Accumulation of genome and macromolecule damage is a hallmark of aging, age-associated degeneration, and genome instability syndromes. Although processes of aging are irreversible, they can be ...modulated by genome maintenance pathways and environmental factors such as diet. Selenium (Se) confers its physiological functions mainly through selenoproteins, but Se compounds and other proteins that incorporate Se nonspecifically also impact optimal health. Bruce Ames proposed that the aging process could be mitigated by a subset of low-hierarchy selenoproteins whose levels are preferentially reduced in response to Se deficiency. Consistent with this notion, results from two selenotranscriptomic studies collectively implicate three low-hierarchy selenoproteins in age or senescence. Experimental evidence generally supports beneficial roles of selenoproteins in the protection against damage accumulation and redox imbalance, but some selenoproteins have also been reported to unexpectedly display harmful functions under sporadic conditions. While longevity and healthspan are usually thought to be projected in parallel, emerging evidence suggests a trade-off between longevity promotion and healthspan deterioration with damage accumulation. We propose that longevity promotion under conditions of Se deficiency may be attributed to 1) stress-response hormesis, an advantageous event of resistance to toxic chemicals at low doses; 2) reduced expression of selenoproteins with paradoxical functions to a lesser extent. In particular, selenoprotein H is an evolutionally conserved nuclear selenoprotein postulated to confer Se functions in redox regulation, genome maintenance, and senescence. This review highlights the need to pinpoint roles of specific selenoproteins and Se compounds in healthspan and lifespan for a better understanding of Se contribution at nutritional levels of intake to healthy aging.
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•Se and selenoproteins credibly impact aging through redox and genome maintenance.•Dietary Se deficiency may promote longevity through stress-response hormesis.•Downregulation of selenoproteins with paradoxical roles may sometimes be beneficial.•Dietary Se deficiency instigates a trade-off between health decline and longevity.
Revisiting Selenium Toxicity Cheng, Wen-Hsing
The Journal of nutrition,
04/2021, Letnik:
151, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The association between selenium (Se) status and disease risk is U-shaped: both insufficient and excess intakes of this nutrient could lead to adverse health effects. Ranging from deficient to ...adequate amounts of intake, dietary Se is largely retained in the body through co-translational incorporation into selenoproteins as selenocysteine residues that confer its physiological functions. Above nutritional and metabolic needs, selenoprotein expression gradually reaches a plateau; the remaining Se is present on any protein through posttranslational modifications and to a lesser extent as low-molecular-weight metabolites, but only a fraction of such dietary Se remains in the body. By definition, the upper intake level (UL) sets the highest amount of daily nutrient intake that is likely to pose no adverse health effects in most people. The US Food and Nutrition Board of the Institute of Medicine sets 55 and 400 µg/d as the RDA and UL for Se, respectively, for all adults.
Cheng examines the nutritional value of green tea, highlighting the study by Kashino et al on whether people should supplement their diet with green tea extracts or drink green tea. Antioxidants ...encompass enzymatic and nonenzymatic forms. Enzymes in the body are de novo synthesized proteins that speed up chemical reactions, whereas bioactive compounds are nonenzymatic and acquired largely through dietary intake. For example, dietary phenolic compounds and flavonoids are known by their antioxidant properties. Furthermore, after being absorbed and delivered to the cells, dietary micronutrients can serve as coenzymes or cofactors to catalyze reactions of enzymes such as the 5 human selenium-dependent glutathione peroxidases.
Cheng discusses the study of Vahter et al about placental and cord blood telomere length in relation to maternal nutritional status. Vahter et al report findings from a population-based mother-child ...cohort of 99 participants in San Antonio de los Cobres Argentina and 9 much smaller nearby villages of a population in the arid Argentinean Andes known for its high elevation ranging from 3180 to 4070 m with few trees and scarce drinking water. The authors concluded that relative telomere length of placenta, but not cord blood, was associated inversely with maternal BMI, body fat percentage, and vitamin B-12 concentration, but positively with 25-hydroxycholecalciferol concentration. Other health parameters, including 7 other nutrients, were not associated with the telomere length.
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ...ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate "paradoxical" outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of "antioxidant" nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that "paradoxical" roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways.
Diet-related obesity is associated with increased intestinal hyperpermeability. High dietary fat intake causes an increase in colonic bile acids (BAs), particularly deoxycholic acid (DCA). We ...hypothesize that DCA modulates the gene expression of multiple cell junction pathways and increases intestinal permeability. With a human Caco-2 cell intestinal model, we used cell proliferation, PCR array, biochemical, and immunofluorescent assays to examine the impact of DCA on the integrity of the intestinal barrier and gene expression. The Caco-2 cells were grown in monolayers and challenged with DCA at physiological, sub-mM, concentrations. DCA increased transcellular and paracellular permeability (>20%). Similarly, DCA increased intracellular reactive oxidative species production (>100%) and accompanied a decrease (>40%) in extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways. Moreover, the mRNA levels of 23 genes related to the epithelial barrier (tight junction, focal adhesion, gap junction, and adherens junction pathways) were decreased (>40%) in (0.25 mM) DCA-treated Caco-2 cells compared to untreated cells. Finally, we demonstrated that DCA decreased (>58%) the protein content of occludin present at the cellular tight junctions and the nucleus of epithelial cells. Collectively, DCA decreases the gene expression of multiple pathways related to cell junctions and increases permeability in a human intestinal barrier model.
Diosgenin, a steroidal saponin obtained from fenugreek (Trigonella foenum graecum), was found to exert anti-carcinogenic properties, such as inhibiting proliferation and inducing apoptosis in a ...variety of tumor cells. However, the effect of diosgenin on cancer metastasis remains unclear. The aim of the study is to examine the effect of diosgenin on migration and invasion in human prostate cancer PC-3 cells.
Diosgenin inhibited proliferation of PC-3 cells in a dose-dependent manner. When treated with non-toxic doses of diosgenin, cell migration and invasion were markedly suppressed by in vitro wound healing assay and Boyden chamber invasion assay, respectively. Furthermore, diosgenin reduced the activities of matrix metalloproteinase-2 (MMP-2) and MMP-9 by gelatin zymography assay. The mRNA level of MMP-2, -9, -7 and extracellular inducer of matrix metalloproteinase (EMMPRIN) were also suppressed while tissue inhibitor of metalloproteinase-2 (TIMP-2) was increased by diosgenin. In addition, diosgenin abolished the expression of vascular endothelial growth factor (VEGF) in PC-3 cells and tube formation of endothelial cells. Our immunoblotting assays indicated that diosgenin potently suppressed the phosphorylation of phosphatidylinositide-3 kinase (PI3K), Akt, extracellular signal regulating kinase (ERK) and c-Jun N-terminal kinase (JNK). In addition, diosgenin significantly decreased the nuclear level of nuclear factor kappa B (NF-κB), suggesting that diosgenin inhibited NF-κB activity.
The results suggested that diosgenin inhibited migration and invasion of PC-3 cells by reducing MMPs expression. It also inhibited ERK, JNK and PI3K/Akt signaling pathways as well as NF-κB activity. These findings reveal new therapeutic potential for diosgenin in anti-metastatic therapy.
Abstract In order to increase the absorption of hydrophilic macromolecules in the small intestine, permeation enhancers such as chitosan (CS) and its derivatives have been evaluated. The aim of the ...current work was to investigate, on molecular levels, the effect of CS on tight junction (TJ) integrity in Caco-2 cells. The observed changes in transepithelial-electrical-resistance measurements and the staining patterns of the monolayer Caco-2 cells demonstrate that CS can transiently and reversibly open the TJs between cells, thus enhancing the paracellular permeability. TJ ultra-structures examined by transmission electron microscopy support the concept that CS did induce transient opening of TJs. We then assessed TJ disruption at the gene and protein expression levels. Our data indicate that exposure to CS followed by recovery resulted in a significant increase in claudin-4 ( Cldn4 ) gene transcription. Additionally, CS treatment induced redistribution of the TJ protein CLDN4 intracellularly following by its degradation in lysosomes, which represented an important contributing factor in TJ weakening, leading to the opening of TJs. The recovery of TJ after CS disruption required CLDN4 protein synthesis. These results suggest that CS regulates TJs by inducing changes in transmembrane CLDN4 protein. Understanding the mechanism of interaction between CS and epithelial cells is of paramount importance and needs to be established to aid further development in the use of CS to mediate the trans-epithelial drug delivery.
Objective
Unprecedently investigate associations of prognostic‐awareness‐transition patterns with (changes in) depressive symptoms, anxiety symptoms, and quality of life (QOL) during cancer patients' ...last 6 months.
Methods
In this secondary analysis study, 334 cancer patients in their last 6 months transitioned between four prognostic‐awareness states (unknown and not wanting to know, unknown but wanting to know, inaccurate awareness, and accurate awareness), thus constituting three transition patterns: maintaining‐accurate‐, gaining‐accurate‐, and maintaining‐inaccurate/unknown prognostic awareness. A multivariate hierarchical linear model evaluated associations of the transition patterns with depressive symptoms, anxiety symptoms, and QOL determined at final assessment and by mean difference between the first and last assessment.
Results
At the last assessment before death, the gaining‐accurate‐prognostic‐awareness group reported higher levels of depressive symptoms (estimate 95% confidence interval = 1.59 0.35–2.84) and the maintaining‐ and gaining‐accurate‐prognostic‐awareness groups suffered more anxiety symptoms (1.50 0.44–2.56; 1.42 0.13–2.71, respectively) and poorer QOL (−7.07 −12.61 to 1.54; −11.06 −17.76 to −4.35, respectively) than the maintaining‐inaccurate/unknown‐prognostic‐awareness group. Between the first and last assessment, the maintaining‐ and gaining‐accurate‐prognostic‐awareness groups' depressive symptoms (1.59 0.33–2.85; 3.30 1.78–4.82, respectively) and QOL (−5.04 −9.89 to –0.19; −8.86 −14.74 to −2.98, respectively) worsened more than the maintaining‐inaccurate/unknown‐prognostic‐awareness group, and the gaining‐accurate‐prognostic‐awareness group's depressive symptoms increased more than the maintaining‐accurate‐prognostic‐awareness group (1.71 0.42–3.00).
Conclusions
Unexpectedly, patients who maintained/gained accurate prognostic awareness suffered more depression, anxiety, and poorer QOL at end of life. Promoting accurate prognostic awareness earlier in the terminal‐cancer trajectory should be supplemented with adequate psychological care to alleviate patients' emotional distress and enhance QOL.
Trial registration: ClinicalTrials.gov:NCT01912846.
As is widely suspected, lysolipid dissociation from liposomes contributes to the intravenous instability of ThermoDox (lysolipid liposomes), thereby impeding its antitumor efficacy. This work ...evaluates the feasibility of a thermoresponsive bubble-generating liposomal system without lysolipids for tumor-specific chemotherapy. The key component in this liposomal formulation is its encapsulated ammonium bicarbonate (ABC), which is used to actively load doxorubicin (DOX) into liposomes and trigger a drug release when heated locally. Incubating ABC liposomes with whole blood results in a significantly smaller decrease in the retention of encapsulated DOX than that by lysolipid liposomes, indicating superior plasma stability. Biodistribution analysis results indicate that the ABC formulation circulates longer than its lysolipid counterpart. Following the injection of ABC liposome suspension into mice with tumors heated locally, decomposition of the ABC encapsulated in liposomes facilitates the immediate thermal activation of CO2 bubble generation, subsequently increasing the intratumoral DOX accumulation. Consequently, the antitumor efficacy of the ABC liposomes is superior to that of their lysolipid counterparts. Results of this study demonstrate that this thermoresponsive bubble-generating liposomal system is a highly promising carrier for tumor-specific chemotherapy, especially for local drug delivery mediated at hyperthermic temperatures.
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