The Utilization of Physiologically Active Molecular Components of Grape Seeds and Grape Marc.

Nutritional interventions may highly contribute to the maintenance or restoration of human health. Grapes (Vitis vinifera) are one of the oldest known beneficial nutritional components of the human diet. Their high polyphenol content has been proven to enhance human health beyond doubt in statistics-based public health studies, especially in the prevention of cardiovascular disease and cancer. The current review concentrates on presenting and classifying polyphenol bioactive molecules (resveratrol, quercetin, catechin/epicatechin, etc.) available in high quantities in Vitis vinifera grapes or their byproducts. The molecular pathways and cellular signaling cascades involved in the effects of these polyphenol molecules are also presented in this review, which summarizes currently available in vitro and in vivo experimental literature data on their biological activities mostly in easily accessible tabular form. New molecules for different therapeutic purposes can also be synthesized based on existing polyphenol compound classes available in high quantities in grape, wine, and grape marc. Therefore an overview of these molecular structures is provided. Novel possibilities as dendrimer nanobioconjugates are reviewed, too. Currently available in vitro and in vivo experimental literature data on polyphenol biological activities are presented in easily accessible tabular form. The scope of the review details the antidiabetic, anticarcinogenic, antiviral, vasoprotective, and neuroprotective roles of grape-origin flavonoids. The novelty of the study lies in the description of the processing of agricultural by-products (grape seeds and skins) of industrial relevance, and the detailed description of the molecular mechanisms of action. In addition, the review of the clinical therapeutic applications of polyphenols is unique as no summary study has yet been done.

Radiomics-based differentiation of lung disease models generated by polluted air based on X-ray computed tomography data.

BACKGROUND: Lung diseases (resulting from air pollution) require a widely accessible method for risk estimation and early diagnosis to ensure proper and responsive treatment. Radiomics-based fractal dimension analysis of X-ray computed tomography attenuation patterns in chest voxels of mice exposed to different air polluting agents was performed to model early stages of disease and establish differential diagnosis. METHODS: To model different types of air pollution, BALBc/ByJ mouse groups were exposed to cigarette smoke combined with ozone, sulphur dioxide gas and a control group was established. Two weeks after exposure, the frequency distributions of image voxel attenuation data were evaluated. Specific cut-off ranges were defined to group voxels by attenuation. Cut-off ranges were binarized and their spatial pattern was associated with calculated fractal dimension, then abstracted by the fractal dimension -- cut-off range mathematical function. Nonparametric Kruskal-Wallis (KW) and Mann-Whitney post hoc (MWph) tests were used. RESULTS: Each cut-off range versus fractal dimension function plot was found to contain two distinctive Gaussian curves. The ratios of the Gaussian curve parameters are considerably significant and are statistically distinguishable within the three exposure groups. CONCLUSIONS: A new radiomics evaluation method was established based on analysis of the fractal dimension of chest X-ray computed tomography data segments. The specific attenuation patterns calculated utilizing our method may diagnose and monitor certain lung diseases, such as chronic obstructive pulmonary disease (COPD), asthma, tuberculosis or lung carcinomas.

In Vitro Inhibition of Colorectal Cancer Gene Targets by Withania somnifera L. Methanolic Extracts: A Focus on Specific Genome Regulation.

An approach that shows promise for quickening the evolution of innovative anticancer drugs is the assessment of natural biomass sources. Our study sought to assess the effect of W. somnifera L. (WS) methanolic root and stem extracts on the expression of five targeted genes (cyclooxygenase-2, caspase-9, 5-Lipoxygenase, B-cell lymphoma-extra-large, and B-cell lymphoma 2) in colon cancer cell lines (Caco-2 cell lines). Plant extracts were prepared for bioassay by dissolving them in dimethyl sulfoxide. Caco-2 cell lines were exposed to various concentrations of plant extracts, followed by RNA extraction for analysis. By explicitly relating phytoconstituents of WS to the dose-dependent overexpression of caspase-9 genes and the inhibition of cyclooxygenase-2, 5-Lipoxygenase, B-cell lymphoma-extra-large, and B-cell lymphoma 2 genes, our novel findings characterize WS as a promising natural inhibitor of colorectal cancer (CRC) growth. Nonetheless, we recommend additional in vitro research to verify the current findings. With significant clinical benefits hypothesized, we offer WS methanolic root and stem extracts as potential organic antagonists for colorectal carcinogenesis and suggest further in vivo and clinical investigations, following successful in vitro trials. We recommend more investigation into the specific phytoconstituents in WS that contribute to the regulatory mechanisms that inhibit the growth of colon cancer cells.

Deuterium depleted water effects on survival of lung cancer patients and expression of Kras, Bcl2, and Myc genes in mouse lung.

Although advances in cancer therapies continue to develop, the shortness of the survival of lung cancer patients is still disappointing. Therefore, finding new adjuvant strategies is within the focus of cancer cure. Based on observations that deuterium depletion inhibits the growth of cancer cell lines and suppresses certain proto-oncogenes, we have conducted a clinical study in 129 patients with small cell and nonsmall cell lung cancers who consumed deuterium-depleted drinking water (DDW) as a nontoxic agent in addition to conventional chemotherapy and radiotherapy. Median survival time (MST) was 25.9 mo in males and 74.1 mo in female patients; the difference between genders was statistically significant (p < 0.05). Median survival of subjects with brain metastasis was 27.1 mo. Cumulative 5-yr survival probabilities were 19%, 52%, and 33% in males, females, and all patients with brain metastasis, respectively. Gene expression analysis in mouse lung indicated that DDW attenuates 7,12-dimethylbenz(a)anthracene (DMBA)-induced expression of Bcl2, Kras, and Myc in females. In conclusion, DDW counteracts the DMBA-induced overexpression of Bcl2, Kras and Myc genes in mouse lung, and it may extend survival of lung cancer patients as a nontoxic anticancer dietary supplement, especially for women with tumors overexpressing cancer-related genes, because MST of DDW-consuming group was 2-4 times longer than it is generally observed in lung cancer patients.

Tartrazine Modifies the Activity of DNMT and HDAC Genes-Is This a Link between Cancer and Neurological Disorders?

In recent years, artificial additives, especially synthetic food colorants, were found to demonstrate wider properties compared to their natural equivalents; however, their health impact is still not totally mapped. Our study aimed to determine the long-term (30 and 90 days) exposure effect of one of the commonly used artificial food colorants, tartrazine, on NMRI mice. The applied dose of tartrazine referred to the human equivalent dose for acceptable daily intake (ADI). Further, we evaluated its impact on the transcription of a range of epigenetic effectors, members of the DNA methyltransferase (DNMT) as well as histone deacetylase (HDAC) families. Following the exposure, organ biopsies were collected from the lungs, kidneys, liver, and spleen, and the gene expression levels were determined by real-time quantitative reverse transcription PCR (RT-qPCR). Our results demonstrated significant upregulation of genes in the tested organs in various patterns followed by the intake of tartrazine on ADI. Since DNMT and HDAC genes are involved in different steps of carcinogenesis, have roles in the development of neurological disorders and the effect of dose of everyday exposure is rarely studied, further investigation is warranted to study these possible associations.

Targeted lactate dehydrogenase genes silencing in probiotic lactic acid bacteria: A possible paradigm shift in colorectal cancer treatment?

Even though the pathophysiology of colorectal cancer (CRC) is complicated and poorly understood, interactions between risk factors appear to be key in the development and progression of the malignancy. The popularity of using lactic acid bacteria (LAB) prebiotics and probiotics to modulate the tumor microenvironment (TME) has grown widely over the past decade. The objective of this study was therefore to determine the detrimental effects of LAB-derived lactic acid in the colonic mucosa in colorectal cancer management. Six library databases and a web search engine were used to execute a structured systematic search of the existing literature, considering all publications published up until August 2022. A total of 7817 papers were screened, all of which were published between 1995 and August 2022. However, only 118 articles met the inclusion criterion. Lactic acid has been directly linked to the massive proliferation of cancerous cells since the glycolytic pathway provides cancerous cells with not only ATP, but also biosynthetic intermediates for rapid growth and proliferation. Our research suggests that targeting LAB metabolic pathways is capable of suppressing tumor growth and that the LDH gene is critical for tumorigenesis. Silencing of Lactate dehydrogenase, A (LDHA), B (LDHB), (LDHL), and hicD genes should be explored to inhibit fermentative glycolysis yielding lactic acid as the by-product. More studies are necessary for a solid understanding of this topic so that LAB and their corresponding lactic acid by-products do not have more adverse effects than their widely touted positive outcomes in CRC management.

A comparative study to optimize experimental conditions of pentylenetetrazol and pilocarpine-induced epilepsy in zebrafish larvae.

A common way to investigate epilepsy and the effect of antiepileptic pharmaceuticals is to analyze the movement patterns of zebrafish larvae treated with different convulsants like pentylenetetrazol (PTZ), pilocarpine, etc. Many articles have been written on this topic, but the research methods and exact settings are not sufficiently defined in most. Here we designed and executed a series of experiments to optimize and standardize the zebrafish epilepsy model. We found that during the light and the dark trials, the zebrafish larvae moved significantly more in the light, independent of the treatment, both in PTZ and pilocarpine-treated and the control groups. As expected, zebrafish larvae treated with convulsants moved significantly more than the ones in the control group, although this difference was higher between the individuals treated with PTZ than pilocarpine. When examining the optimal observation time, we divided the half-hour period into 5-minute time intervals, and between these, the first 5 minutes were found to be the most different from the others. There were fewer significant differences in the total movement of larvae between the other time intervals. We also performed a linear regression analysis with the cumulative values of the distance moved during the time intervals that fit the straight line. In conclusion, we recommend 30 minutes of drug pretreatment followed by a 10-minute test in light conditions with a 5-minute accommodation time. Our result paves the way toward improved experimental designs using zebrafish to develop novel pharmaceutical approaches to treat epilepsy.

In Vitro Determination of Inhibitory Effects of Humic Substances Complexing Zn and Se on SARS-CoV-2 Virus Replication.

(1) Background: Humic substances are well-known human nutritional supplement materials and they play an important performance-enhancing role as animal feed additives. For decades, ingredients of humic substances have been proven to carry potent antiviral effects against different viruses. (2) Methods: Here, the antiviral activity of a humic substance containing ascorbic acid, Se- and Zn2+ ions intended as a nutritional supplement material was investigated against SARS-CoV-2 virus B1.1.7 Variant of Concern ("Alpha Variant") in a VeroE6 cell line. (3) Results: This combination has a significant in vitro antiviral effect at a very low concentration range of its intended active ingredients. (4) Conclusions: Even picomolar concentration ranges of humic substances, Vitamin C and Zn/Se ions in the given composition, were enough to achieve 50% viral replication inhibition in the applied SARS-CoV-2 virus inhibition test.

The Chemopreventive Effects of Polyphenols and Coffee, Based upon a DMBA Mouse Model with microRNA and mTOR Gene Expression Biomarkers.

Polyphenols are capable of decreasing cancer risk. We examined the chemopreventive effects of a green tea (Camellia sinensis) extract, polyphenol extract (a mixture of blackberry (Rubus fruticosus), blackcurrants (Ribes nigrum), and added resveratrol phytoalexin), Chinese bayberry (Myrica rubra) extract, and a coffee (Coffea arabica) extract on 7,12-dimethylbenz[a]anthracene (DMBA) carcinogen-increased miR-134, miR-132, miR-124-1, miR-9-3, and mTOR gene expressions in the liver, spleen, and kidneys of CBA/Ca mice. The elevation was quenched significantly in the organs, except for miR-132 in the liver of the Chinese bayberry extract-consuming group, and miR-132 in the kidneys of the polyphenol-fed group. In the coffee extract-consuming group, only miR-9-3 and mTOR decreased significantly in the liver; also, miR-134 decreased significantly in the spleen, and, additionally, miR-124-1 decreased significantly in the kidney. Our results are supported by literature data, particularly the DMBA generated ROS-induced inflammatory and proliferative signal transducers, such as TNF, IL1, IL6, and NF-κB; as well as oncogenes, namely RAS and MYC. The examined chemopreventive agents, besides the obvious antioxidant and anti-inflammatory effects, mainly blocked the mentioned DMBA-activated factors and the mitogen-activated protein kinase (MAPK) as well, and, at the same time, induced PTEN as well as SIRT tumor suppressor genes.

Two-Year Event-Free Survival Prediction in DLBCL Patients Based on In Vivo Radiomics and Clinical Parameters.

Purpose: For the identification of high-risk patients in diffuse large B-cell lymphoma (DLBCL), we investigated the prognostic significance of in vivo radiomics derived from baseline [18F]FDG PET/CT and clinical parameters. Methods: Pre-treatment [18F]FDG PET/CT scans of 85 patients diagnosed with DLBCL were assessed. The scans were carried out in two clinical centers. Two-year event-free survival (EFS) was defined. After delineation of lymphoma lesions, conventional PET parameters and in vivo radiomics were extracted. For 2-year EFS prognosis assessment, the Center 1 dataset was utilized as the training set and underwent automated machine learning analysis. The dataset of Center 2 was utilized as an independent test set to validate the established predictive model built by the dataset of Center 1. Results: The automated machine learning analysis of the Center 1 dataset revealed that the most important features for building 2-year EFS are as follows: max diameter, neighbor gray tone difference matrix (NGTDM) busyness, total lesion glycolysis, total metabolic tumor volume, and NGTDM coarseness. The predictive model built on the Center 1 dataset yielded 79% sensitivity, 83% specificity, 69% positive predictive value, 89% negative predictive value, and 0.85 AUC by evaluating the Center 2 dataset. Conclusion: Based on our dual-center retrospective analysis, predicting 2-year EFS built on imaging features is feasible by utilizing high-performance automated machine learning.

Olive Oil Improves While Trans Fatty Acids Further Aggravate the Hypomethylation of LINE-1 Retrotransposon DNA in an Environmental Carcinogen Model.

DNA methylation is an epigenetic mechanism that is crucial for mammalian development and genomic stability. Aberrant DNA methylation changes have been detected not only in malignant tumor tissues; the decrease of global DNA methylation levels is also characteristic for aging. The consumption of extra virgin olive oil (EVOO) as part of a balanced diet shows preventive effects against age-related diseases and cancer. On the other hand, consuming trans fatty acids (TFA) increases the risk of cardiovascular diseases as well as cancer. The aim of the study was to investigate the LINE-1 retrotransposon (L1-RTP) DNA methylation pattern in liver, kidney, and spleen of mice as a marker of genetic instability. For that, mice were fed with EVOO or TFA and were pretreated with environmental carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)-a harmful substance known to cause L1-RTP DNA hypomethylation. Our results show that DMBA and its combination with TFA caused significant L1-RTP DNA hypomethylation compared to the control group via inhibition of DNA methyltransferase (DNMT) enzymes. EVOO had the opposite effect by significantly decreasing DMBA and DMBA + TFA-induced hypomethylation, thereby counteracting their effects.

Changes in miR-124-1, miR-212, miR-132, miR-134, and miR-155 Expression Patterns after 7,12-Dimethylbenz(a)anthracene Treatment in CBA/Ca Mice.

Specific gene and miRNA expression patterns are potential early biomarkers of harmful environmental carcinogen exposures. The aim of our research was to develop an assay panel by using several miRNAs for the rapid screening of potential carcinogens. The expression changes of miR-124-1, miR-212, miR-132, miR-134, and miR-155 were examined in the spleen, liver, and kidneys of CBA/Ca mice, following the 20 mg/bwkg intraperitoneal 7,12-dimethylbenz(a)anthracene (DMBA) treatment. After 24 h RNA was isolated, the miRNA expressions were analyzed by a real-time polymerase chain reaction and compared to a non-treated control. DMBA induced significant changes in the expression of miR-134, miR-132, and miR-124-1 in all examined organs in female mice. Thus, miR-134, miR-132, and miR-124-1 were found to be suitable biomarkers for the rapid screening of potential chemical carcinogens and presumably to monitor the protective effects of chemopreventive agents.

The effect of fenugreek on the gene expression of arachidonic acid metabolizing enzymes.

The main bioactive compounds of Trigonella foenum graecum L. (fenugreek) seeds are protodioscin, trigoneoside, diosgenin and yamogenin, which have anticarcinogenic potency through inhibition of cell proliferation and inhibition of prostaglandin synthesis. The effect of fenugreek on ALOX and COX genes was examined in AKR/J H-2(k) mice exposed to dimethylbenz[α]anthracene (DMBA), a potent carcinogen. The expression pattern of these genes was determined by detecting the mRNA expression in various tissues (the lungs, liver, spleen and the kidneys) in four groups of mice. Two groups were fed with normal and two of them with fenugreek containing nutriment. Each group divided into DMBA treated and control groups. Mice were autopsied on day 7 after DMBA treatment for mRNA isolation. Fenugreek consumption itself did not change gene expression compared with the control group. DMBA could increase the expression of ALOX12, ALOX15, ALOX5 genes mainly in all organs. Fenugreek consumption was generally protective in each organ in a different manner. DMBA treatment increased COX2 gene expression, but fenugreek was protective in all tissues examined. In COX1 gene, the fenugreek diet could suppress the expression, except for spleen, independently from carcinogen exposure. Therefore by inhibiting the arachidonic acid metabolism fenugreek may prevent tumorigenesis.

Mixtures of Uncaria and Tabebuia extracts are potentially chemopreventive in CBA/Ca mice: a long-term experiment.

A long-term experimental animal model was developed by our research group for the evaluation of potential chemopreventive effects. The inhibitory effects of agents on carcinogen (7,12-dimethylbenz[a]anthracene (DMBA) induced molecular epidemiological biomarkers, in this case the expression of key onco/suppressor genes were investigated. The expression pattern of c-myc, Ha-ras, Bcl-2, K-ras protooncogene and p53 tumour suppressor gene were studied to elucidate early carcinogenic and potential chemopreventive effects. The consumption of so-called Claw of Dragon tea (CoD™ tea) containing the bark of Uncaria guianensis, Cat's Claw (Uncaria sp. U. tomentosa) and Palmer trumpet-tree (Tabebuia sp. T. avellanedae) was able to decrease the DMBA-induced onco/suppressor gene overexpression in a short-term animal experiment. In a following study CBA/Ca mice were treated with 20 mg/kg bw DMBA intraperitoneally (i.p.) and the expression patterns of onco/suppressor genes were examined at several time intervals. According to the examined gene expression patterns in this long-term experiment the chemopreventive effect of CoD™ tea consumption could be confirmed.

In vivo effects of olive oil and trans-fatty acids on miR-134, miR-132, miR-124-1, miR-9-3 and mTORC1 gene expression in a DMBA-treated mouse model.

Both the intake of beneficial olive oil and of harmful trans-fatty acids (TFAs) in consumed foods are of great significance in tumor biology. In our present study we examined the effects they exert on the expression patterns of miR-134, miR-132, miR-124-1, miR-9-3 and mTOR in the liver, spleen and kidney of mice treated with 7,12-dimethylbenz [a] anthracene (DMBA). Feeding of TFA-containing diet significantly increased the expression of all studied miRs and mTORC1 in all organs examined, except the expression of mTORC1 in the spleen and kidney. Diet containing olive oil significantly reduced the expression of miR-124-1, miR-9-3 and mTORC1 in the liver and spleen. In the kidney, apart from the mTORC1 gene, the expression of all miRs examined significantly decreased compared to the DMBA control. According to our results, the cell membrane protective, antioxidant, and anti-inflammatory effects of olive oil and the cell membrane damaging, inflammatory, and carcinogenic properties of TFA suggest negative feedback regulatory mechanisms. In contrast to our expectations, mTORC1 gene expression in the kidney has not been shown to be an appropriate biomarker-presumably, because the many complex effects that regulate mTOR expression may quench each other.

The effects of flavonoids, green tea polyphenols and coffee on DMBA induced LINE-1 DNA hypomethylation.

The intake of carcinogenic and chemopreventive compounds are important nutritional factors related to the development of malignant tumorous diseases. Repetitive long interspersed element-1 (LINE-1) DNA methylation pattern plays a key role in both carcinogenesis and chemoprevention. In our present in vivo animal model, we examined LINE-1 DNA methylation pattern as potential biomarker in the liver, spleen and kidney of mice consuming green tea (Camellia sinensis) extract (catechins 80%), a chinese bayberry (Morella rubra) extract (myricetin 80%), a flavonoid extract (with added resveratrol) and coffee (Coffee arabica) extract. In the organs examined, carcinogen 7,12-dimethylbenz(a)anthracene (DMBA)-induced hypomethylation was prevented by all test materials except chinese bayberry extract in the kidneys. Moreover, the flavonoid extract caused significant hypermethylation in the liver compared to untreated controls and to other test materials. The tested chemopreventive substances have antioxidant, anti-inflammatory properties and regulate molecular biological signaling pathways. They increase glutathione levels, induce antioxidant enzymes, which decrease free radical damage caused by DMBA, and ultimately, they are able to increase the activity of DNA methyltransferase enzymes. Furthermore, flavonoids in the liver may inhibit the procarcinogen to carcinogen activation of DMBA through the inhibition of CYP1A1 enzyme. At the same time, paradoxically, myricetin can act as a prooxidant as a result of free radical damage, which can explain that it did not prevent hypomethylation in the kidneys. Our results demonstrated that LINE-1 DNA methylation pattern is a useful potential biomarker for detecting and monitoring carcinogenic and chemopreventive effects of dietary compounds.

Effect of 7,12-Dimethylbenz(α)anthracene on the Expression of miR-330, miR-29a, miR-9-1, miR-9-3 and the mTORC1 Gene in CBA/Ca Mice.

BACKGROUND/AIM: Development of malignant tumors is preceded by molecular biological events. Our aim was to establish an assay panel by using miRNAs and other genes for the rapid screening of potential carcinogens or chemopreventive agents. MATERIALS AND METHODS: Six male and 6 female CBA/Ca mice received 20 mg/bwkg 7,12-dimethylbenz(α)anthracene (DMBA) intraperitoneally, and 24 h later RNA was isolated from parenchymal organs. Expression of miR-330, miR-29a, miR-9-1, miR-9-3 and mTORC1 was analysed by real time polymerase chain reaction and compared to non-treated controls. RESULTS: DMBA caused significant alterations in the expression of the studied genes. The most profound changes were the strongly elevated miR-9-3 and mTORC1 expressions in female mice in all organs studied. CONCLUSION: miR-9-3 and mTORC1 expression in female mice were found to be the most suitable biomarkers for rapid identification of possible carcinogenic effects.

Early modification of c-myc, Ha-ras and p53 expressions by chemical carcinogens (DMBA, MNU).

7,12-Dimethylbenz[a]anthracene (DMBA) and N-methyl-N-nitrosourea (MNU) are important environmental carcinogens. Their different biological effects were examined in CBA/Ca H-2(K) haplotype inbred mice on the gene expression of c-myc, Ha-ras and p53 through a 24 hour period. Elevated expression of c-myc and Ha-ras genes was found in the spleen, lung, thymus and lymph nodes 6 and 12 hours after DMBA treatment and in the lung and thymus 3 hours after MNU treatment. In the liver, DMBA induced strong onco/suppressor gene expression as early as 6 hours after the treatment, but MNU increased the p53 gene expression 12 hours after the treatment. The gene expression patterns reflected the different mechanism of the direct acting MNU and metabolically activated DMBA. This phenomenon provides evidence as to the usefulness of detection of onco/supressor key gene expression as early molecular epidemiological biomarkers of carcinogenesis and carcinogenic exposure in animal model, useful in human cancer prevention practice as well.

Early modification of c-myc, Ha-ras and p53 expressions by N-methyl-N-nitrosourea.

Methylnitrosourea (MNU) is a well-known pluripotent direct-acting carcinogen. Formation of MNU following incubation of various meats with additional nitrite under in vitro acidic conditions is possible. It is possible that many species, including humans, are exposed to carcinogenic MNU, generated in their alimentary tract. Previously, an animal model was developed by our research group to investigate the expression of three genes c-myc, Ha-ras and p53 as early molecular epidemiological biomarkers of carcinogenic exposure or carcinogenesis caused by DMBA (dimethylbenz[alpha]anthracene). The aim of this study was to investigate the early effect of MNU on the gene expression levels. MNU is a direct-acting carcinogen which spontaneously and rapidly degrades, so any effect on the gene expression is observed in 24 hours. Our results show the maximum effect in vivo on the gene expression at 12 hours after the MNU treatment; on the other hand, 24 hours after the treatment, the elevated gene expressions decreased in target organs (bone marrow, lung, lymph nodes). Our results correspond to "long-term" experiments of the carcinogenic effect of MNU in different target organs. Our findings suggest that MNU has an impact on the expression of c-myc, Ha-ras and p53 genes in 12 hours, especially in bone marrow. Overexpression of these genes occurs as an early biological effect of exposure to chemical carcinogens. According to our results, the high expression of these genes could indicate MNU exposure and these genes could take part in MNU-induced tumorigenesis.

Asymmetric dimethylarginine levels in preeclampsia - Systematic review and meta-analysis.

OBJECTIVE: Preeclampsia (PE) is the leading cause of maternal and perinatal mortality around the world. The impaired function of fetal-placental vasculature is a key factor in PE. Several studies have investigated the connection between PE and endothelial dysfunction. Also, many authors have examined the changes in asymmetric dimethylarginine (ADMA) as a prominent marker of endothelial dysfunction. Our study aim is to review and analyse the connections between PE and ADMA levels. METHODS: To obtain data we performed a comprehensive literature search in Pubmed, Embase and Web of Science. Standardized mean differences were used to estimate the differences in ADMA levels. RESULTS: The quantitative analysis included 10 studies reporting a total number of 631 PE and 498 healthy pregnant individuals. We found significantly higher ADMA levels in PE patients compared to controls, when comparing the ADMA levels of the patients to the ADMA levels of the controls (z = 5.93, p < 0.001). This difference was present regardless of the measurement method. Regarding the onset of PE, we found significantly higher ADMA levels in patients suffering from early-onset PE when comparing the ADMA levels of the early-onset PE patients to that of the controls (z = 2.82, p = 0.005). However, we did not find such difference when we compared late-onset PE patients' ADMA levels to controls. CONCLUSION: ADMA is significantly higher in PE patients than in the controls. Elevated ADMA levels can play a major role in the development of PE, but more research is needed to clarify the connection between the two.