Bisphenol-A induced cyto-genotoxicity on retinal pigment epithelial cells is differentially modulated by a multi-supplement containing guarana, selenium, and L-carnitine.

Bisphenol A (BPA) may adversely affect human health by inducing oxidative stress and irreversible damage to cells. Bioactive compounds found in some functional foods, individually or in combination, can attenuate the negative effects of BPA exposure; an example is the multi-supplement containing guarana (Gua), selenium (Se), and L-carnitine (LC) -GSC- which has already demonstrated antioxidant, genoprotective, and immunomodulatory activities. This study aimed to determine the effect of GSC and its constituents on oxidative and genotoxic alterations triggered by BPA exposure in the retinal epithelial cell line. The cells exposed to BPA (0.001, 0.01, 0.1, 1, 3, and 10 µM) to determine the lowest concentration required to induce cyto-genotoxicity. ARPE-19 cells were then concomitantly exposed to the selected BPA concentration, GSC, and its components (Gua, 1.07 mg/mL; Se, 0.178 µg/mL; and LC, 1.43 mg/mL). Flow cytometry, biochemical assays, qRT-PCR, genotoxicity, apoptosis, and cellular proliferation. Based on our results, 10 µM of BPA could induce cyto-genotoxic and oxidative alterations. BPA did not alter the Bcl-2/BAX expression ratio but induced Casp3 and Casp8 overexpression, suggesting that apoptosis was induced mainly via the extrinsic pathway. GSC partially reversed the alterations triggered by BPA in ARPE-19 cells. However, Se had unexpected negative effects on ARPE-19 cells. The multi-supplement GSC may attenuate changes in oxidative and genotoxic markers related to exposure of ARPE-19 cells to BPA. our results revealed that the antioxidant, anti-apoptotic, and genoprotective properties of GSC were not universally shared by its individual, once Se did not exhibit any positive impact.

Serum macroelements and microelements levels in periparturient dairy cows in relation to fatty liver diseases.

BACKGROUND: Fatty liver in dairy cows is a common metabolic disease defined by triglyceride (TG) buildup in the hepatocyte. Clinical diagnosis of fatty liver is usually done by liver biopsy, causing considerable economic losses in the dairy industry owing to the lack of more effective diagnostic methods. Therefore, this study aimed to investigate the potential utility of blood biomarkers for the diagnosis and early warning of fatty liver in dairy cows. RESULTS: A total of twenty-four lactating cows within 28 days after parturition were randomly selected as experimental animals and divided into healthy cows (liver biopsy tested, n = 12) and cows with fatty liver (liver biopsy tested, n = 12). Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the macroelements and microelements in the serum of two groups of cows. Compared to healthy cows (C), concentrations of calcium (Ca), potassium (K), magnesium (Mg), strontium (Sr), selenium (Se), manganese (Mn), boron (B) and molybdenum (Mo) were lower and copper (Cu) was higher in fatty liver cows (F). Meanwhile, the observed differences in macroelements and microelements were related to delivery time, with the greatest major disparity between C and F occurring 7 days after delivery. Multivariable analysis was used to test the correlation between nine serum macroelements, microelements and fatty liver. Based on variable importance projection and receiver operating characteristic (ROC) curve analysis, minerals Ca, Se, K, B and Mo were screened as the best diagnostic indicators of fatty liver in postpartum cows. CONCLUSIONS: Our data suggested that serum levels of Ca, K, Mg, Se, B, Mo, Mn, and Sr were lower in F than in C. The most suitable period for an early-warning identification of fatty liver in cows was 7 days after delivery, and Ca, Se, K, B and Mo were the best diagnostic indicators of fatty liver in postpartum cows.

Urine manganese, cadmium, lead, arsenic, and selenium among autism spectrum disorder children in Kuala Lumpur.

Background: The development of autism spectrum disorder (ASD) may stem from exposure to environmental pollutants such as heavy metals. The primary objective of this study is to determine the role of heavy metals of concern such as manganese (Mn), cadmium (Cd), lead (Pb), arsenic (As), and essential trace element selenium (Se) among ASD children in Kuala Lumpur, Malaysia. Method: A total of 155 preschoolers in Kuala Lumpur between the ages 3 to 6 participated in an unmatched case-control study, comprising ASD children (n = 81) recruited from an early intervention program for autism, and 74 children without autism who were recruited from public preschools. Urine samples were collected at home, delivered to the study site, and transported to the environmental lab within 24 hours. Inductively coupled plasma mass spectrometry (ICP-MS) was applied to measure the concentration of heavy metals in the samples. Data were analysed using bivariate statistical tests (Chi-square and T-test) and logistic regression models. Result: This study demonstrated that Cd, Pb, and As urine levels were significantly greater in children without autism relative to those affected with ASD (p < 0.05). No significant difference was in the levels of Se (p = 0.659) and Mn (p = 0.875) between children with ASD and the control group. The majority of children in both groups have urine As, Pb, and Cd values lower than 15.1 µg/dL, 1.0 µg/dL, and 1.0 µg/dL, respectively which are the minimal risk values for noncarcinogenic detrimental human health effect due to the heavy metal's exposure . Factors associated with having an ASD child included being a firstborn, male, and higher parental education levels (adjusted odds ratios (aOR) > 1, p < 0.05). Conclusion: Preschoolers in this study demonstrated low levels of heavy metals in their urine samples, which was relatively lower in ASD children compared to the healthy matched controls. These findings may arise from the diminished capacity to excrete heavy metals, especially among ASD children, thereby causing further accumulation of heavy metals in the body. These findings, including the factors associated with having an ASD child, may be considered by healthcare professionals involved in child development care, for early ASD detection. Further assessment of heavy metals among ASD children in the country and interventional studies to develop effective methods of addressing exposure to heavy metals will be beneficial for future reference.

Molecular Mechanisms of the Therapeutic Effect of Selenium Nanoparticles in Hepatocellular Carcinoma.

This review describes and summarizes, for the first time, the molecular mechanisms of the cytotoxic effect of selenium nanoparticles of various origins on hepatocellular carcinoma cells. The text provides information from recent years indicating the regulation of various signaling pathways and endoplasmic reticulum stress by selenium nanoparticles; the pathways of cell death of liver cancer cells as a result of exposure to selenium nanoparticles are considered. Particular attention is paid to the participation of selenoproteins and selenium-containing thioredoxin reductases and glutathione peroxidases in these processes. Previously, there were no reviews that fully reflected the cytotoxic effects of selenium nanoparticles specifically in hepatocellular carcinoma, despite the fact that many reviews and experimental articles have been devoted to the causes of this disease and the molecular mechanisms of regulation of cytotoxic effects by other agents. The relevance of this review is primarily explained by the fact that despite the development of various drugs and approaches for the treatment and prevention of hepatocellular carcinoma, this disease is still the fourth leading cause of death in the world. For this reason, a complete understanding of the latest trends in the treatment of oncology of various etiologies, especially hepatocellular carcinoma, is extremely important.

Selenium Discrepancies in Fetal Bovine Serum: Impact on Cellular Selenoprotein Expression.

Selenium is an essential trace element in our diet, crucial for the composition of human selenoproteins, which include 25 genes such as glutathione peroxidases and thioredoxin reductases. The regulation of the selenoproteome primarily hinges on the bioavailability of selenium, either from dietary sources or cell culture media. This selenium-dependent control follows a specific hierarchy, with "housekeeping" selenoproteins maintaining constant expression while "stress-regulated" counterparts respond to selenium level fluctuations. This study investigates the variability in fetal bovine serum (FBS) selenium concentrations among commercial batches and its effects on the expression of specific stress-related cellular selenoproteins. Despite the limitations of our study, which exclusively used HEK293 cells and focused on a subset of selenoproteins, our findings highlight the substantial impact of serum selenium levels on selenoprotein expression, particularly for GPX1 and GPX4. The luciferase reporter assay emerged as a sensitive and precise method for evaluating selenium levels in cell culture environments. While not exhaustive, this analysis provides valuable insights into selenium-mediated selenoprotein regulation, emphasizing the importance of serum composition in cellular responses and offering guidance for researchers in the selenoprotein field.

Exploring the Link between Oxidative Stress, Selenium Levels, and Obesity in Youth.

Obesity is a worldwide increasing concern. Although in adults this is easily estimated with the body mass index, in children, who are constantly growing and whose bodies are changing, the reference points to assess weight status are age and gender, and need corroboration with complementary data, making their quantification highly difficult. The present review explores the interaction spectrum of oxidative stress, selenium status, and obesity in children and adolescents. Any factor related to oxidative stress that triggers obesity and, conversely, obesity that induces oxidative stress are part of a vicious circle, a complex chain of mechanisms that derive from each other and reinforce each other with serious health consequences. Selenium and its compounds exhibit key antioxidant activity and also have a significant role in the nutritional evaluation of obese children. The balance of selenium intake, retention, and metabolism emerges as a vital aspect of health, reflecting the complex interactions between diet, oxidative stress, and obesity. Understanding whether selenium status is a contributor to or a consequence of obesity could inform nutritional interventions and public health strategies aimed at preventing and managing obesity from an early age.

Effects of Foliar Dressing with Chemical Nano-Selenum and Na2SeO3 on the Antioxidant System and Accumulation of Se and Bioactive Components in Cyclocarya paliurus (Sweet Tea Tree).

Selenium (Se)-rich Cyclocarya paliurus is popular for its bioactive components, and exogenous Se fortification is the most effective means of enrichment. However, the effects of exogenous Se fortification on the nutritional quality of C. paliurus are not well known. To investigate the nutrient contents and antioxidant properties of C. paliurus following Se treatment, we used a foliar spray to apply Se in two forms-chemical nano-Se (Che-SeNPs) and sodium selenite (Na2SeO3). Sampling began 10 days after spraying and was conducted every 5 days until day 30. The Se, secondary metabolite, malondialdehyde contents, antioxidant enzyme activity, Se speciation, and Se-metabolism-related gene expression patterns were analyzed in the collected samples. Exogenous Se enhancement effectively increased the Se content of leaves, reaching a maximum on days 10 and 15 of sampling, while the contents of flavonoids, triterpenes, and polyphenols increased significantly during the same period. In addition, the application of Se significantly enhanced total antioxidant activity, especially the activity of the antioxidant enzyme peroxidase. Furthermore, a positive correlation between the alleviation of lipid peroxidation and Se content was observed, while methylselenocysteine formation was an effective means of alleviating Se stress. Finally, Na2SeO3 exhibited better absorption and conversion efficiency than Che-SeNPs in C. paliurus.

Exposure to a mixture of metal(loid)s and sleep quality in pregnant women during early pregnancy: A cross-sectional study.

Biological characteristics of pregnant women during early pregnancy make them susceptible to both poor sleep quality and metal/metalloid exposure. However, the effects of metal(loid) exposure on sleep quality in pregnant women remain unknown and unexplored. We aimed to examine the relationship between exposure to a mixture of metal(loid)s and pregnant women's sleep quality during early pregnancy. We recruited 493 pregnant women in the first trimester from prenatal clinics in Jinan, Shandong Province, China, and collected their spot urine samples. All urine specimens were assessed for eight metal(loid)s: arsenic (As), cadmium (Cd), iron (Fe), zinc (Zn), molybdenum (Mo), lead (Pb), selenium (Se), and mercury (Hg). We used the Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality. Linear regression, logistic regression, generalized additive models (GAMs), quantile g-computation, and Bayesian kernel machine regression (BKMR) were applied to investigate the relationships between metal(loid) exposure and sleep quality. The results from single metal(loid) models, quantile g-computation models, and BKMR models consistently suggested that Fe was positively related to women's sleep quality. Moreover, in the quantile g-computation models, As was the most critical contributor to the negative effects of the metal(loid) mixture on sleep quality. In addition, we found significant As by Fe interaction for scores of PSQI and habitual sleep efficiency, Pb by Fe interaction for PSQI and sleep latency, and Hg by Fe interaction for PSQI, suggesting the interactive effects of As and Fe, Pb and Fe, Hg and Fe on sleep quality and specific sleep components. Our study provided the first-hand evidence of the effects of metal(loid) exposure on pregnant women's sleep quality. The underlying mechanisms need to be explored in the future.

Association between serum selenium and non-alcoholic fatty liver disease: Results from NHANES: An observational study.

Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of diseases and stands as the second most prevalent liver disorder in the 21st century. Advanced hepatic fibrosis (AHF) is a crucial indicator of the progression of NAFLD. Selenium (Se) is an indispensable trace element for human physiology; however, excessive intake can lead to poisoning and detrimental effects. Notably, males exhibit significantly higher serum Se levels compared to females. To investigate the correlation between serum Se levels and the prevalence of NAFLD and AHF across different genders. Utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2017-2020, 7271 participants were included. Through descriptive analysis, multivariable logistic regression, subgroup analysis, interaction, and restricted cubic spline regression analysis, the relationship between serum Se levels and the prevalence of NAFLD and AHF was investigated. serum Se levels were significantly higher in both male and female NAFLD groups compared to the non-NAFLD groups (Males: 187.570 vs 183.300, Z = -16.169, P < .001; Females: 184.780 vs 180.130, Z = -4.102, P < .001). After adjusting for confounders, an increase in one quartile of serum Se was associated with a 17.60% increase in NAFLD prevalence in males (OR, 1.176; 95% CI: 1.052-1.315) and a 38.50% decrease in AHF prevalence (OR, 0.615; 95% CI: 0.479-0.789). In females, each quartile increase in serum Se was associated with a 29.10% increase in NAFLD prevalence (OR,1.291;95%CI: 1.155-1.442) and a 51.60% decrease in AHF prevalence (OR, 0.484; 95% CI: 0.344-0.682). serum Se levels are positively correlated with the prevalence of NAFLD and negatively correlated with the prevalence of AHF in both males and females.

Reprogramming Tumor-Associated Macrophages with a Se-Based Core-Satellite Nanoassembly to Enhance Cancer Immunotherapy.

Tumor-associated macrophages (TAMs), as the most prevalent immune cells in the tumor microenvironment, play a pivotal role in promoting tumor development through various signaling pathways. Herein, we have engineered a Se@ZIF-8 core-satellite nanoassembly to reprogram TAMs, thereby enhancing immunotherapy outcomes. When the nanoassembly reaches the tumor tissue, selenium nanoparticles and Zn2+ are released in response to the acidic tumor microenvironment, resulting in a collaborative effort to promote the production of reactive oxygen species (ROS). The generated ROS, in turn, activate the nuclear factor κB (NF-κB) signaling pathway, driving the repolarization of TAMs from M2-type to M1-type, effectively eliminating cancer cells. Moreover, the nanoassembly can induce the immunogenic death of cancer cells through excess ROS to expose calreticulin and boost macrophage phagocytosis. The Se@ZIF-8 core-satellite nanoassembly provides a potential paradigm for cancer immunotherapy by reversing the immunosuppressive microenvironment.

Optimization of fermentation parameters to improve the biosynthesis of selenium nanoparticles by Bacillus licheniformis F1 and its comprehensive application.

BACKGROUND: Selenium nanoparticles (SeNPs) are increasingly gaining attention due to its characteristics of low toxicity, high activity, and stability. Additionally, Bacillus licheniformis, as a probiotic, has achieved remarkable research outcomes in diverse fields such as medicine, feed processing, and pesticides, attracting widespread attention. Consequently, evaluating the activity of probiotics and SeNPs is paramount. The utilization of probiotics to synthesize SeNPs, achieving large-scale industrialization, is a current hotspot in the field of SeNPs synthesis and is currently the most promising synthetic method. To minimize production costs and maximize yield of SeNPs, this study selected agricultural by-products that are nutrient-rich, cost-effective, and readily available as culture medium components. This approach not only fulfills industrial production requirements but also mitigates the impact on downstream processes. RESULTS: The experimental findings revealed that SeNPs synthesized by B. licheniformis F1 exhibited a spherical morphology with diameters ranging from 110 to 170 nm and demonstrating high stability. Both the secondary metabolites of B. licheniformis F1 and the synthesized SeNPs possessed significant free radical scavenging ability. To provide a more robust foundation for acquiring large quantities of SeNPs via fermentation with B. licheniformis F1, key factors were identified through single-factor experiments and response surface methodology (RSM) include a 2% seed liquid inoculum, a temperature of 37 ℃, and agitation at 180 rpm. Additionally, critical factors during the optimization process were corn powder (11.18 g/L), soybean meal (10.34 g/L), and NaCl (10.68 g/L). Upon validating the optimized conditions and culture medium, B. licheniformis F1 can synthesize nearly 100.00% SeNPs from 5 mmol/L sodium selenite. Subsequently, pilot-scale verification in a 5 L fermentor using the optimized medium resulted in a shortened fermentation time, significantly reducing production costs. CONCLUSION: In this study, the efficient production of SeNPs by the probiotic B. licheniformis F1 was successfully achieved, leading to a significant reduction in fermentation costs. The exploration of the practical applications of this strain holds significant potential and provides valuable guidance for facilitating the industrial-scale implementation of microbial synthesis of SeNPs.

Trace Element Deficiency in Systemic Sclerosis-Too Much Effort for Some Traces?

Trace elements are essential for several physiological processes. To date, various data have suggested that inadequate levels of trace elements may be involved in the pathogenesis of different chronic diseases, including immune-mediated ones, or may develop during their course. Systemic sclerosis (SSc) is a complex autoimmune multisystemic disease, primarily characterized by microvascular dysregulation, the widespread activation of the immune system and tissue fibrosis. According to the latest reports regarding the pathogenesis of SSc, the main pathophysiological processes-inflammation, vasculopathy and fibrosis-may include various trace element derangements. The present literature review aims to update the available data regarding iron, zinc, copper and selenium status in SSc as well as to underline the possible implications of these trace elements in the complexity of the pathogenic process of the disease. We observe that the status of trace elements in SSc plays a crucial role in numerous pathogenic processes, emphasizing the necessity for proper monitoring and supplementation. The reported data are heterogenous and scarce, and future studies are needed in order to draw clearer conclusions about their complete spectrum.

A Plea for Monitoring Serum Selenium Levels in Breast Cancer Patients: Selenium Deficiency Is Rare during the First Year of Therapy, and Selenium Supplementation Is Associated with Elevated Risk of Overdosing.

(1) Background: The role of selenium in cancer biology remains poorly understood. Our aim was to study the course of selenium serum levels and the use of selenium supplements during breast cancer therapy. (2) Methods: Serum selenium levels, clinical-pathological data, selenium supplementation, and lifestyle factors were monitored quarterly over one year. (3) Results: A total of 110 non-metastatic breast cancer patients were enrolled in the prospective observational "BEGYN-1" study. At baseline, 2.9% of patients were selenium-deficient (<50 ng/mL), 1.9% were overdosed (>120 ng/mL), and 6.4% received substitution. The median selenium level was 81.5 ng/mL and ranged between 78.7 and 84.5 ng/mL within the year. A total of 25.3% of the patients received supplementation, resulting in significantly higher selenium levels (p < 0.05). A total of 8.7-28.6% of the patients using supplements were overdosed. Selenium levels strongly correlated with mushroom consumption (p = 0.003), but no association was found with therapy or clinical characteristics. (4) Conclusions: Although selenium deficiency is rare, serum selenium levels should be assessed in breast cancer patients. Mushrooms and nuts should be preferred over supplements to correct selenium deficiency. Ruling out selenium deficiency helps prevent the risk of selenosis and avoid unnecessary, costly supplementation in patients who are often financially burdened due to their disease.

Overexpression of Wheat Selenium-Binding Protein Gene TaSBP-A Enhances Plant Growth and Grain Selenium Accumulation under Spraying Sodium Selenite.

Selenium (Se) is an essential trace element for humans. Low concentrations of Se can promote plant growth and development. Enhancing grain yield and crop Se content is significant, as major food crops generally have low Se content. Studies have shown that Se biofortification can significantly increase Se content in plant tissues. In this study, the genetic transformation of wheat was conducted to evaluate the agronomic traits of non-transgenic control and transgenic wheat before and after Se application. Se content, speciation, and transfer coefficients in wheat grains were detected. Molecular docking simulations and transcriptome data were utilized to explore the effects of selenium-binding protein-A TaSBP-A on wheat growth and grain Se accumulation and transport. The results showed that TaSBP-A gene overexpression significantly increased plant height (by 18.50%), number of spikelets (by 11.74%), and number of grains in a spike (by 35.66%) in wheat. Under normal growth conditions, Se content in transgenic wheat grains did not change significantly, but after applying sodium selenite, Se content in transgenic wheat grains significantly increased. Analysis of Se speciation revealed that organic forms of selenomethionine (SeMet) and selenocysteine (SeCys) predominated in both W48 and transgenic wheat grains. Moreover, TaSBP-A significantly increased the transfer coefficients of Se from solution to roots and from flag leaves to grains. Additionally, it was found that with the increase in TaSBP-A gene overexpression levels in transgenic wheat, the transfer coefficient of Se from flag leaves to grains also increased.

Effects of tea infusion on selenium uptake in grapevine.

Increased selenium (Se) content in fruits can supply Se in human body, but the effects of teas on the Se uptake in fruit trees are unknown. The effects of infusions of four teas (green, black, dark, and white) on the Se uptake of grapevine were studied to promote the Se uptake in fruit trees in this study. However, only black tea infusion increased the biomass, photosynthetic pigment content, superoxide dismutase (SOD) activity, peroxidase (POD) activity, and soluble protein content of grapevine. Except for white tea infusion, other tea infusions also increased the catalase (CAT) activity of grapevine. Furthermore, the tea infusions increased the activities of adenosine triphosphate sulfurase (ATPS) and adenosine 5'-phosphosulfate reductase (APR), and decreased the activities of serine acetyltransferase (SAT) and selenocysteine methyltransferase (SMT). Only the dark and white tea infusions increased the shoot total Se content by 86.53% and 23.32%, respectively (compared with the control), and also increased the shoot inorganic Se content and shoot organic Se content. Notably, four tea infusions decreased the organic Se proportion and increased the inorganic Se proportion in grapevine. Correlation and grey relational analyses showed that the root total Se content, ATPS activity, and ARP activity were closely associated with the shoot total Se content. The principal component and cluster analyses also showed that the ATPS activity, APR activity, root total Se content, and shoot total Se content were classified into one category. These findings show that black tea infusion can promote grapevine growth, while dark and white tea infusions can promote the Se uptake in grapevine.

Selenium Supplementation Sensor Based on Direct Electrochemistry of Urinary Selenosugar and Total Selenium.

Emerging point-of-care testing methods are extremely beneficial for personalized assessments of trace element metabolism including selenium (Se). Given the lack of timely evaluation methods for well-received Se fortification, an electrochemical solution was developed based on the recently identified urinary selenosugar (Sel) as a marker. The Se content of crude urine was rapidly determined (∼5 min), and the square-wave voltammetric responses of a Se-selective probe (SeSE) composed of liquid metal amalgam demonstrated comparable performance (e.g., detection limit: 19 nM) to central lab benchtop equipment within the physiological range. Meanwhile, SeSE enabled total urinary Se detection via a mere one-step oxidation. Additionally, SeSE was utilized to jointly assess the apparent internalization and utilization rate of two typical nutrients, selenite and selenomethionine, in a rat nutrition model, demonstrating consistent results with those obtained by HPLC-MS and ICP-MS. Upon systematic standardization directed by Ramaley's theory, SeSE was integrated into a battery-operated portable kit (dubbed "SeEye") with a micro electrochemical drive and tablet PC console for one-stop service trials in a local commercial scenario. This study establishes (1) a nutritive value classifier in a low-cost consumer electronic format and (2) noninvasive diagnostic technology for Se supplementation.

Trace elements in pancreatic cancer.

BACKGROUND: Pancreatic cancer (PCA) is an extremely aggressive malignant cancer with an increasing incidence and a low five-year survival rate. The main reason for this high mortality is that most patients are diagnosed with PCA at an advanced stage, missing early treatment options and opportunities. As important nutrients of the human body, trace elements play an important role in maintaining normal physiological functions. Moreover, trace elements are closely related to many diseases, including PCA. REVIEW: This review systematically summarizes the latest research progress on selenium, copper, arsenic, and manganese in PCA, elucidates their application in PCA, and provides a new reference for the prevention, diagnosis and treatment of PCA. CONCLUSION: Trace elements such as selenium, copper, arsenic and manganese are playing an important role in the risk, pathogenesis, diagnosis and treatment of PCA. Meanwhile, they have a certain inhibitory effect on PCA, the mechanism mainly includes: promoting ferroptosis, inducing apoptosis, inhibiting metastasis, and inhibiting excessive proliferation.

A novel selenium analog of HDACi-based twin drug induces apoptosis and cell cycle arrest via CDC25A to improve prostate cancer therapy.

Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer chemicals has produced exciting progress in cancer treatment. Herein, we developed a novel prodrug via the ligation of dichloroacetate to selenium-containing potent HDAC inhibitors. The effect and mechanism of this compound in the treatment of prostate cancer were also studied. Methods: The concerned prodrug SeSA-DCA was designed and synthesized under mild conditions. This compound's preclinical studies, including the pharmacokinetics, cell toxicity, and anti-tumor effect on prostate cancer cell lines, were thoroughly investigated, and its possible synergistic mechanism was also explored and discussed. Results: SeSA-DCA showed good stability in physiological conditions and could be rapidly decomposed into DCA and selenium analog of SAHA (SeSAHA) in the tumor microenvironment. CCK-8 experiments identified that SeSA-DCA could effectively inhibit the proliferation of a variety of tumor cell lines, especially in prostate cancer. In further studies, we found that SeSA-DCA could also inhibit the metastasis of prostate cancer cell lines and promote cell apoptosis. At the animal level, oral administration of SeSA-DCA led to significant tumor regression without obvious toxicity. Moreover, as a bimolecular coupling compound, SeSA-DCA exhibited vastly superior efficacy than the mixture with equimolar SeSAHA and DCA both in vitro and in vivo. Our findings provide an important theoretical basis for clinical prostate cancer treatment. Conclusions: Our in vivo and in vitro results showed that SeSA-DCA is a highly effective anti-tumor compound for PCa. It can effectively induce cell cycle arrest and growth suppression and inhibit the migration and metastasis of PCa cell lines compared with monotherapy. SeSA-DCA's ability to decrease the growth of xenografts is a little better than that of docetaxel without any apparent signs of toxicity. Our findings provide an important theoretical basis for clinical prostate cancer treatment.

Analysis of culture and RNA isolation methods for precision-cut liver slices from cirrhotic rats.

Precision-cut liver slices (PCLS) are increasingly used as a model to investigate anti-fibrotic therapies. However, many studies use PCLS from healthy animals treated with pro-fibrotic stimuli in culture, which reflects only the early stages of fibrosis. The effects of different culture conditions on PCLS from cirrhotic animals has not been well characterized and there is no consensus on optimal methods. In this study, we report a method for the collection and culture of cirrhotic PCLS and compare the effect of common culture conditions on viability, function, and gene expression. Additionally, we compared three methods of RNA isolation and identified a protocol with high yield and purity. We observed significantly increased albumin production when cultured with insulin-transferrin-selenium and dexamethasone, and when incubated on a rocking platform. Culturing with insulin-transferrin-selenium and dexamethasone maintained gene expression closer to the levels in fresh slices. However, despite stable viability and function up to 4 days, we found significant changes in expression of key genes by day 2. Interestingly, we also observed that cirrhotic PCLS maintain viability in culture longer than slices from healthy animals. Due to the influence of matrix stiffness on fibrosis and hepatocellular function, it is important to evaluate prospective anti-fibrotic therapies in a platform that preserves tissue biomechanics. PCLS from cirrhotic animals represent a promising tool for the development of treatments for chronic liver disease.