Original Articles 2020
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- J. G. Hengstler
Leibniz Research Centre for Working Environment and Human Factors
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- B. C. Behera, Pune, India
- T. Chen, Stanford, CA/USA
- E. Corsini, Milan, Italy
- P. Diel, Cologne, Germany
- C. Esser, Duesseldorf, Germany
- P. B. Farmer, Leicester/UK
- S. Hammad, South Valley/Egypt
- P. Jennings, Innsbruck, Austria
- M. Lotti, Bonn, Germany / Padova, Italy
- P. Micke, Uppsala, Sweden
- A. N. Misra, Ranchi, Jharkhand State, India
- B. Ponugoti, Pennsylvania, PA/USA
- C. Pope, Stillwater, OK/USA
- K. Renganathan, Johnstown, PA/USA
- S. D. Ray, Fort Wayne, IN/USA
- M. Schwarz, Tuebingen, Germany
- J. Timmer, Freiburg, Germany
- H. van Steeg, Bilthoven, The Netherlands
- A. Winterpacht, Erlangen, Germany
- Y. Zhou, New Haven, CT/USA
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Item Clinical characteristics and outcomes of diabetics hospitalized for COVID-19 infection(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-11-16) Mansour, Asieh; Sajjadi-Jazi, Sayed Mahmoud; Kasaeian, Amir; Khosravi, Bardia; Sorouri, Majid; Azizi, Fatemeh; Rajabi, Zeinab; Motamedi, Fatemeh; Sirusbakht, Azin; Eslahi, Masoud; Mojtabbavi, Heila; Ali Reza Sima, Ali Reza; Radmard, Amir Reza; Mohajeri-Tehrani, Mohhamad Reza; Abdollahi, MohammadSome debates exist regarding the association of diabetes mellitus (DM) with COVID-19 infection severity and mortality. In this study, we aimed to describe and compare the clinical characteristics and outcomes of hospitalized COVID-19 patients with and without DM. In this single-centered, retrospective, observational study, we enrolled adult patients with COVID-19 who were admitted to the Shariati hospital, Tehran, Iran, from February 25, 2020, to April 21, 2020. The clinical and paraclinical information as well as the clinical outcomes of patients were collected from inpatient medical records. A total of 353 cases were included (mean age, 61.67 years; 57.51 % male), of whom 111 patients were diabetics (mean age, 63.66 years; 55.86 % male). In comparison to those without DM, diabetic patients with COVID-19 were more likely to have other comorbidities, elevated systolic blood pressure (SBP), elevated blood sugar (BS), lower estimated glomerular filtration rate (eGFR) and elevated blood urea nitrogen (BUN). The association of DM with severe outcomes of COVID-19 infection (i.e. mechanical ventilation, median length of hospital stay and mortality) remained non-significant before and after adjustments for several factors including age, sex, body mass index (BMI), smoking status, and comorbidities. Based on our results DM has not been associated with worse outcomes in hospitalized patients for COVID-19 infection.Item Circ_0010729 knockdown protects cardiomyocytes against hypoxic dysfunction via miR-370-3p/TRAF6 axis(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-11-11) Zhang, Jingjing; Gao, Chuanyu; Zhang, Jing; Ye, FaminFew studies have addressed the mechanism by which circ_0010729 regulates hypoxia-induced cell injury in cardiovascular diseases. However, its role and its regulatory mechanism in myocardial infarction remain to be explored. Cell viability, cycle, apoptosis, and migration were analyzed using cell counting kit-8 assay, flow cytometry, caspase-3 activity assay kit and transwell assay, respectively. Tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) concentrations were examined by enzyme-linked immunosorbent assay. Glucose metabolism was calculated by detecting ATP production, glucose uptake and lactate production. Levels of circ_0010729, miR-370-3p and TNF Receptor Associated Factor 6 (TRAF6) were detected using quantitative real-time polymerase chain reaction or western blot. The direct interaction between circ_0010729 and TRAF6 or miR-370-3p was verified using dual-luciferase reporter assay and RNA immunoprecipitation assay. Under hypoxia condition, cardiomyocytes suffered from cell viability suppression, cell cycle arrest, cell apoptosis promotion, migration reduction, increase of inflammatory factor IL-6 and TNF-α, as well as glycolysis inhibition. Circ_0010729 expression was up-regulated in the cardiomyocytes at different hypoxia-exposed time points. Circ_0010729 knockdown protected cardiomyocytes against hypoxic dysfunction, while circ_0010729 overexpression showed inverse effects. MiR-370-3p was confirmed to directly bind to circ_0010729 or TRAF6. MiR-370-3p inhibition attenuated the protective effects of circ_0010729 knockdown on hypoxia-modulated cardiomyocyte dysfunction. MiR-370-3p restoration protected cardiomyocytes against hypoxic injury via targeting TRAF6. Besides, circ_0010729 indirectly regulated TRAF6 expression via miR-370-3p. This study demonstrated that circ_0010729 knockdown attenuated hypoxia-induced cardiomyocyte dysfunction via miR-370-3p/TRAF6 axis, indicating a potential therapeutic target for myocardial infarction.Item Revealing the astragalin mode of anticandidal action(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-10-29) Ivanov, Marija; Kannan, Abhilash; Stojkovic, Dejan; Glamočlija, Jasmina; Golič Grdadolnik, Simona; Sanglard, Dominique; Soković, MarinaDue to limited arsenal of systemically available antifungal agents, infections caused by Candida albicans are difficult to treat and the emergence of drug-resistant strains present a major challenge to the clinicians worldwide. Hence further exploration of potential novel and effective antifungal drugs is required. In this study we have explored the potential of a flavonoid, astragalin, in controlling the growth of C. albicans, in both planktonic and biofilm forms by microdilution method; and in regulating the morphological switch between yeast and hyphal growth. Astragalin ability to interfere with membrane integrity, ergosterol synthesis and its role in the regulation of genes encoding for efflux pumps has been addressed. In our study, astragalin treatment produced good antimicrobial and significant antibiofilm activity. Anticandidal activity of astragalin was not related to ERG11 downregulation, neither to direct binding to CYP51 enzyme nor was linked to membrane ergosterol assembly. Instead, astragalin treatment resulted in reduced expression of CDR1 and also affected cell membrane integrity without causing cytotoxic effect on human gingival fibroblast cells. Considering that astragalin-mediated decreased expression of efflux pumps increases the concentration of antifungal drug inside the fungal cells, a combinatorial treatment with this agent could be explored as a novel therapeutic option for candidiasis.Item Overexpression and translocation of dynamin 2 promotes tumor aggressiveness in breast carcinomas(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-10-29) Sajed, Roya; Saeednejad Zanjani, Leili; Rahimi, Mandana; Mansoori, Maryam; Zarnani, Amir-Hassan; Madjd, Zahra; Ghods, RoyaDynamin 2 is a GTPase protein that has been implicated in cancer progression through its various roles such as endocytosis, morphogenesis, epithelial-mesenchymal transition (EMT), cellular contractions, and focal adhesion maturation. The increased expression levels of this molecule have been demonstrated with the development of several cancers such as prostate, pancreas, and bladder. However, its clinical significance in breast cancer is unclear yet. In the present study, the membranous, cytoplasmic, and nuclear expression levels of dynamin 2 molecule were evaluated for the first time, using immunohistochemistry (IHC) on tissue microarray (TMA) slides in 113 invasive breast cancer tissues. Moreover, afterward, the association between the dynamin 2 expression and clinicopathological features was determined. Our finding showed that, a higher nuclear expression of dynamin 2 is significantly associated with an increase in tumor stage (P = 0.05), histological grade (P = 0.001), and age of the patients (P = 0.03). In addition, analysis of the cytoplasmic expression levels of this molecule revealed that, there was a statistically significant difference between the expression levels of dynamin 2 among the different breast cancer subtypes (P = 0.003). Moreover, a significant association was found between the increased expression of dynamin 2 membranous and vascular invasion (VI) (P = 0.02). We showed that dynamin 2 protein expression has an association with more aggressive tumor behavior and more advanced disease in the patients with breast cancer; therefore, dynamin 2 molecule could be considered as an indicator of disease progression and aggressiveness.Item Interleukin-6 is associated with tryptophan metabolism and signs of depression in individuals with carbohydrate malabsorption(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-10-28) Enko, Dietmar; Zelzer, Sieglinde; Wenninger, Julian; Holasek, Sandra; Schnedl, Wolfgang J.; Baranyi, Andreas; Herrmann, Markus; Meinitzer, AndreasThe aim of the present study was to investigate possible associations between interleukin-6 (IL-6), interferon-gamma (INF-γ), tumor necrosis factor-alpha (TNF-α), lactoferrin and lipopolysaccharide binding protein (LBP) with TRP metabolism and signs of depression in a large cohort of outpatients referred for carbohydrate malabsorption testing. Serum concentrations of IL-6, INF-γ, TNF-α, lactoferrin, LBP, tryptophan (TRP), kynurenine (KYN) and kynuric acid were determined in 250 adults referred for lactose and fructose malabsorption testing. All participants filled out the Beck Depression Inventory (BDI). Serum IL-6 levels were positively correlated with the BDI score (p = 0.001, ρ = 0.205) and indicators of TRP metabolism (KYN/TRP ratio, KYN) (P-values < 0.05, ρ = 0.176 and 0.136). Ninety-five individuals with a BDI score > 13 showed significantly higher IL-6 serum levels (1.7 [1.0 – 2.8] vs. 1.1 [0.8 – 1.7] pg/mL, p < 0.001) compared to 115 individuals with a BDI score ≤ 13. LBP showed a positive correlation with the KYN/TRP ratio (p = 0.005, ρ = 0.177). IL-6 and LBP were associated with indicators of TRP metabolism. IL-6 was found to be linked to signs of depression. Individuals with the presence of depressive symptoms showed higher serum IL-6 levels compared to individuals without depressive symptoms.Item Downregulation of Sirt1 is correlated to upregulation of p53 and increased apoptosis in epicardial adipose tissue of patients with coronary artery disease(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-10-02) Khanahmadi, Mahdieh; Manafi, Babak; Tayebinia, Heidar; Karimi, Jamshid; Khodadadi, IrajThe higher expression level of p53 in epithelial adipose tissue (EAT) has previously been reported in atherosclerosis. Since we hypothesized that the expression of p53 is modulated by Sirt1, the aim of this study was to determine the expression levels of Sirt1 and p53 and to investigate their correlation to apoptosis in EAT of patients with coronary artery disease (CAD). Thirty-five patients with more than 50 % stenosis in at least one of the main coronary arteries were considered as CAD group while 29 patients with no clinical signs of atherosclerosis who underwent open-heart surgery for valve replacement were classified as control group. EAT biopsy samples were collected from all participants during surgery. Sirt1, p53, Bax, and Bcl‑2 gene expression levels were determined in EAT by qRT-PCR and Western blotting was carried out to assess Sirt1 and p53 protein levels. Hematoxylin and eosin staining was used for histopathological analysis. mRNA and protein levels of Sirt1 in EAT were significantly lower in patients with CAD compared with control group, whereas CAD patients showed greater p53 gene and protein expressions. In addition, inverse correlations were observed between Sirt1 and p53 at both mRNA and protein levels. The Bax and ratio of Bax/Bcl-2 gene expressions were higher in CAD group, but no difference was observed in Bcl-2 expression. Histopathological analysis showed apoptotic bodies and infiltrated immune cells in EAT of CAD group. Our results suggest that the Sirt1-p53 axis may involve in atherosclerosis by promotion of apoptosis.Item Differential engulfment of Staphylococcus aureus and Pseudomonas aeruginosa by monocyte-derived macrophages is associated with altered phagocyte biochemistry and morphology(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-09-30) El Mohtadi, Mohamed; Pilkington, Lisa; Liauw, Christopher M.; Ashworth, Jason J.; Dempsey-Hibbert, Nina; Belboul, Amina; Whitehead, Kathryn A.Knowledge of changes in macrophages following bacterial engulfment is limited. U937-derived macrophages were incubated with Staphylococcus aureus or Pseudomonas aeruginosa. Morphological and biochemical changes in macrophages following host-pathogen interactions were visualized using Scanning Electron Microscopy (SEM) and Fourier-Transform Infrared Spectroscopy (FTIR) respectively. Principal Component Analysis (PCA) was used to assess the variability in the FTIR spectra. Following host-pathogen interactions, survival of S. aureus was significantly lower than P. aeruginosa (P<0.05) and cellular morphology of macrophages was different after incubation with S. aureus compared to P. aeruginosa. Following incubation with S. aureus macrophages were more globular and amorphous in shape whereas long linear pseudopodia were observed following incubation with P. aeruginosa. Distinct FTIR spectra were identified in macrophages post interaction with the different bacteria and PCA analysis demonstrated distinct biochemical differences in the phagocytes following engulfment of the bacteria, with > 99 % of variability in the FTIR spectra explained by the first two principal components. These findings demonstrated that there were clear morphological and biochemical changes in macrophages following engulfment of two different bacterial types suggesting that the biochemical components of the bacterial cell wall influenced the biochemical characteristics and hence the morphology of macrophages in distinct ways.Item In vitro anticancer activity of Scrophularia amplexicaulis extracts on MCF-7 and WEHI-164 cell line(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-09-22) Valiyari, Samira; Beiranvand, Elham; Samimi, Azin; Yaripour, Saeid; Baradaran, Behzad; Delazar, Abbas; Forouzesh, MehdiScrophularia amplexicaulis is an Iranian endemic plant belonging to the Scrophulariaceae family, which is used in traditional medicine to treat many diseases. The aim of this study was to evaluate the in vitro anticancer activity of S. amplexicaulis extracts against human breast carcinoma (MCF-7) and mouse fibrosarcoma (WEHI-164) cell lines. The ground aerial parts of S. amplexicaulis were soxhlet-extracted with n-hexane, dichloromethane and methanol. MTT assay exhibited that dichloromethane and methanol extracts remarkably inhibited the growth of MCF-7 and WEHI-164 cancer cells in a dose-and time-dependent manner with little cytotoxicity on normal cell line HUVEC. Cell death ELISA, TUNEL assay, and the cleavage of poly ADP-ribose polymerase (PARP) uncovered that the cytotoxic effects of dichloromethane and methanol extracts were attributed to apoptosis in cancerous cells. Furthermore, quantitative real-time PCR revealed significant increases in the mRNA expression levels of p-53, caspase-3, caspase-9, Bax, and also a decrease in Bcl-2 expression. These results suggested that the extracts mainly induced apoptosis via a mitochondria-mediated intrinsic pathway. Notably, dichloromethane extract had higher cytotoxic and apoptotic activities than that of methanol extract, against both cancer cell lines, particularly MCF-7 cells. Our results indicate that S. amplexicaulis may serve as a promising source of potent agents for the treatment of human cancers.Item The association of a genetic variant in CDKN2A/B gene and the risk of colorectal cancer(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-09-14) Rahmani, Farzad; Avan, Amir; Amerizadeh, Forouzan; Ferns, Gordon A.; Talebian, Sahar; Shahidsales, SoodabehColorectal cancer is among the most aggressive tumors, and its development involves an interplay between various genetic and environmental familial risk factors. Several genetic polymorphisms have been reported to be associated with colorectal cancer in recent studies. In this current study, we aimed to evaluate the possible relationship between a CDKN2A/B, single nucleotide polymorphisms (SNP) (rs10811661), with the risk of colorectal cancer. A total of 541 individuals with, or without cancer were recruited. DNA was extracted, and genotyped using a Taq-Man based real‐time PCR method. The rs10811661 SNP was associated with an increased risk of colorectal cancer (additive model: OR=3.46, CI= 1.79-6.69, p<0.0001 and recessive model: 5.72, CI= 3.12-10.49, p<0.0001). The distribution of minor alleles in the total population for homozygote allele was 9.2 %, while this was 20.1 % for heterozygotes. In summary, our findings indicate that the rs10811661 polymorphism of the CDKN2A/B gene was strongly related to the occurrence of colorectal cancer suggesting its potential role as a prognostic biomarker for the management of colorectal cancer.Item Negative impact of COVID-19 pandemic on sleep quantitative parameters, quality, and circadian alignment(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-09-11) Salehinejad, Mohammad Ali; Majidinezhad, Maryam; Ghanavati, Elham; Kouestanian, Sahar; Vicario, Carmelo M.; Nitsche, Michael A.; Nejati, VahidThe COVID-19 pandemic has spread worldwide, affecting millions of people and exposing them to home quarantine, isolation, and social distancing. While recent reports showed increased distress and depressive/anxiety state related to COVID-19 crisis, we investigated how home quarantine affected sleep parameters in healthy individuals. 160 healthy individuals who were in home quarantine in April 2020 for at least one month participated in this study. Participants rated and compared their quantitative sleep parameters (time to go to bed, sleep duration, getting-up time) and sleep quality factors, pre-and during home quarantine due to the COVID-19 pandemic. Furthermore, participants’ chronotype was determined to see if sleep parameters are differentially affected in different chronotypes. Time to fall asleep and get-up in the morning were significantly delayed in all participants, indicating a significant circadian misalignment. Sleep quality was reported to be significantly poorer in all participants and chronotypes. Poor sleep quality included more daily disturbances (more sleep disturbances, higher daily dysfunctions due to low quality of sleep) and less perceived sleep quality (lower subjective sleep quality, longer time taken to fall asleep at night, more use of sleep medication for improving sleep quality) during home quarantine. Home quarantine due to COVID-19 pandemic has a detrimental impact on sleep quality. Online interventions including self-help sleep programs, stress management, relaxation practices, stimulus control, sleep hygiene, and mindfulness training are available interventions in the current situation.Item Prosopis juliflora leave extracts induce cell death of MCF-7, HepG2, and LS-174T cancer cell lines(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-09-09) Elbehairi, Serag Eldin I.; Ezzat Ahmed, Ahmed; Alshati, Ali A.; Al-Kahtani, Mohammed A.; Alfaifi, Mohammad Y.; Alsyaad, Khalid M.; Alalmie, Ali Yahya A.; Elimam Ahamed, Mohammed M.; Moustafa, Mahmoud F.; Alhag, Sadeq K.; Al-Abd, Ahmed M.; Abbas, Ahmed M.Prosopis juliflora (P. juliflora) is a widespread phreatophytic tree, which belongs to the Fabaceae family. The goal of the present study is to investigate the potential anti-cancer effect of P. juliflora leave extracts and to identify its chemical composition. For this purpose, MCF-7 (breast), HepG2 (liver), and LS-174T (colorectal) cancer cell lines were cultivated and incubated with various concentrations of P. juliflora leave extracts, and its impact on cell viability, proliferation, and cell cycle stages was investigated. P. juliflora leave extracts induced concentration-dependent cytotoxicity against all tested cancer cell lines. The calculated IC50 was 18.17, 33.1 and 41.9 μg/ml for MCF-7, HePG2 and LS-174T, respectively. Detailed analysis revealed that the cytotoxic action of P. juliflora extracts was mainly via necrosis but not apoptosis. Moreover, DNA content flow cytometry analysis showed cell-specific anti-proliferative action and cell cycle stages arrest. In order to identify the anti-cancer constituents of P. juliflora, the ethyl extracts were analyzed by liquid chromatography-mass spectrometry. The major constituents identified in the ethyl extracts of P. juliflora leaves were hydroxymethyl-pyridine, nicotinamide, adenine, and poly-(methyl methacrylate) (PMMA). In conclusion, P. juliflora ethyl acetate extracts have a potential anti-cancer effect against breast adenocarcinoma, hepatocellular carcinoma, and colorectal adenocarcinoma, and is enriched with anti-cancer constituents.Item Assessment of trimethylamine-N-oxide at the blood-cerebrospinal fluid barrier(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-09-09) Enko, Dietmar; Zelzer, Sieglind; Niedrist, Tobias; Holasek, Sandra; Baranyi, Andreas; Schnedl, Wolfgang J.; Herrmann, Markus; Meinitzer, AndreasRecently, the microbiome-derived trimethylamine-N-oxide (TMAO) was shown to be present in human cerebrospinal fluid (CSF). However, data on the potential of TMAO crossing the blood-CSF barrier are still lacking. This retrospective study aimed at investigating possible associations between the CSF/serum albumin (QALB) and TMAO (QTMAO) quotient and evaluating QTMAO values in individuals with and without blood-CSF barrier dysfunction. A total of 290 patients, who underwent diagnostic lumbar puncture with QALB and QTMAO determination, were evaluated. Serum and CSF TMAO measurements were performed on a tandem mass spectrometry SCIEX QTRAP 4500 (Applied Biosystems, Framingham, MA, USA) coupled with an Agilent 1260 Infinity HPLC system (Agilent Technologies Santa Clara, CA, USA). Serum and CSF albumin were measured on the Atellica® NEPH 630 system (Siemens Healthineers, Erlangen, Germany). CSF TMAO levels were positively correlated with serum TMAO levels (ρ = 0.709, p < 0.001). The QALB was significantly associated with the QTMAO (ß-coefficient = 0.312; p < 0.001). A total of 117 patients with blood-CSF barrier dysfunction had significantly higher median (Q1 – Q3) QTMAO values (4.7 (2.8 – 7.5) vs. 3.8 (2.5 – 5.7) x 10-1, p = 0.002) compared to 173 individuals with normal blood-CSF barrier function. CSF and serum TMAO concentrations were significantly associated in 290 CSF/serum pairs from lumbar punctures of clinical routine. QALB showed a relevant influence on QTMAO. Present results indicate that TMAO may cross the blood-CSF barrier.Item Polygonum minus essential oil modulates cisplatin-induced hepatotoxicity through inflammatory and apoptotic pathways(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-09-09) Abd Rashid, Norhashima; Hussan, Farida; Hamid, Asmah; Adib Ridzuan, Nurul Raudzah; Halim, Syarifah Aisyah Syed Abdul; Abdul Jalil, Nahdia Afiifah; Najib, Nor Haliza Mohamad; Teoh, Seong Lin; Budin, Siti BalkisOxidative stress, inflammation and apoptosis are thought as primary mediators of cisplatin-induced hepatotoxicity. The objective of this study was to determine the protective effect of Polygonum minus essential oil in cisplatin-induced hepatotoxicity. A total of forty-two male rats were randomly divided into seven groups: control, cisplatin, β-caryophyllene 150 mg/kg (BCP), PmEO 100 mg/kg + cisplatin (PmEO100CP), PmEO 200 mg/kg + cisplatin (PmEO200CP), PmEO 400 mg/kg + cisplatin (PmEO400CP) and PmEO 400 mg/kg (PmEO400). Rats in the BCP, PmEO100CP, PmEO200CP, PmEO400CP and PmEO400 group received respective treatment orally for 14 consecutive days prior to cisplatin injection. All animals except for those in the control group and PmEO400 were administered with a single dose of cisplatin (10 mg/kg) intraperitoneally on day 15 and all animals were sacrificed on day 18. PmEO100CP pretreatment protected against cisplatin-induced hepatotoxicity by decreasing CYP2E1 and indicators of oxidative stress including malondialdehyde, 8-OHdG and protein carbonyl which was accompanied by increased antioxidant status (glutathione, glutathione peroxidase, superoxide dismutase and catalase) as compared to cisplatin group. PmEO100CP pretreatment also modulated changes in liver inflammatory markers (TNF-α, IL-1α, IL-1β, IL-6 and IL-10). PmEO100CP administration also notably reduced cisplatin-induced apoptosis significantly as compared to cisplatin group. In conclusion, our results suggested that P. minus essential oil at a dose of 100 mg/kg may protect against cisplatin-induced hepatotoxicity possibly via inhibition of oxidative stress, inflammation and apoptosis.Item Knockdown of CSNK2β suppresses MDA-MB231 cell growth, induces apoptosis, inhibits migration and invasion(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-09-07) Karna, Shibendra Kumar Lal; Lone, Bilal Ahmad; Ahmad, Faiz; Shahi, Nerina; Pokharel, Yuba RajBreast cancer is the most common cancer among women worldwide. Among different types of breast cancer known, treatment of triple-negative breast cancer is a major challenge because of its aggressiveness and poor prognosis; thus, identification of specific drivers is required for targeted therapies of breast cancer malignancy. Protein Casein Kinase (CSNK) is a serine/threonine kinase that exists as a tetrameric complex consisting of two catalytic (α and /or α') and two regulatory β subunits. CSNK2β can also function independently without catalytic subunits and exist as a distinct population in cells. This study aims to elucidate the role of Casein Kinase 2β (CSNK2β) gene in cell proliferation, cell cycle, migration and apoptosis of triple-negative breast cancer MDA-MB-231 cells. The silencing of CSNK2β in MDA-MB-231 cells resulted in decreased cell viability and colony formation. Cell cycle analysis showed a significant arrest of cells in G2M phase. Hoechst and CM-H2DCFDA staining showed nuclear condensation and augmented intracellular reactive oxygen species (ROS) production. Furthermore, silencing of CSNK2β in MDA-MB-231 cells modulated the apoptotic machinery- BAX, Bcl-xL, and caspase 3; autophagy machinery-Beclin-1 and LC3-1; and inhibited the vital markers (p-ERK, c-Myc, NF-κB, E2F1, PCNA, p38-α) associated with cell proliferation and DNA replication pathways. In addition, knockdown of CSNK2β also affected the migration potential of MDA-MB-231, as observed in the wound healing and transwell migration assays. Altogether, the study suggests that CSNK2β silencing may offer future therapeutic target in triple-negative breast cancer.Item Curcumin as an indirect methylation inhibitor modulates the effects of Toxoplasma gondii on genes involved in male fertility(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-08-24) Saki, Jasem; Sabaghan, Mohamad; Arjmand, Reza; Teimoori, Ali; Rashno, Mohammad; Saki, Ghasem; Shojaee, SaeedehToxoplasma gondii is a common protozoan parasite, which infects warm-blooded mammals, including mice and humans, throughout the world. The negative effects of T. gondii infection on the human reproductive system have been documented, especially in females. However, only few studies have examined the effects of T. gondii infection on the male reproductive system. Previous research shows that T. gondii can induce DNA methylation in some gene promoters, which are key regulators of spermatogenesis. Therefore, this study aimed to evaluate the effects of curcumin on the activity of DNA methyltransferases (DNMTs), as well as selected genes, involved in spermatogenesis in spermatogenic cells. In the spermatogenic cells exposed to T. gondii, there was a significant increase in DNMT1 and DNMT3A gene expression and a significant reduction in HSPA1A, MTHR, and DAZL gene expression, compared to the controls. The present results showed that curcumin could regulate changes in T. gondii-mediated gene expression. The effect of T. gondii on DNMT activity was also investigated in this study. A 40 % increase in DNMT activity was observed due to T. gondii infection. However, DNMT activity was restored by treatment with 20 μM curcumin for eight hours. The results revealed that T. gondii increases the NF-κB activity, compared to the control group. The increase in NF-κB activity, induced by T. gondii, was inhibited by curcumin. In conclusion, T. gondii, by increasing DNMT expression and activity, leads to an increase in NF-κB activity in cells. On the other hand, curcumin reduced DNA methylation, induced by T. gondii, owing to its NF-κB-inhibiting properties. Therefore, curcumin, as a hypomethylating agent, can be potentially used to alleviate the negative effects of T. gondii on the male reproductive system.Item Plasma vascular endothelial growth factor B is elevated in non-alcoholic fatty liver disease patients and associated with blood pressure and renal dysfunction(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-08-20) Ye, Xiaofeng; Kong, Wen; Zafar, Mohammad Ishraq; Zeng, Junchao; Yang, Rui; Chen, Lu-LuVascular endothelial growth factor B (VEGF-B) is a critical metabolic regulator in insulin resistance, and lipid distribution. We intended to ascertain the relationship between circulating VEGF-B and non-alcoholic fatty liver disease (NAFLD) in the general public. We recruited a total of 194 general participants for a routine physical health examination; of these, 84 participants were identified with NAFLD and 110 without NAFLD based on ultrasonographic findings. Homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), HbA1c, liver function, kidney function, plasma VEGF-B levels and indexes of metabolic syndrome (blood pressure, fasting plasma glucose, fasting lipids) were evaluated. Plasma VEGF-B values were significantly higher in individuals with NAFLD compared to those without NAFLD (P = 0.022), and analysis of covariance confirmed this result. VEGF-B showed a positive correlation with γ-glutamyl transpeptidase (γ-GT) and HOMA-IR in univariate analysis (q = 0.242; P = 0.001; q =0.174; P = 0.019, respectively). Multiple linear regression analysis showed that γ-GT and ALT were independently correlated with VEGF-B even after adjusted for gender and age (q = 0.286; P = 0.01; q =0.237; P = 0.033, respectively). Moreover, plasma VEGF-B showed a powerful correlation with blood pressure and renal dysfunction. Plasma VEGF-B might be a new clinical variable related to NAFLD and could be a proper biomarker for the early detection of hypertension and renal dysfunction. However, further studies with large cohorts’ size are warranted to validate our findings.Item Association between resilience and a functional polymorphism in the serotonin transporter (SLC6A4) gene(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-08-19) González-Giraldo, Yeimy; Forero, Diego A.Resilience is a mechanism used by humans to adapt to adverse situations. It is a protective factor against mental health problems. This process can be influenced by environmental and genetic factors. Several genes have been associated with interindividual differences in resilience levels, but the results are inconclusive. Therefore, the aim of this meta-analysis was to evaluate the effect of a functional polymorphism (5-HTTLPR) in the SLC6A4 gene on resilience levels. A search in PubMed, HugeNavigator and Google Scholar databases was carried out and 16 studies about the association of 5-HTTLPR polymorphism and resilience in humans were identified. The OpenMeta[Analyst] program was employed to perform statistical analysis using a random-effects model. The final analysis included 9 studies, for a total of 4,080 subjects. Significant results were found when the standardized mean differences (SMD) of LL and SL carriers were compared, (SMD: -0.087 (confidence interval: -0.166 to -0.008; I2: 0 %); P value: 0.031). A significant result was also found in an analysis comparing SS/SL versus LL genotypes (SMD: -0.231; confidence interval: -0.400 to -0.061, P value: 0.008; I2: 0 %). This is the first meta-analysis performed to identify the pooled association of a functional polymorphism in the serotonin transporter gene and resilience. The current results suggest that the L/L genotype is associated with resilience. Further studies are necessary to elucidate the role of genetics on the resilience mechanisms.Item LncRNA HOTAIR promotes MPP+-induced neuronal injury in Parkinson’s disease by regulating the miR-874-5p/ATG10 axis(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-08-05) Zhao, Jingya; Li, Hongli; Chang, NaParkinson’s disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons. Long non-coding RNAs (lncRNAs) play an important role in many neurological diseases, including PD. This study aimed to investigate the role of lncRNA HOX transcript antisense RNA (HOTAIR) in PD pathogenesis and its potential mechanism. SK-N-SH cells were exposed to 1-methyl-4-phenylpyridinium (MPP+) to mimic PD model in vitro. The levels of HOTAIR, miR-874-5p and autophagy-related 10 (ATG10) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assay. Cell viability and apoptosis were assessed by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. The expression of apoptosis-related proteins was measured by western blot. The levels of neuroinflammation-related factors were detected by enzyme-linked immunosorbent assay (ELISA). Commercial kits was used to monitor lactate dehydrogenase (LDH) activity, reactive oxygen (ROS) generation and superoxide dismutase (SOD) activity. The interaction among HOTAIR, miR-874-5p and ATG10 were verified by dual-luciferase reporter assay or RNA immunoprecipitation (RIP) assay. HOTAIR and ATG10 were up-regulated, and miR-874-5p was down-regulated in dose- and time-dependent manners in MPP+-treated SK-N-SH cells. HOTAIR knockdown reduced MPP+-induced neuronal damage. HOTAIR aggrandized MPP+-triggered neuronal injury by sponging miR-874-5p. Also, miR-874-5p attenuated MPP+-triggered neuronal damage by targeting ATG10. Moreover, HOTAIR regulated ATG10 expression via sponging miR-874-5p. HOTAIR promoted MPP+-induced neuronal injury via modulating the miR-874-5p/ATG10 axis in SK-N-SH cells.Item Cytoprotective effects of fermented oyster extracts against oxidative stress-induced DNA damage and apoptosis through activation of the Nrf2/HO-1 signaling pathway in MC3T3-E1 osteoblasts(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-08-04) Park, Cheol; Lee, Hyesook; Han, Min Ho; Jeong, Jin-Woo; Kim, Sung Ok; Jeong, Soon-Jeong; Lee, Bae‐Jin; Kim, Gi‐Young; Park, Eui Kyun; Jeon, You‐Jin; Choi, Yung HyunOsteoblast damage by oxidative stress has been recognized as a cause of bone-related disease, including osteoporosis. Recently, we reported that fermented Pacific oyster (Crassostrea gigas) extracts (FO) inhibited osteoclastogenesis and osteoporosis, while promoting osteogenesis. However, since the beneficial potential of FO on osteoblasts is not well known, in the present study, we investigated the cytoprotective effect of FO against oxidative stress in MC3T3-E1 osteoblasts. Our results demonstrated that FO inhibited hydrogen peroxide (H2O2)-induced DNA damage and cytotoxicity through the rescue of mitochondrial function by blocking abnormal ROS accumulation. FO also prevented apoptosis by suppressing loss of mitochondrial membrane potential and cytosolic release of cytochrome c, decreasing the rate of Bax/Bcl-2 expression and reducing the activity of caspase-9 and caspase-3 in H2O2-stimulated MC3T3-E1 osteoblasts, suggesting that FO protected MC3T3-E1 osteoblasts from the induction of caspase dependent- and mitochondria-mediated apoptosis by oxidative stress. In addition, FO markedly promoted the activation of nuclear factor-erythroid-2-related factor 2 (Nrf2), which was associated with the enhanced expression of heme oxygenase-1 (HO-1). However, inhibiting the expression of HO-1 by artificially blocking the expression of Nrf2 using siRNA significantly eliminated the protective effect of FO, indicating that FO activates the Nrf2/HO-1 signaling pathway in MC3T3-E1 osteoblasts to protect against oxidative stress. Based on the present data, FO is thought to be useful as a potential therapeutic agent for the inhibition of oxidative stress in osteoblasts.Item Exosomes derived from human mesenchymal stem cells preserve mouse islet survival and insulin secretion function(IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, 2020-08-03) Keshtkar, Somayeh; Kaviani, Maryam; Sarvestani, Fatemeh Sabet; Ghahremani, Mohammad Hossein; Aghdaei, Mahdokht Hossein; Al-Abdullah, Ismail H.; Azarpira, NegarIslet cell death and loss of function after isolation and before transplantation is considered a key barrier to successful islet transplantation outcomes. Mesenchymal stem cells (MSCs) have been used to protect isolated islets owing to their paracrine potential partially through the secretion of vascular endothelial growth factor (VEGF). The paracrine functions of MSCs are also mediated, at least in part, by the release of extracellular vesicles including exosomes. In the present study, we examined (i) the effect of exosomes from human MSCs on the survival and function of isolated mouse islets and (ii) whether exosomes contain VEGF and the potential impact of exosomal VEGF on the survival of mouse islets. Isolated mouse islets were cultured for three days with MSC-derived exosomes (MSC-Exo), MSCs, or MSC-conditioned media without exosomes (MSC-CM-without-Exo). We investigated the effects of the exosomes, MSCs, and conditioned media on islet viability, apoptosis and function. Besides the expression of apoptotic and pro-survival genes, the production of human and mouse VEGF proteins was evaluated. The MSCs and MSC-Exo, but not the MSC-CM-without-Exo, significantly decreased the percentage of apoptotic cells and increased islet viability following the downregulation of pro-apoptotic genes and the upregulation of pro-survival factors, as well as the promotion of insulin secretion. Human VEGF was observed in the isolated exosomes, and the gene expression and protein production of mouse VEGF significantly increased in islets cultured with MSC-Exo. MSC-derived exosomes are as efficient as parent MSCs for mitigating cell death and improving islet survival and function. This cytoprotective effect was probably mediated by VEGF transfer, suggesting a pivotal strategy for ameliorating islet transplantation outcomes.