CXCL13 expression is prognostic and predictive for postoperative adjuvant chemotherapy benefit in patients with gastric cancer

Abstract

Background

Chemokine (C-X-C motif) ligand 13 (CXCL13/BLC/BCA-1) is a cytokine from C-X-C chemokine family, which is selectively chemotactic for B cells. Previous research has demonstrated that high CXCL13 expression is correlated to poor prognosis in various cancers. However, the association between CXCL13 expression and gastric cancer is still unclear.

Methods

Intratumoral CXCL13 expression was evaluated by immunohistochemistry using a semi-quantitative method (modified H-score) in a testing set of 214 and a validation set of 227 randomly selected gastric cancer patients resected in 2008 in one institution. The median value was used as the cut-off point. We performed correlative analysis of CXCL-13 expression with clinicopathological variables, Kaplan–Meier analysis for association with overall survival (OS), and multivariate modeling.

Results

High CXCL13 expression was associated with larger tumor diameter and shorter OS. By multivariate analysis, CXCL13 expression was associated with OS independently from clinicopathological factors. Within the T2–4 stage patients group, low CXCL13 expression was associated with longer survival, especially in the subgroup of patients (57.6%) who received adjuvant chemotherapy.

Conclusions

Intratumoral CXCL13 expression appears as an independent prognostic marker for patients after gastric cancer resection. In addition, CXCL13 expression may serve as a predictive biomarker of response to postoperative adjuvant chemotherapy in these patients.

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A Prospective International Multicentre Cohort Study of Intraoperative Heart Rate and Systolic Blood Pressure and Myocardial Injury After Noncardiac Surgery: Results of the VISION Study

BACKGROUND: The association between intraoperative cardiovascular changes and perioperative myocardial injury has chiefly focused on hypotension during noncardiac surgery. However, the relative influence of blood pressure and heart rate (HR) remains unclear. We investigated both individual and codependent relationships among intraoperative HR, systolic blood pressure (SBP), and myocardial injury after noncardiac surgery (MINS). METHODS: Secondary analysis of the Vascular Events in Noncardiac Surgery Cohort Evaluation (VISION) study, a prospective international cohort study of noncardiac surgical patients. Multivariable logistic regression analysis tested for associations between intraoperative HR and/or SBP and MINS, defined by an elevated serum troponin T adjudicated as due to an ischemic etiology, within 30 days after surgery. Predefined thresholds for intraoperative HR and SBP were: maximum HR >100 beats or minimum HR 160 mm Hg or minimum SBP 100 bpm was associated with MINS (odds ratio [OR], 1.27 [1.07–1.50]; P 160 mm Hg was associated with MINS (OR, 1.16 [1.01–1.34]; P = .04) and myocardial infarction (OR, 1.34 [1.09–1.64]; P = .01) but, paradoxically, reduced mortality (OR, 0.76 [0.58–0.99]; P = .04). Minimum HR 100 bpm was more strongly associated with MINS (OR, 1.42 [1.15–1.76]; P

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Impact of Anesthetic Regimen on Remote Ischemic Preconditioning in the Rat Heart In Vivo

Remote ischemic preconditioning (RIPC) seems to be a promising cardioprotective strategy with contradictive clinical data suggesting the anesthetic regimen influencing the favorable impact of RIPC. This study aimed to investigate whether cardio protection by RIPC is abolished by anesthetic regimens. Male Wistar rats were randomized to 6 groups. Anesthesia was either maintained by pentobarbital (Pento) alone or a combination of sevoflurane (Sevo) and remifentanil or propofol (Prop) and remifentanil in combination with and without RIPC. RIPC reduced infarct size in Pento- and Sevo-anesthetized rats (Pento-RIPC: 30% ± 9% versus Pento-control [Con]: 65% ± 6%, P

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Healthcare Simulation Education: Evidence, Theory and Practice, 1st ed.

No abstract available

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The Local, Global Perspective

No abstract available

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A Left Ventricle to Left Atrial Appendage Fistula After Mitral Valve Replacement

No abstract available

http://ift.tt/2iMt3dz

Pressure Waveform Analysis

Monitoring cardiac output is of special interest for detecting early hemodynamic impairment and for guiding its treatment. Among the techniques that are available to monitor cardiac output, pressure waveform analysis estimates cardiac output from the shape of the arterial pressure curve. It is based on the general principle that the amplitude of the systolic part of the arterial curve is proportional to cardiac output and arterial compliance. Such an estimation of cardiac output has the advantage of being continuous and in real time. With "calibrated" devices, the initial estimation of cardiac output by pressure waveform analysis is calibrated by measurements of cardiac output made by transpulmonary thermal or lithium dilution. Later, at each time transpulmonary dilution is performed, the estimation by pressure waveform analysis, which may drift over time, is calibrated again. By contrast, uncalibrated devices do not use any independent measurement of cardiac output. Unlike calibrated devices, they can be plugged to any arterial catheter. Nevertheless, uncalibrated devices are not reliable in cases of significant short-term changes in arterial resistance, as for instance in patients undergoing liver surgery or those with vasodilatory shock receiving vasopressors. Perioperative hemodynamic monitoring is recommended for high-risk surgical patients since it reduces the number of complications in these patients. The pressure waveform analysis monitoring, especially with uncalibrated devices, is suitable for this purpose. In the intensive care setting, hemodynamic monitoring is recommended for patients with acute circulatory failure, who do not respond to initial therapy. Since these patients often experience large changes in arterial resistance, either spontaneously or due to vasoactive drugs, calibrated devices are more suitable in this context. Not only are they more reliable than uncalibrated devices but also they provide a comprehensive hemodynamic assessment through measurements of a variety of transpulmonary thermodilution-related variables. In this review, we summarize the characteristics of the monitoring devices using the pressure waveform analysis and discuss the appropriate use of different devices in the perioperative and intensive care unit settings. Accepted for publication August 30, 2017. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Address correspondence to Jean-Louis Teboul, MD, PhD, Service de réanimation médicale, Hôpitaux universitaires Paris-Sud, Hôpital de Bicêtre, 78 rue du Général Leclerc, Le Kremlin-Bicêtre F-94270, France. Address e-mail to jean-louis.teboul@aphp.fr. © 2017 International Anesthesia Research Society

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Anaesthesia for the Elderly Patient, 2nd ed.

No abstract available

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The Effect of Adding Subarachnoid Epinephrine to Hyperbaric Bupivacaine and Morphine for Repeat Cesarean Delivery: A Double-Blind Prospective Randomized Control Trial

BACKGROUND: Spinal anesthesia has become the most common type of anesthetic for cesarean delivery. The major limitation to spinal anesthesia is that the duration of the anesthetic may not be adequate in the event of a prolonged surgery. Some practitioners add epinephrine to hyperbaric bupivacaine to increase the duration, although its effect has not been fully studied. We therefore aimed to evaluate whether adding epinephrine to the spinal medication prolongs the duration of action of the resultant block in women presenting for repeat cesarean delivery. METHODS: Sixty-eight patients were randomized to receive no epinephrine (NE group), epinephrine 100 µg (low-dose [LD] group), or epinephrine 200 µg (high-dose [HD] group) with a standardized spinal mixture (1.5 mL 0.75% hyperbaric bupivacaine with 0.25 mg morphine). Sixty-five patients were included for primary analysis. Our primary outcome was time to intraoperative activation of the epidural catheter or postoperative regression of sensory blockade to T-10 dermatome level as measured by pinprick sensation; motor recovery was a secondary outcome, and graded via a Modified Bromage scale. RESULTS: Block onset time, vital sign changes, and the incidence of hypotension; nausea, and vomiting were similar among groups. Median difference in time to T-10 regression was greatest in the HD group compared to the NE group (median difference [min] [95% confidence interval]: 40 [15–60]; P = .007), followed by the HD group to the LD group (30 [15–45]; P = .007). Comparisons of LD to NE were not significant, but trended to an increase in T-10 regression time (10 [−15 to 30]; P = .76). Median difference in time to knee extension (Bromage 3) was also greatest in the HD group when compared to both the LD and NE group (median difference [min] [95% confidence interval]: 30 [0–60]; P = .034, 60 [0–93]; P = .007). Median difference time to knee extension (min) between the LD and NE group was also significant (37.5 [15–60]; P = .001]. Pain scores during the procedure were higher in the NE group (median [interquartile range] HD: 0 [0–0], LD: 0 [0–0], NE: 0 [0–3]; P = .02) during uterine closure and were otherwise not significantly different from the other groups. CONCLUSIONS: In this single center, prospective, double-blind, randomized control trial, the addition of epinephrine 200 µg to hyperbaric bupivacaine and preservative-free morphine for repeat cesarean delivery prolonged the duration of the sensory blockade. Motor blockade was similarly prolonged and block quality may have been enhanced. Accepted for publication August 30, 2017. Funding: Funding for this study was procured though the Icahn School of Medicine at Mount Sinai. Clinical Trial # (ClinicalTrials.gov): NCT02369510. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Daniel Katz, MD, Department of Anesthesiology, Pain, and Perioperative Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Pl, KCC 8th Floor Box 1010, New York, NY 10029. Address e-mail to Daniel.Katz@MountSinai.org. © 2017 International Anesthesia Research Society

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Use of 3D Transesophageal Echocardiography and the Clock-Face Model to Localize and Facilitate Closure of a Mitral Paravalvular Defect

No abstract available

http://ift.tt/2iNJpCO

Synthetic regulatory RNAs selectively suppress the progression of bladder cancer

The traditional treatment for cancer is lack of specificity and efficacy. Modular synthetic regulatory RNAs, such as inhibitive RNA (iRNA) and active RNA (aRNA), may overcome these limitations. Here, we synthe...

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Metabolomics guided pathway analysis reveals link between cancer metastasis, cholesterol sulfate, and phospholipids

Abstract

Background

Cancer cells that enter the metastatic cascade require traits that allow them to survive within the circulation and colonize distant organ sites. As disseminating cancer cells adapt to their changing microenvironments, they also modify their metabolism and metabolite production.

Methods

A mouse xenograft model of spontaneous tumor metastasis was used to determine the metabolic rewiring that occurs between primary cancers and their metastases. An "autonomous" mass spectrometry-based untargeted metabolomic workflow with integrative metabolic pathway analysis revealed a number of differentially regulated metabolites in primary mammary fat pad (MFP) tumors compared to microdissected paired lung metastases. The study was further extended to analyze metabolites in paired normal tissues which determined the potential influence of metabolites from the microenvironment.

Results

Metabolomic analysis revealed that multiple metabolites were increased in metastases, including cholesterol sulfate and phospholipids (phosphatidylglycerols and phosphatidylethanolamine). Metabolite analysis of normal lung tissue in the mouse model also revealed increased levels of these metabolites compared to tissues from normal MFP and primary MFP tumors, indicating potential extracellular uptake by cancer cells in lung metastases. These results indicate a potential functional importance of cholesterol sulfate and phospholipids in propagating metastasis. In addition, metabolites involved in DNA/RNA synthesis and the TCA cycle were decreased in lung metastases compared to primary MFP tumors.

Conclusions

Using an integrated metabolomic workflow, this study identified a link between cholesterol sulfate and phospholipids, metabolic characteristics of the metastatic niche, and the capacity of tumor cells to colonize distant sites.

http://ift.tt/2A3EB0a

Metabolomics guided pathway analysis reveals link between cancer metastasis, cholesterol sulfate, and phospholipids

Abstract

Background

Cancer cells that enter the metastatic cascade require traits that allow them to survive within the circulation and colonize distant organ sites. As disseminating cancer cells adapt to their changing microenvironments, they also modify their metabolism and metabolite production.

Methods

A mouse xenograft model of spontaneous tumor metastasis was used to determine the metabolic rewiring that occurs between primary cancers and their metastases. An "autonomous" mass spectrometry-based untargeted metabolomic workflow with integrative metabolic pathway analysis revealed a number of differentially regulated metabolites in primary mammary fat pad (MFP) tumors compared to microdissected paired lung metastases. The study was further extended to analyze metabolites in paired normal tissues which determined the potential influence of metabolites from the microenvironment.

Results

Metabolomic analysis revealed that multiple metabolites were increased in metastases, including cholesterol sulfate and phospholipids (phosphatidylglycerols and phosphatidylethanolamine). Metabolite analysis of normal lung tissue in the mouse model also revealed increased levels of these metabolites compared to tissues from normal MFP and primary MFP tumors, indicating potential extracellular uptake by cancer cells in lung metastases. These results indicate a potential functional importance of cholesterol sulfate and phospholipids in propagating metastasis. In addition, metabolites involved in DNA/RNA synthesis and the TCA cycle were decreased in lung metastases compared to primary MFP tumors.

Conclusions

Using an integrated metabolomic workflow, this study identified a link between cholesterol sulfate and phospholipids, metabolic characteristics of the metastatic niche, and the capacity of tumor cells to colonize distant sites.

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CD31 Expression Determines Redox Status and Chemoresistance in Human Angiosarcomas

Purpose: Angiosarcomas (AS) are soft tissue sarcomas with endothelial differentiation and vasoformative capacity. Most AS show strong constitutive expression of the endothelial adhesion receptor CD31/PECAM-1 pointing to an important role of this molecule. However, the biological function of CD31 in AS is unknown. Experimental Design: The expression levels of CD31 in AS cells and its effects on cell viability, colony formation and chemoresistance was evaluated in human AS clinical samples and in cell lines through isolation of CD31^high and CD31^low cell subsets. The redox-regulatory CD31 function linked to YAP signaling was determined using a CD31 blocking antibody and siRNA approach and was further validated in CD31-knockout endothelial cells. Results: We found that most AS contain a small CD31^low cell population. CD31^low cells had lost part of their endothelial properties, were more tumorigenic and chemoresistant than CD31^high cells due to more efficient reactive oxygen species (ROS) detoxification. Active downregulation of CD31 resulted in loss of endothelial tube formation, nuclear accumulation of YAP, and YAP-dependent induction of antioxidative enzymes. Addition of pazopanib, a known enhancer of proteasomal YAP degradation re-sensitized CD31^low cells for doxorubicin resulting in growth suppression and induction of apoptosis. Conclusions: Human AS contain a small aggressive CD31^low population that have lost part of their endothelial differentiation programs and are more resistant against oxidative stress and DNA damage due to intensified YAP signaling. Our finding that the addition of YAP inhibitors can re-sensitize CD31^low cells towards doxorubicin may aid in the rational development of novel combination therapies to treat AS.

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Clinical and Immunological Biomarkers for Histologic Regression of High Grade Cervical Dysplasia and Clearance of HPV16 and HPV18 after Immunotherapy

Purpose: As previously reported, treatment of high grade cervical dysplasia with VGX-3100 resulted in complete histopathologic regression (CR) concomitant with elimination of HPV16/18 infection in 40.0% of VGX-3100-treated patients compared to only 14.3% in placebo recipients in a randomized PhaseIIb study.  Here, we identify clinical and immunological characteristics that either predicted or correlated with therapeutic benefit from VGX-3100 to identify parameters that might guide clinical decision-making for this disease. Experimental Design: We analyzed samples taken from cervical swabs, whole blood and tissue biopsies/resections to determine correlates and predictors of treatment success.  Results. At study entry, the presence of pre-existing immunosuppressive factors such as FoxP3 and PD-L1 in cervical lesions showed no association with treatment outcome. The combination of HPV typing and cervical cytology following dosing was predictive for both histologic regression and elimination of detectable virus at the efficacy assessment twenty two weeks later (negative predictive value 94%). Patients treated with VGX-3100 who had lesion regression had a statistically significant >2-fold increase in CD137+perforin+CD8+ Tcells specific for the HPV genotype causing disease.  Increases in cervical mucosal CD137+ and CD103+ infiltrates were observed only in treated patients.  Perforin+ cell infiltrates were significantly increased >2-fold in cervical tissue only in treated patients who had histologic CR. Conclusion. Quantitative measures associated with an effector immune response to VGX-3100 antigens were associated with lesion regression. Consequently, these analyses indicate that certain immunologic responses associate with successful resolution of HPV-induced pre-malignancy, with particular emphasis on the upregulation of perforin in the immunotherapy induced immune response.

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A Randomized, Double-blind, Placebo-controlled Phase 2 Study of Ontuxizumab (MORAb-004) in Patients with Chemorefractory Metastatic Colorectal Cancer

Purpose: The purpose of this study was to evaluate the safety and efficacy of ontuxizumab (MORAb-004), a monoclonal antibody that interferes with endosialin (tumor endothelial marker-1 [TEM-1]) function, in patients with chemorefractory metastatic colorectal cancer and to identify a responsive patient population based on biomarkers. Design: This was a randomized, double-blind, placebo-controlled, Phase 2 study. Patients were randomly assigned in a 2:1 ratio to receive weekly intravenous ontuxizumab (8 mg/kg) or placebo plus best supportive care (BSC) until progression or unacceptable toxicity. Tissue and blood biomarkers were evaluated for their ability to identify a patient population that was responsive to ontuxizumab. Results: A total of 126 patients were enrolled. No significant difference between the ontuxizumab and placebo groups was evident for the primary endpoint of progression-free survival (PFS), with a median PFS of 8.1 weeks in each group (hazard ratio of 1.13; 95% confidence interval: 0.76, 1.67; P=0.53). There were no significant differences between groups for overall survival (OS) or overall response rate (ORR). The most common treatment-emergent adverse events (TEAEs) in the ontuxizumab group (vs the placebo group, respectively) were fatigue (53.7% vs 47.5%), nausea (39.0% vs 35.0%), decreased appetite (34.1% vs 27.5%), and constipation (28.0% vs 32.5%). The most common Grade 3/4 TEAE in the ontuxizumab group vs placebo was back pain (11.0% vs 0%). No single biomarker clearly identified patients responsive to ontuxizumab. Conclusion: No benefit with ontuxizumab monotherapy compared with placebo for clinical response parameters of PFS, OS, or ORR was demonstrated. Ontuxizumab was well tolerated.

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Location of mutation in BRCA2 gene and survival in patients with ovarian cancer

Purpose: BRCA2 plays a central role in homologous recombination by loading RAD51 on DNA breaks. The objective of this study is to determine whether the location of mutations in the RAD51-binding domain (RAD51-BD; exon 11) of BRCA2 gene impacts the clinical outcome of OC patients. Experimental Design: A study cohort of 353 women with OC who underwent genetic germline testing for BRCA1 and BRCA2 genes were identified. Progression-free survival (PFS), platinum-free interval (PFI) and overall survival (OS) were analyzed. The Cancer Genome Atlas (TCGA) cohort of OC (n=316) was used as a validation cohort. Results: In the study cohort, 78 patients were carriers of germline mutations of BRCA2. After adjustment for FIGO stage and macroscopic residual disease, BRCA2 carriers with truncating mutations in the RAD51-BD have significantly prolonged 5-year PFS (58%; adjusted Hazard ratio [HR], 0.36; 95% CI, 0.20-0.64; p=0.001) and prolonged PFI (29.7 vs 15.5 months, p=0.011), compared to non-carriers. BRCA2 carriers with mutations located in other domains of the gene do not have prolonged 5-year PFS (28%, adjusted HR, 0.67; 95% CI, 0.42-1.07; p=0.094) or PFI (19 vs 15.5 months, p=0.146). In the TCGA cohort, only BRCA2 carriers harboring germline or somatic mutations in the RAD51-BD have prolonged 5-year PFS (46%; adjusted HR, 0.30; 95% CI, 0.13-0.68; p=0.004) and 5-year OS (78%; adjusted HR, 0.09; 95% CI, 0.02-0.38; p=0.001). Conclusions: Among ovarian cancer patients, BRCA2 carriers with mutations located in the RAD51-BD (exon 11) have prolonged progression-free survival, platinum-free interval and overall survival.

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Global metabolic profiling identifies a pivotal role of proline and hydroxyproline metabolism in supporting hypoxic response in hepatocellular carcinoma.

Purpose: Metabolic reprogramming is frequently identified in hepatocellular carcinoma, which is the most common type of liver malignancy. The reprogrammed cellular metabolisms promote tumor cell survival, proliferation, angiogenesis and metastasis. However, the mechanisms of this process remain unclear in hepatocellular carcinoma. Experimental Design: Theglobal non-targeted metabolic studyin 69 paired hepatic carcinomas and adjacent tissue specimens were performed using capillary electrophoresis-time of flight mass spectrometry (CE-TOF/MS)-based approach. Key findings were validated by targeted metabolomic approach. Biological studies were also performed to investigate the role of proline biosynthesis in HCC pathogenesis. Results: Proline metabolism wasmarkedly changed in HCC tumor tissue, characterized withaccelerated consumption of proline and accumulation of hydroxyproline, which significantly correlated with α-fetoproteinlevels and poor prognosisin HCC.In addition, we found that hydroxyproline promoted hypoxia- and HIF-dependent phenotype in HCC. Moreover, we demonstrated that hypoxia activated proline biosynthesis via upregulation of ALDH18A, subsequently leading to accumulation of hydroxyproline via attenuated PRODH2 activity. More importantly, we showed that glutamine, proline and hydroxyproline metabolic axis supported HCC cell survival through modulating HIF1α stability in response to hypoxia. Finally, Inhibition of proline biosynthesis significantly enhanced cytotoxicity of sorafenib in vitro and in vivo. Conclusions: Our results demonstrate that hypoxic microenvironment activates proline metabolism, resulting in accumulation of hydroxyproline that promotes HCC tumor progression and sorafenib resistance through modulating HIF1α. These findings provide the proof of concept for targeting proline metabolism as a potential therapeutic strategy for hepatocellular carcinoma.

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Hypoxia-inducible PIM kinase expression promotes resistance to anti-angiogenic agents

Purpose: Patients develop resistance to anti-angiogenic drugs, secondary to changes in the tumor microenvironment, including hypoxia. PIM kinases are pro-survival kinases and their expression increases in hypoxia. The goal of this study was to determine whether targeting hypoxia-induced PIM kinase expression is effective in combination with VEGF-targeting agents. The rationale for this therapeutic approach is based on the fact that anti-angiogenic drugs can make tumors hypoxic, and thus more sensitive to PIM inhibitors. Experimental Design: Xenograft and orthotopic models of prostate and colon cancer were used to assess the effect of PIM activation on the efficacy of VEGF-targeting agents. Immunohistochemistry and in vivo imaging were used to analyze angiogenesis, apoptosis, proliferation, and metastasis. Biochemical studies were performed to characterize the novel signaling pathway linking PIM and HIF-1. Results: PIM was upregulated following treatment with anti-VEGF therapies, and PIM1 overexpression reduced the ability of these drugs to disrupt vasculature and block tumor growth. PIM inhibitors reduced HIF-1 activity, opposing the shift to a pro-angiogenic gene signature associated with hypoxia. Combined inhibition of PIM and VEGF produced a synergistic anti-tumor response characterized by decreased proliferation, reduced tumor vasculature, and decreased metastasis. Conclusions: This study describes PIM kinase expression as a novel mechanism of resistance to anti-angiogenic agents. Our data provide justification for combining PIM and VEGF inhibitors to treat solid tumors. The unique ability of PIM inhibitors to concomitantly target HIF-1 and selectively kill hypoxic tumor cells addresses two major components of tumor progression and therapeutic resistance.

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Inhibition of REDD1 sensitizes bladder urothelial carcinoma to paclitaxel by inhibiting autophagy

Purpose: Regulated in development and DNA damage response-1 (REDD1) is a stress related protein and is involved in the progression of cancer. The role and regulatory mechanism of REDD1 in bladder urothelial carcinoma (BUC), however, is yet unidentified. Experimental Design: The expression of REDD1 in BUC was detected by western blot and immunohistochemistry. The correlation between REDD1 expression and clinical features in BUC patients were assessed. The effects of REDD1 on cellular proliferation, apoptosis, autophagy, and paclitaxel sensitivity were determined both in vitro and in vivo. Then the targeted-regulating mechanism of REDD1 by microRNAs was explored. Results: Here the significant increase of REDD1 expression is detected in BUC tissue, and REDD1 is firstly reported as an independent prognostic factor in BUC patients. Silencing REDD1 expression in T24 and EJ cells decreased cell proliferation, increased apoptosis, and decreased autophagy, whereas the ectopic expression of REDD1 in RT4 and BIU87 cells had the opposite effect. Additionally, the REDD1-mediated proliferation, apoptosis, and autophagy are found to be negatively regulated by miR-22 in vitro, which intensify the paclitaxel sensitivity via inhibition of the well-acknowledged REDD1-EEF2K-autophagy axis. AKT/mTOR signaling initially activated or inhibited in response to silencing or enhancing REDD1 expression and then recovered rapidly. Lastly, the inhibited REDD1 expression by either RNAi or miR-22 sensitizes BUC tumor cells to paclitaxel in a subcutaneous transplant sarcoma model in vivo. Conclusion: REDD1 is confirmed as an oncogene in BUC, and antagonizing REDD1 could be a potential therapeutic strategy to sensitize BUC cells to paclitaxel.

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Targeting CDH17 in cancer: when blocking the ligand beats blocking the receptor?

Cadherin-17 (CDH17) has been implicated as pro-tumorigenic for many years but mechanisms have been unclear. A Spanish team have generated antibodies to an RGD-motif in CDH17 that inhibits integrin α2β1 binding to CDH17 and thereby inhibits integrin activation, tumorigenesis and metastasis. These reagents may have therapeutic potential.

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CD31 Expression Determines Redox Status and Chemoresistance in Human Angiosarcomas

Purpose: Angiosarcomas (AS) are soft tissue sarcomas with endothelial differentiation and vasoformative capacity. Most AS show strong constitutive expression of the endothelial adhesion receptor CD31/PECAM-1 pointing to an important role of this molecule. However, the biological function of CD31 in AS is unknown. Experimental Design: The expression levels of CD31 in AS cells and its effects on cell viability, colony formation and chemoresistance was evaluated in human AS clinical samples and in cell lines through isolation of CD31^high and CD31^low cell subsets. The redox-regulatory CD31 function linked to YAP signaling was determined using a CD31 blocking antibody and siRNA approach and was further validated in CD31-knockout endothelial cells. Results: We found that most AS contain a small CD31^low cell population. CD31^low cells had lost part of their endothelial properties, were more tumorigenic and chemoresistant than CD31^high cells due to more efficient reactive oxygen species (ROS) detoxification. Active downregulation of CD31 resulted in loss of endothelial tube formation, nuclear accumulation of YAP, and YAP-dependent induction of antioxidative enzymes. Addition of pazopanib, a known enhancer of proteasomal YAP degradation re-sensitized CD31^low cells for doxorubicin resulting in growth suppression and induction of apoptosis. Conclusions: Human AS contain a small aggressive CD31^low population that have lost part of their endothelial differentiation programs and are more resistant against oxidative stress and DNA damage due to intensified YAP signaling. Our finding that the addition of YAP inhibitors can re-sensitize CD31^low cells towards doxorubicin may aid in the rational development of novel combination therapies to treat AS.

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Clinical and Immunological Biomarkers for Histologic Regression of High Grade Cervical Dysplasia and Clearance of HPV16 and HPV18 after Immunotherapy

Purpose: As previously reported, treatment of high grade cervical dysplasia with VGX-3100 resulted in complete histopathologic regression (CR) concomitant with elimination of HPV16/18 infection in 40.0% of VGX-3100-treated patients compared to only 14.3% in placebo recipients in a randomized PhaseIIb study.  Here, we identify clinical and immunological characteristics that either predicted or correlated with therapeutic benefit from VGX-3100 to identify parameters that might guide clinical decision-making for this disease. Experimental Design: We analyzed samples taken from cervical swabs, whole blood and tissue biopsies/resections to determine correlates and predictors of treatment success.  Results. At study entry, the presence of pre-existing immunosuppressive factors such as FoxP3 and PD-L1 in cervical lesions showed no association with treatment outcome. The combination of HPV typing and cervical cytology following dosing was predictive for both histologic regression and elimination of detectable virus at the efficacy assessment twenty two weeks later (negative predictive value 94%). Patients treated with VGX-3100 who had lesion regression had a statistically significant >2-fold increase in CD137+perforin+CD8+ Tcells specific for the HPV genotype causing disease.  Increases in cervical mucosal CD137+ and CD103+ infiltrates were observed only in treated patients.  Perforin+ cell infiltrates were significantly increased >2-fold in cervical tissue only in treated patients who had histologic CR. Conclusion. Quantitative measures associated with an effector immune response to VGX-3100 antigens were associated with lesion regression. Consequently, these analyses indicate that certain immunologic responses associate with successful resolution of HPV-induced pre-malignancy, with particular emphasis on the upregulation of perforin in the immunotherapy induced immune response.

http://ift.tt/2yhnbQs

A Randomized, Double-blind, Placebo-controlled Phase 2 Study of Ontuxizumab (MORAb-004) in Patients with Chemorefractory Metastatic Colorectal Cancer

Purpose: The purpose of this study was to evaluate the safety and efficacy of ontuxizumab (MORAb-004), a monoclonal antibody that interferes with endosialin (tumor endothelial marker-1 [TEM-1]) function, in patients with chemorefractory metastatic colorectal cancer and to identify a responsive patient population based on biomarkers. Design: This was a randomized, double-blind, placebo-controlled, Phase 2 study. Patients were randomly assigned in a 2:1 ratio to receive weekly intravenous ontuxizumab (8 mg/kg) or placebo plus best supportive care (BSC) until progression or unacceptable toxicity. Tissue and blood biomarkers were evaluated for their ability to identify a patient population that was responsive to ontuxizumab. Results: A total of 126 patients were enrolled. No significant difference between the ontuxizumab and placebo groups was evident for the primary endpoint of progression-free survival (PFS), with a median PFS of 8.1 weeks in each group (hazard ratio of 1.13; 95% confidence interval: 0.76, 1.67; P=0.53). There were no significant differences between groups for overall survival (OS) or overall response rate (ORR). The most common treatment-emergent adverse events (TEAEs) in the ontuxizumab group (vs the placebo group, respectively) were fatigue (53.7% vs 47.5%), nausea (39.0% vs 35.0%), decreased appetite (34.1% vs 27.5%), and constipation (28.0% vs 32.5%). The most common Grade 3/4 TEAE in the ontuxizumab group vs placebo was back pain (11.0% vs 0%). No single biomarker clearly identified patients responsive to ontuxizumab. Conclusion: No benefit with ontuxizumab monotherapy compared with placebo for clinical response parameters of PFS, OS, or ORR was demonstrated. Ontuxizumab was well tolerated.

http://ift.tt/2lvYutA

Location of mutation in BRCA2 gene and survival in patients with ovarian cancer

Purpose: BRCA2 plays a central role in homologous recombination by loading RAD51 on DNA breaks. The objective of this study is to determine whether the location of mutations in the RAD51-binding domain (RAD51-BD; exon 11) of BRCA2 gene impacts the clinical outcome of OC patients. Experimental Design: A study cohort of 353 women with OC who underwent genetic germline testing for BRCA1 and BRCA2 genes were identified. Progression-free survival (PFS), platinum-free interval (PFI) and overall survival (OS) were analyzed. The Cancer Genome Atlas (TCGA) cohort of OC (n=316) was used as a validation cohort. Results: In the study cohort, 78 patients were carriers of germline mutations of BRCA2. After adjustment for FIGO stage and macroscopic residual disease, BRCA2 carriers with truncating mutations in the RAD51-BD have significantly prolonged 5-year PFS (58%; adjusted Hazard ratio [HR], 0.36; 95% CI, 0.20-0.64; p=0.001) and prolonged PFI (29.7 vs 15.5 months, p=0.011), compared to non-carriers. BRCA2 carriers with mutations located in other domains of the gene do not have prolonged 5-year PFS (28%, adjusted HR, 0.67; 95% CI, 0.42-1.07; p=0.094) or PFI (19 vs 15.5 months, p=0.146). In the TCGA cohort, only BRCA2 carriers harboring germline or somatic mutations in the RAD51-BD have prolonged 5-year PFS (46%; adjusted HR, 0.30; 95% CI, 0.13-0.68; p=0.004) and 5-year OS (78%; adjusted HR, 0.09; 95% CI, 0.02-0.38; p=0.001). Conclusions: Among ovarian cancer patients, BRCA2 carriers with mutations located in the RAD51-BD (exon 11) have prolonged progression-free survival, platinum-free interval and overall survival.

http://ift.tt/2ygL5vt

Global metabolic profiling identifies a pivotal role of proline and hydroxyproline metabolism in supporting hypoxic response in hepatocellular carcinoma.

Purpose: Metabolic reprogramming is frequently identified in hepatocellular carcinoma, which is the most common type of liver malignancy. The reprogrammed cellular metabolisms promote tumor cell survival, proliferation, angiogenesis and metastasis. However, the mechanisms of this process remain unclear in hepatocellular carcinoma. Experimental Design: Theglobal non-targeted metabolic studyin 69 paired hepatic carcinomas and adjacent tissue specimens were performed using capillary electrophoresis-time of flight mass spectrometry (CE-TOF/MS)-based approach. Key findings were validated by targeted metabolomic approach. Biological studies were also performed to investigate the role of proline biosynthesis in HCC pathogenesis. Results: Proline metabolism wasmarkedly changed in HCC tumor tissue, characterized withaccelerated consumption of proline and accumulation of hydroxyproline, which significantly correlated with α-fetoproteinlevels and poor prognosisin HCC.In addition, we found that hydroxyproline promoted hypoxia- and HIF-dependent phenotype in HCC. Moreover, we demonstrated that hypoxia activated proline biosynthesis via upregulation of ALDH18A, subsequently leading to accumulation of hydroxyproline via attenuated PRODH2 activity. More importantly, we showed that glutamine, proline and hydroxyproline metabolic axis supported HCC cell survival through modulating HIF1α stability in response to hypoxia. Finally, Inhibition of proline biosynthesis significantly enhanced cytotoxicity of sorafenib in vitro and in vivo. Conclusions: Our results demonstrate that hypoxic microenvironment activates proline metabolism, resulting in accumulation of hydroxyproline that promotes HCC tumor progression and sorafenib resistance through modulating HIF1α. These findings provide the proof of concept for targeting proline metabolism as a potential therapeutic strategy for hepatocellular carcinoma.

http://ift.tt/2lx7rD4

Hypoxia-inducible PIM kinase expression promotes resistance to anti-angiogenic agents

Purpose: Patients develop resistance to anti-angiogenic drugs, secondary to changes in the tumor microenvironment, including hypoxia. PIM kinases are pro-survival kinases and their expression increases in hypoxia. The goal of this study was to determine whether targeting hypoxia-induced PIM kinase expression is effective in combination with VEGF-targeting agents. The rationale for this therapeutic approach is based on the fact that anti-angiogenic drugs can make tumors hypoxic, and thus more sensitive to PIM inhibitors. Experimental Design: Xenograft and orthotopic models of prostate and colon cancer were used to assess the effect of PIM activation on the efficacy of VEGF-targeting agents. Immunohistochemistry and in vivo imaging were used to analyze angiogenesis, apoptosis, proliferation, and metastasis. Biochemical studies were performed to characterize the novel signaling pathway linking PIM and HIF-1. Results: PIM was upregulated following treatment with anti-VEGF therapies, and PIM1 overexpression reduced the ability of these drugs to disrupt vasculature and block tumor growth. PIM inhibitors reduced HIF-1 activity, opposing the shift to a pro-angiogenic gene signature associated with hypoxia. Combined inhibition of PIM and VEGF produced a synergistic anti-tumor response characterized by decreased proliferation, reduced tumor vasculature, and decreased metastasis. Conclusions: This study describes PIM kinase expression as a novel mechanism of resistance to anti-angiogenic agents. Our data provide justification for combining PIM and VEGF inhibitors to treat solid tumors. The unique ability of PIM inhibitors to concomitantly target HIF-1 and selectively kill hypoxic tumor cells addresses two major components of tumor progression and therapeutic resistance.

http://ift.tt/2yigf5t

Inhibition of REDD1 sensitizes bladder urothelial carcinoma to paclitaxel by inhibiting autophagy

Purpose: Regulated in development and DNA damage response-1 (REDD1) is a stress related protein and is involved in the progression of cancer. The role and regulatory mechanism of REDD1 in bladder urothelial carcinoma (BUC), however, is yet unidentified. Experimental Design: The expression of REDD1 in BUC was detected by western blot and immunohistochemistry. The correlation between REDD1 expression and clinical features in BUC patients were assessed. The effects of REDD1 on cellular proliferation, apoptosis, autophagy, and paclitaxel sensitivity were determined both in vitro and in vivo. Then the targeted-regulating mechanism of REDD1 by microRNAs was explored. Results: Here the significant increase of REDD1 expression is detected in BUC tissue, and REDD1 is firstly reported as an independent prognostic factor in BUC patients. Silencing REDD1 expression in T24 and EJ cells decreased cell proliferation, increased apoptosis, and decreased autophagy, whereas the ectopic expression of REDD1 in RT4 and BIU87 cells had the opposite effect. Additionally, the REDD1-mediated proliferation, apoptosis, and autophagy are found to be negatively regulated by miR-22 in vitro, which intensify the paclitaxel sensitivity via inhibition of the well-acknowledged REDD1-EEF2K-autophagy axis. AKT/mTOR signaling initially activated or inhibited in response to silencing or enhancing REDD1 expression and then recovered rapidly. Lastly, the inhibited REDD1 expression by either RNAi or miR-22 sensitizes BUC tumor cells to paclitaxel in a subcutaneous transplant sarcoma model in vivo. Conclusion: REDD1 is confirmed as an oncogene in BUC, and antagonizing REDD1 could be a potential therapeutic strategy to sensitize BUC cells to paclitaxel.

http://ift.tt/2luw3fr

Targeting CDH17 in cancer: when blocking the ligand beats blocking the receptor?

Cadherin-17 (CDH17) has been implicated as pro-tumorigenic for many years but mechanisms have been unclear. A Spanish team have generated antibodies to an RGD-motif in CDH17 that inhibits integrin α2β1 binding to CDH17 and thereby inhibits integrin activation, tumorigenesis and metastasis. These reagents may have therapeutic potential.

http://ift.tt/2yfC0CR

Intensity-based dual model method for generation of synthetic CT images from standard T2-weighted MR images – Generalized technique for four different MR scanners

Recent studies have shown that it is possible to conduct entire radiotherapy treatment planning (RTP) workflow using only MR images. This study aims to develop a generalized intensity-based method to generate synthetic CT (sCT) images from standard T2-weighted (T2w) MR images of the pelvis.

http://ift.tt/2igL9Al

Acute Hematogenous Osteomyelitis in a Five-Month-Old Male with Rickets

Osteomyelitis is defined as an infection of the bone, bone marrow, and the surrounding soft tissues. Most cases of acute hematogenous osteomyelitis in children are caused by Gram-positive bacteria, principally Staphylococcus aureus. We present a case where a 5-month-old male had an acute onset of decreased movement of his left leg and increased irritability and was subsequently diagnosed with rickets and hematogenous osteomyelitis with bacteremia. The case explores a possible association between hematogenous osteomyelitis and rickets.

http://ift.tt/2xCAF53

Effect of Peroral Administration of Chromium on Insulin Signaling Pathway in Skeletal Muscle Tissue of Holstein Calves

Abstract

The objective of this study was to investigate the effects of peroral administration of chromium-enriched yeast on glucose tolerance in Holstein calves, assessed by insulin signaling pathway molecule determination and intravenous glucose tolerance test (IVGTT). Twenty-four Holstein calves, aged 1 month, were chosen for the study and divided into two groups: the PoCr group (n = 12) that perorally received 0.04 mg of Cr/kg of body mass daily, for 70 days, and the NCr group (n = 12) that received no chromium supplementation. Skeletal tissue samples from each calf were obtained on day 0 and day 70 of the experiment. Chromium supplementation increased protein content of the insulin β-subunit receptor, phosphorylation of insulin receptor substrate 1 at Tyrosine 632, phosphorylation of Akt at Serine 473, glucose transporter-4, and AMP-activated protein kinase in skeletal muscle tissue, while phosphorylation of insulin receptor substrate 1 at Serine 307 was not affected by chromium treatment. Results obtained during IVGTT, which was conducted on days 0, 30, 50, and 70, suggested an increased insulin sensitivity and, consequently, a better utilization of glucose in the PoCr group. Lower basal concentrations of glucose and insulin in the PoCr group on days 30 and 70 were also obtained. Our results indicate that chromium supplementation improves glucose utilization in calves by enhancing insulin intracellular signaling in the skeletal muscle tissue.

http://ift.tt/2gY8aLZ

Tracing Tellurium and Its Nanostructures in Biology

Abstract

Tellurium (Te) is a semimetal rare element in nature. Together with oxygen, sulfur (S), and selenium (Se), Te is considered a member of chalcogen group. Over recent decades, Te applications continued to emerge in different fields including metallurgy, glass industry, electronics, and applied chemical industries. Along these lines, Te has recently attracted research attention in various fields. Though Te exists in biologic organisms such as microbes, yeast, and human body, its importance and role and some of its potential implications have long been ignored. Some promising applications of Te using its inorganic and organic derivatives including novel Te nanostructures are being introduced. Before discovery and straightforward availability of antibiotics, Te had considered and had been used as an antibacterial element. Antilishmaniasis, antiinflammatory, antiatherosclerotic, and immuno-modulating properties of Te have been described for many years, while the innovative applications of Te have started to emerge along with nanotechnological advances over the recent years. Te quantum dots (QDs) and related nanostructures have proposed novel applications in the biological detection systems such as biosensors. In addition, Te nanostructures are used in labeling, imaging, and targeted drug delivery systems and are tested for antibacterial or antifungal properties. In addition, Te nanoparticles show novel lipid-lowering, antioxidant, and free radical scavenging properties. This review presents an overview on the novel forms of Te, their potential applications, as well as related toxicity profiles.

http://ift.tt/2yZbAoy

Protective Effect of Selenium on Aflatoxin B1-Induced Testicular Toxicity in Mice

Abstract

Aflatoxins have been considered as one of the major risk factors of male infertility, and aflatoxin B1 (AFB1) is the most highly toxic and prevalent member of the aflatoxins family. Selenium (Se), an essential nutritional trace mineral for normal testicular development and male fertility, has received extensive intensive on protective effects of male reproductive system due to its potential antioxidant and activating testosterone synthesis. To investigate the protective effect of Se on AFB1-induced testicular toxicity, the mice were orally administered with AFB1 (0.75 mg/kg) and Se (0.2 mg/kg or 0.4 mg/kg) for 45 days. We found that that Se elevated testes index, sperm functional parameters (concentration, malformation, and motility), and the level of serum testosterone in AFB1-exposed mice. Moreover, our results showed that Se attenuated the AFB1-induced oxidative stress and the reduction of testicular testosterone synthesis enzyme protein expression such as steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage (P450scc), and 17β-hydroxysteroid dehydrogenase (17β-HSD) in AFB1-exposed mice. These results demonstrated that Se conferred protection against AFB1-induced testicular toxicity and can be attributed to its antioxidant and increased testosterone level by stimulating protein expression of StAR and testosterone synthetic enzymes.

http://ift.tt/2gY84E7

Content of Minerals and Fatty Acids and Their Correlation with Phytochemical Compounds and Antioxidant Activity of Leguminous Seeds

Abstract

The aim of the study was to determine the mineral composition and fatty acid profile in the seeds of selected Fabaceae species and cultivars and to assess their correlations with phytochemicals and antioxidant activity. The Andean lupine was characterised by a particularly high level of Mg and K as well as Cu, Zn, and Fe (P < 0.05). There were various correlations (P < 0.05) between the total phenols and tannins and these elements. The highest contribution of α-linolenic acid (ALA, 18:3, n-3) in total fatty acids was noted in the lentil (13.8 in 100 g⁻¹ fat), common bean (11.9 in 100 g⁻¹ fat), and pea seeds (10.4 in 100 g⁻¹ fat) (P = 0.028). In turn, the white lupine contained the highest content of ALA—0.67 g 100 g⁻¹ seeds; its lowest level was determined in the broad bean—0.03 g 100 g⁻¹ seeds. The seeds exhibited a high proportion of hypocholesterolemic fatty acids (on average 86%). The 2,2-diphenyl-1-picrylhydrazyl antiradical activity was positively correlated with UFA and PUFA (P < 0.05). This indicates great protective potential of legume seeds for prevention and treatment of diet-dependent diseases.

http://ift.tt/2yYbttn

Attenuating Effect of Zinc and Vitamin E on the Intestinal Oxidative Stress Induced by Silver Nanoparticles in Broiler Chickens

Abstract

Silver nanoparticles (AgNPs) have been increasingly used as antimicrobial and disinfectant. However, intestinal model studies have shown that AgNPs induce oxidative stress. Hence, this study aims to investigate the effects of dietary supplemental zinc (Zn) and vitamin E (VE; α-tocopherol acetate) on attenuating AgNP-induced intestinal oxidative stress in broiler chickens. The chickens were divided into two groups as follows: (1) control group fed with a corn–soybean meal basal diet and (2) nano group, received drinking water containing 1000 mg/kg AgNPs. All the nano-exposed birds were divided into six dietary treatment groups, namely, the basal diets supplemented with (1) 60 mg/kg Zn as ZnSO₄, (2) 120 mg/kg Zn, (3) 100 mg/kg VE, (4) 200 mg/kg VE, (5) 60 mg/kg Zn and 100 mg/kg VE, and (6) 120 mg/kg Zn and 200 mg/kg VE. Results showed that the AgNPs significantly reduced the body weights of the broilers after 42 days of oral administration of AgNPs (P < 0.05), and this effect was not alleviated by any of the dietary treatments. The activity of superoxide dismutase (CuZn-SOD) increased in all the AgNP-treated birds (P < 0.05); however, CuZn-SOD did not increase in birds fed with basal diet supplemented with 200 mg/kg VE. In this treatment, the VE exerted an antioxidant effect to prevent the activation of the CuZn-SOD enzyme. Furthermore, supplementing Zn increased the activities of catalase and glutathione peroxidase in the jejunal mucosa (P < 0.05), which were accompanied with increased malondialdehyde levels (P < 0.05) in the broilers. AgNP exposure resulted in a significant messenger RNA (mRNA) upregulation of toll-like receptor 4 (TLR4) and TLR2-1 in the jejunal mucosa (P < 0.05). However, supplemental ZnVE did not reduce TLRs' mRNA expression, except for the diminished TLR2-1 mRNA levels in birds fed with basal diet supplemented with 120 mg/kg Zn and 200 mg/kg VE. We concluded that although dietary Zn and VE supplementation did not attenuate growth depression effect of AgNP, it however attenuates intestinal oxidative stress in AgNP-treated broiler chickens.

http://ift.tt/2gY81rV

Effects of Ag Nanoparticles on Growth and Fat Body Proteins in Silkworms ( Bombyx mori )

Abstract

Ag nanoparticles (AgNPs), a widely used non-antibiotic, antibacterial material, have shown toxic and other potentially harmful effects in mammals. However, the deleterious effects of AgNPs on insects are still unknown. Here, we studied the effects of AgNPs on the model invertebrate organism Bombyx mori. After feeding silkworm larvae different concentrations of AgNPs, we evaluated the changes of B. mori body weights, survival rates, and proteomic differences. The results showed that low concentrations (<400 mg/L) of AgNPs promoted the growth and cocoon weights of B. mori. Although high concentrations (≥800 mg/L) of AgNPs also improved B. mori growth, they resulted in silkworm death. An analysis of fat body proteomic differences revealed 13 significant differences in fat body protein spots, nine of which exhibited significantly downregulated expression, while four showed significantly upregulated expression. Reverse transcription–polymerase chain reaction results showed that at an AgNP concentration of 1600 mg/L, the expression levels of seven proteins were similar to the transcription levels of their corresponding genes. Our results suggest that AgNPs lowered the resistance to oxidative stress, affected cell apoptosis, and induced cell necrosis by regulating related protein metabolism and metabolic pathways in B. mori.

http://ift.tt/2yZbA82

Ameliorated Effects of (−)-Epigallocatechin Gallate Against Toxicity Induced by Vanadium in the Kidneys of Wistar Rats

Abstract

The aim of the study was to assess the protective effect of (−)-epigallocatechin gallate (EGCG), a flavonoid abundant in green tea, against ammonium metavanadate (AMV)-induced oxidative stress in male Wistar rats. Four groups of animals have been used, a control group and three test groups. In the first test group, AMV was intra-peritoneally (i.p) injected daily (5 mg/kg body weight for five consecutive days). The second test group of animals was also injected daily with EGCG (5 mg/kg body weight) during the same period. However, the third test group was i.p. injected with both AMV and EGCG (5 mg/kg body weight for five consecutive days). When given alone, AMV induced an oxidative stress evidenced by an increase of lipid peroxidation levels (expressed as TBARS concentration) in kidney. In these animals, activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were significantly decreased, suggesting significant reduction of the antioxidant defense system at the cell level. Kidney histological sections, showed glomerular hypertrophy and tubular dilatation. In AMV-treated animals receiving EGCG, the oxidative stress was much less pronounced and activities of antioxidant enzymes were kept close to control values. Histopathological changes were less prominent. Our results confirm that green tea and other sources of flavonoids might confer a strong protection against ammonium metavanadate-induced oxidative stress.

http://ift.tt/2gWMS1c

Hypoglycemic and Hypolipidemic Effects of Leucine, Zinc, and Chromium, Alone and in Combination, in Rats with Type 2 Diabetes

Abstract

For the increasing development of diabetes, dietary habits and using appropriate supplements can play important roles in the treatment or reduction of risk for this disease. The objective of this study was to investigate the effects of leucine (Leu), zinc (Zn), and chromium (Cr) supplementation, alone or in combination, in rats with type 2 diabetes (T2D). Seventy-seven adult male Wistar rats were randomly assigned in 11 groups, using nutritional supplements and insulin (INS) or glibenclamide (GLC). Supplementing Leu significantly reduced blood glucose, triglycerides (TG), nonesterified fatty acids (NEFA), low-density lipoprotein (LDL), and increased high-density lipoprotein (HDL) concentrations compared to vehicle-treated T2D animals, and those improvements were associated with reduced area under the 2-h blood glucose response curve (AUC). Supplementation of T2D animals with Zn improved serum lipid profile as well as blood glucose concentrations but was not comparable with the INS, GLC, and Leu groups. Supplementary Cr did not improve blood glucose and AUC in T2D rats, whereas it reduced serum TG and LDL and increased HDL concentrations. In conclusion, supplementation of diabetic rats with Leu was more effective in improving blood glucose and consequently decreasing glucose AUC than other nutritional supplements. Supplementary Zn and Cr only improved serum lipid profile. The combination of the nutritional supplements did not improve blood glucose level. Nevertheless, supplementation with Leu-Zn, Leu-Cr, Zn-Cr, and Leu-Zn-Cr led to an improved response in serum lipid profile over each supplement given alone.

http://ift.tt/2yY23hF

Do Dietary Habits Influence Trace Elements Release from Fixed Orthodontic Appliances?

Abstract

The objective was to investigate the effect of dietary habits on the release of Cr and Ni ions from orthodontic appliances by hair mineral analysis. Patients (N = 47) underwent electronic questionnaire survey to investigate the effect of dietary habits on Cr and Ni levels in hair. The research was carried out on hair sampled at the beginning and in the 4th, 8th, and 12th months of the treatment. The content of Cr and Ni in the collected samples was determined by ICP-OES. The study showed that consumption of acidic dietary products may have the effect on increasing the release of Cr and Ni ions from orthodontic appliances. The release of Cr from orthodontic appliances in patients who consumed fruit juice, coffee, yoghurt, and vinegar was higher. The coefficients enabling comparison of metal ions release pattern at a given sampling points were defined. The comparison of the coefficients yielded the information on the possible magnification of metal ions released as the result of the additional factor consumption of acidic food or drink that intensifies metal ions release. The following magnification pattern was found for chromium: coffee (7.57 times) > yoghurt (2.53) > juice (1.86) > vinegar (1.08), and for nickel: vinegar (2.2) > coffee (1.22) > juice (1.05). Yoghurt did not intensify the release of nickel. Concluding, orthodontic patients should avoid drinking/eating coffee, yoghurt, fruit juices, and vinegar.

http://ift.tt/2gXSmce

Excess Manganese-Induced Apoptosis in Chicken Cerebrums and Embryonic Neurocytes

Abstract

There were many studies about the effect of excess manganese (Mn) on nervous system apoptosis; however, Mn-induced apoptosis in chicken cerebrums and embryonic neurocytes was unclear. The purpose of this study was to investigate the effect of excess Mn on chicken cerebrum and embryonic neurocyte apoptosis. Seven-day-old Hyline male chickens were fed either a commercial diet or three levels of manganese chloride (MnCl₂)-added commercial diets containing 600-, 900-, and 1800-mg/kg-Mn diet, respectively. On the 30th, 60th, and 90th days, cerebrums were collected. Fertilized Hyline chicken eggs were hatched for 6–8 days and were selected. Embryonic neurocytes with 0, 0.5, 1, 1.5, 2, 2.5, and 3 mM Mn were collected and were cultured for 12, 24, 36, and 48 h, respectively. The following research contents were performed: superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) activities; tumor protein p53 (p53), B cell lymphoma-2 (Bcl-2), B cell lymphoma extra large (Bcl-x), Bcl-2-associated X protein (Bax), Bcl-2 homologous antagonist/killer (Bak), fas, and caspase-3 messenger RNA (mRNA) expression; and morphologic observation. The results indicated that excess Mn inhibited SOD and T-AOC activities; induced p53, Bax, Bak, fas, and caspase-3 mRNA expression; and inhibited Bcl-2 and Bcl-x mRNA expression in chicken cerebrums and embryonic neurocytes. There were dose-dependent manners on all the above factors at all the time points and time-dependent manners on SOD activity of 1800-mg/kg-Mn group, T-AOC activity, and apoptosis-related gene mRNA expression in all the treatment groups in chicken cerebrums. Excess Mn induced chicken cerebrum and embryonic neurocyte apoptosis.

http://ift.tt/2yZYAPD

Boric Acid Inhibition of Trichophyton rubrum Growth and Conidia Formation

Abstract

Trichophyton rubrum is a common human dermatophyte that is the causative agent of 80–93% of fungal infections of the skin and nails. While dermatophyte infections in healthy people are easily treatable with over-the-counter medications, such infections pose a higher risk for patients with compromised immune function and impaired regenerative potential. The efficacy of boric acid (BA) for the treatment of vaginal yeast infections prompted an investigation of the effect of BA on growth and morphology of T. rubrum. This is of particular interest since BA facilitates wound healing, raising the possibility that treating athlete's foot with BA, either alone or in combination with other antifungal drugs, would combine the benefits of antimicrobial activity and tissue regeneration to accelerate healing of infected skin. The data presented here show that BA represses T. rubrum growth at a concentration reported to be beneficial for host tissue regeneration. Oxygen exposure increases BA toxicity, and mycelia growing under BA stress avoid colonizing the surface of the growth surface, which leads to a suppression of aerial mycelium growth and surface conidia formation. BA penetrates into solid agar matrices, but the relative lack of oxygen below the substrate surface limits the effectiveness of BA in suppressing growth of embedded T. rubrum cells.

http://ift.tt/2gXSeJM

Evaluation of the Content of Antimony, Arsenic, Bismuth, Selenium, Tellurium and Their Inorganic Forms in Commercially Baby Foods

Abstract

Baby foods, from the Spanish market and prepared from meat, fish, vegetables, cereals, legumes, and fruits, were analyzed to obtain the concentration of antimony (Sb), arsenic (As), bismuth (Bi), and tellurium (Te) as toxic elements and selenium (Se) as essential element. An analytical procedure was employed based on atomic fluorescence spectroscopy which allowed to obtain accurate data at low levels of concentration. Values of 14 commercial samples, expressed in nanograms per gram fresh weight, ranged for Sb 0.66–6.9, As 4.5–242, Te 1.35–2.94, Bi 2.18–4.79, and Se 5.4–109. Additionally, speciation studies were performed based on data from a non-chromatographic screening method. It was concluded that tellurium and bismuth were mainly present as inorganic forms and selenium as organic form, and antimony and arsenic species depend on the ingredients of each baby food. Risk assessment considerations were made by comparing dietary intake of the aforementioned elements through the consumption of one baby food portion a day and recommended or tolerable guideline values.

http://ift.tt/2yYbuxr

Effects of the Oral Administration of K 2 Cr 2 O 7 and Na 2 SeO 3 on Ca, Mg, Mn, Fe, Cu, and Zn Contents in the Heart, Liver, Spleen, and Kidney of Chickens

Abstract

This study aimed to investigate the effects of selenium on the ion profiles in the heart, liver, spleen, and kidney through the oral administration of hexavalent chromium. Approximately 22.14 mg/kg b.w. K₂Cr₂O₇ was added to water to establish a chronic poisoning model. Different selenium levels (0.00, 0.31, 0.63, 1.25, 2.50, and 5.00 mg Na₂SeO₃/kg b.w.) around the safe dose were administered to the experimental group model. Ca, Mg, Mn, Fe, Cu, and Zn were detected in the organs through flame atomic absorption spectrometry after these organs were exposed to K₂Cr₂O₇ and Na₂SeO₃ for 14, 28, and 42 days. Results showed that these elements exhibited various changes. Ca contents declined in the heart, liver, and spleen. Ca contents also decreased on the 28th day and increased on the 42nd day in the kidney. Mn contents declined in the heart and spleen but increased in the kidney. Mn contents also decreased on the 28th day and increased on the 42nd day in the liver. Cu contents declined in the heart and spleen. Cu contents increased on the 28th day and decreased on the 42nd day in the liver and kidney. Zn contents declined in the heart and spleen. Zn contents increased on the 28th day and decreased on the 42nd day in the liver and kidney. Fe contents decreased in the heart and liver. Fe contents increased on the 28th day and decreased on the 42nd day in the spleen and kidney. Mg contents did not significantly change in these organs. Appropriate selenium contents enhanced Mn and Zn contents, which were declined by chromium. Conversely, appropriate selenium contents reduced Ca, Fe, and Cu contents, which were increased by chromium. In conclusion, the exposure of chickens to K₂Cr₂O₇ induced changes in different trace elements, and Na₂SeO₃ supplementation could alleviate this condition.

http://ift.tt/2gVIBei

Effects of Zinc and N -Acetylcysteine in Damage Caused by Lead Exposure in Young Rats

Abstract

This study investigated the toxicity of rats exposed to lead acetate (AcPb) during the second phase of brain development (8–12 days postnatal) in hematological and cerebral parameters. Moreover, the preventive effect of zinc chloride (ZnCl₂) and N-acetylcysteine (NAC) was investigated. Pups were injected subcutaneously with saline (0.9% NaCl solution), ZnCl₂ (27 mg/kg/day), NAC (5 mg/kg/day) or ZnCl₂ plus NAC for 5 days (3rd–7th postnatal days), and with saline (0.9% NaCl solution) or AcPb (7 mg/kg/day) in the five subsequent days (8th–12th postnatal days). Animals were sacrificed 21 days after the last AcPb exposure. Pups exposed to AcPb presented inhibition of blood porphobilinogen-synthase (PBG-synthase) activity without changes in hemoglobin content. ZnCl₂ pre-exposure partially prevented PBG-synthase inhibition. Regarding neurotoxicity biomarkers, animals exposed to AcPb presented a decrease in cerebrum acetylcholinesterase (AChE) activity and an increase in Pb accumulation in blood and cerebrum. These changes were prevented by pre-treatment with ZnCl₂, NAC, and ZnCl₂ plus NAC. AcPb exposure caused no alteration in behavioral tasks. In short, results show that AcPb inhibited the activity of two important enzymatic biomarkers up to 21 days after the end of the exposure. Moreover, ZnCl₂ and NAC prevented the alterations induced by AcPb.

http://ift.tt/2yZqiw2

Iodinated TG in Thyroid Follicles Regulate TSH/TSHR Signaling for NIS Expression

Abstract

Our previous research has suggested that high degree of iodinated thyroglobulin (TG) may inhibit the expression and function of sodium iodide symporter (NIS), but the underlying mechanism remains unclear. In present study, we discuss a newly constructed follicle model in vitro, which was used to simulate the follicular structure of the thyroid and explore the regulatory roles of iodinated TG in the follicular lumen on NIS expression. The results showed that both NIS expression and PKA activity were increased in lowly iodinated TG group, while decreased NIS expression with increased PKC activity was found in highly iodinated TG group. Also, NIS expression was increased in PKA agonist-treated group, while decreased NIS was found in PKC agonist-treated group. Moreover, when the PLC-PKC pathway was blocked by PKC-specific inhibitor, highly iodinated TG significantly promoted the expression of NIS. However, when the cAMP-PKA pathway was blocked by a PKA-specific blocker, highly iodinated TG slightly suppressed NIS expression. TG with a low degree of iodination had the reverse effect on NIS. When the PLC-PKC pathway was blocked, TG with a low degree of iodination slightly promoted NIS expression. However, when the cAMP-PKA pathway was blocked, TG with a low degree of iodination greatly inhibited NIS expression. All these suggested that iodinated TG inhibited the expression of NIS by PLC-PKC pathway and promoted NIS expression via the cAMP-PKA pathway. When highly iodinated TG was present, the PLC-PKC pathway became dominant. In the presence of lowly iodinated TG, the cAMP-PKA became the major pathway.

http://ift.tt/2gXRXGK

Bioaccumulation of Heavy Metals in Various Tissues of Some Fish Species and Green Tiger Shrimp ( Penaeus semisulcatus ) from İskenderun Bay, Turkey, and Risk Assessment for Human Health

Abstract

In this study, concentrations of heavy metals were determined by ICP-MS in the edible tissues of common sole (Solea solea Linnaeus, 1758), whiting (Merlangius merlangus Linnaeus, 1758), silver sillago (Sillago sihama Forsskål, 1775) and muscle-exoskeleton of green tiger shrimp (Penaeus semisulcatus De Haan, 1844), from the seas of İskenderun Bay, Eastern Mediterranean, Turkey, in January–February, 2016. The lowest and highest mean concentrations of Mn, Cr, Cd, Ni, Hg, As, Pb, and Co in fish and shrimp' muscles were found, respectively, as follows: 0.166–0.382, 0.134–0.336, 0.005–0.008, 0.091–0.140, 0.026–0.228, 1.741–29.254, 0.087–0.110, and <0.0005–0.027 mg kg⁻¹; in the skin and exoskeleton, the values were found, respectively, as 0.103–15.819, 0.301–0.778, 0.007–0.026, 0.115–0.513, 0.021–0.243, 1.548–17.930, 0.148–0.295, and <0.0005–0.140 mg kg⁻¹. According to the results, mean concentrations of all metals in the muscles of fish, except for arsenic and chromium, were found to be below certain legal limit values, especially arsenic levels in shrimp that were found to be above all the legal limit values. Also, the hazard quotients (HQ) of individual heavy metals in fish and shrimp, except for As, revealed safe levels for human consumption. However, the HQ values of estimated inorganic As exceeded 1 in the muscles of shrimp (P. semisulcatus), which may constitute a risk to public health.

http://ift.tt/2yZfnlH

Effects of Nano-zinc on Biochemical Parameters in Cadmium-Exposed Rats

Abstract

Cadmium (Cd) is a toxic environmental and occupational pollutant with reported toxic effects on the kidneys, liver, lungs, bones, and the immunity system. Based on its physicochemical similarity to cadmium, zinc (Zn) shows protective effects against cadmium toxicity and cadmium accumulation in the body. Nano-zinc and nano-zinc oxide (ZnO), recently used in foods and pharmaceutical products, can release a great amount of Zn²⁺ in their environment. This research was carried out to investigate the more potent properties of the metal zinc among sub-acute cadmium intoxicated rats. Seventy-five male Wistar rats were caged in 15 groups. Cadmium chloride (CdCl₂) was used in drinking water to induce cadmium toxicity. Different sizes (15, 20, and 30 nm) and doses of nano-zinc particles (3, 10, 100 mg/kg body weight [bw]) were administered solely and simultaneously with CdCl₂ (2–5 mg/kg bw) for 28 days. The experimental animals were decapitated, and the biochemical biomarkers (enzymatic and non-enzymatic) were determined in their serum after oral exposure to nano-zinc and cadmium. Statistical analysis was carried out with a one-way ANOVA and t test. P < 0.05 was considered as statistically significant. The haematocrit (HCT) significantly increased and blood coagulation time significantly reduced in the nano-zinc-treated rats. AST, ALT, triglyceride, total cholesterol, LDL, and free fatty acids increased significantly in the cadmium- and nano-zinc-treated rats compared with the controls. However, albumin, total protein, and HDLc significantly decreased in the cadmium- and nano-zinc-treated rats compared with the controls (P < 0.05). It seems that in the oral administration of nano-zinc, the smaller sizes with low doses and the larger sizes with high doses are more toxic than metallic zinc. In a few cases, an inverse dose-dependent relationship was seen as well. This research showed that in spite of larger sizes of zinc, smaller sizes of nano-zinc particles are not suitable for protection against cadmium intoxication.

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Disparities of Selected Metal Levels in the Blood and Scalp Hair of Ischemia Heart Disease Patients and Healthy Subjects

Abstract

Imbalances in the concentrations of trace metals have become an increasingly recognized source of infirmity worldwide particularly in the development of ischemia heart disease (IHD). Present study is intended to analyze the concentrations of Ca, Cd, Co, Cr, Cu, Fe, K, Li, Mg, Mn, Na, Pb, Sr, and Zn in the blood and scalp hair of the patients and counterpart controls by flame atomic absorption spectrometry after wet-acid digestion. On the average, Cd, Co, Cr, Fe, K, Li, Mn, Na, and Pb revealed significantly elevated concentrations in the blood of the patients compared with the controls (p < 0.05), whereas mean levels of Ca, Cd, Fe, K, Li, Pb, and Sr in the scalp hair were significantly higher in the patients than the controls (p < 0.05). Most of the metals exhibited noticeable disparities in their concentrations based on gender, abode, dietary/smoking habits, and occupations of both donor groups. The correlation study and multivariate statistical analyses revealed some significantly divergent associations and apportionment of the metals in both donor groups. Overall, comparative variations of the metal contents in blood/scalp hair of the patients were significantly different than the controls; thus, evaluation of trace metals status may be indicative of pathological disorders, such as IHD.

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Synergistic Cardioprotective Effects of Combined Chromium Picolinate and Atorvastatin Treatment in Triton X-100-Induced Hyperlipidemia in Rats: Impact on Some Biochemical Markers

Abstract

Hyperlipidemia is one of the major risk factors for atherosclerosis and ischemic heart disease. Chromium (Cr) mineral is playing a crucial role in glucose and lipid homeostasis. The aim of this study was to evaluate the protective effects of combined chromium picolinate (CrPic) and atorvastatin treatment against hyperlipidemia-induced cardiac injury. Seventy-five male albino rats were divided into five groups (15 rats each). Hyperlipidemia was induced by intraperitoneal injection of a single dose of Triton X-100 (300 mg/kg body weight (b.w) (group ІІ). Treatment of hyperlipidemic rats was induced by daily administration of CrPic at a dose of 200 μg/kg b.w/day (group ІІІ), atorvastatin at a dose of 10 mg/kg/day (group IV), and combined treatment with both (group V) by gavage for 7 days. At the end of experiment, serum and heart tissues were obtained. Hyperlipidemia was confirmed by histopathology of heart tissues, marked serum dyslipidemia, increased atherogenic indices, and values of ischemia-modified albumin. In addition to increased values of proprotein convertase subtilisin/kexin type 9, activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase enzyme and high relative expression levels of pentraxin-3 were observed. However, paraoxonase-1 activity was markedly decreased in the hyperlipidemic group. Significant improvement in all assessed parameters was observed in the rat group treated with both CrPic and atorvastatin. It can be concluded that combined CrPic and atorvastatin treatments had synergistic cardioprotective effects against hyperlipidemia which may be through modulating atherosclerosis as well as cardiac and aortic damage and/or activation of anti-inflammatory and anti-oxidant pathways, thus reversing endothelial dysfunction.

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Serum Hepcidin and Soluble Transferrin Receptor in the Assessment of Iron Metabolism in Children on a Vegetarian Diet

Abstract

The aim of this study was to assess the effect of vegetarian diet on iron metabolism parameters paying special attention to serum hepcidin and soluble transferrin receptor (sTfR) concentrations in 43 prepubertal children (age range 4.5–9.0 years) on vegetarian and in 46 children on omnivorous diets. There were no significant differences according to age, weight, height, and body mass index (BMI) between vegetarian and omnivorous children. Vegetarians had similar intake of iron and vitamin B₁₂ and a significantly higher intake of vitamin C (p < 0.05) compared with non-vegetarians. Hematologic parameters and serum iron concentrations were within the reference range in both groups of children. Serum transferrin levels were similar in all subjects; however, ferritin concentrations were significantly (p < 0.01) lower in vegetarians than in omnivores. In children on a vegetarian diet, median hepcidin levels were lower (p < 0.05) but sTfR concentrations significantly higher (p < 0.001) compared with omnivorous children. In the multivariate regression model, we observed associations between hepcidin level and ferritin concentration (β = 0.241, p = 0.05) in the whole group of children as well as between hepcidin concentration and CRP level (β = 0.419, p = 0.047) in vegetarians. We did not find significant associations with concentration of sTfR and selected biochemical, anthropometric, and dietary parameters in any of the studied groups of children. As hematologic parameters and iron concentrations in vegetarians and omnivores were comparable and ferritin level was lower in vegetarians, we suggest that inclusion of novel markers, in particular sTfR (not cofounded by inflammation) and hepcidin, can better detect subclinical iron deficiency in children following vegetarian diets.

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Effect of Peroral Administration of Chromium on Insulin Signaling Pathway in Skeletal Muscle Tissue of Holstein Calves

Abstract

The objective of this study was to investigate the effects of peroral administration of chromium-enriched yeast on glucose tolerance in Holstein calves, assessed by insulin signaling pathway molecule determination and intravenous glucose tolerance test (IVGTT). Twenty-four Holstein calves, aged 1 month, were chosen for the study and divided into two groups: the PoCr group (n = 12) that perorally received 0.04 mg of Cr/kg of body mass daily, for 70 days, and the NCr group (n = 12) that received no chromium supplementation. Skeletal tissue samples from each calf were obtained on day 0 and day 70 of the experiment. Chromium supplementation increased protein content of the insulin β-subunit receptor, phosphorylation of insulin receptor substrate 1 at Tyrosine 632, phosphorylation of Akt at Serine 473, glucose transporter-4, and AMP-activated protein kinase in skeletal muscle tissue, while phosphorylation of insulin receptor substrate 1 at Serine 307 was not affected by chromium treatment. Results obtained during IVGTT, which was conducted on days 0, 30, 50, and 70, suggested an increased insulin sensitivity and, consequently, a better utilization of glucose in the PoCr group. Lower basal concentrations of glucose and insulin in the PoCr group on days 30 and 70 were also obtained. Our results indicate that chromium supplementation improves glucose utilization in calves by enhancing insulin intracellular signaling in the skeletal muscle tissue.

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Tracing Tellurium and Its Nanostructures in Biology

Abstract

Tellurium (Te) is a semimetal rare element in nature. Together with oxygen, sulfur (S), and selenium (Se), Te is considered a member of chalcogen group. Over recent decades, Te applications continued to emerge in different fields including metallurgy, glass industry, electronics, and applied chemical industries. Along these lines, Te has recently attracted research attention in various fields. Though Te exists in biologic organisms such as microbes, yeast, and human body, its importance and role and some of its potential implications have long been ignored. Some promising applications of Te using its inorganic and organic derivatives including novel Te nanostructures are being introduced. Before discovery and straightforward availability of antibiotics, Te had considered and had been used as an antibacterial element. Antilishmaniasis, antiinflammatory, antiatherosclerotic, and immuno-modulating properties of Te have been described for many years, while the innovative applications of Te have started to emerge along with nanotechnological advances over the recent years. Te quantum dots (QDs) and related nanostructures have proposed novel applications in the biological detection systems such as biosensors. In addition, Te nanostructures are used in labeling, imaging, and targeted drug delivery systems and are tested for antibacterial or antifungal properties. In addition, Te nanoparticles show novel lipid-lowering, antioxidant, and free radical scavenging properties. This review presents an overview on the novel forms of Te, their potential applications, as well as related toxicity profiles.

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Protective Effect of Selenium on Aflatoxin B1-Induced Testicular Toxicity in Mice

Abstract

Aflatoxins have been considered as one of the major risk factors of male infertility, and aflatoxin B1 (AFB1) is the most highly toxic and prevalent member of the aflatoxins family. Selenium (Se), an essential nutritional trace mineral for normal testicular development and male fertility, has received extensive intensive on protective effects of male reproductive system due to its potential antioxidant and activating testosterone synthesis. To investigate the protective effect of Se on AFB1-induced testicular toxicity, the mice were orally administered with AFB1 (0.75 mg/kg) and Se (0.2 mg/kg or 0.4 mg/kg) for 45 days. We found that that Se elevated testes index, sperm functional parameters (concentration, malformation, and motility), and the level of serum testosterone in AFB1-exposed mice. Moreover, our results showed that Se attenuated the AFB1-induced oxidative stress and the reduction of testicular testosterone synthesis enzyme protein expression such as steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage (P450scc), and 17β-hydroxysteroid dehydrogenase (17β-HSD) in AFB1-exposed mice. These results demonstrated that Se conferred protection against AFB1-induced testicular toxicity and can be attributed to its antioxidant and increased testosterone level by stimulating protein expression of StAR and testosterone synthetic enzymes.

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Content of Minerals and Fatty Acids and Their Correlation with Phytochemical Compounds and Antioxidant Activity of Leguminous Seeds

Abstract

The aim of the study was to determine the mineral composition and fatty acid profile in the seeds of selected Fabaceae species and cultivars and to assess their correlations with phytochemicals and antioxidant activity. The Andean lupine was characterised by a particularly high level of Mg and K as well as Cu, Zn, and Fe (P < 0.05). There were various correlations (P < 0.05) between the total phenols and tannins and these elements. The highest contribution of α-linolenic acid (ALA, 18:3, n-3) in total fatty acids was noted in the lentil (13.8 in 100 g⁻¹ fat), common bean (11.9 in 100 g⁻¹ fat), and pea seeds (10.4 in 100 g⁻¹ fat) (P = 0.028). In turn, the white lupine contained the highest content of ALA—0.67 g 100 g⁻¹ seeds; its lowest level was determined in the broad bean—0.03 g 100 g⁻¹ seeds. The seeds exhibited a high proportion of hypocholesterolemic fatty acids (on average 86%). The 2,2-diphenyl-1-picrylhydrazyl antiradical activity was positively correlated with UFA and PUFA (P < 0.05). This indicates great protective potential of legume seeds for prevention and treatment of diet-dependent diseases.

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Attenuating Effect of Zinc and Vitamin E on the Intestinal Oxidative Stress Induced by Silver Nanoparticles in Broiler Chickens

Abstract

Silver nanoparticles (AgNPs) have been increasingly used as antimicrobial and disinfectant. However, intestinal model studies have shown that AgNPs induce oxidative stress. Hence, this study aims to investigate the effects of dietary supplemental zinc (Zn) and vitamin E (VE; α-tocopherol acetate) on attenuating AgNP-induced intestinal oxidative stress in broiler chickens. The chickens were divided into two groups as follows: (1) control group fed with a corn–soybean meal basal diet and (2) nano group, received drinking water containing 1000 mg/kg AgNPs. All the nano-exposed birds were divided into six dietary treatment groups, namely, the basal diets supplemented with (1) 60 mg/kg Zn as ZnSO₄, (2) 120 mg/kg Zn, (3) 100 mg/kg VE, (4) 200 mg/kg VE, (5) 60 mg/kg Zn and 100 mg/kg VE, and (6) 120 mg/kg Zn and 200 mg/kg VE. Results showed that the AgNPs significantly reduced the body weights of the broilers after 42 days of oral administration of AgNPs (P < 0.05), and this effect was not alleviated by any of the dietary treatments. The activity of superoxide dismutase (CuZn-SOD) increased in all the AgNP-treated birds (P < 0.05); however, CuZn-SOD did not increase in birds fed with basal diet supplemented with 200 mg/kg VE. In this treatment, the VE exerted an antioxidant effect to prevent the activation of the CuZn-SOD enzyme. Furthermore, supplementing Zn increased the activities of catalase and glutathione peroxidase in the jejunal mucosa (P < 0.05), which were accompanied with increased malondialdehyde levels (P < 0.05) in the broilers. AgNP exposure resulted in a significant messenger RNA (mRNA) upregulation of toll-like receptor 4 (TLR4) and TLR2-1 in the jejunal mucosa (P < 0.05). However, supplemental ZnVE did not reduce TLRs' mRNA expression, except for the diminished TLR2-1 mRNA levels in birds fed with basal diet supplemented with 120 mg/kg Zn and 200 mg/kg VE. We concluded that although dietary Zn and VE supplementation did not attenuate growth depression effect of AgNP, it however attenuates intestinal oxidative stress in AgNP-treated broiler chickens.

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Effects of Ag Nanoparticles on Growth and Fat Body Proteins in Silkworms ( Bombyx mori )

Abstract

Ag nanoparticles (AgNPs), a widely used non-antibiotic, antibacterial material, have shown toxic and other potentially harmful effects in mammals. However, the deleterious effects of AgNPs on insects are still unknown. Here, we studied the effects of AgNPs on the model invertebrate organism Bombyx mori. After feeding silkworm larvae different concentrations of AgNPs, we evaluated the changes of B. mori body weights, survival rates, and proteomic differences. The results showed that low concentrations (<400 mg/L) of AgNPs promoted the growth and cocoon weights of B. mori. Although high concentrations (≥800 mg/L) of AgNPs also improved B. mori growth, they resulted in silkworm death. An analysis of fat body proteomic differences revealed 13 significant differences in fat body protein spots, nine of which exhibited significantly downregulated expression, while four showed significantly upregulated expression. Reverse transcription–polymerase chain reaction results showed that at an AgNP concentration of 1600 mg/L, the expression levels of seven proteins were similar to the transcription levels of their corresponding genes. Our results suggest that AgNPs lowered the resistance to oxidative stress, affected cell apoptosis, and induced cell necrosis by regulating related protein metabolism and metabolic pathways in B. mori.

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Ameliorated Effects of (−)-Epigallocatechin Gallate Against Toxicity Induced by Vanadium in the Kidneys of Wistar Rats

Abstract

The aim of the study was to assess the protective effect of (−)-epigallocatechin gallate (EGCG), a flavonoid abundant in green tea, against ammonium metavanadate (AMV)-induced oxidative stress in male Wistar rats. Four groups of animals have been used, a control group and three test groups. In the first test group, AMV was intra-peritoneally (i.p) injected daily (5 mg/kg body weight for five consecutive days). The second test group of animals was also injected daily with EGCG (5 mg/kg body weight) during the same period. However, the third test group was i.p. injected with both AMV and EGCG (5 mg/kg body weight for five consecutive days). When given alone, AMV induced an oxidative stress evidenced by an increase of lipid peroxidation levels (expressed as TBARS concentration) in kidney. In these animals, activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were significantly decreased, suggesting significant reduction of the antioxidant defense system at the cell level. Kidney histological sections, showed glomerular hypertrophy and tubular dilatation. In AMV-treated animals receiving EGCG, the oxidative stress was much less pronounced and activities of antioxidant enzymes were kept close to control values. Histopathological changes were less prominent. Our results confirm that green tea and other sources of flavonoids might confer a strong protection against ammonium metavanadate-induced oxidative stress.

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Hypoglycemic and Hypolipidemic Effects of Leucine, Zinc, and Chromium, Alone and in Combination, in Rats with Type 2 Diabetes

Abstract

For the increasing development of diabetes, dietary habits and using appropriate supplements can play important roles in the treatment or reduction of risk for this disease. The objective of this study was to investigate the effects of leucine (Leu), zinc (Zn), and chromium (Cr) supplementation, alone or in combination, in rats with type 2 diabetes (T2D). Seventy-seven adult male Wistar rats were randomly assigned in 11 groups, using nutritional supplements and insulin (INS) or glibenclamide (GLC). Supplementing Leu significantly reduced blood glucose, triglycerides (TG), nonesterified fatty acids (NEFA), low-density lipoprotein (LDL), and increased high-density lipoprotein (HDL) concentrations compared to vehicle-treated T2D animals, and those improvements were associated with reduced area under the 2-h blood glucose response curve (AUC). Supplementation of T2D animals with Zn improved serum lipid profile as well as blood glucose concentrations but was not comparable with the INS, GLC, and Leu groups. Supplementary Cr did not improve blood glucose and AUC in T2D rats, whereas it reduced serum TG and LDL and increased HDL concentrations. In conclusion, supplementation of diabetic rats with Leu was more effective in improving blood glucose and consequently decreasing glucose AUC than other nutritional supplements. Supplementary Zn and Cr only improved serum lipid profile. The combination of the nutritional supplements did not improve blood glucose level. Nevertheless, supplementation with Leu-Zn, Leu-Cr, Zn-Cr, and Leu-Zn-Cr led to an improved response in serum lipid profile over each supplement given alone.

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Do Dietary Habits Influence Trace Elements Release from Fixed Orthodontic Appliances?

Abstract

The objective was to investigate the effect of dietary habits on the release of Cr and Ni ions from orthodontic appliances by hair mineral analysis. Patients (N = 47) underwent electronic questionnaire survey to investigate the effect of dietary habits on Cr and Ni levels in hair. The research was carried out on hair sampled at the beginning and in the 4th, 8th, and 12th months of the treatment. The content of Cr and Ni in the collected samples was determined by ICP-OES. The study showed that consumption of acidic dietary products may have the effect on increasing the release of Cr and Ni ions from orthodontic appliances. The release of Cr from orthodontic appliances in patients who consumed fruit juice, coffee, yoghurt, and vinegar was higher. The coefficients enabling comparison of metal ions release pattern at a given sampling points were defined. The comparison of the coefficients yielded the information on the possible magnification of metal ions released as the result of the additional factor consumption of acidic food or drink that intensifies metal ions release. The following magnification pattern was found for chromium: coffee (7.57 times) > yoghurt (2.53) > juice (1.86) > vinegar (1.08), and for nickel: vinegar (2.2) > coffee (1.22) > juice (1.05). Yoghurt did not intensify the release of nickel. Concluding, orthodontic patients should avoid drinking/eating coffee, yoghurt, fruit juices, and vinegar.

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Excess Manganese-Induced Apoptosis in Chicken Cerebrums and Embryonic Neurocytes

Abstract

There were many studies about the effect of excess manganese (Mn) on nervous system apoptosis; however, Mn-induced apoptosis in chicken cerebrums and embryonic neurocytes was unclear. The purpose of this study was to investigate the effect of excess Mn on chicken cerebrum and embryonic neurocyte apoptosis. Seven-day-old Hyline male chickens were fed either a commercial diet or three levels of manganese chloride (MnCl₂)-added commercial diets containing 600-, 900-, and 1800-mg/kg-Mn diet, respectively. On the 30th, 60th, and 90th days, cerebrums were collected. Fertilized Hyline chicken eggs were hatched for 6–8 days and were selected. Embryonic neurocytes with 0, 0.5, 1, 1.5, 2, 2.5, and 3 mM Mn were collected and were cultured for 12, 24, 36, and 48 h, respectively. The following research contents were performed: superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) activities; tumor protein p53 (p53), B cell lymphoma-2 (Bcl-2), B cell lymphoma extra large (Bcl-x), Bcl-2-associated X protein (Bax), Bcl-2 homologous antagonist/killer (Bak), fas, and caspase-3 messenger RNA (mRNA) expression; and morphologic observation. The results indicated that excess Mn inhibited SOD and T-AOC activities; induced p53, Bax, Bak, fas, and caspase-3 mRNA expression; and inhibited Bcl-2 and Bcl-x mRNA expression in chicken cerebrums and embryonic neurocytes. There were dose-dependent manners on all the above factors at all the time points and time-dependent manners on SOD activity of 1800-mg/kg-Mn group, T-AOC activity, and apoptosis-related gene mRNA expression in all the treatment groups in chicken cerebrums. Excess Mn induced chicken cerebrum and embryonic neurocyte apoptosis.

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Boric Acid Inhibition of Trichophyton rubrum Growth and Conidia Formation

Abstract

Trichophyton rubrum is a common human dermatophyte that is the causative agent of 80–93% of fungal infections of the skin and nails. While dermatophyte infections in healthy people are easily treatable with over-the-counter medications, such infections pose a higher risk for patients with compromised immune function and impaired regenerative potential. The efficacy of boric acid (BA) for the treatment of vaginal yeast infections prompted an investigation of the effect of BA on growth and morphology of T. rubrum. This is of particular interest since BA facilitates wound healing, raising the possibility that treating athlete's foot with BA, either alone or in combination with other antifungal drugs, would combine the benefits of antimicrobial activity and tissue regeneration to accelerate healing of infected skin. The data presented here show that BA represses T. rubrum growth at a concentration reported to be beneficial for host tissue regeneration. Oxygen exposure increases BA toxicity, and mycelia growing under BA stress avoid colonizing the surface of the growth surface, which leads to a suppression of aerial mycelium growth and surface conidia formation. BA penetrates into solid agar matrices, but the relative lack of oxygen below the substrate surface limits the effectiveness of BA in suppressing growth of embedded T. rubrum cells.

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Evaluation of the Content of Antimony, Arsenic, Bismuth, Selenium, Tellurium and Their Inorganic Forms in Commercially Baby Foods

Abstract

Baby foods, from the Spanish market and prepared from meat, fish, vegetables, cereals, legumes, and fruits, were analyzed to obtain the concentration of antimony (Sb), arsenic (As), bismuth (Bi), and tellurium (Te) as toxic elements and selenium (Se) as essential element. An analytical procedure was employed based on atomic fluorescence spectroscopy which allowed to obtain accurate data at low levels of concentration. Values of 14 commercial samples, expressed in nanograms per gram fresh weight, ranged for Sb 0.66–6.9, As 4.5–242, Te 1.35–2.94, Bi 2.18–4.79, and Se 5.4–109. Additionally, speciation studies were performed based on data from a non-chromatographic screening method. It was concluded that tellurium and bismuth were mainly present as inorganic forms and selenium as organic form, and antimony and arsenic species depend on the ingredients of each baby food. Risk assessment considerations were made by comparing dietary intake of the aforementioned elements through the consumption of one baby food portion a day and recommended or tolerable guideline values.

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Effects of the Oral Administration of K 2 Cr 2 O 7 and Na 2 SeO 3 on Ca, Mg, Mn, Fe, Cu, and Zn Contents in the Heart, Liver, Spleen, and Kidney of Chickens

Abstract

This study aimed to investigate the effects of selenium on the ion profiles in the heart, liver, spleen, and kidney through the oral administration of hexavalent chromium. Approximately 22.14 mg/kg b.w. K₂Cr₂O₇ was added to water to establish a chronic poisoning model. Different selenium levels (0.00, 0.31, 0.63, 1.25, 2.50, and 5.00 mg Na₂SeO₃/kg b.w.) around the safe dose were administered to the experimental group model. Ca, Mg, Mn, Fe, Cu, and Zn were detected in the organs through flame atomic absorption spectrometry after these organs were exposed to K₂Cr₂O₇ and Na₂SeO₃ for 14, 28, and 42 days. Results showed that these elements exhibited various changes. Ca contents declined in the heart, liver, and spleen. Ca contents also decreased on the 28th day and increased on the 42nd day in the kidney. Mn contents declined in the heart and spleen but increased in the kidney. Mn contents also decreased on the 28th day and increased on the 42nd day in the liver. Cu contents declined in the heart and spleen. Cu contents increased on the 28th day and decreased on the 42nd day in the liver and kidney. Zn contents declined in the heart and spleen. Zn contents increased on the 28th day and decreased on the 42nd day in the liver and kidney. Fe contents decreased in the heart and liver. Fe contents increased on the 28th day and decreased on the 42nd day in the spleen and kidney. Mg contents did not significantly change in these organs. Appropriate selenium contents enhanced Mn and Zn contents, which were declined by chromium. Conversely, appropriate selenium contents reduced Ca, Fe, and Cu contents, which were increased by chromium. In conclusion, the exposure of chickens to K₂Cr₂O₇ induced changes in different trace elements, and Na₂SeO₃ supplementation could alleviate this condition.

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Effects of Zinc and N -Acetylcysteine in Damage Caused by Lead Exposure in Young Rats

Abstract

This study investigated the toxicity of rats exposed to lead acetate (AcPb) during the second phase of brain development (8–12 days postnatal) in hematological and cerebral parameters. Moreover, the preventive effect of zinc chloride (ZnCl₂) and N-acetylcysteine (NAC) was investigated. Pups were injected subcutaneously with saline (0.9% NaCl solution), ZnCl₂ (27 mg/kg/day), NAC (5 mg/kg/day) or ZnCl₂ plus NAC for 5 days (3rd–7th postnatal days), and with saline (0.9% NaCl solution) or AcPb (7 mg/kg/day) in the five subsequent days (8th–12th postnatal days). Animals were sacrificed 21 days after the last AcPb exposure. Pups exposed to AcPb presented inhibition of blood porphobilinogen-synthase (PBG-synthase) activity without changes in hemoglobin content. ZnCl₂ pre-exposure partially prevented PBG-synthase inhibition. Regarding neurotoxicity biomarkers, animals exposed to AcPb presented a decrease in cerebrum acetylcholinesterase (AChE) activity and an increase in Pb accumulation in blood and cerebrum. These changes were prevented by pre-treatment with ZnCl₂, NAC, and ZnCl₂ plus NAC. AcPb exposure caused no alteration in behavioral tasks. In short, results show that AcPb inhibited the activity of two important enzymatic biomarkers up to 21 days after the end of the exposure. Moreover, ZnCl₂ and NAC prevented the alterations induced by AcPb.

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Iodinated TG in Thyroid Follicles Regulate TSH/TSHR Signaling for NIS Expression

Abstract

Our previous research has suggested that high degree of iodinated thyroglobulin (TG) may inhibit the expression and function of sodium iodide symporter (NIS), but the underlying mechanism remains unclear. In present study, we discuss a newly constructed follicle model in vitro, which was used to simulate the follicular structure of the thyroid and explore the regulatory roles of iodinated TG in the follicular lumen on NIS expression. The results showed that both NIS expression and PKA activity were increased in lowly iodinated TG group, while decreased NIS expression with increased PKC activity was found in highly iodinated TG group. Also, NIS expression was increased in PKA agonist-treated group, while decreased NIS was found in PKC agonist-treated group. Moreover, when the PLC-PKC pathway was blocked by PKC-specific inhibitor, highly iodinated TG significantly promoted the expression of NIS. However, when the cAMP-PKA pathway was blocked by a PKA-specific blocker, highly iodinated TG slightly suppressed NIS expression. TG with a low degree of iodination had the reverse effect on NIS. When the PLC-PKC pathway was blocked, TG with a low degree of iodination slightly promoted NIS expression. However, when the cAMP-PKA pathway was blocked, TG with a low degree of iodination greatly inhibited NIS expression. All these suggested that iodinated TG inhibited the expression of NIS by PLC-PKC pathway and promoted NIS expression via the cAMP-PKA pathway. When highly iodinated TG was present, the PLC-PKC pathway became dominant. In the presence of lowly iodinated TG, the cAMP-PKA became the major pathway.

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