Editorial

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Open AccessEditorial

Molecular Toxicology and Cancer Prevention

by Guohui Sun and Chongwen Wang

Molecules 2023, 28(23), 7730; https://doi.org/10.3390/molecules28237730 - 23 Nov 2023

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Molecular toxicology is a field that investigates the interactions between chemical or biological molecules and organisms at the molecular level [...] Full article

(This article belongs to the Special Issue Molecular Toxicology and Cancer Prevention)

Research

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22 pages, 36285 KiB

Open AccessArticle

A Novel Aging-Related Prognostic lncRNA Signature Correlated with Immune Cell Infiltration and Response to Immunotherapy in Breast Cancer

by Zhixin Liu, Chongkang Ren, Jinyi Cai, Baohui Yin, Jingjie Yuan, Rongjuan Ding, Wenzhuo Ming, Yunxiao Sun and Youjie Li

Molecules 2023, 28(8), 3283; https://doi.org/10.3390/molecules28083283 - 07 Apr 2023

Cited by 2 | Viewed by 2090

Abstract

Breast cancer (BC) is among the most universal malignant tumors in women worldwide. Aging is a complex phenomenon, caused by a variety of factors, that plays a significant role in tumor development. Consequently, it is crucial to screen for prognostic aging-related long non-coding [...] Read more.

Breast cancer (BC) is among the most universal malignant tumors in women worldwide. Aging is a complex phenomenon, caused by a variety of factors, that plays a significant role in tumor development. Consequently, it is crucial to screen for prognostic aging-related long non-coding RNAs (lncRNAs) in BC. The BC samples from the breast-invasive carcinoma cohort were downloaded from The Cancer Genome Atlas (TCGA) database. The differential expression of aging-related lncRNAs (DEarlncRNAs) was screened by Pearson correlation analysis. Univariate Cox regression, LASSO–Cox analysis, and multivariate Cox analysis were performed to construct an aging-related lncRNA signature. The signature was validated in the GSE20685 dataset from the Gene Expression Omnibus (GEO) database. Subsequently, a nomogram was constructed to predict survival in BC patients. The accuracy of prediction performance was assessed through the time-dependent receiver operating characteristic (ROC) curves, Kaplan–Meier analysis, principal component analyses, decision curve analysis, calibration curve, and concordance index. Finally, differences in tumor mutational burden, tumor-infiltrating immune cells, and patients’ response to chemotherapy and immunotherapy between the high- and low-risk score groups were explored. Analysis of the TCGA cohort revealed a six aging-related lncRNA signature consisting of MCF2L-AS1, USP30-AS1, OTUD6B-AS1, MAPT-AS1, PRR34-AS1, and DLGAP1-AS1. The time-dependent ROC curve proved the optimal predictability for prognosis in BC patients with areas under curves (AUCs) of 0.753, 0.772, and 0.722 in 1, 3, and 5 years, respectively. Patients in the low-risk group had better overall survival and significantly lower total tumor mutational burden. Meanwhile, the high-risk group had a lower proportion of tumor-killing immune cells. The low-risk group could benefit more from immunotherapy and some chemotherapeutics than the high-risk group. The aging-related lncRNA signature can provide new perspectives and methods for early BC diagnosis and therapeutic targets, especially tumor immunotherapy. Full article

(This article belongs to the Special Issue Molecular Toxicology and Cancer Prevention)

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18 pages, 4579 KiB

Open AccessArticle

BDE-47 Induces Immunotoxicity in RAW264.7 Macrophages through the Reactive Oxygen Species-Mediated Mitochondrial Apoptotic Pathway

by Qian Gao, Zhong-Yuan Zhou, Ya-Ning He, Ming-Hui Dong, Zhao-Ning Wang and Hong-Mei Chen

Molecules 2023, 28(5), 2036; https://doi.org/10.3390/molecules28052036 - 21 Feb 2023

Cited by 2 | Viewed by 2044

Abstract

Polybrominated diphenyl ethers (PBDEs) are classic and emerging pollutants that are potentially harmful to the human immune system. Research on their immunotoxicity and mechanisms suggests that they play an important role in the resulting pernicious effects of PBDEs. 2,2′,4,4′-Tetrabrominated biphenyl ether (BDE-47) is [...] Read more.

Polybrominated diphenyl ethers (PBDEs) are classic and emerging pollutants that are potentially harmful to the human immune system. Research on their immunotoxicity and mechanisms suggests that they play an important role in the resulting pernicious effects of PBDEs. 2,2′,4,4′-Tetrabrominated biphenyl ether (BDE-47) is the most biotoxic PBDE congener, and, in this study, we evaluated its toxicity toward RAW264.7 cells of mouse macrophages. The results show that exposure to BDE-47 led to a significant decrease in cell viability and a prominent increase in apoptosis. A decrease in mitochondrial membrane potential (MMP) and an increase in cytochrome C release and caspase cascade activation thus demonstrate that cell apoptosis induced by BDE-47 occurs via the mitochondrial pathway. In addition, BDE-47 inhibits phagocytosis in RAW264.7 cells, changes the related immune factor index, and causes immune function damage. Furthermore, we discovered a significant increase in the level of cellular reactive oxygen species (ROS), and the regulation of genes linked to oxidative stress was also demonstrated using transcriptome sequencing. The degree of apoptosis and immune function impairment caused by BDE-47 could be reversed after treatment with the antioxidant NAC and, conversely, exacerbated by treatment with the ROS-inducer BSO. These findings indicate that oxidative damage caused by BDE-47 is a critical event that leads to mitochondrial apoptosis in RAW264.7 macrophages, ultimately resulting in the suppression of immune function. Full article

(This article belongs to the Special Issue Molecular Toxicology and Cancer Prevention)

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11 pages, 7781 KiB

Open AccessArticle

Improving the Transduction Efficiency and Antitumor Effect of Conditionally Replicative Adenovirus by Application of 6-cyclohexyl Methyl-β-D-maltoside

by Wenjing Lu, Yaping Fang, Xue Meng, Xiaoli Wang, Wenbo Liu, Mengdong Liu and Ping Zhang

Molecules 2023, 28(2), 528; https://doi.org/10.3390/molecules28020528 - 05 Jan 2023

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Abstract

As a tumor-targeting oncolytic adenovirus (Ad), conditionally replicating adenovirus (CRAd) can access the cell interior by binding to coxsackievirus-Ad receptors (CARs) and specifically replicate and destroy cancer cells without lethal effects on normal cells. The transduction efficiency of CRAd is highly dependent on [...] Read more.

As a tumor-targeting oncolytic adenovirus (Ad), conditionally replicating adenovirus (CRAd) can access the cell interior by binding to coxsackievirus-Ad receptors (CARs) and specifically replicate and destroy cancer cells without lethal effects on normal cells. The transduction efficiency of CRAd is highly dependent on the number of CARs on the cell membrane. However, not all tumor cells highly express CARs; therefore, improving the transduction efficiency of CRAd is beneficial for improving its antitumor effect. In this study, 6-cyclohexyl methyl-β-D-maltoside (6-β-D), as maltoside transfection agent, showed several advantages, including high transfection efficiency, low toxicity, and potential for intensive use and easy operation. With pretreatment of cancer cells with low concentration of 6-β-D (≤5 μg/mL), the transduction efficiency of “model” Ad (eGFP-Ad) was improved 18-fold compared to eGFP-Ad alone. 6-β-D improved the antitumor effect of CRAd while being safe for normal cells, in which treatment with 6-β-D helped the lethal effects of CRAd at a multiplicity-of-infection ratio of 10 (MOI 10) achieve the oncolytic outcomes of MOI 50. This means that if CRAd is combined with 6-β-D, the amount of CRAd used in clinical practice could be greatly reduced without diminishing its curative effect or exposing patients to the potential side effects of high-titer CRAd. Finally, the underlying mechanism of antitumor effect of CRAd + 6-β-D was primarily investigated, and we found that 6-β-D increased the virus’s replication in cancer cells at the early stage of infection and activated the apoptosis signaling pathway at the late stage of the cell cycle. This research will provide an effective technical reference for further improving Ad-mediated cancer gene therapy in clinical practice. Full article

(This article belongs to the Special Issue Molecular Toxicology and Cancer Prevention)

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11 pages, 2771 KiB

Open AccessArticle

8–17 DNAzyme Silencing Gene Expression in Cells via Cleavage and Antisense

by Zhongchun Zhou, Wen Sun and Zhen Huang

Molecules 2023, 28(1), 286; https://doi.org/10.3390/molecules28010286 - 29 Dec 2022

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Abstract

Gene silencing is an important biological strategy for studying gene functions, exploring disease mechanisms and developing therapeutics. 8–17 DNAzyme is of great potential for gene silencing, due to its higher RNA-cleaving activity. However, it is not generally used in practice, due to its [...] Read more.

Gene silencing is an important biological strategy for studying gene functions, exploring disease mechanisms and developing therapeutics. 8–17 DNAzyme is of great potential for gene silencing, due to its higher RNA-cleaving activity. However, it is not generally used in practice, due to its divalent cation dependence and poor understanding of its cellular mechanisms. To address these issues, we have explored its activity in vitro and in cells and found that it can cleave RNA substrates under the simulated physiological conditions, and its gene-silencing activity is additionally enhanced by its RNase H compatibility, offering both cleavage and antisense activities in cells. Further, chemical modifications can facilitate its stability, substrate binding affinity and gene-silencing activity. Our research results suggest that this DNAzyme can demonstrate high levels of activities for both actions in cells, making it a useful tool for exploring biomedical applications. Full article

(This article belongs to the Special Issue Molecular Toxicology and Cancer Prevention)

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12 pages, 2229 KiB

Open AccessArticle

AHNAK Contributes to Hepatocellular Carcinoma Growth by Interacting with IGF-1R

by Kang Li, Ke Song, Yuli Hou, Yuan Tian, Huijuan Wang, Libo Sun, Ang Li and Yonghong Zhang

Molecules 2022, 27(24), 8680; https://doi.org/10.3390/molecules27248680 - 08 Dec 2022

Cited by 1 | Viewed by 1642

Abstract

Neuroblast differentiation-associated protein AHNAK, a large structural scaffold protein, remains mysterious in biological processes. AHNAK plays a suppressive or progressive role in different types of cancers. To investigate the role of the AHNAK in hepatocellular carcinoma (HCC), cell viability assays were performed to [...] Read more.

Neuroblast differentiation-associated protein AHNAK, a large structural scaffold protein, remains mysterious in biological processes. AHNAK plays a suppressive or progressive role in different types of cancers. To investigate the role of the AHNAK in hepatocellular carcinoma (HCC), cell viability assays were performed to determine the cell proliferation of the stable AHNAK-knockdown HepG2 cell line; co-immunoprecipitation (Co-IP) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) were performed on HCC and matched paracancerous (MPC) tissues. The Metascape platform was used for enrichment analyses; the “ComplexHeatmap” package was applied for cluster analyses and visualization. Co-IP, Western botting and immunofluorescence double staining were performed to assess the interactions between AHNAK and insulin-like growth factor 1 receptor (IGF-1R). AHNAK silencing reduced the viability of HepG2 cells; the interactome in HCC and MPC tissues enriched 204 pathways and processes, which partially reflected the signature of HCC field cancerization. AHNAK could co-localize and interact with IGF-1R. These results suggested that the AHNAK complex contributes to HCC growth, potentially by interacting with IGF-1R. Full article

(This article belongs to the Special Issue Molecular Toxicology and Cancer Prevention)

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18 pages, 3783 KiB

Open AccessArticle

Integrated Analysis of Transcriptome and microRNA Profile Reveals the Toxicity of Euphorbia Factors toward Human Colon Adenocarcinoma Cell Line Caco-2

by Lingyue Zou, Wenqiang Bao, Yadong Gao, Mengting Chen, Yajiao Wu, Shuo Wang, Chutao Li, Jian Zhang, Dongcheng Zhang, Qi Wang and An Zhu

Molecules 2022, 27(20), 6931; https://doi.org/10.3390/molecules27206931 - 16 Oct 2022

Cited by 2 | Viewed by 1842

Abstract

Euphorbia factors, lathyrane-type diterpenoids isolated from the medical herb Euphorbia lathyris L. (Euphorbiaceae), have been associated with intestinal irritation toxicity, but the mechanisms underlying this phenomenon are still unknown. The objective of this study was to evaluate the transcriptome and miRNA [...] Read more.

Euphorbia factors, lathyrane-type diterpenoids isolated from the medical herb Euphorbia lathyris L. (Euphorbiaceae), have been associated with intestinal irritation toxicity, but the mechanisms underlying this phenomenon are still unknown. The objective of this study was to evaluate the transcriptome and miRNA profiles of human colon adenocarcinoma Caco-2 cells in response to Euphorbia factors L1 (EFL1) and EFL2. Whole transcriptomes of mRNA and microRNA (miRNA) were obtained using second generation high-throughput sequencing technology in response to 200 μM EFL treatment for 72 h, and the differentially expressed genes and metabolism pathway were enriched. Gene structure changes were analyzed by comparing them with reference genome sequences. After 72 h of treatment, 16 miRNAs and 154 mRNAs were differently expressed between the EFL1 group and the control group, and 47 miRNAs and 1101 mRNAs were differentially expressed between the EFL2 group and the control. Using clusters of orthologous protein enrichment, the sequenced mRNAs were shown to be mainly involved in transcription, post-translational modification, protein turnover, chaperones, signal transduction mechanisms, intracellular trafficking, secretion, vesicular transport, and the cytoskeleton. The differentially expressed mRNA functions and pathways were enriched in transmembrane transport, T cell extravasation, the IL-17 signaling pathway, apoptosis, and the cell cycle. The differentially expressed miRNA EFLs caused changes in the structure of the gene, including alternative splicing, insertion and deletion, and single nucleotide polymorphisms. This study reveals the underlying mechanism responsible for the toxicity of EFLs in intestinal cells based on transcriptome and miRNA profiles of gene expression and structure. Full article

(This article belongs to the Special Issue Molecular Toxicology and Cancer Prevention)

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14 pages, 5669 KiB

Open AccessArticle

Rapid Detection of Aspergillus flavus and Quantitative Determination of Aflatoxin B₁ in Grain Crops Using a Portable Raman Spectrometer Combined with Colloidal Au Nanoparticles

by Huiqin Wang, Mengjia Liu, Yumiao Zhang, Huimin Zhao, Wenjing Lu, Taifeng Lin, Ping Zhang and Dawei Zheng

Molecules 2022, 27(16), 5280; https://doi.org/10.3390/molecules27165280 - 18 Aug 2022

Cited by 3 | Viewed by 1654

Abstract

Aspergillus flavus and Aflatoxins in grain crops give rise to a serious threat to food security and cause huge economic losses. In particular, aflatoxin B₁ has been identified as a Class I carcinogen to humans by the International Agency for Research on [...] Read more.

Aspergillus flavus and Aflatoxins in grain crops give rise to a serious threat to food security and cause huge economic losses. In particular, aflatoxin B₁ has been identified as a Class I carcinogen to humans by the International Agency for Research on Cancer (IARC). Compared with conventional methods, Surface-Enhanced Raman Scattering (SERS) has paved the way for the detection of Aspergillus flavus and Aflatoxins in grain crops as it is a rapid, nondestructive, and sensitive analytical method. In this work, the rapid detection of Aspergillus flavus and quantification of Aflatoxin B₁ in grain crops were performed by using a portable Raman spectrometer combined with colloidal Au nanoparticles (AuNPs). With the increase of the concentration of Aspergillus flavus spore suspension in the range of 10²–10⁸ CFU/mL, the better the combination of Aspergillus flavus spores and AuNPs, the better the enhancement effect of AuNPs solution on the Aspergillus flavus. A series of different concentrations of aflatoxin B₁ methanol solution combined with AuNPs were determined based on SERS and their spectra were similar to that of solid powder. Moreover, the characteristic peak increased gradually with the increase of concentration in the range of 0.0005–0.01 mg/L and the determination limit was 0.0005 mg/L, which was verified by HPLC in ppM concentration. This rapid detection method can greatly shorten the detection time from several hours or even tens of hours to a few minutes, which can help to take effective measures to avoid causing large economic losses. Full article

(This article belongs to the Special Issue Molecular Toxicology and Cancer Prevention)

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14 pages, 4033 KiB

Open AccessArticle

Nicotine Inhibits the Cytotoxicity and Genotoxicity of NNK Mediated by CYP2A13 in BEAS-2B Cells

by Yulin Sun, Hongjuan Wang, Huan Chen, Sen Zhang, Jun Li, Jingni Zhang, Jianlu Tian, Youyu Zhang, Hongwei Hou and Qingyuan Hu

Molecules 2022, 27(15), 4851; https://doi.org/10.3390/molecules27154851 - 29 Jul 2022

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Abstract

Both tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and nicotine can be metabolized by cytochrome P450 2A13 (CYP2A13). Previous studies have shown that nicotine has a potential inhibitory effect on the toxicity of NNK. However, due to the lack of CYP2A13 activity in conventional lung cell [...] Read more.

Both tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and nicotine can be metabolized by cytochrome P450 2A13 (CYP2A13). Previous studies have shown that nicotine has a potential inhibitory effect on the toxicity of NNK. However, due to the lack of CYP2A13 activity in conventional lung cell lines, there had been no systematic in vitro investigation for the key target organ, the lung. Here, BEAS-2B cells stably expressing CYP2A13 (B-2A13 cells) were constructed to investigate the effects of nicotine on the cytotoxicity and genotoxicity of NNK. The results showed more sensitivity for NNK-induced cytotoxicity in B-2A13 cells than in BEAS-2B and B-vector cells. NNK significantly induced DNA damage, cell cycle arrest, and chromosomal damage in B-2A13 cells, but had no significant effect on BEAS-2B cells and the vector control cells. The combination of different concentration gradient of nicotine without cytotoxic effects and a single concentration of NNK reduced or even counteracted the cytotoxicity and multi-dimensional genotoxicity in a dose-dependent manner. In conclusion, CYP2A13 caused the cytotoxicity and genotoxicity of NNK in BEAS-2B cells, and the addition of nicotine could inhibit the toxicity of NNK. Full article

(This article belongs to the Special Issue Molecular Toxicology and Cancer Prevention)

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9 pages, 3251 KiB

Open AccessArticle

Graphene Oxide-Sensitized Surface Plasmon Resonance Biosensor of Porcine Reproductive and Respiratory Syndrome Virus

by Xuemei Liu, Chao Xu, Chunyu Fu, Dongfang Xia, Fuchao Wang, Hongzong Yin and Jun Peng

Molecules 2022, 27(12), 3942; https://doi.org/10.3390/molecules27123942 - 20 Jun 2022

Cited by 3 | Viewed by 1308

Abstract

Biosensor analysis based on the surface plasmon resonance (SPR) phenomenon enables label-free, highly sensitive analyte detection without prior sample purification or processing. However, potential applications of SPR biosensors in virus detection in biological samples remain to be explored. Owing to its excellent biocompatibility [...] Read more.

Biosensor analysis based on the surface plasmon resonance (SPR) phenomenon enables label-free, highly sensitive analyte detection without prior sample purification or processing. However, potential applications of SPR biosensors in virus detection in biological samples remain to be explored. Owing to its excellent biocompatibility and abundance of hydroxyl and carboxyl functional groups, graphene oxide (GO) has been widely used as a biosensor of proteins and metal ions in living cells. The present work explored the effect of GO modification on the sensitivity of an SPR biosensor and used a GO-modified sensor to detect porcine reproductive and respiratory syndrome virus in cell culture, as shown. The GO modification markedly enhanced the sensitivity of the Fourier transform SPR sensor and enabled linear detection of porcine reproductive and respiratory syndrome virus (PRRSV) with a multiplicity of infection in the range 0.2–1.7 (R² = 0.998). Such a GO-modified sensor provides a promising alternative for virus detection. Full article

(This article belongs to the Special Issue Molecular Toxicology and Cancer Prevention)

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11 pages, 812 KiB

Open AccessArticle

Effects of Smoking on Inflammatory-Related Cytokine Levels in Human Serum

by Hongjuan Wang, Huan Chen, Yaning Fu, Min Liu, Jingni Zhang, Shulei Han, Yushan Tian, Hongwei Hou and Qingyuan Hu

Molecules 2022, 27(12), 3715; https://doi.org/10.3390/molecules27123715 - 09 Jun 2022

Cited by 6 | Viewed by 1950

Abstract

Cardiovascular and respiratory diseases, and several cancers resulting from tobacco smoking, are initially characterized by chronic systemic inflammation. Cytokine imbalances can result in inflammation, making it important to understand the pathological mechanisms behind cytokine production. In this study, we collected blood samples from [...] Read more.

Cardiovascular and respiratory diseases, and several cancers resulting from tobacco smoking, are initially characterized by chronic systemic inflammation. Cytokine imbalances can result in inflammation, making it important to understand the pathological mechanisms behind cytokine production. In this study, we collected blood samples from 78 healthy male volunteers, including non-smokers (n = 30), current smokers (n = 30), and ex-smokers (n = 18), and utilized the liquid suspension chip technique to investigate and compare the expression levels of 17 cytokines and chemokines in the human serum of these volunteers. The results demonstrated that the expression levels of CXCL9/MIG and sIL-6R significantly increased after smoking, and continued to increase after quitting smoking. The expression levels of TARC, ITAC, and sVEGFR-3 increased after smoking but decreased after quitting smoking; the expression level of SAA significantly decreased after smoking and showed an upward trend after quitting smoking. Seven cytokines (IL-1β, BCA-1, TNF-α, CRP, ENA-78, MDC, and TNFRII) did not vary between the three groups, while four cytokines (IL-1α, IL-6, IL-8, and SCF) were not detected in any serum sample. In conclusion, this study assessed the physiological production of cytokines and chemokines, highlighting the differences in each due to smoking status. Our results could help evaluate the early development of smoking-related chronic diseases and cancers. Full article

(This article belongs to the Special Issue Molecular Toxicology and Cancer Prevention)

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Review

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12 pages, 755 KiB

Open AccessReview

Toll-like Receptor 4 Inflammatory Perspective on Doxorubicin-Induced Cardiotoxicity

by Natticha Sumneang, Pongpan Tanajak and Thura Tun Oo

Molecules 2023, 28(11), 4294; https://doi.org/10.3390/molecules28114294 - 24 May 2023

Cited by 6 | Viewed by 2184

Abstract

Doxorubicin (Dox) is one of the most frequently used chemotherapeutic drugs in a variety of cancers, but Dox-induced cardiotoxicity diminishes its therapeutic efficacy. The underlying mechanisms of Dox-induced cardiotoxicity are still not fully understood. More significantly, there are no established therapeutic guidelines for [...] Read more.

Doxorubicin (Dox) is one of the most frequently used chemotherapeutic drugs in a variety of cancers, but Dox-induced cardiotoxicity diminishes its therapeutic efficacy. The underlying mechanisms of Dox-induced cardiotoxicity are still not fully understood. More significantly, there are no established therapeutic guidelines for Dox-induced cardiotoxicity. To date, Dox-induced cardiac inflammation is widely considered as one of the underlying mechanisms involved in Dox-induced cardiotoxicity. The Toll-like receptor 4 (TLR4) signaling pathway plays a key role in Dox-induced cardiac inflammation, and growing evidence reports that TLR4-induced cardiac inflammation is strongly linked to Dox-induced cardiotoxicity. In this review, we outline and address all the available evidence demonstrating the involvement of the TLR4 signaling pathway in different models of Dox-induced cardiotoxicity. This review also discusses the effect of the TLR4 signaling pathway on Dox-induced cardiotoxicity. Understanding the role of the TLR4 signaling pathway in Dox-induced cardiac inflammation might be beneficial for developing a potential therapeutic strategy for Dox-induced cardiotoxicity. Full article

(This article belongs to the Special Issue Molecular Toxicology and Cancer Prevention)

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