Selenium Deficiency Promotes Dilatation of the Aorta by Increasing Expression and Activity of Vascular Smooth Muscle Cell Derived Matrix Metalloproteinase-2.

OBJECTIVE: Selenium (Se) is a key part of the body's oxidation defence system. However, it is unclear whether Se affects the development of aortic aneurysm (AA). An animal experiment was conducted to clarify the role of Se in AA development. METHODS: C57BL/6N male mice were fed with a Se deficient (Se-D, < 0.05 mg/kg), Se adequate (Se-A, 0.2 mg/kg), or Se supplemented (Se-S, 1 mg/kg) diet for 8 weeks. Subsequently, an AA murine model (Se-D, n = 11; Se-A, n = 12; Se-S, n = 15) was established using angiotensin II (Ang II, 1 mg/kg/min) for four weeks plus ß-aminopropionitrile (BAPN, 1 mg/mL) for the first two weeks. Saline replaced Ang II, and BAPN was removed during the modelling process for sham mice (Se-A, n = 9). To determine whether Se deficiency promoted aortic dilation via matrix metalloproteinase-2 (MMP-2), the non-specific MMP inhibitor doxycycline (Dox, 100 mg/kg/day) was given to Se-D AA mice (n = 7) for two weeks. RESULTS: The maximum aortic diameter in Se-D AA model mice was significantly increased compared with Se-A AA model mice. MMP-2 expression and activity in the aortic media of Se-D AA model mice was significantly increased compared with Se-A AA model mice. A large number of vascular smooth muscle cells (VSMCs) were found aggregating in the media of the non-dilated aorta of Se-D AA model mice, which was completely inhibited by Dox. The percentage of VSMCs in aortic media of Se-D AA model mice was significantly higher than in Se-A AA model mice. The maximum aortic diameter and occurrence rate of AA in Se-D AA model mice with Dox were significantly reduced compared with Se-D AA model mice. CONCLUSION: Se deficiency promoted dilatation of the aorta in AA model mice by increasing expression and activity of VSMC derived MMP-2, causing abnormal aggregation and proliferation of VSMCs in aortic media.

Detoxification of Selenium Yeast on Mycotoxins and Heavy Metals: a Review.

Mycotoxins are secondary metabolites produced by specific fungi. More than 400 different mycotoxins are known in the world, and the concentration of these toxins in food and feed often exceeds the acceptable limit, thus causing serious harm to animals and human body. At the same time, modern industrial agriculture will also bring a lot of environmental pollution in the development process, including the increase of heavy metal content, and often the clinical symptoms of low/medium level chronic heavy metal poisoning are not obvious, thus delaying the best treatment opportunity. However, the traditional ways of detoxification cannot completely eliminate the adverse effects of these toxins on the body, and sometimes bring some side effects, so it is essential to find a new type of safe antidote. Trace element selenium is among the essential mineral nutrient elements of human and animal bodies, which can effectively remove excessive free radicals and reactive oxygen species in the body, and has the effects of antioxidant, resisting stress, and improving body immunity. Selenium is common in nature in inorganic selenium and organic selenium. In previous studies, it was found that the use of inorganic selenium (sodium selenite) can play a certain protective role against mycotoxins and heavy metal poisoning. However, while it plays the role of antioxidant, it will also have adverse effects on the body. Therefore, it was found in the latest study that selenium yeast could not only replace the protective effect of sodium selenite on mycotoxins and heavy metal poisoning, but also improve the immunity of the body. Selenium yeast is an organic selenium source with high activity and low toxicity, which is produced by selenium relying on the cell protein structure of growing yeast. It not only has high absorption rate, but also can be stored in the body after meeting the physiological needs of the body for selenium, so as to avoid selenium deficiency again in the short term. However, few of these studies can clearly reveal the protective mechanism of yeast selenium. In this paper, the detoxification mechanism of selenium yeast on mycotoxins and heavy metal poisoning was reviewed, which provided some theoretical support for further understanding of the biological function of selenium yeast and its replacement for inorganic selenium. The conclusions suggest that selenium yeast can effectively alleviate the oxidative damage by regulating different signaling pathways, improving the activity of antioxidant enzymes, reversing the content of inflammatory factors, regulating the protein expression of apoptosis-related genes, and reducing the accumulation of mycotoxins and heavy metals in the body.

Expression pattern of secretory-cell-related transcriptional signatures in colon adenocarcinomas defines tumor microenvironment characteristics and correlates with clinical outcomes.

Despite the connection of secretory cells to distinct mucus-containing colon cancer histological subtypes and the interaction of secretory cells with immune cells in the pathogenesis of intestinal inflammatory diseases, whether the secretory cell signatures are associated with tumor microenvironment (TME) heterogeneity and can aid in colon cancer patient classification have not been investigated. Here, by performing the principal component analysis and consensus clustering analysis, we identified four distinct expression patterns based on secretory cell signatures which were significantly associated with different clinical behaviors, TME landscape, pathway activation, genomic mutations, and DNA methylation characteristics. Subsequently, a 'SCS score' model was constructed. The high SCS score indicated a pattern of 'secretory cell subtype 2', which was characterized by stromal infiltration and activation, and predicted poor prognosis and low sensitivity to fluorouracil-based chemotherapy and immunotherapy, but high sensitivity to PI3K catalytic subunit inhibitors. In conclusion, our study comprehensively uncovered the tumor heterogeneity related to secretory cell signature expression patterns. Moreover, the SCS score can supplement routine histopathological assessments to guide personalized therapeutic strategies in colon cancer patients.

Sunflower resistance against Sclerotinia sclerotiorum is potentiated by selenium through regulation of redox homeostasis and hormones signaling pathways.

White mold of sunflower caused by Sclerotinia sclerotiorum is a devastating disease that causes serious yield losses. Selenium (Se) helps plants resist stress. In this study, the resistance of sunflower to S. sclerotiorum was improved after foliar application of selenite. Selenite sprayed on leaves can be absorbed by sunflowers and transformed to selenomethionine. Consequently, sunflowers treated with Se exhibited a delay in lesion development with decrease by 54% compared to mock inoculation at 36-h post inoculation (hpi). In addition, treatment with Se compromised the adverse effects caused by S. sclerotiorum infection by balancing the regulation of genes involved in redox homeostasis. In particular, cat expression on leaves treated with Se increased to 2.5-fold to alleviate the downregulation caused by S. sclerotiorum infection at 12 hpi. Additionally, apx expression on leaves treated with Se decreased by 36% to alleviate the upregulation caused by S. sclerotiorum infection at 24 hpi, whereas expressions of gpx, pox, and nox on leaves treated with Se also successively decreased by approximately 40-60% to alleviate the upregulation caused by S. sclerotiorum infection at 24 and 36 hpi, respectively. The use of Se also enhanced the regulation of genes involved in hormones signaling pathways, in which expressions of AOC and PAL increased to 2.0- and 1.5-fold, respectively, to enhance the upregulation caused by S. sclerotiorum infection at 12 hpi, whereas expressions of AOC and PDF1.2 increased to 2.7- and 1.8-fold at 24 hpi, respectively. In addition, EIN2 expression on leaves treated with Se increased to 1.8-, 2.0-, and 1.5-fold to alleviate the downregulation caused by S. sclerotiorum infection. These results suggest that Se can improve sunflower defense responses against S. sclerotiorum infection aiming a sustainable white mold management.

Protective Effect of NGR1 against Glutamate-Induced Cytotoxicity in HT22 Hippocampal Neuronal Cells by Upregulating the SIRT1/Wnt/ß-Catenin Pathway.

Notoginsenoside R1 (NGR1) is an active compound isolated from Panax notoginseng. Despite the NGR1 having been used as a traditional medicine, little is known about the neuroprotective effects. In this study, we investigate the protective effects of NGR1 against glutamate-induced cytotoxicity in HT22 cells and its possible molecular mechanism. We assessed the toxicity of NGR1 and the protective activity by MTT assay. The levels of oxidative stress indices superoxide dismutase (SOD), glutathione (GSH), and mitochondrial membrane potential (MMP) were measured by the kits. The levels of reactive oxygen species (ROS) and Ca2+ concentration were measured by flow cytometry. Furthermore, we determined the expression of mitochondrial dysfunction related protein PINK1, Parkin, silent mating type information regulation 2 homolog-1 (sirtuin 1; SIRT1), and Wnt/ß-catenin by Western blotting. Here, we discovered that glutamate treatment led to cell viability loss, apoptosis facilitation, Ca2+ upregulation, MMP fluorescence intensity downregulation, and ROS generation of HT22 cells. In parallel, expression of Parkin was declined by glutamate. While, NGR1 treatment alleviated all the above phenomena. We further clarified that NGR1 alleviated glutamate-induced oxidative stress, apoptosis, and mitochondrial dysfunction by upregulating SIRT1 to activate Wnt/ß-catenin pathways. These findings demonstrate that NGR1 alleviated glutamate-induced cell damage, and NGR1 may play a protective role in neurological complications.

[Clinical application of sound therapy in chronic subjective tinnitus].

Chronic subjective tinnitus is an auditory phantom phenomenon perceived by patients only, with no external sound source. It's a common disease and it lacks effective treatments. Sound therapy is an optional treatment which proved to reduce the tinnitus loudness and the negative effects on life. After decades of development, a wide variety of acoustic therapies have been produced, but seldom are likely to thoroughly cure tinnitus. In recent years, some new acoustic treatments based on the hypothesis of mechanisms of tinnitus, are expected to alleviate or even eliminate tinnitus.

All-trans-retinoic acid shifts Th1 towards Th2 cell differentiation by targeting NFAT1 signalling to ameliorate immune-mediated aplastic anaemia.

Severe acquired aplastic anaemia (AA) is a serious disease characterised by autoreactive T cells attacking haematopoietic stem cells, leading to marrow hypoplasia and pancytopenia. Immunosuppressive therapy combined with antithymocyte globulin and ciclosporin can rescue most patients with AA. However, the relapse after ciclosporin withdrawal and the severe side effects of long-term ciclosporin administration remain unresolved. As such, new strategies should be developed to supplement current therapeutics and treat AA. In this study, the possibility of all-trans-retinoic acid (ATRA) as an alternative AA treatment was tested by using an immune-mediated mouse model of AA. Results revealed that ATRA inhibited T-cell proliferation, activation and effector function. It also restrained the Fas/Fasl pathway, shifted Th1 towards Th2 cell development, rebalanced T-cell subsets at a relatively high level and corrected the Th1/Th2 ratio by targeting NFAT1 signalling. In addition, ATRA inhibited Th17 cell differentiation and promoted regulatory T-cell development. Therefore, ATRA was an effective agent to improve AA treatment outcomes.

Do Biologic Therapies for Rheumatoid Arthritis Offset Treatment-Related Resource Utilization and Cost? A Review of the Literature and an Instrumental Variable Analysis.

PURPOSE OF REVIEW: One justification for using expensive biologic therapy in rheumatoid arthritis (RA) has been that it can reduce future healthcare utilization such as joint surgeries and physician visits. However, the evidence to support this assertion is unclear. We conducted a review of the literature for studies which have analyzed the trends in resource use of RA patients, and then undertook a retrospective observational analysis of a Canadian administrative database using instrumental variable methods. RECENT FINDINGS: Our review found a trend in reduced resource utilization prior to the introduction of biologics and no evidence that biologic therapies have specifically contributed to this reduction. Our observational analysis, which overcame some of the epidemiological challenges with determining the influence of biologics on resource utilization, found a possible reduction in other medications but possible increases rather than decreases in physician visits and hospitalizations. However, our sample was not sufficiently large to make definitive conclusions. Over 15 years since the introduction of biologics for RA, no evidence exists supporting the assumption that biologic therapies reduce future healthcare utilization. While such a question is challenging to generate evidence for, and so an absence of evidence does not suggest that the hypothesis is incorrect, an instrumental variable analysis using sufficient data could provide definitive evidence.

Predictors of sensitivity to preoperative chemoradiotherapy of rectal adenocarcinoma.

OBJECTIVES: The purpose of the study was to identify predictive factors of tumor response to preoperative chemoradiotherapy for rectal adenocarcinoma. METHODS: Ninety-eight patients with nonmetastatic rectal adenocarcinoma received preoperative concurrent chemoradiotherapy and underwent mesorectal excision. After treatment, tumor response according to tumor regression grade were evaluated. The correlation of clinicopathologic factors to tumor response was analyzed. RESULTS: The results from a univariate analysis indicated that pretreatment carcinoembryonic antigen level ≤3.0 ng/ml (P = 0.002), non-fixed tumor (P = 0.001), and tumor circumferential extent ≤50% (P = 0.001) were associated significantly with a good tumor response. They also indicated that pretreatment positive lymph nodes (P = 0.032) were associated significantly with a poor tumor response. In multivariate analysis, the results indicated that pretreatment carcinoembryonic antigen level (hazard ratio, 2.930; P = 0.003), tumor mobility (hazard ratio, 2.651; P = 0.002) and circumferential extent of tumor (hazard ratio, 2.394; P = 0.019) independently predicted a good pathologic response rate. Pretreatment positive lymph nodes were not significantly associated with a good response (hazard ratio, 0.361; P = 0.191). CONCLUSIONS: Pretreatment carcinoembryonic antigen level, tumor mobility and circumferential extent of tumor may be helpful in predicting responsiveness in rectal adenocarcinoma to preoperative chemoradiotherapy, although the results should be confirmed in larger, more homogeneous studies.

Cost-effectiveness of hip protectors in the prevention of osteoporosis related hip fractures in elderly nursing home residents.

OBJECTIVE: Hip fracture is a common complication of osteoporosis, resulting in significant morbidity and mortality, with a high financial cost to the healthcare system. Hip protectors have been advocated as an effective method to prevent hip fractures in high-risk individuals. This study models the cost-effectiveness of hip protectors in the prevention of osteoporosis related hip fractures in elderly nursing home residents. METHODS: An incremental cost-effectiveness analysis was performed comparing hip protectors to "no treatment" and to "calcium and vitamin D supplements." The study population was a hypothetical cohort of 1000 nursing home residents. A societal perspective, with a lifetime time horizon, was adopted. Data regarding costs, effectiveness, and quality of life measures were collected from the current literature and from Peace Arch Hospital, a community hospital in White Rock, British Columbia, Canada. Sensitivity analysis was performed. RESULTS: Hip protector use was found to be a dominant strategy compared to no treatment and to calcium and vitamin D supplements. Dominance implies lower cost and higher effect, generating cost-effectiveness ratios less than zero. Dominance with respect to cost and effectiveness of hip protectors in preventing hip fractures persisted when the model was subjected to probabilistic sensitivity analysis. CONCLUSION: Cost-effectiveness analysis suggests that hip protectors could save money while preventing hip fractures and improving quality of life in nursing home residents.