantly higher than that of patients with low values, and male patients were more than female patients (P<0.05). CONCLUSION: Levels of plasma FIB,FAR,and serum CEA,SCC-Ag were closely related to the diagnosis and clinical progress of ESCC. Compared with detection of tumor markers in serum alone,the combined detection of the four methods showed better clinical efficacy in differentiating the clinical progress of ESCC,therefore,they are worthy of clinical applications.

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Incidence and trend of stomach cancer in Nanshan District of Shenzhen from 2011 to 2019

ZHANG Xiaofan, ZHONG Xuan, LUO Jiepeng, OUYANG Binfa, LI Bo, LI Huawen, Peng Xiaolin

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (4): 269-272,278. DOI: 10.3969/j.issn.1004-616x.2022.04.004

Abstract （390）

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OBJECTIVE: To investigate incidence characteristics and trends of stomach cancer in the Nanshan District of Shenzhen city from 2011 to 2019, and to provide bases for prevention and control strategies of gastric cancer. METHODS: Based on the data of stomach cancer which were collected by the Shenzhen Chronic Disease Prevention and Management Office,the incidence and age-standardized rates (ASR) of stomach cancers were calculated. The annual percent change (APC) was used to evaluate the trend of stomach cancer in the District. RESULTS: From 2011 to 2019,there were 498 new cases of stomach cancer. The incidence rate was 7.21×10^-5,the ASR China was 1.399×10^-4,and the ASR world was 1.518×10^-4. The incidence rate of male was 8.35×10^-5,the age-standardized incidence rates for standard Chinese population and for world population were 1.809×10^-4 and 2.090×10^-4,respectively. The incidence rate of female was 5.99×10^-5, the age-standardized incidence rates for standard Chinese population and for world population were 11.71/10⁵ and 1.316×10^-4,respectively. The incidence for male was significantly higher. In terms of age distribution,the incidence began to rise rapidly after the age of 45 and reached a peak at the age group of 80-85 years old, when the incidence was 9.087×10^-4. Over time,the incidence of stomach cancer was stable. CONCLUSION: The incidence of stomach cancer in the Nanshan District of Shenzhen City was stable. The data indicate that strengthening prevention and control on stomach cancer in high-risk male groups over 45 years old is needed.

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Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (5): 395-399. DOI: 10.3969/j.issn.1004-616x.2022.05.011

Abstract （390）

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Expression and clinical significance of SLC50A1 in breast carcinomas

ZHANG Haizhi, WEN Xiaofen, HUANG Binliang, LIN Hui, XUE Wenwu, ZENG De, LIN Danxia

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (5): 373-377. DOI: 10.3969/j.issn.1004-616x.2022.05.007

Abstract （388）

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OBJECTIVE: To investigate expression of SLC50A1 and its significance in breast cancers (BC).METHODS: Plasma samples from 39 BC patients who met the inclusion criteria of this study were investigated using the enzyme-linked immunosorbent assay.The Mann-Whitney U-test and Kendall's Tau-b were used to analyze differences and correlations between SLC50A1 protein levels and their clinical data.The multivariate Cox regression was used to investigate prognostic significance of SLC50A1 according to the results of the log-rank test.Furthermore,the TCGA database was downloaded to compared different expressions of SLC50A1 from 1 109 BC and 113 adjacent normal tissues.RESULTS: Clinical data from the BC patients indicated that SLC50A1 protein expression was associated with metastasis,hormone receptor and Ki67(P< 0.05).Correlation analyses of plasma SLC50A1 levels indicated a positive correlation between plasma SLC50A1 level and CA153,Kendall's Tau-b=0.257(P=0.004).Multivariate Cox regression analyses indicated that SLC50A1 was an independent prognostic factor in BC patients (HR=0.385,P=0.03).The TCGA data analyses indicated that the SLC50A1 expression levels were higher in BC than in adjacent tissues (P<0.01).CONCLUSION: Plasma SLC50A1 levels were increased in advanced BC,and SLC50A1 expression was an independent prognostic factor for BC.SLC50A1 may be useful as a target for prognosis prediction and therapy of BC.

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Comparison of methods to identify test strains in bacterial reverse mutation assays

GAO Mei, TANG Liansheng, ZHENG Zhiyong, MA Hui, QIN Chunxue, CAO Chong

Carcinogenesis, Teratogenesis & Mutagenesis 2024, 36 (1): 58-65. DOI: 10.3969/j.issn.1004-616x.2024.01.010

Abstract （381）

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OBJECTIVE: Compare and analyze the identification methods of test strains in bacterial reverse mutation assays(Ames test) for food, medical devices, cosmetics, chemicals, pesticides and drugs in China, in order to provide references for strain identification methods. METHODS: According to the requirements of national and the profession standard, technical standards and guidelines related to Ames tests, the identification methods of histidine auxotrophy, lipopolysaccharide barrier defect(rfa mutation), ampicillin resistance(R factor), tetracycline resistance(pAQ1 plasmid) and uvrB repair deficiency(sensitivity to ultraviolet light) were analyzed and compared. RESULTS: The results showed that TA97a, TA98, TA100, TA102 and TA1535 strains all required histidine for growth, all had rfa mutations, all had ampicillin resistance except TA1535, and all were sensitive to ultraviolet light and all had no tetracycline resistance except TA102.CONCLUSION: Although the identification methods were different, the criteria and identification results were the same. Each laboratory should specify the method and frequency of identification of test strains to provide fundamental guarantee for the authenticity and reliability of Ames test results.

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Observation of the effects of early embryo cleavage patterns on its developmental potential using time-lapse imaging system

XU Xiaoqin, CHENG Lizi, LUO Xin, YU Wenjuan, HUO Junye, LIU Shuyuan, LIN Xiufeng

Carcinogenesis, Teratogenesis & Mutagenesis 2023, 35 (2): 121-124,138. DOI: 10.3969/j.issn.1004-616x.2023.02.007

Abstract （371）

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OBJECTIVE：To observe cleavage patterns of embryos in early stages by time-lapse imaging system，and to evaluate effects of the cleavage patterns on developmental potential of embryos in early stage. METHODS：From January 2019 to July 2021，development of 1 318 embryos cultured with blastocysts which were recorded by the time-lapse imaging system in the reproductive center were retrospectively analyzed. According to the cleavage mode of two prokaryotic (2PN) fertilized eggs，they were divided into normal and abnormal cleavages. Abnormal cleavages included first cleavage anomaly and non-first cleavage anomaly. Pregnancy outcomes such as rates of high-quality embryo， blastocyst formation， high-quality blastocyst， pregnancy， and abortion of early embryos in different cleavage pattern groups were analyzed on day 3. RESULTS： The D3 high-quality embryo rates were 57.36% and 39.47% respectively； blastocyst formation rates were 66.33% and 36.62% respectively； high-quality blastocyst rates were 60.14% and 27.61% respectively in the normal cleavage group and in the abnormal cleavage group. These were significantly higher than those in the abnormal cleavage group (P<0.01). There was no significant difference in clinical pregnancy and miscarriage rates between the normal cleavage and the abnormal cleavage groups(P>0.05). In the abnormal cleavage group，the rates for D3 high-quality embryos and high-quality blastocysts were 34.45% and 24.64% in the first abnormal cleavage group and they were significantly lower than those in the non-first abnormal cleavage group of 58.02% and 37.66% (P<0.05). There was no significant difference in the rates of clinical pregnancy and abortion between the first cleavage anomaly group and the non-first cleavage anomaly group. CONCLUSION：Abnormal cleavage of embryos reduced developmental potential of early embryo. The earlier the abnormal cleavage occurred，the greater the impact on embryonic development.

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The combination of ¹²⁵I particles and AZD1152 efficiently inhibited proliferation and promoted apoptosis of a triple negative breast cancer cell line

ZHANG Yue, WANG Yaoyi, WU Xueliang, ZHANG Zhisheng, YANG Xiuming, JIANG Yang, QIAO Zhifei, LIANG Wanping, XUE Jun

Carcinogenesis, Teratogenesis & Mutagenesis 2022, 34 (4): 295-299,306. DOI: 10.3969/j.issn.1004-616x.2022.04.009

Abstract （370）

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OBJECTIVE: To study effects of AZD1152 combined with ¹²⁵I particles on proliferations and apoptoses of triple negative breast cancer cells MDA-MB-231. METHODS: Cultured cells were divided into several groups; control, ¹²⁵I particle irradiation, 1 μmol/L AZD1152 treatment with 48 h, treated with ¹²⁵I particle irradiation and 1 μmol/L AZD1152 treated with 48 h. Cell proliferation inhibitory rates were detected using the MTT and cell viability using the CCK-8 assays. Cell ploidies,cell cycles and apoptoses were detected using flow cytometry with cells separately stained by propidium iodide (PI) and by Annexin V/PI double-staining. Expressions of apoptosis-related proteins (Bcl-XL, Bcl-2 and PARP), CyclinB1 and Phosphorylation levels of Histone H3 were analyzed using Western blotting. RESULTS: After treatments for 48 h, cell proliferation inhibitory rates were (0.61±0.32)%,(17.62±1.41)%,(29.67±0.41)%,(53.17±1.26)%,respectively. Cell viability rates were (94.88±0.22)%,(59.21±0.14)%,(42.05±0.17)% (32.12±0.36)%,respectively. The proportions of G2/M phase were (18.99±0.15)%,(38.05±0.23)%,(49.80±0.32)%,(75.52±0.45)%,respectively. The apoptosis rates of MDA-MB-231 cells were (17.48±0.24)%,(29.23±0.02)%,(63.11±0.27)%,with significantly differences in the different groups (P<0.05). Compared with (0.31 ±0.03)% in the control group, the observed increases were significant (P<0.05). Immunofluorescence and flow cytometry analyses showed that multinucleated and polyploid cells appeared in the 1μmol/L AZD1152 group in 48 hours,which were easy to form aneuploid cells. Compared with the irradiated,inhibitor and control groups,the combined irradiation with 1 μmol/L AZD1152 for 48 h effectively down-regulated the expressions of Bcl-2,p-Histone H3,CyclinB1 and promoted Bax and dissection of PARP (P<0.05). CONCLUSION: The combination of ¹²⁵I particles and AZD1152 treatments efficiently inhibited proliferation and promoted apoptosis in breast cancer cell line MDA-MB-231.

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