Depressive symptoms are found to be potential adverse effects of androgen deprivation therapy in older prostate cancer patients: a 15-month prospective, observational study

Abstract

Objectives

To evaluate the association between androgen deprivation therapy (ADT) and depression and to identify the risk factors for depressive symptoms among prostate cancer patients who received ADT.

Methods

We conducted a prospective, longitudinal, controlled study and assessed three groups of older patients: the ADT group (men who were presented with maximum androgen block); the radical prostatectomy group (RP) (PCa control group: men who underwent radical prostatectomy without ADT); and the BPH group (men who had benign prostatic hyperplasia). All patients completed the demographic questionnaire at baseline and the Zung Self-Rating Depression Scale (SDS) at pretreatment baseline, 1 month, 6 months, 9 months, 12 months and 15 months.

Results

A total of 146 patients completed the study during the 15-month follow-up. The SDS scores of the three groups showed significant differences at 1 month (p < 0.001), 6 months (p = .009), 9 months (p < 0.001), 12 months (p < 0.001) and 15 months (p < 0.001). At 9 months, 12% of the men in the ADT group, 4.3% in the RP group and 2% in the BPH group showed depressive symptoms, and there were no significant differences (p = 0.095). However, there were significant differences among the three groups relative to the incidence of depressive symptoms at 12 months and 15 months (p < 0.001, p = 0.007, respectively). The analysis of the ADT subgroup indicated that alcohol consumption ( OR = 6.868; p = 0.046; 95% CI, 1.038 − 45.443) and smoking(OR = 13.661; p = 0.013;95% CI:1.722-108.386)increased the risk for developing depressive symptoms.

Conclusions

ADT use does significantly increase the depressive scores and enhance the incidence of depression among PCa patients who received ADT. Smoking and alcohol consumption are associated with depressive symptoms among PCa patients receiving ADT.

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Depressive symptoms are found to be potential adverse effects of androgen deprivation therapy in older prostate cancer patients: a 15-month prospective, observational study

Abstract

Objectives

To evaluate the association between androgen deprivation therapy (ADT) and depression and to identify the risk factors for depressive symptoms among prostate cancer patients who received ADT.

Methods

We conducted a prospective, longitudinal, controlled study and assessed three groups of older patients: the ADT group (men who were presented with maximum androgen block); the radical prostatectomy group (RP) (PCa control group: men who underwent radical prostatectomy without ADT); and the BPH group (men who had benign prostatic hyperplasia). All patients completed the demographic questionnaire at baseline and the Zung Self-Rating Depression Scale (SDS) at pretreatment baseline, 1 month, 6 months, 9 months, 12 months and 15 months.

Results

A total of 146 patients completed the study during the 15-month follow-up. The SDS scores of the three groups showed significant differences at 1 month (p < 0.001), 6 months (p = .009), 9 months (p < 0.001), 12 months (p < 0.001) and 15 months (p < 0.001). At 9 months, 12% of the men in the ADT group, 4.3% in the RP group and 2% in the BPH group showed depressive symptoms, and there were no significant differences (p = 0.095). However, there were significant differences among the three groups relative to the incidence of depressive symptoms at 12 months and 15 months (p < 0.001, p = 0.007, respectively). The analysis of the ADT subgroup indicated that alcohol consumption ( OR = 6.868; p = 0.046; 95% CI, 1.038 − 45.443) and smoking(OR = 13.661; p = 0.013;95% CI:1.722-108.386)increased the risk for developing depressive symptoms.

Conclusions

ADT use does significantly increase the depressive scores and enhance the incidence of depression among PCa patients who received ADT. Smoking and alcohol consumption are associated with depressive symptoms among PCa patients receiving ADT.

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Deguelin induced differentiation of mutated NPM1 acute myeloid leukemia in vivo and in vitro.

Nucleophosmin (NPM1), a restricted nucleolar localization protein, shuttles between the nucleus and the cytoplasm. Mutated (Mt)-NPM1 protein, which has aberrant cytoplasmic dislocation of nucleophosmin, occurs in approximately one-third of acute myeloid leukemia cases. Deguelin, a rotenoid isolated from several plant species, is a strong antitumor agent. NOD/SCID mice xenografted with human Mt-NPM1 OCI/AML3 cell lines served as in-vivo models. Wright-Giemsa staining and flow cytometry analysis were used for differentiation assays. Associated molecular events were assessed by western blot and histological analyses. Kaplan-Meier estimates were used to calculate survival. Deguelin toxicity in mice was assessed by immunohistochemistry staining and serum markers. Clinical samples were differentiated by flow cytometry analysis. Deguelin induced differentiation by downregulating the Mt-NPM1 protein levels, which was accompanied by a decrease in SIRT1, p21, and HDAC1 and an increase in CEBP[beta] and granulocyte colony-stimulating factor receptor protein expression levels. A low-deguelin dose prolonged survival compared with the control group, and there were no apparent lesions to the brain, liver, heart, and kidney in vivo. In clinical samples, deguelin induced the differentiation of fresh blasts with Mt-NPM1 protein, but not with the wild-type NPM1 protein. Taken together, these findings further provide new evidence that the Mt-NPM1 protein plays an important role in inducing differentiation in vivo and in vitro. Mutated NPM1 protein may be a therapeutic target of deguelin in acute myeloid leukemia with the NPM1 mutation. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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3-Bromopyruvate enhances TRAIL-induced apoptosis in human nasopharyngeal carcinoma cells through CHOP-dependent upregulation of TRAIL-R2.

Past reports have shown that the sensitivity of cancer cells to TRAIL-induced apoptosis is related to their expression of TRAIL-death receptors on the cell surface. However, the level of TRAIL-death receptors expression on cancer cells is always low. Our previous research showed that nasopharyngeal carcinoma (NPC) cells have a poor sensitivity to low doses of TRAIL. Here, we evaluated combined treatment with the energy inhibitor 3-bromopyruvate (3BP) and TRAIL as a method to produce an increased apoptotic response in NPC cells. The results showed that 3BP and TRAIL together produced higher cytotoxicity and increased TRAIL-R2 expression in NPC cells compared with the effects of either 3BP or TRAIL alone. These findings led us to hypothesize that 3BP may sensitize NPC cells to TRAIL. 3BP is a metabolic blocker that inhibits hexokinase II activity, suppresses ATP production, and induces endoplasmic reticulum (ER) stress. Our results showed that 3BP also activated AMP-activated protein kinase, which we found to play an important role in the induction of ER stress by 3BP. Furthermore, the induction of TRAIL-R2 expression and the sensitization of the NPC cells to TRAIL by 3BP were reduced when we inhibited the expression of CHOP. Taken together, our results showed that a low dose of 3BP sensitized NPC cells to TRAIL-induced apoptosis by the upregulation of CHOP, which was mediated by the activation of AMP-activated protein kinase and ER stress. The results showed that 3BP is a promising candidate agent for enhancing the therapeutic response to TRAIL in NPC. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Antitumor activities of the synthetic retinoid ST1926 in two-dimensional and three-dimensional human breast cancer models.

Despite recent advances in chemotherapy, aggressive and metastatic breast cancers remain refractory to targeted therapy and the development of novel drugs is urgently needed. Retinoids are crucial regulators of cellular proliferation, differentiation, and cell death, and have shown potent chemotherapeutic and chemopreventive properties. The major drawback of the use of all-trans retinoic acid (ATRA) in cancer therapy is disease relapse. Therefore, synthetic retinoids, specifically ST1926, have emerged as potent anticancer agents. Given the importance of the microenvironment in modulating the response of cancer cells to chemotherapeutic drugs, we investigated the antitumor activities of ST1926 in two-dimensional (2D) and different three-dimensional (3D) human breast cancer models and compared them with ATRA. We have shown that in 2D cell culture models, ATRA-resistant MCF-7 and MDA-MB-231 cells were sensitive to ST1926 at submicromolar concentrations that spared the 'normal-like' breast epithelial cells. ST1926 induced apoptosis and S-phase arrest, caused DNA damage, and downregulated the Wnt/[beta]-catenin pathway in breast cancer cells in 2D and 3D cell culture models. ST1926-mediated growth inhibition was independent of the retinoid receptor-signaling pathway. Long-term treatments with low submicromolar ST1926 concentrations reduced the anchorage-independent growth and decreased the sphere-forming ability of breast cancer progenitor cells in the sphere formation assay. Furthermore, ST1926 potently induced cell death of breast cancer cells under 3D conditions and spared the lumen-forming ability of normal-like breast epithelial cells. In tested 3D models, ATRA had minimal effects on the growth of breast cancer cells compared with ST1926. In summary, our results highlight the therapeutic potential of ST1926 in breast cancer and warrant its further clinical development. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Clusterin inhibition mediates sensitivity to chemotherapy and radiotherapy in human cancer.

Since its discovery in 1983, the protein clusterin (CLU) has been isolated from almost all human tissues and fluids and linked to the development of different physiopathological processes, including carcinogenesis and tumor progression. During the last few years, several studies have shown the cytoprotective role of secretory CLU in tumor cells, inhibiting their apoptosis and enhancing their resistance to conventional treatments including hormone depletion, chemotherapy, and radiotherapy. In an effort to determine the therapeutic potential that the inhibition of this protein could have on the development of new strategies for cancer treatment, numerous studies have been carried out in this field, with results, in most cases, satisfactory but sometimes contradictory. In this document, we summarize for the first time the current knowledge of the effects that CLU inhibition has on sensitizing tumor cells to conventional cancer treatments and discuss its importance in the development of new strategies against cancer. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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IDH1 or - 2 mutations do not predict outcome and do not cause loss of 5-hydroxymethylcytosine or altered histone modifications in central chondrosarcomas

Abstract

Background

Mutations in isocitrate dehydrogenase (IDH)1 or -2 are found in ~50% of conventional central chondrosarcomas and in up to 87% of their assumed benign precursors enchondromas. The mutant enzyme acquires the activity to convert α-ketoglutarate into the oncometabolite d-2-hydroxyglutarate (d-2-HG), which competitively inhibits α-ketoglutarate dependent enzymes such as histone- and DNA demethylases.

Methods

We therefore evaluated the effect of IDH1 or -2 mutations on histone modifications (H3K4me3, H3K9me3 and H3K27me3), chromatin remodeler ATRX expression, DNA modifications (5-hmC and 5-mC), and TET1 subcellular localization in a genotyped cohort (IDH, succinate dehydrogenase (SDH) and fumarate hydratase (FH)) of enchondromas and central chondrosarcomas (n = 101) using immunohistochemistry.

Results

IDH1 or -2 mutations were found in 60.8% of the central cartilaginous tumours, while mutations in FH and SDH were absent. The mutation status did not correlate with outcome. Chondrosarcomas are strongly positive for the histone modifications H3K4me3, H3K9me3 and H3K27me3, which was independent of the IDH1 or -2 mutation status. Two out of 36 chondrosarcomas (5.6%) show complete loss of ATRX. Levels of 5-hmC and 5-mC are highly variable in central cartilaginous tumours and are not associated with mutation status. In tumours with loss of 5-hmC, expression of TET1 was more prominent in the cytoplasm than the nucleus (p = 0.0001).

Conclusions

In summary, in central chondrosarcoma IDH1 or -2 mutations do not affect immunohistochemical levels of 5-hmC, 5mC, trimethylation of H3K4, -K9 and K27 and outcome, as compared to wildtype.

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Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases

Abstract

Background

Histone 3.3 (H3.3) hotspot mutations in bone tumors occur in the vast majority of giant cell tumors of bone (GCTBs; 96%), chondroblastomas (95%) and in a few cases of osteosarcomas. However, clinical presentation, histopathological features, and additional molecular characteristics of H3.3 mutant osteosarcomas are largely unknown.

Methods

In this multicentre, retrospective study, a total of 106 conventional high-grade osteosarcomas, across all age groups were re-examined for hotspot mutations in the H3.3 coding genes H3F3A and H3F3B. H3.3 mutant osteosarcomas were re-evaluated in a multidisciplinary manner and analyzed for genome-wide DNA-methylation patterns and DNA copy number aberrations alongside H3.3 wild-type osteosarcomas and H3F3A G34W/L mutant GCTBs.

Results

Six osteosarcomas (6/106) carried H3F3A hotspot mutations. No mutations were found in H3F3B. All patients with H3F3A mutant osteosarcoma were older than 30 years with a median age of 65 years. Copy number aberrations that are commonly encountered in high-grade osteosarcomas also occurred in H3F3A mutant osteosarcomas. Unlike a single osteosarcoma with a H3F3A K27M mutation, the DNA methylation profiles of H3F3A G34W/R mutant osteosarcomas were clearly different from H3.3 wild-type osteosarcomas, but more closely related to GCTBs. The most differentially methylated promoters between H3F3A G34W/R mutant and H3.3 wild-type osteosarcomas were in KLLN/PTEN (p < 0.00005) and HIST1H2BB (p < 0.0005).

Conclusions

H3.3 mutations in osteosarcomas may occur in H3F3A at mutational hotspots. They are overall rare, but become more frequent in osteosarcoma patients older than 30 years. Osteosarcomas carrying H3F3A G34W/R mutations are associated with epigenetic dysregulation of KLLN/PTEN and HIST1H2BB.

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Elacestrant (RAD1901), a selective estrogen receptor degrader (SERD), has anti-tumor activity in multiple ER+ breast cancer patient-derived xenograft models

PURPOSE: Estrogen receptor-positive (ER+) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of anti-estrogen therapy. Selective estrogen receptor degraders (SERDs) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER+ breast cancer. <p>EXPERIMENTAL DESIGN: Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER+ breast cancer models, including several patient-derived xenograft models.</p> <p>RESULTS: Elacestrant induces the degradation of ER, inhibits ER-mediated signaling and growth of ER+ breast cancer cell lines in vitro and in vivo and significantly inhibits tumor growth of multiple PDX models. Furthermore, we demonstrate that elacestrant in combination with palbociclib or everolimus can lead to greater efficacy in certain contexts. Finally, elacestrant exhibits significant anti-tumor activity both as a single agent and in combination with palbociclib in two patient-derived breast cancer xenograft models harboring ESR1 mutations.</p> <p> </p> <p>CONCLUSIONS: These data underscore the potential clinical utility of elacestrant as a single agent and as a combination therapy, for both early and late stage ER+ disease.

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Androgen receptor variant AR-V9 is co-expressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance

Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies.  Accordingly, efforts are underway to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC).  The purpose of this study was to understand whether other AR variants may be co-expressed with AR-V7 and promote resistance to AR-targeted therapies.<br /><br /> Experimental Design:  We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models.  Co-expression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively.  Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera.  Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate.   <br /><br />Results: AR-V9 was frequently co-expressed with AR-V7.  Both AR variant species were found to share a common 3' terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously-thought to target AR-V7 uniquely.  AR-V9 promoted ligand-independent growth of prostate cancer cells.  High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR = 4.0, 95% CI = 1.31-12.2, P = 0.02).  <br /><br />Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC.

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Individual and Combined Effects of Arsenic and Lead on Behavioral and Biochemical Changes in Mice

Abstract

Arsenic (As) toxicity has caused an environmental tragedy affecting millions of people in the world. Little is known about the toxic effects of As on neurobehavioral and biochemical changes in vivo. Along this line of metal toxicity, co-exposure of lead (Pb) could aggravate the situation in the host. The present study was designed to explore the combined effects of As and Pb on behavioral changes like anxiety, spatial memory and learning impairment, and blood indices related to organ dysfunction. Exposure of mice to As (10 mg/kg body weight), Pb (10 mg/kg body weight), and As + Pb via drinking water significantly decreased the time spent exploring the open arms while it increased the time spent in the closed arms compared to control mice in the elevated plus maze. The mean latency time of the control group to find the platform decreased significantly during the learning for 7 days compared to all three treated groups in the Morris water maze test, and the As-exposed group spent significantly less time in the desired quadrant as compared to the control group in the probe trial. Both metals posed an anxiety-like behavior and deficits in spatial memory and learning, and also altered blood indices related to liver and kidney dysfunction, and a combined exposure of these metals inhibited the individual accumulation of As and Pb. Taken together, these data suggest that As has more toxic effects on neurobehavioral and biochemical changes than Pb, and there may be antagonism in the effects and accumulation between these two toxicants.

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Combined Effects of Phytoestrogen Genistein and Silicon on Ovariectomy-Induced Bone Loss in Rat

Abstract

This study was performed to evaluate the effect of concomitant supplementation of genistein and silicon on bone mineral density and bone metabolism-related markers in ovariectomized rat. Three-month-old Sprague Dawley female rats were subjected to bilateral ovariectomy (OVX) or sham surgery, and then the OVX rats were randomly divided into four groups: OVX-GEN, OVX-Si, OVX-GEN-Si, and OVX. Genistein and silicon supplementation was started immediately after OVX and continued for 10 weeks. In the OVX-GEN group, 5 mg genistein per gram body weight was injected subcutaneously. The OVX-Si group was given soluble silicon daily in demineralized water (Si 20 mg/kg body weight/day). The OVX-GEN-Si group was given subcutaneous injections of 5 mg genistein per gram body weight, at the same time, given soluble silicon daily (Si 20 mg/kg body weight/day). The results showed that the genistein supplementation in the OVX rats significantly prevented the loss of uterus weight; however, the silicon supplementation showed no effect on the uterus weight loss. The lumbar spine and femur bone mineral density was significantly decreased after OVX surgery; however, this decrease was inhibited by the genistein and/or silicon, and the BMD of the lumbar spine and femur was the highest in the OVX-GEN-Si-treated group. Histomorphometric analyses showed that the supplementation of genistein and/or silicon restored bone volume and trabecular thickness of femoral trabecular bone in the OVX group. Besides, the treatment with genistein and silicon for 10 weeks increased the serum levels of calcium and phosphorus in the OVX rats; serum calcium and serum phosphorus in the OVX-GEN-Si group were higher than those in the OVX-GEN and OVX-Si group (P < 0.05). At the same time, the treatment with genistein and/or silicon decreased serum alkaline phosphatase (ALP) and osteocalcin, which were increased by ovariectomy; serum ALP and osteocalcin in the OVX-GEN-Si group were lower than those in the OVX-GEN and OVX-Si groups (P < 0.05). The results above indicate that genistein and silicon have synergistic effects on bone formation in ovariectomized rats.

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Overexpression of Endogenous Anti-Oxidants with Selenium Supplementation Protects Trophoblast Cells from Reactive Oxygen Species-Induced Apoptosis in a Bcl-2-Dependent Manner

Abstract

The human placenta provides life support for the developing foetus, and a healthy placenta is a prerequisite to a healthy start to life. Placental tissue is subject to oxidative stress which can lead to pathological conditions of pregnancy such as preeclampsia, preterm labour and intrauterine growth restriction. Up-regulation of endogenous anti-oxidants may alleviate placental oxidative stress and provide a therapy for these complications of pregnancy. In this study, selenium supplementation, as inorganic sodium selenite (NaSel) or organic selenomethionine (SeMet), was used to increase the protein production and cellular activity of the important redox active proteins glutathione peroxidase (GPx) and thioredoxin reductase (Thx-Red). Placental trophoblast cell lines, BeWo, JEG-3 and Swan-71, were cultured in various concentrations of NaSel or SeMet for 24 h and cell extracts prepared for western blots and enzyme assays. Rotenone and antimycin were used to stimulate mitochondrial reactive oxygen species (ROS) production and induce apoptosis. Trophoblast cells supplemented with 100 nM NaSel and 500 nM SeMet exhibited significantly enhanced expression and activity of both GPx and Thx-Red. Antimycin and rotenone were found to generate ROS when measured by 2′,7′-dichlorofluorescein diacetate (DCFDA) assay, and selenium supplementation was shown to reduce ROS production in a dose-dependent manner. Rotenone, 100 μM treatment for 4 h, caused trophoblast cell apoptosis as evidenced by increased Annexin V binding and decreased expression of Bcl-2. In both assays of apoptosis, selenium supplementation was able to prevent apoptosis, preserve Bcl-2 expression and protect trophoblast cells from mitochondrial oxidative stress. This data suggests that selenoproteins such as GPx and Thx-Red have an important role in protecting trophoblast cells from mitochondrial oxidative stress and that selenium supplementation may be important in treating some placental pathologies.

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Fluoride Exposure Aggravates the Testicular Damage and Sperm Quality in Diabetic Mice: Protective Role of Ginseng and Banaba

Abstract

Fluoride toxicity is known to pose infertility in fluoride-intoxicated animals as well as in people residing in fluoride endemic zones. The present study addresses the degree of impairments caused due to co-exposure of high fluoride toxicity in diabetic mice. Swiss mice, Mus musculus, were subjected to fluoride toxicity by providing fluoride-supplemented drinking water (600 ppm NaF) for a period of 30 days after the confirmation of streptozotocin-induced diabetes(STZ, 50 mg/kgbw). Consequently, aggravated hyperglycemia and tissue fluoride accumulation were witnessed in fluoride-intoxicated diabetic mice; later, these toxicated mice were treated with ginseng extract (GE) and banaba leaf extract, (BLE) at dose of 150 mg/kgbw/day alone and in combination for 15 and 30-day duration to check the efficacy of phytoextracts in reversing the toxicity. The spermatological indices studied, such as sperm density, motility, viability and morphology as well as the testicular biochemical parameters showed enhanced impairment in reproductive status of fluoride-intoxicated diabetic mice. Further, 15-days administration of GE and BLE in combination at a dose of 150 mg/kgbw/day was found to be beneficial in normalizing the alterations observed upon fluoride intoxication to diabetic mice. However, the correlates showed moderate association between blood glucose levels and the spermatological as well as biochemical indices wherein the tissue fluoride levels correlate least.

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Analysis of Hair Trace Elements in Children with Autism Spectrum Disorders and Communication Disorders

Abstract

The primary objective of the present study is analysis of hair trace elements content in children with communication disorder (CD) and autism spectrum disorder (ASD). A total of 99 children from control, CD, and ASD groups (n = 33) were examined. All children were additionally divided into two subgroups according to age. Hair levels of trace elements were assessed using inductively coupled plasma mass spectrometry. The difference was considered significant at p < 0.01. The obtained data demonstrate that children with CD are characterized by significantly increased hair lithium (Li) (96 %; p = 0.008), selenium (Se) (66 %; p < 0.001), arsenic (As) (96 %; p = 0.005), beryllium (Be) (150 %; p < 0.001), and cadmium (Cd) (72 %; p = 0.007) content, being higher than the respective control values. In the ASD group, hair copper (Cu), iodine (I), and Be levels tended to be lower than the control values. In turn, the scalp hair content of Se significantly exceeded the control values (33 %; p = 0.004), whereas the level of iron (Fe) and aluminum (Al) tended to increase. After gradation for age, the most prominent differences in children with CD were detected in the elder group (5–8 years), whereas in the case of ASD—in the younger group (3–4 years old). Taking into account the role of hair as excretory mechanism for certain elements including the toxic ones, it can be proposed that children suffering from ASD are characterized by more profound alteration of metal handling and excretion in comparison to CD.

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Anemia and Dental Caries in Pregnant Women: a Prospective Cohort Study

Abstract

The objective was to evaluate the effect of anemia during pregnancy on the risk of dental caries development in pregnant women. A prospective cohort including a sample of pregnant women in a prenatal care unit of São Luís, Brazil, was done. The incidence of dental caries during pregnancy, according to Nyvad's criteria, was the outcome. The main independent variables were serum iron, ferritin, hemoglobin, erythrocyte, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red cell distribution width (RDW). Pregnant women (n = 121) were evaluated at two moments: up to 16th week of gestational age (T1) and in the last trimester of pregnancy (T2). Crude and adjusted associations were estimated by the incidence ratio risk (IRR) and respective 95% confidence intervals (95%CI). After adjustment, higher serum concentrations of ferritin (IRR = 0.97, 95%CI 0.95–0.99) in T1, and Fe (IRR = 0.99, 95%CI 0.98–0.99), ferritin (IRR = 0.99, 95%CI 0.98–0.99), erythrocyte (IRR = 0.71, 95%CI 0.50–0.99), hemoglobin (IRR = 0.84, 95%CI 0.73–0.96), hematocrit (IRR = 0.93, 95%CI 0.88–0.98), MCV (IRR = 0.91, 95%CI 0.86–0.96), and MCH (IRR = 0.83, 95%CI 0.74–0.93) in T2, were associated with fewer incidence of dental caries in pregnant women. Iron deficiency anemia during pregnancy is a risk factor for the incidence of dental caries in these women.

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Aluminum Trichloride Inhibited Osteoblastic Proliferation and Downregulated the Wnt/β-Catenin Pathway

Abstract

Aluminum (Al) exposure inhibits bone formation. Osteoblastic proliferation promotes bone formation. Therefore, we inferred that Al may inhibit bone formation by the inhibition of osteoblastic proliferation. However, the effects and molecular mechanisms of Al on osteoblastic proliferation are still under investigation. Osteoblastic proliferation can be regulated by Wnt/β-catenin signaling pathway. To investigate the effects of Al on osteoblastic proliferation and whether Wnt/β-catenin signaling pathway is involved in it, osteoblasts from neonatal rats were cultured and exposed to 0, 0.4 mM (1/20 IC₅₀), 0.8 mM (1/10 IC₅₀), and 1.6 mM (1/5 IC₅₀) of aluminum trichloride (AlCl₃) for 24 h, respectively. The osteoblastic proliferation rates; Wnt3a, lipoprotein receptor-related protein 5 (LRP-5), T cell factor 1 (TCF-1), cyclin D1, and c-Myc messenger RNA (mRNA) expressions; and p-glycogen synthase kinase 3β (GSK3β), GSK3β, and β-catenin protein expressions indicated that AlCl₃ inhibited osteoblastic proliferation and downregulated Wnt/β-catenin signaling pathway. In addition, the AlCl₃ concentration was negatively correlated with osteoblastic proliferation rates and the mRNA expressions of Wnt3a, c-Myc, and cyclin D1, while the osteoblastic proliferation rates were positively correlated with mRNA expressions of Wnt3a, c-Myc, and cyclin D1. Taken together, these findings indicated that AlCl₃ inhibits osteoblastic proliferation may be associated with the inactivation of Wnt/β-catenin signaling pathway.

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Pre-Clinical Study for the Antidiabetic Potential of Selenium Nanoparticles

Abstract

This research was delineated to explore the efficacy of selenium nanoparticles delivered in liposomes (L-Se) in the mitigation of type-2 diabetes mellitus. Adult female Wistar rats were assigned into four groups: group I, the normal control group in which the rats received normal saline solution orally; group II, the diabetic control group in which the rats were injected intraperitoneally with a single dose of streptozotocin (STZ) for induction of diabetes; group III, the metformin (Met)-treated group in which the diabetic rats were treated orally with Met; and group IV, the L-Se-treated group in which the diabetic rats were treated orally with L-Se. All treatments were delivered for 21 days. Blood and pancreas tissue samples were obtained for biochemical analysis, immunohistochemical examinations, and histopathological investigation. The L-Se-treated group showed significant drop in serum glucose and pancreatic malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-α (TNF-α), and prostaglandin F2α (PGF2α) levels associated with significant rise in serum insulin and pancreatic glutathione, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) values, in addition to significant improvement in the immunohistochemical indices (insulin and glucagon). Aforementioned results are appreciated by the histopathological findings of pancreatic tissue. In conclusion, our data have brought about compelling evidence favoring the antidiabetic potency of elemental selenium nanoparticles delivered in liposomes through preservation of pancreatic β cell integrity with consequent increment of insulin secretion and in turn glucose depletion, repression of oxidative stress, potentiation of the antioxidant defense system, and inhibition of pancreatic inflammation.

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Metabolomics and Trace Element Analysis of Camel Tear by GC-MS and ICP-MS

Abstract

Camel tear metabolomics and elemental analysis are useful in getting the information regarding the components responsible for maintaining the protective system that allows living in the desert and dry regions. The aim of this study was to correlate that the camel tears can be used as artificial tears for the evaluation of dryness in the eye. Eye biomarkers of camel tears were analyzed by gas chromatography-mass spectroscopy (GC-MS) and inductively coupled plasma mass spectroscopy (ICP-MS). The major compounds detected in camel tears by GC-MS were alanine, valine, leucine, norvaline, glycine, cadaverine, urea, ribitol, sugars, and higher fatty acids like octadecanoic acid and hexadecanoic acid. GC-MS analysis of camel tears also finds several products of metabolites and its associated metabolic participants. ICP-MS analysis showed the presence of different concentration of elemental composition in the camel tears.

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Beer as a Rich Source of Fluoride Delivered into the Body

Abstract

Fluoride is an element which in the minimum amount is necessary for the proper construction of the teeth and bones. But on the other hand, it increases the synthesis of reactive oxygen species, inflammatory mediators, and impairs the action of enzymes. Beer is the most popular alcoholic beverage in the world. Due to its prevalence and volume of consumption, it should be considered as a potential source of F- and taken into account in designing a balanced diet. Therefore, the aim of this study was to analyze beer samples in terms of F- levels. The concentrations of fluoride were examined using ion-selective electrode Thermo Scientific Orion and statistical analysis was based on two-way ANOVA and t test. When compared to imported beers, Polish beers were characterized by the lowest mean F- concentration (0.089 ppm). The highest mean F- concentrations were recorded in beers from Thailand (0.260 ppm), Italy (0.238 ppm), Mexico (0.210 ppm), and China (0.203 ppm). Our study shows that beer is a significant source of fluoride for humans, which is mainly associated with the quality of the water used in beer production.

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Cardioprotective Effect of Aloe vera Biomacromolecules Conjugated with Selenium Trace Element on Myocardial Ischemia-Reperfusion Injury in Rats

Abstract

The present study was undertaken to evaluate the cardioprotection potential and underlying molecular mechanism afforded by a selenium (Se) polysaccharide (Se-AVP) from Aloe vera in the ischemia-reperfusion (I/R) model of rats in vivo. Myocardial I/R injury was induced by occluding the left anterior descending coronary artery (LAD) for 30 min followed by 2-h continuous reperfusion. Pretreatment with Se-AVP (100, 200, and 400 mg/kg) attenuated myocardial damage, as evidenced by reduction of the infarct sizes, increase in serum and myocardial endogenous antioxidants (superoxide dismutase (SOD), glutathione peroxidase (GSH), and catalase (CAT)), and decrease in the malondialdehyde (MDA) level in the rats suffering I/R injury. This cardioprotective activity afforded by Se-AVP is further supported by the decreased levels of cardiac marker enzymes creatine kinase (CK) and lactate dehydrogenase (LDH), as well as the rise of myocardial Na⁺-K⁺-ATPase and Ca²⁺-Mg²⁺-ATPase activities in I/R rats. Additionally, cardiomyocytic apoptosis was measured by terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining and the result showed that the percent of TUNEL-positive cells in myocardium of Se-AVP-treated groups was lower than I/R rats. In conclusion, we clearly demonstrated that Se-AVP had a protective effect against myocardial I/R injury in rats by augmenting endogenous antioxidants and protecting rat hearts from oxidative stress-induced myocardial apoptosis.

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Tissue-Specific Regulation of the Contents and Correlations of Mineral Elements in Hens by Zinc Oxide Nanoparticles

Abstract

Due to their small size, zinc oxide (ZnO) nanoparticles (NPs) are readily absorbed and easily cross biological barriers, which make them promising candidates as diet additives. However, some studies have reported that ZnO NPs cause toxicity; therefore, their safety and potency as diet additives for farm animals should be established. This study was the first to fully evaluate the effects of ZnO NPs on the homeostasis of eight elements in seven organs/tissues. The regulation of element homeostasis was found to be organ specific with no influence on oxidation status, anti-oxidation capability, or organ damage. ZnO NPs may specifically regulate the homeostasis of mineral elements and affect the following correlations: (1) between the element content in each organ and the concentration of Zn used in ZnSO₄ or ZnO NP treatments; (2) between ZnO NP and ZnSO₄ treatments for the same element in each organ; and (3) between elements (in each organ in ZnSO₄ or ZnO NP treatments) in layers' organs/tissues. The use of ZnO NPs as diet additives for animals should be implemented cautiously because, among other uncertainties, they may affect mineral element content.

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An Optimal Dietary Zinc Level of Brown-Egg Laying Hens Fed a Corn–Soybean Meal Diet

Abstract

An experiment was conducted to estimate the optimal dietary zinc (Zn) level of brown-egg laying hens fed a corn–soybean meal diet from 20 to 40 weeks of age. A total of 120 20-week-old Beijing Red commercial laying hens were randomly allotted by bodyweight to one of five treatments with six replicates of four birds each in a completely randomized design, and fed a Zn-unsupplemented corn–soybean meal basal diet containing 27.95 mg Zn/kg by analysis and the basal diets supplemented with 30, 60, 90, or 120 mg Zn/kg as Zn sulfate (reagent grade ZnSO₄·7H₂O) for a duration of 20 weeks. Laying performance, egg quality, tissue Zn concentrations, and activities of serum alkaline phosphatase (AKP), and liver copper-Zn superoxide dismutase (CuZnSOD) were measured. Regression analyses were performed to estimate an optimal dietary Zn level whenever a significant quadratic response (P < 0.05) was observed. Tibia Zn concentration (P = 0.002) and serum AKP activity (P = 0.010) showed significant quadratic responses to dietary supplemental Zn levels. The estimates of dietary Zn requirements for brown-egg laying hens from 20 to 40 weeks of age were 71.95 and 64.63 mg/kg for tibia Zn concentration and serum AKP activity, respectively. The results from this study indicate that the tibia Zn might be a more suitable and reliable parameter for Zn requirement estimation, and the optimal dietary Zn level would be about 72 mg/kg for brown-egg laying hens fed a corn–soybean meal diet from 20 to 40 weeks of age.

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Fitness Evaluation of Ruditapes philippinarum Exposed to Ni

Abstract

In this study, long-term effects of Ni, a widespread heavy metal in the aquatic ecosystems, have been determined on growth and lethality of the clam Ruditapes philippinarum, a known bioindicator of the marine environment. Three/four-month-old bivalves have been exposed to different concentrations of Ni dissolved in synthetic seawater. Growth and lethality as endpoints after 28 days of treatment have been observed. Obtained results are the following: EC₂₅ = 3.97 ± 0.94 and 9.45 ± 1.59 mg/L and NOEC = 1.56 and 6.25 mg/L for growth and mortality, respectively. Moreover, this study can be considered a new tool for the evaluation of fitness of bivalve clam, together with other biological responses following to the biological impacts of metal pollution.

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Tracing of Zinc Nanocrystals in the Anterior Pituitary of Zinc-Deficient Wistar Rats

Abstract

The aim of this study was to trace zinc nanocrystals in the anterior pituitary of zinc-deficient Wistar rats by using autometallographic technique. Male Wistar rats (30–40 days of age, pre-pubertal period) of 40–50 g body weight were divided into the following: the ZC (zinc control) group—fed with 100 ppm zinc in diet, the ZD (zinc-deficient) group—fed with zinc-deficient (1.00 ppm) diet and the PF (pair-fed) group—received 100 ppm zinc in diet. The experiments were set for 2 and 4 weeks. Pituitary was removed and processed for the autometallographic technique. The control and pair-fed groups retained their normal morphological features. However, male Wistar rats fed on zinc-deficient diet for 2 and 4 weeks displayed a wide range of symptoms such as significant (P < 0.05) decrease in diet consumption, body weight and pituitary weight and decrease in gradation of intensity of zinc nanocrystals in the nuclei. The present findings suggest that the dietary zinc deficiency causes decreased intensity of zinc nanocrystals localization and their distribution in the pituitary thereby contributing to the dysfunction of the pituitary of the male Wistar rats. The severity of zinc deficiency symptoms progressed after the second week of the experiment. Decreased intensity of zinc nanocrystals attenuates the pituitary function which would exert its affect on other endocrine organs impairing their functions indicating that the metabolic regulation of pituitary is mediated to a certain extent by zinc and/or hypothalamus-hypophysial system which also reflects its essentiality during the period of growth.

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The Influence of Fluorine on the Disturbances of Homeostasis in the Central Nervous System

Abstract

Fluorides occur naturally in the environment, the daily exposure of human organism to fluorine mainly depends on the intake of this element with drinking water and it is connected with the geographical region. In some countries, we can observe the endemic fluorosis—the damage of hard and soft tissues caused by the excessive intake of fluorine. Recent studies showed that fluorine is toxic to the central nervous system (CNS). There are several known mechanisms which lead to structural brain damage caused by the excessive intake of fluorine. This element is able to cross the blood-brain barrier, and it accumulates in neurons affecting cytological changes, cell activity and ion transport (e.g. chlorine transport). Additionally, fluorine changes the concentration of non-enzymatic advanced glycation end products (AGEs), the metabolism of neurotransmitters (influencing mainly glutamatergic neurotransmission) and the energy metabolism of neurons by the impaired glucose transporter—GLUT1. It can also change activity and lead to dysfunction of important proteins which are part of the respiratory chain. Fluorine also affects oxidative stress, glial activation and inflammation in the CNS which leads to neurodegeneration. All of those changes lead to abnormal cell differentiation and the activation of apoptosis through the changes in the expression of neural cell adhesion molecules (NCAM), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and MAP kinases. Excessive exposure to this element can cause harmful effects such as permanent damage of all brain structures, impaired learning ability, memory dysfunction and behavioural problems. This paper provides an overview of the fluoride neurotoxicity in juveniles and adults.

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Effect of Feeding and Withdrawal of Vanadium and Vitamin C on Egg Quality and Vanadium Residual Over Time in Laying Hens

Abstract

This experiment examined the egg quality of hens fed vanadium (V) and vitamin C (VC) during storage, as well as the V and VC withdrawal on egg quality and V residual in egg. A total of 360 laying hens (31 weeks old) were randomly allotted into a 3 × 2 factorial arrangement treatments (6 replicates and 10 chicks per replicate) with three levels of dietary V (0, 5, and 10 mg/kg) and two levels of VC (0 and 100 mg/kg) for 19 weeks (feeding V and VC 12 weeks, recovery 7 weeks). The V residual in eggs at 4, 8, and 12th weeks were increased (linear effect, P ≤ 0.01) as V levels increased and was not detected in albumen at 7th week after V withdrawal. Followed by 12-week feeding period, albumen height and Haugh unit of eggs during 2-week storage were decreased (linear and quadratic effect, P < 0.01) by dietary V supplementation. Lightness value was increased (linear effect, P < 0.01), whereas redness and yellowness value of the eggshell were lowered (linear effect, P < 0.01) in V-containing diet. During 7-week withdrawal period, eggs from groups pre-feeding 5 and 10 mg/kg V had lower (linear effect, P < 0.01) overall albumen height and Haugh unit. The reducing effect on albumen height and HU continued to be observed until the seventh week, whereas the bleaching effect on eggshell color disappeared after 1-week withdrawal. The results indicated that feeding 5 or 10 mg/kg V increases egg V residual and reduces egg albumen quality and bleached the shell color, and the impaired albumen quality induced by 10 mg/kg of V lasted at least 6 weeks after changing to no V supplementation diet. The addition of VC did not show to affect egg quality during storage or recovery phase.

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Effect of Gestational Intake of Fisetin (3,3′,4′,7-Tetrahydroxyflavone) on Developmental Methyl Mercury Neurotoxicity in F 1 Generation Rats

Abstract

Methyl mercury (MeHg) is a developmental neurotoxin that causes irreversible cognitive damage in offspring of gestationally exposed mothers. Currently, no preventive drugs are established against MeHg developmental neurotoxicity. The neuroprotective effect of gestational administration of a flavanoid against in utero toxicity of MeHg is not explored much. Hence, the present study validated the effect of a bioactive flavanoid, fisetin, on MeHg developmental neurotoxicity outcomes in rat offspring at postnatal weaning age. Pregnant Wistar rats were simultaneously given MeHg (1.5 mg/kg b.w.) and two doses of fisetin (10 and 50 mg/kg b.w. in two separate groups) orally from gestational day (GD) 5 till parturition. Accordingly, after parturition, on postnatal day (PND) 24, weaning F₁ generation rats were studied for motor and cognitive behavioural changes. Biochemical and histopathological changes were also studied in the cerebral cortex, cerebellum and hippocampus on PND 25. Administration of fisetin during pregnancy prevented behavioural impairment due to transplacental MeHg exposure in weaning rats. Fisetin decreased the levels of oxidative stress markers, increased enzymatic and non-enzymatic antioxidant levels and increased the activity of membrane-bound ATPases and cholinergic function in F₁ generation rats. In light microscopic studies, fisetin treatment protected the specific offspring brain regions from significant morphological aberrations. Between the two doses of fisetin studied, 10 mg/kg b.w. was found to be more satisfactory and effective than 50 mg/kg b.w. The present study shows that intake of fisetin during pregnancy in rats ameliorated in utero MeHg exposure-induced neurotoxicity outcomes in postnatal weaning F₁ generation rats.

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Evaluation of Serum Trace Element Levels and Superoxide Dismutase Activity in Patients with Inflammatory Bowel Disease: Translating Basic Research into Clinical Application

Abstract

The relationship of minerals and trace elements with inflammatory bowel disease (IBD) is complex. Alterations in their metabolism can be induced by the diseases and their complications. To study the role of trace elements in IBD patients' serum zinc and copper and their related enzymes, including superoxide dismutase (SOD), activity were measured in patients with IBD patients as well as in healthy subjects. In addition, the correlation between serum trace element levels, albumin, total protein, urea level, copper/zinc ratio, and disease activity (DA) was determined in these subjects. Serum samples were obtained from 35 patients (19 ulcerative colitis (UC) and 16 Crohn's disease (CD)) in the active phase of the disease and 30 healthy control subjects. Serum levels of zinc, copper, SOD activity, albumin, total protein, and urea were measured. The results were compared between the two groups using independent Student's t test in statistical analysis. Serum levels of zinc, SOD activity, albumin, and total protein were significantly lower (P < 0.05) in patients than controls, while serum urea level was significantly higher in patients compared to controls. Copper concentrations did not differ between patients with IBD (mean ± SD, 58.8 ± 20.7 μg/d) and controls (55.57 ± 12.6 μg/d). Decreased levels of zinc and SOD activity are associated with increased inflammatory processes indicating inappropriate antioxidant system in patients with IBD. Additionally, lower levels of albumin and total protein with higher level of urea reflect metabolic problems in liver system.

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Levels of Metals in Kidney, Liver, and Muscle Tissue and their Influence on the Fitness for the Consumption of Wild Boar from Western Slovakia

Abstract

Due to environmental pollution, wild animals are exposed to various pollutants. Some game animals, such as wild boars are used by people for food, but their meat is not evaluated regarding pollution transfer, since they are unavailable on the official market. The aim of this paper is to present the concentrations of chosen metals (Cd, Co, Cu, Hg, Pb, and Zn) in the kidneys, liver, and muscles of wild boars (n = 40) hunted in eastern Slovakia, as derivatives of physiological distribution and anthropogenic pollution. We found that sex was not a statistically significant factor for metal concentrations. Tissue differences were observed for all the metals studied except for Co. Cd, Cu, and Hg showed the highest median concentrations in kidney tissue with the lowest in muscle tissue (2.73, 3.78, and 0.061 μg/g w.w., respectively). The highest Zn median concentration was noted in the liver tissue with the lowest in muscle tissue. Co and Cu concentrations varied according to the age groups. Correlations between metal concentrations in muscle and kidney tissue were not especially strong; such relationships were not found in liver tissue. Among all the potential relationships of the given metal concentrations between tissues, the only significant relationship, albeit weak, was noted for Pb in muscle and liver tissue. The concentrations found seem not to be extremely high, but according to EU maximum permitted residue levels for Cd and Pb concentrations in meat, none of the samples studied was fully fit for human consumption. TWI and risk was also excessive for both metals.

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Individual and Combined Effects of Arsenic and Lead on Behavioral and Biochemical Changes in Mice

Abstract

Arsenic (As) toxicity has caused an environmental tragedy affecting millions of people in the world. Little is known about the toxic effects of As on neurobehavioral and biochemical changes in vivo. Along this line of metal toxicity, co-exposure of lead (Pb) could aggravate the situation in the host. The present study was designed to explore the combined effects of As and Pb on behavioral changes like anxiety, spatial memory and learning impairment, and blood indices related to organ dysfunction. Exposure of mice to As (10 mg/kg body weight), Pb (10 mg/kg body weight), and As + Pb via drinking water significantly decreased the time spent exploring the open arms while it increased the time spent in the closed arms compared to control mice in the elevated plus maze. The mean latency time of the control group to find the platform decreased significantly during the learning for 7 days compared to all three treated groups in the Morris water maze test, and the As-exposed group spent significantly less time in the desired quadrant as compared to the control group in the probe trial. Both metals posed an anxiety-like behavior and deficits in spatial memory and learning, and also altered blood indices related to liver and kidney dysfunction, and a combined exposure of these metals inhibited the individual accumulation of As and Pb. Taken together, these data suggest that As has more toxic effects on neurobehavioral and biochemical changes than Pb, and there may be antagonism in the effects and accumulation between these two toxicants.

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Combined Effects of Phytoestrogen Genistein and Silicon on Ovariectomy-Induced Bone Loss in Rat

Abstract

This study was performed to evaluate the effect of concomitant supplementation of genistein and silicon on bone mineral density and bone metabolism-related markers in ovariectomized rat. Three-month-old Sprague Dawley female rats were subjected to bilateral ovariectomy (OVX) or sham surgery, and then the OVX rats were randomly divided into four groups: OVX-GEN, OVX-Si, OVX-GEN-Si, and OVX. Genistein and silicon supplementation was started immediately after OVX and continued for 10 weeks. In the OVX-GEN group, 5 mg genistein per gram body weight was injected subcutaneously. The OVX-Si group was given soluble silicon daily in demineralized water (Si 20 mg/kg body weight/day). The OVX-GEN-Si group was given subcutaneous injections of 5 mg genistein per gram body weight, at the same time, given soluble silicon daily (Si 20 mg/kg body weight/day). The results showed that the genistein supplementation in the OVX rats significantly prevented the loss of uterus weight; however, the silicon supplementation showed no effect on the uterus weight loss. The lumbar spine and femur bone mineral density was significantly decreased after OVX surgery; however, this decrease was inhibited by the genistein and/or silicon, and the BMD of the lumbar spine and femur was the highest in the OVX-GEN-Si-treated group. Histomorphometric analyses showed that the supplementation of genistein and/or silicon restored bone volume and trabecular thickness of femoral trabecular bone in the OVX group. Besides, the treatment with genistein and silicon for 10 weeks increased the serum levels of calcium and phosphorus in the OVX rats; serum calcium and serum phosphorus in the OVX-GEN-Si group were higher than those in the OVX-GEN and OVX-Si group (P < 0.05). At the same time, the treatment with genistein and/or silicon decreased serum alkaline phosphatase (ALP) and osteocalcin, which were increased by ovariectomy; serum ALP and osteocalcin in the OVX-GEN-Si group were lower than those in the OVX-GEN and OVX-Si groups (P < 0.05). The results above indicate that genistein and silicon have synergistic effects on bone formation in ovariectomized rats.

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Overexpression of Endogenous Anti-Oxidants with Selenium Supplementation Protects Trophoblast Cells from Reactive Oxygen Species-Induced Apoptosis in a Bcl-2-Dependent Manner

Abstract

The human placenta provides life support for the developing foetus, and a healthy placenta is a prerequisite to a healthy start to life. Placental tissue is subject to oxidative stress which can lead to pathological conditions of pregnancy such as preeclampsia, preterm labour and intrauterine growth restriction. Up-regulation of endogenous anti-oxidants may alleviate placental oxidative stress and provide a therapy for these complications of pregnancy. In this study, selenium supplementation, as inorganic sodium selenite (NaSel) or organic selenomethionine (SeMet), was used to increase the protein production and cellular activity of the important redox active proteins glutathione peroxidase (GPx) and thioredoxin reductase (Thx-Red). Placental trophoblast cell lines, BeWo, JEG-3 and Swan-71, were cultured in various concentrations of NaSel or SeMet for 24 h and cell extracts prepared for western blots and enzyme assays. Rotenone and antimycin were used to stimulate mitochondrial reactive oxygen species (ROS) production and induce apoptosis. Trophoblast cells supplemented with 100 nM NaSel and 500 nM SeMet exhibited significantly enhanced expression and activity of both GPx and Thx-Red. Antimycin and rotenone were found to generate ROS when measured by 2′,7′-dichlorofluorescein diacetate (DCFDA) assay, and selenium supplementation was shown to reduce ROS production in a dose-dependent manner. Rotenone, 100 μM treatment for 4 h, caused trophoblast cell apoptosis as evidenced by increased Annexin V binding and decreased expression of Bcl-2. In both assays of apoptosis, selenium supplementation was able to prevent apoptosis, preserve Bcl-2 expression and protect trophoblast cells from mitochondrial oxidative stress. This data suggests that selenoproteins such as GPx and Thx-Red have an important role in protecting trophoblast cells from mitochondrial oxidative stress and that selenium supplementation may be important in treating some placental pathologies.

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Fluoride Exposure Aggravates the Testicular Damage and Sperm Quality in Diabetic Mice: Protective Role of Ginseng and Banaba

Abstract

Fluoride toxicity is known to pose infertility in fluoride-intoxicated animals as well as in people residing in fluoride endemic zones. The present study addresses the degree of impairments caused due to co-exposure of high fluoride toxicity in diabetic mice. Swiss mice, Mus musculus, were subjected to fluoride toxicity by providing fluoride-supplemented drinking water (600 ppm NaF) for a period of 30 days after the confirmation of streptozotocin-induced diabetes(STZ, 50 mg/kgbw). Consequently, aggravated hyperglycemia and tissue fluoride accumulation were witnessed in fluoride-intoxicated diabetic mice; later, these toxicated mice were treated with ginseng extract (GE) and banaba leaf extract, (BLE) at dose of 150 mg/kgbw/day alone and in combination for 15 and 30-day duration to check the efficacy of phytoextracts in reversing the toxicity. The spermatological indices studied, such as sperm density, motility, viability and morphology as well as the testicular biochemical parameters showed enhanced impairment in reproductive status of fluoride-intoxicated diabetic mice. Further, 15-days administration of GE and BLE in combination at a dose of 150 mg/kgbw/day was found to be beneficial in normalizing the alterations observed upon fluoride intoxication to diabetic mice. However, the correlates showed moderate association between blood glucose levels and the spermatological as well as biochemical indices wherein the tissue fluoride levels correlate least.

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Analysis of Hair Trace Elements in Children with Autism Spectrum Disorders and Communication Disorders

Abstract

The primary objective of the present study is analysis of hair trace elements content in children with communication disorder (CD) and autism spectrum disorder (ASD). A total of 99 children from control, CD, and ASD groups (n = 33) were examined. All children were additionally divided into two subgroups according to age. Hair levels of trace elements were assessed using inductively coupled plasma mass spectrometry. The difference was considered significant at p < 0.01. The obtained data demonstrate that children with CD are characterized by significantly increased hair lithium (Li) (96 %; p = 0.008), selenium (Se) (66 %; p < 0.001), arsenic (As) (96 %; p = 0.005), beryllium (Be) (150 %; p < 0.001), and cadmium (Cd) (72 %; p = 0.007) content, being higher than the respective control values. In the ASD group, hair copper (Cu), iodine (I), and Be levels tended to be lower than the control values. In turn, the scalp hair content of Se significantly exceeded the control values (33 %; p = 0.004), whereas the level of iron (Fe) and aluminum (Al) tended to increase. After gradation for age, the most prominent differences in children with CD were detected in the elder group (5–8 years), whereas in the case of ASD—in the younger group (3–4 years old). Taking into account the role of hair as excretory mechanism for certain elements including the toxic ones, it can be proposed that children suffering from ASD are characterized by more profound alteration of metal handling and excretion in comparison to CD.

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Anemia and Dental Caries in Pregnant Women: a Prospective Cohort Study

Abstract

The objective was to evaluate the effect of anemia during pregnancy on the risk of dental caries development in pregnant women. A prospective cohort including a sample of pregnant women in a prenatal care unit of São Luís, Brazil, was done. The incidence of dental caries during pregnancy, according to Nyvad's criteria, was the outcome. The main independent variables were serum iron, ferritin, hemoglobin, erythrocyte, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red cell distribution width (RDW). Pregnant women (n = 121) were evaluated at two moments: up to 16th week of gestational age (T1) and in the last trimester of pregnancy (T2). Crude and adjusted associations were estimated by the incidence ratio risk (IRR) and respective 95% confidence intervals (95%CI). After adjustment, higher serum concentrations of ferritin (IRR = 0.97, 95%CI 0.95–0.99) in T1, and Fe (IRR = 0.99, 95%CI 0.98–0.99), ferritin (IRR = 0.99, 95%CI 0.98–0.99), erythrocyte (IRR = 0.71, 95%CI 0.50–0.99), hemoglobin (IRR = 0.84, 95%CI 0.73–0.96), hematocrit (IRR = 0.93, 95%CI 0.88–0.98), MCV (IRR = 0.91, 95%CI 0.86–0.96), and MCH (IRR = 0.83, 95%CI 0.74–0.93) in T2, were associated with fewer incidence of dental caries in pregnant women. Iron deficiency anemia during pregnancy is a risk factor for the incidence of dental caries in these women.

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Aluminum Trichloride Inhibited Osteoblastic Proliferation and Downregulated the Wnt/β-Catenin Pathway

Abstract

Aluminum (Al) exposure inhibits bone formation. Osteoblastic proliferation promotes bone formation. Therefore, we inferred that Al may inhibit bone formation by the inhibition of osteoblastic proliferation. However, the effects and molecular mechanisms of Al on osteoblastic proliferation are still under investigation. Osteoblastic proliferation can be regulated by Wnt/β-catenin signaling pathway. To investigate the effects of Al on osteoblastic proliferation and whether Wnt/β-catenin signaling pathway is involved in it, osteoblasts from neonatal rats were cultured and exposed to 0, 0.4 mM (1/20 IC₅₀), 0.8 mM (1/10 IC₅₀), and 1.6 mM (1/5 IC₅₀) of aluminum trichloride (AlCl₃) for 24 h, respectively. The osteoblastic proliferation rates; Wnt3a, lipoprotein receptor-related protein 5 (LRP-5), T cell factor 1 (TCF-1), cyclin D1, and c-Myc messenger RNA (mRNA) expressions; and p-glycogen synthase kinase 3β (GSK3β), GSK3β, and β-catenin protein expressions indicated that AlCl₃ inhibited osteoblastic proliferation and downregulated Wnt/β-catenin signaling pathway. In addition, the AlCl₃ concentration was negatively correlated with osteoblastic proliferation rates and the mRNA expressions of Wnt3a, c-Myc, and cyclin D1, while the osteoblastic proliferation rates were positively correlated with mRNA expressions of Wnt3a, c-Myc, and cyclin D1. Taken together, these findings indicated that AlCl₃ inhibits osteoblastic proliferation may be associated with the inactivation of Wnt/β-catenin signaling pathway.

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Pre-Clinical Study for the Antidiabetic Potential of Selenium Nanoparticles

Abstract

This research was delineated to explore the efficacy of selenium nanoparticles delivered in liposomes (L-Se) in the mitigation of type-2 diabetes mellitus. Adult female Wistar rats were assigned into four groups: group I, the normal control group in which the rats received normal saline solution orally; group II, the diabetic control group in which the rats were injected intraperitoneally with a single dose of streptozotocin (STZ) for induction of diabetes; group III, the metformin (Met)-treated group in which the diabetic rats were treated orally with Met; and group IV, the L-Se-treated group in which the diabetic rats were treated orally with L-Se. All treatments were delivered for 21 days. Blood and pancreas tissue samples were obtained for biochemical analysis, immunohistochemical examinations, and histopathological investigation. The L-Se-treated group showed significant drop in serum glucose and pancreatic malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-α (TNF-α), and prostaglandin F2α (PGF2α) levels associated with significant rise in serum insulin and pancreatic glutathione, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) values, in addition to significant improvement in the immunohistochemical indices (insulin and glucagon). Aforementioned results are appreciated by the histopathological findings of pancreatic tissue. In conclusion, our data have brought about compelling evidence favoring the antidiabetic potency of elemental selenium nanoparticles delivered in liposomes through preservation of pancreatic β cell integrity with consequent increment of insulin secretion and in turn glucose depletion, repression of oxidative stress, potentiation of the antioxidant defense system, and inhibition of pancreatic inflammation.

http://ift.tt/2pMGwng

Metabolomics and Trace Element Analysis of Camel Tear by GC-MS and ICP-MS

Abstract

Camel tear metabolomics and elemental analysis are useful in getting the information regarding the components responsible for maintaining the protective system that allows living in the desert and dry regions. The aim of this study was to correlate that the camel tears can be used as artificial tears for the evaluation of dryness in the eye. Eye biomarkers of camel tears were analyzed by gas chromatography-mass spectroscopy (GC-MS) and inductively coupled plasma mass spectroscopy (ICP-MS). The major compounds detected in camel tears by GC-MS were alanine, valine, leucine, norvaline, glycine, cadaverine, urea, ribitol, sugars, and higher fatty acids like octadecanoic acid and hexadecanoic acid. GC-MS analysis of camel tears also finds several products of metabolites and its associated metabolic participants. ICP-MS analysis showed the presence of different concentration of elemental composition in the camel tears.

http://ift.tt/2pM4dKi

Beer as a Rich Source of Fluoride Delivered into the Body

Abstract

Fluoride is an element which in the minimum amount is necessary for the proper construction of the teeth and bones. But on the other hand, it increases the synthesis of reactive oxygen species, inflammatory mediators, and impairs the action of enzymes. Beer is the most popular alcoholic beverage in the world. Due to its prevalence and volume of consumption, it should be considered as a potential source of F- and taken into account in designing a balanced diet. Therefore, the aim of this study was to analyze beer samples in terms of F- levels. The concentrations of fluoride were examined using ion-selective electrode Thermo Scientific Orion and statistical analysis was based on two-way ANOVA and t test. When compared to imported beers, Polish beers were characterized by the lowest mean F- concentration (0.089 ppm). The highest mean F- concentrations were recorded in beers from Thailand (0.260 ppm), Italy (0.238 ppm), Mexico (0.210 ppm), and China (0.203 ppm). Our study shows that beer is a significant source of fluoride for humans, which is mainly associated with the quality of the water used in beer production.

http://ift.tt/2pMD2RH

Cardioprotective Effect of Aloe vera Biomacromolecules Conjugated with Selenium Trace Element on Myocardial Ischemia-Reperfusion Injury in Rats

Abstract

The present study was undertaken to evaluate the cardioprotection potential and underlying molecular mechanism afforded by a selenium (Se) polysaccharide (Se-AVP) from Aloe vera in the ischemia-reperfusion (I/R) model of rats in vivo. Myocardial I/R injury was induced by occluding the left anterior descending coronary artery (LAD) for 30 min followed by 2-h continuous reperfusion. Pretreatment with Se-AVP (100, 200, and 400 mg/kg) attenuated myocardial damage, as evidenced by reduction of the infarct sizes, increase in serum and myocardial endogenous antioxidants (superoxide dismutase (SOD), glutathione peroxidase (GSH), and catalase (CAT)), and decrease in the malondialdehyde (MDA) level in the rats suffering I/R injury. This cardioprotective activity afforded by Se-AVP is further supported by the decreased levels of cardiac marker enzymes creatine kinase (CK) and lactate dehydrogenase (LDH), as well as the rise of myocardial Na⁺-K⁺-ATPase and Ca²⁺-Mg²⁺-ATPase activities in I/R rats. Additionally, cardiomyocytic apoptosis was measured by terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining and the result showed that the percent of TUNEL-positive cells in myocardium of Se-AVP-treated groups was lower than I/R rats. In conclusion, we clearly demonstrated that Se-AVP had a protective effect against myocardial I/R injury in rats by augmenting endogenous antioxidants and protecting rat hearts from oxidative stress-induced myocardial apoptosis.

http://ift.tt/2pLUrHT

Tissue-Specific Regulation of the Contents and Correlations of Mineral Elements in Hens by Zinc Oxide Nanoparticles

Abstract

Due to their small size, zinc oxide (ZnO) nanoparticles (NPs) are readily absorbed and easily cross biological barriers, which make them promising candidates as diet additives. However, some studies have reported that ZnO NPs cause toxicity; therefore, their safety and potency as diet additives for farm animals should be established. This study was the first to fully evaluate the effects of ZnO NPs on the homeostasis of eight elements in seven organs/tissues. The regulation of element homeostasis was found to be organ specific with no influence on oxidation status, anti-oxidation capability, or organ damage. ZnO NPs may specifically regulate the homeostasis of mineral elements and affect the following correlations: (1) between the element content in each organ and the concentration of Zn used in ZnSO₄ or ZnO NP treatments; (2) between ZnO NP and ZnSO₄ treatments for the same element in each organ; and (3) between elements (in each organ in ZnSO₄ or ZnO NP treatments) in layers' organs/tissues. The use of ZnO NPs as diet additives for animals should be implemented cautiously because, among other uncertainties, they may affect mineral element content.

http://ift.tt/2pMQzbF

An Optimal Dietary Zinc Level of Brown-Egg Laying Hens Fed a Corn–Soybean Meal Diet

Abstract

An experiment was conducted to estimate the optimal dietary zinc (Zn) level of brown-egg laying hens fed a corn–soybean meal diet from 20 to 40 weeks of age. A total of 120 20-week-old Beijing Red commercial laying hens were randomly allotted by bodyweight to one of five treatments with six replicates of four birds each in a completely randomized design, and fed a Zn-unsupplemented corn–soybean meal basal diet containing 27.95 mg Zn/kg by analysis and the basal diets supplemented with 30, 60, 90, or 120 mg Zn/kg as Zn sulfate (reagent grade ZnSO₄·7H₂O) for a duration of 20 weeks. Laying performance, egg quality, tissue Zn concentrations, and activities of serum alkaline phosphatase (AKP), and liver copper-Zn superoxide dismutase (CuZnSOD) were measured. Regression analyses were performed to estimate an optimal dietary Zn level whenever a significant quadratic response (P < 0.05) was observed. Tibia Zn concentration (P = 0.002) and serum AKP activity (P = 0.010) showed significant quadratic responses to dietary supplemental Zn levels. The estimates of dietary Zn requirements for brown-egg laying hens from 20 to 40 weeks of age were 71.95 and 64.63 mg/kg for tibia Zn concentration and serum AKP activity, respectively. The results from this study indicate that the tibia Zn might be a more suitable and reliable parameter for Zn requirement estimation, and the optimal dietary Zn level would be about 72 mg/kg for brown-egg laying hens fed a corn–soybean meal diet from 20 to 40 weeks of age.

http://ift.tt/2pLRXct

Fitness Evaluation of Ruditapes philippinarum Exposed to Ni

Abstract

In this study, long-term effects of Ni, a widespread heavy metal in the aquatic ecosystems, have been determined on growth and lethality of the clam Ruditapes philippinarum, a known bioindicator of the marine environment. Three/four-month-old bivalves have been exposed to different concentrations of Ni dissolved in synthetic seawater. Growth and lethality as endpoints after 28 days of treatment have been observed. Obtained results are the following: EC₂₅ = 3.97 ± 0.94 and 9.45 ± 1.59 mg/L and NOEC = 1.56 and 6.25 mg/L for growth and mortality, respectively. Moreover, this study can be considered a new tool for the evaluation of fitness of bivalve clam, together with other biological responses following to the biological impacts of metal pollution.

http://ift.tt/2pMGAU2

Tracing of Zinc Nanocrystals in the Anterior Pituitary of Zinc-Deficient Wistar Rats

Abstract

The aim of this study was to trace zinc nanocrystals in the anterior pituitary of zinc-deficient Wistar rats by using autometallographic technique. Male Wistar rats (30–40 days of age, pre-pubertal period) of 40–50 g body weight were divided into the following: the ZC (zinc control) group—fed with 100 ppm zinc in diet, the ZD (zinc-deficient) group—fed with zinc-deficient (1.00 ppm) diet and the PF (pair-fed) group—received 100 ppm zinc in diet. The experiments were set for 2 and 4 weeks. Pituitary was removed and processed for the autometallographic technique. The control and pair-fed groups retained their normal morphological features. However, male Wistar rats fed on zinc-deficient diet for 2 and 4 weeks displayed a wide range of symptoms such as significant (P < 0.05) decrease in diet consumption, body weight and pituitary weight and decrease in gradation of intensity of zinc nanocrystals in the nuclei. The present findings suggest that the dietary zinc deficiency causes decreased intensity of zinc nanocrystals localization and their distribution in the pituitary thereby contributing to the dysfunction of the pituitary of the male Wistar rats. The severity of zinc deficiency symptoms progressed after the second week of the experiment. Decreased intensity of zinc nanocrystals attenuates the pituitary function which would exert its affect on other endocrine organs impairing their functions indicating that the metabolic regulation of pituitary is mediated to a certain extent by zinc and/or hypothalamus-hypophysial system which also reflects its essentiality during the period of growth.

http://ift.tt/2q56DGN

The Influence of Fluorine on the Disturbances of Homeostasis in the Central Nervous System

Abstract

Fluorides occur naturally in the environment, the daily exposure of human organism to fluorine mainly depends on the intake of this element with drinking water and it is connected with the geographical region. In some countries, we can observe the endemic fluorosis—the damage of hard and soft tissues caused by the excessive intake of fluorine. Recent studies showed that fluorine is toxic to the central nervous system (CNS). There are several known mechanisms which lead to structural brain damage caused by the excessive intake of fluorine. This element is able to cross the blood-brain barrier, and it accumulates in neurons affecting cytological changes, cell activity and ion transport (e.g. chlorine transport). Additionally, fluorine changes the concentration of non-enzymatic advanced glycation end products (AGEs), the metabolism of neurotransmitters (influencing mainly glutamatergic neurotransmission) and the energy metabolism of neurons by the impaired glucose transporter—GLUT1. It can also change activity and lead to dysfunction of important proteins which are part of the respiratory chain. Fluorine also affects oxidative stress, glial activation and inflammation in the CNS which leads to neurodegeneration. All of those changes lead to abnormal cell differentiation and the activation of apoptosis through the changes in the expression of neural cell adhesion molecules (NCAM), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and MAP kinases. Excessive exposure to this element can cause harmful effects such as permanent damage of all brain structures, impaired learning ability, memory dysfunction and behavioural problems. This paper provides an overview of the fluoride neurotoxicity in juveniles and adults.

http://ift.tt/2pLRWVX

Effect of Feeding and Withdrawal of Vanadium and Vitamin C on Egg Quality and Vanadium Residual Over Time in Laying Hens

Abstract

This experiment examined the egg quality of hens fed vanadium (V) and vitamin C (VC) during storage, as well as the V and VC withdrawal on egg quality and V residual in egg. A total of 360 laying hens (31 weeks old) were randomly allotted into a 3 × 2 factorial arrangement treatments (6 replicates and 10 chicks per replicate) with three levels of dietary V (0, 5, and 10 mg/kg) and two levels of VC (0 and 100 mg/kg) for 19 weeks (feeding V and VC 12 weeks, recovery 7 weeks). The V residual in eggs at 4, 8, and 12th weeks were increased (linear effect, P ≤ 0.01) as V levels increased and was not detected in albumen at 7th week after V withdrawal. Followed by 12-week feeding period, albumen height and Haugh unit of eggs during 2-week storage were decreased (linear and quadratic effect, P < 0.01) by dietary V supplementation. Lightness value was increased (linear effect, P < 0.01), whereas redness and yellowness value of the eggshell were lowered (linear effect, P < 0.01) in V-containing diet. During 7-week withdrawal period, eggs from groups pre-feeding 5 and 10 mg/kg V had lower (linear effect, P < 0.01) overall albumen height and Haugh unit. The reducing effect on albumen height and HU continued to be observed until the seventh week, whereas the bleaching effect on eggshell color disappeared after 1-week withdrawal. The results indicated that feeding 5 or 10 mg/kg V increases egg V residual and reduces egg albumen quality and bleached the shell color, and the impaired albumen quality induced by 10 mg/kg of V lasted at least 6 weeks after changing to no V supplementation diet. The addition of VC did not show to affect egg quality during storage or recovery phase.

http://ift.tt/2q5gPiz

Effect of Gestational Intake of Fisetin (3,3′,4′,7-Tetrahydroxyflavone) on Developmental Methyl Mercury Neurotoxicity in F 1 Generation Rats

Abstract

Methyl mercury (MeHg) is a developmental neurotoxin that causes irreversible cognitive damage in offspring of gestationally exposed mothers. Currently, no preventive drugs are established against MeHg developmental neurotoxicity. The neuroprotective effect of gestational administration of a flavanoid against in utero toxicity of MeHg is not explored much. Hence, the present study validated the effect of a bioactive flavanoid, fisetin, on MeHg developmental neurotoxicity outcomes in rat offspring at postnatal weaning age. Pregnant Wistar rats were simultaneously given MeHg (1.5 mg/kg b.w.) and two doses of fisetin (10 and 50 mg/kg b.w. in two separate groups) orally from gestational day (GD) 5 till parturition. Accordingly, after parturition, on postnatal day (PND) 24, weaning F₁ generation rats were studied for motor and cognitive behavioural changes. Biochemical and histopathological changes were also studied in the cerebral cortex, cerebellum and hippocampus on PND 25. Administration of fisetin during pregnancy prevented behavioural impairment due to transplacental MeHg exposure in weaning rats. Fisetin decreased the levels of oxidative stress markers, increased enzymatic and non-enzymatic antioxidant levels and increased the activity of membrane-bound ATPases and cholinergic function in F₁ generation rats. In light microscopic studies, fisetin treatment protected the specific offspring brain regions from significant morphological aberrations. Between the two doses of fisetin studied, 10 mg/kg b.w. was found to be more satisfactory and effective than 50 mg/kg b.w. The present study shows that intake of fisetin during pregnancy in rats ameliorated in utero MeHg exposure-induced neurotoxicity outcomes in postnatal weaning F₁ generation rats.

http://ift.tt/2pLYXWY

Evaluation of Serum Trace Element Levels and Superoxide Dismutase Activity in Patients with Inflammatory Bowel Disease: Translating Basic Research into Clinical Application

Abstract

The relationship of minerals and trace elements with inflammatory bowel disease (IBD) is complex. Alterations in their metabolism can be induced by the diseases and their complications. To study the role of trace elements in IBD patients' serum zinc and copper and their related enzymes, including superoxide dismutase (SOD), activity were measured in patients with IBD patients as well as in healthy subjects. In addition, the correlation between serum trace element levels, albumin, total protein, urea level, copper/zinc ratio, and disease activity (DA) was determined in these subjects. Serum samples were obtained from 35 patients (19 ulcerative colitis (UC) and 16 Crohn's disease (CD)) in the active phase of the disease and 30 healthy control subjects. Serum levels of zinc, copper, SOD activity, albumin, total protein, and urea were measured. The results were compared between the two groups using independent Student's t test in statistical analysis. Serum levels of zinc, SOD activity, albumin, and total protein were significantly lower (P < 0.05) in patients than controls, while serum urea level was significantly higher in patients compared to controls. Copper concentrations did not differ between patients with IBD (mean ± SD, 58.8 ± 20.7 μg/d) and controls (55.57 ± 12.6 μg/d). Decreased levels of zinc and SOD activity are associated with increased inflammatory processes indicating inappropriate antioxidant system in patients with IBD. Additionally, lower levels of albumin and total protein with higher level of urea reflect metabolic problems in liver system.

http://ift.tt/2q5cuvA

Levels of Metals in Kidney, Liver, and Muscle Tissue and their Influence on the Fitness for the Consumption of Wild Boar from Western Slovakia

Abstract

Due to environmental pollution, wild animals are exposed to various pollutants. Some game animals, such as wild boars are used by people for food, but their meat is not evaluated regarding pollution transfer, since they are unavailable on the official market. The aim of this paper is to present the concentrations of chosen metals (Cd, Co, Cu, Hg, Pb, and Zn) in the kidneys, liver, and muscles of wild boars (n = 40) hunted in eastern Slovakia, as derivatives of physiological distribution and anthropogenic pollution. We found that sex was not a statistically significant factor for metal concentrations. Tissue differences were observed for all the metals studied except for Co. Cd, Cu, and Hg showed the highest median concentrations in kidney tissue with the lowest in muscle tissue (2.73, 3.78, and 0.061 μg/g w.w., respectively). The highest Zn median concentration was noted in the liver tissue with the lowest in muscle tissue. Co and Cu concentrations varied according to the age groups. Correlations between metal concentrations in muscle and kidney tissue were not especially strong; such relationships were not found in liver tissue. Among all the potential relationships of the given metal concentrations between tissues, the only significant relationship, albeit weak, was noted for Pb in muscle and liver tissue. The concentrations found seem not to be extremely high, but according to EU maximum permitted residue levels for Cd and Pb concentrations in meat, none of the samples studied was fully fit for human consumption. TWI and risk was also excessive for both metals.

http://ift.tt/2pLUaoo

Novel androgen receptor co-regulator GRHL2 exerts both oncogenic and anti-metastatic functions in prostate cancer

Alterations to the expression and activity of androgen receptor (AR) co-regulators in prostate cancer is an important mechanism driving disease progression and therapy resistance. Using a novel proteomic technique, we identified a new AR co-regulator, the transcription factor Grainyhead-like 2 (GRHL2), and demonstrated its essential role in the oncogenic AR signaling axis. GRHL2 colocalized with AR in prostate tumors and was frequently amplified and upregulated in prostate cancer. Importantly, GRHL2 maintained AR expression in multiple prostate cancer model systems, was required for cell proliferation, enhanced AR's transcriptional activity, and co-located with AR at specific sites on chromatin to regulate genes relevant to disease progression. GRHL2 is itself an AR-regulated gene, creating a positive feedback loop between the two factors. The link between GRHL2 and AR also applied to constitutively active truncated AR variants (ARVs), as GRHL2 interacted with and regulated ARVs and vice versa. These oncogenic functions of GRHL2 were counterbalanced by its ability to suppress epithelial-mesenchymal transition and cell invasion. Mechanistic evidence suggested that AR assisted GRHL2 in maintaining the epithelial phenotype. In summary, this study has identified a new AR co-regulator with a multifaceted role in prostate cancer, functioning as an enhancer of the oncogenic AR signaling pathway but also a suppressor of metastasis-related phenotypes.

http://ift.tt/2pemPBG

Oncogenic RAS regulates long non-coding RNA Orilnc1 in human cancer

RAS and its downstream cascades transmit cellular signals resulting in increased transcription of genes involved in cell growth and division. Protein-coding gene targets of RAS signaling have been characterized extensively, but long non-coding RNAs (lncRNA) regulated by these processes have not. Using a custom-designed lncRNA microarray, we identified the lncRNA Orilnc1 as a genetic target of RAS that is critical for RAS oncogenicity. Orilnc1 expression was regulated by RAS-RAF-MEK-ERK signaling via the transcription factor AP1. Orilnc1 was highly expressed in BRAF-mutant cancers such as melanoma. Silencing of Orilnc1 blocked tumor cell proliferation and growth in vitro and in vivo. Additionally, Orilnc1 blockade reduced expression of Cyclin E1 and induced G1/S cell cycle arrest in tumor cells. Taken together, our results identify Orilnc1 as a novel, non-protein mediator of RAS/RAF activation which may serve as a therapeutic target in RAS/RAF-driven cancers.

http://ift.tt/2p3eFQn

Beta-blocker drug use and survival among patients with pancreatic adenocarcinoma

Preclinical studies have suggested that β-adrenergic signaling is involved in pancreatic cancer progression. Prompted by such studies, we investigated an association between beta-blocker drug use with improved cancer-specific survival in a large, general population-based cohort of patients with pancreatic ductal adenocarcinoma (PDAC). All patients diagnosed with a first primary PDAC in Sweden between 2006 and 2009 were identified through the Swedish Cancer Register (n=2,394). We obtained information about use of beta-blockers and other medications through linkage with the national Prescribed Drug Register. Cancer-specific mortality was assessed using the Swedish Cause of Death Register. We used multivariable Cox regression adjusted for sociodemographic factors, tumor characteristics, comorbidity score and other medications to estimate hazard ratios (HR) and 95% confidence intervals (CI) for cancer-specific mortality associated with beta-blocker use during the 90 day period before cancer diagnosis. A total of 2,054 (86%) died with pancreatic cancer recorded as the underlying cause of death during a maximum of 5 years follow-up (median 5 months). Patients who used beta-blockers (n=522) had a lower cancer-specific mortality rate than non-users (adjusted HR 0·79; 95% CI 0·70-0·90, p<0·001). This observed rate reduction was more pronounced among patients with localized disease at diagnosis (n=517; adjusted HR 0·60; 95% CI 0·43-0·83, p=0·002), especially for users with higher daily doses (HR 0·54; 95% CI 0·35-0·83, p=0·005). No clear rate differences were observed by beta-blocker receptor selectivity. Our results support the concept that beta-blocker drugs may improve the survival of PDAC patients, particularly among those with localized disease.

http://ift.tt/2peYD1T

Novel androgen receptor co-regulator GRHL2 exerts both oncogenic and anti-metastatic functions in prostate cancer

Alterations to the expression and activity of androgen receptor (AR) co-regulators in prostate cancer is an important mechanism driving disease progression and therapy resistance. Using a novel proteomic technique, we identified a new AR co-regulator, the transcription factor Grainyhead-like 2 (GRHL2), and demonstrated its essential role in the oncogenic AR signaling axis. GRHL2 colocalized with AR in prostate tumors and was frequently amplified and upregulated in prostate cancer. Importantly, GRHL2 maintained AR expression in multiple prostate cancer model systems, was required for cell proliferation, enhanced AR's transcriptional activity, and co-located with AR at specific sites on chromatin to regulate genes relevant to disease progression. GRHL2 is itself an AR-regulated gene, creating a positive feedback loop between the two factors. The link between GRHL2 and AR also applied to constitutively active truncated AR variants (ARVs), as GRHL2 interacted with and regulated ARVs and vice versa. These oncogenic functions of GRHL2 were counterbalanced by its ability to suppress epithelial-mesenchymal transition and cell invasion. Mechanistic evidence suggested that AR assisted GRHL2 in maintaining the epithelial phenotype. In summary, this study has identified a new AR co-regulator with a multifaceted role in prostate cancer, functioning as an enhancer of the oncogenic AR signaling pathway but also a suppressor of metastasis-related phenotypes.

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Oncogenic RAS regulates long non-coding RNA Orilnc1 in human cancer

RAS and its downstream cascades transmit cellular signals resulting in increased transcription of genes involved in cell growth and division. Protein-coding gene targets of RAS signaling have been characterized extensively, but long non-coding RNAs (lncRNA) regulated by these processes have not. Using a custom-designed lncRNA microarray, we identified the lncRNA Orilnc1 as a genetic target of RAS that is critical for RAS oncogenicity. Orilnc1 expression was regulated by RAS-RAF-MEK-ERK signaling via the transcription factor AP1. Orilnc1 was highly expressed in BRAF-mutant cancers such as melanoma. Silencing of Orilnc1 blocked tumor cell proliferation and growth in vitro and in vivo. Additionally, Orilnc1 blockade reduced expression of Cyclin E1 and induced G1/S cell cycle arrest in tumor cells. Taken together, our results identify Orilnc1 as a novel, non-protein mediator of RAS/RAF activation which may serve as a therapeutic target in RAS/RAF-driven cancers.

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Beta-blocker drug use and survival among patients with pancreatic adenocarcinoma

Preclinical studies have suggested that β-adrenergic signaling is involved in pancreatic cancer progression. Prompted by such studies, we investigated an association between beta-blocker drug use with improved cancer-specific survival in a large, general population-based cohort of patients with pancreatic ductal adenocarcinoma (PDAC). All patients diagnosed with a first primary PDAC in Sweden between 2006 and 2009 were identified through the Swedish Cancer Register (n=2,394). We obtained information about use of beta-blockers and other medications through linkage with the national Prescribed Drug Register. Cancer-specific mortality was assessed using the Swedish Cause of Death Register. We used multivariable Cox regression adjusted for sociodemographic factors, tumor characteristics, comorbidity score and other medications to estimate hazard ratios (HR) and 95% confidence intervals (CI) for cancer-specific mortality associated with beta-blocker use during the 90 day period before cancer diagnosis. A total of 2,054 (86%) died with pancreatic cancer recorded as the underlying cause of death during a maximum of 5 years follow-up (median 5 months). Patients who used beta-blockers (n=522) had a lower cancer-specific mortality rate than non-users (adjusted HR 0·79; 95% CI 0·70-0·90, p<0·001). This observed rate reduction was more pronounced among patients with localized disease at diagnosis (n=517; adjusted HR 0·60; 95% CI 0·43-0·83, p=0·002), especially for users with higher daily doses (HR 0·54; 95% CI 0·35-0·83, p=0·005). No clear rate differences were observed by beta-blocker receptor selectivity. Our results support the concept that beta-blocker drugs may improve the survival of PDAC patients, particularly among those with localized disease.

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Cancer Immunotherapy with Cytokine-Induced Killer Cells

Abstract

Cytokine-induced killer (CIK) cells form under certain stimulation conditions in cultures of peripheral blood mononuclear cells (PBMCs). They are a heterogeneous immune cell population and contain a high percentage of cells with a mixed T-NK phenotype (CD3+CD56+). The ready availability of a lymphocyte source, together with the high proliferative rate and potent anti-tumor activity of CIK cells, has allowed their use as immunotherapy in a wide variety of neoplasms. Cytotoxicity mediated by CD3+CD56+ T cells depends on the major histocompatibility antigen (MHC)-independent recognition of tumor cells and the activation of signaling pathways through the natural killer group 2 member D (NKG2D) cell-surface receptor. Clinical trials have demonstrated the feasibility and efficacy of CIK cell immunotherapy even in advanced stage cancer patients or those that have not responded to first-line treatment. This review summarizes biological and technical aspects of CIK cells, as well as past and current clinical trials and future trends in this form of immunotherapy.

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The 150 most important questions in cancer research and clinical oncology series: Questions 25–30

To accelerate our endeavors to overcome cancer, Chinese Journal of Cancer has launched a program of publishing 150 most important questions in cancer research and clinical oncology. In this article, 6 more questi...

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Cancer Immunotherapy with Cytokine-Induced Killer Cells

Abstract

Cytokine-induced killer (CIK) cells form under certain stimulation conditions in cultures of peripheral blood mononuclear cells (PBMCs). They are a heterogeneous immune cell population and contain a high percentage of cells with a mixed T-NK phenotype (CD3+CD56+). The ready availability of a lymphocyte source, together with the high proliferative rate and potent anti-tumor activity of CIK cells, has allowed their use as immunotherapy in a wide variety of neoplasms. Cytotoxicity mediated by CD3+CD56+ T cells depends on the major histocompatibility antigen (MHC)-independent recognition of tumor cells and the activation of signaling pathways through the natural killer group 2 member D (NKG2D) cell-surface receptor. Clinical trials have demonstrated the feasibility and efficacy of CIK cell immunotherapy even in advanced stage cancer patients or those that have not responded to first-line treatment. This review summarizes biological and technical aspects of CIK cells, as well as past and current clinical trials and future trends in this form of immunotherapy.

http://ift.tt/2pMgDUn

Quality assurance of radiotherapy in the ongoing EORTC 1219-DAHANCA-29 trial for HPV/p16 negative squamous cell carcinoma of the head and neck: Results of the benchmark case procedure

The phase III EORTC 1219-DAHANCA 29 intergroup trial evaluates the influence of nimorazole in patients with locally advanced head and neck cancer when treated with accelerated radiotherapy (RT) in combination with chemotherapy. This article describes the results of the RT Benchmark Case (BC) performed before patient inclusion.

http://ift.tt/2pMwv9z

Current Views on the Interval Between Neoadjuvant Chemoradiation and Surgery for Rectal Cancer

Abstract

Neoadjuvant chemoradiation (CRT) has been established as standard treatment for stage II and III rectal cancer, and delayed interval between CRT and rectal resection has emerged as appropriate treatment due to the marked benefits associated with this approach. Despite favorable findings on downstaging and pathological complete response without increasing in morbidity and mortality, no significant improvement in sphincter preservation rate and rectal cancer overall survival has been observed with the current recommended 6–8-week interval. Trials are currently underway and may provide answers regarding the optimal interval between CRT and surgical resection, but until now, the best interval between CRT and surgery remains unclear.

http://ift.tt/2pLHrSS

The 150 most important questions in cancer research and clinical oncology series: Questions 25–30

To accelerate our endeavors to overcome cancer, Chinese Journal of Cancer has launched a program of publishing 150 most important questions in cancer research and clinical oncology. In this article, 6 more questi...

http://ift.tt/2qFBabg

Frequency and pathogenesis of central liver nodules in Alagille syndrome patients

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Real-time fluoroscopic needle guidance in the interventional radiology suite using navigational software for percutaneous bone biopsies in children

Abstract

Background

Navigational software provides real-time fluoroscopic needle guidance for percutaneous procedures in the Interventional Radiology (IR) suite.

Objective

We describe our experience with navigational software for pediatric percutaneous bone biopsies in the IR suite and compare technical success, diagnostic accuracy, radiation dose and procedure time with that of CT-guided biopsies.

Materials and methods

Pediatric bone biopsies performed using navigational software (Syngo iGuide, Siemens Healthcare) from 2011 to 2016 were prospectively included and anatomically matched CT-guided bone biopsies from 2008 to 2016 were retrospectively reviewed with institutional review board approval. C-arm CT protocols used for navigational software-assisted cases included institution-developed low-dose (0.1/0.17 μGy/projection), regular-dose (0.36 μGy/projection), or a combination of low-dose/regular-dose protocols. Estimated effective radiation dose and procedure times were compared between software-assisted and CT-guided biopsies.

Results

Twenty-six patients (15 male; mean age: 10 years) underwent software-assisted biopsies (15 pelvic, 7 lumbar and 4 lower extremity) and 33 patients (13 male; mean age: 9 years) underwent CT-guided biopsies (22 pelvic, 7 lumbar and 4 lower extremity). Both modality biopsies resulted in a 100% technical success rate. Twenty-five of 26 (96%) software-assisted and 29/33 (88%) CT-guided biopsies were diagnostic. Overall, the effective radiation dose was significantly lower in software-assisted than CT-guided cases (3.0±3.4 vs. 6.6±7.7 mSv, P=0.02). The effective dose difference was most dramatic in software-assisted cases using low-dose C-arm CT (1.2±1.8 vs. 6.6±7.7 mSv, P=0.001) or combined low-dose/regular-dose C-arm CT (1.9±2.4 vs. 6.6±7.7 mSv, P=0.04), whereas effective dose was comparable in software-assisted cases using regular-dose C-arm CT (6.0±3.5 vs. 6.6±7.7 mSv, P=0.7). Mean procedure time was significantly lower for software-assisted cases (91±54 vs. 141±68 min, P=0.005).

Conclusion

In our experience, navigational software technology in the IR suite is a promising alternative to CT guidance for pediatric bone biopsies providing comparable technical success and diagnostic accuracy with lower radiation dose and procedure time, in addition to providing real-time fluoroscopic needle guidance.

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