Serum biomarker-based osteoporosis risk prediction and the systemic effects of Trifolium pratense ethanolic extract in a postmenopausal model.

BACKGROUND: Recent years, a soaring number of marketed Trifolium pratense (red clover) extract products have denoted that a rising number of consumers are turning to natural alternatives to manage postmenopausal symptoms. T. pratense ethanolic extract (TPEE) showed immense potential for their uses in the treatment of menopause complications including osteoporosis and hormone dependent diseases. Early diagnosis of osteoporosis can increase the chance of efficient treatment and reduce fracture risks. Currently, the most common diagnosis of osteoporosis is performed by using dual-energy x-ray absorptiometry (DXA). However, the major limitation of DXA is that it is inaccessible and expensive in rural areas to be used for primary care inspection. Hence, serum biomarkers can serve as a meaningful and accessible data for osteoporosis diagnosis. METHODS: The present study systematically elucidated the anti-osteoporosis and estrogenic activities of TPEE in ovariectomized (OVX) rats by evaluating the bone microstructure, uterus index, serum and bone biomarkers, and osteoblastic and osteoclastic gene expression. Leverage on a pool of serum biomarkers obtained from this study, recursive feature elimination with a cross-validation method (RFECV) was used to select useful biomarkers for osteoporosis prediction. Then, using the key features extracted, we employed five classification algorithms: extreme gradient boosting (XGBoost), random forest, support vector machine, artificial neural network, and decision tree to predict the bone quality in terms of T-score. RESULTS: TPEE treatments down-regulated nuclear factor kappa-B ligand, alkaline phosphatase, and up-regulated estrogen receptor ß gene expression. Additionally, reduced serum C-terminal telopeptides of type 1 collagen level and improvement in the estrogen dependent characteristics of the uterus on the lining of the lumen were observed in the TPEE intervention group. Among the tested classifiers, XGBoost stood out as the best performing classification model with the highest F1-score and lowest standard deviation. CONCLUSIONS: The present study demonstrates that TPEE treatment showed therapeutic benefits in the prevention of osteoporosis at the transcriptional level and maintained the estrogen dependent characteristics of the uterus. Our study revealed that, in the case of limited number of features, RFECV paired with XGBoost model could serve as a powerful tool to readily evaluate and diagnose postmenopausal osteoporosis.

Trifolium pratense ethanolic extract alters the gut microbiota composition and regulates serum lipid profile in the ovariectomized rats.

BACKGROUND: Trifolium pratense (red clover) ethanolic extract (TPEE) has been used as a popular over-the-counter remedy for the management of menopausal symptoms. Prolonged consumption of herbal extract has been shown to regulate the composition of gut microbiota. This study was designed to elucidate the influence of TPEE on the gut microbiota composition in the ovariectomized (OVX) rats. METHODS: OVX rats were treated with TPEE at 125, 250, 500 mg/kg/day, or controls (pomegranate extract, 500 mg/kg/day; estradiol, 25 µg/kg/day) for 12 weeks. Gut microbiota analysis was conducted by extracting the microbial DNA from fecal samples and microbiome taxonomic profiling was carried out by using next-generation sequencing. The levels of serum biomarkers were analyzed using enzyme-linked immunosorbent assay (ELISA) kit. The prediction of functional biomarker of microbiota was performed using PICRUSt to investigate the potential pathways associated with gut health and serum lipid profile regulation. To study the correlation between gut microbiota composition and serum lipid levels, Spearman's correlation coefficients were defined and analyzed. Additionally, gas chromatography-mass spectrometry analysis was conducted to uncover additional physiologically active ingredients. RESULTS: TPEE-treated OVX rats showed significant reduction in serum triglycerides (TG), total cholesterols (TCHOL), and LDL/VLDL levels but increase in HDL level. The alteration in the pathways involve in metabolism was the most common among the other KEGG categories. Particularly, TPEE also significantly reduced the relative abundance of sequences read associated with inflammatory bowel disease (IBD) and the peroxisome proliferator-activated receptor (PPAR) signalling pathway. TPEE intervention was seen to reduce the Firmicutes to Bacteroidetes (F/B) ratio in the OVX rats, denoting a reduction in microbial dysbiosis in the OVX rats. Correlation analysis at the phylum level revealed that Bacteriodetes and Proteobacteria were strongly correlated with serum TG, TCHOL and HDL levels. At the species level, Bifidobacterium pseudolongum group was seen to positively correlate with serum HDL level and negatively correlated with serum AST, ALT, LDL/VLDL, TCHOL, and TG levels. CONCLUSIONS: TPEE treatment showed therapeutic benefits by improving the intestinal microbiota composition which strongly correlated with the serum lipid and cholesterol levels in the OVX rats.

Anti-Obesity Effect of Hot Water Extract of Barley Sprout through the Inhibition of Adipocyte Differentiation and Growth.

Barley sprouts are known to have several effective physiological activities. In this study, the anti-obesity effect of a barley sprout hot water extract (BSE) was confirmed. Saponarin was quantitatively analyzed in BSE using HPLC, and the inhibitory effect on 3T3-L1 pre-adipocyte differentiation into adipocytes was confirmed by Oil Red O staining, TG assay, and Western blotting. In addition, the inhibitory effect of BSE on adipocyte growth was confirmed through glucose uptake and lipolysis of adipocytes. C57/BL/6N mice were induced to obesity with a high-fat diet, and BSE was administered to confirm the effect on an animal model. Weight gain, morphological changes in adipose tissue, changes in the food efficiency ratio, and blood biochemical changes were observed, and an improvement effect on fatty liver was confirmed. As a result, the anti-obesity effect of BSE was confirmed in vitro, and it was confirmed that this effect was also effective in vivo and that it could be helpful in the treatment of obesity-related diseases.

Evaluation of a Telehealth Counseling Program for Expatriates.

Background: Health problems for expatriates are common due to their vulnerability to local infectious diseases, psychosocial problems, and chronic diseases, but many problems go largely unmet in this unique population. Introduction: Telehealth counseling was developed and tested for Korean expatriates. We explored the current status of using telehealth counseling systems and showed its feasibility and acceptability in three countries. Materials and Methods: This retrospective study was based on the "Development and demonstration of telehealth counseling program for overseas Koreans" project funded by the Korea Health Industry Development Institute. In this project, we established five Digital Healthcare Centers (DHCs): 3 in Vietnam and 1 each in Uzbekistan and Cambodia. We used data from October 2016 to September 2017; descriptive analysis and one-way ANOVA were used to present detailed information. Results: A total of 442 patients made an appointment for telehealth counseling services. Overall user satisfaction rates were 96.1%. Over two thirds of patients (302/442, 68.3%) completed one-time telehealth counseling. About 13% were referred to primary care, and 17 (3.8%) were referred to specialists or tertiary hospital. The most common diagnostic category was endocrine, nutritional, and metabolic diseases (14%), followed by diseases of the circulatory system (12.3%) for one-time visit patients. Discussion: Our telehealth counseling program for expatriates was feasible and acceptable in three countries. It also has the potential to minimize language barriers and the cost of healthcare usage. Conclusion: Further research for sustainable effective telehealth systems for expatriates will be needed.

Recapitulation of the forward nuclear auxin response pathway in yeast.

Auxin influences nearly every aspect of plant biology through a simple signaling pathway; however, it remains unclear how much of the diversity in auxin effects is explained by variation in the core signaling components and which properties of these components may contribute to diversification in response dynamics. Here, we recapitulated the entire Arabidopsis thaliana forward nuclear auxin signal transduction pathway in Saccharomyces cerevisiae to test whether signaling module composition enables tuning of the dynamic response. Sensitivity analysis guided by a small mathematical model revealed the centrality of auxin/indole-3-acetic acid (Aux/IAA) transcriptional corepressors in controlling response dynamics and highlighted the strong influence of natural variation in Aux/IAA degradation rates on circuit performance. When the basic auxin response circuit was expanded to include multiple Aux/IAAs, we found that dominance relationships between coexpressed Aux/IAAs were sufficient to generate distinct response modules similar to those seen during plant development. Our work provides a new method for dissecting auxin signaling and demonstrates the key role of Aux/IAAs in tuning auxin response dynamics.

Mutations in the TIR1 auxin receptor that increase affinity for auxin/indole-3-acetic acid proteins result in auxin hypersensitivity.

The phytohormone auxin regulates virtually every aspect of plant development. The hormone directly mediates the interaction between the two members of the auxin coreceptor complex, a TRANSPORT INHIBITOR RESPONSE (TIR1)/AUXIN SIGNALING F-BOX protein and an AUXIN/INDOLE-3-ACETIC ACID (Aux/IAA) transcriptional repressor. To learn more about the interaction between these proteins, a mutant screen was performed using the yeast (Saccharomyces cerevisiae) two-hybrid system in Arabidopsis (Arabidopsis thaliana). Two tir1 mutations were identified that increased interaction with Aux/IAAs. The D170E and M473L mutations increase affinity between TIR1 and the degron motif of Aux/IAAs and enhance the activity of the SCF(TIR1) complex. This resulted in faster degradation of Aux/IAAs and increased transcription of auxin-responsive genes in the plant. Plants carrying the pTIR1:tir1 D170E/M473L-Myc transgene exhibit diverse developmental defects during plant growth and display an auxin-hypersensitive phenotype. This work demonstrates that changes in the leucine-rich repeat domain of the TIR1 auxin coreceptor can alter the properties of SCF(TIR1).

Dust exposure and the risk of cancer in cement industry workers in Korea.

BACKGROUND: Cement is used widely in the construction industry, though it contains hazardous chemicals such as hexavalent chromium. Several epidemiological studies have examined the association between cement dust exposure and cancer, but these associations have proved inconclusive. In the present study, we examined the association between dust exposure and cancer in cement industry workers in Korea. METHODS: Our cohort consisted of 1,324 men who worked at two Portland cement manufacturing factories between 1997 and 2005. We calculated cumulative dust exposures, then categorized workers into high and low dust exposure groups. Cancer cases were identified between 1997 and 2005 by linking with the national cancer registry. Standardized incidence ratios (SIRs) were calculated for all workers and the high and low dust exposure groups, respectively. RESULTS: The SIR for overall cancers in all workers was increased (1.35, 95% CI: 1.01-1.78). The SIR for stomach cancer in the high dust exposure group was increased (2.18, 95% CI: 1.19-3.65), but there was no increased stomach cancer risk in the low dust exposure group. The SIR for rectal cancer in all workers was increased (3.05, 95% CI: 1.32-6.02). Rectal cancer risk was similar in the high and low exposure groups. CONCLUSIONS: Our findings suggest a potential association between exposure in the cement industry and an increased risk of stomach and rectal cancers. However, due to the small number of cases, this association should be further investigated in a study with a longer follow-up period and adjustment for confounders.

A synthetic approach reveals extensive tunability of auxin signaling.

Explaining how the small molecule auxin triggers diverse yet specific responses is a long-standing challenge in plant biology. An essential step in auxin response is the degradation of Auxin/Indole-3-Acetic Acid (Aux/IAA, referred to hereafter as IAA) repressor proteins through interaction with auxin receptors. To systematically characterize diversity in degradation behaviors among IAA|receptor pairs, we engineered auxin-induced degradation of plant IAA proteins in yeast (Saccharomyces cerevisiae). We found that IAA degradation dynamics vary widely, depending on which receptor is present, and are not encoded solely by the degron-containing domain II. To facilitate this and future studies, we identified a mathematical model able to quantitatively describe IAA degradation behavior in a single parameter. Together, our results demonstrate the remarkable tunability conferred by specific configurations of the auxin response pathway.

Specification and simulation of synthetic multicelled behaviors.

Recent advances in the design and construction of synthetic multicelled systems in E. coli and S. cerevisiae suggest that it may be possible to implement sophisticated distributed algorithms with these relatively simple organisms. However, existing design frameworks for synthetic biology do not account for the unique morphologies of growing microcolonies, the interaction of gene circuits with the spatial diffusion of molecular signals, or the relationship between multicelled systems and parallel algorithms. Here, we introduce a framework for the specification and simulation of multicelled behaviors that combines a simple simulation of microcolony growth and molecular signaling with a new specification language called gro. The framework allows the researcher to explore the collective behaviors induced by high level descriptions of individual cell behaviors. We describe example specifications of previously published systems and introduce two novel specifications: microcolony edge detection and programmed microcolony morphogenesis. Finally, we illustrate through example how specifications written in gro can be refined to include increasing levels of detail about their bimolecular implementations.

The role of Janus kinase 2 (JAK2) activation in pneumococcal EstA protein-induced inflammatory response in RAW 264.7 macrophages.

In a previous study, we demonstrated pneumococcal EstA-induced inflammatory response through NF-κB and MAPK-dependent pathways. Herein, we tested the hypothesis that the Janus kinase 2 (JAK2) activation and associated signaling cascades may also be involved in EstA-induced inflammatory process in RAW 264.7 macrophages. Our immunoblot analysis indicated EstA-induced activation of JAK2, with the phosphorylated protein detected from 1 to 24 h post-stimulation. As type I interferon (IFN) signaling requires the JAK/STAT pathway, we investigated EstA-induced expression of INF-α4 and INF-ß by semi-quantitative and quantitative RT PCR. Our results indicated both concentration- and time-dependent increases in both IFN-α4 and IFN-ß mRNA expression after EstA challenge, with the highest fold-increases observed at 4 h and 6 h post-stimulation for IFN-α4 and IFN-ß mRNA, respectively. Furthermore, we applied a pharmacological approach to demonstrate the effect of JAK2 inhibition on EstA-induced nitric oxide (NO) and pro-inflammatory cytokine production. The JAK2 inhibitor AG-490 reduced significantly (P < 0.05) EstA-induced NO production and the expression of iNOS mRNA in a concentration-dependent manner. Similarly, EstA-induced IL-1ß and IL-6 production and their respective mRNA expression were markedly suppressed by AG-490. However, AG-490 had no inhibitory effect on both mRNA and protein levels of TNF-α. Taken together, we demonstrate that JAK2 activation and IFN I signaling are integral parts of EstA-induced inflammatory process. Further studies will elucidate the interaction of the different signaling pathways, the specific downstream targets of JAK2, the kinetics of cytokine release, and if EstA could induce the pro-inflammatory mediators to the same extent in alveolar macrophages.

Immunomodulatory activities and subacute toxicity of a novel ß-glucan from Paenibacillus polymyxa JB115 in rats.

Subacute toxicity and immunopharmacological activities of ß-glucan from P. polymyxa JB115 was evaluated in a 28-day feeding study in rats. The white blood cell count, red blood cell count, hematocrit, hemoglobin, thrombocytes (THR) and thrombocytocrit were significantly higher in male fed with ß-glucan than control rats and the insignificant lower eosinophil count, mean corpuscular volume, mean cell hemoglobin and uninfected THR (uTHR) levels were observed in male whereas no marked changes in female rats. No other significant differences in serum chemistry and liver, kidney, and spleen weights were observed. The pathological changes and other abnormal indicators were not detected in urine. Female rats fed with diet supplemented with 0.01% ß-glucan also showed marked increase in the percentage of blood cytotoxic T-lymphocytes compared to that of the control group while not significant differences in the percentage of blood B-lymphocytes. No adverse effects on general condition and behavior, growth, feed and water consumption and feed conversion efficiency were found. The results suggest that consumption of the novel ß-1, 3/1, 6-glucan from P. polymyxa JB115 was not associated with any obvious toxic effects in rats, indicating its safety as a potential immunostimulant or as an adjuvant of some animal vaccines.

Association between Upper Extremity Musculoskeletal Disorders and Psychosocial Factors at Work: A Review on the Job DCS Model's Perspective.

Over years it has been increasingly concerned with how upper extremity musculoskeletal disorders (UEMSDs) are attributed to psychosocial job stressors. A review study was conducted to examine associations between UEMSDs and psychosocial work factors, and to recommend what to consider for the associations. For studies in which the job demand-control-support (DCS) model or its variables were specifically employed, published papers were selected and reviewed. A number of studies have reported relationships between UEMSDs symptoms and psychosocial exposure variables. For example, the findings are: higher numbness in the upper extremity was significantly attributed to by less decision latitude at work; work demands were significantly associated with neck and shoulder symptoms while control over time was associated with neck symptoms; and the combination of high psychosocial demands and low decision latitude was a significant predictor for shoulder and neck pain in a female working population. Sources of bias, such as interaction or study design, were discussed. UEMSDs were shown to be associated with psychosocial work factors in various studies where the job DCS model was addressed. Nonetheless, this review suggests that further studies should be conducted to much more clarify the association between UEMSDs and psychosocial factors.