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Sonicated preparations of Borrelia burgdorferi are able to stimulate unselected resting BALB/c spleen cells to proliferate and to produce immunoglobulin in vitro. FACS analysis of target cells prestained with an integrated cell-surface marker as well as cell-depletion experiments demonstrate that the majority of responding lymphocytes are B cells. Limiting dilution analyses of resting B cells revealed high frequencies of cells producing IgM (F 1/11-1/62) or IgG (F 1/5-1/163) in response to B. burgdorferi sonicate (B.b. sonicate). These numbers were similar to those obtained with lipopolysaccharide (LPS) (IgM: F 1/20-1/84; IgG: F 1/14-1/85) or a synthetic lipopeptide of Braun's Escherichia coli lipoprotein (IgM: F 1/15, 1/19; IgG: F 1/148, 1/34). The mitogenic structure(s) expressed by B. burgdorferi is distinct from LPS, as similar proliferative responses were obtained with B cells from LPS-resistant (C57BL/10ScCr and C3H/HeJ) and LPS-susceptible (C57BL/10ScSn, C3H/HeN) mice. Furthermore, B-cell mitogenic properties were also found in two distinct fractions of a phenol-chloroform-petroleum ether extract of B. burgdorferi: they consisted of a lipoprotein distinct from the outer surface proteins (Osp) A and B and glycolipidlike structures, respectively. These data suggest that spirochetes express a multitude of distinct structures with mitogenic activity for B cells including various lipoproteins as well as glycolipid(s). [ABSTRACT FROM AUTHOR]

Introduction: Recurrent pregnancy loss is the most important fertility problem which affects about 1-5% of pregnant women. One of the possible genetic causes of unknown recurrent pregnancy loss is impairment in angiogenesis system and one of the most important genes is Kinas insert-Domain-Receptor (KDR). It is found on vasculogenic and angiogenic precursor cells in human placenta. Determining the association between single nucleotide polymorphisms (SNPS) (-604, 1719 and 1192) of KDR gene in women with unexplained Recurrent pregnancy loss in comparison with healthy women. Materials and Methods: In this study 110 women with history of recurrent pregnancy loss in the reproductive age as case and 120 healthy women with no history of abortion and at least one healthy child are chosen as control group. Genotyping of these polymorphisms were analyzed using the Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) technique. Results: Genotype frequencies of SNP -604 in women with unexplained recurrent pregnancy loss were as follows TT (26.4%) TC (45.5%) and CC (28.2%) while in normal group genotypes were 30%, 43.4% and 26.7%respectively. Genotypes AA, AT and TT of SNP(1719) presented frequencies of 30%, 2.8%and 67.3% respectively in case group and 3.4%, 32.5% and 64.2% in controls. Distribution of Genotypes in SNP 1192 was 79.1%, 19% and 1.8% for GG, AG and AA in case and 80%, 20% and 0% in the same order in controls . Conclusion: Results of this study demonstrated no association between recurrent pregnancy loss and -604, 1719 and 1192 SNPS of KDR genes. [ABSTRACT FROM AUTHOR]

Mutagenicity testing is a component of the hazard assessment of industrial chemicals, biocides, and pesticides. Mutations induced by test substances can be detected by in vitro and in vivo methods that have been adopted as OECD Test Guidelines. One of these in vivo methods is the Transgenic Rodent Assay (TGRA), OECD test guideline no. 488. An analogous in vitro TGRA has been described, but experience with this test method is limited. In this study, six in vivo TGRA positive mutagens were tested in the in vitro TGRA based on primary MutaMouse hepatocytes. In addition to the functional read-out of the lacZ reporter gene, induced mutations were analysed by next-generation sequencing (NGS). Five of the six in vivo TGRA positive mutagens (N-ethyl-N-nitrosourea (ENU), ethyl methanesulfonate (EMS), mitomycin C (MMC), benzo[a]pyrene (B[a]P), and azathioprine (AZA), but not cyproterone acetate) mutated the lacZ gene in vitro. NGS identified mutations which matched the mutagenic mechanisms described in the literature. The alkylating agent ENU induced a greater proportion of A:T to T:A transversions than did the other alkylating agent, EMS, whereas EMS increased smaller deletions (1-4 bp). G:C to T:A transversions accounted for the majority of mutations identified after treatments with MMC and B[a]P, both of which form monoadducts at the guanine N2 position. AZA induced mainly G:C to A:T transitions, explained by the structural similarity of one of its metabolites to guanine. An increased proportion of mid-size changes (0.3-2.5 kb) was detected only for the crosslinking mutagen MMC. The in vitro TGRA based on primary MutaMouse hepatocytes is a promising in vitro assay for the assessment of mutation induction, reflecting many aspects of the corresponding in vivo TGRA and allowing for mutation spectra analysis to evaluate the induced mutations., Competing Interests: Declaration of Competing Interest Alina Göpfert, Claudia Rülker, Michael Eichenlaub, Bogdan Tokovenko, Martina Dammann, Dorothee Funk-Weyer, Naveed Honarvar and Robert Landsiedel are employees of BASF SE, a chemical company which may use the assay to develop and register commercial products., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In human health risk assessment of chemicals and pharmaceuticals, identification of genotoxicity hazard usually starts with a standard battery of in vitro genotoxicity tests, which is needed to cover all genotoxicity endpoints. The individual tests included in the battery are not designed to pick up all endpoints. This explains why resulting data can appear contradictory, thereby complicating accurate interpretation of the findings. Such interpretation could be improved through application of mathematical modeling. One of the advantages of mathematical modeling is that the strengths and weaknesses of each test are taken into account. Furthermore, the generated predictions are objective and convey the associated uncertainties. This approach was explored by the working group "Predictivity of In Vitro Genotoxicity Testing," convened in the context of the 8th International Workshop on Genotoxicity Testing (IWGT). Specifically, we applied mathematical modeling to a database with publicly available in vitro and in vivo data for genotoxicity. The results indicate that a mammalian in vitro clastogenicity test and a mammalian cell gene mutation test together provide strong predictive weight-of-evidence for evaluating genotoxic hazard of a substance, although they are better in predicting absence of genotoxic potential than in predicting presence of genotoxic potential. Remarkably, the bacterial reverse mutation (Ames) test did not significantly change these predictions when used in combination with in vitro mutagenicity and clastogenicity tests using cells of mammalian origin. However, in case only data from a bacterial reverse mutation test are available for the assessment of genotoxic potential, these do bear weight of evidence and thus can be used. Genotoxicity assays are generally executed in tiers, in which the bacterial reverse mutation test often is the starting point. Thus, it is reasonable to suspect that early in development test results from the bacterial reverse mutation test have influenced the composition of the database studied here. We performed several tests on the robustness of the database used for the analyses presented here, and the forthcoming results do not indicate a strong bias. Further research comparing in vitro genotoxicity data with in vivo data for additional compounds will provide more insights whether it is indeed time to reconsider the composition of the standard in vitro genotoxicity battery., (© 2024 The Author(s). Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagenesis and Genomics Society.)

Background: Alcohol use is associated with a wide spectrum of neurological disorders, including cognitive dysfunction and dementia. Likewise, the high prevalence of cognitive dysfunction and dementia specifies the urgent need to identify modifiable risk factors. Because findings on alcohol and cognitive dysfunction and dementia have been inconsistent, the present dose-response meta-analysis of cohort and case control studies was conducted to evaluate the available evidence., Method and Materials: A systematic search was conducted on PubMed/MEDLINE, Scopus, Embase, and PsychInfo databases and Google Scholar up to April, 2023. In the dose-response meta-analysis, a restricted cubic spline regression model was conducted to evaluate a possible non-linear relation between alcohol intake and the outcomes. Random-effects model was used to perform the meta-analysis and evaluate heterogeneity. Egger's test and a funnel plot were used to assess small study effects. Subgroup analyses were carried out to explore possible sources of heterogeneity., Results: Seventeen eligible studies comprising 80,680 total persons with 4929 cases for dementia and 13,530 total persons with 1579 cases for cognitive dysfunction were included for dose-response analysis. When compared to the reference group of 0 g/day of alcohol intake, the dose-response meta-analysis revealed a significant non-linear (J-shaped) association between alcohol intake and the risk of each of cognitive dysfunction, (lower dose range: 1-30.5 g/day, RR: 0.97; 95 % CI 0.95-0.99; higher dose range: >30.5 g/day, RR: 1.07; 95 % CI 1.01-1.15) and dementia (lower dose range: 1-17.5 g/day, RR: 0.92; 95 % CI 0.88-0.96, higher dose range: >17.5 g/day, RR: 1.23; 95 % CI 1.09-1.35). The lowest risk was achieved at approximately 30 g/day of alcohol for cognitive dysfunction and 15 g/day for dementia. The J-shape association remained with subgroups defined by age (≤65; >65 years) or study duration (<10; ≥10 years) for dementia, and within age >65 and duration <10 years for cognitive dysfunction., Conclusion: We observed a J-shape association between alcohol consumption and both cognitive dysfunction and dementia, with light-to-moderate alcohol intake being associated with a reduced risk in adults. Further studies are needed to clarify more specifically the association between alcohol consumption and six domains of cognitive dysfunction based on diagnostic and statistical manual of mental disorders (DSM) criteria., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The fungicide fluxapyroxad (BAS 700 F) has been shown to significantly increase the incidence of liver tumours in male Wistar rats at dietary levels of 1500 and 3000 ppm and in female rats at a dietary level of 3000 ppm via a non-genotoxic mechanism. In order to elucidate the mode of action (MOA) for fluxapyroxad-induced rat liver tumour formation a series of in vivo and in vitro investigative studies were undertaken. The treatment of male and female Wistar rats with diets containing 0 (control), 50, 250, 1500 and 3000 ppm fluxapyroxad for 1, 3, 7 and 14 days resulted in a dose-dependent increases in relative weight at 1500 and 3000 ppm from day 3 onwards in both sexes, with an increase in relative liver weight being also observed in male rats given 250 ppm fluxapyroxad for 14 days. Examination of liver sections revealed a centrilobular hepatocyte hypertrophy in some fluxapyroxad treated male and female rats. Hepatocyte replicative DNA synthesis (RDS) was significantly increased in male rats given 1500 and 3000 ppm fluxapyroxad for 3 and 7 days and in female rats given 50-3000 ppm fluxapyroxad for 7 days and 250-3000 ppm fluxapyroxad for 3 and 14 days; the maximal increases in RDS in both sexes being observed after 7 days treatment. The treatment of male and female Wistar rats with 250-3000 ppm fluxapyroxad for 14 days resulted in significant increases in hepatic microsomal total cytochrome P450 (CYP) content and CYP2B subfamily-dependent enzyme activities. Male Wistar rat hepatocytes were treated with control medium and medium containing 1-100 μM fluxapyroxad or 500 μM sodium phenobarbital (NaPB) for 4 days. Treatment with fluxapyroxad and NaPB increased CYP2B and CYP3A enzyme activities and mRNA levels but had little effect on markers of CYP1A and CYP4A subfamily enzymes and of the peroxisomal fatty acid β-oxidation cycle. Hepatocyte RDS was significantly increased by treatment with fluxapyroxad, NaPB and 25 ng/ml epidermal growth factor (EGF). The treatment of hepatocytes from two male human donors with 1-100 μM fluxapyroxad or 500 μM NaPB for 4 days resulted in some increases in CYP2B and CYP3A enzyme activities and CYP mRNA levels but had no effect on hepatocyte RDS, whereas treatment with EGF resulted in significant increase in RDS in both human hepatocyte preparations. Hepatocytes from male Sprague-Dawley wild type (WT) and constitutive androstane receptor (CAR) knockout (CAR KO) rats were treated with control medium and medium containing 1-16 μM fluxapyroxad or 500 μM NaPB for 4 days. While both fluxapyroxad and NaPB increased CYP2B enzyme activities and mRNA levels in WT hepatocytes, only minor effects were observed in CAR KO rat hepatocytes. Treatment with both fluxapyroxad and NaPB only increased RDS in WT and not in CAR KO rat hepatocytes, whereas treatment with EGF increased RDS in both WT and CAR KO rat hepatocytes. In conclusion, a series of in vivo and in vitro investigative studies have demonstrated that fluxapyroxad is a CAR activator in rat liver, with similar properties to the prototypical CAR activator phenobarbital. A robust MOA for fluxapyroxad-induced rat liver tumour formation has been established. Based on the lack of effect of fluxapyroxad on RDS in human hepatocytes, it is considered that the MOA for fluxapyroxad-induced liver tumour formation is qualitatively not plausible for humans., Competing Interests: Declaration of Competing Interest M. Goettel, C. Werner, N. Honarvar, S. Gröters, and I. Fegert are all employed by BASF, which manufactures fluxapyroxad. All other authors have been involved in studies on fluxapyroxad funded by BASF. The authors alone are responsible for the content and writing of this article. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Significant variations exist in the forms of ZnO, making it impossible to test all forms in in vivo inhalation studies. Hence, grouping and read-across is a common approach under REACH to evaluate the toxicological profile of familiar substances. The objective of this paper is to investigate the potential role of dissolution, size, or coating in grouping ZnO (nano)forms for the purpose of hazard assessment. We performed a 90-day inhalation study (OECD test guideline no. (TG) 413) in rats combined with a reproduction/developmental (neuro)toxicity screening test (TG 421/424/426) with coated and uncoated ZnO nanoforms in comparison with microscale ZnO particles and soluble zinc sulfate. In addition, genotoxicity in the nasal cavity, lungs, liver, and bone marrow was examined via comet assay (TG 489) after 14-day inhalation exposure., Results: ZnO nanoparticles caused local toxicity in the respiratory tract. Systemic effects that were not related to the local irritation were not observed. There was no indication of impaired fertility, developmental toxicity, or developmental neurotoxicity. No indication for genotoxicity of any of the test substances was observed. Local effects were similar across the different ZnO test substances and were reversible after the end of the exposure., Conclusion: With exception of local toxicity, this study could not confirm the occasional findings in some of the previous studies regarding the above-mentioned toxicological endpoints. The two representative ZnO nanoforms and the microscale particles showed similar local effects. The ZnO nanoforms most likely exhibit their effects by zinc ions as no particles could be detected after the end of the exposure, and exposure to rapidly soluble zinc sulfate had similar effects. Obviously, material differences between the ZnO particles do not substantially alter their toxicokinetics and toxicodynamics. The grouping of ZnO nanoforms into a set of similar nanoforms is justified by these observations., (© 2024. The Author(s).)

The current Organisation for Economic Co-Operation and Development test guideline number 487 (OECD TG No. 487) provides instruction on how to conduct the in vitro micronucleus assay. This assay is one of the gold standard approaches for measuring the mutagenicity of test items; however, it is directed at testing low molecular weight molecules and may not be appropriate for particulate materials (e.g. engineered nanoparticles [ENPs]). This study aimed to adapt the in vitro micronucleus assay for ENP testing and underpins the development of an OECD guidance document. A harmonized, nano-specific protocol was generated and evaluated by two independent laboratories. Cell lines utilized were human lymphoblastoid (TK6) cells, human liver hepatocytes (HepG2) cells, Chinese hamster lung fibroblast (V79) cells, whole blood, and buffy coat cells from healthy human volunteers. These cells were exposed to reference ENPs from the Joint Research Council (JRC): SiO2 (RLS-0102), Au5nm and Au30nm (RLS-03, RLS-010), CeO2 (NM212), and BaSO4 (NM220). Tungsten carbide-cobalt (WC/Co) was used as a trial particulate positive control. The chemical controls were positive in all cell cultures, but WC/Co was only positive in TK6 and buffy coat cells. In TK6 cells, mutagenicity was observed for SiO2- and both Au types. In HepG2 cells, Au5nm and SiO2 showed sub-two-fold increases in micronuclei. In V79 cells, whole blood, and buffy coat cells, no genotoxicity was detected with the test materials. The data confirmed that ENPs could be tested with the harmonized protocol, additionally, concordant data were observed across the two laboratories with V79 cells. WC/Co may be a suitable particulate positive control in the in vitro micronucleus assay when using TK6 and buffy coat cells. Detailed recommendations are therefore provided to adapt OECD TG No. 487 for testing ENP., (© The Author(s) 2024. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society.)

Nanomaterials have outstanding and unprecedented advantageous material properties but may also cause adverse effects in humans upon exposure. Testing nanomaterials for genotoxic properties is challenging because traditional testing methods were designed for small, soluble molecules and may not be easily applicable without modifications. This review critically examines available genotoxicity tests for use with nanomaterials, including DNA damage tests such as the comet assay, gene mutation tests such as the mouse lymphoma and hprt assay, and chromosome mutation tests such as the micronucleus test and the chromosome aberration test. It presents arguments for the relative usefulness of various tests, such as preferring the micronucleus test over the chromosome aberration test for scoring chromosome mutations and preferring mammalian cell gene mutation tests because the Ames test has limited utility. Finally, it points out the open questions and further needs in adapting genotoxicity tests for nanomaterials, such as validation, reference nanomaterials, and the selection of top test concentrations, as well as the relevance and applicability of test systems and the need to define testing strategies. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine., (© 2022 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals LLC.)

Method: This randomized double-blind, placebo-controlled trial was conducted on 75 school-aged children with a diagnosis of ADHD based on DSM-V criteria. Children were randomly allocated to receive either vitamin D3 (2000 IU/day) or a placebo for 3 months. Serum IL-6, TNF- α, and 25(OH) D were assessed before and after the intervention to determine the effects of vitamin D on the highlighted parameters., Results: Serum levels of 25(OH) D increased significantly in the vitamin D group ( P =0.01). However, no significant differences in serum IL-6 and TNF- α were found between both groups at the baseline and at the end of the intervention., Conclusion: The findings revealed that vitamin D supplementation for 3 months is not efficacious in reducing inflammatory cytokines in children with ADHD. Further studies are required to confirm these results., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Mahsa Samadi et al.)

Method: In this double-blind, randomized, placebo-controlled trial, 75 children (aged 6-12) diagnosed with ADHD were randomly assigned into two groups. The supplementation group received vitamin D3 (2000 IU), and the control group received a placebo for 3 months. Blood samples were collected at baseline and after intervention to analyze the 25(OH)D, paraxonase-1 activity (PON-1), Total Antioxidant Capacity (TAC), and 8-isoprostan levels., Results: A significant rise in circulating 25(OH)D was observed in the vitamin D group versus the placebo group at the end of the study. There was no reduction in 8-isoprostan levels in the vitamin D group compared to the placebo group. Serum paraxonase-1 and TAC concentration decreased in both groups, but these alterations were not statistically significant in the treatment group versus the placebo group at the end of the intervention., Conclusion: Vitamin D supplementation for 3 months did not have beneficial effects on biomarkers of oxidative stress status. To confirm these findings, further studies on children are suggested., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Niyaz Mohammadzadeh Honarvar et al.)

Background: Inositol is a sugar-alcohol and recognized as a key component of cell membrane phospholipids. It has crucial role in the cell signaling pathways and contribute to improving glycemic responses. Although some earlier studies have revealed the effect of inositol mediating glucose uptake by improving insulin sensitivity, the benefit of inositol supplementation in patients with overweight and obesity is not completely understood. This study aimed to assess the impact of inositol supplementation on body mass index (BMI) through a systematic review and meta-analysis of controlled clinical trials., Methods: A systematic search was performed to August 2021 in the following databases: PubMed-Medline, Embase, Web of Science and Scopus. Fifteen controlled clinical trials investigating the effect of inositol on adult's BMI were finally included in the study. A random-effects model was employed to estimate the effect size. Subgroup analysis was performed by dose, duration, age, type of inositol. Meta-regression was used to investigate presence of any linear relationship. Begg's and Egger's tests were carried out to detect small study effect., Results: The results of pooled analysis showed that inositol supplementation significantly decreased BMI scores (WMD = -0.41 kg/m 2 ; 95% CI: -0.78, -0.04; p  = 0.028). Subgroup analysis was performed to identify the source of heterogeneity among studies ( I 2  = 73.9%, p  < 0.001), demonstrating supplementation duration, baseline BMI, mean age of participants, type of inositol and dosage were potential sources of heterogeneity. The effect of intervention was more clinically significant in participants with polycystic ovary syndrome (PCOS) and overweight/obesity. Inositol in the form of myo-inositol (MI) had stronger effect on BMI reduction., Conclusion: The meta-analysis suggests that oral inositol supplementation has positive effect on BMI reduction. Inositol supplementation could be considered as an adjunct treatment to improve body mass index., Competing Interests: The authors declare no conflicts of interest., (© 2021 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Background: Aging affects the serum levels of various metabolites which may be involved in the pathogenesis of chronic diseases. The aim of this review article is to summarize the relationship between aging and alterations in the plasma phospholipids and sphingomyelins., Methods: PRISMA guidelines were employed during all steps. MEDLINE (PubMed), Scopus, Embase and Web of Sciences databases and Google Scholar were searched up to October 2020. Cohort studies investigating the relationship between aging and within-person changes in sphingomyelin (SM), phosphatidyl choline (PC), lyso PC (LPC) and phosphatidyl ethanolamine (PE) were included. Newcastle-Ottawa scale was used to assess the quality of included studies., Results: A total of 1425 studies were identified. After removing 610 duplicates and 723 irrelevant studies, full texts of 92 articles were evaluated. Of these 92, 6 studies (including data from 7 independent cohorts) met the inclusion criteria and are included in this review. All study populations were healthy and included both men and women. Results by sex were reported in 3 cohorts for PC, 5 cohorts for LPC, 3 cohorts for SM, and only 1 cohort for PE. In men, PC, SM, PE and LPC decreased with aging, although results for LPC were inconsistent. In women, LPC, SM, and PE increased age, whereas changes in PC were inconsistent., Conclusion: Within-person serum levels of phospholipids and sphingomyelins, decrease during aging in men and increase in women. Notably, however, there were some inconsistencies across studies of LPC in men and of PC in women., (Copyright © 2021. Published by Elsevier B.V.)

Background & Aims: Critically ill patients are provided with the intensive care medicine to prevent further complications, including malnutrition, disease progression, and even death. This study was intended to assess nutritional support and its' efficacy in the Intensive Care Units (ICUs) of Iran., Methods: This cross-sectional study assessed 50 ICU's patients out of 25 hospitals in the 10 major regions of Iran's health system and was performed using the multistage cluster sampling design. The data were collected from patient's medical records, ICU nursing sheets, patients or their relatives from 2017 to 2018. Nutritional status was investigated by modified NUTRIC score and food frequency checklist., Results: This study included 1321 ICU patients with the mean age of 54.8 ± 19.97 years, mean mNUTRIC score of 3.4 ± 2.14, and malnutrition rate of 32.6%. The mean time of first feeding was the second day and most of patients (66%) received nutrition support, mainly through enteral (57.2%) or oral (37%) route during ICU stay. The patients received 59.2 ± 37.78 percent of required calorie and 55.5 ± 30.04 percent of required protein. Adequate intake of energy and protein was provided for 16.2% and 10.7% of the patients, respectively. The result of regression analysis showed that the odds ratio of mNUTRIC score was 0.85 (95% confidence interval [CI] = 0.74-0.98) and APACHE II was 0.92 (95%CI = 0.89-0.95) for the prediction of energy deficiency. Nutrition intake was significantly different from patient's nutritional requirements both in terms of energy (p < 0.001) and protein (p < 0.001). Also, mean mNUTRIC score varied notably (p = 0.011) with changing in energy intake, defined as underfeeding, adequate feeding, and overfeeding., Conclusion: The present findings shown that, provided nutritional care for ICU patients is not adequate for their requirements and nutritional status., Competing Interests: Conflicts of interest None declared., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Obesity and overweight are associated with the burden of chronic diseases. The aim of the present meta-analysis is to determine the efficacy of spirulina in reducing of obesity indices. PubMed, Web of Science, Scopus, EMBASE and Cochrane library databases were searched up to November 2019. Randomized controlled trials comparing spirulina supplementation with a placebo or no treatment for anthropometric indices were included. Meta-analysis was performed using random-effects model. Subgroup analysis and meta-regression were carried out. Publication bias was evaluated using standard methods. Spirulina had ameliorative effects on weight (WMD = -1.85 Kg; 95% CI: -2.44, -1.26; p < .001; I 2 = 82.4%, p < .001), and waist circumference (WMD = -1.09 cm; 95% CI: -2.16, -0.01; p = .046; I 2 = 0.0%, p = .757) while no significant effect was shown on body mass index, even after sensitivity analysis (SMD = -0.53 Kg/m 2 ; 95% CI: -1.25, 0.19; p = .149; I 2 = 92.9%, p < .001); however, spirulina was effective in studies lasted for at least 12 weeks (SMD = -1.25 Kg/m 2 ; 95% CI: -2.21, -0.28; p = .011; I 2 = 90.8%, p < .001). Spirulina supplementation exerts beneficial effects on weight and waist circumference. The ameliorative effect of spirulina on body mass index was revealed in longer duration of supplementation., (© 2020 John Wiley & Sons Ltd.)

Background: The novel coronavirus has become a global threat and healthcare concern. The manifestations of COVID-19 pneumonia in transplant patients are not well understood and may have more severe symptoms, longer duration, and a worse prognosis than in immunocompetent populations., Aims: This study proposed to evaluate the clinical characteristics of COVID-19 pneumonia in kidney transplant recipients., Patients/methods: Clinical records, laboratory results, radiological characteristics, and clinical outcome of 24 kidney transplant patients with COVID-19 pneumonia were evaluated from March 20, 2020, to May 20, 2020., Results: The most common symptom was shortness of breath (70.8%), followed by fever (62.5%) and cough (45.8%). Five patients had leukopenia, and only one patient had leukocytosis, while 75% of the patients had a white blood cell (WBC) count in the normal range, and 79% of recipients developed lymphopenia. All of the patients had an elevated concentration of C-reactive protein and an increase in blood urea levels. Chest CT images of 23 patients (95.8%) showed typical findings of patchy ground-glass shadows in the lungs. Of the 24 patients, 12 were admitted to ICU (invasive care unit), and ten of 24 patients (41.6%) died, and 14 patients were discharged after complete recovery., Conclusion: It seems that COVID-19 is more severe in transplant patients and has poorer outcomes. Multiple underlying diseases, low O 2 saturation, and multilobar view in chest CT scan may be of prognostic value. However, many SARS-CoV-2 demonstrations are similar to those of the general population., (© 2020 Wiley Periodicals LLC.)

Objective: Religious coping is known as one of the successful manners to cure depressed infertile women; however, research findings show that demographic factors (e.g., education level) have played an important role on the relationship between depression and religious coping scores. The goal of this study is to measure the influence of age, job status, and education level on both scores within Iranian infertile women. Method : In this cross sectional study, 1000 women (mean age, 35.96; range, 26-45), who are recruited from different hospitals of Shiraz (Iran), are selected via multistage cluster sampling method. The reliability and validity of the translated versions of the questionnaires have been confirmed. The correlation coefficient (Spearman method), adjusted linear regression coefficient, and ordinal regression coefficient of demographic features with the depression scores/levels (minimal, mild, moderate, and severe) and religious coping scores are determined. Results: A significant negative correlation is found between depression and religious compatibility scores in 1000 infertile women (ρ = -0.318, P = 0.000). In addition, the results have implied the existence of a significant correlation and linear relationship between religious coping and age and job status (P < 0.05). Furthermore, both correlation and ordinal regression of depression intensity with both job status and education level are found to be statistically meaningful (P < 0.05). Conclusion: The negative correlation between religious coping and depression scores has implied the positive role of religious coping in protecting infertile women from depression, especially among employed women. Nevertheless, the correlation of religious coping with education level is not strong enough due to the nonuniform distribution of variables through their range., (Copyright © Psychiatry & Psychology Research Center, Tehran University of Medical Sciences.)

Nongenotoxic chemicals can produce liver tumours in rats and mice by a mitogenic mode of action involving activation of the constitutive androstane receptor (CAR). The aim of this study was to evaluate the usefulness of cultured hepatocytes from normal (wild type; WT) and CAR knockout (KO) rats to screen compounds as potential activators of rat CAR and to validate this test system. Cultured hepatocytes from male Sprague-Dawley WT and CAR KO rats were treated with either 100 and 1000 μM sodium phenobarbital (NaPB), 3-100 μM fluquinconazole (FQZ), or 3-300 μM 3-(difluoromethyl)-1-methyl-N-(3´,4´,6-trifluoro[1,1´-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (TI1) for 96 h. Induction of cytochrome P450 (CYP) enzymes was monitored by measurement of 7-pentoxyresorufin O-depentylase (PROD), 7-benzyloxyresorufin O-debenzylase (BROD) and 7-benzyloxyquinoline O-debenzylase (BQ) activities. Hepatocytes undergoing replicative DNA synthesis (RDS) were labelled by adding 10 μM 5-bromo-2´-deoxyuridine to the culture medium for determination of the hepatocyte labelling index. The treatment of WT, but not of CAR KO, rat hepatocytes with NaPB, FQZ and TI1 increased hepatocyte RDS and induced CYP2B-dependent PROD activity. In contrast, all three compounds increased CYP2B/3A-dependent BROD and CYP3A-dependent BQ activities in both WT and CAR KO rat hepatocytes. Hepatocyte RDS was increased in both WT and CAR KO rat hepatocytes by treatment with 25 ng/ml epidermal growth factor as a positive control. Overall, these results demonstrate that the effects of three CAR activators on RDS and CYP2B enzyme induction are abolished in cultured CAR KO rat hepatocytes. As demonstrated by this validation study, the CAR KO hepatocyte model is a useful in vitro mechanistic tool for the rapid screening of chemicals as potential activators of rat CAR., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

In a 2-year study the herbicide metazachlor (BAS 479H) was shown to significantly increase the incidence of liver tumours in female Wistar rats at a dietary level of 8000 ppm. As metazachlor is not a genotoxic agent, a series of in vivo and in vitro investigative studies were undertaken to elucidate the mode of action (MOA) for metazachlor-induced female rat liver tumour formation. Male and female Wistar rats were given diets containing 0 (control), 200 and 8000 ppm metazachlor for 3, 7, 14 and 28 days. The treatment of male rats with 200 and 8000 ppm metazachlor and female rats with 8000 ppm metazachlor resulted in significant increases in relative liver weight, which was associated with a centrilobular hepatocyte hypertrophy. Hepatocyte replicative DNA synthesis (RDS) was significantly increased in male rats given 8000 ppm metazachlor for 3 and 7 days and in female rats given 200 ppm metazachlor for 7-28 days and 8000 ppm metazachlor for 3-28 days. Significant increases in relative liver weight, centrilobular hepatocyte hypertrophy and hepatocyte RDS were also observed in male and female Wistar rats given and 500 ppm sodium phenobarbital (NaPB) for 3-28 days. The treatment of female Wistar rats with either 8000 ppm metazachlor for 7 days or with 500 ppm NaPB for 3 and 7 days resulted in the nuclear translocation of the hepatic constitutive androstane receptor (CAR). Treatment of male and female Wistar rats with 8000 ppm metazachlor for 14 days resulted in significant increases in hepatic microsomal total cytochrome P450 (CYP) content, CYP2B subfamily-dependent enzyme activities and mRNA levels, together with some increases in CYP3A enzyme activity and mRNA levels. The treatment of male Wistar rat hepatocytes with metazachlor (concentration range 0.5-50 μM) and NaPB (500 μM) for 4 days resulted in increased CYP2B enzyme activities and mRNA levels; with metazachlor and NaPB also producing significant increases in hepatocyte RDS levels. Studies were also performed with hepatocytes from male Sprague-Dawley wild type (WT) rats and CAR knockout (CAR KO) rats. While both treatment with metazachlor and NaPB for 4 days increased CYP2B enzyme activities and mRNA levels in WT rat hepatocytes, only minor effects were observed in CAR KO rat hepatocytes. Treatment with both metazachlor and NaPB only increased RDS in WT but not in CAR KO rat hepatocytes. The treatment of hepatocytes from two male human donors with 0.5-25 μM metazachlor or 500 μM NaPB for 4 days resulted in increases in CYP2B6 and CYP3A4 mRNA levels but had no effect on hepatocyte RDS. EGF as concurrently used positive control demonstrated the expected RDS response in all rat and human hepatocyte cultures. In conclusion, a series of in vivo and in vitro investigative studies have demonstrated that metazachlor is a CAR activator in rat liver, with similar properties to the prototypical CAR activator phenobarbital. A robust MOA for metazachlor-induced female rat liver tumour formation has been established. Based on the lack of effect of metazachlor on RDS in human hepatocytes, it is considered that the MOA for metazachlor-induced rat liver tumour formation is qualitatively not plausible for humans., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: The complications of diabetes are extensive which can be caused by excessive oxidative stress, inflammation and impaired insulin system. Plant-sourced bioactive compounds can reduce inflammation and oxidative stress. The aim of present study was to determine the effect of ginger supplementation on diabetic complications., Methods: The present study is a randomized double blind clinical trial which is conducted with 48 diabetic patients. The participants were randomly divided into two intervention and placebo groups which were received 2 g ginger powder and 2 g wheat flour respectively for 10 weeks. Nuclear factor kappa B (NF-κB) concentration and anthropometric measurements were evaluated at the baseline and at the end of study., Results: The effect of ginger supplementation on hip circumference was marginal and there was no significant effect on BMI and waist circumference. Mean NF-κB p65 concentrations were reduced in ginger supplementation group, however, the amount was not statistically significant., Conclusion: Ginger supplementation had significant effects on anthropometric evaluations. Ginger supplementation decreased mean NF-κB concentration in comparison with placebo, however the significance level was marginal. In order to achieve reliable information, more researches should be complemented with uptake of other diagnostic tools., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

1,4-Naphthoquinone (1,4-NQ; CAS RN 130-15-4), a derivative of naphthalene, is a commonly used pre-cursor in industrial processes. Since the early 1980's 1,4-NQ has been tested in a number of genotoxicity assays, both in vitro and in vivo. There is strong evidence that 1,4-NQ does not induce gene mutations in bacteria or mammalian cells in vitro with predominantly negative Ames tests and negative Hprt and tk mutation studies. However, there is clear evidence of a clastogenic response in vitro from positive micronucleus, sister chromatid exchange and chromosome aberration assays. 1,4-NQ-treated mice and hamsters were, however, negative for micronucleus or chromosomal aberration induction in GLP-compliant studies with clear evidence of target tissue exposure, suggesting an in vitro only effect. Evidence indicates that the mechanism of in vitro clastogenicity is predominantly via ROS generation, and since in vitro mammalian cell tests systems have poor anti-oxidant defence mechanisms, they are particularly sensitive to oxidative DNA damage. On the other hand, healthy mammalian tissues have more efficient anti-oxidant defence mechanisms, and therefore it is not surprising that 1,4-NQ is not genotoxic in vivo., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims Patients with type 2 diabetes mellitus (T2DM) are prone to cardiovascular disease (CVD) due to inflammation process and oxidative stress. ADMA (Asymmetric dimethylarginine) and ICAM-1 (inter-cellular adhesion molecule-1) play an important role in CVD pathogenesis. Ginger as an anti-oxidant and anti-inflammation can effect on these biomarkers. The aim of present study was to characterize the effect of ginger supplementation on ADMA and ICAM-1 serum levels in patients with T2DM. Methods The present study is a randomized double-blind clinical trial which is conducted among 45 diabetic patients (nginger=23, nplacebo=22). The participants were randomly divided into two intervention and placebo groups which were received 2 g ginger powder and 2 g wheat flour for 10 weeks, respectively. ADMA and ICAM-1 concentration were measured by ELISA method. Results Ginger supplementation decreased ADMA serum levels significantly (P=0.002) and sICAM-1 serum levels marginally (P=0.097) in supplementation group after intervention. No significant difference was observed between placebo and supplementation groups. Conclusions Present study was conducted among patients with type 2 diabetes mellitus to investigate the effect of ginger supplementation on ADMA and sICAM-1 levels. There was a significant decrement in ADMA serum concentration and slight reduction in sICAM-1 levels in intervention group. The amount of reduction in both biomarkers was not statistically significant in between-groups comparison.

Afidopyropen is a novel insecticide that acts as a TRPV channel modulator in chordotonal organs of target insects. In two carcinogenicity studies with Fischer rats, an increased incidence of uterine adenocarcinomas was observed at 1000 and 3000 ppm. This finding prompted an investigation of the mechanism of the tumor formation as well as the relevance of this mechanism to humans. The mechanistic work took parallel paths: one path investigated the pharmacokinetic properties of the test substance at the doses where the tumors were found; while the second path examined the key mechanistic events that culminated in uterine adenocarcinomas. The results of the investigation indicated that the tumors only occurred at doses where excretion of test substance was saturated - indicating that homeostatic biological and/or physiological processes were overwhelmed. At the doses where these processes were overwhelmed, the test substance acted through a mechanism of dopamine agonism, triggering a cascade key events that resulted in uterine adenocarcinomas. An analysis of these mechanisms observed in rat showed that they are both quantitatively (pharmacokinetic mechanism) and qualitatively (dopamine agonism mechanism) not relevant to humans. Therefore the uterine adenocarcinomas observed in the rat associated with high doses of Afidopyropen are not expected to pose a carcinogenic risk to humans., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Several lines of evidence suggest that oxidized LDL (Ox-LDL) scavenger receptors play a crucial role in the genesis and progression of diabetic atherosclerosis. This study aimed to elucidate the effect of vitamin D3 on gene expression of lectin-like oxidized LDL receptor-1 (LOX-1), scavenger receptor-A (SR-A), Cluster of Differentiation 36 (CD36), and Cluster of Differentiation 68 (CD68) as the main Ox-LDL receptors in streptozotocin (STZ)-induced diabetic rat aortas., Methods: Eighteen Sprague-Dawley rats were randomly divided into three groups of six rats each. Two rats died during the study so five rats from each group were analyzed at the study's end. Diabetes was induced in overnight starved rats in two of the groups by intraperitoneal injections of 60 mg/kg of STZ. The vitamin D3/diabetic group then received weekly intraperitoneal injections of 5000 IU/kg of vitamin D3 dissolved in cottonseed oil for four weeks, diabetic controls received cottonseed oil, and healthy controls received sterile saline weekly for the same period. At the end of the four-week study period the animals were killed and the aortas were collected to examine the mRNA expression using real-time polymerase chain reaction (RT-PCR)., Results: SR-A and CD36 mRNA expression were significantly greater in the vitamin D3/diabetic rats than in both the diabetic control and healthy control rats. CD68 and LOX-1 expression were greater in the vitamin D3/diabetic rats than in the diabetic control and healthy control rats, respectively., Conclusion: Vitamin D3 may increase the risk of diabetic atherosclerosis by inducing scavenger receptors expression.

While the skin sensitization hazard of substances can already be identified using non-animal methods, the classification of potency sub-categories GHS-1A and 1B is still challenging. Potency can be measured by the dose at which an effect is observed; since the protein-adduct formation is determining the dose of the allergen in the skin, peptide reactivity was used to assess the potency. The Direct Peptide Reactivity Assay (DPRA; one concentration and reaction-time) did not sufficiently discriminate between sub-categories 1A and 1B (56% accuracy compared to LLNA data, n=124). An extended protocol termed 'quantitative DPRA' (three concentrations and one reaction-time), discriminated sub-categories GHS 1A and 1B with an accuracy of 81% or 57% compared to LLNA (n=36) or human (n=14) data, respectively. The analysis of the Cys-adducts was already sufficient; additional analysis of Lys-adducts did not improve the predictivity. An additional modification, the 'kinetic DPRA' (several concentrations and reaction-times) was used to approximate the rate constant of Cys-peptide-adduct formation. 35 of 38 substances were correctly assigned to the potency sub-categories (LLNA data), and the predictivity for 14 human data was equally high. These results warrant the kinetic DPRA for further validation in order to fully replace in vivo testing for assessing skin sensitization including potency sub-classification., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Migraine is a common chronic inflammatory neurological disease with the progressive and episodic course. Much evidence have shown a role of inflammation in the pathogenesis of migraine. Omega-3 fatty acids are an important components of cell membranes phospholipids. The intake of these fatty acids is related to decrease concentration of C-reactive protein (CRP), proinflammatory eicosanoids, cytokines, chemokines and other inflammation biomarkers. Many of clinical trials have shown the beneficial effect of dietary supplementation with omega-3 fatty acids in inflammatory and autoimmune diseases in human, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), multiple sclerosis (MS) and migraine headaches. Therefore, omega-3 fatty acids as an alternative therapy can be potentially important. This review focuses on the pathogenesis of a migraine, with an emphasis on the role of omega-3 fatty acid and its molecular mechanisms.

Background: Lipid and glycemic abnormalities are prevalent in diabetes leading to long term complications. Use of safe and natural foods instead of medications is now considered by many scientists., Objectives: This study aimed at determining the effect of ginger on lipid and glucose levels of patients with type 2 diabetes mellitus., Methods: In a double-blind placebo-controlled trial, 50 patients with type 2 diabetes were randomly allocated to 2 groups of intervention (n = 25) and placebo (n = 25). Each patient received 2000 mg per day of ginger supplements or placebo for 10 weeks. Serum levels of fasting blood sugar (FBS), total cholesterol (TC), triacylglycerol (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and glycosylated hemoglobin (HbA1C) were analyzed. Daily dietary intakes and anthropometric parameters were also determined., Results: Data from 45 patients were analyzed (23 patients in the ginger group and 22 patients in the control group) at the end of the study. Ginger consumption significantly reduced serum levels of fasting blood glucose (-26.30 ± 35.27 vs. 11.91 ± 38.58 mg/dl; P = 0.001) and hemoglobin A1C (-0.38 ± 0.35 vs. 0.22 ± 0.29 %; P < 0.0001) compared to the placebo group. Ginger consumption also reduced the ratio of LDL-C/HDL-C (2.64 ± 0.85 vs. 2.35 ± 0.8; P = 0.009). However, there was no significant change in serum concentrations of triglycerides, total cholesterol, LDL-C, and HDL-C due to the ginger supplements., Conclusions: The current results showed that ginger could reduce serum levels of fasting blood glucose and hemoglobin A1C in patients with diabetes.

Paraoxonase 1 is known as one of the most important ant oxidative enzymes associated with HDL-c, and because of its antioxidant and antiinflammatory activities. EPA has the antioxidant, anti inflammatory, antithrombogenic, and antiarteriosclerotic properties. Therefore, we investigated the effect of EPA supplementation on the serum levels and activity of PON1 in type 2 diabetic patients. This study was designed as a randomized, double-blind, and placebo-controlled clinical trial. Thirty-six patients with type 2 diabetes were given written; informed consent randomly was classified into 2 groups. They were supplemented with 2 g/day of the capsules of EPA or placebo for eight weeks. Blood sample was given for measurement of the serum levels of lipids, the activity of PON1, FBS and HbA1c. The patients supplemented with EPA showed a significant increase in the serum levels and activity of PON1 and the serum ratio of PON1/HDL-c. There were no significant differences between the two groups regarding any demographic, clinical or biochemical data, total energy intake, and macronutrient intake at the baseline during the intervention, except for a significant increase of protein intake and the levels of HbA1c in the placebo group, and a significant increase of HDL-c, as well as a slight reduction of total cholesterol, LDL-c, TG and FBS in the supplement group. EPA is atheroprotective via increase in the serum levels and activity of PON1, as well as change in the serum levels of lipids, FBS and HbA1c.