Occurrence and risk characterization of aflatoxin M1 in milk samples from southeastern Iran using the margin of exposure approach.

This study aimed to investigate Aflatoxin-M1 (AFM1) contamination in pasteurized and raw milk samples consumed in Kerman and Rafsanjan in southeastern Iran. In this cross-sectional study, a total of 100 samples of raw (n = 67) and pasteurized (n = 33) milk were randomly collected from retail stores, supermarkets, and milk transport tankers in the winter of 2020 and the summer of 2021. The level of AFM1 contamination in the collected samples was evaluated by high-performance liquid chromatography with fluorescence detection (HPLC-FD). AFM1 was detected in 95% of samples and its median concentration was 17.38 ng/L. The median concentration of AFM1 in the pasteurized milk samples (24.89 ng/L) was significantly higher than in the raw milk samples (13.54 ng/L). The AFM1 contamination level in 20% (raw = 13% and pasteurized = 7%) of the samples was higher than the maximum permitted level (MPL) recommended by the European Union (i.e., 50 ng/L), whilst 4% (raw = 3% and pasteurized = 1%) of the samples was higher than the Iranian maximum standard limit (i.e., 100 ng/L). The hazard index (HI) was higher than 1 in 16%, 18%, and 35% of total milk samples for men, women, and children, respectively. The AFM1 contamination level in the milk samples collected in southeastern Iran was worrying. The margin of exposure (MoE) values were lower than 10,000 for children. Because aflatoxins are among the most potent carcinogens known, prevention of milk contamination in all stages from the farm to the table can considerably reduce the community's exposure to AFM1 and its consequent health risks.

Prevalence of hypertension in Iran: An updated systematic review and meta-analysis of community-based studies.

Background: Hypertension (HTN) is one of the primary risk factors for heart disease and stroke worldwide. The present meta-analysis was aimed to systematically review and statistically estimate the prevalence rate of pre-hypertension (PHTN) and HTN in the Iranian child/adolescent and adult age groups. Methods: In this study, four International databases, including PubMed, Scopus, Web of Science, and Cochrane, as well as three Iranian databases, including SID, Magiran, and IranMedex, were separately investigated for articles published before January 2021. Also, we estimated the pooled effect size for the prevalence of PHTN and HTN in children/adolescent and adult age groups. Stata software (version 14.0) was used for all statistical analyses. Results: From a total of 1185 articles found in database searches, fifty-one were included in the meta-analysis. The prevalence of HTN in the Iranian adult population was 26.26% (25.11 % and 26.22 % for women and men, respectively). Meanwhile, the prevalence of PHTN and HTN in the child/adolescent age group was 8.97% (95% CI 7.33 - 10.61) and 8.98% (95% CI 7.59 - 10.36), respectively. Conclusions: This study provides information which can be used for various purposes, including study designing. Further nationwide surveys should be carried out to obtain accurate information on the HTN prevalence rate, particularly based on the American College of Cardiology /American Heart Association guidelines in the Iranian population.

Dietary inflammatory index and elevated serum C-reactive protein: A systematic review and meta-analysis.

Diet can affect the inflammatory state of the body. Accordingly, the dietary inflammatory index (DII) has been developed to quantify the inflammatory properties of food items. This study sought to investigate the association between dietary inflammation index (DII) and the odds ratio of elevated CRP (E-CRP) through a systematic review and meta-analysis study. The International electronic databases of PubMed, Web of Science (ISI), and Scopus were searched until May 2023 to find related articles. From 719 studies found in the initial search, 14 studies, with a total sample size of 59,941 individuals, were included in the meta-analysis. The calculated pooled odds ratio (OR) of E-CRP in the highest DII category was 1.39 (95% CI: 1.06, 1.14, test for heterogeneity: p = .63, and I 2 = .0%) in comparison with the lowest DII category. Also, the results of this study showed that each unit increase in DII as a continuous variable generally elicited a 10% increase in the odds of E-CRP (OR 1.10, 95% CI 1.06, 1.14, test for heterogeneity: p = .63, and I 2 = .0%). Subgroup meta-analyses showed that there is a higher E-CRP odds ratio for the articles that reported energy-adjusted DII (E-DII) instead of DII, the studies that measured CRP instead of hs-CRP, and the studies that used 24-h recall instead of FFQ as the instrument of dietary intake data collection. Individuals with a higher DII were estimated to have higher chances of developing elevated serum CRP. This value was influenced by factors such as the participants' nationality, instruments of data collection, methods used to measure inflammatory biomarkers, study design, and data adjustments. However, future well-designed studies can help provide a more comprehensive understanding of the inflammatory properties of diet and inflammatory serum biomarkers.

Lead and arsenic contamination in henna samples marketed in Iran.

Since ancient times, people around the world have used natural cosmetics to improve or change the appearance of their nails, skin, and hair. Henna is a plant-based dye that has been used over the centuries for medical and cosmetic purposes. The present work was aimed to investigate the presence of lead (Pb) and arsenic (As) in various types of commonly consumed henna samples in Iran. A total of thirty-nine henna samples from both local and imported products (3 colors in 13 brands) were randomly collected from popular and herbal medicine markets. The atomic absorption spectrometry (AAS) technique was used for the analysis of the samples. The amount of Pb and As in 100% samples was higher than the calculated limit of quantitation (LOQ). The concentrations of Pb and As in the samples were at the ranges of 9.56-16.94 µg/g and 0.25-1.12 µg/g, respectively. The mean level of Pb was higher in black and red products, compared with the green henna. The levels of Pb and As in 53.85% and 7.7% of the henna samples exceeded the permissible limits recommended by the World Health Organization (WHO), respectively. In addition, the mean levels of Pb and As contamination in the imported samples were significantly higher, in comparison to the local henna samples. To our knowledge, this is the first study assessing Pb and As contamination in the henna samples consumed in Iran. Our study demonstrated that there is a potential risk of exposure to Pb through henna in the Iranian consumers.

Involvement of Nrf2 signaling in lead-induced toxicity.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is used as one of the main protective factors against various pathological processes, as it regulates cells resistant to oxidation. Several studies have extensively explored the relationship between environmental exposure to heavy metals, particularly lead (Pb), and the development of various human diseases. These metals have been reported to be able to, directly and indirectly, induce the production of reactive oxygen species (ROS) and cause oxidative stress in various organs. Since Nrf2 signaling is important in maintaining redox status, it has a dual role depending on the specific biological context. On the one hand, Nrf2 provides a protective mechanism against metal-induced toxicity; on the other hand, it can induce metal-induced carcinogenesis upon prolonged exposure and activation. Therefore, the aim of this review was to summarize the latest knowledge on the functional interrelation between toxic metals, such as Pb and Nrf2 signaling.

Contamination of breast milk with lead, mercury, arsenic, and cadmium in Iran: a systematic review and meta-analysis.

Breast milk is a complete food for the development of the newborn, but it can also be an important route for environmental pollutants transmission to the infants. This study was aimed to evaluate the status of heavy metals including lead (Pb), mercury (Hg), cadmium (Cd) and arsenic (As) in the breast milk of Iranian mothers. The international databases including Scopus, PubMed, Web of Science and the Persian electronic databases including Scientific Information Database, IranMedex and Magiran were examined to find relevant articles published until July 2021. A total of 23 studies examined the levels of toxic metals in Iranian breast milk samples. According to the findings, the pooled average concentrations (µg/L) of Pb, Cd, Hg and As were 25.61, 2.40, 1.29 and 1.16, respectively. The concentration of Hg and Pb in colostrum milk was more than twice of mature milk. The Hg mean concentration in the breast milk of mothers with at least one amalgam-filled tooth was approximately three times that of mothers without amalgam-filled teeth. Risk assessment analysis indicated that the intake of Pb and Hg by infants through breastfeeding can be considered a health concern in Iran. It seems necessary to reduce the Pb exposure of pregnant and lactating women in Iran. However, more extensive studies are needed to clarify the toxic metals' exposure status of infants through breast milk in other parts of the country.

The interplay of aryl hydrocarbon receptor/WNT/CTNNB1/Notch signaling pathways regulate amyloid beta precursor mRNA/protein expression and effected the learning and memory of mice.

The amyloid beta precursor protein (APP) plays a pathophysiological role in the development of Alzheimer's disease as well as a physiological role in neuronal growth and synaptogenesis. The aryl hydrocarbon receptor (AhR)/WNT/Catenin Beta 1 (CTNNB1)/Notch signaling pathways stamp in many functions, including development and growth of neurons. However, the regulatory role of AhR-/WNT-/CTNNB1-/Notch-induced APP expression and its influence on hippocampal-dependent learning and memory deficits is not clear. Male BALB/C mice received 6-formylindolo[3,2-b]carbazole (an AhR agonist), CH223191(an AhR antagonist), DAPT (an inhibitor of Notch signaling), and XAV-939 (a WNT pathway inhibitor) at a single dose of 100 µg/kg, 1, 5 , and 5 mg/kg of body weight, respectively, via intraperitoneal injection alone or in combination. Gene expression analyses and protein assay were performed on the 7th and 29th days. To assess the hippocampal-dependent memory, all six mice also underwent contextual fear conditioning on the 28th day after treatments. Our results showed that endogenous ligand of AhR has a regulatory effect on APP gene. Also, the interaction of AhR/WNT/CTNNB1 has a positive regulatory effect, but Notch has a negative regulatory effect on the mRNA and protein expression of APP, which have a correlation with mice's learning skills and memory.

Aloe vera and Streptozotocin-Induced Diabetes Mellitus.

Diabetes mellitus is defined as prolonged hyperglycemia, which can harm the eyes, kidneys, and cardiovascular and neurological systems. Herbal agents and their derived supplements have been used for treatment of diabetes mellitus as a part of integrated complementary medicine for centuries. Numerous studies have considered Aloe vera (L.) Burm.f, Xanthorrhoeaceae, as an alternative medicine due to its abundant bioactive chemicals, such as alkaloids, anthraquinones, and enthrones, with therapeutical properties including antioxidant, anti-inflammatory, neuro-protective, and anti-diabetic effects. Aloe vera has received considerable attention in traditional medicine for the treatment of several diseases including diabetes mellitus. Numerous studies have investigated the effects of herbal agents on diabetes mellitus using a streptozotocin-induced diabetic model. Thereby, this article reviews the effects of Aloe vera prescription on streptozotocin-induced diabetes mellitus to provide a clear insight into the role of this medicinal plant in several biological functions, such as antioxidant, wound healing, anti-inflammatory, anti-hyperglycemic, and anti-hyperlipidemic in diabetic models. Graphical abstract.

Influence of cellular redox environment on aryl hydrocarbon receptor ligands induced melanogenesis.

Many environmental pollutants, natural compounds, as well as endogenous chemicals exert their biological/toxicological effects by reacting with the aryl hydrocarbon receptor (AhR). Previous evidence shed new light on the role of AhR in skin physiology by regulating melanin production. In this study, we investigated the effect of oxidative imbalance induced by AhR ligands on the melanogenesis process in B16 murine melanoma cells. Exposure to 6-formylindolo[3,2-b] carbazole (FICZ) or benzo-α-pyrene (BαP) led to enhanced expression of CTNNB1, MITF, and TYR genes following increased tyrosinase enzyme activity and melanin content in an AhR-dependent manner. Analysis of the presence of reactive oxygen species (ROS) as well as reduced glutathione (GSH) / oxidized glutathione (GSSG) ratio revealed that treatment with AhR ligands is associated with oxidative stress which can be ameliorated with NAC (N-acetyl cysteine) or diphenyleneiodonium chloride (DPI). On the other hand, NAC and DPI enhanced melanogenesis induced by AhR ligands by reducing the level of ROS. We have shown for the first time that a cellular redox status is a critical event during AhR ligand-induced melanogenesis.

Evaluation of blood lead among painters of buildings and cars.

Exposure to lead-based paints is a major threat to the health of painters. This study aimed to evaluate the blood concentration of lead (Pb) in painters of buildings and cars. The present study was a cross-sectional study in which a semi-structured questionnaire was used to collect the socio-demographic information. Lead concentration in blood samples was determined using the atomic absorption spectrometry method. A total of 32 male painters were selected based on inclusion criteria. The mean blood lead level (BLL) in the painters was 8.1 ± 4.93 µg/dL. Pb levels in car and building painters were 9.42 ± 5.5 µg/dL and 6.7 ± 1.85 µg/dL, respectively. Pb concentration in none of the blood samples was more than 30 µg/dL. The prevalence of BLL ≥ 5 µg/dL and BLL ≥ 10 µg/dL was 97% and 19%, respectively. According to the findings, the rate of BLL among car painters was higher than building painters. Considering the presence of Pb in all blood samples, it seems necessary to increase the awareness of painters about the adverse effects of lead exposure even in low concentrations. However, the sample size in this study was small and more investigations are required in this regard.

Melatonin Supplementation and Anthropometric Indices: A Randomized Double-Blind Controlled Clinical Trial.

Obesity, as the most common metabolic disorder in the world, is characterized by excess body fat. This study is aimed at determining the effects of melatonin supplementation on body weight, nody mass index (BMI), waist circumference (WC), and body fat mass percentage (BFMP) in people with overweight or obesity. Thirty eight overweight or class-I obese adult individuals were recruited in the study (8 men and 30 women). Participants prescribed a weight-loss diet and then randomly were allocated to melatonin or placebo groups. Participants received either a 3-milligram melatonin or placebo tablet per day for 12 weeks. In order to assess differences at the significance level of 0.05, repeated measure ANOVA and paired t-test were used. According to the results, a significant reduction was found in participants' body weight, WC, and BMI in both groups (p = 0.001). However, for the last six weeks, significant reductions of these parameters were observed only in the melatonin group (p = 0.01). The BFMP of participants in the melatonin group showed a significant reduction at the end of the study compared to the initial measurements (p = 0.008). Nevertheless, the results of the present study alone are not sufficient to conclude on the effects of melatonin consumption on anthropometric indices, and it seems that further studies are required in this regard.

Aryl hydrocarbon receptor engagement during redox alteration determines the fate of CD4+ T cells in C57BL/6 mice.

The preservation of the redox homeostasis is critical for cell survival and functionality. Redox imbalance is an essential inducer of several pathological states. CD4+ /helper T cells are highly dependent on the redox state of their surrounding milieu. The potential of the aryl hydrocarbon receptor (AhR) engagement in controlling CD4+ T-cell fate during redox alteration is still challenging. C57BL/6 mice were treated with AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ), AhR antagonist CH223191, an inhibitor of glutathione biosynthesis buthionine sulfoximine (BSO), and the antioxidant N-acetylcysteine (NAC) alone or in combination. Six days later, splenocytes were evaluated for the expression of the redox-related genes and the possible changes in T-cell subsets. FICZ like BSO significantly elevated the expression of HMOX1, GCLC, and GCLM genes but it failed to increase the expression of the Nrf2 gene. Moreover, FICZ + BSO increased while FICZ + CH223191 or NAC decreased the expression of these genes. FICZ also significantly increased Th1 cell numbers but decreased Tregs in a dose-dependent manner. Furthermore, a high dose of FICZ + CH223191 + NAC significantly enhanced Th1, Th17, and Treg cells but its low dose in such a situation increased Th2 and Th17 while decreased Treg cells. AhR engagement during redox alteration can determine the fate of CD4 + T cells, so, AhR agonists or antagonists might be useful in assessing immune responses. However, these results need further verifications in vitro and in animal models of various diseases.

Introducing a delivery system for melanogenesis inhibition in melanoma B16F10 cells mediated by the conjugation of tyrosine ammonia-lyase and a TAT-penetrating peptide.

Hyperpigmentation disorders negatively influence an individual's quality of life and may cause emotional distress. Over the years, various melanogenesis inhibitors (mainly tyrosinase inhibitors) have been developed, most of which with low efficacy or high toxicity. Although metabolic engineering by deviation in the flux of substrate is of considerable interest, trials to develop a melanogenesis inhibitor based on L-tyrosine (L-Tyr) restriction are missing. We propose a novel proteinaceous melanogenesis inhibitor called tyrosine ammonia-lyase (TAL), an enzyme that catalyzes the conversion of L-Tyr to p-coumaric acid and ammonia. Since the cell membrane can act as a barrier for intracellular protein delivery, we have covalently conjugated a recombinant TAL enzyme from Rhodobacter sphaeroides (RsTAL) to a trans-activator of transcription (TAT) cell-penetrating peptide (CPP) to afford the intracellular delivery. The heterologously expressed TAT-RsTAL fusion protein was delivered successfully into B16F10 melanocytes as confirmed by the direct fluorescence microscopy with increased intensity from 30 to 180 min. TAT-RsTAL showed sufficient intracellular activity of about 0.83 ± 0.04 and 0.34 ± 0.03 nmol•mg-1 •s-1 for the native and inclusion body-extracted conjugates, respectively. The conjugate inhibited melanin biosynthesis in B16F10 cells in a time-dependent manner. Melanin accumulation was inhibited by 12.7 ± 6.2%, 28.2 ± 5.7%, and 33.9 ± 2.9% compared to the nontreated control groups after 24, 48, and 72 hr of incubation, respectively. L-Tyr restriction had no significant effect on the cell viability up to a concentration of 100 µgml-1 even after 72 hr. According to the observed hypopigmentary effect of the conjugate in this study, TAT-RsTAL can be suggested as a melanogenesis inhibitor for further investigations.

An Endogenous Ligand of Aryl Hydrocarbon Receptor 6-Formylindolo[3,2-b]Carbazole (FICZ) Is a Signaling Molecule in Neurogenesis of Adult Hippocampal Neurons.

Neurogenesis is a dynamic and physiologic developmental process that affects learning and hippocampal dependent memory. It is regulated by multi-cellular micro-environment and different types of transcription factors. The neurogenesis effects of endogenously activated aryl hydrocarbon receptor (AHR) by its endogenous ligand, 6-formylindolo[3,2-b] carbazole (FICZ), and its interactions with the Wnt/ß-catenin signaling pathway were the main purpose of this study. In accordance, learning and hippocampus-dependent memory were examined. Male BALB/C mice received FICZ, CH223191, and XAV-939 in a single dose of 100 µg/kg, 1 mg/kg, and 5 mg/kg of body weight respectively via intraperitoneal (IP) injection. qRT-PCR for gene analyses and protein assay on the 7th and 28th days were performed. To assess the hippocampal dependent memory, they also underwent contextual fear conditioning on the 28th day after treatment. Our results showed that FICZ treatment led to elevation of the proneural transcription factors ASCL1 and Ngn2, immature neural marker DCX, differentiation neurons marker, NeuN, as well as ß-catenin at mRNA and protein levels. We also indicated that hippocampal dependent memory and learning task were improved by FICZ treatment and impaired by the AHR and Wnt/ß-catenin inhibition. In this study for the first time, we demonstrated that the endogenous ligand of AHR, FICZ, has a positive effect on short- and long-term memory as well as learning skills. This ability is possibly mediated by the AHR-Wnt/ß-catenin cross-talk.

Protective effect of magnesium and selenium on cadmium toxicity in the isolated perfused rat liver system.

The isolated perfused rat liver (IPRL) model has been used into toxicology study of rat liver. This model provides an opportunity at evaluation of liver function in an isolated setting. Studies showed that Cd, in a dose-dependent manner, induced toxic effects in IPRL models, and these effects were associated with aminotransferase activity and lipid peroxidation. The aim of this study was to investigate whether Mg  and/or Se could have protective effects against the Cd toxicity in the IPRL model. Male Wistar rats (9-10 weeks) weighing 260-300 gr were used in this study. They were randomly divided into 8 groups of 4-6 rats per cage. In group 1, liver was perfused by Krebs-Henseleit buffer without MgSO4 (Control). Groups 2-8 were exposed to Mg, Se, Cd, Mg +Se, Cd + Mg, Cd + Se, Cd + Mg + Se respectively in Krebs-Henseleit buffer with no added MgSo4. Biochemical changes in the liver were examined within 90 minutes, and the result showed that the exposure to Cd, lowered glutathione level, while it increased malondialdehyde level and aminotransferase activities in IPRL model. Mg administration during exposure to Cd reduces the toxicity of Cd in the liver isolated while Se administration during exposure to Cd did not decrease Cd hepatotoxicity. Nevertheless, simultaneous treatment with Se and Mg on Cd toxicity have strengthened protective effects than the supplementation of Se alone in the liver.